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Oral Medicine and Pathology

Oral Medicine and Pathology A Guide to Diagnosis and Management

Editors Saman Warnakulasuriya

obe bds fdsrcs dip oral Med Phd dsc

Professor, department of oral Medicine and experimental Pathology King’s college London, UK Honorary consultant oral Medicine King‘s and Guy‘s Hospitals London, UK

WM Tilakaratne

bds Ms fdsrcs Phd frcPath

Professor, department of oral Pathology faculty of dental sciences University of Peradeniya sri Lanka

Foreword Poul erik Petersen

®

JAYPEE BROTHERS MEDICAL PUBLISHERS (P) LTD New Delhi • London • Philadelphia • Panama

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Website: www.jaypeebrothers.com Website: www.jaypeedigital.com © 2014, Jaypee Brothers Medical Publishers All rights reserved. No part of this book may be reproduced in any form or by any means without the prior permission of the publisher. Inquiries for bulk sales may be solicited at: [emailprotected] This book has been published in good faith that the contents provided by the contributors contained herein are original, and is intended for educational purposes only. While every effort is made to ensure accuracy of information, the publisher and the editors specifically disclaim any damage, liability, or loss incurred, directly or indirectly, from the use or application of any of the contents of this work. If not specifically stated, all figures and tables are courtesy of the editors. Where appropriate, the readers should consult with a specialist or contact the manufacturer of the drug or device.

Oral Medicine and Pathology: A Guide to Diagnosis and Management First Edition: 2014 ISBN: 978-93-5025-221-5 Printed at

Dedicated to Our teachers and parents My wife Ranjini and Daughter Roshini Saman Warnakulasuriya My wife Aruni and Son Praveen WM Tilakaratne

Contributors Andrew J Sidebottom

bds Mbchb frcs

Induwara Goonerathne

bds Msc MPhil LLM dip

frcs(oMf)

forensic Med

consultant, oral and Maxillofacial surgeon Nottingham University Hospitals NHs Trust, UK E-mail: [emailprotected]

senior Lecturer in forensic Medicine faculty of Medicine University of Peradeniya, sri Lanka E-mail: [emailprotected]

Andrew Sadler

bds Mbbs fdsrcs frcs

formerly clinical Lecturer and consultant oral surgeon school of Medicine and dentistry Queen Mary, University of London consultant oral and Maxillofacial surgeon United Lincolnshire Hospitals, UK E-mail: [emailprotected] [emailprotected]

Anwar R Tappuni

bds Ldsrcs Phd MrAcds (oM)

fHeA

Jimmy Makdissi

dds MMedsc fdsrcs ddrrcr

senior Lecturer and Honorary consultant department of dental radiology school of Medicine and dentistry Queen Mary, University of London, UK E-mail: [emailprotected]

John Eveson

bds fdsrcs Phd frcPath

Professor, department of oral Pathology University of bristol, UK E-mail: [emailprotected]

clinical senior Lecturer/Honorary consultant department of oral Medicine school of Medicine and dentistry Queen Mary, University of London, UK E-mail: [emailprotected]

Josiah Eyeson

bds fdsrcs

Christoph A Ramseier

KA Moutasim

bds Msc Mfd rcsI Phd

MAs (Periodontology)

consultant oral surgeon eastman dental Hospital London, UK E-mail: [emailprotected]

faculty of Medicine University of southampton, UK E-mail: [emailprotected]

dr Med dent Periodontist ssP efP Assistant Professor department of Periodontology school of dental Medicine University of bern, switzerland E-mail: [emailprotected]

Kobkan Thongprasom

GJ Thomas

Lakshman Samaranayake

bds fdsrcs Mscd Phd frcPath

Professor, experimental Pathology consultant, Head and Neck Pathology southampton Medical school, UK E-mail: [emailprotected]

Helen McParland

bds fdsrcs

department of oral Medicine Guy’s and st Thomas’ NHs foundation Trust London, UK E-mail: [emailprotected]

bsc dds Msc

Professor, department of oral Medicine chulalongkorn University, bangkok, Thailand E-mail: [emailprotected] dsc Hon fdsrcs (edin) bds dds frcPath (UK) fHKcPath MIbiol fcdsHK fHKAM (Path) fHKAM (dsurg)

dean, faculty of dentistry chair of oral Microbiology Tam Wah-ching Professor in dental science The University of Hong Kong King James IV Professor, royal college of surgeons edinburgh, scotland, UK director, Prince Philip dental Hospital, Hong Kong E-mail: [emailprotected]

nt

MAO Lewis

bds Phd fdsrcPs frcPath ffGdP(UK)

Professor and Honorary consultant department of oral surgery Medicine and Pathology dean, school of dentistry cardiff University/cardiff and Vale NHs Trust, UK E-mail: [emailprotected]

Nalin Thakker

bds Msc Phd frcPath

Professor of Molecular Pathology and Genetics school of dentistry, University of Manchester, UK E-mail: [emailprotected]

Nipuna Parahitiyawa

Mbbs d Med (Micro) Phd

senior Lecturer in Microbiology faculty of dental sciences University of Peradeniya, sri Lanka E-mail: [emailprotected]

Paula Farthing

bsc bds fdsrcs Phd frcPath fHeA

Professor of oral and Maxillofacial Pathology school of clinical dentistry University of sheffield, UK E-mail: [emailprotected]

Philip M Preshaw

bds fds rcsed Phd fds (rest

dent) rcsed

Professor, department of Periodontology school of dental sciences and Institute of cellular Medicine Newcastle University, Newcastle upon Tyne, UK E-mail: [emailprotected]

Philip McLoughlin

bds Mbbs fdsrcs frcs

consultant oral and Maxillofacial surgeon department of Maxillofacial surgery Ninewells Hospital, dundee, UK E-mail: [emailprotected]

Ranjit Mendis

bds Phd fdsrcs ffdrcsI

former Professor department of oral Pathology faculty of dental sciences University of Peradeniya, sri Lanka Honorary Visiting fellow division of stomatology and oral surgery school of dental Medicine faculty of Medicine, University of Geneva switzerland E-mail: [emailprotected]

viii

Richard J Cook

bds Mbbs fdsrcs Phd

senior Lecturer in oral Medicine King’s college London Guy’s and st Thomas’ NHs foundation Trust London, UK E-mail: [emailprotected]

Saman Warnakulasuriya

obe bds fdsrcs

dip oral Med Phd dsc

Professor department of oral Medicine and experimental Pathology King’s college London, UK E-mail: [emailprotected]

Sol Silverman Jr

MA dds

Professor department of oral Medicine school of dentistry University of california san francisco, UsA E-mail: [emailprotected]

Stefano Fedele

Md

senior Lecturer department of oral Medicine eastman dental Hospital London, UK E-mail: [emailprotected]

Tommaso Lombardi

Md dMd Pd

Professor and Head Laboratory of oral and Maxillofacial Pathology division of stomatology and oral surgery faculty of Medicine, University of Geneva switzerland E-mail: [emailprotected]

Vinay Hazarey

bds Mds

dean and Professor department of oral Pathology Government dental college Nagpur, Maharashtra, India E-mail: [emailprotected]

WM Tilakaratne

bds Ms fdsrcs Phd frcPath

Professor, department of oral Pathology faculty of dental sciences University of Peradeniya, sri Lanka E-mail: [emailprotected]

Foreword It is a pleasure to have been asked to write a foreword to this excellent book written by well-known experts in the field of oral medicine and pathology. This book has drawn them together in a unique collaboration to provide an outstanding resource on the subject. The book comprises of 24 chapters and includes extensive tables, clinical photographs, microscopic and radiological figures to aid in the understanding of the text. diagnosis and management of oral disorders is an exciting and thoughtprovoking discipline in dentistry. This text is a welcome addition to the available resources in the field and has been produced at low-cost with the needs of the postgraduate students in mind. A complete understanding of oral disorders requires sound clinical knowledge to arrive at a differential diagnosis that needs to be underpinned by information from investigative techniques. This reference book provides a comprehensive approach to both diagnosis and management, thereby making this a singular work. The management of disorders is evidence-based (when available) and will facilitate a good grounding for the trainees as well as for both generalists and specialists to become familiar with current approaches to patient care. The text is edited by two senior colleagues practicing oral medicine and pathology with a broad understanding of the needs of low and middle-income countries, thereby facilitating the educational needs of trainees from many countries while retaining the dynamic knowledge base acquired from highincome countries. Thus, the text provides a global approach to patient care in the field of oral medicine and pathology. I highly recommend this valuable book. readers engaged in diagnosis and management of oral disorders will feel most enriched by the basic information and the practical guidelines provided in this field important to public health. The book is not only helpful in clinical practice but also it will be most instrumental to postgraduate training as well.

Poul Erik Petersen

chief Global oral Health Programme World Health organization chronic disease and Health Promotion 20 Avenue Appia cH-1211 Geneva, switzerland

Preface Oral Medicine and Pathology: A Guide to Diagnosis and Management is aimed at postgraduate students, specialist trainees, interns and all practitioners treating patients with oral diseases or those presenting with manifestations of systemic diseases in the oral cavity. our undergraduate students have a minimum exposure to pathological disorders other than dental caries and periodontal diseases and the book provides a useful resource to their early learning. our objective is to present a comprehensive book on patient management, to improve skills and expertise on oral diagnosis replete with a basic knowledge on both soft and hard tissue pathology. Its concise and easy-to-read format will permit the readers to discuss the case presentations with specialists in the field, and will enable them to make accurate diagnoses in order to jointly manage patients even if they have not had extensive previous experience in oral medicine. We hope, the book will benefit practitioners responsible for the care of the oral cavity and will save them time going to one concise, authoritative source for diagnosis and treatment options, without having to wade through several texts, or in thousands of journal articles. We have endeavored to maintain a basic format and content of clinical manifestations with numerous illustrations, to help in the diagnosis or in making a differential diagnosis. We as the editors have edited chapter contents to maintain consistency in format, depth, and style and to keep up with the advances in management of oral diseases. The book will reflect the many years of our practical experience as well as the extensive clinical and research expertise of the various chapter contributors. We have selected authors from various prestigious institutions from all over the globe. They are well-known experts in their respective fields and this book has drawn them together in a unique collaboration to provide the reader an all-encompassing appraisal of the current state of our knowledge in oral diagnosis and management of pathological conditions that we encounter in day-to-day practice.

Saman Warnakulasuriya WM Tilakaratne

Acknowledgments We take this opportunity to express our gratitude to the people, who have been instrumental in the successful completion of this book. first of all our chapter contributors for accepting our invitation and for their excellent authorship in their respective fields reflecting an up-to-date knowledge and writing succinct text, which made our job as editors much easier. We thank dr Michael escudier of King’s college London, for his contribution by revising and re-drafting self-Assessment Questions that appear at the end of each chapter. christine bell helped us with initial formatting of chapters and illustrations and we thank her for attention to detail. We acknowledge several colleagues, who have helped us in proofreading chapters 5–7; dr bsMs siriwardena, dr rasika ekanayaka, dr rLPr Liyanage and dr s Wadusinghaarachchi. In addition to those named for contributing illustrations, we acknowledge Professor edward odell and others, who have contributed to this publication. We wish to thank dr shankargouda Patil for his invaluable logistic support during preparation of this volume. our thanks are due to shri Jitendar P Vij (Group chairman), Mr Ankit Vij (Managing director), Mr Tarun duneja (director-Publishing), Mr KK raman (Production Manager), Mrs chetna Vohra (senior Manager, business development) and samina Khan (PA to director-Publishing) of M/s Jaypee brothers Medical Publishers (P) Ltd, New delhi, India, and their production team for achieving an excellent standard in producing the first edition of this book.

Contents

WM Tilakaratne •  Odontogenic  Cysts  101  •  Nonodontogenic  Cysts  114  •  Self-assessment  Questions  122

1

25

50

83

100

nt

John Eveson

xvi

•  Non-neoplastic  Salivary  Disorders  222  •  Inflammatory/Infective  Diseases  222  •  Viral  Diseases  226  •  Mucoceles  228  •  Necrotizing  Sialometaplasia  230  •  Sialosis  (Sialadenosis)  231  •  Autoimmune  Disorders  232  •  Neoplastic  Salivary  Disorders  235  •  Benign  Neoplasms  235  •  Malignant  Neoplasms  243  •  Self-assessment  Questions  258

124

157

179

206

221

Lakshman Samaranayake, Nipuna Parahitiyawa

260

coNTeNTs

268

300

331

345

361

•  Fungal  Infections  of  the  Oral  Mucosa  362  •  Oral  Candidiasis  362  •  Candida-associated  Lesions  365  •  Candidiasis  and  Immunocompromised  Hosts  367  •  Oral  Candidiasis  in  HIV  Disease  367  •  Exotic  Fungal  Infections  of  the  Oral  Mucosa  367  •  Oral Viral  Infections  374  •  Bacterial  Infections  of  the  Oral  Mucosa  379  •  Parasitic  Infections  of  the  Oral  Mucosa  381  •  Self-assessment  Questions  382

xvii

nt

Jimmy Makdissi •  Plain  Radiographs  510  •  Computed Tomography  520  •  Cone  Beam  Computed Tomography  522  •  Magnetic  Resonance  Imaging  526  •  Ultrasound  530  •  Sialography  534  •  Sialoendoscopy  539  •  Self-assessment  Questions  539

xviii

383

400

410

426

462

478

509

Christoph A Ramseier

541

•  Understanding ‘Tobacco  Use  Disease’  542  •  Tobacco  Use  Cessation  543  •  Categories  of  Care  543  •  Determinants  of  Behavior  Change  549  •  Barriers  to  be  Overcome  by  the  Dental Team  550  •  Self-assessment  Questions  550

coNTeNTs

553

xix

Chapter

1 Anomalies of Teeth Nalin Thakker

Chapter Outline Developmental Abnormalities of Enamel • Amelogenesis Imperfecta • Environmental Enamel Hypoplasia • Nonspecific Abnormalities • Turner Hypoplasia • Molar Incisor Hypomineralization (MIH) • Dental Fluorosis Developmental Abnormalities of Dentine • Dentinogenesis Imperfecta • Dentine Dysplasia • Dentine Dysplasia Associated with Other Conditions Developmental Abnormalities of Enamel and Dentine • Syndromic Composite Abnormalities of Enamel and Dentine • Regional Odontodysplasia Developmental Abnormalities of Cementum Developmental Abnormalities of Number of Teeth • Hyperdontia • Hypodontia Developmental Abnormalities of Eruption of Teeth • Early Eruption Including Natal Teeth • Delayed or Failure of Eruption of Teeth Developmental Abnormalities Resulting in Early Loss of Teeth

Developmental Abnormalities of Tooth Form and Size • Microdontia and Macrodontia • Dens Invaginatus • Dens Evaginatus and Enamel Pearls • Taurodontism • Gemination • Fusion • Concresence Basic Principles and Management of Patient with Developmental Anomalies of Teeth Acquired Abnormalities of Teeth • Attrition • Abrasion • Erosion • Abfraction Internal and External Root Resorption • Internal Root Resorption • External Root Resorption Tooth Discoloration and Staining • Intrinsic Discoloration • Extrinsic Staining • Internalized Staining Self-assessment Questions

ORAl MEDICINE AND PATHOlOGy: A GuIDE TO DIAGNOSIS AND MANAGEMENT

1

INTRODuCTION This chapter describes some of the main developmental and nondevelopmental abnor­ malities of teeth. Developmental abnormalities of teeth can arise through either inherited mutations in genes involved in tooth development or exposure to environmental factors during the development of teeth, that disrupt or modify the development process. The genes involved in tooth development can be classified into two main groups: genes whose function is critical in tooth development but not other tissues and genes whose function is critical in development of many tissues, including teeth. Pathological mutations of the former result in nonsyndromic conditions in which there are only abnormalities of teeth. In contrast, mutations of the latter result in syndromic conditions in which the abnormalities of teeth are associated with a range of other phenotypic changes. There are numerous syndromic, single gene­ or Mendelian disorders that present with abnormalities of teeth. For brevity, only some of the more common conditions are described below. Their systemic manifestations are not described in detail here but are readily available from Online Mendelian Inheritance in Man (OMIM). The nondevelopmental abnormalities of teeth are those that arise through the action of the environment (e.g. mechanical wear, chemical erosion) on fully developed teeth. The description given below excludes an account on dental caries (see Chapter 2).

DEvElOPMENTAl AbNORMAlITIES OF ENAMEl Amelogenesis Imperfecta Amelogenesis imperfecta is the term given for a group of genetically and phenotypically heterogeneous disorders affecting the enamel. These abnormalities can occur in isolation (nonsyndromic) or as part of a syndrome and generally, affect all teeth resulting in altered structure and appearance of the teeth. The reported prevalence of amelogenesis imperfecta varies between 1 in 700 and 1 in 14,000. The abnormalities and the resultant clinical and histological appearances in amelogenesis imperfecta vary (Table 1.1, Figs 1.1 and 1.2). The consequences of poorly formed or mineralized enamel are rapid breakdown, poor esthetics, predisposition to caries and thermal sensitivity. Management is focused on exclusion of any systemic features, preservation of tooth structure and improvement of esthetics by restorative care such as prosthetic crowns or plastic restorations, prevention of dental caries and maintenance of good oral hygiene, psychological well­being of the individual and genetic counseling.

Nonsyndromic Amelogenesis Imperfecta A number of classifications of the amelogenesis imperfecta based either on morphology, mode of inheritance and/or genetic or biochemical defect have been proposed. Classifications based just on morphology or modes of

ƒ Table 1.1 Phenotypes in amelogenesis imperfecta

2

Defect

Definition

Hypoplastic

Reduced thickness or absence of enamel

Clinical appearances Pitted and ridged enamel

Hypomineralized Normal thickness of the organic matrix (hypocalcified) that is variably under-mineralized

Discolored, rough soft enamel

Hypoplastic and hypomineralized

Combination of the two

Combination of the two

Hypomature

Areas of poorly formed enamel in otherwise normal enamel

Discrete white patches

1 ANOMAlIES OF TEETH

A

B

C

D

Figs 1.1A to D: Amelogenesis imperfecta. (A) Hypoplastic-hypomineralized amelogenesis imperfecta with discolored, rough soft enamel with pits and ridges; (b) Hypomineralized amelogenesis imperfecta with discolored, rough soft enamel; (C) Hypomaturation type amelogenesis imperfecta with whitish patches; (D) Radiographic appearances of hypomineralized amelogenesis imperfecta showing poorly mineralized enamel (Courtesy: Professor I Mackie)

A

B

Figs 1.2A and B: Amelogenesis imperfecta. (A) Ground sections showing hypoplastic amelogenesis imperfecta with thin irregular enamel; (b) Hypomineralized amelogenesis imperfecta with enamel of relatively normal thickness but with poor mineralization (Courtesy: Dr K Hunter)

3

ORAl MEDICINE AND PATHOlOGy: A GuIDE TO DIAGNOSIS AND MANAGEMENT

1

inheritance as primary discriminants are inadequate because of phenotypic and genetic heterogeneity and gene dose dependency of some of the traits resulting in different modes of inheritance. A classification based on molecular pathology provides a sound but possibly somewhat incomplete basis to consider this group of conditions. Amelogenesis imperfecta can be inherited as X­linked or an autosomal recessive or dominant trait. A number of genes with pathogenic mutations have been identified in amelogenesis imperfecta. The genes, the resulting phenotypes and mode of inheritance are shown in Table 1.2. It is presently unclear whether or not all types of nonsyndromic amelogenesis imperfecta reported to date can be attributed to mutations in one of the genes listed in Table 1.2. At least one other type of amelogenesis imperfecta mapping to the distal part of the long arm of the X chromosome has been reported previously. Mutations in AMELX result in a classical X­linked recessive trait with males fully expressing the phenotype whilst females show alternate banding of normal and affected enamel due to Lyonization. Mutations in ENAM can result in either dominant or recessive traits with either localized or generalized hypoplasia respectively suggesting dose­dependency of the trait.

Syndromic Amelogenesis Imperfecta Amelogenesis imperfecta also occurs as part of several Mendelian conditions often with abnormalities of other ectodermal derived tissues. For example, in tricho­dento­osseous syndrome amelogenesis imperfecta is associated with taurodontism and other variable phenotypic changes including curly hair, bony sclerosis and brittle nails. In Jalili syndrome, amelogenesis imperfecta is associated with con­ rod dystrophy. Amelogenesis imperfecta is also seen in some syndromes with abnormalities of calcium metabolism or regulation such as nephrocalcinosis, vitamin D dependent­ and independent­rickets. Abnormalities of enamel have also been reported in numerous other rare Mendelian disorders.

Environmental Enamel Hypoplasia Environmental insults or disturbances during tooth development are associated with enamel defects. These can range from small area of opacity to larger areas of discoloration, pitting, grooves and involvement of the whole crown (Figs 1.3A to C). Change may be distinctive or nonspecific. The timing of disturbance in development is indicated by the position of the defects on the crown and the teeth affected. Thus, disturbances in utero present on deciduous teeth, disturbances in the first two

ƒ Table 1.2 Genes, modes of inheritance and phenotypes in nonsyndromic amelogenesis imperfecta

4

Gene

Chromosomal location

Inheritance

Phenotype

AMELX

Xp22.2

XR

Hypoplasia Hypomineralization Hypomaturation

ENAM

4q13.3

AD

localized hypoplasia

AR

Generalized hypoplasia

FAM83H

8q24.3

AD

Hypomineralization

MMP20

11q22.2

AR

Hypomaturation

KLK4

19q13.33

AR

Hypomaturation

1

B

C

Figs 1.3A to C: Environmental hypoplasia. (A) Enamel hypoplasia localized to one tooth; (b) Enamel hypoplasia of the permanent lower central incisors as result of trauma to deciduous lower central incisors at 18 months (Turner hypoplasia); (C) Enamel hypoplasia characterized by pits affecting upper central and lateral incisors

years present on permanent anterior and first molar teeth, and disturbances in years 4 and 5 on canines, premolars and second molars. A variable prevalence of enamel hypoplasia has been reported but most accounts suggest between 10 and 15 percent in the adult population. In a majority of cases this affects a single tooth, usually buccal surface of anterior teeth.

Nonspecific Abnormalities A variety of environmental factors have been reported to be associated with enamel hypoplasia. These include low birth weight, viral infections, fever, prenatal or neonatal respiratory insufficiency/distress, malabsorption syndromes such as celiac disease, malnutrition, cytotoxic therapy, other drugs, metabolic disorders, parathyroid disorders. Some specific types of environment­ induced hypoplasia are also recognized and are described below.

Turner Hypoplasia This is enamel hypoplasia of variable severity thought to be associated with periapical infection or trauma associated with preceding deciduous teeth (Figs 1.3A to C). Hypoplasia associated with periapical infection is most commonly seen in permanent premolars whilst that due to trauma is more commonly seen in maxillary permanent incisors.

ANOMAlIES OF TEETH

A

Molar Incisor Hypomineralization This is defined as hypomineralization of variable severity associated with systemic factors and affecting one or more permanent first molars with or without incisors involvement. The reported prevalence of molar incisor hypomineralization (MIH) varies between 2.5 and 25 percent. The etiology is unknown but is thought to be associated with many of the factors described above including infections of upper aerodigestive tract, exanthamatous fevers and antibiotics. MIH presents as well delineated white, yellow or brown opacities usually on the buccal or occlusal surfaces. The lesions are asymmetrical in contrast to amelogenesis imperfecta and fluorosis. The teeth are prone to thermal sensitivity and caries. Management includes early diagnosis, remineralization, caries prevention, restorations, extractions if necessary and orthodontic care.

Dental Fluorosis This is defined as developmental abnormality of enamel due to excessive fluoride exposure during tooth development. Excessive intake of fluoride anytime after birth up to the age of approximately 8 years can result in fluorosis with the severity, number and type of teeth involved determined by the dose, the period and the timing of exposure. The key sources of fluoride in this respect are fluoride in the water, supplements and dentrifices.

5

ORAl MEDICINE AND PATHOlOGy: A GuIDE TO DIAGNOSIS AND MANAGEMENT

1

Fluorosed enamel shows both maturation and mineralization defects with retention of amelogenin, increased porosity and subsurface hypomineralization. The prevalence of fluorosis in the permanent teeth varies widely between and within countries and depends on factors such naturally occurring fluoride levels of the water supply, water fluoridation and other supplementation schemes. Some studies indicate that between approximately 10 and 20 percent of the population in areas with water fluoridation may have fluorosis that is of esthetic concern. Clinically the appearances of fluorosis can vary depending on the severity of the fluorosis (Fig. 1.4). Mild changes consist of a few small white specks or streaks to larger opaque areas. More severe changes range from small stained pits to large confluent areas of pitting with prominent brown staining. The defects are symmetrical and diffuse, unlike changes associated with other environmental enamel defects.

DEvElOPMENTAl AbNORMAlITIES OF DENTINE Classically, inherited defects of dentine have been classified into two main broad groups: dentinogenesis imperfecta and dentine dysplasia (Table 1.3).

Fig. 1.4: Fluorosis. Teeth are chalky white in appearance with some teeth showing brown discoloration (Courtesy: Dr Manil Fonseka). Management of fluorosis is focused on improving the esthetics. In mild and moderate fluorosis, combinations of microabrasion, bleaching and restorations will usually suffice. For severe fluorosis, prosthetic crowns may be necessary

Dentinogenesis Imperfecta The prevalence of dentinogenesis imperfecta is thought to be between 1 in 6000 and 1 in 8000 whilst dentine dysplasia is much rarer with reported incidences of about 1 in 100,000. Dentinogenesis imperfecta is further subdivided into three types: dentinogenesis imperfecta occurring with osteogenesis imperfecta (type I) or in isolation (type II

ƒ Table 1.3 Genes, modes of inheritance and phenotypes in dentinogenesis imperfecta and dentine dysplasia

6

Gene

Inheritance

Phenotype

COL1A1 COL1A2

AD

Dentinogenesis imperfecta type I bone fractures Joint hyperextensibility Scleral hue Short stature Deafness

DSPP1

AD

Dentinogenesis imperfecta type II Dentinogenesis imperfecta type III Dentine dysplasia type II

unknown

AD

Dentine dysplasia type II

Nonsyndromic Dentinogenesis Imperfecta (Types II and III) Dentinogenesis imperfecta is a term used to define defects of dentine affecting both primary and secondary dentition resulting in characteristic clinical, radiographic and histological appearances. These include blue­ gray or brown opalescent teeth that show rapid and marked attrition after eruption (Figs 1.5A and B). Radiographically, the teeth have bulbous crowns, narrow roots and pulp canals obliterated by pulp stones (Fig. 1.5C). Histologically, the dentine is abnormal with areas of interglobular dentine, irregular and variably reduced number of tubules, and pulpal calcifications (Fig. 1.5D). These characteristic

changes are seen in dentinogenesis imperfecta type II. In dentinogenesis imperfecta type III, instead of the pulpal obliteration, prominent pulpal enlargement due to hypotrophy of dentine is seen with consequent multiple pulpal exposures and apical infection. Radiographically, the teeth appear as ‘shell teeth’ and mandibular incisors often have apical radiolucent areas due to pulpal exposure and infection. Initially, this phenotype was thought to be limited to a dentinogenesis imperfecta occurring in a tri­racial population of Brandywine, Maryland, USA. However it is has been observed in unrelated families elsewhere and only seen in 2 percent of the Brandywine dentinogenesis imperfecta cohort suggesting this phenotype does not represent a distinct entity but is part of the variable expressivity of dentinogenesis imperfecta.

1 ANOMAlIES OF TEETH

and III). Dentine dysplasia is subdivided into two types based on phenotypic differences: type I or radicular and type II or coronal. However, it is now apparent that dentinogenesis imperfecta types II and III, and dentine dysplasia type II represent a spectrum of phenotypes resulting from mutations in the same gene (DSPP) encoding dentin sialophosphoprotein. Dentinogenesis imperfecta type I arises as part of osteogenesis imperfecta with mutations almost always (but not exclusively) in the two genes (COL1A1 and COL1A2) encoding collagen type 1. The genetic defect in dentine dysplasia type I has not been identified as yet. The specific features of each these conditions are described below. The principle consequences of poorly formed dentine are discoloration of the teeth, shearing of enamel from the dentine, rapid breakdown of teeth, pulpal exposure, and pulpal and periapical infection, and early loss of teeth in association with poorly developed roots. Surprisingly, despite widespread exposure of dentine, thermal sensitivity is not a prominent feature because of dentinal sclerosis. The key principles in management are exclusion of systemic features such as osteogenesis imperfecta, preservation of teeth through protective restorations such as prosthetic crowns, prevention of dental caries and periodontal disease, and genetic counseling.

Syndromic Dentinogenesis Imperfecta Dentinogenesis imperfecta associated with osteogenesis imperfecta (Type I) Dentinogenesis imperfecta is most commonly observed as part of osteogenesis imperfecta and is classified as dentinogenesis imperfecta type I with features that are identical to nonsyndromic dentinogenesis imperfecta type II. It can occur in all types of osteogenesis imperfecta but is most commonly seen in types III and IV and only with missense mutations in either COL1A1 or COL1A2. Occasionally, dentinogenesis imperfecta may be the most penetrant feature of this condition and thus, it is important to seek relevant history and features of osteogenesis imperfecta in all cases of dentinogenesis imperfecta. Dentinogenesis imperfecta associated with other conditions Dentinogenesis imperfecta may be observed as part of other rare conditions with mutations in COL1A1 (Goldblatt syndrome) or COL1A2 (Ehlers Danlos syndrome type VII). It is also observed in other rare syndromes associated with mutations in other genes or for which the genes have yet to be identified.

7

ORAl MEDICINE AND PATHOlOGy: A GuIDE TO DIAGNOSIS AND MANAGEMENT

1

A

B

C

D

Figs 1.5A to D: Dentinogenesis imperfecta. (A and b) Clinical appearances of opalescent teeth with rapid breakdown of the crowns; (C) Radiographic appearances showing bulbous crowns with short narrow roots with obliterated pulp chambers and root canals (Courtesy for Figure 1.5C: Professor K Horner); (D) Histological section of decalcified tooth showing poorly formed dentine with irregular tubules and obliterated pulp chamber (Courtesy for Figure 1.5D: Dr K Hunter)

Dentine Dysplasia Dentine Dysplasia Type I This is the rarest of inherited dentine disorders and is characterized by teeth with virtually normal crowns but abnormal root development hence the alternative name for this condition of radicular dentine dysplasia. Both deciduous and permanent dentitions are affected and clinically presents as mobility of teeth and early tooth loss. The condition is usually diagnosed by radiographic examination either as an incidental finding or following history of early tooth loss. The teeth have short, conical roots with either completely obliterated pulp chambers (deciduous teeth) or almost completely obliterated pulp chambers (permanent teeth). Histologically, teeth have

8

normal enamel with an adjacent narrow zone of normal appearing dentine beyond which there are whorled masses of dysplastic tubular and atubular dentine (Figs 1.6A and B). Apically, the whorled dentine masses are replaced by a less uniform arrangement of dysplastic dentine. Apical radiolucencies are also seen.

Dentine Dysplasia Type II This condition is virtually identical to dentino­ genesis imperfecta type II but largely only affects deciduous dentition (Fig. 1.7) with the perma­ nent teeth either unaffected or having thistle shaped pulp chambers with multiple pulp stones. Thus, differential diagnosis of opalescent primary teeth should include dentine dysplasia (DD) type II in addition to DG.

1 ANOMAlIES OF TEETH

A

B

Figs 1.6A and B: Dentine dysplasia type I. (A) Ground section; (b) Decalcified section; of an affected permanent incisor showing lack of root development, normal enamel with an adjacent zone of normal appearing dentine beyond which there are whorled masses of dysplastic tubular and atubular dentine partially obliterating the pulp chamber (Courtesy: Dr K Hunter)

Dentine Dysplasia Associated with Other Conditions Dentine dysplasia is seen in association with other conditions including disorders of phosphate and/or calcium metabolism.

A

Fig. 1.7: Dentine dysplasia type II. Deciduous teeth show discoloration and rapid breakdown of the crowns whilst the permanent dentition is unaffected (Courtesy: Professor M Dixon)

In familial hypophosphatemic vitamin D­resistant rickets, an X linked dominant condition, enlarged pulp chambers with prominent pulp horns, marked interglobular dentine and increased thickness of predentine (Figs 1.8A and B) are seen in association with bone deformities, osteomalacia and growth retardation. The condition often presents with multiple periapical dental abscesses due to early exposure of the pulp horns in anterior teeth.

B

Figs 1.8A and B: Familial hypophosphatemic vitamin D resistant rickets. (A) Decalcified section of a permanent molar showing abnormal dentine involving the whole tooth; (b) Higher magnification view; showing in detail the marked interglobular dentine and increased thickness of predentine

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Dentine dysplasia with short bulbous roots, pulp stones and partial obliteration of the pulp cavity occurs in hyperphosphatemic tumoral calcinosis, an autosomal recessive disorder, characterized by progressive deposition of calcified masses in soft tissues.

DEvElOPMENTAl AbNORMAlITIES OF ENAMEl AND DENTINE Composite developmental abnormalities involving both enamel and dentine probably occur in many Mendelian syndromes but have not been defined adequately. They have been described in Mendelian disorders of calcium and phosphate metabolism, and collagen some of which are describe below. Non­syndromic composite abnormalities also occur in regional odontodysplasia, a nonhereditary segmental condition of unknown etiology.

Syndromic Composite Abnormalities of Enamel and Dentine The X linked dominant condition familial hypophosphatemic vitamin D­resistant rickets characterized by enlarged pulp chambers with prominent pulp horns, marked interglobular

A

10

dentine and increased thickness of predentine has been described above. Although the changes in dentine are the most prominent features of this condition, the enamel also displays variable hypoplasia. In vitamin D dependent rickets types I and II, the teeth show similar changes in dentine including increased size of pulp chambers, variable mineralization, interglobular dentine, increased thickness of predentine and variably sized tubules. However, the changes in enamel are more prominent and characterized by hypoplastic/hypomineralized yellow–brown enamel. In addition, the teeth do not appear to have the predisposition to early pulpal exposure and development of multiple periapical abscesses seen in familial hypophosphatemic vitamin D­resistant rickets. Ehlers­Danlos syndrome (EDS) is a genetically heterogeneous connective tissue disorder resulting from mutation of genes encoding some types of collagen or proteins necessary for collagen assembly. There are six types of EDS showing either autosomal dominant or recessive modes of inheritance. There is broad spectrum of clinical features ranging from mild to severe that include joint hyperextensibility, skin laxity (Fig. 1.9A), and

B Figs 1.9A and B: Ehlers-Danlos syndrome. (A) Skin laxity; (b) Periapical radiograph of teeth showing roots with pulp stones and dilacerations

1

B

ANOMAlIES OF TEETH

A

Figs 1.10A and B: Regional odontodysplasia. (A) Panoramic radiograph of the jaws showing ‘ghost teeth’ in the upper right quadrant; (b) Histological section of decalcified tooth showing malformed tooth with poorly mineralized enamel lacking normal prism structure and atypical dentine with interglobular dentine and increased width of predentine (Courtesy for Figure 1.10A: Professor K Horner)

tissue and organ fragility leading to aneurysms, bowel rupture or retinal detachment. A wide range of dental anomalies have been reported in EDS. Most commonly these include enamel hypoplasia, large pulpal calcifications or pulp stones, and shortened dilacerated roots (Fig. 1.9B). The dentine is reported to have abnormal tubular structure. The posterior teeth often have accentuated cusps and fissures. Hypodontia and microdontia and failure of eruption of teeth have also been reported.

Regional Odontodysplasia This is a nonhereditary localized condition of the jaws with characteristic clinical and radiographic features. The condition involves several adjacent teeth most commonly in a single arch; however, involvement of more than one arch and all teeth has been reported. Deciduous or permanent dentition can be affected and in about half the cases both are involved. There appears to be a slightly higher incidence in females than in males and the maxilla is more commonly involved than the mandible. Association with vascular nevi, hemangioma, epidermal nevus syndrome and hemifacial hypoplasia has been reported in several cases previously. The most characteristic anomaly is marked hypoplasia of enamel and dentine. Clinically, the teeth are discolored, soft and prone to rapid breakdown. Radiographically, the enamel and dentine are much reduced and the

distinction between the two is lost due to poor mineralization, giving appearance of “ghost teeth” (Figs 1.10A and B). The pulp chambers are enlarged with open apices. Teeth may be missing or fail to erupt. The surrounding soft tissues are often inflamed and there may be periapical inflammation and abscess formation. Histologically the enamel is thinned and has abnormal prism structure. The dentine is also thinned, with increased width of predentine and presence of interglobular dentine (Figs 1.10A and B). The etiology of regional odontodysplasia is unknown. The association with vascular nevi, hemangioma, epidermal nevus syndrome and hemifacial hypoplasia raises the possibility of somatic mutation. Other theories include exposure to teratogenic drugs, vascular or metabolic disturbance, and viral infections. There is a lack of consensus about the management of regional odontodysplasia. A number of factors need to be considered including the state of the affected teeth, presence of apical infection, whether deciduous or permanent dentition is affected, the need to preserve space for permanent dentition and the compromise in esthetics and function.

DEvElOPMENTAl AbNORMAlITIES OF CEMENTuM Abnormalities of cementum are usually only seen in hypophosphatasia. This is characterized

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by deficiencies of bone mineralization and lack of cellular and acellular cementum associated with a deficiency of the enzyme alkaline phosphatase. The deficiency arises from mutations in the ALPL gene and gives rise to several different clinical forms of the condition of varying severity that corresponds to the severity of the enzyme deficiency. The features are best regarded as a continuum and range from early­onset lethal or severe forms characterized by stillbirth, craniosynostosis, bony deformities hypercalcemia and renal damage to milder, late­ onset types characterized by stress fractures and pseudofractures. Premature exfoliation of primary dentition can be seen in isolation (known as odontohypophosphatasia) in the mildest form of the condition or in combination with other features.

DEvElOPMENTAl AbNORMAlITIES OF NuMbER OF TEETH Hyperdontia Hyperdontia is characterized by increase in one or more teeth in the normal dentition (supernumerary teeth). It can arise in isolation (nonsyndromic) or together with other abnormalities (syndromic). Both primary and secondary dentition may be involved. The prevalence in the Caucasian populations is between 1 and 3 percent but is reported to be higher in Mongoloid races. Presence of multiple supernumerary teeth especially nonsyndromic, is rare. Cases with one or two supernumerary teeth commonly involve the anterior maxilla whilst multiple supernumerary teeth most commonly involve premolar regions in both jaws. The teeth can be supplemental or rudimentary. Supplemental teeth are of normal size and shape. The most common supplemental teeth are maxillary lateral incisors followed by premolars and molars. Rudimentary teeth are of small size and have an abnormal shape, e.g. conical. The most common supernumerary tooth is mesiodens, a rudimentary conical tooth arising between the permanent maxillary incisors.

Fig. 1.11: Cleidocranial dysplasia. Panoramic radiograph of the jaws showing multiple unerupted supernumerary teeth (Courtesy: Professor K Horner)

Many Mendelian syndromes are associated with supernumerary teeth. The most common of these include cleidocranial dysplasia (Fig. 1.11), familial adenomatous polyposis, orofacial digital syndrome type I, Nance­ Horan syndrome, tricho­rhino­phalangeal syndrome, Rothmund–Thomson syndrome and Hallerman–Streiff syndrome. Supernumerary teeth are often detected as incidental findings on clinical or radiographic examination. However, they can be associated with a number of clinical problems including interference with eruption, displacement, resorption or dilacerations of adjacent teeth, crowding or spacing (diastema), dentigerous cysts and eruption into nasal or antral cavities.

Hypodontia Hypodontia is characterized by decrease in one or more teeth in the normal dentition. Some authors differentiate this further into complete absence of dentition (anodontia), absence of more than 6 teeth (oligodontia) and absence of less than 6 teeth (hypodontia). The absence of teeth can be in isolation (nonsyndromic) or as part of constellation of features (syndromic). Hypodontia can affect both primary and permanent dentition. The prevalence in pri­ mary dentition is low (about 0.5%) and most commonly involves maxillary incisors lateral incisors followed by mandibular lateral incisors. There is a strong correlation between hypodon­ tia in primary dentition and hypodontia in the permanent dentition.

A

shaped lateral incisors), transposition of permanent teeth, taurodontism and ectopic impacted canines. The principle clinical problems with lack of teeth are lack of function and esthetics coupled with malocclusion.

DEvElOPMENTAl AbNORMAlITIES OF ERuPTION OF TEETH Early Eruption Including Natal Teeth

1 ANOMAlIES OF TEETH

The prevalence of hypodontia in the permanent dentition is between 2 and 10 percent. This most commonly (~80% of cases) involves only one or two teeth. Loss of six or more teeth is extremely rare ( 100000/mL Lactobacillus spp for low caries activity: < 100000/mL S. mutans and < 10000/mL Lactobacillus spp.

APPROACHES FOR PREVENTING DENTAL CARIES INCLUDING DENTAL CARIES VACCINES Caries is a disease process that needs to be managed over a person’s lifetime. The theory is predisposition to dental caries may change during the life time of an individual patient and that while practicing the least invasive dentistry with the objective of good preservation of the dentition should be the practitioner’s approach. This approach relies on accurate diagnosis of the disease and lesions, caries prevention, just-in-time restorations, minimally invasive operative procedures, and the prevention of recurrence. There are many approaches to the prevention of dental caries. These could be summarized as follows: 1. The mechanical removal of the dental plaque or biofilms by efficient and effective oral hygiene measures could almost prevent dental caries. This can be achieved by conventional oral hygiene practices such as tooth brushing and flossing. 2. Use of various plaque control measures, such as the use of mouth washes and tooth pastes containing antimicrobial agents such as chlorhexidine and surfactants, which can reduce formation of biofilms and thereby reduce dental caries. Chlorhexidine can be delivered either by gel, e.g. as a 1 percent gel in custom-fitted vinyl applicators, as a mouth rinse or as a varnish.

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2

3.

4.

5. 6.

7.

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Application of fluoride supplements. These include fluoridated water supplies, salt and milk fluoridation, use of fluoride containing tooth paste, fluoride tablets, fluoride varnishes applied by the dentist especially for children who at high-risk and fluoride mouth rinse program in school. For selfadministered care, fluoride toothpaste is the most powerful intervention for caries prevention because it has high clinical effectiveness and social acceptability. A cochrane review of randomized or quasirandomized controlled trials with blind outcome assessment, comparing fluoride toothpaste with placebo in children aged 16 years or more for at least 1 year, concluded that fluoride toothpastes are clearly effective in prevention of caries. This conclusion is supported by more than 50 years of research. Fluoride functions posteruptively by favorably influencing the kinetics of deand re-mineralization. Fluoride interacts with the enamel of erupted teeth to form fluorapatite. Fluorapatite is more resistant to acid dissolution than hydroxyapatite. Regular dental care with professional prophylaxis at the dentist’s office by the dentist or dental hygienist, with good oral hygiene instructions. For occlusal pits and fissures that are most vulnerable to dental decay, fissure sealants could be used at the dentist’s office. Reduction in the amount and frequency specially reducing between meal consumption of carbohydrates and sugar intake and the use of sugar substitutes such as artificial sweeteners. These sweeteners include cyclamate, aspartame, saccharin, sorbitol and xylitol. Advice to restrict the consumption of sugary snacks and drinks should also be given to all patients as part of general dietary counseling. For the future: a. Replacement therapy and probiotics. Probiotics are live microorganisms which, when administered in adequate numbers, confer a health benefit on the host. There are two main approaches: (a) pre-emptive colonization where key functions within the biofilm are filled by beneficial microorganisms before

the undesirable strain has had a chance to colonize or become established. The initial colonizer becomes integrated into the ecosystem and then excludes the pathogen from gaining a foothold. (b) To derive a more competitive strain that would displace a pre-existing organism from the biofilm. b. Active and passive vaccination. Despite the abundance of experimental evidence for the effectiveness of dental caries vaccines, none exist yet for human use. The mutans streptococci are confirmed pathogens, fulfilling most of Koch’s postulates and carried by around 98 percent of individuals around the world. There is evidence that Streptococcus sobrinus may also contribute to the carious process. A vaccine against dental caries using mutans streptococci (whole cell vaccines), or molecules derived from these bacteria (subunit vaccines), has been proposed for many years. The major factors that are thought to contribute to cariogenicity of mutans streptococci are—acidogenecity, aciduricity, sucrose-independent adhesion and sucrose-dependent adhesion. These properties are required for biofilm formation. These factors are therefore important in the development of appropriate antibodies. Interest has been focused on three groups of antigens in the bacteria- (a) cell-wall proteins, a high molecular weight protein that acts as an adhesin binding to a salivary glycoprotein (b) glucosyltransferases (GTFs) and (c) glucan-binding proteins in the production of suitable and effective anticaries vaccines. 8. Photodynamic therapy. Cariogenic bacteria such as mutans streptococci are susceptible to killing by low power laser light once cells have been treated with low concentrations of a photosensitizer dye such as toluidine blue. When activated, the dye liberates free radicals which are lethal to neighboring cells. Photodynamic therapy has been shown to work well on dental caries biofilms. However, without proper public education on preventive measures prevention of caries

SELF-ASSESSMENT QUESTIONS 1. Describe the etiology and microbiology of dental caries. 2. What laboratory methods are available to study the pathology of dental caries? 3. Describe the detection, clinical appearance and histopathology of caries in enamel. 4. Describe the pathology of caries in dentine and explain the sequelae. 5. Describe the response of the pulpodental complex to caries progression. 6. Describe the underlying pulpal changes occurring in the progression from acute pulpitis through chronic pulpitis to chronic open hyperplastic pulpitis and its sequelae. 7. Describe the changes observed in enamel, dentine and cementum with advancing age. 8. Explain why some superficial enamel cavities cause pain while some deep cavities can be pain-free.

9. Describe the methods available for the detection of caries in a clinical setting. 10. Describe five approaches to the prevention of dental caries.

SUGGESTED READING 1. Berkovitz BKB, Holland GR, Moxham BJ. Oral Anatomy, Embryology and Histology, 3rd edn. Mosby International Ltd; 2002. 2. Blanaid D, Watt RG, Batchelor P, Treasure ET. Essential Dental Public Health. OUP, Oxford; 2002. 3. Darling AI. Dental Caries, Chapter 5. In: Gorlin RJ, Goldman HM (Ed). Thoma’s Oral Pathology, Volume 01, 6th. edn. The CV Mosby Company, St. Louis; 1970. 4. Fejerskov O, Nyvad B, Kidd E AM. Pathology of Dental Caries, Chapter 3. In: Fejerskov O, Kidd EAM (Eds). Dental Caries - The disease and its clinical management. 2nd edn. Oxford: Blackwell Munksgaard; 2008. 5. Le Charpentier Y, Auriol M. Histopathologie bucco-dentaire et maxillo-faciale, Chapter 3. Masson, Paris, 1997. 6. Mendis BRRN, Darling AI. A Scanning electron microscopic and microradiographic study of closure of human coronal dentinal tubules related to occlusal attrition and caries. Archs. Oral Biol. 1979;24:725-33. 7. Samaranayake L. Essential Microbiology for Dentistry, 3rd edn. Churchill Livingstone, Edinburgh; 2006.

2 PATHOLOGY OF DENTAL CARIES

is a challenge. Parents and children should be educated on dietary practices and on oral health maintenance by adequate daily plaque removal. For patients with low salivary flow due to dry mouth arising from conditions such as Sjögren's syndrome, rheumatoid arthritis, diabetes and use of drugs producing xerostomia as a side effect, suitable salivary substitutes could be provided to reduce the development of caries.

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Chapter

3 Periodontal Diseases Philip M Preshaw

Chapter Outline Epidemiology of Periodontal Disease History, Examination and Assessment of Risk Factors • History • Examination • Risk Factor Assessment Diagnosis, Treatment Planning and Empowering the Patient Gingivitis Periodontal Diseases • Chronic Periodontitis • Aggressive Periodontitis Microbiology, Histology and Pathogenesis • Microbiology • Histology and Pathogenesis

• Direct Injury by Plaque Bacteria • Host Derived Inflammatory Mediators • Pathogenesis and Clinical Signs of Disease Periodontal—Systemic Interface • Diabetes • Coronary Heart Disease • Pregnancy Outcomes Treatment of Periodontal Disease • Plaque Control • Root Surface Debridement (RSD) • Adjunctive Treatments • Risk Factor Management • Maintenance Care • Surgical Therapy Self-assessment Questions

INTRODUCTION

EPIDEMIOLOGY OF PERIODONTAL DISEASE Epidemiology describes the study of the distribution of disease in human populations. It is important to distinguish between the incidence of a disease and the prevalence of a disease. Incidence refers to the number of new cases of a disease that develop over a given time period in a population. However, we are unable to identify the exact point in time at which a patient develops periodontitis, and therefore in periodontal epidemiology we do not attempt to measure disease incidence. Instead, we rely on disease prevalence, which refers to the proportion (percentage) of people in a population affected by the disease at a given point in time. To ascertain the prevalence of periodontal disease, we need to be able to accurately and reproducibly define whether or not a patient has the disease. But, how is periodontitis diagnosed or defined? Many studies in the 1960s and 1970s used a very low threshold for defining the presence of periodontitis, or even failed to distinguish between gingivitis and periodontitis,

3 PERIODONTAL DISEASES

Periodontal disease is a common, chronic inflammatory disease of the tooth supporting structures. It is one of the most common diseases known to mankind, and its sequelae, mobile teeth and loss of teeth, can have a major impact on quality of life and nutrition. Good oral health is an essential prerequisite for maintaining good general health. The dental team therefore have a major role in contributing to the health and wellbeing of their patients. Given that periodontal diseases are, for the most part, largely preventable and the tissue destruction that ensues is largely irreversible, it remains the responsibility of the dentist to examine patients carefully, to reach an accurate diagnosis, to communicate their findings to the patient, and to provide appropriate therapy. The first step in improving our management of periodontal diseases is to ascertain the prevalence of these conditions in the population.

which resulted in very high reported prevalence rates in the periodontal literature. Data from research conducted at the time suggested that periodontitis inevitably commenced in early adulthood, and that almost the entire population was affected by the time individuals reached their 40s. Tooth loss was thought to increase gradually with age, in a relatively linear fashion. These observations led to a theory of periodontal disease that we might now refer to as the ‘Old Theory of Periodontitis’ (Box 3.1). Box 3.1: Theories of periodontitis The old theory of periodontitis • Periodontal disease is inevitable following gingivitis • Periodontal disease is uniformly distributed in the population • Disease severity is correlated with plaque levels • There is a linear, progressive loss of attachment over time • The severity of periodontitis increases with age The new theory of periodontitis • Gingivitis and mild periodontitis are common, and gingivitis is present in a majority of most populations • Approximately 10 to 15 percent of most populations exhibit advanced periodontitis • Gingivitis precedes periodontitis but not all sites with gingivitis develop periodontitis • Periodontitis is not a natural consequence of ageing (but older people may present with more loss of attachment as a result of a lifetime of tissue breakdown events) • In some patients, periodontitis may progress with episodes of disease activity interspersed with periods of quiescence, in a nonlinear manner.

Today, we can recognize the methodological shortcomings of these early studies. Guidelines for assigning a diagnosis for the presence of periodontal disease in epidemiological studies have been developed (see reading list). We now realize that although gingivitis and mild periodontitis (characterized by isolated shallow

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pockets of 4–5 mm) are common, advanced periodontitis (characterized by multiple deep pockets of 6 mm or greater) is much less prevalent than previously thought. Although estimations of the prevalence of advanced periodontitis vary according to the population studied, a consistent finding is that advanced periodontal disease affects approximately 10 to 15 percent of adults in most populations. Though this is less than estimates of disease prevalence that were reported previously, this still represents a very large proportion of most populations, with large numbers of people affected. Furthermore, plaque and calculus are almost ubiquitous, and are found in the vast majority of adults. In addition to studying the epidemiology of periodontal disease, researchers have investi­ gated the nature of periodontitis progression. Early studies considered that loss of attachment and alveolar bone destruction continued in a linear fashion over time, and that once periodontitis was initiated, its progression was inevitable. More recent longitudinal monitoring studies have revealed that, for the majority of periodontitis patients, most sites are stable at any given time, and only a relatively small proportion demonstrate disease progression. It must be remembered, however, that these findings are based on repeated examination of patients using a periodontal probe. The periodontal probe is a somewhat crude diagnostic tool. The probe is attempting to identify tissue breakdown events at the base of the pocket that are resulting in microscopic alterations in the epithelial and connective tissue attachment to the tooth, and therefore it is unsurprising that we are unable to identify with any degree of reliability which periodontal sites are actively undergoing breakdown when we examine a patient. Nonetheless, we can summarize the findings of more recent epidemiological surveys into what we can call the ‘New Theory of Periodontitis’, as shown in Box 3.1. This theory reveals that severe forms of periodontitis are found in approximately 10 to 15 percent of most populations, representing a very large number of individuals across the world.

3

Presenting complaint

• In the patient’s own words. • Patients will typically mention bleeding gums, bad breath, mobile teeth, drifting of teeth, gingival recession. However, pain is not usually reported in gingivitis or periodontitis.

History of presenting complaint

• How long has there been a problem? • Has the patient been aware of this for weeks, months, years?

Previous dental history

• Is the patient a regular dental attender? • Has any periodontal treatment been provided in the past? If so, by whom (e.g. dentist, hygienist, periodontist)? • How long did the treatment appointments last? • Was the treatment a simple ‘scale and polish’ or was it more thorough root surface debridement? • If teeth have been lost, why was this?

Use of oral hygiene products

• What is the patient using? • Frequency of tooth brushing? • Are interdental cleaning brushes being used?

Family history

• Do any other family members have periodontal problems (this could potentially indicate aggressive periodontitis, which has a familial aggregation)

PERIODONTAL DISEASES

ƒ Table 3.1 Structured history taking

Social history • Sources of stress in life? Smoking history

• If a current smoker, how many cigarettes per day, and for how many years have they smoked? • If an ex-smoker, when did they quit? For how many years did they smoke, and how many cigarettes did they used to smoke per day?

Medical history

• Record and update the medical history at each visit. • Are there risk factors for periodontal disease, e.g. diabetes? • Are there medical conditions that impact on dental management or provision of periodontal treatment? • Are there nutritional deficiencies or dietary problems? • Which medications does the patient take, and can these impact on periodontal status or treatment?

• Food debris • Purulent exudate from a periodontal pocket • Excessive bacterial growth on the dorsum of the tongue • Necrotizing ulcerative gingivitis. If pain is present, it may indicate necrotising ulcerative gingivitis, or an acute periodontal abscess. Gingival recession that has resulted in exposure of the roots may also result in dentine sensitivity. Pain is not otherwise a typical feature of chronic periodontitis.

Examination The intraoral examination should include several components. An initial assessment of the level of oral hygiene and plaque control is important. The degree of gingival inflammation should be also assessed. All patients should be screened for periodontal disease by probing, and the quickest method is to record the basic periodontal examination (BPE), also known as the Community Periodontal Index of Treatment Needs (CPITN).

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A WHO (World Health Organization) periodontal probe should be used: this has a 0.5 mm diameter ball end and a colored band extending 3.5 to 5.5 mm from the tip. The dentition is divided into sextants, the periodontium around each tooth is probed and the highest score in each sextant is recorded. The score codes assigned are used as a guide to determine the need for periodontal treatment (Table 3.2). If the results of the screening examination indicate the presence of periodontitis (i.e. BPE code 3 or code 4), then a detailed periodontal examination should be undertaken (i.e. full charting). If there is only one tooth in a sextant, no score is recorded for that sextant, and instead, the tooth is assessed together with the teeth in the neighboring sextant. For those patients requiring a full periodontal examination, this should be performed at 6 sites per tooth, together with measurement of gingival recession (and calculation of loss of attachment by addition to the probing depth measurements) and bleeding on probing. Bleeding on probing results from the trauma caused to the epithelial pocket lining and connective tissue by the probe, but given that many factors can affect whether

the tissue bleeds in addition to the degree of inflammation (such as the force of probing, sharpness of the probe tip), presence of bleeding on probing has a low sensitivity for periodontal disease progression. However, absence of bleeding on probing is a good indicator of periodontal stability. Furcation involvement should be assessed with a curved furcation probe (Nabers probe). Classification is as follows: • Class I: The tissue destruction does not exceed more than 3 mm (or not more than one­third the tooth width) into the furcation • Class II: The tissue destruction is >3 mm (or more than one­third the tooth width) into the furcation but does not completely pass through the furcation • Class III: It has through­and­through involvement, and the lesion extends across the entire width of the furcation. A tooth with a furcation involvement is a compromised tooth. It has been estimated that the surface area of the root trunk of the first maxillary molar is approximately 30 percent of the total root surface area. In other words, by the time the furcation can be detected, a significant

ƒ Table 3.2 The basic periodontal examination (BPE) Code*

Probing

Treatment needs

Colored band on the probe is completely visible No calculus detected No bleeding on probing

No need for periodontal treatment

1

Colored band on the probe is completely visible No calculus detected Bleeding on probing

Oral hygiene instruction (OHI)

2

Colored band on the probe is completely visible Calculus detected (supra- or subgingival), or overhanging restoration(s)

OHI: Elimination of plaque-retentive areas, scaling, root surface debridement (RSD)

3

Colored band on probe is partly visible, indicating probing depth of >3.5 mm but 5.5 mm

OHI, RSD. Complex additional treatment may be required. Referral to a periodontal specialist may be necessary.

* The symbol (*) should be added to the score when furcation involvement is present. The score should then be recorded, for example, as 4*, or 3*, etc.

ces (e.g. as a result of an occlusal interference). Secondary occlusal trauma is that which affects periodontally compromised teeth (which have pre­existing attachment loss and bone loss), and may result from either normal or excessive occlusal forces. A classic appearance of a periodontally compromised tooth that also is subject to trauma from occlusion (i.e. secondary occlusal trauma) is that of a crater­like defect with extensive bone loss and a very mobile tooth (Fig. 3.1). This is distinct from the radiographic appearance of a periodontally healthy tooth subject to a traumatic occlusion (i.e. primary occlusal trauma). In the healthy situation, trauma from occlusion (primary occlusal trauma) may result in widening of the periodontal membrane space and increased mobility, but will not cause periodontitis. If the traumatic interference is removed, then the periodontal membrane space returns to normal and mobility decreases. Radiographic investigation is an essential part of the assessment of patients with periodontitis. Modern panoramic machines provide high quality images at reduced radiation exposure compared to full mouth periapicals. Radiographic features that can be identified include: • Pattern of bone loss: horizontal or vertical, localized or generalized, irregular or regu­ lar extent of bone loss, usually described as a proportion or percentage of the root affected • Furcation bone loss

Fig. 3.1: Trauma from occlusion resulting in exacerbation of pre-existing periodontal disease. Radiograph showing generalized horizontal alveolar bone loss affecting between one-third and one-half the root length, being most advanced at molar sites and the maxillary incisors. Extensive vertical defects/crater defect at tooth 47, in traumatic occlusal relationship

3 PERIODONTAL DISEASES

degree of periodontal breakdown has already occurred. Tooth mobility should also be assessed by applying a labiolingual, horizontal force to each tooth, using the handles of dental mirrors. A mobility index can be recorded as: 0 Normal, physiological mobility ( 0.3 mm to 1.0 mm 2 Horizontal mobility 1.0 to 2.0 mm 3 Horizontal mobility > 2.0 mm and/or vertical mobility. Occlusal examination should be under­ taken when indicated. Many patients with periodontitis present with mobile teeth, and occlusal interferences may contribute to this. It is important to note that trauma from occlusion does not cause periodontitis; however, in the presence of pre­existing periodontitis, trauma from occlusion may exacerbate mobility and lead to an increased rate of alveolar bone loss. Fremitus should be assessed, and the presence of traumatic incisal relationships should be determined. Traumatic incisal relationships are classified by the Akerly classification: 1. Lower incisors in compete overbite, contact­ ing palatal mucosa but distal to the palatal gingival margins of the upper anterior teeth. 2. Lower incisors in complete overbite, con­ tacting palatal gingival margins of the upper anterior teeth (can result in localized trauma and recession at the palatal gingival margins of the maxillary anterior teeth). 3. As for class 2, but there is also shearing trauma of the gingival margins at the labial aspects of the lower anterior teeth as the upper incisors slide past the lower incisors (predisposed by lack of posterior support, and class II division 2 overbite). 4. Palatal attrition, i.e. dental trauma as the lower incisors contact the palatal surfaces of the upper incisors. Occlusal trauma can be defined as injury to the attachment apparatus of the teeth as a result of occlusal forces, and is classified as primary occlusal trauma or secondary occlusal trauma. Primary occlusal trauma is occlusal trauma that affects periodontally healthy teeth (i.e. those with normal attachment and bone support), and is usually caused by excessive occlusal for­

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• Variations in root anatomy • Interproximal calculus • Widening of the periodontal membrane space • Overhanging restorations. A decreased alveolar bone height on a radiograph is a historical record of previous periodontal involvement and provides no information on current disease activity.

Risk Factor Assessment Assessment of risk factors (or predisposing factors) is one of the most important parts of the assessment of a patient with periodontitis, yet is often overlooked. Risk factors can be broadly classified as systemic risk factors or local risk factors. Systemic risk factors include smoking and diabetes. Smoking is the most important systemic risk factor for periodontitis and a detailed smoking history must always be recorded. Patients must always be informed of the importance of this risk factor and encouraged to quit. Smoking has wide ranging impacts on inflammation and immune responses, and is a significant negative modifier of multiple types

of periodontitis. It is important to record in the patient notes that the importance of smoking as a risk factor has been explained to the patient. Similarly, poorly controlled diabetes is a major risk factor for periodontitis. However, patients with well controlled diabetes do not appear to be at increased risk for periodontitis. Local risk factors include multiple anatomic and iatrogenic factors that typically are plaque retentive (e.g. overhanging margins of restorations, orthodontic appliances, etc).

DIAGNOSIS, TREATMENT PLANNING AND EMPOWERING THE PATIENT A correct diagnosis is essential for correct treatment planning. It is important not to adopt a ‘one size fits all’ approach to periodontal treatment. The treatment must be individualized to the patient, and that starts with a thorough history to understand the needs of the patient, and requires a correct diagnosis. A diagnosis can be assigned based on the disease criteria established by the American Academy of Periodontology in 1999 (Table 3.3). Reaching a correct diagnosis is dependent on

ƒ Table 3.3 Classification of periodontal diseases Gingival diseases

A. Plaque-induced gingivitis: This is the most common type of gingival condition, and may be associated with plaque only, or further modified by, for example, systemic drugs (e.g. those that cause drug induced gingival overgrowth), or hormonal variations (e.g. those seen in pregnancy) B. Nonplaque induced gingivitis: This includes specific infections (e.g. primary herpetic gingivostomatitis), gingival manifestations of conditions such as lichen planus, and traumatic gingival lesions

Chronic periodontitis

This is the most common form of periodontitis. It is characterized by some/all of the following: • Most prevalent in adults but can occur in children/adolescents • Subgingival calculus commonly found • Associated with a variable microbial pattern • Slow/moderate rate of progression, but may have periods of rapid progression • Can be classified on basis of extent (e.g. localized or generalized) or severity (e.g. amount of attachment loss) • Can be associated with local predisposing factors (e.g. plaque retentive features such as overhangs) • Can be modified by/associated with systemic exposures such as smoking, or conditions such as diabetes Contd...

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Contd... ‘Aggressive periodontitis’ (AP) replaces previously used terms such as ‘rapidly progressive periodontitis’ or ‘juvenile periodontitis’. The primary characteristics of AP are: • Except for the presence of periodontitis, patients are otherwise clinically healthy • Rapid attachment loss and bone destruction (often characterized by very irregular pattern of alveolar bone loss, multiple vertical defects, extensive bone loss) • Familial aggregation (which is why it is important to ask about family members when examining patients with suspected aggressive periodontitis) Secondary characteristics of AP are: • Plaque levels are sometimes less than might be expected given the severity of the periodontal disease (this situation might be typically seen in a very concerned and motivated patient who clearly has a genetic susceptibility and is maintaining good oral hygiene, yet still has advanced disease) • Elevated levels of Aggregatibacter actinomycetemcomitans (especially in localized AP) and Porphyromonas gingivalis • Phagocyte abnormalities and a hyper-responsive macrophage phenotype, including elevated levels of PGE2 and IL-1β (though there is no diagnostic test for a hyperresponsive phenotype and this is essentially a research finding only)

PERIODONTAL DISEASES

Aggressive periodontitis

AP can be further classified as localized (localized to the first molars and incisors, and typically has a circumpubertal onset) or generalized (affecting at least 3 permanent teeth other than first molars and incisors, usually affecting people condyle. It is thought that the maxilla is less commonly affected due to more extensive blood supply, thin cortical plates, relative paucity of medullary tissues which preclude confinement of infections resulting in their spread to surrounding soft tissues or paranasal sinuses. Osteomyelitis is rarely seen in neonates or infants and when present is in the maxilla. This is as a result of uncontrolled middle ear infection or secondary to birth injuries at the time of delivery.

Etiology

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Osteomyelitis is a mixed aerobic and anaerobic bacterial infection. Bacteria that have been associated include the fusobacteria, Porphyromonas,

Prevotella, streptococci and staphylococci families. Historically osteomyelitis was thought to be due to infection by Staphylococcus aureus species only. Osteomyelitis has also been associated with infections by herpes zoster virus, cytomegalovirus, actinomycosis, tuberculosis and syphilis.

Clinical Features Osteomyelitis is characterized by severe throbbing, deep-seated pain and swelling. With disease progression pus accumulates initially within the medullary bone then extends to involve the cortex with eventual perforation of the cortex. The pus then accumulates under the periosteum causing distension of the periosteum. Over time there may be bone expansion due to subperiosteal bone formation with the resulting swelling becoming firm. The overlying gingiva is red, swollen and tender. As the disease progresses, the associated teeth become loose and tender with pus exudation from the gingival crevice and mucosa. Any attached muscle in the region of the jaw affected by the osteomyelitis becomes edematous and this might give rise to trismus and difficulty in swallowing. There may be associated fever, leucocytosis, regional lymphadenopathy and cellulitis. In the case of osteomyelitis of the mandible, the inferior dental nerve may be involved resulting in altered sensation of the lower lip. Acute osteomyelitis of less than a month’s duration is associated with fever, increazed white cell count, lymphadenopathy and localized swelling. Chronic osteomyelitis is often associated with a localized swelling, pain, sinus formation, pus discharge, bony sequestrum, loosening of teeth and pathologic fractures. Radiographic changes as a result of osteomyelitis become evident after ten days. These radiographic changes include loss of trabeculae, radiolucency, ill-defined margins with a fluffy or moth-eaten appearance. Where bony sequestra are present radiopaque areas will be seen within the radiolucent areas. Subperiosteal new bone formation may also be evident. Early bone changes are detectable with Computer Tomographic (CT) scan examination before being visible on plain radiographs. CT scans are better than plain radiographs in

Pathogenesis The process of osteomyelitis is initiated by acute inflammation and its features of hyperemia, increased capillary permeability and infiltration of granulocytes. Proteolytic enzymes are released by the granulocytes resulting in tissue necrosis, destruction of bacteria and vascular thrombosis. Intramedullary pressure increases where there is intramedullary accumulation of pus which is composed of necrotic tissue, dead bacteria with granulocytes. The increased pressure causes vascular collapse, venous stasis and consequently ischemia. As the disease progresses, pus accumulates beneath the periosteum resulting in periosteal elevation from the cortex and further compromise of blood supply. Further pus accumulation causes the cortex to be breached, giving rise to mucosal and/or cutaneous abscesses or fistulae. In the vicinity of the inferior dental canal, pus accumulation may result in the compression of the inferior dental bundle resulting in sensory impairment. As effectiveness of host defences and therapy increases, the process of osteomyelitis may resolve. Chronic osteomyelitis may develop where effect of host defences and therapy are inadequate. In some situations as the inflammatory process regresses, granulation tissue forms around involved bone. New vascularization may result in the lyses of bone leading to separation of dead fragments of bone which become bony sequestra. The bony sequestra may be encased in a sheath of new bone thus becoming an involucrum. The sequestra may revascularize, be resorbed, be quiescent or become chronically infected requiring surgical removal.

Diagnosis A swab of pus sent for microbiological culture would confirm the infective agent. Radiographic features of bone loss are commonly referred to as “moth eaten appearance”. Bony sequestrum, if available, is sent for histological and microbiological examination.

Management Management includes the administration of antibiotics. The route of antibiotic administration is dependent on the presence, or not, of systemic manifestations of infection. In the presence of systemic manifestations of infection the intravenous route is preferred and the selected antibiotic (based on the culture and sensitivity reports) are administered for up to 2 weeks. In the absence of systemic signs the oral route will be adequate for up to 6 weeks. Polymethylmethacrylate beads impregnated with antibiotics such as gentamicin or tobramycin can be placed in the area of osteomyelitis as a source of local antibiotic administration for up to 3 months. Any host factors adversely contributing to the development of osteomyelitis will need to be addressed. Incision and drainage of sites of pus accumulation, removal of involved teeth, decortication, debridement of bony sequestra and necrotic material are likely. The defect arising from resection of infected bone may need reconstruction and the clinical decision will need to be made whether immediate or late bone-graft reconstruction is used.

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revealing lesion extent, extent of cortical erosion and identification of sequestra. Magnetic resonance imaging is the examination of choice in identifying medullary changes.

Complications • Altered sensation especially where the inferior dental nerve is involved. • Pathological fracture of the involved jaw bone. • Chronic osteomyelitis after inadequate treatment. • Cellulitis. • Septicemia in the immunocompromized individual. Box 4.3: Osteomyelitis of jaw bones Key features helpful in diagnosis • Osteomyelitis is an inflammatory disease of bone • Adult males usually affected • Mandible more commonly affected • Characteristics: deep seated pain and swelling • Teeth may become loose • Pus may be present • Systemic signs such as fever, regional lymphadenopathy may be present • Radiolucency with ill-defined margins with a moth-eaten appearance on radiographs.

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Chronic Osteomyelitis

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Chronic osteomyelitis is more common than the acute variant. It results from inadequately treated acute osteomyelitis. The presence of local bone sclerosis is a factor for the development of chronic osteomyelitis. However, it usually develops de-novo as a result of infection by virulent bacteria or in avascular bone. It is characterized by persistent pain, exposed bone and radiographic changes after florid infection. Focal sclerosing osteomyelitis which may arise in the presence of longstanding infection is commoner in the young. Chronic osteomyelitis in the presence of acute necrotising ulcerative gingivitis may result in the development of noma whose treatment comprises of antibiotics and debridement. Antibiotics of the penicillin group with established potency in bone infections in combination with metronidazole is found to be consistently useful in arresting the fulminating acute phase of noma. Overall, the “gold standard” remains that antibiotics administered at the acute phase must be sufficiently broad to cover the spectrum of aerobic and anaerobic organisms inhabiting the periodontium and oropharynx. Improved oral hygiene instructions and strategy also must accompany early phase treatment.

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Actinomycosis Actinomycosis is a slowly progressing chronic infection with granulomatous and suppurative features. Actinomycosis is caused by filamentous, gram-positive, non-acid-fast, nonspore-forming bacteria. They belong to the, genus Actinomyces. Actinomyces organisms grow slowly in anaerobic-to-microaerophilic conditions. The most common isolated species are Actinomyces israeli, Actinomyces gerencseriae, Actinomyces turicensis, Actinomyces radingae, and Actinomyces europaeus. In addition to these microorganisms, almost all actinomycotic lesions contain so-called companion bacteria. The most important of these bacteria is Actinobacillus actinomycetemcomitans. These companion bacteria appear to magnify the low pathogenic potential of actinomycetes. Actinomycosis usually affects soft tissue and occasionally bone. It can affect the mandible

and overlying soft tissues as well as the parotid gland and tongue. Cervicofacial actinomycosis is characterized in the initial stages by softtissue swelling of the perimandibular area. Direct spread into the adjacent tissues occurs over time forming multiple abscesses along with development of fistulas (sinus tracts) that discharge purulent material containing granules with a yellow sulfur-like appearance (termed sulfur granules). It could be difficult to diagnose actinomycosis based on the clinical features alone, direct identification and/or isolation of the infecting organism from a clinical specimen or from sulfur granules is necessary for definitive diagnosis in most cases. A pus sample can be obtained from a draining sinus or by needle aspirate. A gram-stained smear of the specimen may demonstrate the presence of beaded, branched, gram-positive filamentous rods, suggesting the diagnosis of actinomycosis and culture under anaerobic conditions may require 2 to 3 weeks. The preliminary diagnosis of actinomycosis could also be made by examining sulfur granules crushed between 2 slides, stained with 1 percent methylene-blue solution, and examined microscopically for features characteristic of actinomycetes. In most cases of actinomycosis, antimicrobial therapy is the only treatment required, although surgery can be adjunctive in selected cases including incision and drainage of abscesses, excision of sinus tracts. Penicillin G or V is the drug of choice for treating infections caused by actinomycetes though recalictant cases may need doxycycline or augmentin.

Infantile Osteomyelitis Infantile osteomyelitis is a rare condition associated with Staphylococcus aureus infection. It occurs a few weeks after birth, in the usually involving the maxilla. It had a mortality of 30 percent in the preantibiotic era. It is thought to spread via the hematogeneous route or from perinatal trauma of oral mucosa possibly from contaminated human or artificial nipples. It is also possibly a result of spreading infection from the maxillary sinus. Potential complications include the risk of eye involvement, extension to dural sinuses,

Box 4.4: Infantile osteomyelitis Key features helpful in diagnosis • Is rare • Is associated with Staphylococcus aureus • Occurs few weeks after birth • usually affects the maxilla.

osteomyelitis is an irritation induced focal thickening of the periosteum and cortical bone of the tibia as well as the mandible. Children and young adults with a mean age of 13 years are usually affected. It is thought to be as a result of an active periosteal response to low grade infection or irritation in young people. It usually manifests in the premolar and molar areas. It is characterised by the presence of a nontender unilateral bony swelling of the lateral and inferior aspects of the mandible. It is associated with a periapically involved carious tooth and history of dental pain. It can also be due to periodontal infections and trauma. The overlying skin is normal and there is no lymphadenopathy or fever present. Radiographically it presents as well-calcified layers of reactive bone proliferation with a laminated (‘onion skin’) appearance. The apices of involved teeth may have associated radiolucency.

Histology Chronic Recurrent Multifocal Osteomyelitis of Children Chronic recurrent multifocal osteomyelitis (CRMO) of children is an inflammatory disease of the bone which resembles infectious osteomyelitis. Its hallmark is recurring episodes of sterile osteomyelitis that affect children around fourteen years of age. Affected sites include the mandible, tibia, clavicle, fibula, spine and femur. The mandibular lesions are usually bilateral, irregular, mottled, multilocular and located in the rami. They undergo spontaneous remission with antibiotics and surgical debridement having little effect. CROM shows several similarities with synovitis, acne, pustolosis, hyperostosis, osteitis (SAPHO) syndrome and is now believed to belong to autoinflammatory syndromes, a group of genetically-determined disorders characterized by unprovoked (or triggered by minor events) recurrent episodes of systemic inflammation involving various body systems.

There are parallel rows of highly cellular and reactive woven bone in which individual trabeculae are frequently orientated perpendicular to the surface.

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potential facial deformities, loss of teeth due to delayed or inappropriate treatment. Clinical features include facial cellulitis around the orbit, irritability, malaise, hyperpyrexia, anorexia, dehydration, convulsions and vomiting. Pus may be present within the nostril on the affected side. Intraorally the maxilla on the involved side will be swollen, fluctuant with the presence or not of fistulae. CT scan examination is needed to establish the extent of the osteomyelitis. Aggressive intravenous antibiotics are required, together with incision and drainage. Oral antibiotics are advised for a further 2–4 weeks after resolution.

Management Initially treat it is necessary to the dental cause. If there is no improvement, or in the absence of inflammation then carry out a biopsy because conditions such as Ewing’s sarcoma, osteosarcoma and cortical hyperostosis (Caffey’s disease) may have a similar radiographic appearance. Box 4.5: Proliferative periostitis Key features helpful in diagnosis • Chronic, nonsuppurative sclerosing • Affects children and young adults with a mean age of 13-years • Develops in response to low-grade infection or irritation • Involves and molar regions.

Proliferative Periostitis (Periostitis Ossificans)

Chronic Sclerosing Osteomyelitis

Proliferative periostitis (Periostitis ossificans) also referred to as Garrés sclerosing osteomyelitis. Chronic nonsuppurative sclerosing

There are two types of chronic sclerosing osteomyelitis namely the diffuse type and florid osseous dysplasia type.

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Diffuse Chronic Sclerosing Osteomyelitis The diffuse type is an inflammatory, nonsuppurative, painful disease with a protracted course. There may be episodes of recurrent swelling and pain. It affects the whole height of the mandible, usually on one side. It affects mainly the body of the mandible though the angle, ramus and condyle may also be affected. Young adults in the third decade are usually affected with two-thirds being female. Radiographic features include diffuse intramedullary sclerosis, poorly defined margins, occasional areas of radiolucency and radiopacity. It is associated with E. Corrodens, Actinomyces and Bacteroides infection. Management includes the administration of high doses of antibiotics and removal of the source of infection. In some cases it may be necessary to carry out decortication or resection of involved bone and the appropriate reconstruction.

Florid Osseous Dysplasia Radiographic features of opaque masses limited to the alveolar process. Usually present in African and Caribbean women (see Chapter 7).

Diffuse Sclerosing Osteomyelitis Diffuse sclerosing osteomyelitis is an ill-defined group characterized by pain, inflammation, periosteal hyperplasia, sclerosis. There is an obvious infectious process causing sclerosis of bone. It occurs in adulthood with no sex predilection and usually affects the mandible. The sclerosis tends to center on the crestal portion of the tooth-bearing part of the alveolar ridge. Radiographic examination shows radiopaque areas at sites of chronic infection such as apical inflammatory disease.

Histology

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Bone sclerosis and remodelling is present. The Harversian canals are widely scattered with little marrow spaces. There is little inflammatory soft tissue component associated. In cases where inflammation involves the sclerotic bone this results in bone necrosis and subsequent sequestrum formation colonized by bacteria.

Management The aim of treatment is to remove the foci of chronic infection. Areas of sclerosis may remodel or persist. It is important to avoid periodontitis or apical inflammatory disease.

Primary Chronic Osteomyelitis Primary chronic osteomyelitis is characterized by recurrent episodes of pain, swelling and local induration. The active stage may be associated with lymphadenopathy and inferior dental nerve paraesthesia. No fever, pus, sequestra or sinus is present and there is no obvious odontogenic cause. It tends to have two onset peaks namely adolescence and after the fifth decade of life. A mixed pattern of osteolytic and sclerotic areas is seen on radiographs. The osteolytic areas are not continuous as noted in suppurative osteomyelitis. The affected bone becomes thickened and overtime a more sclerotic picture is noted on radiographs. Synovitis-acne-pustulosis-hyperostosisosteomyelitis (SAPHO) and chronic recurrent multifocal osteomyelitis (CRMO) are reported subsets of primary chronic osteomyelitis. SAPHO also affects multiple sites such as the anterior chest wall, sternum, clavicle, spine and ribs. It usually occurs in people < 60 years with a negative result upon microbiological examination. The osteolytic areas tend to be within sclerotic bone. CRMO also affects multiple sites such as the clavicle, humerus, radius and tibia. There may also be skin involvement, e.g. palmoplantar pustulosis psoriasis.

Histology There is evidence of bone remodelling in the areas of sclerosis. There is inter-trabecular fibrosis present as well as scattered lymphocytes and plasma cells. There may be foci of micro-abscesses, hyalinization around small blood vessels and subperiosteal formation. No bone necrosis, bacterial colonization or pus is associated.

Management Treatment results are mixed. It is difficult to eliminate the infection as despite treatment there

Chronic Tendoperiostitis Chronic tendoperiostitis is thought to be a reaction of bone to the chronic overuse of the attached masticatory muscles such as that due to parafunctional behavior. Patients have a mean age of 40 years. It is characterized by recurrent pain, cheek swelling, trismus and no suppuration. Radiographic examination shows sclerotic areas to be related to sites of muscle attachment.

Histology There is evidence of sclerosing and remodelling of cortical and subcortical bone resulting in increased bone volume. Chronic inflammatory cells may also be present.

Management The results after the use of antibiotics, antibiotics-impregnated beads, surgical exploration, decortication, hyperbaric oxygen and steroids have been unsatisfactory. Another suggested treatment modality aims to reduce muscle overuse through employing relaxation techniques, Box 4.6: Chronic tendoperiostitis Key features helpful in diagnosis • Recurrent pain • Cheek swelling • Trismus • No suppuration • Sclerotic areas related to sites of muscle attachment.

soft diet, occlusal splints and muscle relaxant drugs.

Condensing Osteitis (Focal Sclerosing Osteomyelitis) Condensing osteitis (Focal sclerosing osteomyelitis) is characterized by localized areas of bone sclerosis associated with the apices of teeth undergoing pulpitis or pulpal necrosis, e.g. carious teeth, teeth with deep restorations. It usually affects children or young adults. Radiographs show the presence of a radiopaque area at the apex of the tooth with probable widened periodontal ligament space or apical area. It usually involves the premolar or molar areas of the mandible. The radiopacity is not separated from the tooth apex and there is no radiolucent outline.

Management The aim of treatment is to treat the odontogenic cause. Box 4.7: Focal sclerosing osteomyelitis

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are still flare-ups and partial remissions. Various treatment modalities have been proposed with limited success. Long-term antibiotics with or without hyperbaric oxygen, corticosteroids, nonsteroidal anti-inflammatories and calcitonin have all been used. Intravenous bisphosphonates, e.g. alendronate, pamidronate and disodium clodronate are reported to show significant benefit. For example, a single intravenous dose of alendronate is reported to result in pain reduction within twenty four hours, suppression of bone turnover and lead to long-term remission.

Key features helpful in diagnosis • Associated with teeth undergoing pulpitis or pulpal necrosis • usually affects children or young adults • Radiopaque area attached to tooth apex • usually affects mandibular premolar and molar teeth.

Alveolar Osteitis (Dry Socket, Fibrinolytic Alveolitis) A blood clot normally forms within the tooth socket after a dental extraction. The clot then undergoes organization and subsequently progresses with the formation of woven bone. The woven bone then develops into mature bone. Where the clot is lost healing is impaired with the development of alveolar osteitis. The clot is thought to be lost secondary to the transformation of plasminogen to plasmins. This results in lysis of fibrin and formation of kinins which are potent pain mediators. The fibrinolysis can be due to trauma, estrogens, bacterial pyrogens, poor oral hygiene, traumatic

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extractions, presurgical infections, spitting and smoking. The prevalence of alveolar osteitis is reported as 20 percent in those smoking > 1 pack/day and 40 percent in those who smoke on the day of operation or within 24 hours. The frequency is higher in the posterior mandible. There is no sex predilection. It is reported that alveolar osteitis occurs in 1 to 3 percent of all extractions and in 25 to 30 percent after the extraction of impacted third molars. The frequency of alveolar osteitis decreases with prophylactic removal rather than therapeutic removal of third molars. The frequency is reported to be highest in the 40 to 45 years age group with the prevalence highest in the 20 to 40 years age group. After the loss of the blood clot there is exposure of the bare bony socket which tends to be very sensitive. There is severe pain, foul odor, lymphadenopathy and sometimes swelling. The pain may radiate to the ipsilateral ear, temporal regions and eye. Alveolar osteitis may have a duration between 10 to 40 days. Box 4.8: Alveolar ostetitis Key features helpful in diagnosis • loss of blood clot from extraction socket • Severe pain • Foul odor • lymphadenopathy • Duration of 10 to 40 days.

Management Radiographic examination may be needed to rule out the presence of a tooth remnant or a foreign body as the cause of poor healing. Irrigation of the socket with warm saline or chlorhexidine is advised. Prior to placement of a dressing, e.g. alvogyl, the socket should be inspected. Good oral hygiene to reduce the bacterial load may assist healing. To reduce the risk of alveolar osteitis it is suggested that the socket be irrigated postextraction with saline. Another suggested protective measure is to rinse with chlorhexidine on the day of the procedure and several days postup.

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SelF ASSeSSMeNT QueSTIONS 1. Define bisphosphonate related osteonecrosis of the jaws, describe its epidemiology and outline the risk factors associated with its development. 2. Outline the key features which are helpful in the diagnosis of bisphosphonate related osteonecrosis of the jaws. 3. Describe a clinical classification and associated management guideline for bisphosphonate related osteonecrosis of the jaws. 4. Define radiotherapy associated osteonecrosis, describe its epidemiology and outline the risk factors associated with its development. 5. Outline the key features which are helpful in the diagnosis of radiotherapy associated osteonecrosis. 6. Describe the usual clinical presentation and histopathology of radiotherapy associated osteonecrosis. 7. Describe your approach to the prevention of radiotherapy associated osteonecrosis as well as the management of an established case. 8. Define acute osteomyelitis and outline its etiopathogenesis. 9. Describe the management of acute osteomyelitis and outline possible sequelae of the condition. 10. Describe the etiology, clinical presentation and management of alveolar osteitis.

SuggeSTeD ReADINg 1. Almazrooa SA, Woo SB. Bisphosphonate and nonbisphosphonate-associated osteonecrosis of the jaw: a review. J Am Dent Assoc. 2009;140(7): 864-75. 2. Bamias A, Kastritis E, Bamia C, Moulopoulos LA, Melakopoulos I, Bozas G, et al. Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol. 2005;23:8580-7. 3. Lyons A, Ghazali N. Osteoradionecrosis of the jaws: current understanding of its pathophysiology and treatment. Br J Oral Maxillofac Surg. 2008;46(8):653-60. 4. Marx RE, Sawatari Y, Fortin M, Broumand V. Bisphosphonate-induced exposed bone

6. Silverman SL, Landesberg R. Osteonecrosis of the jaw and the role of bisphosphonates: a critical review. Am J Med. 2009;122:S33-45. 7. Sciubba JJ, Goldenberg D. Oral complications of radiotherapy. Lancet Oncol. 2006;7(2):175-83. 8. Teng MS, Futran ND. Osteoradionecrosis of the mandible. Curr Opin Otolaryngol Head Neck Surg. 2005;13(4):217-21.

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(osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg. 2005;63:1567-75. 5. Pitak-Arnnop P, Sader R, Dhanuthai K, Masaratana P, Bertolus C, Chaine A, Bertrand JC, Hemprich A. Management of osteoradionecrosis of the jaws: an analysis of evidence. Eur J Surg Oncol. 2008;34(10): 1123-34.

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Chapter

5 Cysts of the Oral and Maxillofacial Region WM Tilakaratne

Chapter Outline Odontogenic Cysts • Radicular Cyst • Lateral Periodontal Cyst • Residual Cyst • Paradental Cyst • Dentigerous Cyst • Eruption Cyst • Odontogenic Keratocyst (Keratocystic Odontogenic Tumor) • Nevoid Basal Cell Carcinoma Syndrome • Orthokeratinizing Odontogenic Cyst • Gingival Cyst of Newborn • Gingival Cyst of Adults • Lateral Periodontal Cyst and Botryoid Odontogenic Cyst • Glandular Odontogenic Cyst (Sialo-odontogenic Cyst) • Malignant Transformation in Odontogenic Cysts

Nonodontogenic Cysts • Nasopalatine Cyst (Incisive Canal Cyst) • Nasolabial Cyst • Aneurysmal Bone Cyst • Solitary Bone Cyst • Surgical Ciliated Cyst of the Maxilla • Oral Lymphoepithelial Cyst • Cervical Lymphoepithelial Cyst (Branchial Cleft Cyst) • Dermoid and Epidermoid Cyst • Thyroglossal Duct cyst • Developmental Cysts of Foregut Origin • Cystic Hygroma • Parasitic Cysts Self-assessment Questions

INTRODuCTION

5 CySTS OF THE ORAL AND MAxILLOFACIAL REGION

Occurrence of cysts in oral and maxillofacial region is far more common compared to rest of the body. This is especially true when it comes to intraosseous lesions. The majority of intra bony cystic lesions occur as a result of activation of epithelial remnants from enamel organ. This type of a phenomenon of having epithelium within the bone is uncommon in bones other than the mandible and maxilla. Therefore, the prevalence of cystic lesions is common in jaws. Inflammatory odontogenic cysts are responsible for a large majority of cases due to the presence of untreated dental decay in the community (Chapter 2). With the available current scientific findings, odontogenic keratocyst (OKC) has been moved to odontogenic tumor category in 2005 WHO classification. There is still a considerable debate as to whether OKC should be regarded as a true neoplastic lesion or an unusual cystic lesion. The term fissural cyst has been used over the years to denote cystic lesions arising from entrapped epithelium during the closure of embryological lines. However, according to the recent literature such a process does not exist and the term fissural cyst has become a misnomer. Due to the above reason the existence of globulomaxillary cyst, median palatine cyst and median mandibular cyst has been abandoned. The only remaining lesions from the above category appeared to be nasopalatine cyst and nasolabial cyst. Although a true cystic lesion should have a cyst wall, lining and the lumen, there are a few lesions which do not fulfil the above criteria. Aneurysmal bone cyst and solitary bone cyst are the examples from intraosseous cysts and mucous extravasation cyst is a common soft tissue example for the above category. The diagnosis of most cystic lesions needs clinicopathological correlation. Treatment of a cyst is either by enucleation or by marsupialisa­ tion. Recurrence of odontogenic cyst other than OKC and glandular odontogenic cyst is exceptionally uncommon and malignant transformation takes place very rarely.

odontogenic cysts. It arises in relation to apical region, or less commonly to the lateral side of a nonvital tooth, as a result of stimulation of epithelial cell rests of Malassez in a chronic periapical granuloma. It is clear that necrotic pulpal tissue and bacterial products initiate inflammation in the periapical region giving rise to a periapical granuloma. With time a central cavity is formed due to necrosis of cells and subsequently the cavity is lined by proliferating cell rests of Malassez. Although the exact agent stimulating the proliferation of epithelial cell rests is not properly understood, available information suggests that it may well be due to bacterial endotoxins. Invariably inflammation takes place as a result of these toxins, and inflammatory mediators which mediate the reaction such as IL­1 and IL­6 together with other molecules stimulate cell rests of Malassez to proliferate within the periapical granuloma. It was postulated in the past that increased carbon dioxide tension and decreased oxygen tension leading to acidic pH make the surroundings favorable for cell rests to proliferate. There are various theories regarding the expansion of the cyst including increased osmotic pressure in the cavity, increased hydrostatic pressure, epithelial proliferation, various cytokines and matrixmetalloproteinases (MMPs). However, increased hydrostatic pressure within the cyst lumen is considered to be the main factor responsible for expansion of most cystic lesions. Prostaglandin E2 (PGE2), PGI2, IL­1 and IL­6 may also play a role as they are potent cytokines with bone resorbing properties. Box 5.1: Radicular cyst Key features helpful in diagnosis • The most common odontogenic cyst. • Associated with a nonvital tooth. • Presents as a well-defined periapical radiolucency. • Lining epithelium is nonkeratinized stratified squamous and shows arcading pattern. • Cyst wall is inflamed and contains cholesterol clefts.

ODONTOGENIC CySTS Radicular Cyst

Clinical Features

Radicular cyst is the most common cyst in jaw bones accounting for 60 percent of the

Most radicular cysts are asymptomatic and are found on routine dental radiographs of

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nonvital teeth. The maxillary anterior region is the most common site (Fig. 5.1) and maxilla to mandibular ratio is 3:2. The reason for the higher frequency of maxillary involvement is the presence of more non vital teeth in the upper jaw. Although highest number of cases occur in the third decade, the majority are from third to fifth decade. There is a male preponderance which may be due to better care for the anterior teeth by females. A radicular cyst arising in deciduous teeth is a very rare event. Early lesions are bony hard in consistency as there is enough bone surrounding the cystic cavity. However with the enlargement of the cyst, thickness of the overlying bone becomes less and palpation would allow the bone to go in giving rise to “Ping pong ball sign”. Further thinning would cause it to crack on hard palpation like an “Egg shell”. Towards the later stage the cyst is without any overlying bone leading to fluctuant swelling. Pain is usually not a feature of a radicular cyst unless it is infected.

Fig. 5.1: Radicular cyst. A well-demarcated swelling of palate—a radicular cyst arising from upper left lateral incisor

Radiological Features Historically the size of the radiolucency is considered to be of diagnostic importance to differentiate a cyst from a periapical granuloma. The diagnosis of a cyst can be made confidently when the radiolucency is more than 2 cm (Fig. 5.2). However, when the radiolucency is smaller it is difficult to separate a cyst from a granuloma. When the lesion is less than 1 cm in diameter the probability of that being a granuloma is much higher. Other associated features such as cortication, resorption of roots and loss of lamina dura in the apical area are common to both periapical granuloma and a cyst in most cases. Therefore, they may not be definite features to separate the two entities.

Fig. 5.2: Radicular cyst. Well-defined and well corticated radiolucency in relation to multiple nonvital lower anterior teeth (Courtesy: Dr Jimmy Makdissi)

Histopathology

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Histologically, lining epithelium of the radicular cyst is stratified nonkeratinizing with prominent arcading pattern (Fig. 5.3). The thickness of the epithelium varies, with most cysts showing 5 to 20 cells. Keratinization is a very rare feature observed in long standing cysts. Metaplastic changes in the epithelium in terms of mucous cells and respiratory type of epithelium are common findings especially in maxillary cysts.

Fig. 5.3: Radicular cyst. Stratified squamous nonkerartinized epithelium showing arcading pattern and the cyst wall contains a mixed inflammatory infiltrate

Lateral Periodontal Cyst The lateral periodontal cyst is also of inflam­ matory origin. Therefore it is similar to a radicular cyst except that it arises in relation to a lateral root canal. Histological features are more or less identical.

Residual Cyst Fig. 5.4: Radicular cyst. Presence of cholesterol clefts in the cyst wall is a common finding

Hyaline bodies often referred to as hyaline bodies of Rushton are found in the epithelium in some cysts. They can rarely be found in the capsule. Although the origin of hyaline bodies was believed to be of hematogenous in the past, recent evidence shows that it is a secretory product of odontogenic epithelium. The capsule is inflamed with a dense mixed inflammatory infiltrate towards the epithelium. Cholesterol clefts with associated multinucleate giant cells are often present (Fig. 5.4). The lumen contains straw colored fluid containing epithelial debris, soluble proteins and cholesterol crystals. Shimmering effect can be demonstrated when the fluid is held to direct light.

Treatment Radicular cysts have traditionally been treated by enucleation of the cyst and root canal treatment for the affected tooth if it is restorable but rarely for a larger lesion. Marsupialization is advisable in order to preserve the normal structures. However, most clinicians nowadays prefer to treat them with nonsurgical endodontics. The healing of the periapical region takes place due to acute inflammation as a result of instrumentation. There is always a controversy regarding healing of a properly formed cyst after root canal treatment. In order to answer this two types of radicular cysts have been described recently. One is called a “true cyst” where the cystic cavity has no connection with the root canal and the other type is known as a “pocket

A residual cyst is truly a radicular cyst without the causative tooth in situ. If the tooth is extracted without identifying the cystic lesion in the apical region the cyst can remain without symptoms. The diagnosis is usually by routine radiography performed for other treatment procedures or investigations. Histopathology is very similar to that of a radicular cyst. Long standing lesions may not show many inflammatory features as the causative tooth has been removed.

5 CySTS OF THE ORAL AND MAxILLOFACIAL REGION

cyst” where the root canal opens into the cyst cavity. The latter type appears to be rare and it responds better to nonsurgical endodontics.

Paradental Cyst Paradental cyst is defined as a cyst arising on the lateral aspect of a vital tooth as a result of inflammation in the periodontal pocket. The most common site of occurrence is the disto­ buccal side of a partially erupted mandibular third molar. Infected mandibular buccal cyst which occurs in relation to first or second mandibular molars in children is also included in the category of paradental cyst. Recently the former has been named as a juvenile paradental cyst. The exact pathogenesis of the lesion is debatable as there are different views. However, it seems that the epithelium derives either from reduced enamel epithelium or cell rests of Malassez and the cyst forms as a result of expansion of lateral part of the follicle secondary to inflammation in the periodontal pocket. Paradental cysts account for 1 to 4.7 percent of odontogenic cysts. There is a wide variation in the frequency in the published literature due to under diagnosis of the cyst as a result of inadequate clinical information reaching the pathologist and also due to the fact that histopathological features are similar to that of a radicular cyst.

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Clinical and Radiological Features The majority of cysts, in relation to mandibular third molars, usually occur in the third decade with significant male predilection (1:0.5). More than 60 to 70 percent of them have been diagnosed at the buccal or disto­buccal aspect of a partially erupted lower third molar. Juvenile forms of the cyst, which is common in the buccal side of the lower first molar occurs in and around 10 years of age. Most patients reveal a history of repeated attacks of pericoronitis. Pain and swelling are features in some patients and the affected tooth is vital. The above feature would exclude the possibility of an inflammatory periodontal cyst. The juvenile form is characterized by periosteal buccal bone formation in relation to the vital first mandibular molar tooth in a young child. In radiographs, a paradental cyst shows a well defined and well corticated radiolucency on the buccal or more commonly on the disto­ buccal side (Fig. 5.5). Lamina dura is usually intact.

Histopathology The histopathological features of paradental cyst are identical to that of radicular cysts (Fig. 5.3). The lining epithelium is composed of hyperplastic non keratinized stratified squamous epithelium with the cyst wall containing a dense inflammatory infiltrate.

Fig. 5.5: Paradental cyst. Radiolucency on the distal aspect of a partially erupted lower-third molar is the most common presentation (Courtesy: Professor Jos Hille)

Presence of cholesterol crystals in the capsule are a feature in some cases. Removal of the affected tooth with enuclea­ tion of the cyst is the treatment of choice. Box 5.2: Paradental cyst Key features helpful in diagnosis • Radiolucency in disto-buccal side of an impacted lower 3rd molar. • Associated with a vital tooth. • History of pericoronitis. • Lining epithelium is nonkeratinized stratified squamous similar to radicular cyst. • Cyst wall contains inflammatory infiltrate.

Dentigerous Cyst Dentigerous cyst arises in relation to an unerupted tooth. The cyst wall encloses the crown due to expansion of the dental follicle and remains attached to the cemento­enamel junction (Fig. 5.6). Although there are different theories regarding the pathogenesis of dentigerous cyst, the most likely explanation is that the cyst forms as a result of accumulation of fluid between the reduced enamel epithelium and enamel. Hence, the cyst has been classified as of developmental in origin. There has been a view that periapical inflammation of the deciduous tooth may give rise to dentigerous cysts in the developing permanent tooth. However, the above cannot be applied to the most common

Fig. 5.6: Dentigerous cyst. Macroscopic appearance of the cyst shows attachment of the cyst lining to cemento-enamel junction

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Fig. 5.7: Dentigerous cyst. Well-defined and well corticated cystic lesion associated with impacted right lower-third molar covering the crown of the tooth (Courtesy: Dr Jimmy Makdissi)

Box 5.3: Dentigerous cyst Key features helpful in diagnosis • The most common developmental odontogenic cyst. • Associated with an impacted tooth, frequently lower 3rd molar or upper canine. • Presents as a well-defined radiolucency covering crown. • Lining is thin nonkeratinized stratified squamous epithelium. • Cyst lining is attached to cemento-enamel junction. • Cyst wall is not inflamed unless it is infected.

Clinical and Radiological Features Dentigerous cysts account for 16 to 24 percent of odontogenic cysts. The highest frequency is seen in the 2nd and 3rd decades. The most common site of occurrence is the mandibular 3rd molar region followed by maxillary canine, mandibular premolar and maxillary 3rd molar. Males are affected more than females (3:2). The diagnosis is mostly by radiographs when investigated for an unerupted or missing tooth. These are slow growing swellings usually without pain unless infected. Depending on the amount of overlying bone present , consistency on palpation is similar to that of a radicular cyst. The majority present as unilocular radiolucent lesions with well defined and well corticated margins (Fig. 5.7). The appearance alters when the cyst is infected. Multilocularity is a rare presentation. Three different radiological patterns have been described depending on the relationship of the crown to radiolucency.

a. Central (whole crown is enveloped symme­ trically) b. Lateral (one aspect of the crown is envel­ oped) c. Circumferential (almost the entire tooth is enveloped) Rarely, when a radicular cyst arises from a deciduous tooth it mimics a dentigerous cyst in relation to the corresponding permanent tooth. Differentiation between dilated follicle and dentigerous cyst may not be easy radiologically. However, unless the pericoronal space is at least more than 4 to 5 mm, diagnosis of a cyst may not be reasonable.

CySTS OF THE ORAL AND MAxILLOFACIAL REGION

site of occurrence of a dentigerous cyst as there is no overlying deciduous in the lower 3rd molar area. Involvement of the PTCH gene has been implicated in the pathogenesis of the cyst but the evidence supporting the hypothesis is not confirmatory unlike in the case of odontogenic keratocyst. The expansion of the cyst is mostly similar to that of the radicular cyst with increased hydrostatic pressure and osmotic pressure within the cyst lumen. The evidence for the role of cytokine and other inflammatory mediators are lacking as dentigerous cysts expand irrespective of secondary inflammation.

Histopathology Histopathological features reveal that the lining epithelium is of nonkeratinized stratified squamous and usually consists of 2 to 4 cells (Fig. 5.8). Presence of mucous secreting cells in the epithelium is a frequent feature in both maxillary (53%) and mandibular (36%) cysts. Together with mucous cells ciliated epithelium is also present in some lesions. Hyaline bodies of Rushton are found in the cyst epithelium occasionally. The cyst wall is composed of fibrous tissue and especially in noninflamed cysts the appearance is similar to that of follicular tissue. Odontogenic epithelial rests may be present in the cyst wall. When the cyst is inflamed the histopathological features are identical to that of a radicular cyst. Therefore, the clinical and radiological information is mandatory to arrive at the correct diagnosis. In addition, macroscopic

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Fig. 5.8: Dentigerous cyst. The linning is composed of thin nonkeratinized stratified squamous epithelium. Fibrous cyst wall is without inflammatory cells

Fig. 5.9: Eruption cyst. Cyst in relation to erupting lower molar tooth shows a soft tissue shadow of the cyst (Courtesy: Professor Jos Hille)

examination shows the attachment of the cyst to cemento­enamel junction (Fig. 5.6).

Clinical Features

Treatment and Prognosis The majority of dentigerous cysts are enucleated together with the unerupted tooth. However, for dentigerous cysts in children if the tooth is in a favorable position to erupt partial removal of the cyst exposing the tooth followed by orthodontic traction may help to align the tooth to the correct position. Larger cysts can be treated with marsupialization allowing the cyst to decompress and complete removal of the cyst can be carried out later on with a simple surgical procedure. Ameloblastoma arising in dentigerous cyst has been reported although there are arguments for and against. Mucoepidermoid carcinoma arising from mucous secreting cells of the lining has also been reported.

Eruption Cyst

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The eruption cyst is considered as the soft tissue counterpart of dentigerous cyst. Actual frequency of the cyst is difficult to determine as this is rarely biopsied and spontaneous rupture and eruption of the tooth does not indicate further treatment. Therefore, the number of cases in pathology files is much lower than the real occurrence. Pathogenesis is similar to that of dentigerous cyst and the lining epithelium is derived from reduced enamel epithelium.

Although it arises in relation to any erupting tooth, maxillary first permanent molar and incisors are frequently affected. The cyst occurs in relation to both deciduous and permanent teeth. The majority are reported before the age of 10 years with a slight male predilection. Char­ acteristic presentation is a bluish translucent swelling over the crown of an erupting tooth. Most lesions rupture due to trauma. Although there are no radiological changes in most lesions, some may show a soft tissue shadow (Fig. 5.9).

Histopathological Features When a cyst is submitted for histopathological evaluation, surface epithelium is usually included overlying the cyst. Demarcation between con­ nective tissue of the lamina propria and cyst wall is difficult to identify. The connective tissue towards the cyst epithelium is inflamed. Lining epithelium is stratified squamous with 2 to 3 cells in thickness (Fig. 5.10).

Treatment Treatment is not indicated. However, eruption of the affected tooth is facilitated by simple exci­ sion of the overlying epithelium and connective tissue.

Odontogenic Keratocyst (Keratocystic Odontogenic Tumor) Odontogenic keratocyst (OKC) is the second most common developmental odontogenic cyst and the most investigated cyst in terms of its pathogenesis and behavior compared to other cystic lesions. The cyst is known to recur more than all other cysts. In addition, it grows faster and to a larger size than the rest. These differences may have led the researchers to work on this and raise controversy of the nature of the lesion as to whether it is a cyst or a true neoplastic lesion. Accordingly, WHO in its 2005 classification renamed OKC as “keratocystic odnotogenic tumor”. However, the debate on accepting the term is going on and it will take some more years for clinicians and pathologists to understand the issue comprehensively. OKC is also associated with nevoid basal cell carcinoma syndrome (NBCCS) or Gorlin Goltz syndrome. OKC arises either from dental lamina or from its remnants. However, some cysts are thought to arise from basal cell proliferation of surface epithelium. Arising from the enamel organ before dental hard tissue formation is a theory that has very little evidence for justification. Identification of mutations in PTCH gene which is considered to be the mutated oncosuppressor gene in NBCCS has shed new dimensions to the pathogenesis of OKC. It reveals that syndromic patients as well as a minority of sporadic lesions show mutations in PTCH gene leading the trend

5 CySTS OF THE ORAL AND MAxILLOFACIAL REGION

Fig. 5.10: Eruption cyst. Fibrous cyst wall is lined by thin nonkeratinized epithelium similar to reduced enamel epithelium

towards the neoplastic nature of the lesion. The cyst has two inherent features in terms of high growth potential and ability for recurrence than other odontogenic cysts. Expansion of the cyst may have different mechanisms to those of radicular and dentigerous cysts. There may be ways other than fluid related expansion in OKC. Growth of the epithelium is shown to play a key role as the growth potential of cystic epithelium is higher than other cystic lesions and in some cases similar to ameloblastoma. Matrixmetalloproteinases (MMPs) and IL­1 have also been implicated in expansion. OKC recurs more frequently than other odontogenic cysts. There are several reasons suggested including presence of satellite or daughter cysts, thin and fragile cystic epithelium with increased possibility of leaving fragments during surgery, extension of the cyst between roots, flat epithelial connective tissue interface, intrinsic growth potential of the epithelium and cyst arising from proliferation of basal cells of the surface epithelium. In addition syndromic patients develop multiple new cysts as well as recurrences. Diagnosis of the cyst is usually by radiography and histopathology. Fine needle aspiration biopsy is not a pathognomonic investigation. Soluble protein content in the cyst fluid is usually less than 5 g/dL whilst it is more than 5 g/dL in radicular and dentigerous cyst.

Clinical and Radiological Features It has been reported that OKC accounts for up to 4 to 10 percent of odontogenic cysts, with 40 to 60 percent of the patients in 2nd and 3rd decades. It is rare in the 1st decade. Diagnosis of OKC in syndromic patients is earlier (10–30 years) than that of nonsyndromic patients (15–45 years). Although there is a male predilection (1.5:1) for nonsyndromic patients, a slight female dominance has been reported for syndromic patients. Seventy percent of the lesions occur in the mandible with half of these located close to angle of the mandible (Fig. 5.11). Usually presents as a slow growing painless swelling although some may complain of pain. Large mandibular lesions tend to be associated with paresthesia of the lower lip. When a cyst shows visible swelling it has already developed to a larger lesion because of the extension within

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Fig. 5.11: Odentogenic keratocyst. A large bony hard swelling in the left body and angle of the mandible in a young boy

larger lesions. Displacement of adjacent teeth is a feature but significant resorption of roots is not common. When the lesion is larger, perforation of the cortical plate may be seen. Multilocular radiolucency in the angle of the mandible is an important clinical scenario as several lesions should be considered in the differential diagnosis. The most important one in the list is ameloblastoma because an ameloblastoma is a true tumor, there is prominent bucco­ lingual expansion, paresthesia of the lower lip and resorption of roots compared to OKC in most patients. The other lesions which should be excluded with clinicopathological correlation are ameloblastic fibroma, central giant cell granuloma, odontogenic myxoma and aneurysmal bone cyst. Smaller cysts in between roots of two teeth mimic the appearance of lateral periodontal cyst.

Histopathology

Fig. 5.12: Odentogenic keratocyst. Large multilocular radiolucency with well-defined and corticated margins in the right angle and ramus of the mandible (Courtesy: Dr Jimmy Makdissi)

the medullary cavity without giving rise to a swelling. For the same reason some patients are unaware of the cyst until it causes a pathological fracture. OKC in the maxilla, especially in close relation to the antrum, may give rise to proptosis and diplopia due destruction or lifting up of the orbital floor. Radiologically, OKC presents either as a unilocular or multilocular radiolucency with well defined and well corticated margins in most patients (Fig. 5.12). However, some unilocular lesions with scalloped borders may be misinterpreted as multilocular. When this occurs at the angle of the mandible anteroposterior extension appears to be more pronounced than buccolingual. The inferior dental canal is usually displaced downward in

Histopathologically the cyst lining shows a char­ acteristic stratified squamous parakeratinized epithelium of uniform thickness containing 5 to 10 cells. The surface of the epithelium is cor­ rugated (Fig. 5.13A). Cysts with orthokeratin on the surface do not show characteristic features of OKC. Therefore it has been described as a separate entity in recent literature as orthokeratinizing odontogenic cyst. Basal budding is present in some cases. The basal cells show palisading and the nuclei are hyperchromatic (Fig. 5.13B). Epithelial connective tissue interface is flat. The cyst wall is composed of dense fibrous tissue and contains satellite cysts up to 7 to 25 percent of the cases. The lumen contains keratin. When the cyst is infected epithelium tends to be hyperplastic and the surface keratin is lost making confirmation of the diagnosis difficult.

Treatment Most OKCs are treated with enucleation and surface curettage of the cystic cavity. Carnoy’s solution is used for chemical cauterization of the cavity by some surgeons. However, it is not unusual to observe aggressive lesions demanding more radical treatment with resection of the segment and subsequent bone graft. Decompression is also indicated for

5

B Figs 5.13A and B: Odontogenic keratocyst. (A) Stratified squamous parakeratinized epithelium with a corrugated surface; (B) Typical basal palisading; hyperchromatism

larger lesions allowing shrinkage of the cyst with peripheral bone formation and removal of the cyst later on with simple enucleation. Recurrence rates may vary from 5 to 60 percent according to the literature due to various reasons, more realistic recurrence rate appears to be around 30 percent. Box 5.4: Odontogenic keratocyst Key features helpful in diagnosis • Presents as a multilocular or unilocular radiolucency. • May mimic ameloblastoma when presents as large multilocular lesions. • Majority of the patients are in 2nd and 3rd decades. • Lining epithelium is parakeratinized stratified squamous and shows basal palisading. • Cyst wall is uninflamed and may contain satellite cysts. • Cyst may be associated with nevoid basal cell carcinoma syndrome. • Behavior is more aggressive than other odontogenic cysts.

Nevoid Basal Cell Carcinoma Syndrome Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disease which shows multisystem manifestations as a result of mutations in PTCH gene mapped in

chromosome 9q22.3­q31. In order to diagnose the syndrome there should be at least two major criteria or one major and two minor criteria. Major criteria include: • More than two basal cell carcinomas (BCC) or one in patients younger than 20 years • Histologically proven odontogenic kerato­ cyst • Three or more palmar or plantar pits • Calcification of falx cerebri • Bifid ribs • First degree relative with the syndrome. Minor criteria include: • Macrocephaly • Congenital abnormalities such as cleft lip or palate, frontal bossing, coarse facies, hypertelorism • Skeletal deformities such as syndactyly • Ovarian fibroma • Radiologic abnormalities such as bridging of sella turcica, vertebral abnormalities (spina bifida occulta). Basal cell carcinoma syndrome (BCCS) are found in more than 90 percent of the patients (Figs 5.14A and B) who are over 40 years and 75 to 80 percent of them present with OKCs. In addition to BCC a minority may develop other tumors such as medulloblastoma, meningioma, cardiac fibroma and fetal rhabdomyoma. Except for aggressive BCCs which can bring about a fatal outcome, most others are not life threatening. OKCs are treated in the same way as nonsyndromic cysts. Regular follow­up is

CySTS OF THE ORAL AND MAxILLOFACIAL REGION

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A

Figs 5.14A and B: Nevoid basal cell carcinoma syndrome. Characteristic facial appearance with hypertelorism and slightly prognathic mandible. Note: (A) The small BCC; (B) calcification of falx cerebri

mandatory to identify new lesions which may arise during the course of the disease.

Orthokeratinized Odontogenic Cyst Orthokeratinized odontogenic cyst (OOC) has been recognized as a new entity in the recent past. It was classified as the orthokeratinized variant of OKC. However, due to histopathological as well as behavioral differences it is justifiable to label this as a separate entity. Approximately, up to 15 percent of keratinizing cysts in jaw bones are OCCs.

Clinical and Radiological Features Clinical and radiological features are mostly similar to that of OKC. However, there is a significant male predominance to the disease (2:1). The majority of them occur in the angle of the mandible and simulate dentigerous cysts. Although many of those present as unilocular radiolucencies, some have multilocularity.

Histopathology 110

B

Histopathological features are different from OKC. Lining is stratified squmous with marked orthokeratin on the surface showing a very

Fig. 5.15: Orthokeratinized odontogenic cyst. Lining epithelium is composed of markedly orthokeratinized straitified squamous epithelium and basal palisading is not present

prominent granular cell layer (Fig. 5.15). The epithelium is much thinner than OKC in some cases mimicking the appearance of dermoid/ epidermoid cyst. The characteristic corrugated surface and basal palisading seen in OKC is not present.

Treatment This is much less aggressive in behavior compared to OKC and needs only enucleation

Gingival Cyst of Newborn Historically two types of gingival cysts are described in infants under the names of Epstein’s pearls and Bohn’s nodules. The former is of developmental non odontogenic in origin and the latter is odontogenic in origin. Bohn’s nodules arise from remnants of dental lamina known as glands of Serres. Epstein pearls may arise as a result of epithelial inclusions at the line of fusion of nasal processes and palatine shelves. It has also been suggested that they may arise due to abortive glandular differentiation leading to formation of small cysts.

Clinical Features Bohn’s nodules occur on alveolus of infants who usually are less than 3 months (Fig. 5.16A). Although these lesions are very common ranging from 50 to 94 percent according to different studies, the need to perform a biopsy is unlikely as they undergo spontaneous involution. Clinically they appear as small white nodules.

A

Epstein pearls are also known as midpalatal raphae cysts and occur in relation to midpalatine raphae (Fig. 5.16B). Radiological changes are not evident as these are present within the soft tissue.

Histopathology Histopathologically both lesions share similar appearances. They are small circular structures lined by thin parakeratinized stratified squa­ mous epithelium. Lumen is filled with keratin. However, there is no basal palisading which helps to differentiate them from odontogenic keratocyst.

Treatment Treatment is not indicated as these lesions undergo spontaneous involution. It may be nec­ essary to squeeze out the contents to enhance the process of involution.

5 CySTS OF THE ORAL AND MAxILLOFACIAL REGION

and surface curettage. The recurrence rate of approximately 2 percent is justifiable evidence to suggest that OCC is a separate entity.

Gingival Cyst of Adults Gingival cyst of adults (GCA) is a soft tissue lesion present on the gingival mucosa with minimal radiological changes. Various theories have been put forward regarding the pathogenesis,

B

Figs 5.16A and B: Gingival cyst of newborn. (A) Bohn’s nodules on the maxillary alveolus; (B) Epstein pearls on the midpalatal region (Courtesy: Dr Dilip George)

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including its origin from epithelial rests of dental lamina, cystic degeneration of surface epithelial projections and traumatic implantation of surface epithelium. Recent evidence suggests that it arises from junctional epithelium which is a derivative of reduced enamel epithelium.

Clinical and Radiological Features Gingival cyst of adults (GCA) accounts for 0.06 to 0.08 percent of odontogenic cysts. This is mostly diagnosed in the 5th to 6th decade. Females are affected more than males (2:1). Mandibular lesions are more common and the preferred site appear to be attached gingiva on the buccal or labial surface in relation to canine to premolar area. Patients usually present with slow growing well circumscribed pink or bluish swellings and most lesions are less than 1 cm in diameter. Related teeth are vital. Swelling is fluctuant as there is no overlying bone.

Histopathology Histopathologically most of the cyst wall is uninflamed except towards the junctional epithelium. Lining epithelium is thin stratified squamous non keratinized consisting of 2 to 4 cell layers. Frequently epithelial cells are either flat or cuboidal simulating the appearance of reduced enamel epithelium. Localized areas of epithelial thickening are seen in some cases. Treatment is by simple surgical excision and recurrence is unlikely.

Lateral Periodontal Cyst and Botryoid Odontogenic Cyst

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Both these lesions are developmental in origin with considerable similarities in terms of location, histology and radiological features. The term lateral periodontal cyst (LPC) implies that it occurs on the lateral aspect of the periodontium. However, inflammatory LPC and OKC can arise in the same location. Botryoid variant can extend beyond this site to periapical area as well. Three possibilities have been discussed with regards to pathogenesis, including origin from reduced enamel epithelium, remnants of dental lamina and cell rests of Malassez. Reduced enamel epithelium theory suggests

that it arises as a dentigerous cyst on the lateral side of the tooth with expansion of the follicle and subsequent eruption of the tooth.

Clinical and Radiological Features Both entities are uncommon and LPC accounts for about 0.5 to 0.7 percent of the odontogenic cysts. Botryoid type is even rarer. Fifth and sixth decades of life show the highest frequency. The majority of the cases are reported from incisor, canine and premolar areas of the mandible. Lateral periodontal cyst (LPC) is usually diagnosed on routine radiographs as most of them are without any symptoms. Pain is a feature in occasional cases. The clinical appearance simulates gingival cysts of adults to some extent as some cases may be fluctuant. Those who have botryoid variant can present with a significant swelling compared to LPC. Radiologically most lesions are less than 1 cm in diameter and presents in between mid­ radicular area of two roots. Associated root resorption is unlikely. The botryoid type is usually multilocular but some cases are unilocular. However, they grow to a much larger size than the LPC and can extend into periapical area.

Histopathology Diagnosis of LPC should be reached by excluding gingival cyst of adult, inflammatory LPC and collateral type of OKC. Histopathologically LPC shows an uninflamed cyst wall and characteristic lining composed of nonkeratinized stratified squamous epithelium with focal areas of proliferation of the epithelium giving rise to epithelial plaque formation (Fig. 5.17). The reason for localized epithelial proliferation is not clear. The main difference between LPC and botryoid odontogenic cyst is the multicystic nature of the latter and the cystic spaces are separated by thin fibrous septae.

Treatment Lateral periodontal cyst (LPC) is treated by enucleation of the cyst without sacrificing the adjacent tooth. However, botryoid cysts in some patients give rise to recurrence after simple enucleation. Therefore, regular follow­up is indicated.

Histopathology

Fig. 5.17: Lateral periodontal cyst/Botryoid cyst. The cyst is lined by stratified squamous nonkeratinized epithelium with prominent epithelial plaque for mation. The cyst wall is uninflamed

Glandular Odontogenic Cyst (Sialo-odontogenic Cyst) The sialo­odontogenic cyst was first described in 1987 by Padayachee and Van Wyk. A year later Gardner et al, introduced the term glandular odontogenic cyst (GOC). This is an aggressive lesion compared to other odontogenic cysts except OKC. It shares histological similarities with LPC, botryoid cyst and low grade central muco epidermoid carcinoma, hence the accurate diagnosis is a must. Although, there was a controversy about the origin of the lesion, it is accepted that the cyst is of odontogenic origin. The main confusion was based on the glandular differentiation in the cystic epithelium. It shows the pluripotential nature of odontogenic epithelium than anything else. Moreover, a few cases have been reported with hyaline bodies which is claimed to be a secretory product of odontogenic epithelium providing evidence for odontogenic nature.

Clinical and Radiological Features Glandular odontogenic cyst (GOC) is an uncommon lesion comprising of 0.17 to 0.2 percent of odontogenic cysts. Peak incidence of the cyst is in the 6th decade. There is a slight

The cyst lining is composed of non keratinized stratified squamous epithelium of varying thickness. Superficial layer of the lining epithelium shows either cuboidal or columnar cells with cilia (Figs 5.18A and B). Epithelial plaque formation is seen similar to that of LPC and botryoid cyst. Because of the presence of pseudoglandular spaces containing PAS and mucicarmine positive material and microcysts within the epithelium, low grade central mucoepidermoid carcinoma should be excluded. Goblet cells are also found on the upper layers of the epithelium. The cyst wall is usually uninflamed as the cyst is of developmental in origin.

5 CySTS OF THE ORAL AND MAxILLOFACIAL REGION

male preponderance. The anterior mandible is the frequently reported site of occurrence. Pain is a feature in some patients. Glandular odontogenic cyst (GOC) presents as a multilocular or unilocular radiolucency with well defined borders in most cases. However, features supporting aggressive behavior such as perforation of cortical plates, root resorption and displacement have also been reported.

Box 5.5: Glandular odontogenic cyst Key features helpful in diagnosis • Most patients are in 6th decade of life. • Anterior mandible is the most common site. • Presents as a unilocular or multilocular radiolucency with resorption and displacement of adjacent teeth. • Lining epithelium is non keratinized stratified squamous with surface cells showing columnar appearance with cilia. • Mucoepidermoid carcinoma should be excluded as pseudoglandular differentiation and goblet cells are frequently present.

Treatment Small unilocular lesions are treated by enuclea­ tion and surface curettage. Large multilocular lesions need marginal or segmental jaw resection. Marsupialization is recommended for larger lesions in order to preserve adjacent vital structures. However, a second surgery should be followed with enucleation and curettage of the bony cavity. Recurrence rates have been

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A

B

Figs 5.18A and B: Glandular odontogenic cyst. (A) Cyst lining is composed of stratified squamous nonkeratinized epithelium with a few pseudoglandular spaces; (B) Papillary configurations and cilia formation

reported up to 55 percent confirming the aggressive nature of the cyst. Regular follow­up is mandatory.

Malignant Transformation in Odontogenic Cysts Malignant transformation of odontogenic cysts is a rare phenomenon. Most of the reported cases have shown malignant changes into squamous cell carcinoma. However, rarely mucoepidermoid carcinoma arising in relation to dentigerous cyst has been reported. According to the literature malignant change may vary from 0.13 to 2 percent. Sixth and seventh decades are to accountable for most cases and it appears that the lower figure is more realistic. Male to female ratio appears to be 2:1 and the mandible is affected four times more commonly than the maxilla. Malignant transformation is seen in odontogenic keratocyst, radicular cyst, dentigerous cyst, lateral periodontal cyst and residual cyst. It is known that most intraosseous carcinomas of jaw bones arise from cystic lesions. In order to confirm the diagnosis a few possibilities such as arising from surface epithelium, metastatic deposit and cystic degeneration of a solid epithelial tumor should be excluded. Evidence of epithelial dysplasia in the cystic epithelium and transition of dysplastic cystic epithelium to squamous cell carcinoma can be identified in a majority of the cases.

NONODONTOGENIC CySTS Nasopalatine Cyst (Incisive Canal Cyst) Nasopalatine duct cyst (NPC) arises within the nasopalatine canal or soft tissue of the palate at the opening of the canal. NPC is by far the most common nonodontogenic cyst in jaw bones accounting for more than 75 percent. Overall 10 percent of all cysts in jaw bones are of this type. The current literature reveals that the entity median palatine cyst is a posteriorly placed NPC. Exact pathogenesis of NPC is not known. Out of the theories put forward by various people relating to different structures, cystic degeneration of the remnants of the nasopalatine duct appears to be the most reasonable.

Clinical and Radiological Features The most common age group to be affected is 3rd to 6th decade of life. There is a marked male predilection (2.5:1). The majority of patients present with a swelling of the midline of the anterior palate. Some complain of swelling of the mid anterior labial sulcus. If the lesion is larger, it is visible from both sides together with lifting of the anterior nasal floor. Displacement of two upper central incisors may present. Positive vitality testing is helpful in excluding the possibility of a radicular cyst. Smaller lesions are usually diagnosed during routine radiological examination. When

5

Histopathology Microscopically, lining epithelium is nonkerati­ nized stratified squamous in over 70 percent of the cases. However, it is very frequent to have various other types of epithelium, at least in part of the lining including, pseudostratified columnar, cuboidal or rarely simple columnar type (Fig. 5.20). Goblet cells are also seen in some cases. Although NPC is developmental in origin inflammatory cells are present in the cyst wall of most cases as a secondary phenomenon. Another characteristic feature is the presence of neurovascular bundle within the capsule. Mu­ cous glands are also present in up to 30 percent of the cases.

Treatment Treatment is by enucleation. Some lesions are biopsied before enucleation as clinical diagnosis

Fig. 5.20: Nasopalatine cyst. Lining epithelium is comprised of stratified squamous in areas and pseudostratified columnar ciliated in others

may not be confirmatory. Once complete enu­ cleation is achieved recurrence is unlikely.

CySTS OF THE ORAL AND MAxILLOFACIAL REGION

interpreting a radiograph for NPC, reference should always be made to a possible anatomical variation of a larger incisive fossa in order to avoid over diagnosis leading to unnecessary treatment. NPC is a round to oval radiololucency in between roots of upper central incisors (Fig. 5.19). Intact lamina dura with positive vitality further enhance the accuracy of clinical diagnosis.

Nasolabial Cyst Nasolabial cyst (NLC) is a rare developmental cyst in the soft tissues of the nasolabial fold. Bilateral cysts are present up to 10 percent. Pathogenesis of the cyst is attributed to two theories. One of them is the fissural cyst concept relating it to development from epithelial remnants from the line of fusion of maxillary, lateral nasal and medial nasal processes. But this is unlikely as fissural theory has almost been abandoned now. Most likely the origin is from epithelial remnants of the lower part of nasolacrimal duct.

Clinical and Radiological Features

Fig. 5.19: Nasopalatine cyst. Well-defined radiolucency in between the roots of upper central incisors extending into palate (Courtesy: Dr Jimmy Makdissi)

The nasolabial cyst has a marked female predilection unlike other cystic lesions (3.5:1). Fourth and fifth decades of life show the highest frequency. Swelling of upper lip lateral to the midline with elevation of alar of the nose is the characteristic clinical presentation. Some lesions can grow­up to a reasonable size causing nasal obstruction and difficulty in wearing upper denture. Rupture of the cyst results in a discharging sinus either into oral or nasal cavity. Radiological features are not very prominent unlike other intra bony cysts. Saucerization of alveolus is usually seen above the apices of

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ABCs especially in extragnathic skeleton occur without a pre­existing lesion.

Clinical and Radiological Features

Fig. 5.21: Nasolabial cyst. Fibrous cyst wall is lined by pseudostratified columnar epithelium with some areas containing cilia

upper incisor teeth as a radiolucency. There can be changes in the nasal aperture.

Histopathology Lining epithelium of NLC is usually pseu­ dostratified columnar mostly without any cilia. Presence of cilia though is a feature in some cases. Goblet cells can be found in abundance in some cases. Rare cases may show cuboidal or flat squamous epithelium focally. The cyst wall contains inflammatory cells as a secondary phenomenon (Fig. 5.21).

Treatment Treatment is by enucleation of the cyst from an intra oral approach. If the lesion extends into the nasal side, it is advisable to excise the affected part of the nasal mucosa. Recurrence is unlikely.

Aneurysmal Bone Cyst

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Aneurysmal bone cyst (ABC) is a non­ epithelialized cyst that rarely occurs in jaw bones. Definite pathogenesis of the cyst is not known. Trauma, vascular malformation and bleeding into a pre­existing lesion have been considered as possible mechanisms. Presence of ABC within fibro­cemento­osseous lesions such as cemento ossifying fibroma and fibrous dysplasia is well documented. Central giant cell granuloma and giant cell tumor can also be associated with ABC. In contrast most

Aneurysmal bone cyst represents approximately 0.5 percent of cysts in jaw bones and jaw lesions account for 2 percent of all ABCs. Long bones and vertebral column are the common sites for the lesion. There is no significant gender difference. The posterior mandible is the most common site in jaw bones (Figs 5.22A and B). The lesion is frequently seen in young people especially in the 2nd decade of life. Usual presentation is a rapidly growing swelling with most patients complaining of pain. Because of the faster growth, cortical perforation or “egg­ shell crackling’’ can be present. Most lesions present as multilocular lesions whereas a minority shows a unilocular radiolucency. Marked cortical expansion is a feature with some presenting with cortical perforation. There is ballooning expansion of the affected bone. This should be included in the differential diagnosis of multilocular radiolucency in the angle of the mandible with other lesions described under OKC. Reactive bone formation can give rise to radio­opacities within the radiolucency in some cases.

Histopathology Ameurysmal bone cyst (ABC) does not have a cyst lining. However, there is a pseudolining in some cases with giant cells and granulation tissue (Fig. 5.23). Large vascular spaces are present within the cyst wall. Extravasated blood and hemosiderin pigment is present. Some areas of the lesion are very similar to giant cell granuloma. Osteoid and woven bone formation is a feature. Especially, solid type ABCs can mimic the appearances of fibro cemento osseous lesions.

Treatment Treatment is by enucleation and curettage. Bleeding is to be expected during surgery. Some aggressive lesions with significant bone loss need segmental surgery and reconstruction. Recurrence has been reported from 8 to 44 percent in different studies.

5

B

Figs 5.22A and B: Aneurysmal bone cyst. (A) young girl with a large swelling of the right posterior body of the mandible; (B) Cystic cavity (Courtesy: Dr DK Dias)

CySTS OF THE ORAL AND MAxILLOFACIAL REGION

A

for this failure is not clear. Prevalence of SBC is 0.5 to 1 percent according to literature. Rarely this lesion is associated with fibrocemento­ osseous lesions.

Clinical and Radiological Features

Fig. 5.23: Aneurysmal bone cyst. Pseudolining of granulation tissue and giant cells. Cyst wall is markedly vascular

Solitary Bone Cyst (Simple Bone Cyst, Traumatic Bone Cyst, Hemorrhagic Bone Cyst, Unicameral Bone Cyst) Solitary bone cyst (SBC) is a rare cystic lesion in jaw bones. It usually presents in long bones. Although pathogenesis of this lesion is uncertain, the most likely cause appears to be trauma leading to intramedullary hemorrhage. It is suggested that failure to organize the hematoma leads to cyst formation. The reason

The majority of SBCs are diagnosed in the 2nd decade of life. There is no significant gender difference. Over 90 percent of the reported cases are from mandible. Swelling can be the presenting feature in some. History of a trauma can be elicited in most patients. Identification of SBC is usually accidental in routine radiographs (Fig. 5.24). Unilocular radiolucency with well defined borders is common and scalloping is frequently observed in relation to the upper border in between roots. Occasional cases may show root resorption. Presence of bony septae gives rise to multilocular appearance in a minority of lesions.

Histopathology Solitary bone cyst (SBC) is a nonepithelial cyst. The amount of tissue received for diagnostic purposes can be very small. Fibrous and granulation tissue with admixed fibrin and multinucleate giant cells are present (Fig. 5.25). Red blood cells and hemosiderin pigment are also seen.

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Fig. 5.24: Solitary bone cyst. unilocular radiolucency with well-defined and well corticated margins in the right body of the mandible (Courtesy: Dr Jimmy Makdissi) Fig. 5.26: Surgical ciliated cyst of the maxilla. Noninflamed fibrous cyst wall is lined by pseudostratified columnar ciliated epithelium

Clinical and Radiological Features The highest incidence is in 5th and 6th decades. Males are affected more than females (2:1). Patients reveal a history of maxillary surgery but the time gap between the surgery and development of the cyst can vary. Swelling and pain are associated features. Some may present with a chronic discharging sinus. Although most cases are unilocular radio­ lucencies minority can present as multilocular Fig. 5.25: Solitary bone cyst. There is no lining lesions. Large cystic lesions show evidence of epithelium and the cyst wall contains fibrous and thinning of the sinus wall. granulation tissue with fibrin deposits

Histopathology Treatment Treatment is usually by curettage. The cyst cavity is empty compared to other cystic lesions. Recurrence is very unusual.

Surgical Ciliated Cyst of the Maxilla (Postsurgical Maxillary Cyst)

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This rare cyst occurs subsequent to a surgical procedure in the maxilla. In most patients it appears to be the Caldwell­Luc operation to gain access to antral cavity. It shows a higher prevalence in Japan compared to rest of the world. Entrapment of antral epithelium in the healing bony wound is suggested as the possible pathogenesis.

The cyst is lined by pseudostratified columnar ciliated epithelium (Fig. 5.26). Squamous metaplasia is seen in some. The cyst wall shows features of inflammation in varying intensities.

Treatment Enucleation of the cyst is the usual treatment. However, larger lesions may benefit by marsupialization before enucleation.

Oral Lymphoepithelial Cyst Oral lymphoepithelial cyst (OLC) is a rare soft tissue lesion of the oral mucosa with exact histopathological similarities to cervical lymphoepithelial cyst. Pathogenesis of OLC is attributed to several mechanisms. Some cases

5

Fig. 5.27: Oral lymphoepithelial cyst. The cyst is lined by thin parakeratinized stratified squamous epithelium. Note: The lymphoid tissue with germinal centers in close proximity to the epithelium

Treatment

CySTS OF THE ORAL AND MAxILLOFACIAL REGION

may arise as a result of epithelial inclusions within lymphoid tissue whilst others arise due to cystic dilatation of minor salivary gland ducts or tonsillar crypts following obstruction. The floor of the mouth and lateral border of the tongue appear to be the sites for more than 95 percent of the cases. Slight male predilection is evident. Although, OLC occurs at any age, 3rd decade is the most common. Histopathologically, the cyst is lined by a thin stratified squamous epithelium which is usually parakeratinized (Fig. 5.27). Occasional cases may be orthokeratinzed. Pseudostratified columnar ciliated epithelium with goblet cells can be found in a minority. The most characteristic feature is the presence of lymphoid tissue with proper germinal centers in some OLC. Except in rare cases lymphoid infiltrate is found below the epithelium in the entire cyst.

Treatment of OLC is by enucleation. After com­ plete removal of the lesion it should not recur.

Cervical Lymphoepithelial Cyst (Branchial Cleft Cyst) Cervical lymphoepithelial cyst (CLC) arises as a developmental anomaly from the second branchial arch in 90 percent of the cases. Rarely, it arises from the 1st and 3rd arch. Developmental anomalies arising from branchial arches present as sinuses, fistulae, cysts or combinations of above. The cyst arises most likely as a result of incomplete obliteration of branchial cleft with entrapment of epithelial remnants. Most patients present in 3rd and 4th decade of life as a swelling along the anterior border of sternocleidomastoid in the upper neck. It is a fluctuant swelling ranging from 2 to 10 cm in diameter. Bilateral presentation has rarely been reported. Histopathological features of OLC and CLC are very much similar (Fig. 5.27). Recurrence is unlikely once surgically removed. Although malignant transformation of the cystic epithe­ lium has been reported, it is exceptionally rare.

Dermoid and Epidermoid Cyst The dermoid and epidermoid cyst in the oral mucosa appears to represent a simpler

Fig. 5.28: Dermoid cyst. Typical presentation of dermoid cyst in the floor of the mouth

version of a teratoma. Although by definition a teratoma should have tissues from all three germ layers, these lesions have tissues mostly from ectoderm. It should be noted that the more common type of epidermoid cyst that we see in the skin is a different entity and arises from the infundibulum of the hair follicle. A sebaceous cyst is the common synonym that has been used over the years incorrectly for epidermoid cyst of the skin. The most common intraoral location for dermoid/epidermoid cyst is the midline of the floor of the mouth (Fig. 5.28). It rarely occurs in other sites such as the tongue. When the cyst occurs in the floor of the mouth it can arise either above or below the geniohyoid muscle giving rise to intraoral or extraoral swelling

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A

B Figs 5.29A and B: Dermoid cyst/epidermoid cyst. Both lesions are lined by orthokeratinized epithelium. Dermoid cyst contains sebaceous glands in the cyst wall

respectively. Intraoral swelling lifts the tongue upwards and extraoral swelling gives rise to double chin appearance. This is a slow growing painless swelling. Most cases are diagnosed in children and some cysts are present from birth.

Histopathology The cyst is lined by stratified squamous ortho­ keratinized epithelium which is very similar to the epidermis (Figs 5.29A and B). The only difference between a dermoid and an epidermoid is the presence of skin appendages in the former. The cystic cavity is filled with keratin. Some lesions may have a range of other tissues and epithelia and they probably are choristomal cysts described under a different name below. Treatment is by surgical excision and recurrence is uncommon. Exceptionally rarely malignant transformation into squamous cell carcinoma has been reported.

Thyroglossal Duct Cyst

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The third week of embryonic life shows evidence of the developing thyroid gland as a proliferation of endodermal cells in the area later in the development known as foramen cecum. Then the thyroid anlage descends to the neck below the thyroid cartilage. An epithelial tract (thyroglossal duct) is formed along this line and maintains its attachment to tongue. By the

10th week of development the duct disintegrates leaving epithelial residues which later turn into thyroglossal duct cyst in some people. Approximately 70 percent of the develop­ mental cysts in the neck are of this type. Intraoral lesions are rare and amount up to 2 percent of the cases. Most cases are diagnosed in the 1st and 2nd decade of life. The cyst usually presents as a midline swelling of the neck in any location from foramen cecum to suprasternal notch. Majority of these lesions occur below the hyoid bone. A painless, slow growing, fluctuant swelling is the usual presentation. Difficulty in speaking and breathing has been reported in rare cases. Lateral presentation is exceedingly rare. Histologically, the cyst is lined by pseu­ dostratified columnar epithelium with cilia in some cases. Some areas can have stratified squamous epithelium. Lesions which are close to the oral cavity tend to have frequent squamous epithelium. The cyst wall contains thyroid tissue in up to 50 percent of the cases. The amount of thyroid tissue present may vary and serial sections are necessary to identify this feature in some lesions (Fig. 5.30). Treatment is by surgical excision. However, it is advisable to remove the entire tract together with the cyst in order to avoid possible recurrence. The accepted surgical technique is known as Sistrunk procedure where cyst is removed together with muscle surrounding the tract and midline segment of the hyoid bone.

5

Fig. 5.30: Thyroglossal duct cyst. The cyst lining is composed of stratified squamous and respiratory type epithelium. Inset shows thyroid tissue from another part of the cystic lesion

Developmental Cysts of Foregut Origin (Gastrointestinal Choristomal Cysts, Heterotopic Gastrointestinal Cysts, Oral Alimentary Tract Cyst, Foregut Duplication Cyst) Cysts of foregut origin occur in the neck as well as in the oral cavity. The most common site in the oral cavity is the tongue and is known as a lingual foregut cyst by some. This is essentially presence of tissue foreign to a particular site. Therefore the term gastrointestinal choristoma or choristomal cyst may be more appropriate. The majority of these cases especially in the tongue are seen in infants and children except for a few cases reported in adults. There is a male predilection. Usual presentation is a swelling of the mid dorsal surface of the tongue without surface mucosal changes. Cases have also been reported from the ventral surface and also from the floor of the mouth. Histopathologically, the cyst lining shows a marked diversity. It can be gastric, intestinal, respiratory or stratified squamous epithelium (Fig. 5.31). According to the author’s experience, the majority of lesions have a combination of different types in the same cyst. It is very rare to have only a single type of epithelium. Treatment is by simple surgical excision.

Cystic Hygroma

CySTS OF THE ORAL AND MAxILLOFACIAL REGION

Fig. 5.31: Developmental cysts of foregut origin. Note: The presence of gastric, respiratory and stratified squamous epithelium in the same cyst

Cystic hygroma is a cavernous type of lymphangioma. Although this can occur in any anatomic site of the body, the neck is the most preferred site. Classically they present in the posterior triangle of the neck. Eighty to ninety percent of the lesions are diagnosed before the age of 2 years. There is no sex predilection. The lesion is a multilobulated painless mass with a bluish color. Histopathologically, the lesion is composed of dilated lymphatic spaces lined by endothelial cells. Treatment is by complete surgical excision. There is a significant possibility of recurrence.

Parasitic Cysts Parasitic cysts are exceedingly rare lesions in the oral mucosa. Hydatid cyst and cysticercosis have been reported from the oral cavity. Although cysticercosis caused by Taenia solium is a common parasitic infection around the world, oral lesions are very rare. This disease is caused by the larval form of cysticercus cellulosae of the pig tapeworm Taenia solium. The most common intraoral location is the tongue as it prefers vascular organs. Management of these patients should be carried out by the relevant medical experts as involvement of other organs and lesions in the brain can be a common presentation.

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A hydatid cyst is a rare human disease and it is caused by the larval form of Echinococcus granulosus (Dog tapeworm).

SELF-ASSESSMENT quESTIONS 1. Give a classification for cystic lesions of the oral and maxillofacial region. 2. Discuss the importance of clinicopathologi­ cal correlation in arriving at an accurate diag­ nosis of a cystic lesion of the oral and maxil­ lofacial region. 3. Describe the pathogenesis of a radicular cyst. 4. Describe how a cyst expands using radicular cysts and odontogenic keratocyst as examples. 5. Compare and contrast radicular cyst, denti­ gerous cyst and odontogenic keratocyst. 6. Describe the pathogenesis of dentigerous cyst. 7. Describe the reasons for and against for clas­ sifying odontogenic keratocyst as a neoplastic lesion (keratocystic odontogenic tumor). 8. Describe the advantages of marsupialization as a treatment option for cystic lesions. 9. Describe the pathogenesis, histological and radiological features of developmental non­ odontogenic cysts. 10. List the nonepithelial cysts in the oral and maxillofacial region and comment on their etiopathogenesis and management.

SuGGESTED READING 1. Barreto DC, Gomez RS, Bale AE, Boson WI, De Marco L. PTCH gene mutations in odontogenic keratocysts. J Dental Research. 2000;79:1418­22. 2. Carter LC, Carney YL, Perez­Pudlewski D. Lateral periodontal cyst; multifactorial anal­ ysis of a previously unreported series. Oral Surg Oral Med Oral Pathol. 1996;81:210­6. 3. Chaudhry AP, Yamane GM, Scharlock SE, SunderRaj M, Jain R. A clinico­pathological study of intraoral lymphoepithelial cysts. J Oral Med. 1984;39:79­84. 4. Cohen MM. Naevoid basal cell carci­ noma syndrome; molecular biology and new hypothesis. Int J Oral Maxillofac Surg. 1999;28:216­33. 5. Craig GT. The paradental cyst. A specific inflammatory odontogenic cyst. Br Dent J. 1976;141:9­14.

6. David VC, O'Connell JE. Nasolabial cyst. Clin Otolaryngol Allied Sci. 1986;11:5­8. 7. Gardner DG, Kessler HP, Morency R, Schaffner DL. The glandular odontogenic cyst: an apparent entity. J Oral Pathol. 1988;17:359­66. 8. Gurol M, Burkes EJ, Jacoway J. Botryoid odontogenic cyst; analysis of 33 cases. J Periodontal. 1995;66:1069­73. 9. Jorgenson RJ, Shapiro SD, Salinas CF, Levin LS. Intraoral findings and anomalies in neo­ nates. Pediatrics. 1982;69:577­82. 10. Kaffe I, Naor H, Calderon S, Buchner A. Radiological and clinical features of aneurys­ mal bone cyst of the jaws. Dentomaxillofac Radiol. 1999;28:167­72. 11. Katz AD, Hachigian M. Thyroglossal duct cysts; a thirty year experience with emphasis on occurrence in older patients. Am J Surg. 1988;155:741­4. 12. King RC, Smith BR, Burk JL. Dermoid cyst in the floor of the mouth. Review of the literature and case reports. Oral Surg Oral Med Oral Pathol. 1994;78:567­76. 13. Lin LM, Huang GT, Rosenberg PA. Proliferation of epithelial cell rests, forma­ tion of apical cysts, and regression of apical cysts after periapical wound healing. J Endod. 2007;33:908­16. 14. Lin LM, Ricucci D, Lin J, Rosenberg PA. Nonsurgical root canal therapy of large cyst­like inflammatory periapical lesions and inflammatory apical cysts. J Endod. 2009;35:607­15. 15. Li TJ, Kitano M, Chen XM, Itoh T, Kawashima K, Sugihara K, Nozoe E, Mimura T. Orthokeratinized odontogenic cyst: a clinico­ pathological and immunocytochemical study of 15 cases. Histopathology. 1998;32:242­51. 16. Mass EW, Kaplan I, Hirshberg A. A clinical and histopathological study of radicular cysts associated with primary molars. J Oral Pathol Med. 1995;24:458­61. 17. Mervyn Shear, Paul M Speight. Cyst of the oral and maxillofacial regions. 2007, Blackwell Munksgaard, Oxford. 18. Nair PNR. New perspectives on radicular cyst: do they heal? Inter Endod. 1998;31:155­60. 19. Nxumalo TN, Shear M. Gingival cyst in adults. I Oral Pathol Med. 1992;21:309­13. 20. Saito Y, Hoshina Y, Nagamine T, Nakajima T, Suzuki M, Hayashi T. Simple bone cyst.

23. Williams TP, Connor Jr FA. Surgical man­ agement of the odontogenic keratocyst: aggressive approach. J Oral Maxillofac Surg. 1994;52:964­6. 24. Woolgar JA, Rippin JW, Brown RM. A com­ parative study histologic study of odonto­ genic keratocyst in basal cell nevus syndrome and non syndrome patients. J Oral Pathol. 1987;16:75­80.

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A clinical and histopathologic study of fif­ teen cases. Oral Surg Oral Med Oral Pathol. 1992;74:487­91. 21. Swanson KS, Kaugars GE, Gunsolley JC. Nasopalatine duct cyst: an analysis of 334 cases. J Oral maxillofac Surg. 1991;49:268­71. 22. Van der Waal I, Rauhamaa R, Van der Kwast WA, Snow GB. Squamous cell carcinoma aris­ ing in the lining of odontogenic cysts; Report of 5 cases. Int J Oral Surg. 1985;14:146­52.

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Chapter

6 Odontogenic Tumors Vinay Hazarey, WM Tilakaratne

Chapter Outline Ameloblastoma • Ameloblastoma—Solid/Multicystic Type • Ameloblastoma—Extraosseous/Peripheral Type • Ameloblastoma—Desmoplastic Type • Ameloblastoma—Unicystic Type Squamous Odontogenic Tumor Calcifying Epithelial Odontogenic Tumor Adenomatoid Odontogenic Tumor Keratocystic Odontogenic Tumor Ameloblastic Fibroma Ameloblastic Fibro-odontoma Odontomas Calcifying Cystic Odontogenic Tumor

Dentinogenic Ghost Cell Tumor Odontogenic Fibroma Odontogenic Myxoma Benign Cementoblastoma Malignant Ameloblastoma Ameloblastic Carcinoma Primary Intraosseous Squamous Cell Carcinoma Clear Cell Odontogenic Carcinoma Ghost Cell Odontogenic Carcinoma Ameloblastic Fibrosarcoma Ameloblastic Fibrodentinosarcoma (AFDS) and Fibro-odontosarcoma (AFOS) Self-assessment Questions

inTrODUcTiOn

BEnign TUMOrS Odontogenic epithelium with mature, fibrous stroma without odontogenic ectomesenchyme • Ameloblastoma, solid/multicystic type • Ameloblastoma, extraosseous/peripheral type • Ameloblastoma, desmoplastic type • Ameloblastoma, unicystic type • Squamous odontogenic tumor • calcifying epithelial odontogenic tumor • Adenomatoid odontogenic tumor • Keratocystic odontogenic tumor

6 ODOnTOgEnic TUMOrS

Odontogenic tumors are a rare group of neoplasms. A thorough knowledge is necessary to evaluate and predict their occurrence, clinical features, radiological features, histopathology and pathogenesis, biological behavior and treatment options. Odontogenic tumors show a spectrum of pathological entities arising from abnormal odontogenesis. The correct interplay of dental tissues leads to normal tooth development. However, variations during any developmental stage lead to malformations, developmental anomalies, hamartomas and neoplasms. The development of a normal tooth depends upon inductive influences exerted by one tissue on another. It has long been believed that the main inductive effect is exerted by the odontogenic epithelium on adjacent mesodermal tissues. This results in formation of dental papilla and later appearance of odontoblasts on its surface. When dentine formation starts, the final functional maturation of ameloblasts takes place and enamel is deposited on the dentine surface in the crown area. Therefore, dentine does not form in the absence of odontogenic epithelium and enamel normally does not form unless some dentine has already been laid down. From these considerations it can be suggested that variations in the degree of induction exerted by the odontogenic epithelium may result in a marked variation in the pattern of tumors developed from these tissues. It is not suggested that each pattern necessarily indicates a distinct and separate type of tumor—rather, there is continuum of interactions leading to spectrum of odontogenic tumors. Odontogenic tumors are neoplasms originating from dental tissues or their formative elements. They are classified on the basis of inductive potential of odontogenic tissues. As the different dental tissues exhibit a mutual interdependence, classification helps in understanding the biological behavior and growth potential of these lesions. Thoma and Goldman in 1946 suggested that odontogenic tumors should be divided into tumors of ectodermal, mesodermal, and mixed origin. This classification forms the nucleus of the classification adopted by the

ƒ Table 6.1 WHO histological classification of odontogenic tumors

Odontogenic epithelium with odontogenic ectomesenchyme, with or without hard tissue formation • Ameloblastic fibroma • Ameloblastic fibrodentinoma • Ameloblastic fibro-odontoma • Odontoma, complex type • Odontoma, compound type • Odontoameloblastoma • calcifying cystic odontogenic tumor • Dentinogenic ghost cell tumor Mesenchyme and/or odontogenic ectome-senchyme with or without odontogenic epithelium • Odontogenic fibroma • Odontogenic myxoma/myxofibroma • cementoblastoma MAlignAnT TUMOrS Odontogenic carcinomas • Metastasizing (malignant) ameloblastoma • Ameloblastic carcinoma—primary type • Ameloblastic carcinoma—secondary type (dedifferentiated), intraosseous • Ameloblastic carcinoma—secondary type (dedifferentiated) • Peripheral • Primary intraosseous squamous cell carcinoma—solid type • Primary intraosseous squamous cell carcinoma derived from keratocystic odontogenic tumor • Primary intraosseous squamous cell carcinoma derived from odontogenic cysts • clear cell odontogenic carcinoma • ghost cell odontogenic carcinoma Odontogenic sarcomas • Ameloblastic fibrosarcoma • Ameloblastic fibrodentino–and fibro-odonto-sarcoma

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American Academy of Oral Pathologists in 1950. Pindborg et al in 1970 suggested classification for WHO Histological Typing of Odontogenic Tumors, Jaw cysts and Allied Lesions. The WHO in 2005 revised this classification and introduced a range of new entities with a better understanding of pluripotential nature of the odontogenic epithelium. WHO histological classifiation of odontogenic with benign and malignant tumors are depicted in Table 6.1.

AMElOBlASTOMA Ameloblastoma is the second most common tumor amongst odontogenic tumors. The WHO defines it as a locally invasive neoplasm of epithelial odontogenic origin without any inductive changes in the connective tissue. It can occur at either intraosseous (central) or extraosseous (peripheral) location. Intraosseous neoplasms are usually aggressive in clinical behavior and often locally invasive. These neoplasms can invade the soft and hard tissues of jaws. Prior to it being called an ameloblastoma by Ivy and Churchill in 1930, it was called an adamantinoma. The Greek term adamantinoma envisages a tumor containing hard tissues. There is no evidence of any hard tissues, since there is no induction. Adamantinomas are tumors of long bones and should not be confused with an

A

126

odontogenic neoplasm, ameloblastoma. The first case of ameloblastoma was described by Cusack in 1827. The first case of ameloblastoma developing in dentigerous cyst was reported by Cahn.

Solid/Multicystic Type Clinical Features In the early stages, it is asymptomatic and may be diagnosed upon routine radiographic examination. It may present as a variably sized swelling of the jaw (Fig. 6.1A). Usually the swelling is slow growing and may take a few years to cause facial disfigurement. Thinning and expansion of buccal and lingual cortical plates may occur, often presenting clinically as eggshell crackling. Complete destruction of either cortical plates may present as a firm, or fluctuant swelling. Displacement and mobility of adjoining teeth can occur. An untreated ameloblastoma can cause unsightly disfigurement of the face and pathological fracture (Fig. 6.1B). A tooth or teeth may be clinically missing as ameloblastoma may be associated with an impacted tooth, giving it dentigerous cyst-like features. Pain and facial disfigurement are features of advanced tumors. Ameloblastomas are more common in the mandible (80%) than in the maxilla (20%).

B

Figs 6.1A and B: Ameloblastoma. (A) Slow growing tumor at the right angle of the mandible; (B) A long standing tumor with marked disfigurement of the face

6 ODOnTOgEnic TUMOrS

A

B

Figs 6.2A and B: Ameloblastoma. (A) Multilocular radiolucency is the most common radiological presentation; (B) Some cases mimic the appearance of dentigerous cyst

Approximately 60 percent are located in the ramus and body of the mandible, 30 percent in the premolar-molar area and 10 percent in the anterior mandible. Maxillary lesions located in the premolar area cause palatal and buccal expansion. The distribution amongst males and females is almost equal. The average age of patients reporting to clinics is in between the 3rd and 4th decade, often with a history of 3 to 4 years duration. However, the age range varies from 4 to 92 years. The mean age of patients at the time of diagnosis is 35.9 years.

Radiological Features Radiographically, it presents more commonly as a multilocular radiolucency (multicystic) (Fig. 6.2A) and less commonly as a unilocular radiolucency. The periphery is well-defined and often corticated and scalloped. Multilocular lesions show numerous coarse curved septa dividing the internal structure into multiple compartments giving it a honeycomb (smaller locules of uniform size) or soap bubble (larger locules of variable size) appearance. Unilocular lesions are similar to odontogenic cysts and are often difficult to distinguish from a dentigerous cyst when associated with an impacted or

unerupted tooth (Fig 6.2B). Resorption of the roots and displacement of involved teeth are common. However, desmoplastic ameloblastoma resembles fibro-osseous lesions and presents as a mixed radiodense lesion.

Histopathological Features The WHO defines an ameloblastoma as a neoplasm without inductive changes in the connective tissue. The epithelial proliferations can give rise to two main histopathological types defined as follicular and plexiform. In the follicular subtype, the tumor epithelium is arranged into follicles which possess a peripheral layer of tall columnar cells resembling preameloblasts or internal dental epithelium. These cells show hyperchromatism and reversed polarity of the nuclei. The central part of these follicles shows resemblance to stellate reticulum (Fig. 6.3A). As the center of the follicles undergoes metaplastic change, the follicular variant is qualitatively described as acanthomatous, granular cell or basal cell subtypes. The acanthomatous variant shows extensive squamous metaplasia and keratin formation within the follicle (Fig. 6.3B). In Granular cell variant, transformation of stellate reticulum

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Figs 6.3A to D: Ameloblastoma solid/multicystic type. (A) Follicular type showing numerous follicular structures with peripheral ameloblast-like cells and central stellate reticulum cells; (B) central cells show squamous metaplasia in acanthomatous type; (c) granular cell changes in granular cell ameloblastoma; (D) Plexifom type with odontogenic epithelium arranging into a branching pattern

cells to granular cells is seen (Fig. 6.3C). The granules are large, round and PAS positive. These acidophilic granules are similar ultrastructurally and histochemically to lysosomes. The Plexiform variant is characterized by a branching network of odontogenic epithelium (Fig. 6.3D). The peripheral cells of these strands are not as columnar as in the follicular variant and stellate reticulum is very scanty. It is suggested that follicular and plexiform nomenclature has no clinical significance.

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Ameloblastomas may arise from the basal layer of dental lamina, remnants of Hertwig’s root sheath or epithelial cell rest of Malassez. Basal layers of oral epithelium and cell rests of Serres are also thought to be important in the pathogenesis of peripheral ameloblastomas. Mutation in genes during odontogenesis is responsible for neoplasia. The fos-oncogene and

tumor-necrosis-factor-receptor-1 are the most over-expressed genes. Some genes including sonic Hedgehog (SHH), cadherins 12 and 13 and transforming growth factor β1 (TGF-β1) are under-expressed according to different studies.

Treatment Surgical excision is the treatment of choice. Segmental osteotomies are usually adequate for unicystic ameloblastomas. However, large lesions may require a hemimandibulectomy or maxillectomy. Enucleation as a treatment for any form of ameloblastoma is controversial. Tumors are radio-resistant. Ameloblastoma is an aggressive neoplasm known for recurrences, especially if inadequately excised. Inadequate excision is responsible for high rates of recurrence. The malignant potential exists for intraosseous ameloblastoma and these malignant counterparts are known

Extraosseous/Peripheral Type The extraosseous/peripheral ameloblastoma is the extraosseous counterpart of the intraosseous solid/multicystic ameloblastoma. Syn-onyms are soft tissue ameloblastoma, ameloblastoma of mucosal origin and ameloblastoma of the gingiva. It may arise from odontogenic epithelial remnants within the gingival lamina propria or from the basal cell layer of the gingival epithelium. Peripheral ameloblastoma accounts for 1.3 to 10 percent of all ameloblastomas.

Clinical Features Although, it occurs at any age from 9 and 92 years, most are reported from 5th to 7th decade and the mean age is significantly higher than for the intraosseous counterpart. The male:female ratio is 1.9:1 with the mandible affected more than the maxilla. It appears as a painless, firm and exophytic growth with a smooth, pebbly or papillary surface. Rarely, the intraosseous ameloblastoma may extend to the gingival tissues and merge with the gingival

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epithelium, creating an exophytic peripheral ameloblastoma like lesion.

Radiological Features Apart from a superficial erosion or depression (saucerization or cupping) of the bone crest due to pressure resorption, there is rarely any significant bone involvement.

Histopathological Features

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and classified as malignant ameloblastomas. The recurrence rate is 33 percent. Peripheral (extraosseous) lesions are nonaggressive and the recurrence is rare. Regular follow-up is essential to identify early recurrence.

A peripheral ameloblastoma consists of odontogenic epithelium with the same histomorphological cell types and patterns similar to solid/ multicystic ameloblastoma. Some lesions are located entirely within the connective tissue of the gingiva, showing no continuity with the surface epithelium, whereas others seem to fuse with, or originate from the mucosal epithelium. Squamous cells in the acanthomatous areas of the peripheral ameloblastoma may show ghost cell formation and in some parts of the tumor islands, vacuolated or clear cells occur in discrete clusters. Basal cell metaplasia is a common feature. The stroma is made up of mature, fibrous connective tissue (Fig. 6.4A). Peripheral odontogenic fibroma, peripheral variant of squamous odontogenic tumor and odontogenic gingival epithelial hamartoma (OGEH) mimic the appearance of peripheral ameloblastoma. Some lesions are histologically

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Figs 6.4A and B: (A) Peripheral ameloblastoma composed of basaloid islands of odontogenic epithelium below the surface epithelium; (B) Desmoplastic ameloblastoma shows strands of ameloblast-like cells arranged in a dense and hyalinized fibrous stroma

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very similar to basal cell carcinoma. The present view is that peripheral ameloblastoma and OGEH represent the same lesion.

Desmoplastic Type Desmoplastic ameloblastoma is a distinct variant of the ameloblastoma with 150 cases reported in the literature. It is described as “ameloblastoma with pronounced desmoplasia” by Eversole in 1984. The mean age of desmoplastic ameloblastoma is 42.9 years. This variant of ameloblastoma is common in the anterior region of jaws with slight preponderance to the maxilla. Three distinct radiologic variants have been described: • Unilocular containing varying amount of radiopaque material • Multilocular containing varying amount of radiopaque masses • Mixed pattern mostly mimicking the appearances of fibro-osseous lesions. Histopathologically, it shows collagenous mature connective tissue stroma in which odontogenic islands are compressed or squeezed by the stromal tissue, giving rise to stretched out tail-like islands (Fig. 6.4B). The lesional tissue shows a combination of fibro-osseous and odontogenic architecture. The desmoplastic variant has a relatively low recurrence potential. Central stellate reticulum-like cells are often scanty in the epithelial proliferation and the cells making up the periphery of the strands and cords often are flattened or cuboidal rather

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than tall and columnar in appearance. Reversed polarity of nuclei and subnuclear vacuole formation may be difficult to recognize. Marked immunoexpression of TGF-β has been observed and may explain the significant desmoplasia in the tumor.

Unicystic Type The unicystic variant is common in the younger age group and has a relatively low recurrence rate. Unicystic ameloblastomas are commonly associated with impacted teeth. Two main histopathological variations are identified: in the subtype referred to as luminal type, a relatively innocuous epithelial lining at least in part, shows cuboidal or columnar basal cells with hyperchromatic nuclei, nuclear palisading with reversed polarity, cytoplasmic vacuolation with intercellular spacing and subepithelial hyalinization (Fig. 6.5A). These histopathological criteria are described by Vicker and Gorlin (1970). Sometimes, a cyst lining similar to the luminal type with a nodule projecting into lumen of the cyst is evident. The nodule comprises odontogenic epithelium with a plexiform pattern resembling that seen in the plexiform ameloblastoma (Intraluminal type). The name plexiform unicystic ameloblastoma has been used for these lesions. The second variety is referred to as a mural ameloblastoma showing part of the wall of the cyst infiltrated by typical plexiform or rarely follicular ameloblastoma (Fig. 6.5B).

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Figs 6.5A and B: Unicystic ameloblastoma. (A) luminal type is composed of odontogenic epithelium with peripheral basal cells showing reversed polarity and surface stellate reticulum-like cells; (B) The epithelium proliferates into cyst wall in mural type

Box 6.1: Ameloblastoma—key features helpful in diagnosis • Second most common benign odontogenic tumor • Occur equally in men and women, most commonly in 3rd and 4th decades of life • Slow growing locally aggressive neoplasm causing facial asymmetry, expansion of the jaw bones and displacement of the teeth • More often multilocular radiolucency and less often unilocular cyst-like radiolucency • Histologically, tumor cells resemble ameloblast-like cells in the odontogenic apparatus.

SqUAMOUS ODOnTOgEnic TUMOr Pullon et al in 1975 first described a particular odontogenic tumor located in the periodontium as squamous odontogenic tumor (SOT). It is defined as a benign, but locally infiltrative neoplasm consisting of islands of welldifferentiated squamous epithelium in a fibrous stroma. The epithelial islands occasionally show foci of central cystic degeneration. It may arise from epithelial rests of Malassez located in the periodontal ligament. Peripheral SOTs may originate in gingival surface epithelium as a “dropping off” phenomenon, or from remnants of dental lamina. Some consider that SOT may have a hamartomatous nature.

Clinical Features The age range is between 8 to 74 years with a mean age of 38.7 years. Males are affected more

than females (1.4:1). Squamous odontogenic tumor usually occurs intraosseously and probably develops in the periodontal ligament between the roots of vital erupted permanent teeth. The mandible is affected more than the maxilla. Mobility of teeth and moderate pain are possible indicators of an underlying tumor. A rare peripheral variant is also seen. SOTs in the maxilla are more aggressive than in the mandible.

Radiological Features

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The luminal and intraluminal variants are treated conservatively with enucleation and curettage. However, the mural variant needs to be treated in a similar way to solid multicystic ameloblastomas. According to some, enucleation may not be appropriate to treat any type of ameloblastoma. The histopathological diagnosis of a unicystic ameloblastoma is exceptionally important as various subtypes have different treatment options and prognosis. Serial sectioning of the biopsy is mandatory to exclude the presence of conventional ameloblastomas. Unicystic ameloblastomas have lower recurrence rates of 10 to 20 percent.

Squamous odontogenic tumor shows a welldefined unilocular and triangular radiolucency between the roots of adjacent teeth. Extensive lesions may have a multilocular pattern, involving the mandible or maxillary sinuses. The peripheral variant of SOT may reveal some saucerization of underlying bone which is explained as a pressure phenomenon rather than a result of neoplastic infiltration.

Histopathological Features Histologically, SOT is composed of islands of well-differentiated squamous epithelium in a fibrous stroma (Fig. 6.6). Individual islands reveal a peripheral layer of cuboidal or even flat epithelial cells. Islands may undergo microcysts formation and individual cell keratinization. Some islands may contain calcified material. Mitotic activity of tumor cells is not increased.

Fig. 6.6: Squamous odontogenic tumor. islands of benign squamous epithelium arranged in a fibrous stoma

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These islands are surrounded by mature connective tissue with little or no inflammatory response. SOT may be confused with other conditions including ameloblastoma and rarely squamous cell carcinoma. Histopathological misinterpretation may thus lead to over treatment or under treatment.

Treatment Conservative surgical procedures such as enucleation, curettage or local excision are the accepted modalities of treatment. However, tumors in the maxilla need radical treatment because of aggressive potential of SOTs in this location. Recurrences are rare in mandibular lesions. Box 6.2: Squamous odontogenic tumor Key features helpful in diagnosis • rare odontogenic tumor • its location between roots of vital teeth suggests origin from epithelial rests of Malassez located in the periodontal ligament • Males are affected more commonly than females • Average age of occurrence is 38 years. • Mandible more commonly affected than maxilla • clinically manifests as mobility of teeth, swelling and moderate pain • radiographically presents as well-defined unilocular and triangular radiolucency between the roots of adjacent teeth • Histopathology shows islands of well-differentiated squamous epithelium in a fibrous stroma.

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cAlciFying EPiTHEliAl ODOnTOgEnic TUMOr Calcifying epithelial odontogenic tumor (CEOT) is an uncommon, benign, odontogenic neoplasm. The calcifying epithelial odontogenic tumor was first introduced into the scientific literature almost 50 years ago by Jens Pindborg. CEOT is a locally invasive epithelial odontogenic neoplasm, and is characterized by the presence of amyloid material that may become calcified. Commonly it is called Pindborg’s tumor. Odontogenic epithelium is evidently the origin of this tumor but the particular cell remains unknown. The original hypothesis by Pindborg was that the tumor arises from the stratum intermedium of the enamel organ still remains the most likely cause. Its reduced invasiveness, compared to ameloblastoma may be explained by the reduced invasive potential and reduced activity of the stratum intermedium compared to the growth potential of the dental lamina.

Clinical Features Calcifying epithelial odontogenic tumor (CEOT) accounts for approximately 1 percent of all odontogenic tumors occurring in patients between 20 and 60 years of age, with a mean around 40 years. There is no gender predilection. Most cases are intraosseous; approximately 6 percent arise in extraosseous locations. Intraosseous tumors affect the mandible more often than the maxilla with a ratio of 2:1. There is usually a predilection for the premolar/ molar region (Fig. 6.7A). It presents as a hard, painless slow-growing lesion. Uncommon

B Figs 6.7A and B: calcifying epithelial odontogenic tumor. (A) Usually presents as a swelling in the posterior mandible; (B) radiologically, it shows a lesion with mixed radiodensity

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Figs 6.8A and B: calcifying epithelial odontogenic tumor. (A) Epithelial component consists of sheets of polygonal cells that often have distinct intercellular bridges and the stroma contains amyloid; (B) Amyloid showing apple green birefringence with polarized microscope after staining with congo red

peripheral variant of Pindborg’s tumor presents clinically as a nodular mass on gingival mucosa, frequently in an anterior location.

Radiological Features An early tumor may be completely radiolucent. As the tumor matures most lesions become mixed radiolucent-radiopaque lesions. Moreover, the radiographic picture shows a spectrum ranging from a unilocular to a multilocular radiolucency (Fig. 6.7B). This is frequently associated with the crown of an impacted tooth often a mandibular third molar, or may appear in place of a tooth. In some, the radioopacity is so complete that it resembles a bone tumor. In almost all cases, the radiographic border between tumor and surrounding bone appears to be well-defined and circumscribed. CEOT as a radiolucency resembles the presentation of other radiolucent jaw lesions, such as dentigerous cyst, odonto-genic keratocyst, ameloblastoma, and odontogenic myxoma. The mixed radiolucentradiopaque lesion suggests a calcifying odontogenic cyst, ameloblastic fibro-odontoma and even desmoplastic ameloblastoma. Sometimes, the radiographic picture resembles tumors in bone such as ossifying fibroma, osteoblastoma, or even osteosarcoma if the lesion shows diffuse margins.

Histopathological Features The CEOTs are unencapsulated and infiltrating tumors. The characteristic epithelial component consists of sheets and islands of polygonal cells that often have distinct intercellular bridges (Fig. 6.8A). The nuclei are centrally located and often have a prominent nucleolus. The nuclei may be pleomorphic, hyperchromatic, and bizarre in appearance. Binucleated cells may be frequent. Although multinucleated giant cells may be observed, increased numbers and/or abnormal mitotic figures are distinctly uncommon and if present would be a cause for concern. Clear cells are sometimes present. Rounded, pale eosinophilic masses may be found within the sheets of tumor cells and can undergo calcification, often in the form of Liesegang rings. The surrounding tissue may also contain large clumps of homogeneous eosinophilic material. The eosinophilic material stains positive for amyloid with Congo red, crystal violet, and Thioflavine T. When exposed to a polarized microscope positive areas demonstrate apple green birefringence (Fig. 6.8B).

Treatment The CEOT is a locally invasive tumor. Small tumors may be enucleated, but larger ones

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require local resection. An overall recurrence rate of about 14 percent has been reported. A relatively higher recurrence rate of 22 percent has been noted for the clear cell variant. Longterm follow-up is recommended. Box 6.3: Calcifying epithelial odontogenic tumor Key features helpful in diagnosis • Accounts for less than 1 percent of all odontogenic tumors • no gender predilection • Average age of occurrence is 40 years • Mandible twice more commonly affected than maxilla • clinically manifests as a hard, painless slowgrowing swelling • radiographically presents as a well-defined unilocular or multilocular radiolucency • Histopathologically shows sheets and islands of polygonal cells with prominent intercellular bridges and pleomorphic hyperchromatic nuclei • liesegang rings and amyloid-like material is also evident.

ADEnOMATOiD ODOnTOgEnic TUMOr Adenomatoid odontogenic tumor (AOT) is a benign lesion with a slow but progressive growth. It occurs in both intraosseous and peripheral forms. Bernier and Tiecke introduced the term adenoameloblastoma. In 1961, Gorlin et al introduced the term ameloblastic adenomatoid tumor. In 1968, Abrams et al. suggested the term odontogenic adenomatoid tumor. Philipsen and Birn proposed the name adenomatoid odontogenic tumor in 1969. AOT accounts for 2 to 7 percent of all odontogenic tumors. The long-term debate as to whether AOT is an anomalous developmental hamartomatous growth or a true benign neoplasm has not been settled. Meanwhile, investigators who prefer to consider AOT to be a hamartoma point to the limited size of most cases (attributed to its minimal growth potential) and to the lack of recurrence to support their belief. Those who prefer to consider AOT to be a nonaggressive noninvasive benign neoplasm presumably believe that the limited size of most cases stems

Fig. 6.9: Adenomatoid odontogenic tumor. it presents in varying associations in relation to teeth. (F: Follicular, E1, E2, E3, E4: Extrafollicular)

from the fact that most are detected early (often on a routine dental radiograph) and removed before the slow-growing tumor reaches a clinically noticeable size. Depending on the location, AOT has been classified into follicular and extra-follicular variants (Fig. 6.9). Immunohistochemical studies revealed differences between the duct- and nonductforming cells; the nonduct-forming columnar cells expressed amelogenin reactivity, whereas the duct-forming cells showed no reactivity to amelogenin or the other enamel matrix protein (enamelin and sheathlin) antibodies. The tumor cells immediately adjacent to the droplets also demonstrate cytoplasmic positivity to the enamel protein, sheathlin. These findings provide additional support for the odontogenic origin of AOT and indicate that some of the epithelial tumor cells display features that are consistent with neoplastic (pre)ameloblasts in a state of arrested development, yet they apparently are metabolically active enough to produce basement membrane and enamel matrix proteins.

Clinical Features The age range varies between 3 and 82 years. More than two-thirds are diagnosed in the second decade of life and 90 percent are found before the age of 30. The male:female ratio is 1:1.9. AOT almost exclusively occurs

Radiological Features The intraosseous, follicular AOT shows a well-defined, unilocular radiolucency around the crown and often part of the root of an unerupted permanent tooth, mimicking a dentigerous cyst. If not associated with an unerupted tooth (extrafollicular type), AOT presents as a unilocular radiolucent lesion (Fig. 6.10B). In two thirds of the intraosseous variant, the radiolucency shows discrete radiopaque foci towards the periphery. AOT that appears without radiographic evidence

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of calcification is most suggestive of the more common dentigerous cyst. The peripheral variant may disclose erosion (saucerization) of the alveolar bone crest.

Histopathological Features The most striking pattern is that of variably sized solid nodules of cuboidal or columnar cells of odontogenic epithelium forming nests or rosettelike structures with minimal stromal connective tissue. Between the epithelial cells and in the center of the rosette-like configurations, eosinophilic amorphous material is present (Fig. 6.11). Conspicuous within the cellular areas are appearance of tubular or duct-like appearance. The duct-like spaces are lined by a single row of columnar epithelial cells, with the nuclei polarized away from the luminal surface. The lumen may be empty or contain eosinophilic material or cellular debris. These nodules may contain pools of amorphous amyloid-like material and globular masses of calcified substances. Melanin pigmentation of both lesional tissue and stroma cells has been described. Occurrence of a hyaline, dysplastic material or calcified osteodentin may be found in AOTs. CEOT-like areas are occasionally found in AOTs.

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intraosseously with a preference for the maxilla over the mandible with a ratio of 2.1:1. The rare peripheral type occurs almost exclusively in the anterior maxillary gingiva. Intraosseous AOTs may be found in association with unerupted permanent teeth (follicular type), in particular the four canines that account for 60 percent with the maxillary canines alone accounting for 40 percent. Most AOTs are asymptomatic. When growth of the intraosseous variant causes cortical expansion, it may present as a palpable bony-hard swelling with or without slight pain (Fig. 6.10A). The intraosseous AOTs may cause displacement of neighbouring teeth. The peripheral variant presents as an epulis-like lesion of the gingiva.

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Figs 6.10A and B: Adenomatoid odontogenic tumor. (A) Usually present as a bony hard swelling in relation to maxillary canine; (B) radiographically a unilocular radiolucency mimicking the appearance of a dentigerous cyst

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Fig. 6.11: Adenomatoid odontogenic tumor. Odontogenic epithelium forming nests or rosettelike structures with frequent duct like structures

Treatment Although there may be expansion of the alveolar bone overlying central lesions, the cortex is almost invariably intact. Because of the uniformly benign biological behavior of nearly all typical AOTs and the consistent presence of a well-developed fibrous capsule, conservative complete surgical excision usually accomplished by enucleation and curettage is the treatment of choice. Recurrences are extremely rare. Box 6.4: Adenomatoid odontogenic tumor Key features helpful in diagnosis • Accounts for 2 to 7 percent of all odontogenic tumors • Average age of occurrence is second decade of life • Maxilla twice more commonly affected than mandible • Often associated with impacted teeth especially canines • radiographically presents as well-defined unilocular radiolucency often associated with crown of an impacted tooth. Two-third of the cases show discrete calcific foci • Histologically shows variably sized solid nodules of cuboidal or columnar cells of odontogenic epithelium forming nests or rosettelike structures with eosinophilic “material” in the center and interspersed with structures of tubular or duct-like appearance.

Odontogenic keratocyst (OKC) has been one of the most controversial pathological entities of the maxillofacial region since Philipsen first described it in 1956. The WHO’s recent classification of head and neck tumors reclassified keratocyst as a benign neoplasm recommending the term “keratocystic odontogenic tumor” (KCOT). The former orthokeratinized variant of the OKC is at present not recognized as being part of the spectrum of a KCOT. Multiple OKCs are indicative of the presence of nevoid basal cell carcinoma syndrome (NBCCs). In the earlier literature, OKC was described as a cholesteatoma by Hauer in 1926 and Kostecka in 1929. The term ‘odontogenic keratocyst’ was introduced by Philipsen in 1956, and subsequently in a paper by Pindborg and Hansen (1963), the designation ‘keratocyst’ was used to describe any jaw cyst in which keratin was formed to a large extent. It was believed that this cyst arises from primordial odontogenic epithelium that led to the term ‘primordial cyst’ Shear (1960); Shear and Altini (1976); Pindborg et al (1971). The term ‘primordial cyst’ has now fallen into disuse. A benign unicystic or multicystic, intraosseous tumor of odontogenic origin, with a characteristic lining of parakeratinized stratified squamous epithelium and potentially aggressive, infiltrative behavior. It may be solitary or multiple. The frequency of OKC has been reported to vary from 3 to 11 percent of odontogenic cysts (see Chapter 5 on Cysts of the Oral and Maxillofacial Region).

AMElOBlASTic FiBrOMA Ameloblastic fibroma (AF) is a locally aggressive neoplasm arising from enamel organ and odontogenic mesenchyme of the primitive dental pulp. In 1891, Kruse first described cystic tumors of the mandible, which are known today as ameloblastic fibromas. AF consists of odontogenic ectomesenchyme resembling the dental papilla and epithelial strands and nests resembling dental lamina and enamel organ. Dental hard tissues are not present. If there is dentine formation, the lesion is referred to as ameloblastic fibrodentinoma (AFD). AF is a rare

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Clinical Features Most cases of AF present as a painless swelling or are discovered due to disturbances of tooth eruption. It usually grows to a certain size, sometimes large, then ceases to grow and does not extend beyond its own capsule. Less commonly, it exhibits continued slow growth. The mean age is 14.8 years. It is essentially a tumor that occurs in children and teenagers. There is no sex predilection. The mandibular molar area is the preferred site, but the tumor may occur in any location.

Radiological Features Radiographically, the tumor presents as a well demarcated radiolucency, often in connection with a malpositioned tooth. It may be either unilocular or multilocular, and may be associated with the crown of an impacted tooth and mimic a dentigerous cyst. Due to the age of occurrence, the mass frequently displaces developing teeth. It may also resorb roots and displace the inferior alveolar canal.

Histopathological Features The epithelial component of AF consists of branching and anastomosing epithelial strands that form knots of varying size. These have a peripheral rim of columnar cells similar to the inner enamel epithelium that embraces a loosely arranged spindle-shaped epithelium identical to stellate reticulum (Fig. 6.12). The epithelial strands lie in a myxoid and cell-rich stroma with

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odontogenic tumor. The relative frequency of AF ranges from 1.5 to 4.5 percent. Ameloblastic fibroma has the same histogenesis as odontoma. It arises from odontogenic epithelium of the enamel organ and odontogenic mesenchyme of the primitive dental pulp. It too, represents an aborted attempt at tooth formation, but it occurs prior to any enamel or dentine formation. Intermediate in this spectrum of aborted tooth formation attempts is the ameloblastic fibroodontoma, which actually forms some dentine and enamel, but much less organized than in odontoma. Fig. 6.12: Ameloblastic fibroma. islands and strands of neoplastic odontogenic epithelium are arranged in a hypercellular stroma

stellate-shaped fibroblasts with long slender cytoplasmic extensions resembling embryonic tooth pulp. The amount of epithelium may vary. The epithelial component resembles ameloblastoma. In contrast to the follicular type of ameloblastoma, these follicular islands in AF seldom demonstrate microcyst formation. The odontogenic epithelial cells are strongly positive for cytokeratin and immature dental papilla like mesenchymal tissue, especially around the dental lamina-like odontogenic epithelium, is positive for tenascin. Vimentin staining is observed in some areas of dental papilla-like cells and in the basement membrane of the epithelium. These findings suggest that AF develops at the early stage of tooth formation. Histological features similar to AF, may be observed in the hyperplastic dental follicle.

Treatment Ameloblastic fibroma usually requires only local excision and curettage as it is an encapsulated mass that is readily removed. The tumor usually does not invade the neurovascular bundle or even the inferior alveolar canal. Therefore, nerve preservation is usually achieved. Most ameloblastic fibromas are sufficiently large and destructive and strongly suggest need of resection rather than enucleation and curettage. Recurrence may occur but this does not justify initial aggressive treatment. The reappearance

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of a tumor may represent renewed growth of the residual tumor rather than true recurrence. Such recurrent lesions should be treated more aggressively. AF rarely transforms into an ameloblastic fibrosarcoma. Box 6.5: Ameloblastic fibroma Key features helpful in diagnosis • Essentially occurs in children and teenagers • Presents as either unilocular or multilocular well-demarcated radiolucency, often in connection with a malpositioned tooth • Branching and anastomosing epithelial strands in a myxoid stroma resembling embryonic tooth pulp • represents an aborted attempt at tooth formation, prior to any enamel or dentine formation.

AMElOBlASTic FiBrO-ODOnTOMA Ameloblastic fibro‐odontoma (AFO) is a tumor which has intermediate features between an ameloblastic fibroma and an odontome. It represents a limited proliferation of odontogenic epithelium of the enamel organ and odontogenic mesenchyme of the primitive dental pulp. This proliferation comprises the soft tissue recapitulation of the dental follicle, which then produces some enamel but mostly dentine. Ameloblastic fibro‐odontoma may be a hamartoma representing an aberrant or aborted attempt at tooth formation. This aborted attempt at tooth formation or aberrancy occurs during the formation of enamel and dentine. This is in contrast to ameloblastic fibroma, in which the aborted attempt occurs before hard tissues are formed. In an odontome the aborted attempt occurs during the formation of enamel and dentine. Therefore, all three lesions share some features of developmental disturbances of tooth formation. However, ameloblastic fibroma shows more features of a true neoplasm.

Clinical Features The AFO is less common than AF. The mean age is between 8 to 12 years. There is no gender or site

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predilection. AFO presents as an asymptomatic jaw expansion that may resorb tooth roots, displace developing teeth and inferior alveolar canal.

Radiological Features Radiographically, AFO exhibits a wellcircumscribed unilocular or multilocular radiolucency with varying levels of radio-opacity depending on the extent of mineralization. AFO is often associated with an unerupted tooth.

Histopathological Features The AFO is composed of soft and hard tissues. These circumscribed tumors combine the histological features of ameloblastic fibroma and odontoma. Thus, in addition to the presence of dental papilla‐like tissue with epithelial strands and islands, as seen in the ameloblastic fibroma, there is inductive change with formation of dentine and enamel (Fig. 6.13). Occasionally, tumors may show inductive changes limited to formation of dentine. These have been called ameloblastic fibro-dentinomas but they merely represent a minor variation of an ameloblastic fibro‐odontoma.

Fig. 6.13: Ameloblastic fibro-odontoma. There is evidence of inductive changes with dentine and enamel formation in addition to the features of ameloblastic fibroma

Box 6.6: Ameloblastic fibro-odontoma

ODOnTOMAS Odontomas are the most common types of odontogenic tumors. Odontomas are considered to be developmental anomalies (hamartomas) rather than true neoplasms. Broca first coined the term ‘‘odontome’’ in 1866. He defined it as a tumor formed by an overgrowth of complete dental tissue. This term was expanded over time to include many odontogenic tumors or cysts. In a landmark paper, Thoma and Goldman narrowed the term ‘‘odontoma’’ to include tumors that were composed of welldifferentiated tooth structure. Shafer and Gorlin defined odontoma as a tumor that has developed and differentiated enough to produce enamel and dentine. The origin of odontoma is unknown. Several theories have been proposed, including trauma and infection. It seems that these conditions are more likely to result in a hypoplastic tooth germ rather than an odontoma. Odontomas have been associated with dilacerated roots in the anterior maxilla. This association could represent the dual result of trauma. As tooth formation occurs early in life and odontomas have been found in unusual locations such as the inner ear, nasopharynx, palate, and soft tissues of the jaw indicating that pathogenesis is likely to involve an embryologic disturbance. Odontomas are actually mixed odontogenic hamartomas. They arise from both the odontogenic epithelium, which produce enamel,

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Key features helpful in diagnosis • AFO shows features of both neoplasm and hamartoma. • represents an aborted attempt at tooth formation or aberrancy occurs during the formation of enamel and dentine. • Essentially occurs in children and teenagers. • Presents as either unilocular or multilocular well-demarcated radiolucency, often in connection with a malpositioned tooth. • Shows presence of dental papilla-like tissue with epithelial strands and islands along with inductive changes with the formation of dentine and enamel.

and the odontogenic mesenchyme producing dentine via odontoblast differentiation. As they are composed of both cell types and form products of both cell types, they have previously been termed ‘‘composite” odontomas. This nomenclature has been abandoned since it is assumed that they are composites of two tooth forming cell lines, as are all teeth. Odontomas represent an attempt to duplicate tooth formation but in a distorted fashion. Odontomas are most likely hamartomas of aborted tooth formation, of which there are two general types. One type, which forms multiple small tooth-like structures, is called the compound odontoma. The other type forms an amorphous calcified mass and is called the complex odontoma. Odontoma, complex type (OC) is a tumorlike malformation (hamartoma) composed of hap hazardly arranged enamel, dentine and sometimes cementum.

Clinical Features Compound odontomas occur more often anterior to the mental foramen with a predilection to the maxilla whereas, complex odontomas occur posterior to the mental foramen with increased frequency in the mandible. There is no sex predilection. Most occur in children and young adults. It is doubtful whether new odontomas arise after the age of 25 years. Odontomas usually form hard, painless masses and are small rarely exceeding the diameter of the associated impacted tooth. Most lesions are discovered as incidental radiographic findings. However, they can be associated with significant signs and symptoms. The most common symptom is an impacted permanent tooth or a retained deciduous tooth. In one study, Budnick found that 61 percent of odontomas were associated with impacted teeth. Swelling was the second most common complaint (Fig. 6.14A).

Radiological Features The compound odontoma presents as a radiopaque mass in which the outline of miniature teeth may be noticed. The complex

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A

B

C

D

Figs 6.14A to D: Odontoma. (A) Swelling of the right side angle of the mandible; (B) Uniformly radiopaque lesion representing a complex odontome; (c) Histologically compound odontome shows tooth like structures; (D) complex odontome is composed of irregularly arranged dental hard tissue, mostly dentine

odontoma will present as a dense amorphous and irregularly shaped mass (Fig. 6.14B). In both a well-demarcated border, with adjacent bone can usually be seen. An odontoma in its early stage of formation, when calcification of its distorted dentine is incomplete appears as a mixed radiodense lesion but has a welldemarcated border with bone. Both compound, as well as complex odontomas if superimposed over roots, may also suggest the appearance of cementoblastoma or, if not discovered until after the age of 30 years, periapical cemento-osseous dysplasia and early florid cemento-osseous dysplasia. In addition, complex odontomas bear a radiographic resemblance to osteoblastoma, ossifying fibroma, and even lingual tori or osteomas that are projected over the mid mandible and therefore appear as

a central lesion. Ameloblastic fibro-odontoma also mimics the appearance of an immature odontoma radiologically.

Histopathological Features Odontomas are composed essentially of mature dental tissues namely enamel, dentine, cementum and pulp. They are arranged in discrete tooth-like structures (compound odontoma) (Fig. 6.14C) or as unstructured sheets of dental hard tissue (complex odontoma) (Fig. 6.14D). In addition, components of the enamel organ may be present. The bulk of the tumor usually consists of dentine that is normal in appearance. Cementum may be cellular or acellular, and enamel may be mature or consist only of matrix. Occasionally, epithelial ghost

Treatment Conservative surgical excision is the treatment of choice for odontomas, results in little or no chance of recurrence. Complications of odontoma include infection, malocclusion, delayed eruption or noneruption of adjacent teeth and cyst formation. Box 6.7: Odontomas Key features helpful in diagnosis • Occurs in children and young adults • compound odontoma has predilection for anterior maxilla and complex odontoma for posterior part of the mandible. • Presents as a mixed radiopaque lesion with well-demarcated border. • Mature dental tissues, enamel, dentine, cementum, and pulp tissue may be arranged in discrete tooth like structures (compound odontoma) or as unstructured sheets (complex odontoma).

cAlciFying cySTic ODOnTOgEnic TUMOr The calcifying odontogenic cyst (COC) was first described as a distinct clinical entity by Gorlin and his colleagues in 1962. Gold (1963) chose a similar, but not identical term for the lesion, namely ‘Keratinizing and calcifying odontogenic tumor’. The so-called calcifying odontogenic cyst represents a heterogeneous group of lesions that exhibits a variety of clinicopathologic and behavioural features. Because of this diversity, there has been confusion and disagreement on the terminology and classification of these lesions. The 1992 WHO classification includes this cyst and all its variants in the category of odontogenic tumors. Fejerskov and Krogh suggested the term ‘calcifying ghost cell odontogenic tumor’ and Freedman and his associates suggested the name ‘cystic calcifying odontogenic tumor’. It is a rare, well circumscribed solid or cystic lesion

derived from odontogenic epithelium and ectomesenchyme. It has become obvious that calcifying cystic odontogenic tumor (CCOT) has a spectrum with one end as a cystic lesion and the other presenting as a more solid tumor. Praetorius et al in 1981 classified COCs into two entities, a cyst (type 1) and a neoplasm (type 2). Type 1 was further subclassified as type 1A (simple unicystic), type 1B (odontome producing), and type 1C (ameloblastomatous), and the term dentinogenic ghost cell tumor was proposed for the type 2 lesion (neoplasm). In the 2005 WHO classification dentinogenic ghost cell tumor is a separate entity.

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cell keratinization may be seen with a fibrous capsule and a small amount of supporting fibrous tissue, or possibly a dentigerous cyst may arise from compound odontoma.

Clinical Features Swelling is the most frequent complaint and occurs in about half of the reported cases, only rarely has there been pain. Intraosseous lesions may produce a bony expansion and may be fairly extensive. Lingual expansion may sometimes be observed. Occasionally, the CCOT may perforate the cortical plate and extend into the soft tissues. CCOT is predominantly an intraosseous lesion, although 13 to 30 percent of cases have appeared as peripheral (extraosseous). Both the intraosseous and extraosseous forms occur in equal frequency in the mandible and maxilla. About 65 percent of cases were found in the incisor and canine region. The mean age is 33 years and most cases are diagnosed in the second and third decade of life. CCOTs that are associated with odontomas tend to occur in younger patients, with a mean age of 17 years. The peripheral lesions on the gingiva, present as painless swelling or nodule, which may resemble fibrous epulis or peripheral giant cell granuloma.

Radiological Features Calcifying cystic odontogenic tumor is an expansile lesion and sometimes discovered on routine radiographic examination. It is usually unilocular with a well-defined radiolucency. Radiopaque structures within the lesion either irregular calcification, or tooth-like densities may be seen. Radiological differential diagnose

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Figs 6.15A and B: calcifying cystic odontogenic tumor. (A) radiologically, it presents as a lesion of mixed radiodensity. note the lesion in the anterior maxilla; (B) Histologically, the tumor is characterized by the presence of ghost cells, calcification and the basal layer showing cells similar to ameloblasts with reversed polarity

include tumors (Fig. 6.15A).

with

mixed

radiodensity

Histopathological Features The epithelial lining has characteristic odontogenic features with a prominent basal layer consisting of palisaded columnar or cuboidal cells and hyperchromatic nuclei which are polarized away from the basement membrane (Fig. 6.15B). The epithelium may be regular 6 to 8 cells thick over part of its length and be continuous with parts that may be very thin and others that are considerably thickened. Budding from the basal layer into the adjacent connective tissue and epithelial proliferations into the lumen are frequently seen. Multiple daughter cysts may be present within the fibrous wall and a foreign-body reaction to herniated ghost cells may be conspicuous. Melanin deposits are sometimes present in the epithelial lining. The most remarkable feature of the CCOT is the presence of ghost cells which are found in groups, particularly in the thicker areas of the epithelial lining. The spinous cells in such situations may be widely separated by intercellular oedema and the epithelium around the ghost cells is often convoluted. The ghost cells or shadow cells are enlarged, ballooned, ovoid or elongated epithelial cells. They are eosinophilic and although the cell outlines are usually well defined, they may

sometimes be blurred so that groups of them appear fused. A few ghost cells may contain nuclear remnants but these are in various stages of degeneration and in the majority all traces of chromatin have disappeared leaving only a faint outline of the original nucleus. The ghost cells represent an abnormal type of keratinization and have an affinity for calcification. Atubular dentinoid (dysplastic dentine) is often found in the wall close to the epithelial lining and often in relation to the epithelial proliferations. It is frequently described as being found, particularly in contact with masses of ghost cells, then the tumor is better described as a dentinogenic ghost cell tumor. Calcification within ghost cells is common. The cells are positive for cytokeratins and involucrine which is characteristic of terminal differentiation of keratinocytes. Some ghost cells in the linings of COCs are strongly stained with amelogenin, a protein that is unique to enamel matrix. Therefore, the presence of ghost cells in jaw tumors represents evidence of ameloblastic differentiation.

Treatment Calcifying cystic odontogenic tumor is treated by surgical enucleation or local excision. In the presence of a complex odontome, conservative removal is still adequate. An ameloblastoma or one of its variants with foci of ghost cells must

be treated as a conventional ameloblastoma rather than CCOT.

Key features helpful in diagnosis • Majority of patients in 2nd and 3rd decades • Usually presents as a unilocular radiolucency with radiopaque foci • Most remarkable feature is the presence of ghost cells • Atubular dentinoid (dysplastic dentine) is often found in contact with masses of ghost cells.

DEnTinOgEnic gHOST cEll TUMOr Dentinogenic ghost cell tumor (DGCT) was considered a solid variant of the calcifying odontogenic cyst in the past. DGCT is a locally invasive neoplasm characterized by ameloblastoma-like islands of epithelial cells in a mature connective tissue stroma. Aberrant keratinization may be found in the form of ghost cells in association with varying amounts of dysplastic dentine.

Clinical Features Dentinogenic ghost cell tumor (DGCT) occurs as an intraosseous and less commonly as an extraosseous variant. The age range is from the second to the ninth decade. DGCT is somewhat more common in men than in women. It may

A

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Box 6.8: Calcifying cystic odontogenic tumor

occur in any tooth-bearing area of the jaws (Fig. 6.16A). The extraosseous variant shows a predilection for the anterior part of the jaws, while the intraosseous variant most often affects the canine to first molar region. The tumor is usually asymptomatic. The extraosseous variant presents as sessile, sometimes pedunculated, exophytic nodule of the gingival or alveolar mucosa. There may be bony expansion and in some cases resorption of cortical bone with extension into soft tissues. Adjacent teeth may be displaced and mobile.

Radiological Features Radiographs of extraosseous DGCT show saucerization of the underlying bone in about 20 percent of the cases. Teeth in the affected area may be displaced. Radiographs of intraosseous DGCT show a radiolucent to mixed radiolucent/radiopaque appearance depending on the amount of calcification. The borders are usually well-demarcated. Most are unilocular. Resorption of adjacent teeth is a common finding.

Histopathological Features There is no difference between the microscopic features of the intra- and extraosseous variants. Sheets and rounded islands of odontogenic epithelium are seen in a mature connective tissue. The epithelium of the tumor islands resembles that of an ameloblastoma, mitoses

B Figs 6.16A and B: Dentinogenic ghost cell tumor. (A) A large lesion in the anterior mandible; (B) in addition to the features of ccOT. Note: Presence of dentine

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are not seen. Small cysts may form in the epithelial islands. A characteristic feature is the transformation of epithelial cells into ghost cells. Individual, as well as large islands of ghost cells, may be seen. Where basal layer cells are transformed into ghost cells the basement membrane disappears. When ghost cells extrude into the fibrous connective tissue a foreign body reaction can be seen. Some ghost cells undergo calcification. DGCT forms dysplastic dentine in small amounts (Fig. 6.16B) where ghost cells can become trapped. DGCT can be distinguished from an ameloblastoma by the presence of large numbers of ghost cells and dysplastic dentine but it may be difficult to distinguish from a multicystic calcifying cystic odontogenic tumor (CCOT). Malignant transformation of a DGCT into an odontogenic ghost cell carcinoma occurs rarely.

Treatment Intraosseous DGCT may require wide local resection, particularly if the tumor is radiologically ill-defined. Recurrences have been reported in some intraosseous cases, and malignant transformation has been documented. Box 6.9: Dentinogenic ghost cell tumor Key features helpful in diagnosis • A locally invasive neoplasm characterized by ameloblastoma-like islands of epithelial cells in a mature connective tissue stroma • Aberrant keratinization may be found in the form of ghost cells in association with varying amounts of dysplastic dentine • Age range is from the second to the ninth decade • radiolucent to mixed radiolucent/radiopaque appearance depending on the amount of calcification • A characteristic feature is the transformation of epithelial cells into ghost cells.

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Odontogenic fibroma (OF) is a rare neoplasm characterized by varying amounts of odontogenic epithelial rests in a mature, fibrous

stroma. This has been a controversial diagnosis. At present the term OF is applied to two histological types of lesions namely the epithelium-poor type (formerly termed simple type) and the epithelium—rich type (formerly termed complex or WHO-type). Solid fibrous masses associated with crowns of unerrupted teeth consisting of hyperplastic dental follicles have been misdiagnosed as OF in the past. It has been suggested that the epithelium-poor type of OF derives from the dental follicle whereas the epithelium-rich type arises from the periodontal ligament.

Clinical Features Odontogenic fibroma appears to occur more frequently in children and young adults, although a few cases have been reported in older persons. Female predilection has been noted with a ratio of 2.2:1. It has a preponderance for occurrence in the mandible, with most lesions found in the mandibular molar/premolar area. Topographically, two variants can be distinguished; an intraosseous or central type and an extraosseous or peripheral type. It presents as a slow growing, progressive but painless swelling, often with cortical expansion (Fig. 6.17A).

Radiological Features It appears as a unilocular radiolucent area with well defined, often sclerotic borders. Rarely, the occurrence of calcified material may produce a mixed radiolucent/radiopaque appearance. Larger lesions show scalloping of the margins. Adjacent teeth may be displaced. Some tumors are associated with the crown of an unerupted tooth.

Histopathological Features Despite the controversy, two histological types have been described: the epithelium-poor type and the epithelium-rich type. The epitheliumpoor type of OF is a noninfiltrating connective tissue lesion resembling a dental follicle. It shows minimal cells with dispersed delicate collagen fibers. Fibromyxoid quality is evident due to

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A

B Figs 6.17A and B: Odontogenic fibroma. (A) clinical appearance of a lesion; (B) The tumor is composed of fibrous stroma containing inactive stands of odontogenic epithelium

the presence of ground substances. Remnants of occasional inactive-looking odontogenic epithelium appear as small irregular islands and cords (Fig. 6.17B). Calcifications are seen occasionally. The epithelium-rich type of OF is composed of cellular, fibroblastic connective tissue interwoven with less cellular and often vascular areas. Islands or strands of inactive-looking odontogenic epithelium are very frequently observed. This type shows foci of calcified material considered to be metaplastically produced dysplastic cementum/ osteoid/dentine. The rarity of the central odontogenic fibroma excludes it from most differential diagnosis lists. Most presentations suggest the more common radiolucent odontogenic cysts and tumors such as odontogenic keratocyst, ameloblastoma, or odontogenic myxoma as well as ameloblastic fibroma. In younger individuals, the presentation also suggests central giant cell granuloma.

Treatment Odontogenic fibromas can be treated by enucleation and curettage. They readily separate from their bony crypt and show no evidence of bony infiltration. Recurrence rate is considered low.

Box 6.10: Odontogenic fibroma Key features helpful in diagnosis • Occurs in children and young adults • Female predilection • Presents as a slow growing progressive swelling • Appears as a unilocular radiolucency with well-defined sclerotic borders • Epithelium-poor type resembles a dental follicle and epithelium-rich type is cellular.

ODOnTOgEnic MyxOMA Odontogenic myxoma (OM) is a benign neoplasm arising from odontogenic mesenchymal tissue with similar growth characteristics, clinical and radiographic presentation to those of ameloblastoma. It shows infiltrative growth but does not metastasize. Myxomas of jaws, by contrast, show a close structural resemblance to dental mesenchyme, occasionally contains epithelial rests, affect the tooth-bearing areas of the jaws and a tooth is frequently absent. In 1947, Thoma and Goldman first described myxomas of the jaws. Since then OM has been a subject of continuous scientific debate and has been discussed avidly. OM is an intraosseous neoplasm characterized by stellate and spindleshaped cells embedded in an abundant myxoid or mucoid extracellular matrix. When a

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relatively greater amount of collagen is evident, the term myxofibroma may be used. Evidence which support odontogenic origin has been perpetuated by almost exclusive occurrence in the tooth-bearing areas of the jaws, frequent occurrence in young individuals and association with an unerupted tooth or a developmentally absent tooth, histologic resemblance to dental mesenchyme, especially the dental papilla; and the occasional presence of sparse amounts of odontogenic epithelium. The neoplasm’s odontogenic derivation is believed to originate from the primitive mesenchymal portion of the developing tooth germ (dental follicle, dental papilla, periodontal ligament) as an inductive effect of nests of odontogenic epithelium on mesenchymal tissue or as a direct myxomatous change of fibrous tissue in an odontogenic fibroma. While myxomas do occur in long bones, these are rare and are thought to arise from pluripotential mesenchymal stem cells. The jaws also contain a small population of nonodontogenic pluripotential mesenchymal stem cells that may give rise to a myxoma. However, the much greater incidence of myxomas in the jaws parallels the much greater amount of primitive mesenchyme associated with 20 primary and 32 permanent tooth formations, increasing the likelihood of a myxoma. Though unproven, myxomas in the jaws are thought to originate from odontogenic mesenchyme rather than from somatic mesenchyme and are thus termed OMs. The frequency of OM varies in different parts of the world between 3 to 20 percent of all odontogenic tumors. In most studies, OM is the third most frequent odontogenic tumor (after odontoma and ameloblastoma).

Clinical Features Small OMs are asymptomatic. Large OMs cause painless expansion. Cortical perforation may occur when the tumor is large. The age range varies from 1 to 73 years, with a mean age of 30 years. The majority is diagnosed in the 2nd to 4th decades. Cases in individuals younger than 15 years are common, in contrast to the

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rarity of ameloblastomas in that age group. OM is slightly more common in females. Two-thirds of OMs are located in the mandible. The myxoma differs from the ameloblastoma in site preference. While ameloblastoma is much more commonly seen in the third molar areas, particularly in the mandible, odontogenic myxoma is evenly distributed throughout the jaws. Tooth displacement and root resorption may be seen. Some cases show displacement of the inferior alveolar canal, indicative of its benign nature.

Radiological Features The radiographic features of OM are variable, ranging from small unilocular lesions to large multilocular neoplasms, which often displace teeth or, less frequently, resorb roots. The multilocular trabecular pattern has been described as honey comb, soap bubble, tennis racket, spider web and stepladder pattern (fine residual bony trabeculae arranged at right angles to one another) in appearance (Fig. 6.18A). Most multilocular myxomas are greater than 4.0 cm whilst unilocular myxomas tend to be smaller. The borders of the tumor are usually well-defined and corticated but can be poorly defined or diffuse. Larger OMs may present with periosteal reactions. Only 5 percent of myxomas are associated with unerupted teeth. CT may reveal fine bony septae and allows for anatomic delineation. Advanced imaging studies such as CT and MRI should be used to clearly define tumor margins and to identify the true extent of the myxoma before surgery is performed. The radiographic differential diagnosis due to multilocular radiolucency strongly suggests an ameloblastoma or keratocystic odontogenic tumor. If the individual is younger than 15 years, the possibility of an ameloblastic fibroma increases. Other multilocular radiolucent lesions include central giant cell granuloma (increasingly likely in individuals between 5 and 15 years of age) and central hemangiomas (cavernous or arteriovenous types), which may also present as “honeycombed’’ radiolucencies.

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A

B Figs 6.18A and B: Odontogenic myxoma. (A) radiographically it presents as a multilocular radiolucency; (B) note the marked myxoid stroma and cells with long cytoplasmic processes

Histopathological Features Odontogenic myxoma is usually a well delineated, nonencapsulated gray-white to tanyellow mass that can be rubbery, soft, or gelatinous in texture. The margins usually are ill defined in gelatinous specimens. On the cut surface, it is typically glistening, translucent, homogeneous and depending on the amount of collagen present, fine white bands of collagen may be visible macroscopically. OM is characterized by randomly oriented stellate, spindle-shaped and round cells with long, fine, anastomosing pale or slightly eosinophilic cytoplasmic processes extending from the centrally placed nucleus (Fig. 6.18B). Cells are evenly dispersed in an abundant mucoid or myxoid stroma that contains only a few fine collagen fibres. Binucleated cells, mild pleomorphism and mitotic figures may occur. Rests of odontogenic epithelium are not obvious in most lesions and are not required for establishing the final diagnosis. Some OMs may permeate into the marrow spaces in a pseudomalignant pattern. OMs are unencapsulated and extend to surrounding bone by expansion rather than cellular growth, possibly as a result of the large content of hyaluronic acid. Some OMs have a tendency to produce collagen fibres and are designated

myxofibroma. There is no evidence that more collagenous variants behave differently. Odontogenic myxoma is strikingly similar microscopically to myxoid, enlarged or ‘hyperplastic’ dental follicle and the dental papilla of a developing tooth. Misdiagnosis of these entities should be avoided by correlation with the clinical and radiographic features. The clinical differential diagnosis is essentially similar to that of ameloblastoma. The microscopic differential diagnosis should also include myxoid nerve sheath tumors, chondromyxoid fibroma, lowgrade myxoid fibrosarcoma and other myxoid sarcomas.

Treatment Curative treatment of an odontogenic myxoma is accomplished by resection with 1.0 to 1.5 cm bony margins. Recurrence is expected with enucleation and curettage procedures but may not be clinically detected for 5 years or more. Seeding of tumor cells can occur because of the loose gelatinous consistency of the tumor, resulting in unresectable recurrences. Therefore, enucleation and curettage is not advised. Recurrence rates from various studies average about 25 percent but in spite of this, the prognosis is good. Recurrence usually follows incomplete removal within two years but may occur much later.

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Box 6.11: Odontogenic myxoma Key features helpful in diagnosis • Majority of patients in the 2nd to 4th decades • ranges from small unilocular lesions to large multilocular neoplasms • Stellate and spindle shaped cells evenly dispersed in an abundant mucoid or myxoid stroma with varying amounts of fine collagen fibers • Although a benign neoplasm, it exhibits insidious local invasion by the loose, gelatinous nature of tissue but does not metastasize.

BEnign cEMEnTOBlASTOMA Benign cementoblastoma (BC) is characterized by proliferation of cementoblasts forming disorganized cementum around the apical one half of a tooth root. Described initially in 1930 by Norberg, CB is a rare tumor of mesenchymal odontogenic origin consisting of cementum tissue with functional cementoblasts. CB accounts for 0.2 percent and 6.2 percent of odontogenic tumors. True cementoma is a synonym for BC. Cementoblastomas are odontogenic tumors and are derived from ectomesenchymal cells of the periodontium, including cementoblasts. It is thought to evolve in three stages. The first stage is characterized by periapical osteolysis, followed by a cementoblastic stage and then inactive stage of maturation and calcification. BC is considered a neoplasm with unlimited growth potential. Its etiology is unknown and trauma does not seem to play a role.

Radiological Features Radiographically, the tumor is well-defined and is mainly of a radiopaque or mixeddensity, surrounded by a thin radiolucent zone. Mixed radioopque-radiolucent lesion may be amorphous or may have a wheel-spoke pattern. Root resorption, loss of root outline and obliteration of the periodontal ligament space are common findings. The distinguishing feature of a CB is its peripheral radiolucent margin to adjacent bone and its obliteration of one half of the root. These features distinguish it from other radiopaque lesions that may become superimposed over tooth roots, such as osteoblastoma, ossifying fibroma and odontoma. These features also distinguish a small CB from hypercementosis and focal bone sclerosis, so called condensing osteitis.

Histopathological Features Benign cementoblastoma has a thin fibrous capsule that is usually continuous with the periodontal membrane. The tumor consists of sheets of cementum-like material continuous with the root. It consists of dense masses of acellular cementum-like material in a fibrous, sometimes rather vascular stroma that may contain multinucleated cells (Fig. 6.19). Tumor mass blends with the root showing simultaneous root resorption. Invasion of the root canal is common. Proliferating cementum is lined

Clinical Features The most common finding is a painful swelling at the buccal and lingual/palatal aspect of alveolar ridges. Vitality of involved tooth remains intact. Lower-lip paresthesia or a pathological fracture of the mandible is rarely reported. The age ranges from 8 to 44 years. There is no distinct gender predilection. The majority of CBs are located in the mandible, particularly related to the permanent first molar. Association with a primary tooth is exceptionally rare.

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Fig. 6.19: cementoblastoma. irregularly arranged cementum in a fibrovascular stroma

Treatment Treatment of choice is early surgical removal due to its capacity for persistent growth, expansion and involvement of adjacent structures. The tumor is readily enucleated and it usually does not recur. Because of its capsule, apparently bulbous mass is readily separated from the surrounding bone. In case of incomplete removal, together with the associated tooth, recurrence is not uncommon. Box 6.12: Benign cementoblastoma Key features helpful in diagnosis • Tumor with proliferation of cementoblasts forming disorganized cementum. • Presents in 2nd decade. • radiopaque or mixed-density, surrounded by a thin radiolucent zone. • Dense masses of acellular cementum-like material in a fibrous stroma.

MAlignAnT AMElOBlASTOMA (METASTASizing AMElOBlASTOMA) Ameloblastoma is considered as a benign tumor that can be locally invasive and shows high recurrence rate depending on initial type of treatment. Ameloblastomas rarely metastasize or undergo malignant transformation. This malignant behavior is present in less than 2 percent of ameloblastomas. Emura first described metastasis of ameloblastoma to cervical lymph nodes. In 1932 Vorzimar and Perla described metastasis to lungs. Malignant ameloblastoma (MA) is an ameloblastoma that metastasizes in spite of a benign histologic appearance. In the WHO classification (2005) it is included under odontogenic carcinomas. Origin of MA is most likely to be the same as that of nonmalignant ameloblastoma, however

precise mechanism by which slow growing cytologically none malignat tumor spreads to distant location is not clear. MA is usually preceded by multiple local recurrences of primary tumor hence, it is suggested that possible mechanism of metastasis may be related to local recurrence which increases aggressiveness or malignant behavior of the tumor and also spillage or implantation of tumor cells in blood or lymphatic during surgical intervention. Metastasis occurs through blood vessels, lymphatics or by aspiration.

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by numerous plump cells. Cementoclasts may also be present, and reversal lines are prominent. Some of the cemental material may be uncalcified, particularly at the periphery of the mass. Tumor cementum is often arranged perpendicular to the capsule. The fibrous stroma is highly vascular. In the more mature parts of the tumor, basophilic reversal lines may produce a pattern similar to Paget’s disease of bone.

Clinical Features Malignant ameloblastoma do not show any specific clinical features distinct from conventional ameloblastoma. There is predilection for occurrence of tumor in the mandible than maxilla (7.6:1). Mean age of occurrence is 34 years and male to female ratio is 1.2:1. Common signs and symptoms are swelling of jaw, pain, delayed tooth eruption, ulceration and tooth mobility. Factors which may contribute for metastasis are duration of tumor, extend and size of tumor and initial type of surgery. Most common sites of metastasis are lungs (75%), bone (25%), cervical lymph node (18%), liver (11%), brain (10%), other nodes, spleen and kidney (3.5%). The time lapse from diagnosis to metastasis appears to be 9 to 10 years.

Radiological Features Radiological features are similar to conventional ameloblastoma. CT and MRI are useful in accurate evaluation of the extension of tumor.

Histopathological Features The histopathological features are indistinguishable from conventional ameloblastoma. MA does not show cytological atypia or mitotic activity. It is the clinical behavior which determines its malignant status (Fig. 6.20).

Treatment Adequate initial surgical treatment of primary neoplasm plays the most important role in prevention of postoperative metastasis. Radical resection and primary reconstruction is the most

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applied when morphologic features of typical ameloblastoma are noted in some areas.

Clinical Features

Fig. 6.20: Malignant ameloblastoma. cytologically benign follicles of ameloblastoma in a lymph node

accepted therapeutic modality. Neck dissection for cervical lymph nodes and lobectomy of lung metastasis is done with preservation of lung function. Box 6.13: Malignant ameloblastoma Key features helpful in diagnosis • Majority of patients are in 3rd and 4th decade • radiologic features are similar to conventional ameloblastoma • Histopathological features are indistinguishable from conventional ameloblastoma • Does not show cytological atypia or mitotic activity.

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Ameloblastic carcinoma (AC) is the malignant epithelial odontogenic tumor that histologically retain the features of ameloblastic differentiation and exhibits cytological features of malignancy. The term AC was introduced by Shafer in 1974 and WHO (2005) recognises different subtypes. They are ameloblastic carcinoma (a) primary type, ameloblastic carcinoma (b) secondary type (dedifferentiated) intraosseous and ameloblastic carcinoma—secondary type (dedifferentiated) peripheral. AC may arise in a pre-existing benign ameloblastoma. The term “dedifferentiated ameloblastoma” has been

Ameloblastic carcinomas are twice more common than malignant ameloblastoma. There is a predilection for occurrence in the mandible over maxilla. The mean age of occurrence is in the range of 15 to 84 years. It is more common in males with male-to-female ratio of 1.4:1. Common signs and symptoms are, swelling, pain, trismus, dysphonia, rapid growth and paresthesia.

Radiological Features The radiologic features show ill-defined large multilocular radiolucency, perforation of cortical plates, extension into neighboring tissue and occasionally foci of calcification.

Histopathological Features Ameloblastic carcinoma shows odontogenic epithelial cells arranged in the form of islands, cords and sheets with infiltrative pattern within the stroma of mature fibrous tissue. Island and cords show outer layer of tall columnar to cuboidal ameloblast like cells. The central cells are stellate reticulum like in appearance and hypercellular without an orderly pattern. The epithelial cells show characteristics features of malignancy such as nuclear hyperchromatism, mild pleomorphism, and increased mitotic activity with occasional abnormal forms (Fig. 6.21). Mitotic figures may attain a count of 2 to 5 per high-power field. In some cases individual cell keratinization and keratin formation may be seen. Necrosis and dystrophic calcifications may also be observed. Rare cases of AC may reveal clear cell differentiation. Aneuploidy has been found to be more frequently present in the ameloblastic carcinoma and may be used as a strong predictor of malignant potential of a questionable lesion.

Treatment The treatment of choice is radical surgery with neck dissection. Local recurrences and

Solid Type

Fig. 6.21: Ameloblastic carcinoma. Strands of ameloblastic epithelium showing cytological atypia with mitotic figures

metastasis to the neck and lung seem to be common. Box 6.14: Ameloblastic carcinoma Key features helpful in diagnosis • Presents as a large ill-defined multilocular radiolucency • Histologically retains the features of ameloblastic differentiation but exhibits cytological features of malignancy • Demonstrates greater cytologic atypia and mitotic activity.

PriMAry inTrAOSSEOUS SqUAMOUS cEll cArcinOMA Primary intraosseous squamous cell carcinoma (PIOSCC) is a central jaw carcinoma derived from odontogenic epithelial remnants. Central squamous cell carcinoma of the jaw was first described by Loos in 1913. Pindborg et al suggested the term primary intraosseous carcinoma, which was accepted by the World Health Organisation (WHO) classification in 1992. In the WHO classification (2005), it is included under odontogenic carcinomas and subcategories include primary intraosseous squamous cell carcinoma—solid type, primary intraosseous squamous cell carcinoma derived from keratocystic odontogenic tumor and primary intraosseous squamous cell carcinoma derived from odontogenic cysts.

The male:female ratio approaches 2:1 with a mean age of 55 years, although cases have been encountered during infancy. PIOSCC is more often found in the body and posterior mandible than the maxilla. Maxillary cases are most frequently seen in the anterior segment. Most cases are asymptomatic and are discovered incidentally during the course of routine dental radiographs. Persistent pain and swelling of the jaw seems to be an important presenting symptom of PIOSCC. Other symptoms that may be observed are perineural invasion of the inferior alveolar nerve causing paresthesia of the lip. It spreads both regionally and distantly.

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Clinical Features

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Radiological Features Radiographically, PIOSCCs are osteolytic. The margins of the radiolucency are often irregular, diffuse, ill defined and noncorticated. Larger extensive lesions may show cortical bone expansion and destruction.

Histopathological Features The PIOSCC is characterized by islands of neoplastic squamous epithelium with the features of squamous cell carcinoma. The PIOSCC may reveal a distinct odontogenic pattern with basal-type cells forming alveoli or arranged in to plexiform pattern with palisading of the peripheral cells. Keratinization is not marked. In order to arrive at the diagnosis, the possibility of metastatic squamous cell carcinoma has to be excluded.

Derived from Keratocystic Odontogenic Tumor When a squamous cell carcinoma arises within the jaw bones without connection to the oral mucosa in the presence of a keratocystic odontogenic tumor (KCOT) is termed as Primary intraosseous squamous cell carcinoma derived from keratocystic odontogenic tumor. Although the epithelium of the KCOT seems to have a higher mitotic activity than that of other odontogenic cysts, there is little evidence that

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the KCOT is associated with malignant change more often than any other type of odontogenic cyst.

to the oral mucosa, and in the presence of an odontogenic cyst other than keratocystic odontogenic tumor.

Clinical Features

Clinical Features

Most of these lesions are encountered in older patients, 40 years and above, with male predilection. The mandible is involved much more frequently than the maxilla. Early lesions are generally insidious, usually presenting as a benign odontogenic cyst and the diagnosis of carcinoma is only made after microscopic examination. In others, symptoms such as pain, swelling, loosening of teeth, nonhealing extraction sockets, and paresthesia are common.

In a series of 28 patients the mean age was 56 years and age ranges from 4 to 90 years. Male-to-female ratio is almost 2:1. Ratio of mandibular to maxillary lesions is 3:1. Clinical symptoms are nonspecific and include pain and swelling.

Radiological Features Radiographically, early lesions are often indistinguishable from any odontogenic cyst. In some, the margins of the radiolucent defect appear irregular and ragged. Late lesions are obviously destructive. A multilocular appearance with cortical destruction and frequent soft tissue extension characterizes these late-stage neoplasms.

Histopathological Features Histopathologically, it shows a well differentiated squamous cell carcinoma with recognizable KCOT. Epithelial dysplasia of varying degrees is often present. The main differential diagnosis should include squamous odontogenic tumor, central high-grade mucoepidermoid carcinoma and metastatic lesions.

Treatment The treatment of choice for the PIOSCCs ex KCOT is radical surgery with or without neck dissection. Due to the small number of cases of PIOSCCs ex KCOTs, no relevant information on recurrence rate, frequency of metastasis, or prognosis are available. Long-term follow-up, as with patients with oral cancer, is mandatory.

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This is defined as a squamous cell carcinoma arising within the jaws without connection

Radiological Features The radiographic features may mimic any type of odontogenic cyst. PIOSCCs ex odontogenic cysts are nonspecific and are characterized by a radiolucency surrounded by a relatively well defined radiopaque border.

Treatment Odontogenic cysts with PIOSCCs can not be differentiated clinically and radiographically from conventional cysts, most of them are enucleated at first stage surgery. After the histopathologic diagnosis has been established the treatment of choice for the PIOSCCs ex odontogenic cyst is radical surgery.

clEAr cEll ODOnTOgEnic cArcinOMA Clear cell odontogenic tumor (CCOT), first described as a separate entity by Hansen et al and later by Waldron et al in 1985, and is an unusual intraosseous tumor histologically characterized by odontogenic epithelial cells with clear vacuolated cytoplasm. Since all the cases showed locally aggressive behavior, but no evidence of lymph node or distant metastasis, they considered CCOT to be a benign, locally aggressive lesion. In the past it was called clear cell ameloblastoma and clear cell odontogenic tumor and was considered a benign tumor in the previous WHO classification of 1992. Additional cases of CCOT, which were published later, also confirmed the tumor’s potential to metastasize. As a result, the tumor is now considered to be a malignant neoplasm, and the name has been changed to clear cell odontogenic carcinoma (CCOC).

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Clinical Features

Radiological Features Radiographically, CCOC appears as a poorly delineated unilocular or multilocular radiolucent lesion with prominent bone destruction. Root resorption and root divergence is present in a majority of cases.

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Clear cell odontogenic tumor tends to occur in older adults; the mean age at diagnosis is approximately 60 years and ranges from 17 to 89 years. The tumor has a strong female predilection. The male:female ratio is 1:1.6. The most frequently affected site is the mandible, and the maxillary:mandibular ratio is 1:7.7 with the posterior region of the mandible consisting of 90 percent of the cases. The CCOC usually causes swelling of the jaws, loosening of teeth and associated pain in some patients. Fig. 6.22: clear cell odontogenic carcinoma. islands of clear cells with some islands showing peripheral palisading and reversed polarity of basal cells

renal cell carcinoma and clear cell variant of calcifying epithelial odontogenic tumor.

Histopathological Features

Treatment

The majority of tumors show biphasic pattern. A classic case of CCOC demonstrates budding and branching cords, islands and sheets of neoplastic polygonal epithelial cells. Lesional cells exhibit central to eccentric small dark uniform nuclei and there is little evidence of nuclear pleomorphism or mitotic activity. The cells exhibit abundant pale cytoplasm with clear cells showing distinct cell borders. Cords of dark-staining basaloid cells with scanty eosinophilic cytoplasm may also be seen. Tumor islands display peripheral ameloblastomatous palisaded columnar cells (Fig. 6.22). However, no evidence of central stellate reticulum, squamous differentiation or cystic change is observed. Some tumors contain (monophasic pattern) islands of entirely clear cells. Many of the tumor cells contain abundant delicate and coarse diastase degradable PAS-positive granules, which are negative for mucin and amyloid. Cytokeratin 19 and EMA immunostaining pattern together with histopathological features may help in the final diagnosis of CCOC. Since clear cells are frequently seen in other neoplasms in the oral and maxillofacial region, it is important to rule out lesions such as salivary gland tumors, melanotic tumors, metastatic

The CCOC exhibits an aggressive growth pattern and frequently recurs. The tumor can metastasize to regional lymph nodes and lungs, as well as to bone. Therefore radical resection with tumor-free margins is the treatment of choice, and long-term follow-up is mandatory. Adjuvant radiotherapy is a rational option for tumors that have eroded cortical bone. Box 6.15: Clear cell odontogenic carcinoma Key features helpful in diagnosis • Presents as poorly delineated unilocular or multilocular radiolucent lesion with prominent bone destruction • Occurs in older adults • Female predilection • composed of cells showing uniform nuclei and clear cytoplasm • Demonstrates an aggressive clinical course, with invasion of contiguous structures and a tendency to recur.

gHOST cEll ODOnTOgEnic cArcinOMA Ghost cell odontogenic carcinoma (GCOC) is a malignant odontogenic epithelial tumor

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with features of calcifying cystic odontogenic tumor and/or dentinogenic ghost cell tumor. Synonyms are calcifying ghost cell odontogenic carcinoma, malignant epithelial odontogenic ghost cell tumor, carcinoma arising in a calcifying odontogenic tumor, malignant calcifying odontogenic cyst, malignant calcifying ghost cell odontogenic tumor and dentinogenic ghost cell ameloblastoma.

Clinical Features The tumor is rare and it occurs more commonly in Asians than other races. There is a predilection for occurrence in the maxilla than mandible (2:1). The mean age of occurrence at the time of diagnosis is 37 years ranging from 13 to 73 years. Male-to-female ratio is 2.6:1. Common symptoms are swelling of jaws with paresthesia, displacement of roots and root resorption. Large lesions in the maxilla often destroy the sinus wall and involve nasal and orbital cavities and extend to adjacent structures. Biological behavior of the tumor is variable from slowly growing locally invasive tumor to highly aggressive rapidly growing tumor. It shows expansile multiloculated to poorly demarcated radiolucency with radiopaque material.

Histopathological Features A malignant neoplasm generally characterized by two types of epithelial cells. The malignant component of some tumors is found in nests, strands, and islands of varying size dominated by small, round, undifferentiated basaloid cells with hyperchromatic nuclei, frequent mitoses, and cytologic atypia. Masses of ghost cells, some of which may show dystrophic calcification, often intermingle with small basaloid cells. Small deposits of dentinoid in close association with ghost cells may or may not be present. In some tumors, the epithelial component is formed predominantly by large cells with vesicular nuclei admixed with few cells showing squamous differentiation. Areas of necrosis with an acute and chronic inflammatory cell infiltrate are frequent findings. In addition to the malignant epithelial component, one may

find a typical, simple unicystic type of calcifying odontogenic cyst. The cyst is lined by stratified epithelium that has a distinct basal cell layer of columnar cells overlaid by a loose, stellate reticulum-like epithelium of variable thickness. Foci of ghost cells are scattered within the epithelial lining. Nests of tumor cells invade and destroy the surrounding bone, skeletal muscle, and connective tissue. The stroma consists of a mature, fibrous connective tissue which may occasionally show desmoplasia.

Treatment The treatment of the tumor is by initial radical surgery combined with radiation therapy. The biologic behavior of GCOC appears to be unpredictable. Some cases have been associated with long-term survival following definitive surgery. However, others show poor clinical outcomes with locally recurrent disease or metastases. Box 6.16: Ghost cell odontogenic carcinoma Key features helpful in diagnosis • Ameloblastic carcinoma with ghost cell keratinization • Presents as an expansile multiloculated to poorly demarcated radiolucency mixed with radiopaque material • Variable biologic behavior.

AMElOBlASTic FiBrOSArcOMA Ameloblastic fibrosarcoma (AFS) is an odontogenic tumor with a benign epithelial and a malignant ectomesenchymal component. It is regarded as the malignant counterpart of the ameloblastic fibroma.

Clinical Features There is a wide age range (3–89 years) with a mean age of 27.5 years at diagnosis. Patients with AFS derived from a pre-existing AF have a mean age of 33 years. Sixty-three percent of reported cases have occurred in males and 37 percent in females. The mandible is the most commonly affected site (78%), followed

Radiological Features

one case with histologic documentation of metastasis to lymph nodes. Due to the fact that, metastasis is rare in AFS survival seems to be good.

AMElOBlASTic FiBrODEnTinOSArcOMA AnD FiBrO-ODOnTOSArcOMA

Radiographically, radiolucency with irregular and indistinct margin is characteristic. Large radiolucencies with a multilocular appearance and gross expansion and thinning of the cortical bone may be seen. In cases where radioopacities are observed within radiolucent areas, diagnosis of ameloblastic fibrodentinosarcoma or ameloblastic fibro-odontosarcoma is likely.

Ameloblastic fibrodentinosarcoma (AFDS) and fibro-odontosarcoma (AFOS) are exceedingly rare malignant odontogenic sarcomas. The WHO classification of 1992 differentiated between odontogenic sarcomas without dental hard tissues (ameloblastic fibrosarcomas) and those revealing evidence of dentinoid (ameloblastic fibrodentinosarcoma) or dentinoid plus enameloid fibro-odontosarcoma.

Histopathological Features

Clinical and Radiological Features

The histologic pattern of AFS resembles ameloblastic fibroma in which the epithelial tissue is benign but the connective tissue component is malignant. The malignant ectomesenchymal component consistently takes up more than 70 percent of the tumor area compared to 30 percent by odontogenic epithelium. The epithelium is composed of budding and branching cords of small polygonal epithelial cells admixed with islands and knots. Larger islands have peripheral columnar cells with hyperchromatic nuclei. The mesenchymal component of the neoplasms shows a marked increase in cellularity. A hypercellular connective tissue stroma displaying mitotically active cells surrounds the epithelial component. Recurrent tumors tend to show greater stromal cellularity and mitotic rate.

Pain and swelling are frequently associated with the lesions. Oral mucosal ulceration and or bleeding were usually related to occlusal trauma. Mobility of teeth and tissue proliferation through extraction sockets were noted in some cases. Radiographically, AFDS and AFOS have to be differentiated from ameloblastic fibrosarcoma by the presence of radiopaque foci in an otherwise radiolucent lesion.

Treatment Radical extensive surgery, usually partial or total mandibulectomy or maxillectomy is the treatment of choice. In some cases post surgical radiotherapy or adjuvant chemotherapy should be considered. Metastasis seems to be rare in AFSs. Out of 49 AFS cases, there was only

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by the maxilla (20%). In both jaws the posterior region is the site of predilection. Pain and swelling are the most common findings. Ulceration and bleeding, as well as paresthesia of the lower lip have also been reported. Involvement of cervical and submandibular lymph nodes in cases of AFS seems to be uncommon.

Histopathological Features Both AFDS and AFOS consist of epithelial and ectomesenchymal component, including dentinoid, some of which may be dysplastic. However AFOS shows enameloid in addition to dentinoid material. The epithelial component consists of follicles and strands of odontogenic epithelium as observed in ameloblastic fibromas. Intraepithelial and stromal microcysts may form. Some epithelial islands may show ghost cells representative of a presence of intracellular keratinization. The malignant ectomesenchymal component shows increased cellularity, pleomorphism, hyperchromatism and increased mitotic activity, as in ameloblastic fibrosarcomas.

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Box 6.17: Ameloblastic fibrodentinosarcoma and fibro-odontosarcoma Key features helpful in diagnosis • Exceedingly rare • Pain, swelling, ulceration, bleeding, mobility of teeth • radiographically, presence of radiopaque foci in an otherwise radiolucent lesion • Histological picture resembles ameloblastic fibroma except the presence of cytological atypia.

3.

4.

Treatment The treatment of choice for both AFDS and AFOS is radical surgery.

5.

SElF-ASSESSMEnT qUESTiOnS

6.

1. Give a classification for odontogenic tumors. 2. Discuss the behavior of the different types of ameloblastoma in relation to histopathology. 3. Comment on the statement “Odontome is a hamartoma”. 4. Comment on the statement “Ameloblastic fibroma, ameloblastic fibro-odontoma and odontoma may be a spectrum of a same disease”. 5. Explain the justification of odontogenic keratocyst being regarded as an odontogenic tumor. 6. Describe the clinicopathological findings of adenomatoid odontogenic tumor. 7. Discuss the differential diagnosis of a multilocular radiolucency at the angle of the mandible. 8. Describe the options available for the treatment of an ameloblastoma. 9. Write an account of odontogenic tumors with ghost cell differentiation. 10. What is the difference between malignant ameloblastoma and ameloblastic carcinoma?

SUggESTED rEADing 1. Braunshtein E, Vered M, Taicher S, Buchner. A. Clear cell odontogenic carcinoma and clear cell ameloblastoma: a new case and

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7.

8.

9.

10.

11.

12.

comparative analysis of the literature. J Oral Maxillofac Surg. 2003;61(5):1004-10. Chirapathomsakul D, Sastravaha P, Jansisyanont PA. Review of odontogenic keratocysts and the behavior of recurrences. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006;101:5-9. Eversole LR, Duffey DC, Powell NB. Clear cell odontogenic carcinoma. A clinocpathologic analysis. Arch otolaryngol Head Neck Surg. 1995;121:685-9. Ling Lin Y, Dean K White. Textbook of Odontogenic Tumors: Reichart squamous odontogenic tumor: Oral and Maxillofacial Surgery Clinics of North America. 2004;16: 355-7. Marx, Stern. Oral and Maxillofacial Pathology: a Rationale for Diagnosis and Treatment Ilinos; Quintessence Publishing; 2003. Okada H, Yamamoto H, Tilakaratne WM. Odontogenic Tumors in Sri Lanka: Analysis of 226. Cases J Oral Maxillofac Surg. 2007;65: 875-82. Shear M. The aggressive nature of the odontogenic keratocyst: is it a benign cystic neoplasm? Part 1. Clinical and early experimental evidence of aggressive behavior. Oral Oncology. 2002;38:219-26. Shear M. The aggressive nature of the odontogenic keratocyst: is it a benign cystic neoplasm? Part 2. Proliferation and genetic studies. Oral Oncology. 2002;38:323-31. Siriwardena BS, Tennakoon TM, Tilakaratne WM. Relative frequency of odontogenic tumors in Sri Lanka: Analysis of 1677 cases. Pathol Res Pract. 2012;208(4):225-30. Siriwardena BSMS, Tilakaratne WM, Rajapaksha. Clear cell odontogenic car-cinoma—a case report and review of literature. Int. J Oral Maxillofac Surg. 2004;33: 512-4. Thosaporn W, Iamaroon A, Pongsiriwet S. A comparative study of epithelial cell proliferation between the odontogenic keratocyst, orthokeratinized odontogenic cyst, dentigerous cyst, and ameloblastoma. Oral Diseases. 2004;10:22-6. World Health Organization Classification of Tumors Pathology and Genetics of Head and Neck Tumors Lyon; IARC Press; 2005.

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Fibrocemento-osseous Lesions and Related Conditions WM Tilakaratne

Chapter Outline Classification Cemento-osseous Dysplasias • Periapical Cemental Dysplasia • Focal Cemento-osseous Dysplasia • Florid Cemento-osseous Dysplasia • Familial Gigantiform Cementoma Fibrous Dysplasia • Monostotic and Craniofacial Fibrous Dysplasia • Polyostotic Fibrous Dysplasia Cemento-ossifying Fibroma • Conventional Cemento-ossifying Fibroma • Juvenile Aggressive Cemento-ossifying Fibroma

• Juvenile Trabecular Cemento-ossifying Fibroma (JTOF) • Juvenile Psammomatoid Cemento-ossifying Fibroma (JPOF) Related Conditions • Cherubism • Paget’s Disease • Central Giant Cell Granuloma • Osteopetrosis • Other Conditions Self-assessment Questions

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Fibrous Dysplasia

Fibrocemento-osseous lesions are a very diverse group of lesions of jaw bones. The disease categories vary from developmental, reactive, dysplastic to neoplastic processes. Characteristic features of all the diseases in this category is the replacement of bone by fibrous tissue and subsequent mineralization in this form of bone, cementum or just calcification. Many lesions contain an admixture of these hard tissue components. Further, there are controversies in relation to their classification, diagnosis, and management of these lesions. The definitive diagnosis should be reached with the correlation of clinical findings, histopathological features and radiological/ imaging analysis because of the histological similarities among the different lesions in the group. Diagnosis is important as treatment modalities are different for these conditions and more importantly some lesions in the group may not need any treatment once the diagnosis is established. It should be stressed that in the absence of clinical and radiological information a pathologist should only offer the diagnosis as consistent with a fibrocemento-osseous lesion for a given biopsy. The above approach avoids the possibility of inappropriate treatment for some of the lesions in the group.

• Monoostotic fibrous dysplasia • Polyostotic fibrous dysplasia • Polyostotic fibrous dysplasia with endocrinopathy (McCune–Albright syndrome) • Polyostotic fibrous dysplasia with pigmentation (Jaffe-Lichtenstein syndrome) • Craniofacial fibrous dysplasia.

ClAssiFiCATiOn Cemento-osseous Dysplasias Nonhereditary • Periapical cemental dysplasia • Focal cemento-osseous dysplasia • Florid cemento-osseous dysplasia.

Hereditary Familial gigantiform cementoma.

Fibrocemento-osseous Neoplasms • Conventional cemento-ossifying fibroma • Juvenile aggressive cemento-ossifying fibroma.

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CeMenTO-OsseOus DysPlAsiAs Periapical Cemental Dysplasia (Periapical Cemento-osseous Dysplasia) Periapical cemental dysplasia (PCD) is a reactive fibrocemento-osseous lesion described by Stafne in 1934. Since 1992, the WHO recognized this as a fibrocemento-osseous lesion. This entity was previously described under many different names such as fibrocementoma, periapical osteofibroma, local osteofibroma, periapical fibrous dysplasia, periapical cementifying dysplasia and multiple cementomas. Although aetiology of the condition is unknown, it appears to originate from elements of the periodontal ligament. It is considered as a reactive process.

Clinical and Radiological Features The clinical features of PCD are well-established and remarkably constant. There is a marked predilection for females (14:1) and blacks. The lesions are most often detected in patients over the age of 30 and are rare before the age of 20. The most common presentation is a middle age female with multiple periapical radiolucencies in relation to lower anterior teeth. The affected teeth are vital. A single tooth may be affected but multiple lesions are often the norm. The affected teeth are invariably asymptomatic. Initial presentation of PCD is usually a circumscribed radiolucency in relation to the periapical region. With time it shows increasing amounts of calcification resulting in a progressive pattern that successively evolves from radiolucent to mixed density, to radiopaque (Figs 7.1A and B). The mature lesions show a radiopaque lesion with a radiolucent rim at the periphery. Rarely in some

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B

Figs 7.1A and B: Periapical cemental dysplasia. Multiple radiolucencies in the periapical area of lower anterior teeth. Mature lesions are more radiopaque (Courtesy: Professor Jos hille)

Fig. 7.2: Periapical cemental dysplasia. Thin irregular trabeculae of bone and cementum-like areas in a loosely arranged fibrous stroma

lesions, calcification is not always predictable and in fact they regress, some stay unchanged and some resolve. The size of the lesion usually does not exceed 0.5 cm. However, rare lesions may reach a diameter of 1.0 to 1.5 cm. Depending on the age of the lesion they can be divided in to three phases and histopathological features of these stages are correlated with the radiological findings. The early stage is the radiolucent phase or the osteolytic stage, followed by mixed radiodense lesion and finally the radiopaque stage representing a mature lesion.

Differential Diagnosis

Histopathological Features Histopathological features are not pathognomonic for PCD as other reactive dysplasias share similar features. However, three radiological stages are correlated with histopathology. Stage 1 or the osteolytic stage shows cellular fibrous tissue containing frequent small blood vessels. The lesion is usually unencapsulated and hard tissue formation is not evident. When it matures into a lesion with a mixed radiodensity, evidence of hard tissue formation begins to appear, ranging from dysplastic bone, trabeculae of woven bone and foci of cementum-like tissue (Fig. 7.2). Finally, the bulk of the lesion is replaced by hard tissue with less fibrous and vascular tissue components and the lesion becomes radiopaque.

When a patient presents with classical clinical and radiological features, the clinician may not have any difficulty in arriving at the diagnosis, even without histopathological features unlike other reactive/dysplastic cemento-osseous dysplasias. If the lesion is a single lesion it may mimic the appearances of various other lesions depending on the stage. Periapical granuloma is the nearest differential diagnosis at the radiolucent stage. The affected tooth in PCD is usually vital, unlike in the case of periapical granuloma. Mature lesions and lesions with mixed radiodensity should be differentiated from entities such as condensing osteitis and focal sclerosing osteomyelitis. As rare cases may grow up to 1.5 cm in size and when present as a single lesion, differential diagnosis should include odontogenic tumors with hard tissue formation. Histologically most of the diseases in fibrocemento-osseous lesions have similar histology. However, focal cemento-osseous dysplasia (FCOD) and florid cemento-osseous dysplasia are the nearest differential diagnosis. FCOD is strikingly vascular compared to two other cemental dysplasias.

FibrOCeMenTO-OsseOus lesiOns AnD relATeD COnDiTiOns

A

Treatment and Prognosis Periapical cemental dysplasia (PCD) is a selflimiting condition and very rarely enlarges to

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a clinically palpable lesion. Exceptionally rare cases have been reported to have paresthesia or anaesthesia due to impinging on the mental nerve. Practically treatment is not indicated except taking follow-up radiographs in 6 to 12 months intervals. Box 7.1: Periapical cemental dysplasia Key features helpful in diagnosis • Predilection for middle-aged black females • One or more (0.5 cm or less) circumscribed lesions in periapical areas of vital lower anterior teeth. Painless and accidental findings in radiographs • radiographic appearances may vary from radiolucent, mixed density to radiopaque • histologically, cellular fibrous tissue with woven bone, cementum-like areas and calcifications.

Radiographically, they are usually well circumscribed with or without a sclerotic border and may be radiolucent, mixed radiodense or radiopaque in appearance (Fig. 7.3). Most lesions are less than 1.5 cm in diameter and rarely exceed 2.0 cm.

Histopathological Features Focal cemento-osseous dysplasia (FCOD) is comprised of connective tissue stroma containing loose collagen fibers with sinusoidallike vascular spaces adjacent to thick irregular bony trabeculae and irregular shaped cementoid calcifications (Fig. 7.4). Free hemorrhage

Focal Cemento-osseous Dysplasia Focal cemento-osseous dysplasia (FCOD) often presents as an asymptomatic, focal and circumscribed lesion in tooth bearing areas. FCOD may represent the most common fibrocemento-osseous lesion of jaw bones. This lesion has previously been described by various names such as osseous dysplasia, reaction of bone to injury and localized fibro-osseous cemental lesion. The present name of FCOD was introduced by Tormich and Summerlin in 1989. It is known that some of these lesions have been diagnozed as cemento-ossifying fibroma in the past leading to over treatment, especially if the lesion is diagnosed without adequate clinical and radiological details.

Fig. 7.3: Focal cemento-osseous dysplasia. late stage of FCOD in the edentulous left lower molar area showing radiopaque lesion (Courtesy: Dr rD Jayasinghe)

Clinical and Radiological Features

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Focal cemento-osseous dysplasia (FCOD) shows a high female predilection of 8:1. The condition predominantly occurs in the 4th and 5th decades with an average age of 38. Because of the fact that the lesion is painless and nonexpansile, it is usually discovered during routine radiographic examination. Seventy percent of the cases occur in the tooth-bearing areas, especially in the posterior mandible, although many occur in edentulous areas where a tooth was previously extracted.

Fig. 7.4: Focal cemento-osseous dysplasia. Thin irregular bony-trabeculae and cementum-like tissue arranged in between cellular fibrous-tissue. The lesion is significantly vascular

Differential Diagnosis The main clinical, radiographic, and microscopic differential diagnosis of FCOD appears to be cemento-ossifying fibroma (COF). Although PCD shows similar features to FCOD in occasional cases, proper clinicopathological correlation allows the clinician to come to a definitive diagnosis. The differentiation between FCOD and COF is important as the two lesions are totally different in terms of pathogenesis and behavior. Both lesions are more common in the posterior mandible although a significant number of COFs occur in the maxilla. Both tend to be circumscribed and can be radiolucent, mixed radiodense, or radiopaque. Displacement, root resorption, cortical expansion and characteristically expansion of the inferior border of the mandible may present in COF unlike in FCOD. A notable difference between the two lesions is the intraoperative findings. Ossifying fibroma tends to shell out as a solid mass, whereas FCOD is adherent to surrounding bone, and as a result, is removed in gritty, hemorrhagic tissue fragments. In FCOD, lesional tissue tends to blend with the cortex and medullary bone in contrast to the encapsulation evident in COF. As mentioned previously, FCOD is composed of loose collagen fibers with sinusoidal-like vascularity adjacent to thick irregular bony trabeculae and uneven cementoid calcifications whereas COF shows a hypovascular, uniformly cellular, often storiform stroma with intermixed dense collagen. The calcified components are often thin, separate, bony trabeculae with osteoblastic rimming and calcifications/cementum-like areas. The definitive diagnosis should be reached with clinico-pathological correlation.

Treatment and Prognosis Focal cemento-osseous dysplasia (FCOD) does not need treatment once the diagnosis is established. The lesions typically persist without remarkable change and sometimes regress.

However, occasional cases have subsequently developed into florid cemento-osseous dysplasia (FLCOD). Progression from a solitary to multiple site involvement supports the theory of FCOD as being part of a spectrum of a single disease process. Box 7.2: Focal cemento-osseous dysplasia Key features helpful in diagnosis • Painless, nonexpansile, usual location is posterior part of the mandible • Most often presents as a circumscribed radiolucency with opacities, less than 1.5 cm in diameter • Difficult to remove surgically, resulting in small hemorrhagic gritty fragments in the biopsy • Thick curvilinear trabeculae of woven and/or lamellar bone and/or oval calcifications in a more loosely arranged fibrous stroma than in cemento-ossifying fibroma • sinusoid-like vascular spaces adjacent to bony trabeculae and free hemorrhage.

Florid Cemento-osseous Dysplasia

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is interspersed throughout the lesion. Increased vascularity in the lesion is obvious as macroscopic features also show brown hemorrhagic fragments. Presence of simple bone cysts is a feature in some cases.

Florid cemento-osseous dysplasia (FLCOD) presents as multiple masses of cementoosseous tissue in tooth bearing areas of jaw bones, frequently affecting the posterior regions. FLCOD has been recognized under many names including multiple enostosis, chronic diffuse sclerosing osteomyelitis/osteitis, gigantiform cementoma and sclerotic cemental masses. The current term florid cemento-osseous dysplasia was introduced by Melrose et al in 1976.

Clinical and Radiological Features Florid cemento-osseous dysplasia commonly occurs in middle age females. The majority of the patients are in the fourth and fifth decades with a mean age of 42 years. It shows bilateral symmetrical involvement in most cases. However, it is not unusual to find cases with extensive involvement of all four posterior quadrants of jaws. Many patients are partially or totally edentulous when the condition is first discovered. Until the lesions expand to a noticeable size, the diagnosis may be an accidental finding in radiographs.

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Radiographically, it shows all the phases described previously under PCD. Lesions start as variably well demarcated and corticated radiolucencies with patchy sclerosis developing within them with time. In mature lesions the margin is diffuse and poorly defined. The most common radiographic presentation is multiple confluent sclerotic lobular masses admixed with less well-defined areas of a mixed radiodense pattern in different sites (Figs 7.5A and B). Well-defined radiolucent areas representing simple bone cysts are a frequent finding. The above feature is usually seen in mature lesions with the bulk of the lesion showing radiopaque areas. Cortical expansion may be a feature when simple bone cysts become larger. In rare cases, radiopaque lesions may mimic the appearances of Paget’s disease. It is not uncommon to observe fusion of lesional tissue with roots of adjacent teeth.

A

Histopathological features described are invariably in cases of late stage as the lesions are not diagnosed until they grow into a reasonable size. Most of the biopsy specimens of FLCOD show benign fibro-osseous tissue containing bone which ranges from woven bone to densely sclerotic lamellar bone and large areas of cementum-like calcifications (Figs 7.6A and B). They contain prominent pagetoid reversal and resting lines. Marrow spaces are also replaced by lesional tissue. When a lesion progresses into the final radiopaque stage, individual trabeculae fuse and form lobular masses of mostly acellular cemento-osseous material. Inflammatory cells are absent unless there is secondary infection. Solitary bone cyst formation is more frequent in FLCOD than in other types of cemento-osseous dysplasias.

B

Figs 7.5A and B: (A) early lesions showing multiple radiolucencies and scattered radiopacities within; (b) An advanced case with numerous radiopaque lesions (Courtesy: Professor Jos hille)

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Histopathological Features

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Figs 7.6A and B: (A) Florid cemento-osseous dysplasia. bone and cementum-like areas in a dense fibrous stroma; (b) Mature-lesions show dense cementum and lamellar bone. reduced vascularity leads to nonvital bone and infection

Differential Diagnosis

Treatment and Prognosis Treatment is usually not indicated unless infection supervenes leading to osteomyelitis. Therefore, asymptomatic patients should be kept under regular follow-up and clear instructions should be given to prevent secondary infection. This includes good oral hygiene measures in order to prevent periodontal disease and tooth loss. Further, in asymptomatic patients, surgical intervention for diagnostic purposes is not recommended as altered osseous tissue is very susceptible to infection. Management of the symptomatic patient is more problematic mainly due to the nature of hard tissue which has less blood supply and may be surrounded by dead bone. Symptoms usually appear due to extraction of teeth, biopsy procedures and exposure of sclerotic masses as a result of continuous alveolar atrophy under a denture. It is evident that even antibiotics and/or surgical excision of the sclerotic bone are not always successful in controlling the complications of infection. However, removal of dead bone and antibiotic treatment may enhance healing. When simple bone cysts arise within the

Box 7.3: Florid cemento-osseous dysplasia

areas • initially, proliferation of cellular fibrous tissue with trabeculae of woven bone and oval calcifications • late-stage lesions show acellular, avascular and sclerotic bony masses • superimposed infection lead to osteomyelitis.

Familial Gigantiform Cementoma (Familial Florid Cemento-osseous Dysplasia) This is a rare hereditary condition with radiographic and histological features almost identical to FLCOD. In some cases these may grow at an alarmingly high rate causing visible jaw deformity and various abnormalities of teeth eruption including impaction, malposition and malocclusion. Clinical features, diagnosis, differential diagnosis and treatment are very similar to that of FLCOD except the few differences highlighted in the key features helpful in diagnosis. Surgical reduction is indicated in cases growing fast leading to disfigurement.

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Differential diagnosis is a challenge only in focal forms of fibrocemento-osseous dysplasias as the clinical and radiological features are distinct in the florid form. However, mature lesions may mimic the appearances of Paget’s disease radiographically. Serum alkaline phosphatise is markedly raised in Paget’s and it is very unusual for the disease to be restricted only to jaw bones. FLCOD and chronic diffuse sclerosing osteomyelitis (CDSO) are frequently confused with each other partly because of the terms that have been used synonymously for both in the past. CDSO is a primary inflammatory/ infective condition in the mandible mostly in patients with chronic periodontal disease. It is characterized by repeated episodes of mild swelling and pain. Histological features may mimic the appearances of FLCOD with secondary infection. It is unusual to find the classic multiple site and at times symmetrical involvement seen in FLCOD.

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Box 7.4: Familial gigantiform cementoma Key features helpful in diagnosis • Autosomal dominant inheritance with variable expressivity • Multiple quadrant involvement of radiopaque lesions similar to FlCOD • Absence of gender and racial predilection • Onset at a younger age compared to other cemento-osseous dysplasias • histopathological features are identical to FlCOD.

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Historically, fibrous dysplasia (FD) is identified as a developmental and tumor-like fibrocemento-osseous lesion of unknown etiology, characterised by replacement of normal bone by proliferating cellular fibrous tissue with subsequent mineralization. FD is subdivided into monostotic FD, polyostotic FD, craniofacial FD and FD with associated syndromes such as polyostotic FD with endocrinopathy (McCune-Albright syndrome) and polyostotic FD with pigmentation (JaffeLichtenstein syndrome). Recently, etiology of FD took a new turn when Cohen and Howell described that somatic mutation in the GNAS 1 (guanine nucleotide-binding protein, α stimulating activity polypeptide 1) gene causing different types of FD depending on the time of mutation. The mutation appears to be a sporadic postzygotic mutation. When mutation occurs in an undifferentiated stem cell in early embryonic life that mutation express in osteoblasts, melanocytes and endocrine cells causing polyostotic FD with pigmentation and endocrinopathy or McCune-Albright syndrome. If the mutation takes place at a later stage after migration and differentiation of skeletal progenitor cells, FD appears in multiple bones causing polyostotic FD. When mutation takes place postnatally, mutated cells are restricted to a single site and the resultant FD appears in one bone, referred to as monostotic FD.

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Box 7.5: Fibrous dysplasia Key features helpful in diagnosis • Onset is usually in the 1st and 2nd decades, slowly growing painless swelling. • Commonly in the maxilla with some involvement of adjacent bones. • radiographically it shows ground-glass appearance with ill defined borders. • Trabeculae of woven bone with minimal or occasional osteoblastic rimming in a background of cellular fibrous stroma blending into surrounding bone. • Mature lesions show woven or rarely lamellar bone formation parallel to each other.

Monostotic Fibrous Dysplasia and Craniofacial Fibrous Dysplasia The monostotic form accounts for 80 to 85 percent of cases of FD. Although the term “monostotic” can be readily applied to cases of FD affecting the mandible alone (Fig. 7.7A), this is generally not so for FD affecting the maxilla or other facial bones. When the maxilla is affected, disease process can extend into zygoma, sphenoid and palatine bone, etc (Fig. 7.7B). Therefore, the term craniofacial dysplasia is preferred for such cases (Fig. 7.8B). Common patterns of contiguous involvement include maxilla-zygoma sphenoid-frontal-

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Figs 7.7A and B: Fibrous dysplasia. (A) young male patient with both maxillary and mandibular expansion; (b) in a female showing involvement of maxilla and zygoma (Courtesy: Dr T sabesan)

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Polyostotic Fibrous Dysplasia; Polyostotic Fibrous Dysplasia with Endocrinopathy (McCune-Albright Syndrome); Polyostotic Fibrous Dysplasia with Pigmentation (Jaffe-Lichtenstein Syndrome) Polyostotic FD is characterized by the involvement of multiple bones. The disease starts earlier than the monostotic form. Most cases start to show features in the first decade of life. Although the skull bones, including mandible and maxilla may be involved in polyostotic form, the features are dominated by the involvement of long bones. Pathological fractures of affected long bones have been described as a frequent finding unlike in jaw bones.

Clinical and Radiological Features The majority of polyostotic and syndromic forms are easily diagnosed on clinical and radiological investigations alone. Three percent of the polyostotic form has endocrinopathies, precocious puberty and Café-au-lait type pigmentation. The above combination is defined as McCune-Albright syndrome. Caféau-lait spots are prominent macules on the trunk and thighs with markedly irregular

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nasal bones and frontal-sphenoid-temporalzygoma bones. Although multiple bones are affected the lesional distribution is restricted to contiguous bones within a defined anatomical area which is not a typical feature in polyostotic form of the disease. Therefore, it is justifiable to use the term craniofacial FD for lesions of this nature. Clinically, craniofacial FD presents as a painless enlargement of the affected bone, most often during the first and second decades of life. Maxilla affects much more frequently than the mandible when craniofacial FD occurs in the jaws and the maxillary sinus is commonly involved. There is no significant gender predilection. Lesion usually presents as a painless slow growing bony lump. Occasional cases may show rapid growth. Early lesions are radiolucent, although with time typically the lesion starts to show ground-glass appearance (Fig. 7.8A) with indistinct borders that blend into the surrounding uninvolved bone. Mandibular lesions often present with bucco-lingual expansion and involvement of the lower border. Inferior dental canal may displace superiorly. Narrowing of periodontal spaces may be a feature in some cases. Maxillary lesions usually cause obliteration of the sinus and/or displacement of the sinus floor superiorly. Increase density of bones of the skull base has also been described in craniofacial FD (Fig. 7.8B).

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Figs 7.8A and B: Fibrous dysplasia. (A) Characteristic “ground glass” appearance in a periapical radiograph; (b) CT shows involvement of multiple cranial bones in a case of craniofacial fibrous dysplasia (Courtesy: Dr rD Jayasinghe and Dr Jimmy Makdissi)

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borders. Sexual precocity is the most common endocrine manifestation in syndromic patients and menstruation and other secondary sexual characteristics appear in the first year of life. Jaffe-Lichtenstein syndrome is a combination of skin pigmentation with polyostotic FD without endocrine abnormalities. Radiological examination reveals a marked variation in the number of bones involved, ranging from a few, to 75 percent of the skeleton, in rare cases. The margins of extragnathic FD appear well defined compared to jaw lesions which are mostly poorly-defined. Radiological features change with the maturation of the lesion similar to other fibrocemento-osseous lesions. Early lesions may be radiolucent with gradual transition to ground glass appearance and mature lesions are mostly radiopaque.

Histopathological Features Histopathological features vary with the age of the lesion similar to radiological features. Hematoxylin and eosin sections show mostly loose fibrous tissue and the arrangement may vary from lesion-to-lesion, or at times within the lesion, ranging from whorled, fascicular or random configuration. Mitotic activity in fibroblasts is a rare event although it may be observed in rapidly growing lesions. Hard tissue formation starts to appear with the continuation of the disease process and the

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irregular trabeculae of mostly woven bone without a prominent osteoblastic rim is characteristic. Rimming may be evident focally in some cases. Bony trabeculae do not join each other especially in early lesions giving the characteristic appearance (Fig. 7.9A). Although different sites share similar histopathological features, jaw lesions may have some differences. Features such as marked ossification, lamellar maturation, very variable size and shape of bony trabeculae, cementum-like mineralization can lead to a broad differential diagnosis with other cemento-osseous conditions of jaw bones. In older lesions with lamellar maturation, together with reversal and resting lines, is indicative of normal bone turn over. Mature lesions after many years show parallel arrangement of bony trabeculae which can be either woven or more often lamellar bone (Fig. 7.9B). Cystic degeneration appears to be a rare event in jaw lesions of FD.

Differential Diagnosis Diagnosis of FD is usually by clinicopathological correlation as it can be confused with other cemento-osseous lesions as well as lesions forming reactive-bone. The latter consists of periosteal reactions in osteomyelitis, lesions of hyperparathyroidism, giant cell granuloma and low grade osteosarcoma. The above problem is common when the biopsy is taken from

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Figs 7.9A and B: Fibrous dysplasia. (A) irregular bony trabeculae in a fibrocellular stroma is characteristic in early lesions; (b) A mature lesion shows prominent parallel arrangement of bone with lamellar differentiation

Although rare, sarcomas can arise in craniofacial FD, usually osteosarcoma or fibrosarcoma. Most have occurred in patients who had received radiation therapy. The above treatment option is contraindicated for FD because of the known risk. A few examples have been reported in the literature of spontaneous malignant transformation.

Treatment and Prognosis

Ossifying fibroma and cementifying fibroma are now considered to be one and the same lesion. Both these lesions frequently contain bone and cementum-like tissue. Techniques which have been used to differentiate bone and cementum in these lesions yielded inconclusive results. It is accepted that most pathologists find it difficult to differentiate bone and cementum when it is not fully formed by conventional histopathological methods. Therefore, the term cemento-ossifying fibroma is accepted as the appropriate term.

Management of FD is a clinical challenge to surgeons, at least in some cases. Single mandibular lesions may be surgically resected without much of a problem. More complex maxillary lesions, especially true craniofacial FD can pose significant problems in management and patients may need several surgeries at different stages. Regrowth can be expected in 25 to 50 percent of the cases following contouring procedures. Although growth of most lesions stops when skeletal maturation is reached, some cases show late reactivation. Medical treatment for FD has been tried by some centers with variable results. Bisphosphonates appear to work well for children rather than for adult patients as osteonecrosis is a common complication of the drug in adults. It has been reported that bisphosphonates reduce bone pain and bone turn over in these patients.

CeMenTO-OssiFyinG FibrOMA Cemento-ossifying fibroma (COF) is the true neoplastic disease in the category of fibrocemento-osseous lesions. This is classified under bone related lesions in the WHO classification of odontogenic tumors in 2005 together with fibrous dysplasia and osseous dysplasias. COF is defined as a well demarcated lesion composed of fibrocellular tissue and mineralized tissue of varying appearances. In addition to the conventional type of COF, WHO recognizes juvenile COF as a separate entity presenting in two different ways, namely juvenile trabecular ossifying fibroma (JTOF) and juvenile psammomatoid ossifying fibroma (JPOF).

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the periphery of a slow growing lesion. It is important to remember that cortical expansion due to periosteal reaction is very common in children and adolescents due to low grade chronic osteomyelitis of dental origin. Therefore, diagnosis of such cases with a superficial biopsy should be avoided. The most difficult practical differential diagnosis histologically would be FD and other cemento-osseous lesions. These have been discussed under different entities. It should be emphasised that the importance of clinical and radiological features aid the interpretation of histopathology to arrive at the definitive diagnosis. Differentiation of cemento-ossifying fibroma (COF) from FD is very necessary as the two disease entities should be treated differently, as the former is a neoplastic process. If the biopsy is taken with the intact capsule of COF, differentiating it from FD is straightforward. However, if the biopsy is from the central part of the lesion it may show similar features. Looking for features such as osteoblastic rimming in COF and blending of lesional tissue with surrounding normal bone in FD may be helpful, in addition to radiological features and clinical features. Though rare, intramedullary and parosteal osteosarcoma, with the help of cytological features, should be differentiated from FD.

Conventional Cemento-ossifying Fibroma

Clinical and Radiological Features Cemento-ossifying fibroma (COF) commonly occurs in young to middle aged adults. The majority of the patients are in third and fourth decades. There is a striking female predilection. The most common site of involvement is the posterior mandible accounting for 80 percent

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of the cases. The maxillary posterior region appears to be the next most common site. Usual presentation is a slowly growing, painless and expansile bony hard lump (Fig. 7.10). Although the majority of COFs are a few centimeters in diameter, cases have been reported expanding more than 10 centimeters under the label of giant COF. The tumors usually do not perforate the cortex. Radiologically, COF is a well demarcated round or oval, mostly unilocular lesion

Histopathological Features

Fig. 7.10: Cemento-ossifying fibroma presenting as a bony hard swelling in the posterior body of the mandible in a young adult

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(Figs 7.11A and B) with extremely rare cases showing multilocularity. The features depend on the age of the lesion similar to other fibrocemento-osseous lesions. Early lesions are radiolucent. When hard tissue formation begins the tumor tends to show mixed radio density. However, towards the later stages the whole lesion may appear radiopaque. Adjacent teeth may be displaced and resorption of roots is seen in some examples.

A well demarcated margin is identifiable at the edges of the excision (Fig. 7.12A). The lesional tissue ranges from fibrocellular tissue to densely sclerotic tissue. The majority of COFs consist of dense fibrous connective tissue with varying degrees of cellularity. It is frequently hypercellular with numerous fibroblasts which have a storiform pattern, whorled pattern or rarely random arrangement. An occasional multinucleated giant cell may be seen. The stromal vascularity is not marked. The calcified components consist of thin separate trabeculae of woven bone that may be lined by osteoblasts (Fig. 7.12B). Lamellar bone can be present but is not a constant finding. Cementum-like deposits of cellular or acellular spherules may also be present, either alone, or in combination with the bony trabecular component. Both bony and cementum-like areas fuse into thick

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Figs 7.11A and B: Cemento-ossifying fibroma. (A) CT image showing a well circumscribed lesion in the body of the mandible; (b) radiographic view of a COF with mixed radiodensity and displaced teeth

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Figs 7.12A and B: Cemento-ossifying fibroma. (A) Capsule around the tumor help in differentiating COF from other lesions of the group; (b) bone, cementum-like areas and calcifications in a fibrocellular stroma. Osteoblastic rimming is evident focally

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Figs 7.13A and B: Cemento-ossifying fibroma. (A) Macroscopic appearance of a COF; (b) Cystic changes within the tumor

bony islands in mature lesions. Sclerotic lesions are susceptible to osteomyelitis. Large tumors may develop aneurysmal bone cysts within the lesion, but it is not a common feature unlike in some other fibrocemento-osseous lesions (Figs 7.13A and B).

Differential Diagnosis Although differentiation of this lesion from other lesions should be achieved with the clinicopathological correlation similar to

other fibrocemento-osseous conditions, histological and radiological demonstration of encapsulation or at least good demarcation lead to the diagnosis of COF. Radiological differential diagnosis of COF includes demarcated lesions with mixed radiodensity such as focal cementoosseous dysplasia, calcifying epithelial odontogenic tumor, adenomatoid odontogenic tumor, ameloblastic fibro-odontoma and complex odontoma, etc. However, early tumors which are radiolucent may mimic various other tumors which present as unilocular radiolucencies. Radiologically, it is not difficult to differentiate COF from other cemento-osseous lesions as most of the conditions of the latter do not have demarcated margins. Histopathological differential diagnosis is more challenging as the features of COF are identical to some other fibrocemento-osseous lesions. The histopathological distinction of FCOD and COF is quite difficult, if not impossible. Because of the histopathological overlap between these two lesions, large number of FCODs has been misdiagnosed as COF, when the diagnosis is arrived without proper clinicopathological correlation. Macroscopic features in the biopsy are sometimes helpful as FCOD is usually received as multiple haemorrhagic fragments. The above differentiation is mandatory as two entities have completely different treatment

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options and more importantly the two lesions behave differently as well. Although other fibrocemento-osseous lesions such as fibrous dysplasia, periapical cemental dysplasia and florid cemento-osseous dysplasia have very similar histopathological features to COF, proper assessment of radiological and clinical features lead to the correct diagnosis.

features. Further, there is no general agreement among pathologists with regard to the proper terminology, histopathologic features, or criteria for separating these lesions from conventional ossifying fibromas. WHO recognizes two different types of COFs under aggressive types namely, juvenile trabecular cemento-ossifying fibroma (JTOF) and juvenile psammomatoid cemento-ossifying fibroma (JPOF).

Treatment and Prognosis

Juvenile Trabecular Cemento-ossifying Fibroma (JTOF)

Simple enucleation is the treatment of choice for most tumors. Larger tumors may need reconstruction of the area by bone grafts. Prognosis of the tumor is usually very good as the tumor is significantly separated from the surrounding tissue. Therefore, recurrence is not a common event. Malignant transformation has not been reported. Box 7.6: Conventional cemento-ossifying fibroma Key features helpful in diagnosis • slow growing solitary lesion • Majority in the mandible • radiographically, a well demarcated lesion with smooth, often sclerotic borders • During surgery it “shells out” from surrounding bone • Cellular fibrous stroma, often with storiform pattern, cellularity varies depending on the age of the lesion • histologically, irregular bone trabeculae, some with osteoblastic rimming • Cementum-like areas or globular calcifications may present.

This is an aggressive lesion which needs to be differentiated from osteosarcoma as some histopathological features are suspicious of malignancy.

Clinical and Radiological Features Age of presentation may vary from 2 to 25 years with the majority of cases being diagnosed before 15 years of age. Maxilla affects more frequently than the mandible. There is a slight male predominance. Symptoms are related to the site of involvement and include swelling, epistaxis, proptosis, exophthalmos, and diplopia. Pain is a rare presentation. The growth rate of tumors appears to have a relationship to the age of the patient. Some cases progress slowly but others, particularly those in young children, often grow very rapidly alarming the clinicians to suspect a malignancy (Fig. 7.14). Radiologically,

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It is known that a subset of COFs which occur in young patients tend to have a different behavior. Many believe that these lesions are unique because of their reported tendency to occur in children and adolescents, complex histologic features, and purported tendency for locally aggressive growth. Controversy exists as not all juvenile types exhibit locally aggressive behavior and not all lesions reported in this group have the same histopathological

Fig. 7.14: Juvenile trabecular cemento-ossifying fibroma. rapidly growing lesion of juvenile aggressive COF affecting the maxilla of a young patient (Courtesy: Dr Kumara ekanayake)

Box 7.7: Juvenile trabecular cementoossifying fibroma Key features helpful in diagnosis • Mean age of occurrence is 12 years • either jaw is affected but with slight maxillary predominance • Well demarcated radiographically; radiolucent with small opacities • highly cellular fibrous stroma with ribbons and strands of cellular osteoid with prominent osteoblastic rimming • remains with woven bone throughout • Variable presence of myxoid areas with cystic degeneration.

Histopathological Features Histologically lesions are uniform and show highly cellular fibrous stroma with ribbons and strands of cellular osteoid with numerous osteoblasts on their surface (Fig. 7.15). Osteoclasts may also be prominent in relation to osteoid. Irrespective of the age of the lesion lamellar differentiation of woven bone is not present. Precaution should be taken to differentiate this from osteosarcoma especially with narrow osteoid rims and mitoses are frequent. Focal areas show myxoid and cystic

Fig. 7.15: Juvenile trabecular cemento-ossifying fibroma. highly cellular fibrous stroma with areas of myxoid change containing cellular osteoid and bony trabeculae

degeneration. Hemorrhage may be a feature in some tumors. Differential diagnosis from other fibrocemento-osseous lesions is not a challenge on the basis of the arrangement of strands of osteoid. Some lesions may resemble fibrous dysplasia but blending with adjacent tissue is not a feature of JTOF. Lesions with increased cellularity and mitoses should be differentiated from osteosarcoma.

Treatment and Prognosis Excision of the lesion is the treatment of choice. These tumors have a tendency for local recurrence with reported rates ranging from 25 to 58 percent. However, radical surgery does not appear to be appropriate because recurrences may be managed by local excision. Although some lesions have a very aggressive course, malignant transformation has not been reported.

Juvenile Psammomatoid CementoOssifying Fibroma (JPOF) Juvenile psammomatoid cemento-ossifying fibroma is the other aggressive type of COF. This is a lesion which occurs predominantly in orbit and paranasal sinuses than jaw bones.

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a tumor shows a well-defined unilocular or rarely multilocular radiolucent lesion that may contain fine specks of radio-opacities.

Clinical and Radiological Features This is a progressively growing lesion. The age of occurrence ranges from 7 to 60 years. Facial asymmetry is usually present at the time of diagnosis. Other symptoms may include exophthalmos, bulbar displacement, proptosis, impaired vision, nasal obstruction, periorbital pain, headache, and sinusitis especially if orbit and sinuses are affected. Out of the two jaws, maxillary lesions are predominant and only 10 percent of the jaw tumors appears to be in the mandible. Males are affected twice as often as females. Radiographically, most of the tumors are well demarcated and range from completely radiolucent to spotty mixed radiodensity. Mixed-density lesions with areas of definite loculations are typical in cases involving the cranial vault. Clouding or obliteration of the sinuses resembling sinusitis may be a feature in tumors affecting paranasal sinuses.

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Fig. 7.16: Juvenile psammomatoid cementoossifying fibroma. Characteristic psammomatous type calcifications arranged in a richly cellular fibrous stroma

Histopathological Features Microscopically, the tumor is characterized by a fibrovascular stroma containing small ossicles resembling psammoma bodies (Fig. 7.16). The number and size of calcified bodies increase with age. The above structures tend to contain reversal lines in mature lesions. Hypercellularity of the lesion is a prominent feature and whorled pattern is more evident in less mineralized lesions. Some lesions are predominantly myxoid with very less amount of fibrocemento-osseous tissue. These myxoid areas may undergo cystic change with edema, hemorrhage and clusters of multinucleated giant cells mimicking the appearance of an aneurysmal bone cyst. Mitotic figures may be seen, but are never prominent. Some lesions may be difficult to separate from conventional COF histologically. However, extremely cellular stroma with closely packed ossicles and myxoid areas with hemorrhage, multinucleated giant cells, and cystic degeneration are not typically seen in conventional COF.

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Differentiation of COF from other fibrocementoosseous lesions should be achieved with clinico-pathological correlation. FCOD appears

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Box 7.8: Juvenile psammomatoid cementoossifying fibroma Key features helpful in diagnosis • Majority of the cases occurs in childhood or adolescence, some cases may occur in adults • Common sites to be involved are orbit and paranasal sinuses than jaws • Well demarcated mixed density with loculated radiolucent areas or obliteration of sinus • Variable cellularity often with whorled pattern containing closely packed calcified bodies resembling psammoma bodies • Definite myxoid component is evident in most cases.

relATeD COnDiTiOns Cherubism Cherubism is an autosomal dominant disease with a high degree of penetrance and variable expressivity. There is almost 100 percent penetrance in males and 70 percent in females. The disease produces a characteristic facial profile with painless symmetrical expansion of the mandible. The name cherubism is related to the similar appearance of affected individuals to little angels or cherubs in Renaissance paintings. Genetic mutations that take place in the disease have been identified as SH3BP2 gene located in chromosome 4.

Clinical and Radiological Features The disease usually starts during the age of 3 to 5 years in a large number of patients and rarely affects as early as the first year of life. Diagnosis is usually made a few years after the onset of the disease and starts regressing after puberty in most cases. The characteristic appearance of chubby cheeks is due to bilateral symmetrical enlargement of the mandible (Figs 7.17A and B). Another feature frequently reported is the upward look of eyes (eyes to heaven appearance) due to the involvement of the

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Figs 7.17A and B: Cherubism. Characteristic appearance of a patient with chubby cheeks and upward eyes (Courtesy: Dr AMO Peries)

orbital floor and the infraorbital rim. Maxillary involvement is much less common than the mandible. Failure in eruption of teeth, malocclusions, missing teeth and V-shaped palate are some of the other associated features. Radiographically, bilateral symmetrical and multilocular radiolucent lesions with sclerotic and well defined margins are characteristic of cherubism. In addition, root resorption, displacement of teeth and agenesis of some teeth may be present.

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age show much higher recurrences of up to 90 percent in some series. A second curettage appears to be curative in most cases. Multiple recurrences have been reported in patients less than 5 years of age.

Histopathological Features Histopathological features are similar to giant cell granuloma and Brown tumor of hyperparathyroidism. The main feature is the presence of osteoclast like giant cells in a fibrovascular stroma. Shape of the fibroblasts may range from plump to spindle. Hemosiderin laden macrophages are common. Perivascular cuffing of capillaries by collagen and eosinophilic deposits is a useful diagnostic feature (Fig. 7.18).

Treatment and Prognosis Since most cases undergo involution after puberty follow-up is essential and almost all the facial features return back to normal by fourth decade. Surgical intervention is indicated for severe cases and early surgical intervention has shown good results.

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Fig. 7.18: Cherubism. Fibrous stroma containing multinucleate giant cells, hemosiderin pigments are evident focally. Perivascular cuffing is shown in a single blood vessel

Paget’s Disease Paget’s disease or osteitis deformans is characterised by impaired and abnormal bone remodelling as a result of an imbalance in bone deposition and resorption. Although Sir James Paget described the disease as a chronic inflammatory disease, the exact etiology is not known up to date. The disease can either affect a single bone (monostotic form) or more frequently multiple bones (polyostotic form). Recent evidence shows a genetic predisposition of the disease and up to 30 percent of the patients have a positive family history. One such locus has been identified in chromosome 18q-21-22. Although viral etiology has been suggested over the years due to identification of paramyxovirus particles in osteoclasts, existence of a cause and effect relationship has not been established.

Clinical Features Patients are usually more than 40 years of age with a male predilection. The prevalence shows a wide regional variation and people from Europe and America are prone to develop the disease much more frequently than Asians and Africans. The exact incidence is difficult to predict as a large number of cases are identified only during the postmortem examination. Involvement of the skull is common resulting

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in increase in head size and shape, leading to frequent presenting compliant of increased hat size. At the same time, involvement of various foramina may lead to compression of multiple cranial nerves leading to paralysis and loss of hearing and sight. Involvement of weight bearing bones may result in a bowing deformity. The maxilla is more commonly affected than the mandible (Fig. 7.19). Gradual increase in the size of jaw bones lead to spacing of teeth and dentures may become tight. Jaw involvement predisposes the patients to develop osteomyelitis of the maxilla which is an uncommon site in a healthy individual.

Radiological Features Radiological features of the disease vary according to the stage of the disease. The early osteoclastic phase shows diffuse radiolucency. A circumscribed area of radiolucency in the skull in the early stage of the disease is defined as osteoporosis circumscripta. Radiological features of Paget’s disease show similarities to various stages of fibrous dysplasia. When the disease is advanced, the radiological features are more sclerotic giving rise to “cotton wool appearance” (Fig. 7.20). Radiographs of jaw bones reveal hypercementosis, loss of lamina dura in some patients and ankylosis of teeth in advanced cases.

Treatment and Prognosis

Fig. 7.20: Paget’s disease. radiographic features of the patient in Figure 7.19. note the involvement of facial bones containing extremely sclerotic bone and peripheries are similar to “cotton wool” appearance

Diagnosis of the disease is not challenging as most of the clinical and radiographic features are characteristic. Serological tests show markedly increased alkaline phosphatase levels with normal calcium and phosphorous levels. Markers of bone resorption may be identified in urine. N-telopeptides, C-telopeptides and pyridinoline cross-link assays are useful in this context. Treatment is required only in symptomatic cases. Bone pain can be controlled by simple analgesics such as aspirin. In order to reduce the bone turn over parathyroid hormone antagonists, namely calcitonin and biphosphonates have been recommended. Development of osteosarcoma with a poor prognosis has been reported in 1 percent of the patients with Paget’s disease.

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vascular. When the disease is in the sclerotic phase, osteoblasts predominate and the woven bone matures to lamellar bone with very little osteoclastic activity. Biopsy is not indicated in most cases for the diagnosis. Biopsy procedures in late cases in jaw bones may predispose the patient to osteomyelitis.

Central Giant Cell Granuloma

Fig. 7.21: Paget’s disease. irregular trabeculae of bone with prominent resting and reversal lines

Histopathological Features As the hallmark of the disease is imbalance between bone formation and deposition, active phases of starting bone formation is revealed by the presence of numerous resting and reversal lines. Characteristic mosaic appearance is produced due to the same reason. The osteoclastic phase is characterised by numerous osteoclasts surrounding bony trabeculae (Fig. 7.21). Fibrous tissue, which is present at this phase, appears to be highly

Central giant cell granuloma (CGCG) is a lesion which occurs centrally inside the mandible and maxilla. The behavior of this lesion is not uniform as some lesions behave in an aggressive way. The term “reparative granuloma” used in the past has become obsolete. A more aggressive entity known as giant cell tumor is a true neoplastic lesion unlike giant cell granuloma. However, giant cell lesion found in hyperparathyroidism is known as Brown tumor and is histopathologically identical to CGCG.

Clinical Features The lesion is commonly found in the 10 to 30 years old age group with a female predilection. Anterior mandible and maxilla are the most common sites for occurrence and 75 percent of the cases have been reported in the mandible crossing the midline. The majority of these lesions are asymptomatic and are found in

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Fig. 7.22: Central giant cell granuloma. Multilocular radiolucency from canine to first molar area in the mandible

Fig. 7.23: Central giant cell granuloma. Frequent giant cells of varying size and mononuclear cells in a background of fibrovascular tissue. note the marked vascularity

radiological investigations. However, less numbers of patients may present with pain, paresthesia and cortical perforation.

bone formation may be lacking in aggressive forms.

Radiological Features Central giant cell granuloma (CGCG) presents as either unilocular or multilocular radiolucent lesion (Fig. 7.22). The defect is usually well delineated but cortication of margins is not a common finding. Aggressive lesions show resorption of roots. When they are multilocular, the appearances are similar to other multilocular lesions such as ameloblastoma. Differentiation between Brown tumor of hyperparathyroidism and CGCG is not possible unless other associated features such as loss of lamina dura and generalized “ground glass appearance is present in the former”.

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The lesion is composed of giant cells in a background of mononuclear cells and fibrous tissue (Fig. 7.23). Less aggressive forms show giant cells arranged into nodules and separated by thick fibrous tissue septae. Foci of osteoid and woven bone are also present. The lesion can be vascular and hemosiderin pigments are common. More aggressive forms show an increased amount of mononuclear cells and giant cells with less fibrous tissue. In addition,

Treatment and Prognosis The accepted treatment for most CGCGs is by curettage. Recurrence rates have been reported ranging from 11 to 50 percent. Recurrent lesions respond either to recurettage or surgical excision. Different treatment modalities such as corticosteroids, calcitonin and interferon-α have shown variable results for aggressive lesions.

Osteopetrosis (Marble Bone Disease, Albers-Schonberg Disease) Osteopetrosis is a generalized hereditary condition in which bone becomes denser than normal due to defective bone resorption combined with continuous bone formation and endochondral ossification. The disease starts at birth or in early infancy is known as infantile form and inherited as autosomal recessive trait whereas the adult form is less severe and inherited as an autosomal dominant trait.

Clinical Features The most of the clinical features in the disease are due to lack of bone resorption and continuous bone formation resulting in reduced marrow

Radiological Features There is generalized increase in bone density and obliteration of normal architecture leading to radiopacity of the whole skeleton. Sinuses are either obliterated or reduced in size. Unerupted teeth are a feature in the severe form. Pathological fractures may present in radiographs.

Histopathological Features The bone is dense and sclerotic with marrow spaces either obliterated or replaced by fibrous tissue. Globular amorphous bone deposition in the marrow spaces is a feature. Although there are numerous osteoclasts, function may not be evident as Howship’s lacunae are missing.

Treatment and Prognosis Prognosis depends on the type of disease, as the majority of infantile types succumb to the disease in the first decade. The adult form has a long survival. Bone marrow transplantation is necessary to restore the hematopoietic function. Oral calcitriol combined with a calcium-free diet has provided improvement for some patients. In addition, supportive therapy such as blood transfusions and antibiotics may be necessary and osteomyelitis of the jaw bones have successfully been treated with resection of the affected part with antibiotics and hyperbaric oxygen.

Other Conditions Chronic sclerosing osteomyelitis is presented in Chapter 4 and aneurysmal bone cyst and solitary bone cyst in Chapter 5.

selF-AssessMenT quesTiOns 1. Give a classification for fibrocemento-osseous lesions of jaw bones. 2. Discuss the importance of clinicopathological correlation in the diagnosis of fibrocemento-osseous lesions. 3. Discuss the radiological differential diagnosis of fibrocemento-osseous lesions. 4. Discuss the management of fibrocementoosseous lesions. 5. Compare and contrast focal cemento-osseous dysplasia and cemento-ossifying fibroma. 6. Describe the different clinical presentations of fibrous dysplasia. 7. Using the knowledge of histopathology describe the changing pattern of radiological features of fibrocemento-osseous lesions. 8. Cemento-ossifying fibroma is a tumor with diverse histopathology and behavior. Discuss the statement critically. 9. Compare and contrast lesions presenting with giant cells as a main component. 10. What are the dental implications of patients with Paget’s disease and osteopetrosis?

7 FibrOCeMenTO-OsseOus lesiOns AnD relATeD COnDiTiOns

spaces leading to normocytic anemia. Patients present with hepatosplenomegally as a result of extramedullary hematopoiesis. Increased susceptibility to infection is a common feature and patients may present to clinics with osteomyelitis. Facial deformities appear in the form of a broad face, hypertelorism, frontal bossing and snub nose common in the infantile type. Narrowing and obliteration of bony foramina of the skull base lead to deafness and blindness. Pathological fractures of bones are not unusual in these patients. About 40 percent of the patients with the adult form are asymptomatic and diagnosis may result after routine radiological examinations for other diseases.

suGGesTeD reADinG 1. Chapurlat RD. Medical therapy in adults with fibrous dysplasia of bone. J Bone Miner Res. 2007;21:114-9. 2. Collins MT. Spectrum and natural history of fibrous dysplasia of bone. J Bone Miner Res. 2006;21:99-104. 3. Lan Su, Weathers DR, Waldron CA. Distinguishing features of focal cementoosseous dysplasias and cemento-ossifying fibromas. Oral Surg Oral Med Oral Pathol. 1997;84:301-9. 4. MacDonald-Jankowiski DS, Fibro-osseous lesions of the face and jaws. Clinical Radiology. 2004;59:11-25. 5. Panda N, Parida PK, Sharma R, Bapuraj JR. A clinicoradiologic analysis of symptomatic craniofacial fibro-osseous lesions. Otolaryngol Head and Neck Surg. 2007;136:928-33.

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6. Slootweg PJ. Maxillofacial fibro-osseous lesions; classification and differential diagnosis. Semin Diagn Pathol. 1996;13:104-12. 7. Summerlin DJ, Tormich CE. Focal cementoosseous dysplasia: clinicopathologic study. Oral Surg Oral Med Oral Pathol. 1994;78: 611-20. 8. Waldron CA. Fibrocemento-osseous lesions of the jaws. J Oral Maxillofac Surg. 1984; 43:249-62.

9. Williams HK, Mangham C, Speight P. Juvenile aggressive ossifying fibroma. An analysis of eight cases and a comparison with other fibro osseous lesions. J Oral Pathol Med. 2000;29:13-18.

Chapter

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Soft Tissue and Bone Tumors KA Moutasim, GJ Thomas

Chapter Outline Soft Tissue Tumors and Tumor-like Lesions Reactive Lesions • Epulides • Fibrous Epulis • Pyogenic Granuloma • Peripheral Giant Cell Granuloma (Giant Cell Epulis) Fibrous Lesions • Fibroepithelial Polyp • Denture-induced Fibro-epithelial Hyperplasia • Papillary Hyperplasia of the Palate • Squamous Papilloma • Focal Epithelial Hyperplasia (Heck’s Disease) • Nodular Fasciitis Vascular Lesions • Pyogenic Granuloma Neural Lesions • Traumatic Neuroma Other Reactive Lesions • Oral Focal Mucinosis • Verruciform Manthoma Benign and Malignant Tumors Fibrous Tumors • Myofibroma/Myofibromatosis • Myofibrosarcoma • Fibromatosis (Desmoid Tumor, Aggressive Fibromatosis) • Fibrosarcoma • Fibrous Histiocytoma • Malignant Fibrous Histiocytoma Vascular Tumors • Hemangioma • Sturge-Weber Syndrome • Lymphangioma

• Angiosarcoma • Kaposi’s Sarcoma Neural Tumors • Granular Cell Tumor • Neurofibroma • Schwannoma (Neurilemmoma) • Neuromas of the MEN Syndrome • Malignant Peripheral Nerve Sheath Tumor Adipose Tumors • Lipoma • Liposarcomas • Muscle Tumors • Leiomyomas • Leiomyosarcomas • Rhabdomyomas • Rhabdomyosarcomas Bone Tumors and Tumor-like Lesions • Tori and Exostoses • Osteoma • Gardner’s Syndrome • Ostochondroma • Osteoblastoma • Osteosarcoma Cartilage-forming Tumors • Chondroma • Chondrosarcoma Other Tumors of Bone • Hemangiomas • Ewing’s Sarcoma • Langerhans Cell Histiocytosis • Myeloma • Metastatic Tumors Self-assessment Questions

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iNTRODuCTiON Most oral soft-tissue masses are reactive lesions, representing a localized hyperplastic inflammatory response to chronic trauma or inflammation. These lesions result from the proliferation of normal connective tissue elements, particularly fibrous and vascular tissue, and usually contain a variable infiltrate of inflammatory cells. Although a number of pathological conditions is distinguished, often according to clinical or pathological features, they all represent variations of the same pathogenic process. In addition to inflammatory and reactive lesions, there are over 200 types of soft tissue tumors with many variant patterns. Soft tissue tumors can be challenging for establishing a diagnosis and the clinical presentations could be very similar.

SOFT TiSSuE TuMORS AND TuMOR-LiKE LESiONS The most common soft tissue tumors encountered in the oral cavity are reactive lesions, e.g. epulides and fibroepithelial polyps.

Fibrous Epulis A ‘fibrous epulis’ has a firm texture, and similar color to that of the adjacent gingivae.

Histopathology Fibrous epulides are usually composed of bundles of mature, cellular fibrous tissue covered by hyperplastic stratified squamous epithelium. The surface epithelium may be ulcerated, and a mild-to-moderate inflammatory infiltrate is often present. Foci of metaplastic bone formation are commonly found within the fibrous tissue (Fig. 8.1B).

REACTiVE LESiONS Epulides

Pyogenic Granuloma

Epulides are common swellings that present clinically on the gingiva (‘Epulis’ is Greek for ‘on the gum’). These are hyperplastic lesions

When an epulis presents with a significant vascular component, it is termed a pyogenic granuloma. Clinically, this presents as a soft,

A

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associated with trauma and chronic irritation (commonly due to subgingival calculus deposits), arising most commonly on the anterior interdental gingivae. They are more common in women. Clinically, an epulis may be sessile or pedunculated (supported by a stalk) (Fig. 8.1A). Color and consistency will vary depending on the vascularity and the degree of fibrous proliferation within the lesion. Most epulides are either fibrous or vascular (pyogenic granuloma).

B

Figs 8.1A and B: Fibrous epulis. (A) Clinical appearance; (B) Histopathologically, it is composed of mature fibrous tissue covered by hyperplastic stratified squamous epithelium (Clinical Picture Courtesy: Dr T Sabesan)

8

B Figs 8.2A and B: Pyogenic granuloma. The surface is ulcerated, beneath which are proliferating endothelial cells forming small vascular spaces containing red blood cells

purple-red lump, which may hemorrhage spontaneously. These lesions may present on sites other than the gingivae, including the buccal and labial mucosae. The ‘pregnancy epulis’ is simply a pyogenic granuloma presenting during pregnancy. As to be expected, it is most common in woman of childbearing age, most arising during the first trimester of pregnancy.

Histopathology Pyogenic granuloma and pregnancy epulis are commonly ulcerated, and characterized by sheets of proliferating endothelial cells, which form capillary spaces of variable size. These are supported by a loose, edematous fibrous stroma, with an inflammatory infiltrate usually present (Figs 8.2A and B).

Peripheral Giant Cell Granuloma (Giant Cell Epulis) The peripheral giant cell granuloma originates from the periodontal membrane, and is a relatively frequent reactive lesion found on the gingiva or alveolar ridge. It occurs over a wide age range, though it is more common between the 5th and 6th decades, and shows a slight female predominance. Clinically, the lesion often has a red, brown or bluish color, is commonly ulcerated and located interdentally. Radiographs are essential to exclude a central

SOFT TiSSuE AND BONE TuMORS

A

giant cell granuloma which, if the cortical bone is perforated, could present similarly. For central lesions, hyperparathyroidism must be excluded.

Histopathology Histologically, the lesion is characterized by the presence of focal aggregates of variably-sized, osteoclast-like multinucleate giant cells, set in a vascular stroma of plump mononuclear cells. Extravasated red blood cells and hemosiderin deposition are often present (Figs 8.3A and B).

Management Epulides are generally managed by surgical excision under local anesthetic. It is best to defer treatment of a pregnancy epulis until after delivery, since lesions may regress spontaneously. Notably, some pregnancy epulides have a tendency for recurrence, particularly if excised during the most vascular phase.

FiBROuS LESiONS Fibroepithelial Polyp These are common, hyperplastic lesions that present as pale, firm swellings varying in size from a few millimeters to a centimeter or so, and may be pedunculated or sessile. Trauma is thought to be involved in the pathogenesis, and as such these lesions commonly present on the

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A

B Figs 8.3A and B: Giant cell epulis (giant cell granuloma) composed of focal aggregates of multinucleated giant cells admixed with mononuclear cells in a vascular stroma

buccal mucosa along the occlusal line. When fibroepithelial polyps arise on the hard palate under the fitting surfaces of dental prostheses they become flattened and leaf-like, and are sometimes referred to as ‘leaf fibroma’.

Histopathology Fibroepithelial polyps are composed of bundles of mature collagen containing scattered fibroblasts. Inflammation is usually mild or absent. The overlying surface epithelium is of variable thickness and usually hyperkeratinized (Fig. 8.4).

Denture-induced Fibroepithelial Hyperplasia These are hyperplastic mucosal overgrowths associated with ill-fitting dental prostheses, particularly lower dentures. They present as firm, leaf-like swellings usually on the labial and vestibular sulci embracing the denture flanges. Females are affected more commonly than males. Often, the patient will have been wearing an ill-fitting denture for a number of years before presentation and will generally have been asymptomatic.

Histopathology 182

The microscopic appearance is the same as a fibroepithelial polyp; bundles of mature colla-

Fig. 8.4: Fibroepithelial polyp. The lesion is covered by keratinized acanthotic stratified squamous epithelium

gen interspersed with scattered fibroblasts and covered by variably hyperplastic and hyperkeratinized stratified squamous epithelium.

Management Fibroepithelial hyperplasias are generally excised under local anesthetic with removal of the underlying cause of chronic trauma (smoothing sharp tooth cusps, trimming overextended dentures or fitting new dentures) to prevent recurrence.

Papillary Hyperplasia of the Palate

Histopathology The mucosa is composed of multiple papillary projections consisting of proliferating fibrous and granulation tissue covered by hyperplastic stratified squamous epithelium. A chronic inflammatory infiltrate is frequently present (Fig. 8.5). The degree of epithelial hyperplasia may be marked, producing a pseudoepitheliomatous appearance, with deep, branching rete processes that may mimic the invasive appearance of squamous cell

Management The patient should be advised to remove the dental appliance at night and to practice appropriate oral and denture hygiene. Topical antifungal therapy is used to treat underlying candidal infection. Surgical excision of papillary tissue and the fabrication of new dental prostheses can then be carried out.

Squamous Papilloma

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This condition presents on the hard palate, usually seen in middle-age to elderly female patients, almost invariably under an ill-fitting upper denture. The exact etiology is unknown, but it is thought that the chronic trauma from a rocking denture predisposes to the condition, and also potentiates the growth of fungal microorganisms. Clinically, there are multiple pin-point projections on the anterior hard palate vault, giving a cobblestone or pebbled appearance to the palate. Occasionally, the hyperplasia may also extent onto the edentulous ridges. There is frequently an overall erythematous appearance, particularly when Candida is present.

carcinoma. However, cellular atypia is not a feature of this disease and it has no malignant potential.

Squamous papilloma is a local, human papilloma virus (HPV)-induced epithelial hyperplasia, presenting clinically as a solitary, usually pedunculated nodule, which is white with a papillary surface (Fig. 8.6A). HPV-6 and HPV-11 are most commonly associated (found in around 50-68% of papillomas). Although squamous papillomas can occur at any age, they are more common in patients aged 30 to 50 years.

Histopathology The lesion is composed of hyperplastic stratified squamous epithelium, forming finger-like projections which are hyperkeratinized (giving the lesion a white appearance). The epithelium surrounds cores of vascular fibrous tissue, and there is sometimes a mild infiltrate of chronic inflammatory cells in the stroma (Fig. 8.6B). Superficial keratinocytes may have a koilocytic appearance similar to other HPV-induced lesions (a koilocyte is a keratinocyte with a pyknotic nucleus surrounded by a clear zone). Lesions most commonly have a stalk but can be sessile. It is important to remember that a number of different oral lesions have a papillary or verruciform appearance.

Management Fig. 8.5: Papillary hyperplasia. There are multiple papillary projections consisting of proliferating fibrous and granulation tissue covered by hyperplastic stratified squamous epithelium. A chronic inflammatory infiltrate is present

Squamous papillomas are treated by conservative excision and recurrence is unlikely. Although associated with HPV infection, the lesions appear to have low infectivity and are not contagious.

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A

B

Figs 8.6A and B: Squamous cell papilloma. (A) An exophytic, papillary and whitish lesion is the characteristic presentation; (B) Histopathologically it shows hyperplastic stratified squamous epithelium, forming finger-like projections (Courtesy: Dr AM Attygalla)

Focal Epithelial Hyperplasia (Heck’s Disease) Heck’s disease (focal epithelial hyperplasia) is a condition with a strong genetic predisposition that was originally described in Native Americans and Inuits of Greenland. It is now known to exist in numerous ethnic groups and populations, and to be associated with HPV-13 infection (and possibly HPV-32). Since transmission is by casual contact, it is not uncommon for multiple family members to be affected, particularly children. Clinically, Heck’s disease most commonly presents as multiple raised plaques on the labial and buccal mucosae, and tongue. Occasionally, lesions may impart a ‘cobblestoned’ appearance to the mucosa, in which case Crohn’s disease or orofacial granulomatosis should be considered in the differential diagnosis.

Histopathology The lesions are composed of markedly acanthotic stratified squamous epithelium which has widened rete processes, producing a sessile, exophytic growth pattern. The epithelial surface may be hyperkeratinized, but it lacks the striking papillary pattern seen in squamous

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Fig. 8.7: Focal epithelial hyperplasia (Heck’s disease). Hyperplastic epithelium containing virally damaged cells and mitosoid bodies (Courtesy: Dr B Almeda)

papilloma. Mitosoid bodies (keratinocytes with collapsed nuclei resembling mitoses) may be seen in the suprabasal epithelial layers (Fig. 8.7). Presence of HPV can be demonstrated with immunohistochemistry (Fig. 8.8).

Management In many cases, intervention is unnecessary and lesions regress spontaneously. Some lesions are managed by conservative excision.

Management

Fig. 8.8. immunohistochemical stain for HPV showing strong positivity in surface cells in Heck’s disease (Courtesy: Dr B Almeda)

Nodular fasciitis, despite its worrying clinical presentation and pathological appearances, is a self-limiting lesion that is treated by simple surgical excision. Spontaneous regression without treatment has also been reported. Larger lesions, particularly if situated deeply within tissues, may need a wider excision. Recurrence rates are low, and reported to range from 1 to 6 percent.

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abnormal mitotic forms are not present. There is usually a mild-to-moderate infiltrate of chronic inflammatory cells, and extravasated erythrocytes.

VASCuLAR LESiONS Pyogenic Granuloma Nodular Fasciitis Although there is some evidence that nodular fasciitis contains clonal chromosomal abnormalities, this is regarded as a reactive lesion. Although self-limiting and benign, it often presents as a rapidly growing mass with sometimes alarming histological appearances, and can be mistaken for a malignant process. It usually occurs in the superficial fascia, commonly on the angle of the mandible or the zygomatic prominence, but may also affect intraoral sites, particularly the buccal mucosa and lips. Children and young adults are most commonly affected, with no particular gender predilection. Trauma is often implicated in the etiopathogenesis. Cranial fasciitis, a particular form of nodular fasciitis, is seen in infants and involves the soft tissue of the scalp. Nodular fasciitis may also show prominent intravascular growth (intravascular fasciitis).

Histopathology Histologically, nodular fasciitis consists of haphazardly arranged fibroblasts within a mucoid or myxoid connective tissue. The fibroblasts are plump and large, and resemble those of granulation tissue, with pleomorphic cells sometimes seen. Mitoses are common, reflecting the rapid growth of the lesion, but

Most pyogenic granulomas arise on the gingiva (see under epulides), but they can also arise at other intraoral sites including the lips, buccal mucosa and tongue. The clinical and histological appearances are, however, the same.

NEuRAL LESiONS Traumatic Neuroma Traumatic neuromas can occur at any age, and result from the reactive proliferation of a damaged nerve as a result of trauma or surgery. The lesion presents as a small, smooth, submucosal nodule, which in some cases, may be extremely painful on pressure. Sites most commonly affected within the mouth are the tongue, lower lip, and alveolar mucosa close to the mental foramen.

Histopathology The lesion is poorly circumscribed, and is characterized by numerous haphazardly arranged, proliferating nerve fibers embedded within fibrovascular tissue (Fig. 8.9).

Management Traumatic neuroma is treated by simple surgical excision. The lesion occasionally recurs.

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Fig. 8.9: Traumatic neuroma consisting of numerous proliferating nerve fascicles and fibrous tissue

Fig. 8.10: Oral focal mucinosis consisting of a nodule of loose myxoid connective tissue covered by stratified squamous epithelium

OTHER REACTiVE LESiONS

are the alveolar mucosa and gingiva. The lesion has a similar clinical appearance to a viral papilloma, presenting as a soft, slightly raised, sessile nodule with a papillary surface.

Oral Focal Mucinosis Oral focal mucinosis is an uncommon lesion, and is probably due to overproduction of hyaluronic acid by fibroblasts. The lesion primarily occurs in young adults, and has a female predilection. The sites most commonly affected are the gingiva and hard palate, with the lesion presenting as a soft, sessile nodule with normal or pale surface color.

Histopathology The lesion is composed of an unencapsulated area of loose myxoid or ‘mucinous’ connective tissue. This contains mild-to-moderate fibroblast numbers which sometimes have delicate fibrillar processes. The overlying epithelium may be atrophic or hyperplastic (Fig. 8.10).

Management Treatment is by surgical excision. Lesions do not recur.

Verruciform Xanthoma The verruciform xanthoma occurs generally in middle aged and older patients. It has a female predilection. The sites most commonly affected

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Histopathology Histologically, a verruciform xanthoma has a papillary surface, which is usually hyperkeratinized. The diagnostic feature of the lesion is found within the connective tissue papillae between the epithelial rete processes, which are packed with foamy histiocytes or xanthoma cells (Figs 8.11A and B).

Management Treatment is by surgical excision, and recurrence is rare.

BENiGN AND MALiGNANT TuMORS Benign neural and vascular tumors are relatively common in the oral cavity, but intraoral soft tissue sarcomas are rare. The lesions all present similarly, either as superficial nodules or deep-seated masses. Benign tumors are usually freely mobile, whereas sarcomas infiltrate into adjacent structures and are fixed. Features such as rapid growth, pain and ulceration are more likely to be found in malignant tumors. For all spindle cell and pleomorphic sarcomas, it is

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B

Figs 8.11A and B: Verruciform xanthoma. The lesion has a papillary, hyperkeratinized surface. The diagnostic feature of the lesion is found within the connective tissue papillae between the epithelial rete processes which are packed with foamy histiocytes or xanthoma cells

important to exclude the possibility of spindle cell (poorly differentiated) squamous cell carcinoma and melanoma, which occur more frequently within the oral and maxillofacial region. Immunochemistry plays an essential role in the diagnosis of soft tissue tumors (Table 8.1) with genetic analysis also being increasingly important.

ƒ Table 8.1 immunological markers helpful to differentiate cell lineages Cell/tissue type

Immunochemical marker

Myofibroblast

Smooth muscle actin (SMA)

Epithelial

Cytokeratins

Skeletal muscle

Desmin, myoglobin, myo-D1

Smooth muscle

SMA, Calponin

Endothelial (vascular)

CD31, CD34, factor Viiirelated antigen

Neural

S100, Leu7, myelin basic protein

Melanocyte

S100, HMB45, Melan A, tyrosinase

Hematolymphoid (lymphocytes, etc.)

CD45

SOFT TiSSuE AND BONE TuMORS

A

FiBROuS TuMORS Myofibroma/Myofibromatosis Solitary and multicentric myofibromas (myofibromatosis) are benign tumors composed of myofibroblasts (contractile, smooth musclelike fibroblasts), with a predilection for the soft tissues of the head and neck. Solitary lesions are more common than multicentric disease, and although these tumors can occur at any age, most (~ 90%) occur in children aged 2 and under, representing the most common fibrous proliferation in childhood. It should be, noted, however, that oral lesions tend to present in children and adolescents, rather than infants, and are usually solitary, with the tongue most commonly affected. Myofibromatosis involving the oral cavity is extremely rare. Superficial lesions present as painless, firm, exophytic nodule on the skin or the oral mucosa, whereas deeper tumors form palpable masses.

Histopathology Myofibromas are generally well-circumscribed spindle cell tumors composed of cellular areas which alternate with fascicular or hyalinized areas, producing a nodular appearance (Fig. 8.12). The tumor cells are positive for smooth muscle actin (SMA), but negative for desmin.

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Management Low-grade myofibrosarcomas are prone to recurrence (recurrence rate is around 27%), but rarely metastasize. Tumors should be treated by complete, but conservative, excision.

Fibromatosis (Desmoid Tumor, Aggressive Fibromatosis)

Fig. 8.12: Myofibroma. A spindle cell lesion with a vaguely nodular appearance. The margin of the tumor is well demarcated

Management Local surgical excision is curative; but recurrences may occur.

Myofibrosarcoma Myofibrosarcomas are relatively rare. They can occur at any age, but low-grade tumors have a predilection for the head and neck (up to 30% of cases), particularly affecting the tongue, face and neck. Such low-grade tumors are usually slow-growing, arising in the deep soft tissues and also intraosseously.

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Tumors usually infiltrate into adjacent tissues, and are most commonly composed of fascicles or broad sheets of spindle cells, similar in appearance to fibrosarcoma. Some tumors are focally myxoid, giving a nodular-fasciitislike appearance. Although the tumor cells are relatively uniform, nuclear atypia is present, but may be only focal. Mitotic activity is variable. Most low-grade myofibrosarcomas are immunoreactive for SMA and desmin. High grade (pleomorphic) myofibrosarcoma tends to affect the extremities, and histologically has the same appearance as malignant fibrous histiocytoma, but contains SMA-positive cells.

Fibromatosis is a fibroblastic proliferation of cells arising from the musculoaponeurotic tissues of the body. Although fibromatosis does not metastasise, it is a locally aggressive tumor that is currently classified as a tumor of borderline malignancy. Fibromatosis is relatively rare, with around 10 to 15 percent of cases affecting the head and neck, and may be seen in association with Gardner’s syndrome. It occurs primarily in children and young adults, with no gender predilection. Clinically, the lesions are painless, deep-seated and show slow, progressive growth and infiltration into adjacent structures. Fibromatosis usually develops adjacent to the mandible.

Histopathology The tumor consists of long, sweeping fascicles of uniform, spindle cells, which infiltrate into adjacent tissues. The tumor cells are arranged around numerous small, dilated blood vessels, and cellularity may vary from region to region. Around 90 percent of cases show nuclear positivity for beta-catenin, which may be helpful in the differential diagnosis of these lesions.

Management Fibromatosis is treated by surgical excision, including a thin margin or normal tissue. In the head and neck, this is often difficult, if not impossible, due to the anatomical complexity of the region. The difficulty in obtaining clear surgical margins is reflected in the relatively high recurrence rates of head and neck fibromatoses (reported as 25–50% in larger series).

Fibrosarcoma Before the advent of advanced immunohistochemical and genetic diagnostic techniques,

Histopathology Fibrosarcomas are diffusively infiltrative tumors composed of long, interlacing fascicles of atypical, mitotically-active fibroblasts. Fibrosarcoma is a diagnosis of exclusion, with tumor cells showing negative immunoreactivity for markers such as cytokeratin, S-100, desmin, CD34, CD99. Limited tumor expression of SMA may be seen, making distinction from myofibrosarcoma somewhat arbitrary.

Management Fibrosarcomas are treated by wide local excision, with more radical surgery required for poorly differentiated lesions. Metastasis is uncommon, and usually a late event. The overall 5-year survival rate for head and neck fibrosarcoma is 20 to 35 percent.

Fibrous Histiocytoma This tumor is also called a dermatofibroma when occurring in the skin, but is rare in the oral cavity. It occurs predominantly in the vestibule and buccal mucosa, usually in middle aged or older patients, presenting as an asymptomatic mass. Tumor cells show fibroblastic and histiocytic features, and this varied microscopic appearance has lead to the use of numerous diagnostic terms (xanthogranuloma, dermatofibroma).

Histopathology The tumor is usually poorly demarcated. As with other fibroblastic tumors, plump spindled

fibroblasts are present, commonly arranged in a storiform (irregular and whorled) pattern. Additionally, rounded histiocyte-like cells are present which may contain lipid (foamy histiocytes) or sometimes form multinucleate giant cells. The cells are arranged in a fibrous stroma. Nuclear atypia is absent, and immunohistochemical markers are generally negative, but SMA may be positive.

Management Fibrous histiocytomas are treated by surgical excision, with recurrence rates reported at 5 to 10 percent. Recurrence is higher in more deeply-seated lesions.

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fibrosarcomas were regarded as one of the most common soft tissue malignancies. It is now evident that many of the tumors originally thought to be fibrosarcomas were spindlecell malignancies of other types. The term ‘fibrosarcoma’ is now used to define a fascicular spindle cell malignancy that is negative for all other connective tissue markers. This tumor usually affects the soft tissues of the lower extremities, and is relatively rare in the head and neck region, and may be associated with previous radiotherapy. Fibrosarcoma tends to occur in middle aged adults, presenting as a deep-seated soft tissue mass.

Malignant Fibrous Histiocytoma (Undifferentiated Pleomorphic Sarcoma, Pleomorphic Fibrosarcoma) Malignant fibrous histiocytoma (MFH) is one of the less common sarcomas affecting the head and neck region, usually occurring in older adults (50-70 years), and similar to other sarcomas, presenting as a deep-seated soft tissue mass. MFH is a malignant fibroblastic mesenchymal tumor, and is not derived from histiocytes as originally believed. It has been suggested that this lesion does not exist as a separate entity, but represents the pleomorphic progression of various other sarcoma types. However, it is clear that many pleomorphic sarcomas lack specific histological or immunochemical differentiation features. Thus, similar to fibrosarcoma, MFH is also a diagnosis of exclusion.

Histopathology Malignant fibrous histiocytoma has a wide spectrum of appearances, and is generally divided into five different types: pleomorphicstoriform, myxoid, inflammatory, giant-cell and angiomatoid. Most MFHs are of the pleomorphic-storiform type, and consist of a storiform proliferation of bizarre, pleomorphic spindle to epithelioid cells showing high-grade features, including necrosis and abnormal mitotic forms. Multinucleated giant cells may be present, and in sufficient numbers to categorize the tumor as a giant cell variant. Tumors may

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also contain inflammatory or myxoid areas, and areas of vascular proliferation—thus the five different tumor subtypes.

Management Malignant fibrous histiocytoma is treated by radical surgical resection, with or without chemoradiotherapy. Recurrence is common, and occurs in at least 40 percent of lesions, with a similar number metastasizing. Five-year survival is around 30 percent.

VASCuLAR TuMORS Hemangioma Although widely referred to as tumors, hemangiomas represent abnormal hamartomatous proliferations of vascular tissue rather than true neoplasms. They are particularly common in the head and neck, and can present at any age, but often during childhood and adolescence. They most frequently affect the lips, tongue, labial and buccal mucosae. Clinically, they can be flat or raised with an occasionally lobulated surface, and are mostly solitary although multiple lesions can occur. Their color ranges from red to bluish/ purple, and the lesions typically blanch under pressure (Fig. 8.13). Trauma can precipitate hemorrhage, but otherwise patients are asymptomatic, unless the lesions are part of an angiomatous syndrome (e.g. Sturge-Weber syndrome).

Histopathology Hemangiomas are abnormal proliferations of endothelial cells, and can be broadly classified into capillary, cavernous and mixed types depending on the size of the vascular spaces formed. These spaces are generally filled with red blood cells, which can occasionally thrombosis (Fig. 8.14A).

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Fig. 8.13: Hemangioma: A large hemangioma of the right buccal mucosa (Courtesy: Dr AM Attygalla)

Special investigations (ultrasonography, MRI) should be undertaken to study the lesion and associated possible feeder vessels. Surgical incision into a suspected hemangioma should

be avoided. Oral hemangiomas are usually excised, but can be treated with cryosurgery, laser ablation or intralesional injection of corticosteroids or sclerosing agents.

Sturge-Weber Syndrome (Encephalotrigeminal Angiomatosis) This condition is characterized by venous malformations involving the leptomeninges over the cerebral cortex causing neurological symptoms, in combination with hemangiomas over branches of the trigeminal nerve, presenting as the characteristic ‘Port-wine stain’. Hemangiomas may also present intraorally. Neurological symptoms can present as convulsions, learning disabilities and hemiparesis on the contralateral side of the lesion. ‘Port-wine’ facial hemangiomas may also be present in isolation.

Lymphangioma Like hemangiomas, these represent hamartomatous malformations of the lymphatic system, presenting most commonly during infancy or early childhood. They arise most commonly on the tongue, where they cause macroglossia, but can affect any part of the oral cavity. Lymphangiomas often have a characteristic papillary, multinodular surface. Cystic hygromas are lymphangiomas that affect the developing lymphatics in the neck and can

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Figs 8.14A and B: (A) Hemangioma; (B) Lymphangioma. The connective tissue contains numerous irregular and dilated endothelial-lined spaces filled with red blood cells or lymph respectively

cause gross enlargement on the affected side. They can be potentially life-threatening, if they involve vital structures.

Histopathology On microscopy, lymphangiomas appear as thinwalled endothelial-lined spaces filled with clear fluid (lymph), with occasional lymphocytes or scanty red blood cells. Like hemangiomas, they can be classified as cavernous or capillary, depending on the size of the spaces. The prominent lymphatic vessels in lymphangiomas are characteristically in direct apposition to the overlying epithelium (Fig. 8.14B).

Management Many lymphangiomas undergo spontaneous regression. Progressive lesions can be amenable to surgical excision. Other options include sclerosing agents and intralesional corticosteroid therapy.

Angiosarcoma Angiosarcoma is a rare malignancy of endothelial cell origin. More than half of all angiosarcomas are found in the head and neck region, most commonly on the scalp. It is rare in the oral cavity but when occurring, may present intraosseously, or as a submucosal

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mass. Clinically, angiosarcoma usually affects older individuals (>65 years), and presents as a rapidly-growing red or purplish submucosal mass, which is fixed to underlying tissues, that may ulcerate and bleed spontaneously.

Histopathology The histopathological appearances vary greatly. Well-differentiated tumors may be composed of atypical endothelial cells forming obvious vascular channels, but there may be little evidence of vasoformation in poorly differentiated lesions. Tumors are immunoreactive for vascular markers including CD31, CD34 and factor VIII-related antigen.

Management Angiosarcomas are usually treated by wide local excision with radiotherapy sometimes used for multifocal lesions. The overall survival rate is poor (5-year survival rate 10–15%), with 50 percent of patients dying within 15 months.

Kaposi's Sarcoma Kaposi's sarcoma (KS) is a vascular tumor of lymphatic endothelial origin, associated with HHV-8 infection. KS can be classified into four different clinical subtypes: classic/ sporadic, endemic African/lymphadenopathic,

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B Figs 8.15A and B: Kaposi sarcoma. Advanced lesions are composed of fascicles of elongated, uniform spindle cells separated by slit-like vascular spaces

AIDS-associated, and iatrogenic/transplantassociated. In non-endemic areas, most cases of head and neck KS are associated with immunosuppression, particularly HIV infection. AIDS-associated KS is the most aggressive form of the disease, found in around 10 percent of patients with AIDS. It occurs at a much younger age than the classic form, most frequently in the 4th decade of life. The clinical appearance varies according to stage, with earlier lesions appearing as a flat red-to-blue patch. Later lesions appear as a purplish-red plaque or nodule, which may be ulcerated.

Histopathology Advanced lesions are composed of fascicles of elongated, uniform spindle cells separated by slit-like vascular spaces (Figs 8.15A and B). The tumor contains extravasated erythrocytes and chronic inflammatory cells. The tumor cells are positive for HHV-8, and usually positive for vascular markers (CD31, CD34).

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Radiation and/or chemotherapy are the treatments of choice, with the use of surgery generally limited to diagnostic biopsy. Chemotherapeutics include azidothymidine, vincristine and vinblastine. Antiretroviral therapy also has helped in managing proliferating KS lesions.

NEuRAL TuMORS Granular Cell Tumor The granular cell tumor is an uncommon benign neoplasm of neural origin. The granular cells were thought to be of primitive striated muscle origin; hence the term “granular cell myoblastoma” was originally used to describe these tumors. It is now evident that the granular cells are of nerve sheath origin, and are most likely to be Schwann cells. Granular cell tumor has a female predilection, and may occur at any age, but most commonly presents in the 4th decade of life. The head and neck is a favored site for this tumor, typically presenting on the tongue. However, any site in the oral cavity may be affected. Clinically, the lesion presents as a painless, firm, polypoid mass with an intact surface epithelium. It can grow up to 5 cm in size, and usually has a slightly yellowish surface. Multiple lesions may occasionally occur. The congenital gingival granular cell tumor (congenital epulis) is a related lesion that presents as a polypoid mass in the newborn, most commonly on the maxillary alveolar ridge. It can be pedunculated or sessile; and is more common in girls than boys.

Histopathology The granular cell tumor is typically unencapsulated, and composed of uniform sheets of

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Figs 8.16A and B: Granular cell tumor. The epithelium overlying the tumor is hyperplastic giving a pseudoepitheliomatous appearance which could be mistaken for a squamous cell carcinoma. The tumor cells (arrow) are in the deeper tissue showing large, and polyhedral shape with abundant granular cytoplasm

eosinophilic cells with an abundant granular cytoplasm. The cells generally have a plump, polyhedral morphology, with small, bland nuclei (Figs 8.16A and B). The overlying epithelium invariably displays pseudoepitheliomatous hyperplasia, which can result in the misdiagnosis of this lesion as a squamous cell carcinoma if the granular cells are overlooked or if the biopsy is superficial. Ultrastructurally, the cellular granules appear to be comprised of phagolysosomes. Immunohistochemically, granular cell tumors are positive for the S-100 protein, confirming their neural origin.

Management Surgical excision under local anesthetic is the treatment of choice. Recurrence is uncommon.

Neurofibroma Neurofibroma is a benign neoplasm of the nerve sheath that can present as a solitary tumor or as multiple lesions in the neurofibromatosis syndrome (von Recklinghausen’s disease), associated with mutations or abnormalities of the NF-1 gene. Solitary neurofibromas can occur at any age but is more common in teenagers and young adults; usually presenting as a slowly-

growing, asymptomatic mass. The favored sites intraorally are the tongue and buccal mucosa. Neurofibromas may occur as part of the generalized syndrome of neurofibromatosis (usually neurofibromatosis type 1, also called von Recklinghausen neurofibromatosis). NF type 1 is inherited as an autosomal dominant trait, and is characterized by multiple neurofibromas which occur anywhere in the body, including the oral cavity. Oral involvement is seen in around 70 percent of cases. In addition to neurofibromas, the syndrome also presents with Café-au-lait cutaneous pigmentation (which may precede the neural lesions), neurological symptoms and bone abnormalities. Notably, the neurofibromas in neurofibromatosis can undergo malignant transformation in around 10 percent of cases, although this is uncommon in oral lesions. Malignant transformation is exceptionally rare in solitary neurofibromas.

Histopathology Neurofibromas are unencapsulated but welldemarcated tumors containing a variety of spindle cells, including Schwann cells and fibroblasts in a myxoid stroma, which can contain mast cells and lymphocytes (Fig. 8.17A). The plexiform neurofibroma has characteristic pathological

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Figs 8.17A and B: (A) Neurofibroma composed of a variety of spindle cells, including Schwann cells and fibroblasts in a myxoid stroma; (B) The plexiform neurofibroma has a multinodular appearance

features, and is found almost exclusively in patients with NF-1. Grossly, the multinodular or fusiform enlargement of the involved nerve leads to a ‘bag of worms’ appearance. Histologically, there is tortuous expansion of the nerve, with increased endoneural matrix and separation of nerve fascicles, combined with a proliferation of Schwann cells, fibroblasts and axons in a collagen-rich matrix (Fig. 8.17B). Immunohistochemistry for S-100 is helpful in establishing diagnosis. Marked cytologic and nuclear atypia should alert to the possibility of malignant transformation.

Management Simple surgical excision of a solitary neurofibroma is curative. Whilst surgical excision of the multiple lesions in neurofibromatosis is often helpful, more extensive disease may render surgery difficult. Malignant transformation to a neurosarcoma is a sign of poor prognosis.

Schwannoma (Neurilemmoma)

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Schwannoma is a common benign tumor of the Schwann cells of the nerve sheath (neurilemma), and up to 45 percent of all schwannomas affect the head and neck region. It can occur at any age (usually between 25–55 years), and has no particular gender predilection. The head and neck is a favored site for schwannomas; and when they arise in the oral cavity, the tongue is

the most common site. The clinical presentation is usually that of an asymptomatic, slow-growing solitary nodule.

Histopathology Unlike neurofibromas, schwannomas are encapsulated tumors with a biphasic growth pattern; the “Antoni A” pattern typically shows palisaded spindle cells, with parallel elongated nuclei, with “Antoni B’’ areas consisting of more haphazardly arranged spindle cells within a myxoid stroma. Palisadal areas contain prominent eosinophilic areas referred to as Verocay bodies (Fig. 8.18). S-100 protein is positive on immunohistochemistry.

Management Surgical excision is curative; with recurrence unlikely.

Neuromas of the MEN Syndrome The multiple endocrine neoplasia (MEN) syndromes are characterized by tumors of at least two endocrine glands. They are inherited in an autosomal dominant manner. MEN Type III (also known as MEN Type IIb) is characterized by medullary thyroid carcinoma, adrenal pheochromocytoma and multiple mucosal neuromas, which may involve the oral cavity. Mutation of the oncogene RET underlies the

Histopathology Fig. 8.18: Schwannoma showing characteristic a “Antoni A” pattern of palisaded spindle cells, with parallel elongated nuclei (Verocay body)

development of MEN Type III. Clinically, the mucosal neuromas in MEN Type III are small, multiple nodules that appear in childhood. Intraorally, the sites of predilection are the tongue, lips and buccal mucosa.

Histopathology Microscopically, mucosal neuromas typically present as enlarged, tortuous nerve bundles in a myxoid stroma. Immunohistochemistry for S-100 is positive.

Management The neuromas themselves are treated by simple surgical excision. However, in an undiagnosed individual, the onset of multiple neuromas is highly suggestive of MEN Type III and should alert the clinician to arrange for appropriate endocrine investigations for the other components of the syndrome.

Malignant Peripheral Nerve Sheath Tumor Also referred to as malignant schwannoma or neurofibrosarcoma, the malignant peripheral nerve sheath tumor (MPNST) is a rare malignancy that is believed to be of Schwann cell origin. Intraorally, the sites most commonly affected are the tongue and soft palate. MPNSTs may arise de novo, or from malignant transformation

The spindle cell arrangement can closely resemble that of fibrosarcomas, and as such differentiation on histological grounds may be difficult. The cells may have a wavy nuclear outline, and cellular and nuclear atypia is commonly pronounced, with high mitotic activity. The fascicles of cells are usually less organized than in fibrosarcoma. Immunohistochemistry usually reveals patchy positivity for S-100 protein. Other markers of nerve sheath differentiation such as Leu-7 and myelin basic protein are also useful.

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of neurofibromas (particularly type 1 NF). Adults in the 3rd to 5th decade of life are most commonly affected. Whilst there is no particular gender predilection in de novo MPNSTs, those that arise on a background of type 1 NF seem to be more common in men, typically a decade or so earlier than in non-syndrome patients. Clinically, MPNSTs are usually slow-growing, and may present with pain or paresthesia, or with muscle atrophy and weakness.

Management The MPNSTs are resistant to chemotherapy and radiotherapy, and wide surgical excision is the treatment of choice. Recurrences are common, and distant metastasis occurs in at least 50 percent of cases. Tumors associated with NF-1 behave more aggressively. Prognosis is dependent on the overall clinical, radiological and histological features at diagnosis, with a 5-year survival of 40 to 75 percent.

ADiPOSE TuMORS Lipoma Lipomas are benign neoplasms of fat cells. In the oral cavity, they most commonly arise on the buccal mucosa, tongue and floor of the mouth. Clinically, they present as a slow growing, asymptomatic soft mass, with an intact epithelial surface (Fig. 8.19A). On microscopy, the tumor presents as lobules of mature adipocytes separated by fine connective tissue (Fig. 8.19B). Simple surgical excision is curative with minimal likelihood of recurrence.

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Figs 8.19A and B: Lipoma. (A) Circumscribed and yellowish lesion on the buccal mucosa; (B) Consisting of mature adipocytes separated by delicate connective tissue septa (Courtesy: Dr AM Attygalla)

Liposarcomas Liposarcomas are rarely seen in the head and neck. They tend to present in middle age, most commonly affecting the tongue and buccal mucosa intraorally. Because of their tendency to grow slowly, they may be mistaken for a benign process. Several histological subtypes are recognized. The most common type affecting the head and neck is the well-differentiated (lipomalike) variant. Histologically, this resembles a lipoma but is not encapsulated, shows greater variation in the size and shape of adipocytes, and contains scattered lipoblasts. Wide local excision is the treatment of choice, with postoperative radiotherapy considered if excision is incomplete or surgical margins are close. Recurrence is common, with 5-year survival rate for well-differentiated liposarcomas reported to be 85 to 100 percent (67% for all subtypes).

Muscle Tumors Smooth muscle neoplasms are generally rare in the oral cavity. When they arise, they most commonly affect the tongue, hard palate and buccal mucosa, and are usually derived from vascular smooth muscle. They can present in any age group.

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Leiomyomas are benign neoplasms that present clinically as generally asymptomatic, slow-

growing masses. Histologically, they present as interlacing fascicles of spindle cells with elongated, cigar-shaped nuclei. The tumors are strongly immunoreactive for smooth muscle actin, and show variable desmin positivity. Leiomyomas are treated by conservative excision. Recurrence is rare.

Leiomyosarcomas Leiomyosarcomas are malignant neoplasms that are exceedingly rare in the oral cavity. Although well-differentiated lesions resemble leiomyoma, atypical spindle cells can be found, and the tumors are more commonly composed of interlacing fascicles of pleomorphic, mitotically active spindle cells (Fig. 8.20). As with leiomyomas, immunohistochemistry for muscle markers, particularly smooth muscle actin, is helpful to distinguish them from other spindle cell malignancies. Treatment is by radical excision, sometimes with adjuvant chemotherapy or radiotherapy. The 5-year survival is 35 to 50 percent.

Rhabdomyomas Rhabdomyomas are rare benign neoplasms of striated muscle, with a predilection for the head and neck. They are generally categorized into three subtypes: fetal, juvenile and adult. They are most frequent in the 5th to 6th decade of life, most commonly affecting the floor of the mouth, tongue and soft palate.

Rhabdomyosarcomas

Histopathology Adult rhabdomyomas characteristically are composed of large polygonal cells with abundant eosinophilic cytoplasms, closely resembling mature skeletal muscle cells. Indeed, crossstriations may be present (Figs 8.21A and B). Rhabdomyomas are positive for desmin, myoglobin and muscle-specific actin on immunohistochemistry.

Management Treatment is by conservative excision. Recurrence is reported, but rare.

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Fig. 8.20: Leiomyosarcoma. A malignant spindle cell tumor showing marked nuclear pleomorphism. immunochemistry is required to distinguish this from other malignant spindle cell tumors

Rhabdomyosarcomas are one of the most common soft tissue sarcomas of children and young adults. They are malignant tumors of skeletal muscles, generally divided into three types: embryonal (including botryoid), alveolar and pleomorphic. Around two-thirds of rhabdomyosarcomas arise in the head and neck, where they present as a rapidly growing mass. The embryonal subtype forms the majority of head and neck lesions. In the oral cavity, the tongue and soft palate are the most commonly affected sites. Botryoid rhabdomyosarcomas present as grape-like polypoid growths, which may cause obstruction.

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Histopathology The histological appearances vary according to subtype: embryonal rhabdomyosarcomas are composed of primitive mesenchymal cells of varying form (round, spindle and ‘strap’ cells). The strap cells are more differentiated, with brightly eosinophilic cytoplasm and cross-striations. Alveolar rhabdomyosarcoma (ARMS) is composed of nests of primitive round cells which are discohesive, producing a pseudoglandular appearance. ARMS are almost invariably associated with one of two chromosomal translocations: t(2;13) (q35;q14) found in around 80 percent of cases, or t(1;13) (p36;q14) in around 20 percent of cases. Pleomorphic rhabdomyosarcoma is composed

B Figs 8.21A and B: Rhabdomyoma. The tumor is well-circumscribed and composed of large, eosinophilic polyhedral cells, with spider cells seen in places

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of anaplastic, round to, —spindled tumor cells, showing high-grade features including frequent mitoses and necrosis. Immunochemical analysis for markers of skeletal muscle (desmin, myogenin, muscle-specific actin), as well as genetic analysis, are required for accurate diagnosis.

Management The treatment regime consists of radical surgery followed by chemotherapy (usually a combination of vincristine, dactinomycin and cyclophosphamide). Postoperative radiotherapy may be used if complete surgical excision is not possible. The prognosis of rhabdomyosarcomas depends on the subtype with 5-year survivals of 66 percent (embryonal), 50 percent (alveolar) and < 30 percent (pleomorphic). Survival for botryoid subtypes is nearly 90 percent.

BONE TuMORS AND TuMOR- LiKE LESiONS Tori and Exostoses The term exostosis is used clinically to describe bony protuberances and outgrowths of mature bone. The precise name given to an exostosis is usually in reference to its site of occurrence. Thus, torus mandibularis and torus palatinus are bony exostoses that arise in the mandible and the palate, respectively. These are entirely benign lesions, which are generally asymptomatic. The etiology is unknown but some studies have demonstrated a possible autosomal dominant mode of inheritance in some patients. Torus palatinus presents clinically as a nodular, bony mass in the midline of the hard palate. It is more common in females than males, and usually presents in young adulthood. Torus mandibularis usually arises on the lingual surface of the mandible in the premolar area, above the mylohyoid ridge. It is almost always bilateral. Bony exostoses may present in other sites in the oral cavity; for example on the posterior maxillary buccal alveolar ridge, where they are often multiple.

Histology Exostoses are typically composed of dense lamellar bone with small marrow spaces filled with fibrofatty tissue.

Management Tori and exostoses are generally asymptomatic, and thus require no treatment unless the overlying mucosa is frequently traumatized, or if the lesions interfere with dental prostheses. In these instances, surgical excision is the treatment of choice, with recurrence generally rare.

Osteoma Osteomas are benign neoplasms of bone. They consist of mature bone of either the compact or cancellous type. Periosteal osteomas arise on the outer surface of bone, whilst endosteal osteomas are within the bone. The etiology is relatively unknown, but it is thought that previous trauma or infection may contribute to the pathogenesis. Although osteomas present frequently in the head and neck, particularly the paranasal sinuses, they are rarer in the jaws. Clinically, an osteoma presents as a slowgrowing, solitary hard mass, more commonly in the mandible than the maxilla. Multiple osteomas occur as part of Gardner’s syndrome.

Gardner’s Syndrome Gardner’s syndrome is a rare autosomal dominant familiar disorder characterized by multiple osteomas of the jaws (particularly the mandible), intestinal polyps and epidermoid cysts. Dental anomalies such as multiple supernumerary and impacted teeth and odontomes may also be present. The polyps arise most commonly in the colon and have a high-risk of malignant transformation to adenocarcinoma.

Histopathology Osteomas are broadly classified into two types. The compact type consists of mature, dense lamellar bone with few marrow spaces, similar

Management Surgical excision of an osteoma is curative. The presence of multiple osteomas raises the possibility of Gardner’s syndrome, especially since they may precede the onset of the other features of the syndrome.

Osteochondroma Osteochondromas consist of a mixture of cartilage and bone. Whether or not they are a true neoplastic process or merely representative of aberrant cartilage growth on a bony surface is unknown. In the head and neck, osteochondromas have been reported in the jaws (particularly the mandibular condyle), as well as in the sinuses and skull bones.

Histopathology On microscopy, the osteochondroma consists of chondrocytes forming a cartilaginous cap on top of, and in direct contact with the medullary cavity of a bony stalk.

Osteoblastoma Osteoblastomas present rarely in the mandible or the maxilla. Osteoblastomas are twice as common in men, than women and the majority are diagnosed before the age of 30. Dull, occasionally severe pain often accompanies the lesion, which usually presents as a localized swelling. Radiographically, the lesions are wellcircumscribed with an occasionally sclerosed margin and a mixed radiolucent and radiopaque center.

Histopathology Osteoblastomas are composed of thin, irregular bone trabeculae in a fibrous, highly vascular stroma. Osteoblasts line the trabeculae, with numerous osteoclasts also present. The cortical bone is intact, and nuclei are generally bland with no atypia; which help distinguish this tumor from osteosarcoma.

Management Surgical excision or curettage is curative. Soft tissue tumors with any odontogenic origin, e.g. Cemento-ossifying fibromas are covered in Chapter 7.

Osteosarcoma Osteosarcoma refers to a heterogenous group of malignant bone tumors that have histopathological evidence of osteogenic differentiation, but differ in their location, clinical behavior and pathological appearance. The most commonly occurring conventional (or classical) osteosarcoma, arises within the bone and can be subdivided into osteoblastic, chondroblastic and fibroblastic variants depending on the predominant cell type and matrix formed (bone, cartilage or fibrous). Conventional osteosarcoma needs to be distinguished from the centrally occurring low-grade intramedullary osteosarcoma and the subperiostially occurring parosteal osteosarcoma; both have better prognosis. There are also several other histological variants. Osteosarcoma most often affects appendicular bones and is relatively rare in the jaws, with the mandible more commonly affected. Elsewhere in the body, osteosarcomas present during childhood and adolescence, but in the jaws they tend to present later in the 3rd and 4th decades of life. Osteosarcomas of the jaw can arise de novo or on the background of a pre-existing condition, such as Paget’s disease or as a complication of radiotherapy. Syndromes associated with an increased risk of osteosarcoma include hereditary retinoblastoma and Li-Fraumeni syndrome. Osteosarcomas present as painful swellings associated with tooth displacement, mobility and loss (Fig. 8.22A). Paresthesia may also be present, particularly when the inferior alveolar nerve is affected. Maxillary osteosarcomas may be associated with nasal obstruction, sinus symptoms and visual disturbances. Radiographic features of osteosarcoma are variable. Early lesions present with symmetrically widened periodontal ligament spaces and localized bone resorption around involved dental structures. Foci of radiolucency or

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in appearance to exostoses. The cancellous type consists of lamellar trabeculae with fibrofatty marrow.

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B Figs 8.22A and B: Osteosarcoma. (A) Mandibular lesion showing involvement of both buccal and lingual plates; (B) Radiograph shows characteristic sun-ray appearance (Courtesy: Dr AM Attygalla)

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B Figs 8.23A and B: Osteosarcoma (osteoblastic subtype) consisting of pleomorphic, osteoid-forming osteoblasts

radio-opacity may be present, depending on the degree of calcification within the tumor. Advanced tumors exhibit an irregular, moth-eaten radiographic appearance with ragged radio-opacities. The classic “sun-ray” appearance of osteosarcomas is seen when tumorous bone formation radiates outward from the affected periosteum, but this is not a diagnostic feature (Fig. 8.22B).

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Most jaw tumors are of the classical type. Tumors are composed of a sarcomatous stroma containing malignant osteoblasts, which give rise to osteoid, the unmineralized precursor of bone. Malignant osteoblasts have a variable appearance

and may appear spindled, epithelioid, polygonal or round. Tumors often have a heterogeneous appearance with osteoblastic, chondroblastic and fibroblastic elements all present, and tumors arbitrarily designated as osteoblastic, chondroblastic or fibroblastic depending on the predominant type of extracellular matrix present (Figs 8.23A and B).

Management Osteosarcomas of the jaws behave differently to those of long bones; the major complication is local recurrence, with metastasis often a late stage event. Surgery is therefore the main treatment for osteosarcoma, with wide, en bloc resection recommended. This may be combined

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Fig. 8.25: Chondrosarcoma consisting of pleomorphic chondrocytes forming a myxochondroid matrix

with neoadjuvant or adjuvant chemotherapy. The role of chemotherapy is currently unclear in jaw tumors, but patients with high-grade tumors may benefit. Adjuvant radiotherapy is advocated for tumors which have been incompletely excised. The 5-year survival rate is around 60 to 80 percent.

chondroma should alert to revisiting the original diagnosis.

CARTiLAGE-FORMiNG TuMORS Chondroma Chondromas are benign tumors of cartilage that present rarely in the head and neck. In the jaws, they tend to favor the anterior maxilla and the coronoid and condylar processes of the mandible. They are mostly diagnosed in the 5th decade of life. They present as radiolucencies on radiography, with occasional foci of radioopacity within.

Histopathology Chondromas consist of bland, well-lobulated mature hyaline cartilage (Fig. 8.24). The chondrocytes show no atypical features and nuclei are well-defined. Chondromas can be difficult to distinguish from well-differentiated chondrosarcomas, and as such all chondromas should be viewed with a high index of suspicion.

Management Surgical excision is the treatment of choice, with minimal likelihood of recurrence. A recurring

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Fig. 8.24: Chondroma consisting of well-defined lobules of mature cartilage

Chondrosarcoma Chondrosarcomas are malignancies of cartilage origin. Similar to osteosarcomas, they are a heterogeneous group of tumors. Clinical behavior is variable; over 90 percent are low– to-intermediate grade tumors, which grow slowly and have a low incidence of metastasis. Though generally rare in the jaws, they are most common in the anterior maxilla, followed by the mandibular condyle and coronoid processes. They tend to present in adulthood and middle age, and have no particular gender predilection. There is a 25 to 30 percent risk of chondrosarcoma developing in Ollier’s disease and Maffucci’s syndrome. The clinical presentation is that of a painful swelling with associated tooth mobility and paresthesia. Metastasis is uncommon. Radiographic features are variable, usually presenting as an ill-defined, mottled radiolucency.

Histopathology Chondrosarcomas usually contain hyaline-type cartilage containing chondrocytes that have enlarged nuclei (Fig 8.25). Chondosarcomas are usually hypercellular, and the degree of cellularity increases with tumor grade. Highgrade lesions contain pleomorphic cells with large, atypical nuclei. The finding of mitotic activity in any cartilage lesion is suggestive

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of malignancy. However, mitoses are not invariably present even in high-grade tumors.

Management Chondrosarcomas tend to recur and wide surgical resection to achieve clear margins is required, particularly since chondrosarcoma infiltrates between normal bone trabeculae. Tumors are generally radioresistant, although proton beam therapy has been successfully used. Prognosis depends primarily on adequate excision with reported five-year survival rates of 43 to 95 percent.

OTHER TuMORS OF BONE Hemangiomas Intrabony hemangiomas, like soft tissue hemangiomas, are hamartomatous proli-ferations of blood vessels. When they arise in the jaws, they present most commonly in the posterior mandible. The female to male ratio is 2:1, and they are normally detected in the first two decades of life. They present as firm, slowly growing, expansile alveolar lesions. Gingival bleeding from associated teeth is an occasional feature, in addition to pain and tooth mobility. Radiographic examination reveals a multilocular swelling with a characteristic soap-bubble appearance and resorption of roots within the lesion.

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Ewing’s sarcoma is a poorly differentiated neuroectodermal tumor closely related to the primitive neuroectodermal tumor (PNET). Less than 3 percent of Ewing’s sarcomas arise in the maxillofacial region, most commonly the mandibular ramus. They have a slight male predilection and generally present in adolescents and young adults, with 90 percent occurring in patients under 30 years of age. The clinical presentation is that of a painful mass that may be associated with mucosal ulceration, loosening of teeth and facial deformity. Systemic symptoms include leukocytosis and elevated temperature. Radiographic features showing irregular, moth-eaten radio-opacities

are generally non-specific, and can mimic an infective process. Periosteal reaction can result in an onion-skin radiographic appearance.

Histopathology Ewing’s sarcoma is composed of sheets of uniform, densely packed small round blue cells with finely granular nuclear chromatin. Geographic necrosis and degeneration of individual cells is frequently present. The tumor cells are positive for CD99 by immunochemistry. FISH is used to demonstrate the characteristic chromosomal translocation t(11;22)(q24;q12) resulting in the fusion of the EWS and FLI-1 genes, which is found in more than 90 percent of cases.

Management Treatment is by wide surgical resection with neoadjuvant multi-agent chemotherapy. Chemotherapeutic agents include vincristine, doxorubicin, etoposide, cyclophosphamide and ifosfamide. Five-year survival rates have improved to over 65 percent.

Langerhans Cell Histiocytosis Formerly known as Histiocytosis X, Langerhans cell histiocytosis is a rare spectrum of diseases characterized by a monoclonal proliferation of bone marrow-derived Langerhans cells. It can present in isolation, or in disseminated, multi-organ form. The term “histiocytosis X” was used previously to encompass eosinophilic granuloma (solitary disease), Hand-SchüllerChristian syndrome (triad of skull defects, exophthalmus and diabetes insipidus) and Letterer-Siwe syndrome (systemic disease with fever, otitis media, hepatosplenomegaly, lymphadenopathy, bone and cutaneous lesions). Many cases do not fit into these rigid categories, and a more useful categorization incorporates unifocal disease, multifocal unisystem disease and multifocal multisystem disease. Langerhans cell histiocytosis presents mostly in the 2nd or 3rd decade of life, and has a male predilection. It has a tendency to favor the skull bones, but can present in any

Histopathology On microscopy, Langerhans cell histiocytosis is characterized by the proliferation of Langerhans cells with characteristic reniform nuclei and indented nuclear membranes, arranged in sheets or clusters (Fig. 8.26). An inflammatory infiltrate composed mainly of eosinophils, lymphocytes and polymorphonuclear leukocytes is also usually present. Multinuclear giant cells may occasionally be seen. Electron microscopy of Langerhans cells shows characteristic rod-shaped granules (Birbeck bodies) within the cytoplasm. Langerhans cells are positive for S-100 protein and CD1a antigen on immunohistochemistry.

Management Treatment varies depending on the location and extent of disease. Solitary lesions are generally

Fig. 8.26: Langerhans cell histiocytosis composed of Langerhans cells with characteristic reniform nuclei and indented nuclear membranes, arranged in sheets or clusters. An inflammatory infiltrate of eosinophils is present

managed by curettage and low-dose radiation therapy, and usually have a good prognosis. Involved teeth are sacrificed at surgery. Longterm follow-up to monitor for recurrent or additional disease is essential. Multifocal disease generally requires more aggressive treatment, with corticosteroids, chemotherapy and immunosuppressive therapy frequently used in addition to surgery. Acute, disseminated disease generally has a poor prognosis.

Myeloma Myeloma is a plasma cell dyscrasia that generally presents as a disseminated disease affecting multiple bones (multiple myeloma), although it may also occur as a solitary lesion (plasmacytoma). It is characterized by the neoplastic expansion of a clone of immunoglobulin-producing plasma cells, and in most patients by the presence of monoclonal gammaglobulins in the serum (most commonly IgG). Multiple myeloma most commonly affects the skull, vertebrae, sternum, ribs and pelvic bones. Around 14 percent of patients have oral involvement, and it is most commonly diagnosed in the 5th to 6th decade of life. The radiographic appearance of multiple myeloma shows multiple, well-demarcated, punchedout radiolucencies producing the so-called ‘pepper-pot’ skull appearance. By definition, bone marrow aspiration must show at least 10 percent plasma cells to fulfil the diagnostic criteria of myeloma. In addition to high levels of immunoglobulin in serum, immunoglobulin fragments can also pass in urine (Bence-Jones protein). The disease symptoms present as organs are infiltrated by malignant plasma cells. Thus, bone pain and pathological fractures can be seen. Anemia, thrombocytopenia and leukopenia as a result of bone marrow infiltration can lead to bleeding problems and susceptibility to infections. Hypercalcemia and renal failure are possible sequelae of advanced disease. Myeloma presents more commonly in the mandible than the maxilla. Pain, paresthesia and loosening of involved teeth may present, in addition to mucosal swellings and intraoral ulceration may occur. Myeloma is frequently complicated by amyloidosis (Chapter 17).

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bone. Mucosal and cutaneous involvement in the head and neck are common. Mucosal swelling, ulceration and loose teeth are common symptoms when it presents in the oral cavity. Radiographic appearance shows solitary or multiple osteolytic lesions, with loss of alveolar bone (with involved teeth appearing to “float in space”) and occasionally, severe destruction of the jaw bones. However, radiographic appearance can also be relatively inconspicuous, with minimal, periapical bone loss mimicking inflammatory dental lesions.

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Solitary plasmacytoma and extramedullary plasmacytoma (arising outside the bone) are rare, but they mostly arise in the head and neck region. They can present as swellings in the oral cavity. Immunohistochemical analysis shows heavy and light chain positivity.

Histopathology Myeloma is composed of sheets of neoplastic plasma cells with minimal supporting stroma. Cell morphology can be strikingly similar to normal plasma cells. Immunohistochemical stains for plasma cell markers (CD138) and also kappa (κ) and lambda (λ) immunoglobulin light chains to confirm antibody restriction (i.e. monoclonality), should be undertaken when a diagnosis of myeloma is suspected.

Management The management of myeloma is dependent on symptoms, and is by chemotherapy. Bone marrow transplantation is an option in selected cases. Due to the chronic, progressive nature of the disease, careful monitoring is essential.

Metastatic Tumors An estimated 1 percent of neoplasms are thought to metastasize to the jaws, the majority of those presenting in mandible. The most common neoplasms that spread to the jaws are breast, lung, prostate, colorectal and renal carcinomas. The primary mode of metastasis to the jaws is via the hematogenous route, with most patients being middle-aged and female. Clinically, the angle and body of the mandible are most frequently affected, with swelling, pain, paresthesia and tooth mobility all being potential symptoms. Radiographic appearance can be variable and nonspecific, with some metastases presenting as irregular, motheaten radiolucencies, and others exhibiting an osteoblastic appearance.

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Metastatic tumor deposits can show great variability histologically, dependent on their tissue of origin. Immunohistochemical analysis

is often helpful in determining the site of the primary tumor.

Management Further investigations to determine the extent of metastatic disease is important. Often, jaw metastasis is representative of more disseminated disease and thus the prognosis is generally poor.

SELF-ASSESSMENT QuESTiONS 1. List the common reactive connective tissue lesions that occur in the oral cavity. 2. How does a reactive lesion differ from a neoplastic one? 3. Discuss the role of radiographs in the diagnosis of a giant cell epulis (giant cell granuloma)? 4. List the common benign tumors affecting the oral cavity. 5. What are the clinical symptoms and signs that are more likely to be found in malignant tumors? 6. Describe two hamartomatous “vascular tumors” occurring in the head and neck. 7. Name and describe two syndromes that may be associated with oral neural tumors. 8. Describe the clinical presentation, histopathology and management of two hematological malignancies that can affect the jaws. 9. How do osteosarcomas of the oral cavity differ from osteosarcomas of the axial skeleton? 10. List the most common metastatic cancers of the jaws and describe the clinical and radiographic features of such tumors.

SuGGESTED READiNG 1. Bennett JH, Thomas G, Evans AW, Speight PM. Osteosarcoma of the jaws: a 30-year retrospective review. Oral Surg Oral Med Oral Pathol. 2000;90: 323-333. 2. Fletcher CDM. Distinctive soft tissue tumors of the head and neck. Mod Pathol. 2002;15:324–30 3. Jordan RC, Regezi AJ. Oral spindle cell neoplasms: a review of 307 cases. Oral Surg Oral Med Oral Path Oral Radiol Endod. 2003;95:717-24. 4. Mendenhall WM, Fernandes R, Werning JW, Vaysberg M, Malyapa RS, Mendenhall

8. Vered M, Allon I, Buchner A, Dayan D. Clinicopathologic correlations of myofibroblastic tumors of the oral cavity. I. Nodular fasciitis. J Oral Pathol Med. 2007;34:426-35. 9. Vered M, Allon I, Buchner A, Dayan D. Clinicopathologic correlations of myofibroblastic tumors of the oral cavity. II. Myofibroma and myofibromatosis of the oral soft tissues. J Oral Pathol Med. 2007;36:304-14. 10. Wright BA, Jackson D. Neural tumors of the oral cavity: a review of the spectrum of benign and malignant oral tumors of the oral cavity and jaws. Oral Surg Oral Med Oral Pathol. 1980;49:509-22.

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NP. Head and neck osteosarcoma. Am J Otolaryngol. 2010 [Epub ahead of print] 5. Nowparast B, Howell FV, Rick GM. Verruciform xanthoma: a clinicopathologic review and report of fifty-four cases. Oral Surg Oral Med Oral Pathol. 1981;51:619-25. 6. Peters E, Cohen M, Altini M, Murray J. Rhabdomyosarcoma of the oral and paraoral region. Cancer. 1989;63:963-6. 7. The Pathology and Genetics of Head and Neck Tumors (World Health Organisation Classification of Tumors). Barnes L, Eveson JW, Reichart P, Sidransky D (Eds). IARC Press. 2005.

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9 Diseases of the Maxillary Antrum Philip McLoughlin

Chapter Outline Growth and Anatomy of the Maxillary Sinuses Acute and Chronic Maxillary Sinusitis Fungal Infections of the Maxillary Sinuses • Aspergillosis • Blastomycosis • Cryptococcosis • Actinomycosis Mucoceles and Antral Pseudocysts • Mucoceles • Antrochoanal Polyps • Antroliths Tumors of the Maxillary Antrum Benign Tumors of the Maxillary Sinuses • Schneiderian Papillomas • Fungiform (Epithelial Papilloma) • Inverted Papilloma

• Oncocytic Papilloma (Cylindrical Cell Papilloma) Malignant Tumors of the Maxillary Antrum • Squamous Cell Carcinoma • Adenoid Cystic Carcinoma • Adenocarcinoma and Variants • Malignant Melanoma • Verrucous Carcinoma • Lymphomas and Related Tumors • Sarcomas • Metastatic Tumors to the Maxillary Sinus Sinonasal Neuroendocrine Tumors • Esthesioneuroblastoma • Sinonasal Undifferentiated Carcinoma • Small Cell Neuroendocrine Carcinoma Self-assessment Questions

INTRODUCTION

GROwTh AND ANATOMy OF ThE MAxILLARy SINUSES The maxillary sinus is the first paranasal sinus to form. At around the 70th day of gestation a small ridge develops just above the inferior turbinate bone. Shortly after an evagination starts just above this ridge and enlarges laterally from the nasal cavity. At birth a rudimentary sinus is present measuring approximately 7 × 4 × 4 mm with its longest dimension in the anteroposterior axis. From birth the growth rate of the maxillary sinus is estimated to be 2 mm vertically and 3 mm anteroposteriorly each year. At the end of the first year of life the lateral margin of the sinus extends under the medial portion of the orbit. By the 9th year the lateral sinus margin extends to the malar bone and the lateral growth ceases by the 15th year. By 8 years of age the maxillary sinus floor is at the level of the nasal floor. There is, however, some variation in growth after this time. If the sinus continues a downward growth pattern it reaches the plane of the hard palate by 12 years of age. The final downward growth of the sinus, however, does not cease until the third molar has erupted. In 20 percent of adults the most dependent part of the maxillary sinus is above the nasal cavity floor, 15 percent of it lies at the same level as the nasal floor and below the level of the nasal floor in 65 percent of adults. Growth anomalies occur in about 10 percent of people, usually in the form of hypoplasia. Hypoplasia of the maxillary sinus results from trauma, infection, surgical intervention or irradiation during the development of the bone. Underdevelopment is also a feature of second branchial arch anomalies as in Treacher Collins syndrome and mandibulofacial dysostosis. In thalassemia major, the demand for bone marrow is so great that the maxillary sinus often fails to pneumatise.

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The maxillary sinus is found in the body of the maxilla which lies directly above the oral cavity. The size of the sinuses varies and right and left may even be different in the same skull. As it has a close relationship to the mouth many of the disorders affecting the maxillary sinus may manifest in the oral cavity and vice versa.

The maxillary sinus lies within the body of the maxilla, the most superior point being directly beneath the orbital apex. The anterior sinus wall is the facial surface of the maxilla with the infraorbital foramen perforating this about 1cm below the orbital rim. The floor of the sinus is lowest near the second premolar and first molar teeth and usually lies 3 to 5 mm below the nasal floor. Occasionally tooth roots of premolar, and less commonly canine teeth, project into the antrum. Sometimes there is dehiscent bone over the tooth roots such that they are separated from the main sinus cavity by sinus mucosa only. The maxillary sinus ostia is located high on the medial wall, drainage is through the ethmoid infundibulum and then into the nasal fossa. This path of drainage is necessarily aided and accomplished by intact ciliary action of cilia located in the maxillary sinus lining epithelium (Box 9.1). Box 9.1: Anatomy and physiology Key features helpful in diagnosis • The maxillary sinus is closely related to dental roots and the orbit and its contents • In the majority of adults the most dependent part of the sinus is below the nasal floor • Ciliary action is necessary for normal sinus drainage • hypoplasia is a common abnormality

ACUTE AND ChRONIC MAxILLARy SINUSITIS Sinusitis is a common disease in the oral and maxillofacial region. In order to understand the disease, thorough knowledge about anatomy of the maxillary sinus and other paranasal sinuses are exceptionally important.

Etiological factors Maxillary sinusitis has over a dozen described etiologies, ranging from the well-known IgE mediated hay fever affecting sinus mucosa, to the involvement in systemic diseases such as cystic fibrosis and Wegener’s granulomatosis. However, over 90 percent of established maxillary sinusitis is of infective origin and the pathology and pathogenesis is remarkably similar irrespective of the causative agent. Although

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unremitting sinusitis may raise the question of a more sinister underlying pathology. A variety of infective agents can affect the sinonasal mucosa, causing acute or chronic inflammation with, or without secondary polyp formation. A large number of tissue neutrophils is a good lead to this possibility. The most commonly implicated viruses are rhinoviruses, parainfluenza and influenza viruses, adenoviruses and respiratory syncytial virus. The onset of mucopurulent discharge means that secondary bacterial infection has occurred as a result of obstruction of the sinus ostium by swollen nasal mucosa. Decreasing sinus aeration results in lower oxygen availability, and an alteration of the normal resident flora culminating in acute bacterial sinusitis. Clinically, this manifests as facial pain centerd over the maxilla, worsened by stooping. If left unchecked the infection can spread becoming a pansinusitis with more paranasal sinuses involved and rarely, lead to secondary intracranial involvement.

Clinicopathological and radiological features In cases of noncomplicated viral infections, maxillary sinus imaging is usually normal or shows minimal sinus mucosal thickening. In overt bacterial colonization with pyogenic strains, mucosal thickening with a fluid level may be evident (Figs 9.1A and B). Plain radiography is non-specific under these circumstances and

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computerized tomography is the standard investigation (Figs 9.2A and B). Direct sinus puncture will produce the best bacterial cultures. The most commonly implicated pathogens are Streptococcus pneumoniae, Haemophilus influenzae, and alpha-hemolytic streptococci, with less commonly Staphylococcus aureus and Pseudomonas strains being isolated. In cases of chronic sinusitis with persistent low sinus, oxygen availability anaerobes predominate including peptostreptococci, Bacteroides spp., and fusobacteria. It is estimated that 10 to 20 percent of maxillary sinus infections are secondary to dental infection or secondary to tooth extraction. As acute bacterial sinusitis results from sinus ostial obstruction, it presents as an isolated event rather than a generalized process, so the most common picture is a unilateral sinusitis rather than a pansinusitis. Even when both maxillary antra are involved one side is generally more severely affected, asymmetry being the hallmark of bacterial disease. On the other hand, pansinusitis is usually found in patients with an allergic sinusitis, because the allergic process is a systemic rather than truly local event. Chronic sinusitis results from either persistent acute inflammation (Fig. 9.3) or repeated bouts of acute sinusitis. Up to one third of patients with acute sinusitis go on to develop the chronic form of the disease. Such chronic disease results in an atrophic, sclerosing, or hypertrophied polypoid mucosa, although

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Figs 9.1A and B: (A) Occipitomental plain radiograph of a patient with mucosal thickening in acute right maxillary sinusitis; (B) Fluid level in right maxillary sinus. (Courtesy: Dr Jimmy Makdissi)

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Figs 9.2A and B: (A) Axial CT cut showing profound left maxillary sinusitis, but with involvement of the right side in addition. Opacity of the sphenoid sinuses implies a pansinusitis; (B) MRI appearance of right maxillary sinusitis

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with a low grade intestinal type adenocarcinoma, both may show a lining of a single layer of columnar epithelium with goblet cells and the low grade adenocarcinoma often displays very little pleomorphism. Close clinical and pathological correlation is advised. The history of sinusitis, lack of tumor mass and chronically inflamed lamina propria indicate hyperplastic maxillary sinusitis rather than the malignant alternative.

Treatment

Fig. 9.3: Endoscopic nasal view showing inflamed and thickened nasal and sinus mucosa, the sinus ostium is being surgically widened for improved drainage

these varied changes may coexist. Ciliary function in chronically inflamed and scarred mucosa becomes less than optimal rendering it vulnerable to further infection, the reinfection cycle so often seen in this condition. Reactive bone is found in the chronically inflamed sinus wall being the periosteal reaction to inflammation, thick sclerotic new bone may be the result consolidating the ostial blockage. Occasionally, the chronically inflamed mucosa develops a papillary hyperplasia, resulting in the so titled papillary hyperplastic sinusitis, which can be confused histologically

Acute bacterial sinusitis usually resolves with an appropriate course of an antibiotic. The insidious chronic disease more often dictates surgical intervention. Open approaches to the maxillary sinus were first described in the early 1700s. The wellknown Caldwell-Luc operation (Fig. 9.4) was first described in the United States by George Walter Caldwell in 1893 and then by Henri Luc of France in 1897. Subsequent advances in the understanding of the physiologic drainage pattern of the maxillary sinus led to intranasal middle meatus antrostomy in the late 1960s and the early 1970s. Functional endoscopic sinus surgery (FESS) is based on the surgical approach performed by Messerklinger and Wigand in Europe via the ostiomeatal complex. FESS has become the standard surgical treatment for chronic maxillary sinusitis, with external approaches being used as an adjunct in more complicated cases or in tumor management (Box 9.2).

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Fig. 9.4: Intraoperative photograph showing the traditional Caldwell-Luc access to the maxillary sinus

Box 9.2: Acute and chronic sinusitis Key features helpful in diagnosis • The most common etiology in acute sinusitis is bacterial infection. • Plain radiographic imaging may be unhelpful and CT should be used • Chronic sinusitis results from prolonged osteomeatal blockage and compromised ciliary action • Surgical treatment is usually performed using a functional endoscopic technique

FUNGAL INFECTIONS OF ThE MAxILLARy SINUSES Aspergillosis Clinical and Pathological Features

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Seven pathogenic species are generally implicated, of these Aspergillus fumigatus accounts for 90 percent of cases, the remainder attributable to A. niger and A. flavus. A. flavus is particularly prevalent in the Middle-East and especially parts of Saudi Arabia. Aspergillosis infection of the maxillary sinuses is indeed a global infection, occurring worldwide and at any age. It is a filamentous fungus found naturally in soil and dried grass and decaying food.

Aspergillosis of the maxillary sinus is considered to occur in three identifiable forms: i. Noninvasive; either as an aspergilloma or allergic in type. ii. Semi-invasive; being locally destructive without true invasion. iii. Invasive; representing true fungal tissue invasion which can be either nonfulminant or fulminant in nature. Noninvasive aspergillosis results in the formation of an aspergilloma (fungus ball) which behaves and mimics chronic sinusitis, indeed suspicion should be aroused of aspergillosis in a refractory case of maxillary sinus infection. The characteristic feature is a gray/brown exudate within the maxillary sinus cavity. Calcification, visible as deposits on radiographs may occur. Histological sections show the presence of numerous large branching and septate fungal hyphae (Figs 9.5A and B). Allergic Aspergillus sinusitis is similar in nature to allergic bronchopulmonary aspergillosis and is a mixed manifestation of a type I and type III immune responses generated by Aspergillus antigens. It particularly affects young adults with a history of asthma. The sinus is filled with thick mucus as well as crystal like structures known as Charcot-Leydun crystals. The diagnosis in each case is by microscopy and treatment with an appropriate course of antifungal such as ketoconazole or amphotericin. The uncommon invasive aspergillosis is very much like a malignant neoplasm which spreads to invade adjacent structures, even involving soft tissues. Proptosis of the eye may be a presenting feature and progression is slow with bone destruction often seen radiographically. Serological tests for aspergillosis antigens are usually positive. In its fulminant form aspergillosis is a rapidly progressive, destructive infection with a significant mortality usually affecting immunocompromised patients. Intracranial extension is not uncommon and may affect 20 percent of those with fulminant disease. The types of maxillary sinus aspergillosis (listed above) not confined entities but represent a progressive spectrum of the disease. It is also described as a range of disease activity, with early stage disease which may then progress to an invasive form over a period of time.

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B Figs 9.5A and B: Aspergillosis. (A) Branching and septate fungal hyphae in a h&E section; (B) Grocott stain showing hyphae in black color

The invasive form usually arises de novo, in immunocompromised patients.

Treatment The noninvasive disease requires surgical debridement and sinus ventilation. Adjuvant antifungal agents may be needed in the semiinvasive phase. Allergic aspergillosis responds to antifungal agents and local corticosteroids if mild, but may require surgical debridement and systemic steroids in more severe cases. Invasive and fulminant forms require more radical resective surgery with systemic antifungal agents such as amphotericin or ketoconazole (Box 9.3). Box 9.3: Fungal infections of the maxillary sinuses Key features helpful in diagnosis • Aspergillosis represents a spectrum of disease from indolent to fulminating and invasive • An allergic form of aspergillosis particularly affects young adults with a history of asthma • Invasive aspergillosis invades bone and may extend into the orbit and intracranially • There is a significant mortality in the immunocompromised • Less commonly sinusitis may be due to blastomycosis, cryptococcosis or actinomycosis.

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Blastomycosis This is an uncommon fungal infection of the maxillary sinus caused by Blastomyces dermatidis. This fungus is again found endemically in soil, which produces spores that are readily inhaled. The spores can cause an intense inflammatory reaction and readily affects the nasal cavity and maxillary sinuses. However, the most affected organs are the lungs. Today the disease is almost confined to certain parts of North America particularly Ohio and Mississippi. Rarely does a disseminated blastomycosis supervene, usually in the immunocompromised, where the outcome can be fatal. The disease most often presents as a chronic maxillary sinusitis and responds to oral antifungal agents such as Amphotericin.

Cryptococcosis This is caused by the inhalation of yeast like fungus, Cryptococcus neoformans. The fungus is found in bird excreta. It usually presents as pansinusitis with nasal ulceration. Treatment with antifungal agents most often results in complete resolution.

Actinomycosis Human infection is by Actinomyces israelii. In the head and neck, the usual presentation

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is a cervicofacial actinomycosis. Trauma is a potential initiating factor although other causes are reported in the maxillary sinus, either as a result of hematogenous spread or as direct extension from the oral cavity through an oral antral communication after tooth extraction; in this instance it requires surgical drainage and an appropriate dose of a penicillin group of antibiotic or equivalent (Box 9.3).

MUCOCELES AND ANTRAL PSEUDOCySTS Mucoceles Mucoceles and antral pseudocysts are common expansive lesions to develop in the maxillary sinus. Antral pseudocysts are mostly accidental findings presenting as dome shaped lesions in dental panoramic radiographs (Fig. 9.6). The reason for the causation of antral pseudocyst is accumulation of inflammatory exudates below the sinus epithelium causing elevation of the mucosa. It is not uncommon and may be found in 2 to 14 percent of the population. Mucocele is defined as a mucosecretory respiratory epithelium surrounding mucoid secretions. Mucoceles can be an incidental finding in 10 percent of people. True sinus mucoceles occur due to obstruction of sinus ostium. They are formed when a sinus becomes obstructed and completely filled with secretions; the mucocele is often therefore larger than the obstructed sinus. A mucous retention cyst is a mucoid filled cyst that develops when a minor gland duct becomes obstructed. It can, similarly, be an incidental finding in 10 percent of people. Radiologically therefore, the definition of a mucocele is reserved for the sinus that is airless and represents an enlarged sinus cavity filled with mucoid secretions. Progressive expansions resulting in thinning of the surrounding bone can be visualized radiographically. Occasionally an antral mucocele may elevate the orbital floor with resultant diplopia. When the same mucocele collapses enophthalmos may be the result.

Fig. 9.6: Bilateral antral pseudocysts (antral polyps) (Courtesy: Dr Jimmy Makdissi)

Treatment Radiography, occasionally with CT scan confirmation, may be all that is required to make a clinical diagnosis. Symptomatic and erosive maxillary sinus mucoceles are treated by simple enucleation. Pathological examination is usually unrewarding.

Antrochoanal Polyps Clinical and Pathological Features The antrochoanal polyp is a large solitary unilateral polyp usually in the posterior aspect of the maxillary sinus. It may extend through the ostium of the antrum into the middle meatus of the nose giving the appearance of a nasal polyp. Maxillary antral choanal polyps are more common in males and young patients typically up to 40 years of age. Up to 50 percent of patients with antral polyps give an allergic history. There is little difference histologically between antral and nasal polyps. Antral polyps seem to have fewer mucus glands and fewer eosinophils than ordinary nasal polyps. Atypical stromal cells representing a reactive change are sometimes visible.

Treatment Radiographically the polyp appears as an increased soft tissue density often with an opacification of the maxillary sinus; almost 40 percent of patients have coexistent bilateral

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maxillary sinusitis. Antral polyps are benign in their behavior. They appear to be self-limiting in size and cause no local bony or soft tissue erosion. Complete removal results in negligible recurrence (Box 9.4). Box 9.4: Antrochoanal polyps Key features helpful in diagnosis • Close association with a history of allergy • Forty percent of patients have coexistent sinusitis • Benign, self-limiting, no bone erosion

Antroliths Clinicopathological Features Antroliths are calcified masses that occur in the maxillary sinus. Stones arising in the antral cavities are uncommon and the development is similar to that of a sialolith. They may form around a nidus or concentrated mucus which continues to grow because of the precipitation of calcium salts in concentric layers. Antroliths are very rare. They are usually asymptomatic but may be associated with dull pain mimicking chronic sinusitis. Other features reported include facial pain, nasal obstruction, epistaxis, purulent or blood stained discharge, foul smelling postnasal drip and oral antral fistula. Occasionally patients give a history of tooth extraction. Radiographically a dense, irregular, well defined mass may be identified in the antrum (Fig. 9.7). Although, the nidus for calcification is usually endogenous, in some cases an exogenous source may be implicated such as tooth roots, or foreign bodies such as dental materials, glass and even paper and stone. Focal antral calcification has been seen in sinuses filled with a fungus ball of Aspergillus. The differential diagnosis of antroliths include ectopic teeth root fragments, osteoma or cementoma, condensing osteitis in the periapical tissue, any form of local bony exostosis and foreign bodies. Large antroliths may even mimic neoplasia.

Treatment A CT scan usually reveals an isolated benign, calcified, well-circumscribed lesion, and in

Fig. 9.7: Antrolith presenting as a well-defined radiopaque mass inside the antral cavity (Courtesy: Dr Jimmy Makdissi)

the absence of symptoms surgical intervention is far from mandatory. Large and obstructing antroliths may require surgical enucleation (Box 9.5). Box 9.5: Antroliths Key features helpful in diagnosis • Rare occurrence of a calcified mass forming around a nidus often of foreign material • Usually asymptomatic, but may mimic a chronic sinusitis, or present with acute nasal symptoms or a postnasal drip • Radio dense well-demarcated lesions may remain untreated in the absence of symptoms

TUMORS OF ThE MAxILLARy ANTRUM Benign Tumors of the Maxillary Sinuses While the numbers of papillomas arising in the maxillary sinuses are significant, other true benign tumors are remarkably rare. Most of the benign tumors of the maxillary antrum arise from adjacent anatomical areas, such as the maxillary alveolus and nasal cavity. The majority from the former site being largely odontogenic, such as the ameloblastoma and keratocystic odontogenic tumor, while salivary

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tumors, fibrous lesions and even osteomas can penetrate into the sinus from an origin in the nasal cavity. Mostly benign tumors in this situation present with facial asymmetry, facial pain or nasal discharge or bleeding. CT usually demonstrates a well-defined mass with surrounding bone remodeling or expansion reflecting the slow growth of the tumor. The notable exception to this rule is the rare juvenile angiofibroma, usually originating in the nasopharynx and invading the maxillary sinus, accompanied by significant bony destruction similar to a malignant tumor.

Schneiderian Papillomas The schneiderian membrane is a ciliated respiratory epithelium derived from ectoderm that lines the paranasal sinuses and gives rise to three distinct papillomas (fungiform, inverted and oncocytic). Collectively Schneiderian papillomas are uncommon, accounting for around 4 percent of all sinonasal tumors (Box 9.6).

Fungiform (Epithelial Papilloma) Clinicopathological Features Fungiform papilloma comprises 20 to 50 percent of all schneiderian papillomas, occurring primarily in young and middle aged males. Primary involvement of the maxillary sinus is unusual, the papilloma tending to spread there from the lateral nasal wall. These papillomas can be multifocal but most often unilateral. Epistaxis and nasal obstruction are typical presenting features. There is evidence that the papilloma is etiologically related to the human papillomavirus (HPV) particularly types 6 and 11. Fungiform papillomas range in size from a few millimeters up to several centimeters. The typical microscopic appearance is of papillary fronds with delicate fibrovascular cores covered by epithelium up to 20 cells thick. The epithelium varies from squamous through transitional to ciliated respiratory type. Surface keratinization is absent unless the papilloma is subjected to the trauma of nose picking. Mitoses are rare and it is generally agreed that fungiform papillomas are not associated with an increased incidence of malignant transformation.

Treatment Complete surgical excision is the treatment of choice. Prognosis is excellent, but recurrence is possible, particularly where there is a viral association.

Inverted Papilloma Clinicopathological Features Inverted papillomas constitute the majority of all Schneiderian papillomas, up to 70 percent in some series. It is five times more common in men than women. Isolated lesions can occur in the paranasal sinuses without nasal involvement and indeed, inverted papillomas have been reported in unusual sites such as the posterior pharyngeal wall and hypopharynx. Ectopic migration of schneiderian membrane during embryogenesis is the proposed etiology in these instances. Nasal obstruction and epistaxis are the principle presenting features, although inverted papillomas are painful in about 10 percent of the cases. Inverted papilloma was for a long time suspected of having a viral origin. However, viral inclusions were not routinely demonstrated, both polymerase chain reaction (PCR) and hybridization techniques failed to demonstrate HPV, although involvement of Epstein Barr Virus (EBV) cannot be excluded. Microscopically, inverted papillomas appear as hyperplastic strands of epithelium that grow endophytically into the underlying stoma. The epithelium is non-keratinized squamous and multilayered up to 30 cells thick (Fig. 9.8). Mitoses are not numerous and are usually confined to the parabasal and basal epithelium. In 10 to 20 percent of inverted papillomas surface keratinization can be seen, with up to 20 percent displaying varying degrees of dysplasia. Inverted papillomas are occasionally complicated by malignant transformation into squamous cell carcinoma and to a much lesser extent, verrucous, mucoepidermoid and adenocarcinoma. The incidence of malignant change is given variously from 20 to 25 percent, although an overall figure of around 10 percent is generally accepted. The carcinoma may arise within the papilloma (carcinoma ex-inverted papilloma) and display a gradation of histological change

Oncocytic Papilloma (Cylindrical Cell Papilloma) Clinicopathological Features

Fig. 9.8: Inverted papilloma: Nonkeratinized hyperplastic strands of epithelium extend endophytically into the underlying stoma

Fig. 9.9: Oncocytic papilloma (Cylindrical cell papilloma): The cells show small dark nuclei and eosinophilic cytoplasm and the cells are similar to oncocytes. Small cysts filled with neutrophils forming microabscesses within the epithelium may be present

from dysplasia to carcinoma in situ to invasive malignancy. However, paradoxically carcinoma may also rise in the site or where an inverted papilloma was excised many years previously.

Treatment Treatment of choice is surgical removal and unchecked inverted papilloma has a potential to enlarge to occupy the entire maxillary sinus.

Oncocytic papilloma is the least common variety constituting only about 5 percent of the total. It shares many features in common with the inverted papilloma, although has distinct microscopic features. It shows an equal sex incidence and tends to occur in patients over the age of 50. There is little, if any association of the oncocytic papilloma with human papillomavirus. Microscopically, a mixed exophytic and endophytic pattern of growth is seen. The tumor comprises a multilayered, tall columnar epithelium up to 8 cells thick. The cells show small dark nuclei and eosinophilic cytoplasm and the cells are similar to oncocytes. Small cysts filled with neutrophils, forming microabscesses within the epithelium, may be present (Fig. 9.9). The stroma varies from edematous to fibrous and may contain inflammatory cells. Malignant change arises in between 4 and 17 percent of all oncocytic papillomas. It is mainly squamous carcinomas but mucoepidermoid and sinonasal undifferentiated carcinoma have also been reported. As with inverted papilloma, the carcinoma may actually arise in the papilloma itself coincident with a gradation of histologic changes of dysplasia through to invasive carcinoma.

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Lateral rhinotomy and en bloc excision of the affected lateral nasal wall is the appropriate treatment modality. Recurrence potential is significant and even after the most thorough surgery is 16 percent.

Treatment Surgical excision is the most effective treatment, this may require lateral rhinotomy and medial maxillectomy as inadequate excision carries a recurrence rate of 25 to 30 percent. Endoscopic sinus surgery has modified the surgical management of papillomas in general. Those confined within the maxillary sinus are considered amenable to endoscopic removal,

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whereas those tumors invading through the sinus walls require radical open surgery. Box 9.6: Schneiderian papillomas Key features helpful in diagnosis • Comprise fungiform, inverted and oncocytic varieties • Fungiform is the most benign • Inverted is the most common, malignant change possible, recurrence potential significant • Oncocytic papilloma comprises 5 percent, similar behavior to inverted type

MALIGNANT TUMORS OF ThE MAxILLARy ANTRUM The anatomical location of the maxillary sinuses makes them extremely close to vital structures such as the orbit, skull-base, infratemporal fossa, nasal and oral cavities, all within immediate proximity. The maxillary antral carcinoma can grow to a considerable size before presentation and as such aggressive therapy may be needed in an anatomically complex region. It makes these tumors highly challenging for the oncology team. Although rare, maxillary antral malignancies show few if any signs while the tumor is in its early stages. This is further complicated as the initial manifestations such as unilateral epistaxis and nasal obstruction are signs and symptoms of many common but much less serious conditions. Because the location of the maxillary sinus is adjacent to important structures such as skull-base, orbits, cranial nerves and vital vascular structures means that by the time ominous signs and symptoms occur the neoplasm is often advanced. As such, presenting features include severe headache, visual disturbance and cranial neuropathy. Similarly, attempts at curative resection may cause significant associated morbidity. Malignancies of the maxillary sinuses are rare. They are more common in Asia and Africa than in Europe and the United States. In the western world they comprise typically just 3 percent of all head and neck cancers, though in parts of Asia the maxillary sinus carcinoma becomes the second most common head and

neck cancer, after nasopharyngeal carcinoma. Men are affected five times more commonly than women. The vast majority of these tumors occur beyond the age of 45 years. Risk factors for cancer of the maxillary sinus, although extensively investigated, remain complicated, multifactorial and perhaps controversial. It is well established that squamous cell carcinoma and adenocarcinoma of the maxillary sinus are associated with exposure to nickel and asbestos dust, mustard gas and isopropyl oil, chromium or dichlorodiethyl sulphide. Exposure to wood dust, as an example is found to increase the risk of squamous cell carcinoma and adenocarcinoma very significantly. These exposures commonly occur in the furniture making industry, the leather industry and the textile business. There is no better example of a head and neck malignancy where a careful, social and employment history should be asked. Recent studies provide mounting evidence to connect viral infection and maxillary antral carcinoma. Studies suggest that epidermal growth factor receptor and transforming growth factor alpha may be found to elevated levels, associated with carcinogenic change with an inverted papilloma. The human papillomavirus (HPV) and Epstein-Barr (EBV) infection may also be an early event between the multifactorial processes of malignant transformation in maxillary sinus cancers (Box 9.7). Box 9.7: Malignant tumors of the maxillary sinus Key features helpful in diagnosis • The anatomical location and relations of the maxillary sinuses mean that many tumors present in their later stages and with major local complications • Presenting features such as epistaxis and nasal obstruction occur in many less serious conditions and further delay diagnosis • Maxillary sinus carcinoma shows marked geographical variation in its incidence, being far more common in Asia than the west • Exposure to wood dust significantly increases the risk of both squamous cell carcinoma and adenocarcinoma • There is evidence to connect viruses such as hPV and EBV with maxillary sinus carcinoma

Squamous Cell Carcinoma Squamous cell carcinoma comprises over 80 percent of all malignancies that arise in the paranasal sinuses. The vast majority, over 70 percent occur in the maxillary sinus. Several variants of carcinoma are often considered subtypes of squamous cell carcinoma of the maxillary sinuses. These include verrucous carcinoma, basaloid squamous cell carcinoma, spindle-cell carcinoma and transitional or cylindrical cell carcinoma. The term squamous cell carcinoma indicates malignancies that have standard features widely understood to represent that entity. Presentation is varied; they include nasal obstruction, nasal discharge, epistaxis, cranial neuropathies and pain. More advanced lesions can alter the patient’s facial features in a noticeable way, causing facial asymmetry or proptosis. Visual disturbances and cranial nerve paresthesias are not uncommon in the advanced tumor invading the orbit, very occasionally the patient may present with mobility and protrusion of maxillary teeth when a mass arises from the floor of the maxilla or as a lump on the hard palate. Backward extension of the tumor sometimes leads to trismus, involving the pterygoid region. Clinical evaluation is similarly a function of the stage of the tumor, it can vary from little more than a mass or a small ulcer to advanced disease which can fungate into the oral cavity or on to the facial skin. An occipitomental view of the skull will indicate a radiopaque antrum and destruction of the antral walls. Biopsy is necessary for diagnosis and classification. Some disease conditions such as Wegener’s granulomatosis may simulate the presentation of squamous carcinomas and is discussed in Chapter 20.

Treatment The prognosis has considerably improved in those presenting early. Unlike other squamous cell carcinomas of the head and neck, lymph node involvement is rare and elective lymph

Adenoid Cystic Carcinoma Clinicopathological Features Adenoid cystic carcinoma accounts for approximately 10 percent of cancers in the maxillary sinus. Therefore, it is the second most common malignancy in this site. Three histological subtypes are described; tubular, cribriform and solid based on particular growth patterns. The importance of the subtypes is centered on the fact that the solid form carries a much poorer prognosis than either cribriform or tubular and is discussed in Chapter 10.

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Clinicopathological Features

node dissection is not usually advocated. Local radical surgery followed by radiotherapy forms the mainstay of curative treatment; modern neoadjuvant radiotherapy may have a role in selected cases. The overall five years survival rate is in the order of 60 percent irrespective of stage. High recurrence rates are usually encountered particularly in advanced disease.

Treatment Cervical lymph node involvement is rare and elective neck dissection is not indicated in most cases; perineural invasion is common, it is found in approximately 50 percent of presenting cases. Late recurrence is frequent and may occur many decades after initial presentation and treatment. Surgery is the mainstay of management with radiation utilized for advanced disease, perineural invasion or surgically unfavorable margins. Overall disease free survival rates are approximately 60 percent at five years but comes down to 20 percent at fifteen years (Box 9.8). Box 9.8: Maxillary sinus adenoid cystic carcinoma Key features helpful in diagnosis • Accounts for 10 percent of maxillary sinus cancers • Solid form carries a poor prognosis • Perineural invasion is found in nearly 50 percent of presenting cases • Late recurrence is frequent

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Clinicopathological Features Adenocarcinoma of the maxillary sinus is historically important and is associated with specific risk factors, such as exposure to wood dust but also varnishes and other organic compounds. Both low and high grade adenocarcinomas are described and each can cause obstructive symptoms. However, pain, paresthesia and oral ulceration are more commonly found in high grade, poorly differentiated tumors. Irrespective of grade local spread to the orbits and skull-base is not an infrequent complication of the maxillary adenocarcinoma. Distant spread is unusual, when it occurs lung, liver and bone are the sites most often affected. Metastases to cervical lymph nodes are uncommon irrespective of tumor differentiation.

Treatment Treatment is surgical resection with postoperative radiotherapy for advanced disease, unfavorable histology or positive surgical margins. Adenocarcinoma of the maxillary sinus rarely affects lymph nodes and makes elective neck dissection unnecessary. The prognostic outlook for low grade adenocarcinoma is far better than for the high grade tumors of the maxillary sinus; low grade adenocarcinoma has a 5-year survival rate of approximately 80 percent whereas only 35 percent of patients with high grade disease are alive at 3 years.

Malignant Melanoma Clinicopathological Features

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This is a rare disorder of the paranasal sinus mucosa accounting for no more than 1 percent of all malignant melanomas. However, 55 percent of the mucosal melanomas occur in the head and neck and 20 percent of these are found in the maxillary sinus. The clinical appearance of the lesion is that of a firm gray/white or pink/black ulcerated mass. Black coloration is not unusual, although predominance is an ulcerated pink mucosal color which can lead to confusion with an advanced squamous cell carcinoma. Biopsy is mandatory. However, histologically mucosal

melanoma can be extraordinary variable in appearance. Immunohistochemistry plays an important role as the mucosal melanoma shows typical positivity for S–100 and HMB–45. These makers are listed in Chapter 8.

Treatment The primary therapeutic approach is surgical resection. Retrospective data exists that demonstrates the improved local regional control with postoperative radiation, which is therefore often recommended for advanced disease. Chemotherapy is reserved for disseminated disease and palliation, even with the best therapy median survival is less than two years. Large size and extensive tumor thickness are considered as poor prognostic factors (Box 9.9). Box 9.9: Maxillary sinus malignant melanoma Key features helpful in diagnosis • Rare tumor, accounts for only 1 percent of all melanomas • Clinical appearance may be pigmented but predominantly ulcerated and pink mucosal color • Surgery is the main modality of treatment • Overall survival is poor

Verrucous Carcinoma Clinicopathological Features Verrucous carcinoma is a type of squamous carcinoma usually characterized by its fungating appearance and papillary nature. Verrucous carcinoma has the potential to progress to a more aggressive conventional squamous cell carcinoma. Verrucous carcinomas may cause damage by local destruction but do not metastasise unless they contain a component of squamous cell carcinoma. This component is found in approximately 20 percent of verrucous carcinoma. This may pose as a problem with treatment planning, particularly when considering an elected neck dissection. The rate of local invasion of verrucous carcinoma is also slower than usually seen with squamous cell carcinoma. Verrucous carcinomas in the head and neck are frequently associated with synchronous or metachronous tumors.

Treatment

Lymphomas and Related Tumors Primary lymphoma of the maxillary sinus is unusual. Typically the patients are aged 60 years and over. Large tumors may cause facial deformity and asymmetry. Management is similar to that generally accepted for non-Hodgkin lymphoma after staging. Chemo-therapy and radiotherapy are the main modalities of treatment, returning median survival rates close to 80 percent at five years. A controversial type of malignant tumor is the T-cell/natural killer (NK) cell lymphoma. Throughout history it has received numerous labels including lethal midline granuloma, midline malignant reticulosis, lymphomatoid granulomatosis, angiocentric lymphoproliferative lesion and T-cell/NK cell lymphoma. According to the current knowledge this lesion is most likely a T-cell lymphoma. This tumor is an aggressive lesion presenting with obstructive symptoms, bone and soft tissue destruction and hemorrhage. It has strong viral associations and presents over a wide-age range. Modern management of T-cell lymphoma is with chemotherapy with or without radiotherapy. Survival rates up to 70 percent at five years have been reported.

Sarcomas The maxillary sinus contains nerves, blood vessels, lymphatics, smooth and skeletal muscle, fibrous tissue and bone. However, it is surprising that the malignant tumors arising from those structures occur very rarely. Fibrosarcoma, leiomyosarcoma, rhabdomyosarcoma, liposarcoma, peripheral nerve sheath tumors amongst others have been reported. Rhabdomyosarcoma is one of the more frequent sinus malignancies in children. It has also been reported in adults. Symptoms are similar to those of other tumors and patients present

Metastatic Tumors to the Maxillary Sinus Metastatic tumors are uncommon in the maxillary antrum. Those tumors displaying a natural tendency to metastasize to bone are usually implicated including prostate, breast, kidney, lung and thyroid. In addition, melanoma, gastrointestinal adenocarcinoma and hepatocellular carcinoma have all been reported to metastasize to the maxillary sinus. There are a small number of metastatic lesions that may cause pathological uncertainty.

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Local resection by maxillectomy is the first line treatment. If the resection specimen contains a portion of squamous cell carcinoma further neck dissection may be considered. Overall, survival is better than many maxillary carcinomas, typically 70 percent at 5 years.

in an advanced stage. Small localized lesions may be amenable to surgery. A combination of radiotherapy and chemotherapy is more often employed. Even with radical treatment overall survival is poor, below 50 percent at five years is a typical figure.

SINONASAL NEUROENDOCRINE TUMORS Sinonasal neuroendocrine tumors are a potentially confusing entity. They are a small group of four tumors: 1. Esthesioneuroblastoma (ENB) 2. Sinonasal undifferentiated carcinoma 3. Neuroendocrine carcinoma 4. Small cell carcinoma. Studies show an overall survival of ENB of up to 93 percent at five years. Five years survival rates for undifferentiated and neuroendocrine carcinomas are typically 60 percent, whereas the highly malignant small cell carcinoma is little over 30 percent survival at five years.

Esthesioneuroblastoma Esthesioneuroblastoma, also called olfactory neuroblastoma is an uncommon tumor that invades the maxillary sinus at an early stage. It is typically thought to originate from olfactory cells near the cribriform plate but ectopic cells do occur and they contribute tumors primarily at alternative sites. Usual presentation is with nasal obstruction and epistaxis, most patients are in the fifth decade. Treatment of ENB has changed dramatically in recent times with the advent of craniofacial

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resection, which has significantly increased the five years survival. Five years survival is optimized by using craniofacial surgical resection with postoperative radiotherapy. There is some evidence that chemotherapy may add an additional benefit in the most advanced tumors. Despite a good five-year survival rate late recurrence is not uncommon, occurring in approximately one third of cases. Cervical lymph node metastases at presentation is less than 5 percent overall but cervical nodes may become involved in up to 30 percent of cases in total. Prophylactic neck dissection is recommended when the tumor is advanced at presentation.

Sinonasal Undifferentiated Carcinoma Sinonasal undifferentiated carcinoma is an uncommon tumor of the maxillary sinus. It is an aggressive tumor frequently advanced at presentation and therefore usually treated by combined therapy unlike ENB. Tumor recurrence is common and response to further treatment is disappointing, consequently the two-year and five-year survival rates are similar. The current modality of treatment of advanced disease favors neoadjuvant chemotherapy followed by surgical resection. The tumor appears to show chemosensitivity, an unusual feature in a head and neck malignancy.

Small Cell Neuroendocrine Carcinoma The small cell neuroendocrine carcinoma is similar to its counterpart carcinoma of the lungs. It is an unusual but reported tumor in the maxillary sinuses and occurs in a wide age range. It is an aggressive tumor, often advanced at presentation, in fact multiple paranasal sinuses may be involved. Cervical lymph node metastases and indeed pulmonary metastases are usually early. Treatment attempts using combinations of surgery, chemotherapy and radiotherapy return equally poor results. The median survival is typically less than two years.

SELF-ASSESSMENT qUESTIONS 220

1. Give a classification for diseases of the maxillary antrum.

2. Describe the anatomy and physiology of the maxillary antrum. 3. Discuss the clinicopathological features of acute and chronic sinusitis. 4. Outline the treatment of acute and chronic sinusitis. 5. Discuss the fungal infections which may affect the maxillary sinus. 6. Describe the clinicopathological features and management of antroliths 7. Write an account of papillomas of the maxillary sinus. 8. Describe the geographic distribution and other risk factors for the development of malignant tumors of the maxillary antrum. 9. Describe the clinicopathological features of malignant tumors of the maxillary sinus. 10. Describe the imaging modalities available to diagnose antral diseases.

SUGGESTED READING 1. Acheson ED, Hadfield EH, Macbeth RG. Carcinoma of the nasal cavity and accessory sinuses in woodworkers. Lancet. 1967:11; 311-2. 2. Batsakis JG, Rice DH, Solomon AR. The pathology of head and neck tumors: squamous and mucous-gland carcinomas of the nasal cavity, paranasal sinuses, and larynx, part 6. Head Neck Surg. 1980;2:497-508. 3. Busquets JM, Hwang PH. Endoscopic resection of sinonasal inverted papilloma: a meta-analysis. Otolaryngol Head Neck Surg. 2006;134:476-82. 4. Corey JP, Romberger CF, Shaw GY. Fungal diseases of the sinuses. Otolaryngol Head Neck Surg. 1990;103:1012-5. 5. Lanza DC, Kennedy DW. Adult rhinosinusitis defined. Otolaryngol Head Neck Surg. 1997;117:S1-7. 6. Lehmann P, Bouaziz R, Page C, et al. Sinonasal cavities: CT imaging features of anatomical variants and surgical risk. J Radiol. 2009;90:21-9. 7. Lund V. The evolution of surgery on the maxillary sinus for chronic rhinosinusitis. Laryngoscope. 2002;112:415-9. 8. Narayana Swamy KV, Chandre Gowda BV. A clinical study of benign tumors of nose and paranasal sinuses. Ind J Otolaryngol Head Neck Surg. 2004;56:265-8.

Chapter

10 Salivary Gland Disorders John Eveson

Chapter Outline Non-neoplastic Salivary Disorders Developmental Disorders Inflammatory/Infective Diseases • Acute Suppurative Sialadenitis • Recurrent Parotitis (Juvenile Parotitis) • Chronic Obstructive Sialadenitis and Sialolithiasis • Post-irradiation Sialadenitis Viral Diseases • Mumps • HIV-associated Salivary Gland Disease • Other Viral Infections of Salivary Glands Mucoceles • Extravasation Mucoceles • Retention Mucoceles (Mucous Retention Cysts) Necrotizing Sialometaplasia Sialosis (Sialadenosis)

Autoimmune Disorders • Sjögren’s Syndrome Neoplastic Salivary Disorders Benign Neoplasms • Pleomorphic Adenoma • Warthin’s Tumor • Canalicular Adenoma • Basal Cell Adenoma Malignant Neoplasms • Acinic Cell Carcinoma • Mucoepidermoid Carcinoma • Adenoid Cystic Carcinoma • Polymorphous Low-grade Adenocarcinoma • Epithelial-myoepithelial Carcinoma • Salivary Duct Carcinoma • Carcinoma ex-pleomorphic Adenoma Self-assessment Questions

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There are three pairs of major salivary glands— parotid, submandibular and sublingual glands. In addition there are numerous minor salivary glands dispersed throughout the oral cavity particularly in the lips and palate. Most nonneoplastic disorders of major salivary glands represent acute or chronic infections of these glands, obstruction to the salivary flow caused by calculi being responsible in most cases. Common inflammatory, autoimmune and neoplastic disorders are presented here.

nOn-nEOPLASTIC SALIVARy DISORDERS

Fig. 10.1: Salivary inclusions in parotid lymph node

Developmental Disorders Aplasia/agenesis: Congenital absence of one or more salivary glands is very rare, but occasionally the parotid gland is absent. Absence of all major salivary glands is even rarer. Salivary aplasia can be associated with other orofacial developmental anomalies. Duct atresia: This is failure of a duct to canalize and it is also rare. It usually affects the submandibular duct. Absence of a patent duct lumen results in the formation of retention cysts in the submandibular and sublingual glands and progressive atrophy of the glandular parenchyma. Heterotopia (ectopia): It is relatively common to find salivary ducts and sometimes acini in the upper cervical and intraparotid lymph nodes (Fig. 10.1). These inclusions are known as Neisse Nicholson rests and they may be important in the pathogenesis of Warthin tumor. Occasionally salivary tissue is seen in the middle ear and other head and neck sites. Stafne's bone cavity is a cyst-like area in the medial aspect of the angle of the mandible, below the mylohyoid line (Fig. 10.2). It is due to an invagination into the lingual plate which is usually filled with an extension of the submandibular gland or fibrofatty tissue. Much less commonly, an analogous defect can be seen in the anterior lingual aspect of the mandible. Accessory ducts and lobes: These are regarded as normal anatomical variations rather than anomalies. A distinct accessory duct and lobe in

Fig. 10.2: Stafne bone cavity presenting as a cyst-like radiolucent area below the mylohyoid line

the parotid is present in as many as 50 percent of patients. Accessory ducts and lobes are, however, very rare in the submandibular gland.

InfLAMMATORy/InfECTIVE DISEASES Acute Suppurative Sialadenitis Ascending infection is most common in the parotid gland, possibly because it has a shorter and wider duct than the submandibular gland and lacks the sphincter-like mechanism seen in the submandibular papillae. In addition, the serous salivary secretion of the parotid gland has less bacteriostatic activity than the mucinous submandibular saliva. Ascending parotitis was considerably more common in the past, and in preantibiotic days

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could be fatal. Debilitated and dehydrated post-surgical patients were particularly at risk from infection ascending from the oral cavity as a result of a combination of reduced salivary flow and oral sepsis. This type of presentation is now rare. Most cases are secondary to chronic xerostomia, usually as a consequence of Sjögren's syndrome and radiation damage, or less commonly, tricyclic medication. Occasionally, the infection is secondary to sialolithiasis or presents spontaneously.

Clinical Features The parotid gland shows the cardinal signs of inflammation, i.e. it is red, hot, swollen and painful (Fig. 10.3). Pyrexia and regional lymphadenopathy are common. Pus may discharge into the oral cavity through parotid duct (Fig. 10.4). In severe cases, abscesses may develop and these can discharge onto the face as fistulae. The most common causative organism are Staphylococcus aureus and Viridans streptococci. However, the infection is often mixed and a wide variety of other bacteria has been incriminated, including gram-negative bacilli, coliform organisms and anaerobes.

Fig. 10.3: Acute suppurative parotitis causing a large facial swelling

Histopathology Initially there is hyperemia, edema and neutrophil accumulation. Ducts, and then acinar tissue, are progressively destroyed, leading to formation of microabscesses. In cases that are left untreated, or when the patient is immunocompromised, there can be extensive macro-abscess formation and destruction of large areas of the gland. As the infection resolves there is progressive fibrosis. This can result in distortion of the ductal architecture and permanent loss of secretory acinar tissue. This in turn can cause stagnation of saliva which predisposes the gland to further inflammatory episodes.

Treatment and Prognosis If possible, pus should be obtained for culture and antibiotic sensitivity. In order to limit contamination from the mouth, the mucosa around the duct orifice should be wiped

Fig. 10.4: Bead of pus milked from inflamed parotid gland

clean with a sterile swab, and any pus present should be milked by forward pressure on the parotid gland. It is prudent to have the microbiology swab ready before milking the gland, as it is common to lose the bead of pus if you do not. As staphylococci are frequently the causative organism, flucloxacillin is usually the first empirical choice, but is changed if the microbiological findings dictate. Metronidazole can be added because of the frequency of anaerobic infections. Sialography is contraindicated at this stage as it can force more organisms back into the gland and could result in bacteremia or septicemia. Early treatment with antibiotics, fluids to correct any dehydration and stimulation of salivary flow

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by sialagogues is usually effective. Severe cases may require emergency hospital admission for intravenous fluids and antibiotics.

and reactive germinal follicle formation. In addition, there can be extensive acinar atrophy and interstitial fibrosis.

Recurrent Parotitis (Juvenile Parotitis)

Treatment and Prognosis

Clinical Features

Despite the lack of a proven bacterial etiology, many cases respond well to antibiotics, including long-term and continuous low-dose penicillin. Progressive damage to the glands in adults can make treatment difficult and may necessitate removal of the affected gland.

Recurrent parotitis is a rare but well characterized condition in children, typically starting at about 6 years of age: it often resolves spontaneously around adolescence. Boys are affected twice as often as girls. Patients usually present with recurrent unilateral or bilateral parotid pain and swelling, particularly at mealtimes. Heat, redness, fluctuation and pyrexia are absent. The condition is often initially interpreted as ‘recurrent mumps’. Sialography shows widespread punctuate and globular sialectasis (Fig. 10.5A) and ultrasound, which is increasingly the investigation of choice, shows multiple small hyopechogenic areas. The cause of recurrent parotitis is uncertain but suggestions include congenital sialectasis, viral and bacterial infections and autoimmunity. Recurrent parotitis in adults is much more common and is usually due to obstruction and/ or xerostomia.

Histopathology Microscopy shows cystic dilatation of interlobular ducts with florid periductal lymphoplasmacytic infiltration (Fig. 10.5B)

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Chronic Obstructive Sialadenitis and Sialolithiasis Chronic obstructive sialadenitis is relatively common and affects the submandibular glands much more frequently than the parotid glands. This is due to the more viscid, mucinous secretion and narrower duct of the submandibular gland and its predisposition to form calculi. The very high concentration of calcium in the secretory material of the submandibular gland, which is higher than in the parotid, may also be contributory. In addition, trauma to Wharton’s duct in the floor of the mouth can lead to periductal fibrosis and obstruction. Salivary calculi consist predominantly of calcium phosphate and carbonate which crystallize around an organic matrix derived from mucus plugs, cellular debris from the duct

B

Figs 10.5A and B: (A) Sialogram of recurrent juvenile sialadenitis showing extensive punctuate sialectasis; (B) Histology showing dilated interlobular ducts and dense periductal lymphocytic infiltration

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Clinical Features Most patients are 30 to 60 years old and the condition is uncommon in children. About 80 percent of cases involve the submandibular gland and ~20 percent the parotid gland. Calculi can also develop in minor salivary glands, particularly those in the upper lip. Calculi are predominantly single but multiple stones are not rare. They can develop within the gland itself or the extra glandular excretory ducts. In the submandibular gland the most common location (~60%) is at the junction of Wharton’s duct and the hilum of the gland (Fig. 10.6), where the duct bends around the distal aspect of the mylohyoid muscle. The next most common location is the anterior aspect of the duct in the floor of the mouth. Many cases are asymptomatic but common symptoms in the early stages include pain and swelling, particularly following eating. With progressive damage to the gland, the acute symptoms may subside and then patients often present with a hard, often painless but tender submandibular mass, or a suppurative inflammatory exacerbation. Parotid calculi can also produce symptoms at mealtimes but are often spontaneously flushed out of the gland as a gritty discharge. Larger and more solid parotid calculi can cause more persistent diffuse swelling of the gland and discomfort on eating.

Fig. 10.6: Radiograph of a calculus in submandibular duct

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walls or bacterial colonies. An important factor is the precipitation of calcium present at high concentration in stagnant secretory material deposited on membranous debris.

Fig. 10.7: Chronic sialadenitis showing acinar atrophy, duct dilatation, interstitial fibrosis and patchy chronic inflammatory infiltration

Histopathology The main features are varying degrees of acinar atrophy, ductal dilatation and chronic inflammatory infiltration, usually predominantly lymphocytic, with widespread interstitial fibrosis in the later stages (Fig. 10.7). Focal foreign body type granulomas with giant cells are sometimes present (Fig. 10.8). Squamous metaplasia and concentrically laminated calculi may be seen in the dilated ducts. Microscopically, calculi have a lamellated or radial structure and the duct walls may undergo squamous metaplasia (Fig. 10.9).

Fig. 10.8: noncaseating epithelioid granulomas in obstructed submandibular gland

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Box 10.1: Salivary calculi

Fig. 10.9: Laminated calculus in a dilated minor salivary gland duct

Diagnosis and Treatment Diagnosis is made on the basis of clinical observation, palpation and imaging. Plain radiography is very useful for submandibular calculi as 80 to 90 percent are radiopaque and thus readily visualized. However, in the parotid gland only 10 to 20 percent can be detected using this technique. Sialoliths in the accessible parts of the submandibular duct can sometimes be removed manually, sometimes using basket retrieval, or after surgical exposure. Recently, conservative surgical techniques have been used for more proximal stones but most of these cases require the removal of the entire submandibular gland. When protracted inflammation has rendered the gland virtually functionless, excision again may be the only solution. In the parotid gland distal calculi can sometimes be removed by incision into Stenson’s duct but often require more extensive surgery with an extraoral approach. A nonsurgical alternative treatment for both parotid and submandibular stones is extracorporeal shock wave lithotripsy, and in selected cases this can be very successful.

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The major and minor salivary glands are particularly sensitive to the effects of ionizing radiation. During the initial treatment, all patients undergoing radiotherapy develop

Key features useful in diagnosis • Most patients 30–60 years old; slight male predominance • Location: Submandibular gland 80 percent, parotid gland 20 percent • Radiopaque stones: Submandibular gland 80 percent, parotid gland 20 percent • Calculi consist of calcium phosphate and carbonate and organic nidus • May be asymptomatic • Pain and swelling on, or just, before eating • Treated mainly by surgery: Basket retrieval and extracorporeal shock wave lithotripsy sometimes used.

acute sialadenitis when the irradiated field includes the parotid or submandibular glands. The involved glands become swollen and painful within 24 hours and severe xerostomia quickly follows. The symptoms usually resolve spontaneously within a week. However, the long-term effects can be much more debilitating. There is obliterative endarteritis and progressive acinar destruction together with interstitial fibrosis. The loss of functional secretory parenchyma can lead to profound and intractable xerostomia.

VIRAL DISEASES Mumps The mumps virus is the most common cause of acute parotitis but many cases are subclinical. It is caused by a highly contagious paramyxovirus which is typically spread by salivary droplets. Mumps is usually a disease of childhood, but may affect nonimmune adults when it can be much more serious. The incubation period is 2 to 3 weeks and prodromal symptoms include, fever, malaise, headache and myalgia. The clinical onset usually begins with pain and swelling of one or more commonly both parotid glands and there may be associated xerostomia. The submandibular glands may also be involved. Occasionally, there are systemic complications, including encephalitis, pancreatitis, orchitis

HIV-associated Salivary Gland Disease Clinical Features Between 1 and 10 percent of adult HIV positive patients develop salivary gland swellings due to lymphocytic infiltration, often with cyst formation (HIV-associated lymphoepithelial cysts). Cases of parotid gland Kaposi's sarcoma, however, are surprisingly rare. HIV-associated lymphoepithelial cysts are seen predominantly in children born to infected mothers and young adults. The parotid glands are mainly affected and clinically apparent disease is rare in other major and minor salivary glands. There are slow growing, painless and typically bilateral swellings of the parotid glands which can become massively enlarged. The swellings develop early in the course of the disease and are usually associated with persistent cervical lymphadenopathy. There may be other signs and symptoms of HIV infection including fever, fatigue, diarrhea and wasting. Xerostomia is an inconsistent symptom that appears to be more prevalent in children. Unlike patients with Sjögren's syndrome, most patients with HIV-associated sialadenitis are males in a considerably younger age group. An autoantibody picture typical of Sjögren's syndrome is also not associated with the sicca syndrome of HIV infection: SS-A or SS-B antibodies are not present and rheumatoid or

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Fig. 10.10: Parotid gland mumps showing striking vascular hyperemia, acinar cell vacuolation and lymphocytic infiltration. Interstitial lymphoid infiltrate are predominantly CD8 positive

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and oophoritis. Immunity following a first attack is absolute and lifelong so apparent cases of ‘recurrent mumps’ will invariably be due to some other cause. If there is any doubt about the diagnosis, it can be confirmed by an enzymelinked immunoadsorbent assay for the mumps S and V antigen or by a nested polymerase chain reaction. There are no specific remedies apart from supportive treatments and most cases resolve without complications within two weeks. Microscopy is rarely undertaken but shows striking hyperemia, diffuse interstitial edema and a dense lymphoplasmacytic and histiocytic infiltration (Fig. 10.10). Despite the often severe acinar cell vacuolation and ductal dilatation, most cases show a full functional recovery.

antinuclear factors are no more frequent than in the general population.

Histopathology Gross examination of the affected glands shows multiple cysts of variable sizes but some may be several centimeters in diameter. The superficial lobe is usually affected more severely than the deep lobe. Microscopy shows multiple cysts in an ill-defined matrix of densely packed lymphocytes, together with large and conspicuous reactive follicles (Figs 10.11 and 10.12). The cysts are lined mainly by nonkeratinized stratified squamous epithelium that is permeated by lymphocytes. These include monocytoid B cells and smaller numbers of T cells. The T cells in the ducts and interstitial lymphoid infiltrate are predominantly CD8 positive. Focally, the ductal epithelium proliferates to form solid lymphoepithelial lesions similar to those seen in Sjögren's syndrome. An important difference, however, is that in Sjögren's syndrome the infiltrate is mainly of CD4 lymphocytes, but in HIV infection there is typically dense CD8 lymphocytic infiltration. Focal periductal lymphocytic infiltration similar to that seen in Sjögren's syndrome can also be detected in labial gland biopsies. Here, once again, the lymphocytes are predominantly CD8 positive T cells.

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Fig. 10.11: HIV-associated sialadenitis showing multiple cysts and dense lymphocytic infiltration

individuals and following transplacental transmission. Congenital cytomegalovirus infection (salivary gland inclusion disease) gives rise to a characteristic picture with double-contored ‘owl-eye’ intracytoplamic viral inclusion bodies in the intralobular duct cells (Fig. 10.13). Acute parotitis may rarely be caused by a range of other viruses including Coxsackie, echo, Epstein-Barr or choriomeningitis viruses.

MuCOCELES Fig. 10.12: HIV-associated sialadenitis showing epithelial-lined cysts, dense lymphocytic infiltrate and epithelial islands

Mucoceles are the most common cystic lesions of salivary glands and are seen almost exclusively in the minor glands. There are three main types: extravasation, retention and superficial.

Treatment and Prognosis

Extravasation Mucoceles

The parotid swellings tend to be persistent and a rapid increase in size could herald the development of a hematolymphoid tumor such as a Burkitt-type high grade B-cell lymphoma. On the other hand, the swellings can shrink dramatically following antiretroviral therapy.

These account about 85 to 90 percent of mucoceles. Most are considered to be due to trauma to the excretory duct and escape of mucus into the surrounding tissues. The lower lip accounts for about half of the cases (Fig. 10.14). Other common sites include the buccal mucosa, floor of the mouth, ventrum of the tongue (up to and including the tip), and the soft palate. Mucoceles are uncommon in the upper lip (~5%) and the possibility of a salivary neoplasm should always be considered when dealing with cysts at this site. The peak incidence of mucoceles is in the second and third decades: occasional cases are multiple.

Other Viral Infections of Salivary Glands

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Fig. 10.13: Congenital cytomegalovirus of parotid gland showing the characteristic “owl-eye” inclusion bodies

Cytomegalovirus is a member of the Herpesvirus group that infects the majority of the population. However, most cases are subclinical and clinically significant infections are seen predominantly in immunocompromised

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Fig. 10.15: Large ranula in the floor of the mouth

Fig. 10.17: Extravasation mucocele. High power showing numerous foamy macrophages (mucinophages)

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Fig. 10.14: Extravasation mucocele in the lower lip forming a domed, bluish swelling

a fibrous overgrowth. Mucoceles rarely exceed 1 cm in diameter except in the floor of the mouth where they can be several centimeters in size and are called ranulae (Fig. 10.15). Microscopy of early lesions shows illdefined pools of mucus and acute inflammatory infiltration. Eventually, a central cavity becomes more defined and the cyst is lined initially by granulation tissue (Fig. 10.16). This undergoes progressive fibrosis and the cyst is then lined by compressed macrophages many of which are foamy and contain mucus (mucinophages) (Fig. 10.17). Similar cells are present in the cyst cavity and are distinctive in fine needle aspirates.

Retention Mucoceles (Mucus Retention Cysts)

Fig. 10.16: Mucocele showing early cavitation and the cyst starting to be lined by macrophages

Mucoceles typically form bluish, domed swellings which occasionally fluctuate in size or may appear when eating. Some patients tend to nibble on them so they can eventually resemble

These are less common (10-15%) and are usually seen in older patients. The etiology is uncertain but it is generally believed that they are due to intermittent duct obstruction. They form unicystic cavities that are lined by modified duct epithelium. This is usually cuboidal or columnar but occasionally there is squamous, mucous or oncocytic metaplasia. Some mucoceles are located immediately beneath the oral epithelium and raise a small subepithelial blister. These superficial mucoceles are seen most frequently in the region of the palatoglossal fold but they can present in other intraoral sites. They are frequently multiple and recurrent. For unknown reasons, they appear to be much more common in women than men. Superficial mucoceles have been reported in

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Box 10.2: Mucoceles Key features useful in diagnosis • Most common oral soft tissue cysts. • 85–90 percent extravasation—due to ductal damage and salivary escape—cysts lined by compressed macrophages and fibrous tissue. • 10–15 percent retention—due to intermittent duct obstruction—cysts lined by epithelium. • Age: extravasation 2nd and 3rd decades: retention 5th to 7th decades. • Sites—50 percent lower lip, rest in cheek, tongue, floor of mouth. Rare in upper lip.

overlying mucosa and the cyst is removed, together with the related minor salivary gland. Mucoceles in the tongue have a distinct tendency to recur, probably because the associated minor glands are mainly located deeply within the lingual musculature and are damaged further by surgery. In these circumstances, cryotherapy or diathermy may be of value.

nECROTIzInG SIALOMETAPLASIA Necrotizing sialometaplasia is a relatively rare benign and self-limiting inflammatory lesion. It is typically seen in the palate although it can also be found in other minor oropharyngeal glands and occasionally major salivary glands. The main problem with this lesion is that it can simulate malignancy, both clinically and microscopically and this can lead to an erroneous diagnosis of cancer, usually squamous cell carcinoma or mucoepidermoid carcinoma.

Clinical Features

patients with intraoral lichen planus and graft versus host disease. Superficial mucoceles are more common than is generally appreciated as they rupture readily to form shallow ulcers that rapidly heal, so there may be little to see clinically. Because they form subepithelial blisters (Fig. 10.18), these lesions are sometimes confused with mucocutaneous vesiculating disorders, particularly mucous membrane pemphigoid and occasionally pemphigus vulgaris, both clinically and microscopically.

Necrotizing sialometaplasia is of uncertain cause, though it may be associated with cigarette smoking and is sometimes seen after trauma. Bilateral lesions account for about 20 percent of cases and have been reported in the palates of patients with bulimia nervosa. For unexplained reasons, it is much more frequent in the USA than in Britain. The condition predominantly affects middle-aged males (M:F 3:1). In most cases, the patient develops a relatively painless, but often deeply ulcerated (Fig. 10.19), swelling on the hard palate, midway between the midline and gingival margin. The lesion, which may be several centimeters in diameter, can clinically resemble a carcinoma but resolves spontaneously within one to three months (Fig. 10.20).

Treatment and Prognosis

Histopathology

Mucoceles often spontaneously rupture but regeneration of the overlying epithelium can result in the secretion reaccumulating. Although surgery is often necessary, sometimes it is worthwhile delaying active treatment, as the cyst may spontaneously resolve. If removal is indicated, an incision is made through the

Microscopically, there is coagulative necrosis of minor salivary gland tissue with ghost outlines of the acinar cells retaining a lobular distribution. There is often mucous extravasation and a mixed inflammatory infiltrate which is florid in advanced lesions. There is regenerative hyperplasia of the adjacent salivary ducts, often

Fig. 10.18: Superficial mucocele forming a subepithelial blister covered by attenuated oral epithelium

Fig. 10.19: necrotizing sialometaplasia causing a nondescript but deep ulcer at the junction between the hard and soft palates

Differential Diagnosis The lesion needs to be distinguished from squamous carcinoma and mucoepidermoid carcinoma (see mucoepidermoid carcinoma for details).

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with striking pseudoepitheliomatous squamous metaplasia forming islands and cords of epithelium. There is no significant cellular atypia but occasional morphologically normal mitotic figures can be seen. Mucous metaplasia may also be present. When the lesion has ulcerated there may be irregular hyperplasia of the overlying or adjacent oral epithelium which may extend into the underlying tissue as pseudoepitheliomatous down-growths (Fig. 10.21).

Treatment and Prognosis Conservative treatment, including antiseptic mouthwashes and local or systemic analgesics, is all that is required and the lesion resolves spontaneously over time.

SIALOSIS (SIALADEnOSIS)

Fig. 10.20: necrotizing sialometaplasia causing massive ulceration in the center of the palate mimicking a malignant ulcer

Sialosis is an uncommon condition characterized by noninflammatory, non-neoplastic, persistent swellings of the salivary glands, particularly the parotid glands. It is commoner in women than men and the peak incidence is in the 30 to 60 years age range.

Clinical Features

Fig. 10.21: necrotizing sialometaplasia showing structured necrosis and ghost outlines of the infarcted mucous glands and pseudoepitheliomatous hyperplasia of the adjacent salivary ducts

In most cases, there are bilateral and painless parotid swellings producing a hamster-like appearance (Fig. 10.22). Unilateral cases have been described and in some patients aplastic or hypoplastic parotid glands are present on the contralateral side. Sialosis has been reported rarely in the submandibular gland and intraoral minor glands in the palate. Occasionally patients may experience xerostomia or sialorrhea. The stimulated salivary flow rate and sialochemistry are usually within the standard range, apart from a raised potassium concentration. Sialography is usually normal, although some have described narrowing of the smaller ducts in sialograms.

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Fig. 10.22: Sialosis (sialadenosis) showing bilateral parotid swellings

The cause of sialosis is uncertain but some cases have been associated with a variety of diseases, (Table 10.1) particularly diabetes mellitus, liver disorders and bulimia. It has been postulated that a unifying etiopathogenesis for sialosis is related to peripheral autonomic nerve dysfunction. ƒ Table 10.1 Conditions associated with sialosis Hormonal • Diabetes mellitus • Ovarian insufficiency • Acromegaly • Hypothyroidism • uremia Metabolic • Cirrhosis • Alcoholism • Malnutrition • Bulimia • Chronic pancreatitis • Chronic renal failure Drugs • Iodine containing drugs • Antihypertensives • Isoprenaline • Lead • Mercury • naproxen

Fig. 10.23: Sialosis (Sialadenosis) of parotid gland showing hypertrophy of the serous acinar cells

Histopathology Sialosis is rarely biopsied but microscopy shows that the acinar cells are swollen (hypertrophied) usually with densely packed zymogen granules but sometimes showing vacuolated cells with a loss of cytoplasmic granules (Fig. 10.23). Occasionally, there is a mixed population. In some cases, there is extensive fatty infiltration and parenchymal atrophy, but inflammation is typically absent.

Treatment and Prognosis Nutritional and drug-related sialosis can regress if the associated factors are eliminated but in cases due to diabetes mellitus and chronic alcohol abuse, sialosis usually persists despite treatment.

AuTOIMMunE DISORDERS Sjögren’s Syndrome Sjögren's syndrome is one of the most common, chronic autoimmune disorders affecting about 0.5 percent of the population. It is characterized by dry mouth and dry eyes. The histological hallmark of Sjögren's syndrome is the development of lymphoepithelial sialadenitis (LESA). Affected glands show focal acinar atrophy associated with multifocal periductal lymphocytic infiltration and the development of lymphoepithelial lesions (‘epimyoepithelial

ƒ Table 10.2 Diseases most commonly associated with secondary Sjögren's syndrome

Clinical Features There are two main forms of the disease: primary and secondary. Primary Sjögren's syndrome (sicca syndrome) consists of dry mouth and dry eyes in the absence of any other connective tissue disease. The glandular destruction tends to be severe and is often associated with extraglandular disease. Secondary Sjögren's syndrome is the combination of dry eyes, dry mouth and a connective tissue disorder, usually rheumatoid arthritis. The sicca symptoms are frequently less severe than in the primary type. The percentages shown in Table 10.2 are the proportion of patients with a connective tissue disorder who also have Sjögren's syndrome. Because rheumatoid arthritis is far-and-away the most common connective tissue disorder, they form the bulk of patients likely to be seen. On the other hand, because Sjögren's syndrome is so common in patients with primary biliary cirrhosis, it is often possible through the appropriate investigations, to make a diagnosis of potentially serious hepatic disease in an otherwise symptomless patient. There is a F:M ratio of about 9:1. Most patients are middle aged or elderly, but much younger patients can also be affected. Intermittent enlargement of the major salivary glands, particularly the parotid, affects approximately 20 percent of patients, and there is persistent enlargement in about 5 percent. Sometimes, the principle complaint is not a dry mouth itself, but one of its consequences such as disturbed taste, impaired speech, intraoral soreness or difficulty in swallowing dry food. The oral mucosa can appear dry and wrinkled but frequently seems to be unremarkable. However, there may be no obvious flow of saliva from the parotid ducts and frothy or stringy saliva, particularly in the lower vestibular sulci

Rheumatoid arthritis (15%)

Systemic lupus erythematosus (30%)

Systemic sclerosis (scleroderma)

Dermatomyositis

Polyarteritis nodosa

Primary biliary cirrhosis (70%)

10 SALIVARy GLAnD DISORDERS

islands’). The damage is progressive and leads to increasing functional impairment. The etiology of Sjögren’s syndrome is unknown but a variety of viral and genetic factors have been causally associated. Lesions closely resembling LESA can be seen in patients with HIV and hepatitis C infections but a direct role of viruses in the pathogenesis of Sjögren's syndrome is yet to be established.

Fig. 10.24: Sjögren's syndrome showing characteristic lobulated tongue and angular stomatitis

and floor of the mouth. In long-standing cases, the tongue becomes partially depapillated and develops a very characteristic lobulated dorsal surface (Fig. 10.24). Candidal infections are very common and these lead to redness, glazing and soreness of the oral mucosa. Obvious candidal plaques are not frequently seen but may be present in protected mucosal reflections. Angular stomatitis is also common. The xerostomia predisposes to rampant dental caries affecting the cervical collars of the teeth particularly severely. Oral dryness changes the balance of the oral flora and this, together with the compromised secretory function, predisposes patients to acute suppurative parotitis. The dry eyes associated with Sjögren's syndrome (keratoconjunctivitis sicca) can be the most debilitating aspect of the condition. It results in burning, itching and blurring of vision. Thick secretions tend to accumulate in the conjunctival sac and the conjunctiva may become severely erythematous.

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In addition, significant numbers of patients with Sjögren's syndrome, including those with the primary form, can display a wide range of extraglandular manifestations, as shown in Table 10.3.

Diagnosis Patients frequently have nonspecific markers of inflammation such as a raised erythrocyte sedimentation rate and raised C-reactive protein. There is also frequently mild anemia, leukopenia and thrombocytopenia. About half of patients have polyclonal hypergammaglobulinemia. Autoantibodies, particularly rheumatoid factor and rheumatoid arthritis precipitin (RAP), are found in 90 and 75 percent, respectively, of cases of secondary Sjögren's syndrome, but in only 50 and 5 percent, respectively, in primary disease. SS-A (Ro) antibodies are more specific and found in 5 to 10 percent of cases of the primary disease, but in 50 to 80 percent of cases of secondary disease. SS-B (La) antibodies are found in about 75 percent of cases of primary disease, but in 5 percent or less of secondary disease. Gastric ƒ Table 10.3 Extraglandular manifestations of Sjögren's syndrome Musculoskeletal Hematolymphoid

Gastrointestinal

Cutaneous

Respiratory Renal

Vascular

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Rheumatoid arthritis, nonerosive arthritis, myasthenia gravis Generalized lymphadenopathy, non-Hodgkin lymphoma (40x risk), Waldenström’s macroglobulinemia Hepatitis (primary biliary, chronic active), pancreatitis, pernicious anemia Rashes of systemic lupus erythematosus or dermatomyositis, purpura Parenchymal lung involvement (common but rarely serious) Glomerulonephritis, renal calculi, renal tubular acidosis, interstitial nephritis Raynaud’s syndrome, vasculitis leading to peripheral neuropathies, including benign sensory trigeminal neuropathy

parietal cell, thyroid microsomal, thyroglobulin and smooth muscle autoantibodies may also be detected.

Histopathology The characteristic microscopical feature of Sjögren's syndrome is lymphoepithelial sialadenitis (LESA). The initial lesion in the salivary gland is a polyclonal B-and T-cell lymphocytic infiltration aggregating focally around small, intralobular ducts. This periductal infiltrate spreads centrifugally, destroying and replacing the surrounding salivary parenchyma (Fig. 10.25A). Reactive lymphoid follicles with germinal centers form in the increasingly dense lymphoid infiltrate which becomes more mixed and contains plasma cells, immunoblasts and histiocytes. Adjacent focal infiltrates eventually fuse and spread throughout the entire salivary lobule but do not cross the interlobular septa. At the same time, the intralobular ducts undergo proliferation of their luminal cells which eventually obliterates the duct lumen forming solid cords. In two dimensional sections these appear as islands. These were previously called epimyoepithelial islands (Fig. 10.25A) but, as the role of myoepithelial cells in their formation is questionable, they are now simply called epithelial islands. These islands frequently contain eosinophilic, hyaline droplets consisting of basement membrane material such as type IV collagen and laminin. In addition, they are infiltrated by variable numbers of monoclonal monocytoid or marginal zone B cells. Squamous metaplasia of the epithelial islands is an uncommon feature. Focal periductal lymphocytic sialadenitis can be seen in the minor salivary glands of patients with Sjögren's syndrome. However, in minor glands the characteristic lymphoepithelial lesions with ductal proliferation are uncommon. The number and distribution of the lymphocytic foci mirror, to a degree, the extent of the disease present in major glands, and biopsies of minor glands from the lower lip have been used for diagnostic purposes (Fig. 10.25B). The number of defined, focal aggregates adjacent to normal appearing mucous acini and containing more than 50 lymphocytes in 4 mm2 of tissue is

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B

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A

Figs 10.25A and B: (A) Sjögren's syndrome. Late stage lymphoepithelial sialadenitis showing total acinar destruction and replacement by lymphocytes and an epithelial island containing hyaline deposits; (B) Labial gland biopsy showing multifocal, periductal, lymphocytic sialadenitis

counted in at least four lobules. A focus score of 1 or more is consistent with a diagnosis of Sjögren's syndrome.

Treatment and Prognosis This is dealt with in Chapter 11.

nEOPLASTIC SALIVARy DISORDERS Salivary gland tumors are a diverse and complex range of neoplasms. They form only about 3 percent of tumors in the head and neck but in the current World Health Organization classification there are 13 benign and 24 malignant named epithelial tumors, and many of these have defined variants (Table 10.4). In addition, some benign tumors have a propensity to recur or to progress to malignancy, and some malignant tumors behave in a relatively low grade manner. In this Chapter, only the most common and clinically signifcant tumors will be considered in detail.

BEnIGn nEOPLASMS Pleomorphic Adenoma Pleomorphic adenoma has been defined as ‘a tumor of variable capsulation characterized

microscopically by architectural rather than cellular pleomorphism. Epithelial and modified myoepithelial elements intermingle most commonly with tissue of mucoid, myxoid or chondroid appearances’. Synonyms include mixed tumor and benign mixed tumor.

Clinical Features Pleomorphic adenoma is the most common salivary gland tumor and accounts for between about half and two thirds of all tumors seen in the parotid, submandibular glands and minor glands. It is rare in the sublingual gland where, for unknown reasons, most of the tumors are malignant. The tumor has a wide age range with a peak incidence in the fourth and fifth decades. As with many other salivary neoplasms, children and adolescents can be affected. There is a female preponderance of about 2:1. About 80 percent arise in the parotid gland with most of the rest developing in the submandibular (~10%) and intraoral minor salivary glands (~10%). In the major glands, pleomorphic adenoma usually forms a slow-growing, painless swelling (Fig. 10.26A). This tends to be smooth, firm and mobile. In larger tumors particularly, the surface may be knobbly or bosselated. Deep lobe tumors may present as a parapharyngeal mass. Minor gland pleomorphic adenomas usually form painless, mobile, submucosal swellings.

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ƒ Table 10.4 WHO histological classification of tumors of the salivary glands 2005 Malignant epithelial tumors

Benign epithelial tumors

• • • • • • • • • • • • • • • • • • • • • • •

• Pleomorphic adenoma • Myoepithelioma • Basal cell adenoma • Warthin tumor • Oncocytoma • Canalicular adenoma • Sebaceous adenoma • Lymphadenoma – Sebaceous – nonsebaceous • Ductal papillomas – Inverted ductal papilloma – Intraductal papilloma – Sialadenoma papilliferum • Cystadenoma Soft tissue tumors • Hemangioma Hematolymphoid tumors • Hodgkin lymphoma • Diffuse large B-cell lymphoma • Extranodal marginal zone-B cell lymphoma Secondary tumors

Acinic cell carcinoma Mucoepidermoid carcinoma Adenoid cystic carcinoma Polymorphous low-grade adenocarcinoma Epithelial-myoepithelial carcinoma Clear cell carcinoma, not otherwise specified Basal cell adenocarcinoma Sebaceous carcinoma Sebaceous lymphadenocarcinoma Cystadenocarcinoma – Low-grade cribriform cystadenocarcinoma Mucinous adenocarcinoma Oncocytic carcinoma Salivary duct carcinoma Adenocarcinoma, not otherwise specified Myoepithelial carcinoma Carcinoma ex-pleomorphic adenoma Carcinosarcoma Metastasizing pleomorphic adenoma Squamous cell carcinoma Small cell carcinoma Large cell carcinoma Lymphoepithelial carcinoma Sialoblastoma

A

B

Figs 10.26A and B: (A) Large pleomorphic adenoma of the submandibular gland; (B) Pleomorphic adenoma at the junction of the hard and soft palates

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In the palate, however, they typically present as unilateral swellings at the junction of the hard and soft palates (Fig. 10.26B). Here they tend to

be fixed to the underlying mucoperiosteum. In addition, at this site particularly, they may ulcerate as a result of masticatory trauma.

Histopathology

Differential Diagnosis

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Pleomorphic adenomas, as their name implies, can show a very wide range of morphological diversity. The principle elements are epithelial cells, modified myoepithelial cells and mesenchymal. The epithelial component shows a variety of cell types and architectural configurations. Cell types include cuboidal, basaloid and squamous epithelial cells and the myoepithelial cell component can be spindle, plasmacytoid or clear. The cellular elements can form sheets, cords or duct-like structures (Fig. 10.27A). The latter are frequently double layered with an inner layer of duct lining cells and an outer layer of myoepithelial cells which often have clear cytoplasm and small, hyperchromatic and angular nuclei. The duct lumina may contain eosinophilic secretions and may also dilate to form microcysts. Squamous metaplasia, with or without keratinization, is common (Fig. 10.27B). A very characteristic feature of some tumors is the formation of so-called hyaline or plasmacytoid cells which are modified myoepithelial cells (Fig. 10.27C). These tend to form sheets of loosely adherent cells. The mesenchymal component is a product of the myoepithelial cells and can be mucoid, myxoid, cartilaginous or hyalinized (Fig. 10.27D). It sometimes forms the main element of the tumor. The tumor cartilage has the same structure as normal cartilage and stains for both type II collagen and the proteoglycan keratan sulfate. Occasionally bone forms either by a process resembling endochondral ossification or stromal osseous metaplasia. Mucoid areas are sparsely cellular and contain scattered myoepithelial cells whose cytoplasm tends to merge with the surrounding stroma. There is a distinct tendency for pleomorphic adenomas progressively to scar and be replaced by fibrous and elastic tissue. In old tumors there may be extensive dystrophic calcification. Pleomorphic adenomas are often encapsulated but the capsule varies in both thickness and extent (Fig. 10.27D). Some tumors, particularly those that are predominantly mucoid, may show little evidence of a capsule and tumor is in direct continuity with the surrounding salivary parenchyma (Fig. 10.27E). In addition,

tumors can show invasion of the capsule and sometimes the tumor bulges through small gaps in the capsule to produce what look like satellite tumors (Fig. 10.27F). There is a tendency for the tumor to split away from the capsule during surgical and pathological manipulation. This was thought by surgeons to offer a plane of cleavage but the split is intratumoral and leaves tumor adherent to the capsule. In minor gland pleomorphic adenomas the capsule is often a poorly formed or absent.

When tumors show the characteristic combination of epithelial and mesenchymal components the diagnosis is relatively straight forward but in limited biopsy material there can be problems. For example, double-layered duct-like structures, as described previously, can be seen in both adenoid cystic carcinoma and epithelial myoepithelial carcinoma and it may not be possible to make the distinction in small biopsies. Areas of squamous metaplasia are common in pleomorphic adenomas but these show no cellular atypia and the presence of other components, particularly plasmacytoid cells and stromal elements, should prevent confusion with squamous carcinoma.

Treatment and Prognosis Although pleomorphic adenoma is a benign tumor it has a tendency both to recur and undergo malignant transformation. Recurrences are mainly seen in the major glands, particularly the parotid, and they are usually multifocal. Surgery in the parotid gland is complicated by the presence of the facial nerve. In attempts to preserve this nerve, initially surgeons used to curette the tumor or remove it by dissecting around the ‘capsule’. However, the relationship between the tumor and its capsule described previously militates against the success of this procedure and recurrence rates of over 50 percent have been recorded in the older literature. Most surgeons now use either superficial parotidectomy or one of its limited variants to remove these tumors. Mucoid tumors are particularly prone

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A

B

C

D

E

F

Figs 10.27A to F: (A) Low power of pleomorphic adenoma showing double-layered duct-like structures; (B) Duct-like structures containing eosinophilic secretions and a focus of squamous metaplasia; (C) Plasmacytoid (hyaline) and spindle-shaped myoepithelial cells; (D) Discrete fibrous capsule, myxochondroid areas and duct-like structures; (E) no obvious capsule and a ‘satellite’ nodule that is usually attached to the main tumor mass by a thin isthmus; (f) Capsular invasion

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to recurrence as their diffluent nature leads to a high-risk of intraoperative rupture and it is probable that the low biological requirements of such tumors allows implanted cells to survive. In recent years the reported rate of recurrence is around about 5 percent but the longer cases

are followed up, the more likely recurrences will be detected. Radiotherapy has been used to both prevent and treat recurrences but its value is debatable. The risk of malignant change is discussed in the section covering carcinoma ex-pleomorphic adenoma.

Box 10.3: Pleomorphic adenoma

Warthin’s Tumor Warthin’s tumor is defined as ‘a tumor composed ofglandularandoftencysticstructures,sometimes with a papillary cystic arrangement, lined by characteristic bilayered epithelium, comprising inner columnar eosinophilic or oncocytic cells surrounded by smaller basal cells. The stroma contains a variable amount of lymphoid tissue with germinal centers’. Synonyms include adenolymphoma, cystadenolymphoma, and papillary cystadenoma lymphomatosum. Analysis of the X chromosome-linked human androgen receptor gene has shown that Warthin’s tumor is nonclonal, and this makes its neoplastic status questionable.

Clinical Features Warthin’s tumor is the second most common neoplasm of the salivary glands and arises virtually exclusively in the parotid gland and para-parotid lymph nodes. It is much less frequent in dark-skinned individuals than Caucasians. Over the last 60 years, the M:F has gone from 10:1 to parity. This has been linked with the increasing frequency of women who smoke cigarettes, as it is known that the incidence of these tumors in smokers is eight times that of nonsmokers. Most patients are in the 50 to 70 years age group. Warthin’s tumor usually presents as a slow-growing, soft, mobile mass in the parotid gland. It is uncommon for tumors to exceed 4 cm in size. Pain, rapid

Histopathology Warthin’s tumor is circumscribed and usually has a thin, fibrous capsule which may be incomplete. It has papillary cystic spaces of varying sizes (Fig. 10.28A) and these contain viscous clear or brownish fluid. Occasionally tumors are unicystic and some can be solid. The microscopical features are very characteristic. The tumor has two major components: epithelial and lymphoid (Fig. 10.28B). The proportion of these components is variable and either can predominate. The cysts are lined by a double layer of epithelial cells which often project into the cystic spaces as papillary infoldings. In the luminal layer, the cells are tall and columnar and contain oncocytic (i.e. pink and granular) cytoplasm (Fig. 10.28C). The nuclei are oval and bland and are located centrally or form a palisaded row towards the luminal end of the cell. The cell surface often shows apocrine blebbing and occasionally cilia are seen. The cytoplasm of the abluminal cells is similar, but these cells are cuboidal in shape and are less regular and abundant. Foci of squamous and mucous metaplasia are relatively common (Fig. 10.28D). The cystic cavities may contain variable amounts of eosinophilic material and cholesterol clefts. The stroma consists of reactive lymphoid tissue consisting of polyclonal B and T cells, usually together with reactive follicles. Sometimes, the tumor shows a close resemblance to a normal lymph node and has a defined capsule and subcapsular sinus. Microscopic foci of inflammation, squamous metaplasia, degeneration and fibrosis are common. In some cases, however, there is virtual obliteration of the lymphoid and sometimes the epithelial component, and replacement by necrotic, inflammatory and fibrous tissue. This appearance has been called the ‘infected’, ‘infarcted’ or ‘metaplastic’ variant of Warthin’s tumor. In some cases, there is extensive squamous metaplasia that can be confused with malignancy. In

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Key features helpful in diagnosis • Most common salivary neoplasm: ~60 percent of parotid, submandibular and minor gland tumors. • f:M 2:1 Peak incidence 4th and 5th decades. • Slow-growing, painless, mobile mass. • Well circumscribed mass with variable encapsulation. • Epithelial component: Duct-like structures and sheets. • Myoepithelial component: Plasmacytoid (hyaline cell), epithelioid, spindle cell, clear. • Mesenchymal component: Myxoid, myxochondroid, hyalinized, osseous.

expansion and sometimes facial nerve weakness can be seen in tumors that become inflamed or infarcted. Warthin’s tumor is the most common salivary neoplasm showing multifocally, both unilaterally and bilaterally, and may be seen in association with other salivary tumors.

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A

B

C

D

Figs 10.28A to D: (A) Low power of Warthin’s tumor showing two of several nodules in the same parotid gland; (B) Papillary projections of oncocytic epithelium projecting into cystic spaces and a dense lymphocytic stroma; (C) Palisaded luminal cells and less numerous basal cells, in addition there are both ‘light’ and ‘dark’ (pyknocytes) cells; (D) Mucous metaplasia

addition, epithelioid granulomas, with or without multinucleated giant cells, can form and these have sometimes been misinterpreted as tuberculosis or sarcoidosis.

Differential Diagnosis

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Typical Warthin’s tumor is the easiest salivary neoplasm to diagnose microscopically. Papillary cystadenoma closely resembles Warthin’s tumor but lacks a lymphoid component. As described previously, the infarcted variant is the type most likely to lead to confusion. This will probably become more frequent with the increasing use of fine needle aspiration biopsies. The presence of tumor tissue within an intra- or para-parotid lymph node, particularly if cystic, means that a metastasis may need to be considered. In such a case, the tumor is likely to show obvious cytological features of malignancy and misdiagnosis is unlikely.

Treatment and Prognosis If the diagnosis can be confidently made on diagnostic imaging and/or fine needle Box 10.4: Warthin's tumor Key features helpful in diagnosis • Second most common salivary tumor—seen almost exclusively in parotid. • f:M ~ 1:10 Peak incidence in 6th and 7th decades. • Slow-growing painless mass can be multifocal and bilateral. • Circumscribed, usually cystic mass with intraluminal papillary ingrowths. • Epithelial component—double-layered and oncocytic with columnar luminal cell and cuboidal basal cells. Mucous and squamous metaplasia. • Mesenchymal component—dense masses of polyclonal B and T lymphocytes and germinal centers.

from the loosely collagenized and sparsely cellular stroma. There is a distinct tendency for the stroma to undergo degeneration producing microcystic spaces containing a network of congested and dilated capillaries. There may be areas of inflammation, interstitial hemorrhage and hemosiderin deposition.

Canalicular Adenoma

Differential Diagnosis

Canalicular adenoma is defined as ‘a tumor composed of columnar epithelial cells arranged in thin, anastomosing cords with a beaded pattern. The stroma is characteristically paucicellular and highly vascular. Synonyms include basal cell adenoma (canalicular type), monomorphic adenoma (canalicular type) and monomorphic adenomatosis of minor salivary glands.

The main differential diagnoses are basal cell adenoma and adenoid cystic carcinoma. The bilayered nature of canalicular adenoma and the characteristic stromal degeneration helps to distinguish the tumor from the trabecular and tubulotrabecular variants of basal cell adenoma. Occasional tumors have components resembling both neoplasms and it may not be possible to make a meaningful distinction. Adenoid cystic carcinomas are likely to show invasion and have a different nuclear morphology. It is important to not to interpret multifocality as evidence of local infiltration.

Clinical Features Canalicular adenoma is uncommon and is seen almost exclusively in minor glands, particular the upper lip (80%) and adjacent buccal mucosa. It is seen predominantly in adults, with a mean age of about 65 years: there is a slight female preponderance. Occasional cases are bilateral or multifocal. Canalicular adenoma usually presents as a slow-growing, painless, mobile swelling that can appear cystic or solid. The overlying oral mucosa may appear normal or have a bluish hue. Tumors are typically 1 to 2 cm in diameter.

Histological Features Canalicular adenomas are well circumscribed and variably encapsulated (Fig. 10.29A). They are usually multicystic but sometimes tumor tissue is no more than a focal area of mural thickening in a single cyst. Foci of adenomatous change can sometimes be present in adjacent minor salivary gland lobules. The tumor forms parallel rows of single columnar or, less commonly, cuboidal epithelial cells. These rows may be focally opposed, but at intervals the rows tend separate forming a characteristic ‘beaded’ appearance. The cells are cytologically bland and have eosinophilic cytoplasm and round nuclei with finely granular basophilic nuclei. The cellular cords are usually sharply demarcated

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aspiration biopsy, active treatment may not be necessary. Conservative surgery is usually curative and the few cases of ‘recurrence’ are probably due to the development of new tumors. Malignant change in the epithelial and lymphoid elements of Warthin’s tumor has been reported, but it is very rare.

Treatment and Prognosis Complete, conservative surgical excision is usually curative. Recurrence is likely to be the result of multifocality. Box 10.5: Canalicular adenoma Key features helpful in diagnosis • uncommon and seen almost exclusively in minor glands, particularly upper lip (~80%). • Slight female predominance, peak incidence in 7th decade. • Slow-growing painless mass which can appear cystic or solid. • Can be multifocal and bilateral. • Well circumscribed and variably encapsulated. • Parallel rows of single columnar cells with focal separation producing a ‘beaded’ appearance. • Degenerative stroma forming micro- and macrocyts.

Basal Cell Adenoma Basal cell adenoma is defined as ‘a rare benign neoplasm characterized by the basaloid appearance of the tumor cells and absence of the myxochondroid stromal component present in pleomorphic adenoma’.

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Basal cell adenomas are rare and account for about 2 percent of salivary gland tumors. The large majority affect the major salivary glands, particularly the parotid (75%). The few reported cases in minor glands have mainly involved the upper lip. The tumors are usually seen in older individuals with a mean age at presentation of 58 years. In most subtypes, there is F:M of about 2:1 but in the membranous variant there is no sex predilection. The tumors usually present as a painless, mobile, solid mass that is usually less than 3 cm in diameter.

Histopathology Basal cell adenomas are well circumscribed and encapsulated and may contain cystic spaces (Fig. 10.29B). Microscopy shows the tumor is composed of basaloid cells arranged in cords, sheets, nests and duct-like structures. There are two main cell types: one has scanty eosinophilic cytoplasm and round, basophilic nuclei with indistinct nucleoli and the other has a large pale nucleus and abundant cytoplasm. The cells are cytologically bland and there are few, if any, mitoses. Basal cell adenoma can be subclassified into four subtypes: trabecular, tubular, solid and membranous, but some tumors can display more than one architectural pattern. All the variants can show cystic change. The most common subtype is solid and forms sheets of variable size and shape. The peripheral cells are cuboidal or columnar and often show palisading. These cells have the immunological characteristics of modified myoepithelial cells. There may be focal areas of cellular whorling and squamous eddies, sometimes with focal keratinzation, can be seen. Some tumors contain cribriform, pseudocystic areas. The islands are sharply demarcated from the loosely cellular fibrous stroma. In the trabecular variant the cells are arranged as interconnecting narrow cords. In some of these cases, the stroma is richly cellular and the cells have myoepithelial characteristics. The tubular variant is very uncommon and consists of duct-like structures surrounded by one or more layers of basaloid cells enclosing eosinophilic secretions. Most cases show

combinations with trabecular patterns and some pathologists merge the two variants into a tubulotrabecular subtype (Fig. 10.29C). The membranous variant (dermal analog tumor) is rare and microscopically resembles cutaneous eccrine dermal cylindroma. The growth pattern is similar to that of the solid variant but the cell islands are surrounded by thick and distinctive hyaline membrane and coalescing globules of similar material are present in the intercellular area (Fig. 10.29D). This variant is often multifocal and bilateral.

Differential Diagnosis The main differential diagnoses are basal cell adenocarcinoma, adenoid cystic carcinoma, pleomorphic adenoma and canalicular adenoma. Basal cell adenocarcinoma can show limited cellular atypia and mitotic activity and is distinguished from basal cell adenoma largely on the basis of evidence of invasion. Although cribriform areas can occasionally be seen in basal cell adenoma, the tumor is noninvasive and has different nuclear morphology from adenoid cystic carcinoma. Areas resembling basal cell adenoma can sometimes be seen in pleomorphic adenoma. However, basal cell adenomas themselves lack the other characteristic features of pleomorphic adenoma such as plasmacytoid cells, myxochondroid matrix, etc. Canalicular adenomas have characteristic double-layered trabeculae and lack evidence of myoepithelial differentiation.

Treatment and Prognosis Basal cell adenoma is essentially benign and conservative excision is usually curative. However, the membranous variant can be multifocal and bilateral and this may lead to apparent recurrence in about a quarter of affected patients. In addition, this variant may have coexisting cutaneous tumors including multiple dermal cylindromas (turban tumors of the scalp), trichoepitheliomas, basal cell tumors and others. Exceptionally, basal cell adenomas can progress to form basal cell adenocarcinomas and, even more rarely, other forms of carcinoma.

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Figs 10.29A to D: (A) Canalicular adenoma showing the characteristic bilayered columnar epithelium and stromal degeneration; (B) Basal cell adenoma showing solid variant; (C) Tubulotrabecular variant; (D) Membranous variant (dermal analog tumor) containing solid islands of tumor with peri- and intratumoral hyaline material Box 10.6: Basal cell adenoma Key features helpful in diagnosis • Rare: About 2 percent of salivary tumors and large majority seen in major glands. • f:M 2:1 Peak incidence in 6th decade. • Slow-growing painless mobile mass: Membranous variant can be multifocal and bilateral and associated with cutaneous neoplasms. • Well circumscribed encapsulated mass. • Basaloid epithelial and myoepithelial cells in solid, trabecular, tubular and membranous configurations. • Some tumors have ‘myoepithelial cell-rich’ stroma.

MALIGnAnT nEOPLASMS Acinic Cell Carcinoma Acinic cell carcinoma is defined as ‘a malignant epithelial neoplasm of salivary glands in

which at least some of the neoplastic cells demonstrate serous acinar differentiation, which is characterized by cytoplasmic zymogen secretory granules. Salivary ductal cells are also a component of this neoplasm’. Synonyms include acinic cell adenocarcinoma and acinous cell carcinoma.

Clinical Features Acinic cell carcinoma accounts for about 3 to 6 percent of all salivary gland tumors and between 7 and 17.5 percent of malignant salivary neoplasms in major series. About 80 to 90 percent of cases arise in the parotid gland and most of the remainder involve the minor glands of the oral cavity, particularly the upper lip, buccal mucosa and palate. The tumor is relatively uncommon in the submandibular and sublingual glands. There is a slight female preponderance and the tumor affects a wide

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age range (3–91 years) with a mean of 44 years. Acinic cell carcinoma usually presents as a slow-growing, mobile mass, although some cases may be fixed and nodular. About half the patients complain of pain or tenderness and 5 to 10 percent show involvement of the facial nerve.

Histopathology Macroscopically, the tumors are usually circumscribed, round or lobulated and they rarely exceed 3 cm in diameter. Microscopy can show a very wide range of cell types and morphological configurations. The archetypal cell is acinic and closely resembles normal serous cells. These cells are round or polyhedral and have abundant, pale, basophilic cytoplasm which contains dense, grayish or blue zymogen granules. These may be fine or moderately coarse and are periodic acid Schiff positive and diastase resistant. The nuclei are round, uniform, and typically located peripherally. They are usually darkly stained and basophilic or occasionally more vesicular. Other cell types include intercalated ductal, nonspecific glandular, vacuolated and clear cells. Intercalated duct cells are smaller than the acinar cells and are cuboidal in shape. They have less cytoplasm which is eosinophilic or amphophilic. The nuclei are usually centrally located. These cells surround central duct-like spaces of variable sizes. Nonspecific glandular cells are polygonal or round and are smaller than acinar cells. Their cytoplasm is amphophilic and they usually aggregate as sheets of cells with indistinct cytoplasmic borders. The nuclei are larger and more vesicular than in the other cell types and, in addition, they may show mild pleomorphism and occasional mitotic figures. Vacuolated cells are common and are sometimes a conspicuous component of the tumor. They are round or polygonal and contain clear, PAS/D negative cytoplasmic vacuoles of variable sizes and occasional zymogen granules. The nuclei have an open chromatin pattern and may also show mild pleomorphism. Cells with clear cytoplasm and distinct cell membranes may be seen singly or in small foci but they are rarely a conspicuous feature. They do not contain glycogen and, in some cases, may be a fixation or processing artefact.

A wide variety of growth patterns can be seen in acinic cell carcinoma, including solid, microcystic, papillary—cystic and follicular, and tumors may contain several of these architectural subtypes. The solid type usually consists of sheets or nodules of closely aggregated, cytologically bland acinar cells (Fig. 10.30A) and sometimes smaller numbers of nonspecific glandular cells or intercalated ductal cells. The microcystic pattern is the most common and consists of numerous small spaces within more solid tumor, producing a lattice–like pattern (Fig. 10.30B). In addition to the acinar cells, these tumors may contain intercalated ductal and vacuolated cells. The cystic spaces can enlarge and there may be intracystic papillary proliferation. In this papillary-cystic variant, luminal cells may show conspicuous hob-nailing and typical acinic cells may be inconspicuous (Fig. 10.30C). This variant often shows intratumoral and intracystic hemorrhage and phagocytosis of hemosiderin by tumor cells. The follicular pattern is uncommon but distinctive, and consists of multiple cystic spaces of varying sizes (Fig. 10.30D). These are lined predominantly by cells of the intercalated duct type and contain homogeneous, eosinophilic and proteinaceous material. The intercystic areas consist predominantly of nonspecific glandular cells. Psammoma bodies are an occasional but sometimes conspicuous feature of acinic cell carcinomas. The stroma is usually scanty and composed of delicate fibrovascular tissue but may become more dense and hyalinized. Infiltration of the stroma by lymphocytes is common, but some tumors show very striking tumor-associated lymphoid proliferation, together with germinal center formation. These tumors tend to be of the solid or microcytic type, are well circumscribed, and have a low MIB-1 proliferation index. This variant has been termed ‘well-differentiated acinic cell carcinoma with abundant lymphoid stroma’ and preliminary data suggest that it has more favorable prognosis.

Differential Diagnosis The cellular and architectural variability of acinic cell carcinoma can make precise diagnosis difficult. Solid tumors especially, can

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Figs 10.30A to D: (A) Acinic cell carcinoma. Solid type showing granular basophilic cells that resemble normal serous acinar cells; (B) Microcystic pattern and lymphocyte-rich stroma; (C) Papillary-cystic variant; (D) follicular pattern

closely resemble normal salivary serous acini or sialadenitis, particularly in limited material. The lack of other structures such as intercalated or striated ducts should aid recognition. Papillary variants need to be distinguished from cystadenocarcinoma and the presence of zymogen granules and vacuolated cells may help. The microcystic spaces contain mucicarmine-positive secretions and can be misinterpreted as mucocytic differentiation in a mucoepidermoid carcinoma. These tumors, however, lack other characteristic features of mucoepidermoid carcinomas, including intermediate and epidermoid cells. The follicular variant of acinic cell carcinoma resembles follicular thyroid carcinoma but in equivocal cases staining for thyroglobulin avoids confusion.

Treatment and Prognosis The average recurrence rate is about 35 percent and the average rate of metastasis and diseaseassociated death is about 16 percent but these figures mask a very wide range in the literature. In a meta analysis of over 2000 cases, the 5and 10-year survival was 82 and 68 percent respectively. Multiple recurrences, locoregional or distant metastases, usually to lung or bone, are associated with an unfavorable outcome. Tumors in the minor glands have a better prognosis than those in major glands, and submandibular gland tumors have a particularly poor prognosis. There are no universally accepted histological grading schemes for this tumor, and no consistent relationship between the main histological subtypes and prognosis.

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Histological features that may be associated with a poor prognosis, however, include high mitotic frequency, cellular pleomorphism, necrosis, perineural or vascular invasion, stromal desmoplasia and widespread invasion. Clinical staging at presentation appears to be the best predictor of clinical outcome. Large size (> 6 cm diameter) and the involvement of the deep lobe of the parotid gland are associated with a worse outcome. Multiple recurrences, multinodularity and the presence of regional or distant metastases are indicators of poor prognosis. Superficial parotidectomy is the usual treatment and neck dissection is not undertaken unless there is good evidence of regional metastasis. Failure to remove the tumor completely at the first excision is another indicator of poor outcome. Box 10.7: Acinic cell carcinoma Key features helpful in diagnosis • Accounts for 3–6 percent salivary tumors: 80–90 percent parotid and minor glands next most common location. • f:M ~ 1.5:1 Wide age range (3–91) with peak incidence in 5th decade. • Slow-growing, mobile or fixed mass with variable pain and/or facial nerve involvement. • usually less than 3 cm often circumscribed but nonencapsulated. • Characteristic serous acinar cells with other cell types including nonspecific glandular, intercalated duct, vacuolated and clear. • Diverse architectural patterns including solid, microcystic, papillary-cystic and follicular.

Mucoepidermoid Carcinoma Mucoepidermoid carcinoma is defined as ‘a malignant glandular epithelial neoplasm characterized by the proliferation of mucous, intermediate and epidermoid cells, with columnar, clear and oncocytic features’.

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Mucoepidermoid carcinoma is the commonest primary malignant salivary neoplasm in most major series (12–29%). It can be seen in both adults and children and the mean age is around

45 years. About half of the cases affect the major glands, particularly the parotid gland (45% of cases). The tumor can involve a wide range of intraoral sites including the palate, buccal mucosa, lips, retromolar pad, tongue and floor of mouth. Rare, central (intraosseous) cases have been reported, mainly involving the body and angle of mandible. There is a slight female predominance of about 1.5:1. Mucoepidermoid carcinoma usually presents as a slow-growing, painless, fixed mass. The tumor may be tender, and in advanced tumors there may be neural involvement, trismus and dysphagia. Intraoral tumors may present as a bluish red, fluctuant swelling that closely resembles a mucocele or a vascular blemish.

Histopathology Mucoepidermoid carcinoma may appear macroscopically circumscribed or partially encapsulated but they are almost invariably invasive. Mucoepidermoid carcinomas form sheets, islands and duct-like structures together with cysts of variable sizes (Fig. 10.31A). The cysts contain mucinous secretions and commonly rupture spreading mucus and tumor cells into the surrounding tissue and evoking a florid inflammatory reaction. The tumor consists predominantly of three cell types: epidermoid, intermediate and mucous. The proportion of each cell type can vary widely between tumors and sometimes within a single tumor mass. Less common cell types include columnar cells, clear cells and oncocytes. Intermediate cells usually predominate and range from small basal cells with scanty, basophilic cytoplasm and small, central, hyperchromatic nuclei to large, oval cells with more abundant, eosinophilic cytoplasm. Intermediate cells usually form sheets and may be the basal layer of intratumoral cysts (Fig. 10.31B). Epidermoid cells may be relatively uncommon and are polygonal in shape, with ovoid or elongated, vesicular nuclei and abundant eosinophilic cytoplasm. Individual cell keratinization or keratin pearl formation is usually only seen following a biopsy or fine needle aspiration. Mucocytes are large with pale, slightly blue and sometimes foamy cytoplasm that is positive for mucicarmine, Alcian blue

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Figs 10.31A to D: (A) Mucoepidermoid carcinoma consisting predominantly of cysts lined by mucous cells and sparse numbers of intermediate cells; (B) Predominantly solid tumor consisting of intermediate cells and mucocytes, some of which are columnar; (C) Prominent intermediate and clear cells; (D) High grade mucoepidermoid carcinoma showing pleomorphic epidermoid and mucous cells

and periodic acid Schiff. They may be single or form aggregates and they frequently line cysts or duct-like structures. Sometimes broad papillary projections, often covered in mucous cells, extend into the cystic lumina. In some tumors mucocytes may be so uncommon that they may be difficult to detect without special stains. Clear cells have distinct cell boundaries, small, centrally located, hyperchromatic nuclei and water clear cytoplasm (Fig. 10.31C). They tend to form sheets and may be the predominant element of the tumor. Columnar cells are uncommon and are usually seen lining cyst. Oncocytes are also uncommon but rarely the entire tumor can show oncocytic metaplasia. Mucoepidermoid carcinomas can be graded as low, intermediate and high. Lowgrade tumors are cytologically bland, and the tumors are predominantly cystic with a high mucous cell content. Higher grade tumors tend to be more solid, show evidence of

cytological atypia, a high mitotic frequency, neural invasion and necrosis (Fig. 10.31D). Some pathologists ascribe numerical values to a variety of histopathological characteristics and define the grades using a point scoring system.

Differential Diagnosis Necrotizing sialometaplasia can be confused with mucoepidermoid carcinoma. In necrotizing sialometaplasia, however, the epithelial islands have a lobular distribution and there are usually areas showing transition from obvious ducts. In addition, there are no intermediate cells and cyst formation is not a feature. High grade tumors can resemble squamous cell carcinoma but lack evidence of keratinization, and also show foci of mucocytic differentiation. Clear cell variants need to be distinguished from epithelial myoepithelial carcinomas by the lack of an inner, duct-lining

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cell component and clear cell carcinoma (NOS) by the presence of more characteristic areas elsewhere in the tumor.

Clinical Features Treatment and Prognosis Prognosis depends on a variety of factors including clinical stage, site, histological grading and surgical margins. The majority of tumors are low grade and the prognosis is generally good with a 5 years survival rate of over 95 percent. A small proportion of these tumors unexpectedly undergo metastasis so protracted follow-up is essential. In tumors with a high clinical stage or histological grading, and cases of incomplete surgical removal, the 5 years survival rate falls to less than 45 percent. In addition, tumors in the submandibular gland, floor of mouth and tongue have a poorer prognosis. The treatment of choice is complete surgical excision with a neck dissection if there is good evidence of locoregional metastasis. Radiotherapy has a limited impact on the course of the disease. Box 10.8: Mucoepidermoid carcinoma Key features helpful in diagnosis • Most common primary malignant salivary neoplasm (12–29%). • Over half of cases involve parotid gland and most of the remainder affect the mouth and respiratory tract. • f:M ~ 1.5:1 Wide age range including children with peak incidence in 5th decade. • Slow-growing, often painless, fixed mass: symptoms include pain, nerve involvement and trismus. Tumors in minor glands may ulcerate. • May be circumscribed but usually nonencapsulated and infiltrative and variably cystic. • Cell types include intermediate, epidermoid and mucous cells and less commonly clear, columnar and oncocytic. • May be predominantly cystic or solid and inflammation is common. • Tumors graded as low, intermediate or high.

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configurations, including tubular, cribriform and solid patterns’.

Adenoid cystic carcinoma is defined as ‘a basaloid tumor consisting of epithelial and myoepithelial cells in variable morphologic

Adenoid cystic carcinoma accounted for 4.4 percent of all salivary gland tumors and 11.8 percent of malignant salivary neoplasms in the largest reported series. It affects a wide age range, with a peak incidence in 50 to 70 year olds. There is a female preponderance of about 1.5:1. The most common sites are the parotid (21%), palate (17%) and submandibular gland (15%). Minor glands of the mouth and the upper aerodigestive tract account for about half of all cases. Tumors usually present as a slow growing but widely infiltrative mass of long duration and they can be mobile or fixed. They may be tender or painful, and cranial nerve lesions, particularly facial nerve palsy, can be the presenting feature. Tumors of minor glands often show ulceration of the overlying mucosa.

Histopathology Adenoid cystic carcinoma is composed of luminal ductal cells and abluminal, modified myoepithelial cells. The latter predominate and have indistinct cell borders and frequently sparse, amphophilic or clear cytoplasm. The nuclei are uniform in size, basophilic and may be round or angular (peg-shaped). The ductal cells surround small and sometimes indistinct lumina; they are cuboidal and have more abundant, eosinophilic cytoplasm and round, uniform nuclei that may contain small nucleoli. There are three main morphological patterns: cribriform (cylindromatous), tubular and solid, in that order of frequency. A mixture of these patterns may be seen. The cribriform variant consists of islands of modified myoepithelial cells containing rounded, pseudocystic areas forming a characteristic ‘Swiss cheese’ appearance (Fig. 10.32 A). The pseudocysts are basophilic and mucoid, or consist of hyaline, eosinophilic material. They are composed of glycosaminoglycans and reduplicated basement membrane material. Foci of ductal cells are present within the myoepithelial areas but may require careful examination to detect. The tubular variant is double layered and has

Differential Diagnosis It is important to distinguish adenoid cystic carcinoma from polymorphous low-grade adenocarcinoma in tumors from minor salivary glands. Polymorphous low-grade adenocarcinoma consists of a uniform cell population with cytologically bland, round or oval and vesicular nuclei and pale eosinophilic cytoplasm, whereas cells in adenoid cystic carcinoma often have clear cytoplasm and angular, hyperchromatic nuclei and may show mitotic activity. The MIB-1 proliferative index is reported to be nearly 10x higher in adenoid cystic carcinoma than polymorphous lowgrade adenocarcinoma with no overlap zone. Smooth muscle markers of myoepithelial differentiation are positive in adenoid cystic carcinoma but negative in polymorphous low-grade adenocarcinoma. In addition, this tumor shows a much wider spectrum of histomorphological differentiation. Even when

cribriform areas are present in polymorphous low-grade adenocarcinoma they are typically focal and adenoid cystic carcinoma does not show papillary differentiation or the single cord arrangement of cells seen in polymorphous lowgrade adenocarcinoma. Although both adenoid cystic carcinoma and polymorphous lowgrade adenocarcinoma show neural invasion, in polymorphous low-grade adenocarcinoma this is often associated with a striking whorling arrangement of single file cords of cells or small ducts, and is seen predominantly within or very close to the main tumor mass. Occasional foci in pleomorphic adenoma can resemble adenoid cystic carcinoma, but the presence of typical myxochondroid matrix and plasmacytoid or spindle-shaped cells helps to avoid confusion. Basaloid squamous cell carcinoma can resemble solid variants of adenoid cystic carcinoma but typically involves the hypopharynx and glottal region, which are uncommon sites for adenoid cystic carcinoma. Both can show islands with cribriform configurations, hyaline material surrounding tumor nests and solid areas with comedonecrosis, but basaloid squamous carcinoma also has evidence of squamous differentiation and usually involves the overlying mucosa. The distinction from epithelial-myoepithelial carcinoma is covered under that entity.

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conspicuous ductal differentiation (Fig. 10.32B). There is an inner layer of eosinophilic, ductlining cells and the abluminal myoepithelial cells may show clear cytoplasm and irregular, angular nuclei or be morphologically similar to the luminal layer. Occasionally, foci of squamous, sebaceous or oncocytic metaplasia are present. The least common, solid variant consists of islands or sheets of basaloid cells with larger and less angular nuclei (Fig. 10.32C). Duct-lining cells may be few and inconspicuous and comedonecrosis is common. Mitoses are sparse in the cribriform and tubular patterns but may be frequent, often together with extensive apoptosis, in the solid type. The stroma is usually fibrous and cases where hyalinization is so abundant that tumor cells are attenuated into strands have been reported as a sclerosing variant (Fig. 10.32D). Perineural or intraneural invasion is common and frequently conspicuous and the tumor can extend along nerves and their branches over a wide area (Fig. 10.33). The tumor may invade bone extensively before there is any radiological evidence of bone destruction. Lymph node involvement is uncommon (~ 5% of cases) and is usually due to contiguous spread rather than lymphatic permeation or embolization.

Treatment and Prognosis The average 5 and 10-year survival rates are about 60 and 40 percent respectively but the majority of patients usually die of, or with, the tumor. Local recurrence is very common, especially in the first 5 years after surgery. The main prognostic factors are site, clinical stage and histological pattern. Bone involvement and failure of primary surgery are associated with poor prognosis. Correlations between tumor morphology, grading and outcome have yielded conflicting results, particularly after 10 years follow-up due to the overall poor longterm prognosis. The tubular and cribriform variants have been reported to have a better outcome than tumors with a solid component, especially if this exceeds 30 percent of the tumor volume. Some studies suggest that tumor size and clinical stage are more reliable indicators

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Figs 10.32A to D: (A) Adenoid cystic carcinoma showing the characteristic cribriform (cylindromatous) pattern; (B) High power of tubular variant with double-layered duct-like structures; (C) Solid variant with foci of comedonecrosis; (D) Extensive stromal hyalinization and attenuation of the tumor islands

of prognosis. Adenoid cystic carcinomas in the submandibular gland have a poorer prognosis than those in the parotid. The relationship between perineural invasion and survival is also contentious but invasion of larger nerves appears to correlate with more aggressive behavior. In a review of the literature, Barrett and Speight (2002) found 23 percent (range 2–86%) of patients had clinical evidence of neurological deficit. Histological evidence of perineural invasion was reported in 51 percent (range 8–86%) of cases. Facial nerve palsy was an indicator of poor prognosis but histological evidence of perineural invasion appeared not to be an independent factor but was associated with other adverse features such as clinically large and more aggressive tumors. In addition, large follow-up studies of patients with adenoid cystic carcinoma have found that both histological grades and perineural invasion are unreliable predictors of behavior and suggest that clinical

stage is a better guide to prognosis. Lymph node involvement is relatively uncommon Box 10.9: Adenoid cystic carcinoma Key features helpful in diagnosis • Accounts for about 12 percent of malignant salivary gland neoplasms. • Parotid most common site (~20%) and half of cases involve the mouth and upper aerodigestive tract. • f:M ~ 1.5:1 Wide age range but rare in children, peak incidence in 6th and 7th decades. • Slow-growing, variably painful mass: neural involvement, particular facial nerve palsy, is common. • Composed of duct-lining cells and modified myoepithelial cells. • Main patterns are cribriform, tubular and solid • Stroma often extensively hyalinized. • Perineural invasion common and may be extensive.

Histopathology

but distant metastases to lung, bone, brain and liver are seen in 40 to 60 percent of cases. Wide local excision, together with adjuvant radiotherapy, offers the best hope of local control.

Polymorphous Low-grade Adenocarcinoma Polymorphous low-grade adenocarcinoma has been defined as ‘a malignant epithelial tumor characterized by cytological uniformity, morphological diversity, an infiltrative growth pattern, and low metastatic potential’. Synonyms include terminal duct carcinoma and lobular carcinoma.

Clinical Features Polymorphous low-grade adenocarcinoma is seen almost exclusively in the minor glands where it is one of the most common malignant tumors, accounting for about 25 percent of malignancies in these sites. The palate is the most frequent location (~60%) and other sites include the lips, particularly the upper, buccal mucosa, retromolar trigone and base of tongue. Most cases arise in the 50 to 70 years age group and there is a female predominance of 2:1. The tumor usually presents as a slow-growing painless mass which can be mobile or fixed and rarely exceeds 3 cm in diameter. Ulceration and bleeding are uncommon features.

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Fig. 10.33: Adenoid cystic carcinoma showing conspicuous perineural invasion

Polymorphous low-grade adenocarcinoma usually appears grossly to be circumscribed but has infiltrative margins. Tumors rarely exceed 3 cm in diameter. The hallmark of the tumor is cytological uniformity and morphological diversity. The cells are isomorphic and cytologically bland. They have abundant eosinophilic cytoplasm, small- to mediumsized, round or oval nuclei containing pale and finely dispersed chromatin and relatively inconspicuous nucleoli. Mitoses are infrequent and necrosis is not a feature. The most common architectural configurations are lobular, nests or theques, cribriform areas and fascicular, duct-like structures of varying sizes (Figs 10.34A and B). There may be focal papillary or papillary-cystic areas. In the lobular areas, there may be palisading of the peripheral cells. The duct-like structures are usually composed of a single layer of small cuboidal cells. Both true tubular structures and pseudocystic spaces, with or without pale-staining mucoid contents, result in a cribriform appearance. The areas showing a cribriform pattern are usually localized. Columns of single tumor cells can be seen forming an “Indian-file” arrangement, especially towards the periphery of the tumor. These cells particularly, often show concentric whorling around small nerves and sometimes small vessels or duct-like structures, within or close to the edge of the tumor (Fig. 10.34C). Areas of oncocytic or squamous metaplasia are occasionally seen. It is common to see foci of pre-existing salivary parenchyma within the main tumor mass. Stromal fibrosis, elastosis and mucinosis are often present but chondroid or myxochondroid differentiation is not a feature (Fig. 10.34D). The tumor tends to abut immediately below the oral epithelium (Fig. 10.35) and shows invasion into the surrounding minor gland parenchyma.

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Differential Diagnosis The differential diagnosis of polymorphous lowgrade adenocarcinoma includes pleomorphic adenoma, adenoid cystic carcinoma

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Figs 10.34A to D: (A) Polymorphous low-grade adenocarcinoma showing pale-staining cells forming sheets, islands, single-layered duct-like structures and cribriform patterns; (B) Duct-like structures of variable sizes; (C) Perineural whorling of small, single-layered duct-like structures and single-file cells; (D) Stromal hyalinization and elastosis

pleomorphic adenoma is circumscribed and contains other characteristic features such as cartilaginous differentiation and plasmacytoid myoepithelial cells. In addition, the tubular structures in pleomorphic adenoma are bilayered. The distinction from adenoid cystic carcinoma is covered under that tumor. Papillary cystadenocarcinomas usually show a more uniform architecture and display more obvious cytological features of malignancy. Fig. 10.35: Polymorphous low-grade adenocarcinoma abutting directly under the oral epithelium and forming papillary configurations

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and papillary cystadenocarcinoma. Both pleomorphic adenoma and polymorphous low-grade adenocarcinoma consist of cytologically bland cells and show a variety of architectural configurations. However,

Treatment and Prognosis Most polymorphous low-grade adenocarcinomas are cured by conservative and, in some cases, incomplete surgical excision. However, 9 to 17 percent of tumors recur and 9 to 15 percent involve regional lymph nodes. Despite this, the overall prognosis is excellent with more distant metastasis and death due to tumor being rare. Tumors with a significant papillary configuration

Box 10.10: Polymorphous low-grade adenocarcinoma Key features helpful in diagnosis • Seen almost exclusively in minor glands and accounts for about 25 percent of salivary malignancies in these sites. • Palate (60%) most common site: others include lip (especially upper) buccal mucosa, retro- molar pad, base of tongue. • f:M 2:1 peak incidence in 6th to 8th decades. • Slow-growing, painless, mobile or fixed mass. ulceration uncommon. • Circumscribed, usually nonencapsulated. • Cytologically uniform and bland cells with pale staining nuclei and sparse mitotic activity. • Morphologically diverse with multiple architectural patterns in single tumor mass. • Characteristic concentric whorling of tumor around small nerves.

Epithelial-myoepithelial Carcinoma Epithelial-myoepithelial carcinoma is defined as ‘a malignant tumor composed of variable proportions of two cell types, which typically form duct-like structures. The biphasic morphology is represented by an inner layer of duct lining, epithelial-type cells and an outer layer of clear, myoepithelial-type cells’. It has many synonyms including clear cell adenoma, glycogen-rich adenoma, tubular carcinoma, clear cell myoepithelioma, glycogen-rich adenocarcinoma and others.

Clinical Features Epithelial-myoepithelial carcinoma is uncommon accounting for about 1 percent of all salivary tumors. The mean age is about 60 years and the tumor is rare in children. There is a 2:1 female predominance. Most cases arise in the parotid (75%) or submandibular glands (10–12%). They usually present as a long-standing, painless mass and nerve involvement is uncommon. In the mouth, the palate and tongue are the usual sites and the tumors may ulcerate.

Histopathology The tumor forms a circumscribed mass that is usually nonencapsulated and is often lobulated or multinodular. Most tumors range from 2 to 8 cm in diameter and cystic areas are relatively common. Epithelial myoepithelial carcinoma is biphasic and consists of double-layered, duct- like structures (Fig. 10.36A). There is usually an inner layer of single cells that can be cuboidal or columnar and have a central round or oval nucleus with finely granular, densely eosinophilic cytoplasm. Cells in the outer layer are polygonal and form single or multiple layers. They have abundant, clear cytoplasm which is rich in glycogen, and vesicular, eccentrically placed nuclei. The proportion of these two cell types is widely variable, as is their distribution. The duct-like structures may be widely separated by fibrous or more hyaline connective tissue or they may aggregate forming cohesive sheets with a thequal or nested architecture. In some cases, the clear cells are the predominant feature and duct-lining cells may be infrequent and form small, solid islands that may not be immediately apparent (Fig. 10.36B). Sometimes, the inner and outer layers are composed of morphologically similar cells which both may have clear (Fig. 10.36C) or nonclear cytoplasm. About 20 percent of cases contain cystic or papillary areas. Squamous or oncocytic metaplasia, usually of the inner duct-lining cells, is an uncommon feature. Most tumors are cytologically bland with infrequent mitoses and necrosis is uncommon. Although many tumors show limited parenchymal invasion, in about 30 percent of cases there is perineural invasion and 10 percent show angiolymphatic involvement. Rare cases of de-differentiated epithelial-myoepithelial carcinoma have been reported and the tumor may be a component of carcinoma ex-pleomorphic adenoma.

10 SALIVARy GLAnD DISORDERS

appear to have a higher incidence of cervical lymph node metastasis and some consider these to be variants of papillary cystadenocarcinoma.

Differential Diagnosis The main differential diagnosis of epithelial myoepithelial carcinoma are other salivary gland tumors containing double layered ductlike structures and tumors composed mainly of

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A

B

C

Figs 10.36A to C: (A) Epithelial-myoepithelial carcinoma showing discrete double-layered ductlike structures with inner duct-lining cells and outer, clear, myoepithelial cells; (B) Predominantly of separate nests of clear, myoepithelial cells and infrequent duct-lining cells; (C) Epithelialmyoepithelial carcinoma forming cohesive sheets of nested and predominantly clear cells

clear cells. Double-layered, duct-like structures can be seen in pleomorphic adenoma and the tubular variant of adenoid cystic carcinoma. However, the clear cells in these tumors usually have less abundant cytoplasm and their nuclei are typically more hyperchromatic and angular. In addition, these features are usually only a focal aspect of a more typical tumor. In biopsy material, the distinction may be difficult or cannot be made with confidence. Many salivary neoplasms, both benign and malignant, can show focal or extensive areas composed of clear cells. These include pleomorphic adenoma, myoepithelioma, oncocytoma, mucoepidermoid carcinoma, clear cell carcinoma and metastatic renal carcinoma. Precise differentiation of these tumors from epithelial myoepithelial carcinoma is outside the scope of this Chapter.

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Epithelial myoepithelial carcinoma is a low to intermediate grade tumor with a relatively high rate of recurrence (~30–40%) and metastasis to regional lymph nodes and distant sites such as lung, liver and kidney (5–25%). Notwithstanding

this, the long term prognosis is generally good with a 10 year survival rate of over 80 percent. Clinical factors associated with a poor outcome include incomplete surgical excision, larger tumors, rapid growth and tumors involving minor glands. Microscopical features associated with more aggressive behavior include nuclear hyperchromasia, aneuploidy, high mitotic frequency, angiolymphatic invasion and necrosis. The treatment of choice is surgery together with neck dissection when there is evidence of spread to the regional lymph nodes. Adjuvant radiotherapy has been used in advanced or recurrent cases, but its value is questionable.

Salivary Duct Carcinoma Salivary duct carcinoma is defined as ‘an aggressive adenocarcinoma which resembles high-grade breast ductal carcinoma’.

Clinical Features Salivary duct carcinoma can arise ab initio and is also a frequent component of carcinoma ex-pleomorphic carcinoma when there may

10

Box 10.11: Epithelial myoepithelial carcinoma

be a history of a previous long-standing tumor. It forms about 2 percent of all salivary tumors and about 10 percent of malignant salivary neoplasms. There is a wide age range but most patients are over 50 years old and the tumor is rare in children and young adults. There is a distinct male predominance of about 4:1. Over 95 percent of cases affect the parotid gland but occasional cases have been reported in the submandibular and minor oropharyngeal glands and elsewhere. They usually present as rapidly expanding, painful masses often with necrosis, hemorrhage, ulceration and nerve involvement.

Histopathology Salivary duct carcinoma usually shows macroscopical evidence of hemorrhage, necrosis and widespread invasion. Microscopically, the tumor closely resembles high grade ductal carcinoma of the breast. Typically, it consists of large, duct-like structures with cribriform areas, characteristic ‘Roman bridging’ and central (comdeo-like) necrosis (Fig. 10.37). Solid, papillary and squamous areas can also be present. The tumor cells are pleomorphic and show obvious cytological features of

Fig. 10.37: Salivary duct carcinoma showing large pleomorphic cells forming duct-like structures with ‘Roman bridging’ and comedonecrosis

SALIVARy GLAnD DISORDERS

Key features helpful in diagnosis • Accounts for about 1percent of all salivary tumors. • Most common in parotid (~75%) and submandibular (~10%) glands. • f:M ~ 2:1 Wide age range with peak incidence in 6th and 7th decades. • Slow-growing, usually painless mass: nerve involvement uncommon. • Circumscribed, usually nonencapsulated mass which may be lobulated or cystic. • Double-layered duct-like structures with inner cuboidal cells and outer clear myoepithelial cells in variable proportions. • Duct-like structures may be widely separated by stroma or aggregate into sold sheets. Papillary and cystic areas present in about 20 percent cases. • Perineural and angiolymphatic invasion relatively uncommon.

malignancy. They have pink, granular and sometimes frankly oncocytic cytoplasm. The nuclei are large and hyperchromatic and show abundant and often abnormal mitoses, together with florid apoptosis. Sometimes, these tumors are biphasic and have a spindle cell, pseudosarcomatous component. Mucinrich and micropapillary variants have also been reported. The stroma usually shows extensive fibrosis and heavy inflammatory cell infiltration. Most tumors show evidence of perineural and angiolymphatic involvement.

Differential Diagnosis The possibility of metastatic breast carcinoma should be considered, even in men. If clinical examination is equivocal, immunophenotyping of the tumor may be helpful. Salivary duct carcinomas are androgen receptor-positive, estrogen receptor-negative, and progesterone receptor-negative. Some salivary duct carcinomas can resemble poorly differentiated squamous cell carcinoma or high grade mucoepidermoid carcinomas. Usually, however, more typical areas showing ductal or cribriform features are seen elsewhere in the tumor. Mucous cells are not a feature of salivary duct carcinoma. Predominantly papillary tumors need to be distinguished from papillary cystadenocarcinoma but these do not show the extreme cellular pleomorphism that is characteristic of salivary duct carcinoma. Some salivary duct carcinomas

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show extensive oncocytic elements but other characteristic features such as the cribriform architecture help to differentiate the tumor from oncocytic carcinoma.

Treatment and Prognosis Salivary duct carcinoma is very aggressive with a local recurrence rate of about 30 percent and locoregional metastatic frequency of 60 percent. About half of the cases show distant metastases to lung, brain, bone and elsewhere. Tumors showing over-expression of HER-2/ neu protein have a particularly poor outcome. Treatments include radical surgery, usually with neck dissection, and adjuvant radiotherapy. Recently, anti-androgen and transtuzumab (Herceptin) systemic therapy has been tried for patients with advanced disease and preliminary results suggest this form of treatment may offer some hope in the future. Box 10.12: Salivary duct carcinoma Key features helpful in diagnosis • Accounts for ~10 percent of all malignant salivary neoplasms. Can arise ab initio or as a component of carcinoma ex-pleomorphic adenoma. • M:f ~4:1 Peak incidence in 6th and 7th decades. • Rapidly-growing painless mass often with necrosis, ulceration and facial nerve involvement. • usually solid, infiltrative mass with areas of hemorrhage and necrosis. • Resembles high-grade ductal carcinoma of the breast, often with comedonecrosis: solid, papillary and squamous areas may be present. • Cells cytologically pleomorphic with high mitotic frequency and florid apoptosis. • Local, neural and angiolymphatic invasion may be extensive.

Carcinoma Ex-pleomorphic Adenoma

256

Carcinoma ex-pleomorphic adenoma has been defined as ‘a pleomorphic adenoma from which an epithelial malignancy is derived’. Synonyms include carcinoma arising in a benign mixed tumor, carcinoma ex benign mixed tumor, carcinoma arising in pleomorphic adenoma and malignant mixed tumor.

Clinical Features In a major review of the literature, carcinoma ex-pleomorphic adenoma accounted for about 3.6 percent of all salivary tumors and 12 percent of salivary malignancies. The true frequency may be higher as some of these carcinomas may overgrow and obliterate the original benign pleomorphic adenoma. The large majority (~70–80%) arise in the parotid gland, with smaller numbers in the submandibular, sublingual and minor glands. In the latter, the palate is the most common location. Most cases are seen in the sixth and seventh decades and there is no sex predilection. The typical presentation is that of rapid growth of a preexisting and often long-standing swelling, but in some cases the tumor appears to arise ab initio. In addition, some cases can be seen in the site where a pleomorphic adenoma had been removed previously. As the tumor progresses pain, fixation and neural involvement become increasingly frequent. Many cases show evidence of locoregional metastasis at the time of presentation.

Histopathology Grossly, carcinoma ex-pleomorphic adenoma is poorly circumscribed and infiltrative. The preexisting pleomorphic adenoma may be seen as a more defined area of tumor and/or a focus of scarring. In many tumors both the benign and malignant components are clearly visible (Fig. 10.38A) but in some cases there can be extensive scarring and identifying remnants of the pre-existing tumor may be difficult. Sometimes the benign elements have been totally effaced and the diagnosis can only then be inferred on the basis of the clinical history. The malignant component is most frequently a poorly differentiated adenocarcinoma (NOS) or a salivary duct carcinoma, although most other types of salivary malignancies have been reported. It is common for the tumors to have two or more defined malignant elements. Although many tumors show gross nuclear pleomorphism, frequent and often abnormal mitoses and necrosis, occasionally there is

10

B

Figs 10.38A and B: (A) Carcinoma developing adjacent to a benign pleomorphic adenoma; (B) Severe dysplasia within the substance of an otherwise benign pleomorphic adenoma. This has been called intracapsular carcinoma, carcinoma in situ in pleomorphic adenoma and noninvasive carcinoma ex-pleomorphic adenoma

minimal cytological atypia. In many cases, there is evidence of neural and angiolymphatic invasion. Carcinoma ex-pleomorphic can be subclassified into noninvasive, minimally invasive (1.5 mm of invasion). It is not rare to find focal or more widespread areas of dysplastic cells in pleomorphic adenomas without evidence of frank invasion, despite extensive sampling. This is termed noninvasive carcinoma ex-pleomorphic adenoma although a number of other names have been used, including in-situ carcinoma, intracapsular carcinoma or severely dysplastic pleomorphic adenoma (Fig. 10.38B).

Differential Diagnosis Secondary changes in pleomorphic adenoma following fine needle aspiration, open biopsy or spontaneous infarction include necrosis, increased mitotic activity and squamous metaplasia, and these should not be confused with malignancy. Carcinomas often arise in old, scarred pleomorphic adenomas and these should be extensively sampled. Other tumors that can show widespread hyalinization include adenoid cystic carcinoma, salivary duct carcinoma and polymorphous low-grade adenocarcinoma. Identification of remnants of

SALIVARy GLAnD DISORDERS

A

pleomorphic adenoma such as myxochondroid elements, cytologically bland ducts or plasmacytoid cells should allow appropriate classification of carcinoma ex-pleomorphic adenoma. One of the most important distinctions is between non-invasive and invasive carcinoma ex-pleomorphic adenoma, as this has significant prognostic implications.

Box 10.13: Carcinoma ex-pleomorphic adenoma Key features helpful in diagnosis • Accounts for ~12 percent of all salivary malignancies: large majority arise in the parotid gland with smaller frequency in submandibular and minor glands. • M:f 1:1 peak incidence in 6th and 7th decades. • usually painless but rapid growth of a pre- existing and often long-standing swelling or site of previous surgery. neural involvement common. • Tumor poorly circumscribed and infiltrative. Remnants of benign element may be seen. • Original pleomorphic adenoma or extensive scar together with one or more malignant elements, most commonly poorly differentiated adenocarcinoma (nOS) or salivary duct carcinoma. • Tumors can be non-invasive, minimally invasive or frankly invasive.

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Carcinoma ex-pleomorphic adenoma is usually treated by wide local excision together with neck dissection. Adjuvant radiotherapy is often used for widely invasive and non-resectable tumors. If the carcinomatous component is cytologically low-grade or minimally invasive, adjuvant radiation therapy may not be deemed necessary. Noninvasive carcinomas have a prognosis similar to that of conventional pleomorphic adenoma. Invasive carcinoma ex-pleomorphic adenoma shows a range of behavior. Minimally invasive tumors have a relatively good prognosis but tumors with a depth of invasion of more than 1.5 mm are usually high-grade and stage are associated with a poor prognosis. Local recurrence is seen in up to half of the cases and about 70 percent show regional or distant metastasis to sites including brain, lung, liver and bone (especially spine). The 5 year survival rates vary from 25 to 56 percent and the longer term prognosis is even worse.

SELf-ASSESSMEnT quESTIOnS 1. Provide a classification for salivary gland disorders. 2. Describe the clinicopathological features and treatment of acute and chronic sialadenitis. 3. Describe the clinical features, investigation and treatment of obstructive salivary gland disease. What are the reasons for increased prevalence of salivary calculus in submandibular glands? 4. Describe the etiopathogenesis, presentation and management of mucoceles. 5. What is sialosis? Describe the clinicopathological presentation of sialosis and list the associated conditions. 6. Compare and contrast primary and secondary Sjogren’s syndrome. 7. Compare and contrast the clinicopathological features, behavior and management of the two most common benign parotid gland tumors. 8. Give an account of mucoepidermoid carcinoma including a note on its differential diagnosis. 9. Discuss the differential diagnosis of malignant minor salivary tumors. 10. Describe the role of imaging modalities in the diagnosis and treatment of salivary gland

disease. What is the role of sialography in current practice?

SuGGESTED READInG 1. Auclair PL. Tumor-associated lymphoid proliferation in the parotid gland. A potential diagnostic pitfall. Oral Surg Oral Med Oral Pathol. 1994;77:19-26. 2. Barnes L, Eveson JW, Reichart P, Sidransky D (Eds). Tumors of the Salivary Glands. World Health Organization Classification of Tumors. Pathology and Genetics of Head and Neck Tumors. Lyon, IARC Press. 2005. 3. Barrett A, Speight P. Chapter 19. The controversial adenoid cystic carcinoma. The implications of histological grade and perineural invasion. In: M McGurk, Renehan A (Eds). Controversies in the management of salivary gland disease. Oxford University Press. 2002. pp.211-7. 4. Brandwein MS, Ivanov K, Wallace DI, et al. Mucoepidermoid carcinoma: A clinicopathologic study of 80 patients with special reference to histologic grading. Am J Surg Pathol. 2001;25:835-45. 5. Brannon RB, Fowler CB, Hartman KS. Necrotizing sialometaplasia. A clinicopathologic study of sixty-nine cases and review of the literature. Oral Surg Oral Med Oral Pathol. 1991;72:317-25. 6. Brook I. Acute bacterial suppurative parotitis: microbiology and management. J Craniofac Surg. 2003;14:37-40. 7. Castle JT, Thompson LD, Frommelt RA, Wenig BM, Kessler HP. Polymorphous low grade adenocarcinoma: a clinicopathologic study of 164 cases. Cancer. 1999;86:207-19. 8. Dave SP, Pernas FG, Roy S. The benign lymphoepithelial cyst and a classification system for lymphocytic parotid gland enlargement in the pediatric HIV population. Laryngoscope. 2007;117:106-13. 9. Di Palma S, Skalova A, Vanieek T. Noninvasive (intracapsular) carcinoma ex-pleomorphic adenoma: recognition of focal carcinoma by HER-2/neu and MIB1 immunohistochemistry. Histopathology. 2005;46: 144-152. 10. Ellis GL, Auclair PL. Tumors of the salivary glands. Atlas of Tumor Pathology, 4th Series, Fascicle 9. Armed Forces Institute of Pathology, Washington DC. 2008.

17. Sitheeque M, Sivachandran Y, Varathan V, et al. Juvenile recurrent parotitis: clinical, sialographic and ultrasonographic features. Int J Paediatr Dent. 2007;17:98-104. 18. Teymoortash A, Tiemann M, Schrader C, et al. Characterization of lymphoid infiltrates in chronic obstructive sialadenitis associated with sialolithiasis. J Oral Pathol Med. 2004;33:300-304. 19. Teymoortash A, Werner JA. Tissue that has lost its track: Warthin's tumor. Virchows Arch. 2005;446:585-8. 20. Vitali C, Bombardieri S, Jonsson R, et al. Classification criteria for Sjögren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis. 2002;61:554-8. 21. Waldron CA, El-Mofty S, Gnepp DR. Tumors of the intraoral minor salivary glands: A demographic and histologic study of 426 cases. Oral Surg Oral Med Oral Pathol. 1988;66:323-33. 22. Yoon AJ, Beller DE, Woo VL, et al. Bilateral canalicular adenomas of the upper lip. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006;102:341-3.

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11. Eveson JW, Cawson RA. Salivary gland tumors: a review of 2410 cases with particular reference to histologic types, site, age, and sex distribution. J Pathol. 1985;146:51-8. 12. Gomez DR, Hoppe BS, Wolden SL, et al. Outcomes and prognostic variables in adenoid cystic carcinoma of the head and neck: A recent experience. Int J Radiat Oncol Biol Phys. 2008;70:1365-72. 13. Huvos AG. Stage means more than grade in adenoid cystic carcinoma. Am J Surg. 1992;164:623-8. 14. Lewis JE, Olsen KD, Sebo TJ. Carcinoma expleomorphic adenoma: pathologic analysis of 73 cases. Hum Pathol. 2001;32:596-604. 15. Nabili V, Tan JW, Bhuta S, et al. Salivary duct carcinoma: a clinical and histologic review with implications for trastuzumab therapy. Head Neck. 2007;29:907-912. 16. Seethala RR, Barnes EL, Hunt JL. Epithelialmyoepithelial carcinoma: a review of the clinicopathologic spectrum and immunophenotypic characteristics in 61 tumors of the salivary glands and upper aerodigestive tract. Am J Surg Pathol. 2007;31:44-57.

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Chapter

11 Xerostomia MAO Lewis

Chapter Outline Saliva • Physiology of Salivary Secretion • Constituents of Saliva • Functions Xerostomia • Signs and Symptoms

• Etiopathogenesis • Clinical Assessment • Investigations • Management Self-assessment Questions

INTRODUCTION

SALIVA Saliva in the mouth is referred to as mixed or whole saliva since it is a combination of the secretion from all the glands. Saliva keeps the mouth wet, makes it possible to chew and swallow, helps in digestion, protects teeth from decay and prevents bacterial and fungal infections.

Physiology of Salivary Secretion The glands which produce saliva consist of three major paired glands, the sublingual, submandibular and parotid, and more than 600 minor (accessory) glands which are distributed throughout the mouth but principally within the lips, cheeks and palate. The parotid glands account for 60 percent of the total salivary tissue, with the submandibular and sublingual providing a further 30 and 5 percent respectively. Examination of the anatomy of salivary gland tissue reveals a complex structure of secretory units consisting of saliva producing cells (acini) and secretory ducts. The acinar cells are either serous, which produce a watery secretion or mucous which secrete a viscous form of saliva. The major glands contain different proportions of serous and mucous acinar cells and this determines the type of saliva produced by a particular gland. The parotid

11 XEROSTOMIA

The presence of adequate amounts of normal saliva within the mouth is crtical to maintaining oral health. This chapter presents an overview of the production of saliva and describes the consequences of reduced salivary secretion. The term xerostomia is widely used to describe the symptoms suffered due to altered salivary function. It should not be used as a diagnosis but rather as a clinical description that would prompt further investigation of the patient to determine the underlying cause. Xerostomia is an extremely frequent complaint amongst Western communities, having been reported in between 17 and 29 percent of some populations studied. An understanding of the investigation and management of xerostomia is an essential component of oral health care.

gland is predominantly made up of serous cells whilst the remaining glands are mainly mucous. An exeption to this generalization are the glands of von Ebner which are situated aound the circumvallate papillae on the tongue and produce a watery secretion that is believed to assist the sensation of taste. The initial fluid formed in either type of acinar celli is secreted into a ductal system, which is made up of three types of duct, namely intercalated, striated and excretory. Considerable modification of the protein and ion content of the fluid may occur within the duct before it enters the mouth. The striated ducts, which are well developed in the parotid and submandibular glands, are important sites of ion exchange, particularly sodium and chloride. The extent of exchange and level of these and other ions are influenced by flow rate which can vary considerabley between unstimulated and stimulated conditions. Formation of saliva is under neural control, mainly through parasympathetic nerves conducting stimuli from the salivary nuclei within the brain. The parasympathetic fibers from the superior salivary nuclei travel to the submandibular and sublingual glands via the facial nerve and chorda tympani. Supply to the parotid gland is from the inferior salivary nuclei through otic ganglion and glossophayngeal nerve. Sympathetic supply to all the major glands is provided by the spinal chord via fibers from the superior cervical ganglion. Increased salivary flow is predominantly a result of parasympathetic activity that produces vasodilation in the blood vessels within the glands. A range of stimuli, including smell, taste and chewing, can lead to increased salivary secretion although the exact processes are not fully understood. In contrast, it is well recognized that anxiety can cause reduced flow. Salivary secretion under goes a diurnal variation with a peak in mid afternoon and a fall to almost zero at night. The mean unstimulated flow rate throughout the day is 0.3 mL/minute. In the past the total amount of saliva produced in a day has been reported to be in the region of 1.5 liter, although more recently it has been thought that this is an overestimate and a figure of 0.7 liter is nearer the actual amount. Under unstimulated conditions the majority (60–65%) of saliva comes from submandibular

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glands with a further 20 to 30 percent from the parotid glands and 2 to 5 percent from sublingual glands. The relative contributions of the major glands changes significantly on stimulation and during eating. In these circumstances the parotid gland contributes 50 percent of stimulated saliva. It is important to remember that the “fluid” within the mouth is not just the product of the salivary glands but also conatins exudates from the gingival crevicular tissues, microorganisms, desquamated epithelial and white blood cells.

Constituents of Saliva Saliva is 99.4 percent water with organic and inorganic solids accounting for only 0.6 percent of its content, although this does change depending on whether flow is stimulated or not. There are also differences between different glands. Although information is available for individual glands, from a clinical point of view it is probably ƒ Table 11.1 Inorganic and organic components of saliva Inorganic

Organic

Sodium

Protein

Potassium

Serum albumin

Calcium

Gamma globulin

Magnesium

Mucoprotein

Chloride

Amylase

Hydrogen carbonate

Lysozyme

Phosphate

Proline-rich proteins

Thiocyanate

Histidine-rich proteins

Iodide

Lactoferrin

Fluoride

Fibronectin

appropriate to just look at mixed saliva (Table 11.1). The three most important ions in relation to the teeth are calcium and phosphate because of their direct relationship with mineralized tissues and hydrogen carbonate due to its buffering property (see blelow).

Functions Saliva has a wide range of functions (Table 11.2), many of which go unrecognized until salivary production is altered or reduced. A marked reduction of saliva flow can have a devastating physical effect on the teeth due to uncontrolled dental caries, in addition to causing a distressing psychological impact on the sufferer as a result of difficulty in eating and talking. The acid buffering capacity of saliva is one of its most important functions. Ceratin bacterial species within the mouth have the ability to rapidly metabolize carbohydrates to acid end products leading to a reduction in plaque pH.

ƒ Table 11.2 Functions and properties of saliva Function

Property

Acid buffer

High bicarbonate content buffers acid produced by plaque bacteria

Ion reservoir

Saliva is saturated with calcium and phosphate, which at neutral pH prevents demineralization

Pellicle formation

Salivary proteins are essential for protective diffusion barrier on tooth surfaces

Lubricant

Statherin Carbohydrate Blood group products Glucose Lipids Cortisol Amino acids Urea

262

Ammonia

Cleansing Taste

Physically clears food from teeth and soft tissues

XEROSTOMIA Xerostomia is a common symptom often caused by a decrease in the amount of saliva or a change in the quality of saliva.

on the dorsum of the tongue (Fig. 11.2). There is also likely to be evidence of food retention between the teeth (Fig. 11.3), candidosis and angular cheilitis. The teeth are prone to cervical caries and existing restorations may fail due to recurrent caries (Fig. 11.4). Patients with xerostomia are also predisposed to recurrent episodes of suppurative sialadenitis, particularly of the parotid gland.

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Measurement of plaque pH over time is called a Stephan curve and can demonstrate the rate of recovery of salivary pH following ingestion of fermentable carbohydrate. Demineralization of enamel will occur at a pH less than 5.5. The ability of saliva, in relation to its bicarbonate content, to buffer bacterial acid is a major protective factor. Unstimulated saliva contains bicarbonate at a concentration of 1 mmol/l but levels up to 60 mmol/l are present in stimulated flow. Chewing of sugar-free gum can produces carbonate levels in the region of 15 mmol/l.

Etiopathogenesis A frequent cause of reduced salivary flow is an adverse side effect of drug therapy. More than 500 different medications have been implicated in causing dry mouth. However, the

Signs and Symptoms A range of symptoms and signs of xerostomia have been described. The main symptoms are generalized oral discomfort, sometimes described as burning (not to be confused with burning mouth syndrome in which salivary production is normal), difficulty in talking or swallowing, altered taste, failing dental restorations, and if worn, poor retention of dentures. Usually a reduction in saliva flow of more than 50 percent is required before clinical symptoms develop. Lack of saliva will produce a generalized erythema of the oral mucosa (Fig. 11.1) and a lobulated/fissured appearance

Fig. 11.2: Lobulated and fissured tongue

Fig. 11.1: Atrophic mucosa with areas of erythema in the palate

Fig. 11.3: Dry mouth with food retention between the teeth

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Fig. 11.4: Failing restorations and dental caries ƒ Table 11.3 Examples of drugs associated with producing reduced salivary secretion Category of drug

Generic name

Trade name

Tricyclic antidepressants

Amitriptyline Dosulepin

(generic) Prothiaden

Fluoxetine Venlafaxine

Prozac Efexor

Chlorphenamine

Piriton

Diuretics

Furosemide

Lasix

Anticholinergic agents

Atropine Oxybutin

(generic) Ditropan

Antipsychotic agents

Pimozide

Orap

Antiparkinsonian agents

Levadopa

(generic)

Sedative and anxiolytic agents

Diazepam

Valium

Antihistamine

true incidence and severity of xerostomia with particular drugs has been difficult to establish. Nevertheless, certain types of medication are well recognized as producing this problem (Table 11.3) either by blocking stimulation from the autonomic nerve supply or inhibiting the ion exchange system. A reduced production of saliva may also be due to the presence of the auto-immune disease Sjögren’s syndrome, which is characterized by destruction of glandular acini. Sjögren’s syndrome may be either primary Sjögren’s

syndrome, in which the patient has xerostomia and dry eyes due to lacrimal gland disease, or secondary Sjögren’s syndrome, in which the sufferer has a connective tissue disorder in addition to xerostomia and/or dry eyes. Sjögren’s syndrome is a relatively frequent disorder with an estimated prevalence of between 1 and 3 percent of the UK population, with a high percentage of cases occurring in middle-aged females. An increasing number of individuals receive radiotherapy to the head and neck as a part of the contemporary treatment of malignant disease. Unfortunately, salivary tissue is particularly sensitive to radiation and despite efforts to limit gland exposure by altering and refining the direction of the beam, patients frequently suffer reduced salivary production. Loss of fluid secondary to raised blood sugar levels and increase micturition associated with diabtetes also leads to reduced salivary production. Rarer causes of xerostomia included acute anxiety, cystic fibrosis, graftversus-host disease, thyroid disorders, HIV infection, hepatic disease, renal failure, and sarcoidosis. Reduced salivary production due to the congenital absence of the salivary glands has been reported but is extremely rare. Historically, increasing age has been implicated as a factor involved in reduced salivary production. However, it is now generally accepted that this association is unfounded. Recent research has revealed that parotid gland output is maintained throughout life. The situation is complicated by the fact that elderly individuals are more likely to being taking one or more medication or have systemic disorders that impact on salivary gland function.

Clinical Assessment It has been shown that the presence of reduced salivary production can be correlated with a positive response to one of the five following questions: • Does your mouth usually feel dry? • Does your mouth feel dry while eating a meal? • Do you have difficulties swallowing food? • Do you sip liquids to aid in swallowing dry foods? • Does the amount of saliva in your mouth seem too little, too much or you do not notice it?

Investigations Specific measurement of salivary flow rates is rarely performed outside specialist clinics. However, a crude assessment of salivary output can be achieved by collecting unstimulted saliva in a container. A level of less than 0.16 mL/ minute has been proposed as being indicative of reduced function. Stimulated parotid flow rate can be measured by collection of output in Carlsson-Crittened cups placed over the parotid orifice and stimulating saliva by placement of 1 mL 10 percent citric acid on the dorsum of the tongue. Less than 5 mL/in 5 minutes can be interpreted as reduced function. Investigation of xerostomia should include a full range of tests that will ensure that the underlying cause is identified. Routine hematological investigation must include fasting blood glucose to exclude hyperglycemia secondary to undiagnosed or poorly controlled diabetes. Blood should also be taken to determine the presence of rheumatoid factor, antinuclear antibody, SS-A and SS-B (two specific markers for Sjögren’s syndrome).

Two distinct forms of imaging have been used to investigate the salivary glands. Sialography involves the infusion of a radioopague contrast fluid up into the gland through the main excretory duct. Radiographs will reveal any structural defects within the gland. A characteristic radiographic “snow-storm effect”, known as punctuate sialectasis, is seen within the parotid gland in patients with Sjögren’s syndrome (Fig. 11.5). Scintigraphy is a technique that investgates glandular function rather than structure by measuring the active uptake of a radio-labeled marker, such as technetium-99m, after intravenous infusion. This technique is not in widespread use. More recently, ultrasound imaging is being used to investigate salivary glands since it provides a relatively simple and noninvasive assessment. Examination of the minor salivary glands has been used as a method of determining the presence of disease in the major glands. The minor glands are easily accessible in the lower lip (Fig. 11.6). The procedure known as labial gland biopsy is considered one of the most helpful diagnostic tools for Sjögren’s syndrome. Examination of at least five lobules of minor gland needs to performed. Histopathological feaures supportive of Sjögren’s syndrome include acinar loss, duct dilation, periductal fibrosis and most importantly a focal lymphocytic infiltrate. If the patient complains of dry eyes, and it is useful to aseses lacrimal gland function by undertaking a Schirmer’s test. This involves the

Fig. 11.5: Sialogram of the parotid gland showing sialectasis

11 XEROSTOMIA

These questions should be asked prior to examination of the patient. The medical history, especially drug history, should be obtained since this will also identify any previous exposure to radiotherapy or known presence of connective tissue disorder. An impression of the patient’s general health can be gained by their appearance. Extraoral evidence of rheumatoid or other connective tissue, such as changes in the hands or facial features, can indicate the possible presence of Sjögren’s syndrome. It is also worth remembering that severe deformities in the hands as a result of rheumatoid arthritis will limit the patient’s manual dexterity in relation to maintaining oral hygiene if dry mouth is present. Intraoral examination in health should reveal saliva pooling in the floor of the mouth. Furthermore, external pressure applied to the major salivary glands should produce clear saliva at the duct openings. In addition, to being reduced in amount, any saliva that is present may be frothy in nature. The buccal mucosa becomes sticky and will adhere to the face of a dental examination mirror placed against it.

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11

placement of a filter paper strip under the lower eyelid for a period of five minutes. On removal the strip should show at least 5 mm of wetting.

Management Successful management of xerostomia requires investigation of all the possible causes as described above. If the patient’s drug history

Fig. 11.6: Removal of salivary tissue during a labial gland biopsy

reveals a medication that is recognized as causing reduced salivary flow and the onset of symptoms followed the start of therapy then consideration should be given to changing the drug in question. If this situation involves a tricyclic antidepressant, such as amitriptyline, then it is worthwhile suggesting a change to an SSRI since the severity of xerostomia does appear to be less with these newer drugs. However, on many occasions it is possible to change the medication, which presents a difficult management scenario. If diabetes is discovered then establishment of glycemic control often leads to resolution of the symptoms of xerostomia. Management of xerostomia should focus on the relief of symptoms and prevention of the oral effects of lack of saliva. Artificial saliva substitutes, based on either carboxymethylcellulose or mucin, are commercially available and provide a form of saliva replacement. A number of preparations have been formulated in spray and gel formats (Table 11.4). Some preparations are based on animal gastric mucin and this must be taken into acount when advising

ƒ Table 11.4 Topical saliva replacement products listed in the British National Formulary (BNF) Product

Content

Saliva orthana® spray

Mucin, xylitol and sodium fluoride

Saliva orthana® lozenge

Mucin and xylitol in sorbitol basis

Glandosane® spray

Carmellose, sorbitol, potassium chloride, magnesium chloride, calcium chloride, dipotassium hydrogen phosphate

Luborant® spray Biotène oral balance® gel Bioxtra® gel

266

flavor)

Carmellose, calcium chloride, magnesium chloride, potassium chloride, sodium chloride and dibasic sodium phosphate

Salivix®

Sugar free, reddish amber, acacia, malic acid and other ingredients

SST tablet

Sugar free, citric acid, malic acid and other ingredients

Salinum®

Sugar-free, linseed extract (containing polysaccharides) with dipotassium phosphate

SUMMARY Saliva is an essential fluid for oral health and its absence has a major impact on the soft and hard tissues within the mouth. Unfortunately, the signs and symptoms of xerostomia are frequently encountered in the dental surgery. Full investigation of such patients is required to determine the underlying causes of reduced salivary flow. A variety of forms of symptomatic

and preventive treatment are available and these need to be provided in order to minimize the impact of this condition on sufferers.

SELF-ASSESSMENT QUESTIONS 1. Describe the production of saliva. 2. Discuss the role of saliva and hence the effects of xerostomia on the oral cavity. 3. Discuss the differential diagnosis of patient reporting a dry mouth. 4. How would you investigate xerostomia? 5. Describe a graded approach to the management of xerostomia.

11 XEROSTOMIA

their use in vegetarians and certain religious or ethinic groups. Patients should also be advised to take frequent sips of water to moisten the mucosa. Chewing of sugar-free gum or pastilles produces salivary flow from the remaining functional tissue and is found to be helpful by many patients. Salivary stimulants (sialogues) based on glycerine and lemon preparations should only be used in edentulous patients since their low pH will encourage dental caries in dentate individuals. The benefit of systemic pilocarpine, a drug that stimulates acetylcholine receptors within exocrine glands, has been disappointing since although salivary flow can be obtained prior to meals patients often complain of significant adverse events, in particular sweating. Cevimeline hydrochloride is another cholinergic agent that has been recommended for patients with Sjögren’s syndrome but also has significant side effects that limit its use. Rigorous oral hygiene measures and preventive regimens, such as daily fluoride mouthwash or professionally applied topical fluoride therapy, should be instituted to reduce the risk of dental caries. Dietary advice should be given especially concerning the limitation of sugar intake. Opportunistic candidal infections should be treated with a systemic antifungal, such as fluconazole.

SUGGESTED READING 1. Dawes C. Physiological factors affecting salivary now rate, oral sugar clearance, and the sensation of dry mouth in man. J Dent Res. 1987;66:648-53. 2. Edgar WM, O’Mullane DM. Saliva and Dental Health. London: British Dental Association; 1990. 3. Ferguson DB. Oral Bioscience. London: Churchill Livingstone; 1999. 4. Fox PC. Management of dry mouth. Dent Clin North Amer. 1997;41:863-75. 5. Ghezzi EM, Lange LA, Ship JA. Determination of variation of stimulated salivary flow rates. J Dent Res. 2000;79:1874-8. 6. Guggenheimer G, Moore PJ. Xerostomia. Etiology, recognition and treatment. JADA. 2003;134;61-9. 7. Lavelle C, Smith PM. Salivary gland function. In: Scully C (Ed). Oxford Handbook of Applied Dental Sciences. Oxford: Oxford University Press; 2002 pp. 157-63. 8. Lewis MAO, Jordan R CJ. A Colour Handbook of Oral Medicine, 2nd Edn. London: Manson; 2012.

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Chapter

12 Potentially Malignant Disorders Sol Silverman Jr, Kobkan Thongprasom, Saman Warnakulasuriya

Chapter Outline Leukoplakia • Demography • Epithelial Dysplasia and Malignant Transformation • Lichenoid Dysplasia • Cell and Molecular Markers • Ploidy Status of Oral Leukoplakia • Clinical Features • Risk Factors Erythroplakia Diagnosis and Adjunctive Techniques Screening for Oral Leukoplakia and Erythroplakia • Management Oral Lichen Planus • Etiology and Immunopathogenesis

• Clinical Types • Desquamative Gingivitis • Oral Lichenoid Lesions • Systemic Diseases of Interest • Diagnosis and Histopathology • Management • Biologics Oral Submucous Fibrosis • Pathogenesis • Clinical Features • Grading of OSF • Histopathology • Malignant Transformation • Management Self-assessment Questions

INTRODUCTION

ƒ Table 12.1 List of potentially malignant disorders Leukoplakia

Lichen planus

Erythroplakia

Submucous fibrosis

Erythroleukoplakia

Discoid lupus erythematosus

Palatal lesions in reverse smokers

Syphilis Sideropenic dysphagia Actinic keratosis

LEUKOPLAKIA Leukoplakia is a term that is best described as a white plaque that can occur on any mucosal surface, that cannot be wiped off, and does not represent a specific disease entity. Several definitions have been used by various authors and working groups (Table 12.2) and uniformity of terminology is important to ensure that the scientific community is studying and discussing the same disorder. At the last WHO Collaborating Center’s Workshop (2005) the following definition was proposed: “White plaques of questionable risk having excluded (other) known diseases or disorders that carry no increased risk for cancer”. This allows exclusion of other benign conditions that appear clinically white when selecting the clinical diagnosis of leukoplakia. Leukoplakia remains a clinical diagnosis based on features noted at the initial examination.

12 POTENTIALLY MALIGNANT DISORDERS

Squamous cell carcinoma of the oral cavity is often preceded by oral potentially malignant disorders (OPMD), the term recommended at a workshop coordinated by the WHO Collaborating Center for Oral Cancer/Precancer to entail what were earlier referred to as “precancer” or “premalignant lesions and conditions”. The term OPMD is preferred as it conveys that not all lesions and conditions described under this term may transform to cancer. The full list of OPMDs encountered in clinical practice is given in Table 12.1. In this chapter we consider those that are common and important including oral leukoplakia, erythroplakia, lichen planus and oral submucous fibrosis (OSF) as part of the spectrum of OPMD. The global prevalence of

OPMD has been reported at 1 to 5 percent. In a screening program undertaken in Sri Lanka, the prevalence of oral precancer in the 1980s was reported as 4.2 percent, but higher prevalences are described from other parts of South and SE Asia, e.g. Taiwan (12.7%), and in some Western Pacific countries, e.g. Papua New Guinea (11.7%). Such wide geographical variations are due to life-styles specific to the country or region.

ƒ Table 12.2 Definitions of oral leukoplakia proposed in the past decades Working group

Definition

WHO (1978)

A white patch or plaque that cannot be characterized clinically or pathologically as any other disease

First International Conference on oral leukoplakia. Malmo, Sweden (1984)

A white patch or plaque that cannot be characterized clinically or pathologically as any other disease and is not associated with any physical or chemical causative agent except use of tobacco A predominantly white lesion of the oral mucosa that cannot be characterized as any other definable disease

WHO (1997)

A predominantly white lesion of the oral mucosa that cannot be characterized as any other definable lesion

Warnakulasuriya (2007)

Leukoplakia should be used to recognize white plagues of questionable risk having excluded (other) known diseases or disorders that carry no increased risk for cancer

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12 Demography Leukoplakia occurs in both sexes and in all ethnic groups and is significantly more prevalent in males. The male:female ratio on average approaches 3:1, and peak age of 40 to 49 years is consistently reported in many studies. A predominance of the buccal mucosa as a typical location has been noted mainly in

ƒ Table 12.3 Reported prevalence of oral potentially malignant disorders (OPMD) Author

Country (year)

Sampling method

Definition used

Age group (years)

Disease entity

Prevalence percent

Thomas et al

PNG (2008) Sri Lanka (2008) Taiwan (2005)

Random

Axell 1984

>18

Leukoplakia

11.7

MSSC

WHO 1994

>30

OPMD

11.3

Random

WHO 1980

>15

USA (2003)

MSSC*

Kramer 1978 Kramer 1980 WHO 1994

>20

OPMD Leukoplakia Erythroplakia Lichen planus OSF Leukoplakia

12.7 7.4 1.9 2.9 1.6 0.5–0.3 4.1 2.6

Scheifele et al

Ministry of Health Sri Lanka of Sri Lanka (2003)

Reichart et al Nagao et al

Zain et al

Banoczy et al Ikeda et al Axell et al

270

South Asia. A pooled estimate from 23 studies yielded a point prevalence of 2.6 percent. There are few studies that document the rate of occurrences geographically (Table 12.3). In a US national survey of 16,128 individuals the prevalence figure of 0.42 percent is one of the lowest reported so far. A word of caution is needed in interpreting these data as various authors have used different definitions and

35–44 and 65–74

Spain (2002) Stratified WHO 1978 Randomized Axell 1984 Germany Stratified Axell 1976 (2000) Randomized Zain 1995 Japan (2000) All invited to WHO 1980 a screening program

>30

OPMD Leukoplakia and Erythroplakia OSF Leukoplakia

35–44 65–74 Male >40 Female >20

Leukoplakia Leukoplakia Leukoplakia Lichen planus

1.6 1.0 0.19 0.21

Malaysia (1997)

Stratified WHO 1978 Randomized Axell 1978

>25

The Netherlands (1996) Hungary (1991) Japan (1991)

Waiting room

Axell 1984

13–93

Leukoplakia Erythroplakia OSF Lichen planus Leukoplakia

0.96 0.01 0.06 0.38 0.6

Random

Axell 1984

Factory workers Stratified, random

Axell 1984

All ages groups 18–63

Leukoplakia Lichen planus Leukoplakia

1.3 0.1 2.5

Axell 1976

>15

Lichen planus

1.9

Sweden (1987)

MSSC*

0.4 1.6

Contd...

12

Contd...

Country (year)

Axell et al Warnakulasuriya et al Ariyawardena et al

Sweden (1987) Sri Lanka (1984) Sri Lanka (2007)

Warnakulasuriya et al

India (2011)

Sampling method

Definition used Age group (years)

Disease entity

Prevalence percent

Axell 1987

>15

Leukoplakia

3.6

Population screening Estate Workers

WHO 1978

>20

OPMD

4.2

WHO 1978

>15

Industrial workers

WHO 1978 Axell 1984

>20

Leukoplakia Erythroplakia OSF Leukoplakia

4.6 0.03 1.6 5.0

*MSSC: Multistage stratified cluster Modified from Johnson, Jayasekara, Amarasinghe 2011. Periodontology. 2000;vol57:2011;p.27

A

POTENTIALLY MALIGNANT DISORDERS

Author

B Figs 12.1A and B: Leukoplakia of the tongue and the most common histologic finding of hyperkeratosis without evidence of dysplasia. There is still a risk of transformation

criteria to detect oral leukoplakia. To further complicate prevalence rates, all leukoplakias are not the same, having different etiologies, variable clinical features, and different biologic potentials/risks. These variations require a variety of clinical approaches regarding management, which can be complex and leading to uncertain outcomes.

Epithelial Dysplasia and Malignant Transformation The basis for the malignant potential for leukoplakia remains an enigma. The hyperkeratosis that leads to the clinical manifestation is a biochemical process, and the association between this process in oral epithelium and

the potential for carcinogenesis remains unknown (Figs 12.1 and 12.2). The magnitude of surface keratinization is of no importance. The malignant potential is based upon a number of studies that have reported a more than expected occurrence of carcinomas in patients with oral leukoplakia (Table 12.4). A projected microscopic progression is illustrated in Figures 12.3A to D. Studies in cell markers may someday reveal an answer. In addition to some particular clinical features such as the site, associated erythema (redness), nodularity that an experienced clinician can recognize, there are microscopic changes that offer clues as to the degree of risk. These are the degrees of epithelial dysplasia that can be seen and to some extent quantified. Criteria used for diagnosing

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A

B

Figs 12.2A and B: Two cases of oral leukoplakia of lateral tongue with a homogeneous appearance

Investigator (Country)

Year

Number

Malignant transformation (%)

Years observed (mean)

Silverman (India)

(1976)

4762

0.1

Gupta (India, Bhavnagar)

(1980)

360

0.3

Gupta (India, Ernakulam)

(1980)

410

2.2

Roed-Petersen (Denmark)

(1971)

331

3.6

Einhorn (Sweden)

(1967)

782

4.0

Pindborg (Denmark)

(1968)

248

4.4

Kramer (England)

(1969)

187

4.8

Banoczy (Hungary)

(1977)

670

5.9

Silverman (USA)

(1968)

117

6.0

Silverman (USA)

(1984)

257

17.5*

Lind (Norway)

(1987)

157

8.9

Schepman (Netherlands)

(1998)

166

12.0

Holmstrup (Demark)

(2006)

236

12.0

Arduino (Italy)

(2009)

207

7.2

~1

Warnakulasuriya (UK)

(2011)

335

6.9

10 (4.2)

*Includes PVL

272

oral epithelial dysplasia are listed in Table 12.5. These features could be broadly categorized as changes to the architecture (strata) of the epithelium and those that manifest as cellular atypia the more prominent or numerous they are, the more severe the grade of dysplasia. There is great variability in their interpretation of the presence, degree and significance of the

individual criteria. The following microscopic features have been suggested as a guidance by WHO experts to grade epithelial dysplasia to mild, moderate or severe.

Mild Dysplasia In general architectural disturbance limited to the lower third of the epithelium, accompanied

12

B

C

D

Figs 12.3A to D: Illustrations depicting increasing incidence of cellular atypia in progression of sections from leukoplakia with atypia, to squamous cell carcinoma. Note progression of cellular changes from: (A) Focal keratosis to; (B) Leukoplakia with atypia to; (C) Carcinoma in situ to; (D) Squamous cell carcinoma. Cellular maturation patterns are normal in focal keratosis when compared to the remaining specimens

POTENTIALLY MALIGNANT DISORDERS

A

ƒ Table 12.5 Criteria used for diagnosing dysplasia Architecture

Cytology

Irregular epithelial stratification

Abnormal variation in nuclear size (anisonucleosis)

Loss of polarity of basal cells Abnormal variation in cell size (anisocytosis) Increased number of mitotic figures

Abnormal variation in cell shape (cellular pleomorphism) Increased nuclear-cytoplasmic ratio

Premature keratinization in single cells (dyskeratosis) Increased nuclear size Keratin pearls within rete ridges

Atypical mitotic figures Increased number and size of nucleoli Hyperchromasia

by minimal cytological atypia defines the minimum criteria of dysplasia (Fig. 12.4)

Moderate Dysplasia Architectural disturbance extending into the middle third of the epithelium is the initial criterion for recognizing this category. Consideration is then given to the degree of cytological atypia. The presence of marked atypia may indicate that a lesion should be categorized as severe dysplasia despite not extending into the upper third of the epithelium. Alternatively lesions with mildly atypical features extending

into the middle third of the epithelium may merit being graded as moderate dysplasia (Fig. 12.5).

Severe Dysplasia Recognition of severe dysplasia starts with greater than two-thirds of the epithelium showing architectural disturbance with associated cytologic atypia. However, as noted in the previous paragraph, architectural disturbance extending into the middle-third of the epithelium with sufficient cytologic atypia is upgraded from moderate to severe dysplasia (Fig. 12.6).

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Fig. 12.4: Mild epithelial dysplasia—architectural changes are limited to the lower-third of the epithelium, cellular atypia is mild

ƒ Table 12.6 Interobserver agreement in the diagnosis of epithelial dysplasia Kappa scores

Agreement (%)

Brothwell et al

0.51 (0.42–0.58)

77 (75–85)

Karabulut et al

0.35 (0.27–0.45)

55 (49–69)

Abbey et al

0.46 (0.29–0.57)

82 (66–86)

Kappa values (0.35–0.51) for a diagnosis of the presence or absence of epithelial dysplasia represent only fair to moderate agreement

Fig. 12.5: Moderate epithelial dysplasia— architectural changes extend to middle-third of the surface epithelium, cellular atypia is moderate

274

Fig. 12.6: Epithelial dysplasia graded as severe— architectural changes extend to upper-third, cellular atypia including increased mitoses

Dysplastic changes remain somewhat controversial as to predicting transformation to carcinoma and effective management. The varying degrees of epithelial dysplasia (mild, moderate, severe) remain our best available cell/tissue markers at this time in assessing risks for transformation but there is considerable subjectivity and only moderate agreement among observers on grading (Table 12.6). In a recent study, we have found that three grades

of dysplasia have independent prognostic value, both for transformation and time to transformation.

Lichenoid Dysplasia The term lichenoid dysplasia has been used when the inflammatory response associated with dysplasia is dense, concentrated subepithelially within the upper lamina propria. This terminology has been controversial and the histological appearance misjudged as of lichen planus with dysplasia (Fig. 12.7). The term lichenoid dysplasia implies a dysplastic lesion with a lichenoid inflammatory response.

Cell and Molecular Markers It is clear from a large number of reported studies that multiple genes/pathways are involved in the progression of a normal epithelium to metaplastic/dysplastic states to eventually cancer. While there are numerous papers citing work on epithelial cell markers and neoplastic risk, none have the specificity to definitively aid the clinician regarding management. The applicability of gene aberrations and altered protein expression in identifying dysplastic lesions and predicting their outcome is far from proven, especially if these findings are considered in isolation. Even a ‘cocktail’ of markers has not offered the specificity or practicality needed. Some molecular alterations in genes/ pathways which include cellular signaling, cell cycle, apoptosis, genomic stability, cytoskeleton and angiogenesis to predict neoplastic potential include the following examples: Loss of heterozygosity in patients with leukoplakia and/or dysplasia as evidenced by missing chromosome arms (mainly 3, 9, 17) that contain known tumor suppressor genes seem to be particularly important to predict subsequent transformation to carcinoma. The same problem of inadequate

12 POTENTIALLY MALIGNANT DISORDERS

Fig. 12.7: Oral epithelial dysplasia with a lichenoid process—sometimes referred to as lichenoid dysplasia in the literature, a term that should be avoided

specificity exists in looking at biomarkers in dysplasia. A systematic review included seven biomarkers (p53, p73, cathepsin L, matrix metalloproteinases (MMP 1,2,9) and survivin). Growth factor receptors (EGFR), other cell cycle markers (cyclin A, B1, D), cell proliferation markers (Ki67, Mcm2) and other molecular markers that control apoptosis (e.g. pRB) have also been examined. All show wide variations in results, some with a degree of association for progression to cancer, but lack the accuracy of useful predictive positive/negative values for transformation. It is likely that morphological features seen in dysplasia are due to genetic changes in the epithelium but it is unlikely that the mutations involved are the same ones as associated with progression to cancer. Therefore, the latitude for error, as well as the lack of availability and cost, renders these approaches premature to use in the clinical management and not at the level for making definitive decisions regarding the most appropriate treatment.

Ploidy Status of Oral Leukoplakia Chromosomal instability and DNA aneuploidy are fundamental to development of malignancy. Preneoplastic oral epithelium may show aneuploidy and it is hypothesized that DNA aneuploidy may predict malignant transformation. The prevalence of aneuploidy may also increase as lesions progress, as noted in sequential biopsies. Large scale genomic changes (DNA ploidy) can be measured using karyometry, flow cytometry and image-based analysis. Unfortunately, data from early studies are retracted and the predictive value of ploidy analysis remains untested in a routine diagnostic setting. One study has shown that epithelial dysplasia is correlated with DNA ploidy status and few have shown a predictive value for transformation. The likely prognostic markers of value are shown in Table 12.7. The combined use of the dysplasia grade and ploidy status could provide the highest predictive value for transformation.

Clinical Features All leukoplakias are not the same as well as occurring on any mucosal surface

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12

A

B

Figs 12.8A to C: Predominantly white lesions of tongue, all consistent with a diagnosis of oral leukoplakia but with varied clinical appearance

Fig. 12.9: A white patch with a red component clinically labeled erythroleukoplakia

ƒ Table 12.7 Factors indicating worse prognosis • Female gender • Long duration (with continuation of habits) • Idiopathic leukoplakia • Location—Floor of mouth/Ventral tongue • Nonhomogeneous types erythroplakia (speckled) • Presence of Candida • Severity of dysplasia • DNA aneuploidy.

276

C

(Figs 12.8A to C). A range of clinical features along with patient history indicate various differences in probable causative factors, malignant potential and risk. A red component in the leukoplakia (erythroleukoplakia) indicates an increased risk for dysplasia and/ or malignancy (Fig. 12.9). This also indicates

that the diagnostic biopsy should include the red component, since this is the most likely area of dysplasia or even an early carcinoma. Some anatomical sub-sites such as floor of mouth or ventral tongue are traditionally considered as having higher risk. In the absence of a tobacco history, a leukoplakia is considered “idiopathic”, though rare, are considered to have a higher risk of transformation. The leukoplakia with the greatest potential for malignant transformation is termed proliferative verrucous leukoplakia (PVL) (Figs 12.10A and B). In this form, the clinical lesion increases in size over a period of time and can occur at multiple oral mucosal sites. As PVL progresses, it becomes exophytic/ wart-like in appearance, and often occurs without any evident etiologic factor. Selecting representative biopsy sites can be difficult, but critical to an accurate assessment. It is found most frequently in women over 40, but can occur in younger women and in men. Margins are difficult to ascertain, so recurrences after treatment are common, accounting for an always guarded prognosis. This form can start as an unimpressive limited, flat white change, or some may have a lichenoid appearance that with time extends and becomes exophytic. PVL can show all degrees of dysplasia, transforming frequently into verrucous carcinoma or invasive carcinoma with varying degrees of cellular differentiation. The diagnosis is based upon a combined clinical-microscopic assessment.

Differential Diagnosis There are some white patches seen on the oral mucosa that should not be confused as oral leukoplakia (Table 12.8). Keratotic changes (focal keratosis) from labial and cheek mucosal

12

B Figs 12.10A and B: Classical clinical and microscopic appearance of proliferative verrucous leukoplakia

POTENTIALLY MALIGNANT DISORDERS

A

ƒ Table 12.8 White patches that should be distinguished from leukoplakia and need exclusion to diagnose leukoplakia Disorder

Diagnostic features

White sponge nevus

Noted in early life, family history, large areas Biopsy not indicated involved, genital mucosa may be affected

Frictional keratosis

History of trauma, mostly along the occlusal Biopsy if persistent after elimination plane, an etiological cause apparent, mostly of cause particularly in a tobacco user reversible on removing the cause

Morsicatio buccarum

Habitual cheek-lip biting known, irregular whitish flakes with jagged out line

Biopsy not indicated

Chemical injury

Known history, site of lesion corresponds to chemical injury, painful, resolves rapidly

Not indicated

Acute pseudomem- The membrane can be scraped off leaving branous candidosis an erythematous raw surface Leukoedema

Biopsy

Swab for culture

Bilateral on buccal mucosa, could be made Not indicated to disappear on stretching (retracting), racial Other forms of lichen planus (reticular) found in association

Biopsy consistent with lichen planus

Lichenoid reaction

Drug history, or to an amalgam restoration

Biopsy consistent with lichenoid reaction

Discoid lupus erythematosus

Circumscribed lesion with central erythema, white lines radiating

Biopsy consistent with DLE supported by immunofluoresence and other investigations

Skin graft

Known history

Not indicated

Hairy leukoplakia

Bilateral tongue keratosis, other features of HIV disease

Specific histopathology with koilocytosis; EBV demonstrable on ISH

Leukokeratosis nicotina

Smoking history, grayish white palate, swol- Not indicated len minor salivary glands and dilated orifices

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12

sucking or biting habits (Figs 12.11A and B) and alveolar ridge keratosis (ARK) related to overlying denture irritation are termed frictional keratoses. These forms of keratoses have little to essentially no potential for malignant transformation and are not considered under the term leukoplakia. On the buccal mucosa, when present along the occlusal plane, these changes are often termed as linea alba. Frictional keratoses in labial/buccal gingivae are rare clinical findings and also generally do not belong to the category of oral leukoplakia. Leukoedema (Figs 12.12A and B) is sometimes confused with leukoplakia. But leukoedema is flat, soft, grayish in color, and a manifestation of immature keratin, epithelial

A

hyperplasia and often some vacuolization. While in some patients this is an early stage of mucosal response to irritation, e.g. tobacco, it is often a racial disorder without any risk for neoplasia. Leukoedema tends to disappear on stretching the affected area of mucosa leaving a normal pink color of the mucosa. White sponge nevus (WSN), a keratin defect, can be confused with leukoplakia because of the epithelial hyperplasia and some increase in surface keratin (Figs 12.13A and B). While WSN is a genetic defect, affecting keratin genes 4 and 13, clinical penetrance is not always apparent early in life or in a large number of family members. It is not associated with a risk for malignant transformation.

B Figs 12.11A and B: (A) Frictional keratosis from lip sucking causing focal keratosis; (B) Cheek irritation causing linea alba

A

278

B Figs 12.12A and B: Leukoedema of buccal mucosa. The white appearance will fade away on stretching the tissue leaving normal pink color

12

B Figs 12.13A and B: Asymptomatic white sponge nevus (genetic keratin defect)

The presence of Candida in leukoplakia frequently confuses the clinical picture. In some instances, a trial of antifungal medicine will partially or completely modify the white plaque. Actually, candidal organisms are capable of invading the upper layers of the epithelium and stimulating keratin formation that clinically cannot be wiped off (Fig. 12.14). The evidence remains controversial as to whether candidalassociated leukoplakia has an increased risk for malignant transformation. Hairy leukoplakia comprising immature keratin is associated with infection with EBV in immunosuppressed or HIV seropositive subjects, and carries no documented risk for malignant transformation (Figs 12.15A and B). Table 12.8 lists oral white lesions that need to be excluded while diagnosing oral leukoplakia. A schematic diagram (Fig. 12.16) explains the procedures to follow when investigating oral leukoplakia to achieve a correct diagnosis.

Risk Factors The most common cause associated with leukoplakia is the use of combustible and/or smokeless tobacco and this remains the most troublesome problem during its management. The combustible forms (smoking) include the use of cigarettes, pipes, cigars and bidi. All of these forms carry an increased risk for leukoplakia and particularly among heavy users the subsequent risk for transformation to

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A

Fig. 12.14: Candidal leukoplakia on lateral tongue

malignancy. The variable clinical responses to the chemical and heat irritants depend upon the years and frequency of usage, the tobacco leaf and processing, combined with other factors such as genetic mutations, alcohol intake, and other forms of irritation such a betel quid use. Discontinuing the habit(s) is often difficult, but it is critically important in the management and control of leukoplakia. Obviously, nontobacco users can develop leukoplakia, referred to as idiopathic leukoplakia with a potential for malignant transformation, and leukoplakia can remain in ex-smokers who have discontinued the habit for a period of time. So a predictable biologic outcome remains as a variable risk. The noncombustible (smokeless) forms of

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A

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Figs 12.15A and B: Hairy leukoplakia in an HIV seropositive patient. On the right, classical microscopic feature of koilocytosis due to EBV associated cytopathic damage is seen in the upper layers of the epithelium

Fig. 12.16: A schematic diagram pointing out the steps to follow when investigating oral leukoplakia

tobacco (ST) include snuff, referred to as snus in Scandinavia, chewing tobacco, gutka, and many other novel substances/forms. Nitrosamine content and availability of ST varies widely. Keratinization and transformations depend upon the product and usage. Time for development of leukoplakia and carcinoma vary widely, but usually involves many years. Prospective, well-designed epidemiologic studies are not available for definitive transformation figures. Tobacco cessation can be by ‘cold turkey’ based upon will-power, by the use of counseling, incorporating nicotine replacement therapy, and using pharmacologic approaches (see Chapter 24). Smokeless tobacco

(particularly snuff) associated with leukoplakia at the mucosal site of the habit is often reversible after cessation. So cessation and potential disappearance of the leukoplakia is rewarding and can be an approach to cancer prevention. Using one of these approaches is helpful to a limited degree; and combinations are the most effective. However, even with compliance and after one year follow-up, the successful cessation results are on average less than 20 percent. Betel quid chewing is strongly associated with causation of oral leukoplakia. Betel quid entails different combinations of betel leaf with added tobacco, slaked lime, flavorings with areca nut as the main ingredient (Fig. 12.17). A

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Fig. 12.20: Erythroleukoplakia in the floor of mouth in a heavy smoker and alcohol drinker that transformed into a squamous carcinoma

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Fig. 12.18: Erythroleukoplakia arising from a betel quid-induced lichenoid lesion

smokers, erythroplakias have been the first signs of malignancy (Fig. 12.20).

DIAGNOSIS AND ADJUNCTIVE TECHNIQUES

Fig. 12.19: Clinically presenting as painful erythroplakia of soft palate. On biopsy—squamous cell carcinoma

betelquid induced patch which first appeared as a lichenoid lesion and later changed to erythroleukoplakia is shown in Figure 12.18. In populations not adding tobacco to betel quid (e.g. Taiwan), the population attributable-risk of areca nut use was estimated at 73.2 percent.

ERYTHROPLAKIA While quite infrequent, some dysplastic or early malignant lesions clinically will be all red with well circumscribed clinical margins. These lesions are termed erythroplakias and can represent an early carcinoma (Fig. 12.19). While these lesions can be mistaken for irritation or infection, if they persist a biopsy is mandated to rule out dysplasia or malignancy. In some reports from populations of drinkers and

The definitive diagnosis for leukoplakia and erythroplakia is made by biopsy, usually an incisional biopsy. As indicated previously, biomarkers that have a useful predictive value are not yet available, so the presence or absence of epithelial cell dysplasia becomes helpful in lesion management and assessing malignant potential. Often, adjunctive techniques become useful for many reasons: • Accelerating biopsy when there are otherwise reasons for delay • Identifying the best area(s) for biopsy sampling • To help determine margins • For follow-up care. Low level evidence-based data is available, indicating a benefit of several adjunctive techniques for clinicians and patients regarding early detection by accelerating biopsy in evaluating leukoplakic lesions. At the present time, high level evidencebased data (controlled randomized prospective trials) are not yet reported to conclusively reflect the usefulness or lack of usefulness of these techniques, including cytodiagnosis (using a brush biopsy), vital staining (toluidine blue) (Figs 12.21A to D), and various forms of optical diagnostic techniques including

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Figs 12.21A to D: Staining technique with 1 percent aqueous toluidine blue: (A and B) Application in asymptomatic erythroleukoplakia; biopsy showed severe dysplasia; (C) Toluidine blue retention after application of 1 percent acetic acid destaining; (D) Biopsy using a 5 mm dermatological punch that showed microinvasive squamous carcinoma

autofluorescence and chemiluminescence (Figs 12.22A and B). Their sensitivity in detecting a white or red patch is good but their specificity to detect oral dysplasia remains low. However, many reports do indicate their usefulness in accelerating appropriate tests to establish the diagnosis.

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It must be emphasized that screening involves a thorough head and neck examination, a systematic visual examination of the oral mucosa (oral cavity) and use of adjunctive techniques (if necessary) to accelerate biopsy. Following screening any suspicious lesions found should be referred to a specialist for biopsy. The purpose is to properly assess the leukoplakia for the most appropriate management, as well as to make certain that malignant transformation has not

already taken place. The differential diagnosis (Table 12.8) must always be considered in order to obtain the optimal, expedient, and most accurate lesion identification. As an example, frictional keratosis is the most common white lesion and would be encountered more frequently during screening. Furthermore, lichen planus, a quite common auto-immune mucocutaneous disease, would present as keratosis. Its plaque like form can mimic homogeneous leukoplakia, and erythematous forms may mimic erythroleukoplakia, or even carcinoma. Therefore, persistent lesions for which a diagnosis has not been established must be thoroughly evaluated. Organized screening programs to detect OPMDs have been conducted in India, Sri Lanka, Malaysia, Taiwan, Japan and the UK with some benefit to these populations. The majority have used visual screening for the case-detection and a program in Taiwan in

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B Figs 12.22A and B: (A) Newer optical techniques to detect leukoplakia. Loss of fluorescence with VelScope; (B) Enhanced whiteness under chemilumine scence using Vizilite

addition used toluidine blue. Annual screening conducted in India and Japan has established that new cases/lesions can be found by periodic screening. The role of screening as a mechanism to discover new lesions cannot be understated.

Management If oral leukoplakia and erythroplakia can be effectively recognized, diagnosed and appropriately treated, a proportion of oral and oropharyngeal cancers could be prevented. The natural history of oral leukoplakia- the most common OPMD lesion encountered in the oral cavity—remains unclear. Presence of oral dysplasia significantly increases the rate of transformation to cancer and this may increase with the grade. It is therefore argued that treatment of dysplastic lesions may prevent cancer development in high-risk persons with oral leukoplakia. A recent metaanalysis has provided evidence that surgical treatment of oral leukoplakia may reduce the risk of transformation but does not completely eliminate this risk. Whether we can prevent malignancy by treating precursor lesions by surgery or chemoprevention remains a complex issue. It is one of the most important problems in oral medicine and needs further research. Management depends upon signs, symptoms, clinician experience, grading of

dysplasia (± ploidy data) and patient wishes/ compliance. Obviously, the most important part of management is knowing the microscopic and clinical classifications, since risk for transformation is the end point to be prevented. If removing an identified irritant will reverse a lesion, that is optimal treatment. In a persistent leukoplakia that has been already diagnosed/ evaluated, management considerations include careful follow-up, incorporating adjunctive techniques, and biopsy for any changes in signs and symptoms. Discontinuing tobacco habits and other irritants (e.g. betel quid) are essential to optimal outcomes. Definitive treatment is by surgical removal. As mentioned earlier, a recent systematic review concluded that surgical excision reduces malignant transformation but does not totally eliminate the risk. The use of laser has been effective, but any means of removal that works for the operator is in order (Figs 12.23A to C). The problem is one of including adequate margins to minimize chances for recurrence. The benefit of laser surgery in oral leukoplakia is that recurrences following treatment are far fewer compared with knife excision. In the leukoplakias that have a genetic basis, minimal margins with close follow-up for recurrence is a viable option. Extensive excisions are sometimes difficult in trying to attain biologically clear margins, as well as maintaining optimal comfort

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Figs 12.23A to C: Leukoplakia with moderate dysplasia controlled with CO2 laser removal: (A) Original lesion; (B) Immediately after laser removal; (C) at 5 weeks

and function for the patient. In situations such as proliferative verrucous leukoplakia, recurrences are common. While the use of adjunctive techniques to assist identify ‘safe’ margins may be helpful, they are not evidencebased or reliable. Their utility is based upon the reports of experienced clinicians. If any existing habits are not discontinued, the prognosis for successful recovery is poor. Although there have been extensive studies utilizing chemoprevention none have shown any clinical utility. The first tried were vitamin A and retinoids (retinoic acid); the results have been poor. Firstly, because all patients do not have an effective response in modifying the lesion; and secondly, high dosages must be used. In most patients, adverse side effects will occur, such as dry skin, pruritus, rash, angular cheilitis, and an increase of serum triglycerides. If there has been a response and the medicines are discontinued, unfortunately, the leukoplakia recurs (Figs 12.24 and 12.25). The other chemotherapeutic agent that has undergone a prospective randomized trial is lycopene. Lycopene is a carotenoid, a cyclic isomer of beta-carotene and is a natural pigment synthesized by plants, predominantly accumulated in tomatoes. A Japanese group has shown that serum levels of lycopene, among men with oral leukoplakia was significantly lower than controls. A clinical trial on 58 subjects with leukoplakia when given 8 mg or 4 mg lycopene per day for 3 months showed clinical responses of 80 and 66 percent respectively, but the study did not follow consort guidelines. More recently NSAIDs have drawn the most attention as chemoprevention agents. The ideal chemopreventive agent remains to be discovered. Radiation plays no role.

Photodynamic therapy using a lesion sensitizer combined with a laser beam of a specific wave length to cause localized photo damage and cell death has not been adequately tested but may be useful in the future. Assessing and modifying tobacco usage in young individuals is particularly important since it is at the time in life (adolescents) that adult tobacco habits are formed. While tobacco use is more prevalent in boys, usage by girls is increasing. Smoked tobacco contains numerous carcinogens (estimated to average around 60), increases the risk to those exposed individuals to develop precancerous or malignant transformations. Solutions to the problems associated with smoking depend upon passing and implementing tobacco control laws, taxes, counseling, decreased access and control of media advertising. Practical methods of tobacco cessation for patients encountered in clinical practice are given in Chapter 24. Management also includes a thorough orientation to the patient regarding leukoplakia and periodic follow-up. Again, re-biopsy is indicated only when there are clinical changes in either signs and/or symptoms. Often, the use of an adjunctive technique might indicate the best area to sample in order to evaluate the most dangerous portion of the lesion. However, the signs and/or symptoms, including the use of markers that might yield accurate positive or negative predictive values for any specific leukoplakia are not readily available or reliable. So once again the clinical classification of the lesion, together with the histologic findings, still remain the most useful factors to support therapeutic recommendations.

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B Figs 12.25A and B: A successful outcome following retinoid therapy

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Oral lichen planus (OLP) is a chronic inflammatory mucocutaneous disease affecting 0.5 and 2.2 percent of the population, mostly in middle ages. The disease appears as bilateral white lesions with considerable variation in its clinical appearance. Both the oral mucosa and skin are usually involved, but the oral lesions often occur in the absence of skin lesions. It is a cell-mediated immune condition leading to a delay in the maturation of mucosal epithelium which is responsible for hyperkeratosis. There are various types of OLP and some forms can affect the quality-of-life in affected patients. Moreover, malignant transformation in patients with longstanding OLP has been documented. In general, patients with OLP are symptomfree but may complain of roughness of the mucosa. In asymptomatic subjects, the condition is often first noted by the dental practitioners. Those with symptoms often complain of burning sensation to soreness but may experience bouts of severe pain, interfering with speaking, eating and swallowing during episodes of ulcerative (erosive) forms of OLP. These symptoms could interfere with their quality-of-life.

Etiology and Immunopathogenesis Oral lichen planus is a chronic inflammatory condition of unknown etiology. The disease mechanism involves a cell mediated immune response to an unidentified antigen. A role for immune dysregulation in the pathogenesis of OLP specifically involving the cellular immune system has been reported in many studies. The

A

inflammatory infiltrate in OLP lesion consists primarily of T cells and macrophages. A recent study showed that activated CD8+ T lymphocytes can be found within the epithelium and adjacent to damaged basal cell keratinocytes in the OLP lesions. The basal keratinocyte degeneration observed in OLP is attributed to cytotoxic CD8+ T lymphocytes. The triggering antigen is unknown. Moreover, mast cell degranulation in OLP releases proinflammatory mediators such as tumor necrosis factor-alpha, chymase and tryptase that play an important role in the pathogenesis of OLP. There are many factors involved in the pathogenesis of OLP such as matrix metalloproteinases, chymase, tryptase and proinflammatory cytokines. Recently, TNF-a which is one of the proinflammatory cytokine has been reported in the pathogenesis and inflammatory process of OLP.

Clinical Types of OLP Oral lichen planus may present in various patterns and these presentations are divided into clinical types described by the criteria of the International Consensus Meeting in Chamonix, France, 2003. A variety of clinical presentations such as reticular, papular, plaque type, atrophic, and ulcerative types are described below.

Reticular Type Reticular lichen planus is the most common type occurring on the buccal mucosa. Lesions may be localized to one area but usually involve the entire buccal mucosa (Figs 12.26A and B)

B Figs 12.26A and B: Reticular lichen planus—bilateral presentation

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Papular Type In this type, pinhead size papules are present spaced apart but distributed close enough that the lesion has a pebble white or gray appearance. Individual small white raised papules may be obvious and these sometimes coalesce. Papular type of OLP closely resembles Fordyce’s granules (Fig. 12.27).

Fig. 12.27: Early papular eruption on buccal mucosa, that eventually leads to reticular form

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occurring bilaterally, extending to the vestibular and retromolar area, and appear as interlacing raised lines forming a latticework. This type is also seen as keratotic white striae arranged in a reticular pattern on the lateral margins of the tongue.

Plaque Type In this type of OLP, the keratotic areas are raised and appear as white plaques. Plaque type OLP closely resembles leukoplakia, but reticular elements could always be recognized in the periphery of the lesions. These white patches can be present with or without erythematous areas and the clinicians should differentiate plaque type OLP from leukoplakia or lupus erythematosus (Fig. 12.28).

Atrophic Type In this type, the thin epithelium overlying the basal area is weakened and this epithelium is easily lost leading to shallow erosions (Fig. 12.29). The OLP lesions of this type may present as erythematous areas with or without keratotic white striae. Patients usually complain of burning sensation or soreness when eating hot and spicy food. When atrophic OLP affects the gingivae, the disease may present as desquamative gingivitis.

Fig. 12.28: Plaque type oral lichen planus with adjacent annular lesions

Ulcerative (Erosive) Type Atrophic or erosive form of OLP may rupture leaving a raw ulcerated area. Ulcerative form of OLP lesions present with serous exudates, surrounding erythema combined with white striae at the margins of the ulcer (Fig. 12.30). The ulcerative form of OLP may result in mucosal bleeding, soreness and fibrosis.

Fig. 12.29: Atrophic oral lichen planus. Note: There is no surface ulceration

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Fig. 12.30: Ulcerative oral lichen planus with associated reticular striae at margins

Fig. 12.32: Desquamative gingivitis often a manifestation of lichen planus

Fig. 12.31: Bullous lichen planus affective gums

Fig. 12.33: Pigmentation in long-standing oral lichen planus

Bullous Type This is a rare type and vesicles or bullae may occur from time to time. It is very important to differentiate this type from pemphigus or mucous membrane pemphigoid (Fig. 12.31).

Desquamative Gingivitis Desquamative gingivitis (DG) may be a manifestation of several diseases such as mucous membrane pemphigoid (MMP), pemphigus vulgaris (PV) and lichen planus. However, DG is a term indicating a clinical manifestation and not a diagnosis.

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Gingival presentation of DG is characterized by erythema with epithelial desquamation, atrophy, edema, and/or presence of vesiculobullous lesions. The gingival presentation (Fig. 12.32) of OLP may involve both free and attached gingiva affecting all quadrants of the mouth. Hyperkeratotic striae may be evident at the periphery. Patients may present as symptom-free or report a burning sensation. Severe pain is uncommon. Deep brown/black pigmented areas around white striae (Fig. 12.33) may be found associated with active OLP or mostly with burnt out lesions of OLP and is more common in dark skinned people.

Oral Lichenoid Lesions

Fig. 12.35: Positive patch test result. Contact hypersensitivity to several dental materials

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Oral lichenoid lesions (OLLs) and lichen planus (OLP) exhibit similar clinical and histopathological features. Several OLLs are recognized, those due to contact hypersensitivity to restorations, in association with a systemic medication (OLDR) or presenting with chronic graft verus host disease (cGVHD). It is beyond this chapter to discuss all three conditions, but it is prudent to consider oral lichenoid contact lesions (OLCL) arising due to contact with metal restorations and GVHD. During follow-up studies some authors have attributed a small risk of OLCL and cGVHD transforming to cancer. The distinguishing feature of OLCL is the lesions direct topographic relationship to the suspected causative agent, most commonly an amalgam restoration (Fig. 12.34). With

the removal and replacement of the putative causative material, OLCL should resolve within several months. In fact, OLCL cannot be distinguished from OLP both clinically and histopathologically. Skin patch testing (Fig. 12.35) might be helpful to the dentist in confirming a lichenoid reaction and in the determination of a suitable replacement dental material. The test substances such as mercury-containing amalgam, or salts have commonly been used. The standard tests take into account that mercury from amalgam restorations may be in the form of metal, organic substances, or organic salts. Few patients react to all three forms. There is no worldwide consensus regarding the allergens used but generally it is accepted that 5 percent amalgam and 1 percent ammoniated mercury are suitable for screening. The tests are usually carried out with additional European series and other dental materials to screen for additional allergens. These substances are applied to normal skin on the back and read after 72 hours exposure. A skin reaction with erythema (Fig. 12.35) and effusion with possible papulovesicles (eczema reaction) is considered a positive reaction. Positive patch test reactions to those suspected substances have been reported with conflicting results between 8 and 78.9 percent. Some studies did not find the value of patch testing. Therefore, the value of cutaneous patch testing in OLCL remains controversial as there is a debate about the validity of extrapolating skin reactions to mucosal responses. Oral cGVHD may also be considered a potential risk factor for the development of oral carcinoma following allogenic hemopoietic stem cell transplantation among long term survivors. Lichenoid lesions are also encountered in betel quid users at the site of placement of the quid after prolonged use. The main distinguishing feature is from the patient’s history that these OLCL arise when the quid is habitually placed and stored mostly in the buccal sulcus. The clinical appearance consists of white, linear, wavy parallel nonelevated streaks associated with a plaque like patch, the lines occasionally radiating from central erythema.

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Systemic diseases such as hypertension, diabetes mellitus, hepatitis C infection, etc. have been reported in association with OLP in many studies. As OLP occurs predominantly in middle age or older adults, many drugs used in the treatment of systemic diseases can trigger the development of OLDR. The association between OLP and systemic diseases may also be coincidental because OLP is common. Therefore, OLP apparently associated with systemic diseases is possibly to be due to drug side-effects rather than specific associations with the systemic diseases. However, there are no evidence-based studies on these aspects.

Fig. 12.36: Microscopic features of oral lichen planus. Main feature at this magnification is a dense subepithelial infiltrate of chronic inflammatory cells

Diagnosis and Histopathology Oral lichen planus can be clinically diagnosed by the chronicity of the history, the presence of oral and/or skin lesions, the characteristic clinical features, e.g. presence of striae and its bilateral occurrence. The oral manifestations alone may be sufficient for a correct diagnosis. Definite diagnosis of OLP is by histological examination of lesional tissue and undertaking a biopsy is important prior to commencement of treatment of this disease particularly to differentiate plaque type OLP from oral leukoplakia or erosive/ulcerative lesions from conditions such as DLE. Oral lichen planus is characterized by a range of features seen under the microscope (Figs 12.36 to 12.38). Requisite histopathologic features include: liquefactive degeneration of basal cells, presence of apoptosis and a band like infiltrate of lymphocytes within the lamina propria that immediately intermingles with basal region of the surface epithelium. Additional features often present although not a prerequisite to diagnosis include: “saw-toothed” rete ridges, hyper ortho and/or parakeratosis, acanthosis or atrophy, separation of surface epithelium from underlying connective tissue, isolated individual hyaline or colloid bodies (“Civatte bodies”) within the prickle cell layers. Disqualifying features include: any cellular atypia amounting to dysplasia, presence of heterogeneous round cell infiltrate, i.e. the presence of substantial numbers of plasma

Fig. 12.37: Oral lichen planus at a higher magnification showing loss of basal cells with several apoptoses

Fig. 12.38: A marked thickening of the basement membrane and migration of lymphocytes towards the epithelium

Management The management of OLP will vary widely both between patients, and for individual patients. Because of its recalcitrant (and chronic) nature, various factors such as patients’ medical history, presenting symptoms, treatment compliance as well as possible drug interaction must be considered. Plaque and calculus deposits are associated with an increased incidence of erythematous and erosive gingival lesions in many cases of OLP. Thus, improvement of oral hygiene is essential for eliminating dental plaque accumulation and can enhance healing of the lesions. Furthermore, there is a possibility of dental restorations inducing oral lichenoid lesions that may sometimes improve after replacement of amalgam with other restorative

materials. Anxiety, depression and psychic disorders have been reported in association with OLP patients. Stress has also been found to be the most frequent cause of acute exacerbations in those patients. Reassurance is useful, and some patients may require stress management. Various treatment regimens have been attempted to improve the refractory lesion and to reduce associated pain (Table 12.9), but a complete cure of OLP has not yet been accomplished because of its recalcitrant nature and lack of an apparent cause. Guidelines for

ƒ Table 12.9 Empirical treatments for oral lichen planus (Adapted from Scully et al 1998)

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cells within the infiltrate, diffuse extension of infiltrate to involve deeper submucosal tissues or frank perivascular distribution of the infiltrate. Histopathological findings are the same irrespective of clinical type or anatomical location of the lesion. Dysplastic changes when present termed lichenoid dysplasia remains a controversial topic and precludes a diagnosis of lichen planus. The term lichenoid dysplasia is considered above under leukoplakia and dysplasia. Direct immunofluorescence is usually not required to make a diagnosis of OLP as there are no specific features that could be attributable to the disease. When in doubt however, this additional step is useful in the differential diagnosis of erosive and bullous types from pemphigus, mucous membrane pemphigoid or lupus erythematosus in that OLP would yield negative results by the absence of antibody binding at BMZ. Direct immunofluorescence of OLP biopsies demonstrates a shaggy band of fibrinogen in the basement membrane zone in 90 to 100 percent of cases. The presence of fibrin deposition may be used as an additional marker in the diagnosis of lichen planus. IgM-stained cytoid bodies that are present in large numbers are also considered to be suggestive of lichen planus. DIF however, has no pathognomonic features and should only be used to differentiate when OLP clinically resembles MMP or DLE.

Immunomodulators Immunosuppressive agents

Anti-fungals

Corticosteroids

Azoles Griseofulvin Polyenes

Systemic: Prednisone Methylprednisolone Topical:

Surgery

Betamethasone Clobetasol Fluocinolone acetonide Fluocinonide Fluticasone Hydrocortisone Triamcinolone

Conventional Cryosurgery Laser surgery Grafting UV radiation UV light PUVA

Intralesional: Dexamethasone Hydrocortisone Methyl prednisolone Triamcinolone Others immunosuppressive agents Cyclosporin Interferon alpha Interferon beta Pimecrolimus Tacrolimus Thalidomide Azathioprine Immunostimulants Levamisole

Others Eiconol Enoxaparin Glycyrrhizin Mesalazine, etc. Retinoids Acitretin Etretinate Fenretinide Iso-tretinoin Tazarotene Temarotene Tretinoin

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the management of OLP have been published by the British Association of Oral Medicine. Topical steroids have been found to be an effective treatment of symptomatic OLP in reducing pain and inflammation. They can be used as the first line drugs in the treatment of OLP and there have been no reported serious sideeffects. Topical steroids such as triamcinolone acetonide 0.1 percent paste, betamethasone sodium phosphate 500 ug (0.5 mg dissolved in 10 ml of water rinsed for 3 minutes, 4 times daily), clobetasol propionate 0.05 percent ointment (2 ml four times daily), fluocinonide 0.05 percent, fluocinolone acetonide 0.1 percent or fluticasone spray (50 ug; 2 puffs 4 times daily) are recommended as a first line therapy of oral lichen planus. Systemic corticosteroids should be reserved for acute exacerbation, multiple or widespread lesions or those unresponsive to topical steroids. Cyclosporine (1.5% or 100 mg/ml or 16 mg in bio-adhesive gel three times daily) or other immunosuppressive drugs in the family of calcineurin inhibitors such as tacrolimus (0.03%) and pimecrolimus (1% cream) when used locally have also been reported for their effectiveness. Possible mechanisms of action of tacrolimus include the suppression of the activation and differentiation of T lymphocytes, via the inhibition of nuclear gene transcription of interleukin (IL)-2 and other several proinflammatory cytokines, such as IL-4 and IL-5. In some studies adverse effects (increased burning sensation) were noted. Previous studies have documented that the use of retinoids such as tretinoin and etretinate may improve the clinical and histological state of OLP lesions. Although a systemic form of retinoid such as etretinate has provided effective treatment for severe OLP, signs of recurrence are commonly seen after discontinuation of therapy. Because of the possible side-effects of retinoids and the fact that complete remission is rarely seen, both systemic and topical retinoids should only be used as an adjuvant therapy. Other treatments that have been tried include aloe vera in two clinical trials and curcumin as an adjunctive treatment to prednisone. Desquamative gingival lesions of OLP have also been treated with 20 mg doxycycline twice daily or 50 mg daily for 8

weeks until symptoms resolve. The utility of doxycycline in a nonbacterial disorder suggests a potent anti-inflammatory property of the drug. Surgical excision is recommended for isolated plaques or nonhealing erosions because it provides excellent tissue specimens for histopathologic diagnosis and may cure localized disease. CO2 laser has been used in the treatment of plaque-like of OLP. Free soft-tissue grafts have also been used for localized areas of erosive ulcerative OLP and the symptomatic OLP completely disappeared after the treatment with free gingival graft after follow-up. The management of OLP is often frustrating both to the patient and the practitioner. Twenty-eight randomized controlled trials included for analysis in a Cochrane review in 2011 on “Interventions for Treating Oral Lichen Planus” found only weak evidence showing the superiority of the assessed interventions over placebo for palliation of symptomatic OLP. These evaluations were based on relief of pain and reducing areas of ulceration as measures of effective treatment. There is weak evidence to suggest that aloe vera may be effective in reducing pain and clinical signs of OLP. The treatment is only for reducing pain but no cure for OLP. Cyclosporin may reduce pain and clinical signs of OLP. Toxic side-effects were commonly seen in drugs taken internally (systemic) whereas minimal side-effects were found in those applied to the oral mucosa.

Biologics As the outcome from present treatment options remain less than satisfactory novel biologic therapies that directly and or indirectly target T cells to treat OLP may be considered in the future. Biologics may be classified by their structure and function; Structurally they include receptor fusion proteins, monoclonal antibodies and recombinant cytokines. Functionally they could be divided into T-cell or cytokine modulators (or both). Examples of biologics that have been used in other inflammatory mucosal disorders include: Alefacept, Efalizumab, TNF–a inhibitors, Basiliximab, BCG-PSN, Rituximab. Appropriateness of these agents in terms of disease control, toxicity and

safety and costs to health services need to be researched.

The risk of malignancy in oral lichen planus is small. Follow up studies mostly conducted is USA and Europe estimated a range of MT rates close to 1 percent. In one study transformation rates were high for lichenoid lesions compared with OLP. In long standing atrophic or erosive and plaque like forms particularly affecting lateral margins of the tongue there might be a higher malignant potential. At present there is no clear evidence to suggest a particular type of OLP may carry a higher risk. The appropriate follow-up period for the early detection of any malignancy changes would depend on availability of service provision in both primary and secondary care facilities. After the first visit, OLP patients should be reviewed at frequent intervals during active treatment to assess response to treatment and to ensure that the patients apply the topical corticosteroid appropriately. Active treatment should be continued until erythema, ulceration and symptoms can be controlled. Photographic records of both initial presentation and during periodic follow-up are recommended (Figs 12.39A and B). Many patients with OLP remain asymptomatic and their disease may burn out after some duration. Management will vary from individual to individual. Long-term followup is required for patients whose disease is

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Malignant Transformation

recalcitrant in nature and who do not respond to medications. Patients should be educated on regarding the potential side-effects of steroid use and should be monitored to detect any such effects. Moreover, patients should understand the potentially chronic and relapsing course of OLP, as well as the need for surveillance in view of potentially malignant nature of OLP. Systemic steroid should be reserved for the treatment of recurrences with acute symptoms. If the response is satisfactory after a short burst of therapy and slow taper the patients continue to use a topical steroid until achieving symptom control. It is recommended that the lesion should be evaluated once or twice a year by their dentists. Candidal superinfection on the surface lesions of OLP during steroid use, should be treated with antifungal drugs. Those with gingival involvement need professional prophylaxis to improve their poor oral hygiene. Surveillance for possible malignant transformation in OLP is recommended, though a small group who undergo rapid development of aggressive cancers may not benefit: clear guidelines on periodical follow-up do not exist. Re-biopsy is indicated only if the lesions appear atypical or are clinically suspected of malignant change.

ORAL SUBMUCOUS FIBROSIS Oral submucous fibrosis (OSF) is a chronic, insidious disease that affects the submucosal tissues of the oral cavity with loss of fibroelasticity. The disease manifests with

B Figs 12.39A and B: An ulcerative oral lichen planus successfully treated with topical application of fluocinolone acetonide 0.1 percent in orabase

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blanching and stiffening of the oral mucosa leading to limitation in opening of the mouth. The presence of fibrous bands in lips, cheeks and soft palate is a hallmark of the disease. OSF was first described by Schwartz in 1952 among five Indian females living in Kenya and he coined the term Atrophia idiopathica (trophica) mucosae oris. Several other descriptive terms have been attributed, submucosal fibrosis of palate and pillars, diffuse oral submucous fibrosis, idiopathic scleroderma of the mouth, idiopathic palatal fibrosis, and sclerosing stomatitis. The number of reported cases of OSF has rapidly risen in India from an estimated 250,000 in 1980 to 2 million cases in 1993. Our current understanding of the pathology of OSF includes overlapping phases, an early inflammatory phase and the later fibrosis phase. In essence the disease could be described as a collagen metabolic disorder with changes observed in the extracellular matrix of the lamina propria and submucosa of the oral

cavity due to both increased collagen synthesis and/or reduced collagen degradation.

Pathogenesis There is now conclusive evidence that OSF is caused by areca nut, a masticatory substance used by Asians. Several mechanisms and biological pathways have been proposed for the pathogenesis of the disorder, a schematic diagram illustrates these factors in Flow chart 12.1, all based on the constituents of areca nut and genetic susceptibility to the disease. In essence the disease could be described as a collagen metabolic disorder with changes observed in the extracellular matrix of the lamina propria and submucosa of the oral cavity due to both increased collagen synthesis and/or reduced collagen degradation. Several chemicals in areca nut including arecoline, tannins and copper appear to upregulate the molecular process of deposition and/or

Flow chart 12.1: A schematic diagram to explain proposed pathogenic pathways in oral submucous fibrosis

and intolerance to spicy foods that are often the mainstay of their diet, leaving an individual handicapped both physically and psychologically. A commonly encountered initial symptom is a burning sensation of the mouth, particularly when consuming spicy foods. Another frequently mentioned early symptom is the appearance of vesicles on the soft palate and anterior pillars of fauces though difficult to observe in clinical settings. There is gradual loss of papillae on the dorsal tongue surface. During the course of progression the labial and buccal mucosae show blanching and the mucosal texture feels tough and leathery (Figs 12.40A and B). Stomatitis and superficial ulceration may intervene. Gradually palpable fibrous bands appear on the lips, buccal mucosa (Figs 12.41 to 12.43) and soft palate (Fig. 12.44) contributing to a distorted, shortened or shrunken uvula (Fig. 12.44). The fibrosis is symmetrically bilateral but rarely unilateral in a quid chewer who prefers to carry the quid on a particular side of the oral cavity. Other OPMDs discussed earlier, namely oral leukoplakia or erythroplakia may be seen in association.

Grading of OSF Based on the above clinical features the disease can be graded. In 1987, Warnakulasuriya introduced a grading system based on mouth opening and semiquantitative physical features. Many grading systems have subsequently evolved over the decades, some based on clinical features, others on histology and

Clinical Features In general, chronic chewers with OSF seem to complain of three problems: inability to open their mouths a burning sensation

A

12 POTENTIALLY MALIGNANT DISORDERS

degradation and remodeling of extracellular matrix molecules contributing to collagen deposition underneath the oral epithelium. The process is influenced by increased secretion of inflammatory cytokines and growth factors. One of the key molecules found to be increased in OSF is TGF β. Extracellular matrix (ECM) remodeling phases are somewhat similar to phases of granulation tissue formation and the disease progression eventually leads to loss of ECM including elastin. Disequilibrium of ECM remodeling process is noted and has been examined in numerous studies. In areca nut chewers chronic inflammation is self-perpetuating and the process distorts the microenvironment as a result of aberrantly active transcription factors. Hypoxia has been reported to be associated with many disorders of fibrosis and Tilakaratne et al described hypoxiainducible factor a (HIF-a) is upregulated both in protein and mRNA levels in OSF and contributes to progression of the disorder. These authors further examined any genetic instability in OSF and described loss of heterozygocity in around 50 percent of OSF cases, predominantly in chromosome 13. These hot-spots of LOH losses harbored known onco-suppressor genes. Upregulation of aVβ6 integrin has also been described which may promote fibrosis and carcinomatous invasion.

B Figs 12.40A and B: Leathery appearance of oral submucous fibrosis

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Fig. 12.41: Classical features with submucosal banding

Fig. 12.43: Fibrosis of buccal mucosa and additionally oral leukoplakia (Grade 4A—see Table 12.10)

Fig. 12.42: Early oral submucous fibrosis. While mouth opening is maintained fibrous bands are just noticeable

Fig. 12.44: Fibrosis affecting palatine arches and uvula

some by combination of both. Histological changes considered are based on hyalinization, thickened collagen bundles, reduced vascularity and fibrosis extending to muscle layers. Epithelial changes (dysplasia) are mostly ignored in these grading systems. The Grading System proposed by Warnakulasuriya and adopted at by the Vth World Workshop on Oral Medicine (Table 12.10) is a useful guide.

ƒ Table 12.10 Disease grading system for oral submucous fibrosis (OSF) (Warnakulasuriya, 2010)

Histopathology

296

There is a spectrum of microscopic changes in the affected oral mucosa and many of the features are observed as the disease evolves. Changes are noted both in the epithelial compartment as well as in connective tissue, involving both lamina propria (Fig. 12.45)

Grade 1 B urning, depapillation, blanching or leathery mucosa (disease triad for OSF)– mouth opening - >35 mm Grade 2 M oderate limitation of opening 20–35 mm Grade 3 S evere OSF, limitation of opening < 20 mm Grade 4A OSF co-existing with other potentially malignant disorder, e.g. leukoplakia or erythroplakia Grade 4B OSF with oral epithelial dysplasia Grade 5 O SF co-existing with squamous cell carcinoma

vessels. The inflammatory reaction is marked, occasionally eosinophils are predominant.

Fig. 12.45: Microscopic appearance of fibrosis affecting the lamina propria

Study of the natural history of OSF shows that it is an insidious disorder that progresses with time. OSF is now a well-recognized potentially malignant disorder of the oral cavity. In a long-term follow-up study in India the annual transformation rate was approximately 0.5 percent. There are no established markers to identify who may be predisposed to the disease, the presence of gene polymorphisms is the likely explanation. A possible role of NQO1 C609T gene polymorphism in OSF subjects and subsequent malignant transformation has been recently described. There are however, no established markers to identify the risk of malignancy in affected individuals.

POTENTIALLY MALIGNANT DISORDERS

Malignant Transformation

12

Management

Fig. 12.46: Fibrosis extending deep to striated muscle

and submucosa. Marked atrophy of the epithelium is often noted and rete ridges may be completely lost resulting in an atrophic looking mucosa. Hyper ortho- or parakeratosis may be seen. In the early phases, the connective tissue is characterized by a finely fibrillar collagen, dispersed in edematous stroma with a strong fibroblastic response. The blood vessels could be dilated or congested. A spray of inflammatory cells mainly polymorphonuclear leukocytes are present immediately beneath the epithelium. As the disease progresses juxta-epithelial area shows early hyalinization, collagen deposition progresses and in late stages may be seen to occupy the full with of submucosa extending to muscle (Fig. 12.46), with obliteration of blood

The treatment of patients with oral submucous fibrosis remains unsatisfactory. The primary objective is to obtain any improvement in mouth opening (interincisal distance) and tongue protrusion to enable resumption of normal eating, chewing and speech. There are other expected gains in reducing the severity of burning symptoms, reduction of discomfort or pain by repopulating the tongue papillae. One would expect to prevent cancer as a longer term objective for all patients under care. A recent systemic review of published literature considered at the Vth World Workshop of Oral Medicine identified 4 RCTs (3 medical and one physical) conducted in India and Nepal. In clinical practice there are a number of treatments for OSF, ranging from medical interventions, surgical interventions, physical therapy, and of course habit control (i.e. cessation of areca nut use). Often a combination of strategies is used. There is a range of reported medical interventions including dietary supplementation (vitamins, antioxidants), anti-inflammatory agents (principally corticosteroids) and proteolytic agents (such as hyaluronidase and placental extracts). Based on the fact that occlusive blood vessels due to the deposition of collagen fibers could

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restrict nutrients and therapeutic substances from reaching the affected tissue, some groups have tried modulators that could improve vascularity. These include Pentoxifylline, Buflomedial Hydrochlorid and Nylidrin. To improve microcirculation tea pigments that are oxidized products of polyphenols derived from tea leaves have also been used in the management of OSF. Interferon-Gamma an antifibrotic factor/ cytokine was reported to be effective. This effect is attributed to the downregulation of fibroblast proliferation and a breakdown of collagen synthesis.Milkfromcowsimmunizedwithhuman intestinal bacteria, which may suppress the inflammatory reaction and modulate the cytokine production was also reported in one study. Such agents may be administered orally, topically or via submucosal injection. Surgical interventions are generally reserved for more severe cases of OSF. All surgical approaches begin with the surgical excision and ablation of fibrosed bands (scalpel excisions versus laser removal), and then generally followed by numerous reconstructive approaches ranging from pedicled flaps (derived from tongue flap, buccal pad, palatal island flap, nasolabial flap and temporal facia) and grafting procedures, to free flaps. Myotomy and coronoidectomy has also been attempted to release the tendons of temporalis muscle. Physical therapy may be used as a single modality intervention or combined with other interventions (principally surgical interventions).

CONCLUSION

298

Oral and pharyngeal mucosal lesions that have malignant potential have been welldocumented. By far the most common are the leukoplakias. If these lesions can be effectively recognized, diagnosed and appropriately treated, a number of OPC could be prevented. These features are discussed and illustrated in this chapter. Control of OPMDs involves many factors. Genetic predisposition and mutations are basic to carcinogenesis. Much research is being directed at identifying and modifying implicated genes to limit/prevent these transformations. For the most part,

gene mutations are both time-related and influenced by environmental influences. Thus aging is the most frequently associated factor in the development of cancer; therefore, aging itself becomes a significant risk. The paradox, of course, is that one of the goals of medicine is to lengthen life. There is solid evidence that abstaining from tobacco-use and limiting alcohol intake and abstaining from areca nut chewing will prevent many cancers from occurring in OPMDs. Screening for OPMDs and their effective management could lead to a reduction in the incidence of cancer in the screened population and thereby contribute to control of oral cancer. Community-orientated screening programs and communication also increase public awareness and knowledge of oral cancer and potentially malignant oral disorders.

ACKNOWLEDGMENTS Professor Thongprasom would wish to acknowledge Chulalongkorn University Press for reuse of few illustrations she has included in the section on oral lichen planus. We thank Wiley Blackwell for reuse of Figures 12.4 to 12.6.

SELF-ASSESSMENT QUESTIONS 1. Compare and contrast various definitions used for oral leukoplakia and explain few difficulties if any for applying the current definition. 2. What is the natural history of oral leukoplakia and what further research may help to understand the gaps in our knowledge? 3. Explain the role of areca nut in the causation of OPMDs. 4. Compare and contrast methods of dysplasia grading. Outline additional sub features that may be applied to refine each microscopic feature used in current practice. 5. Discuss the sensitivity and specificity of adjunctive methods in the diagnosis of (1) OPMDs and (2) oral dysplasia. 6. Discuss the pathogenesis of oral lichen planus. 7. Why are current therapies failing in the management of ulcerative or symptomatic oral lichen planus?

SUGGESTED READING 1. Bhargava K, Smith LW, Mani NJ, Silverman S. A follow-up study of oral cancer and precancerous lesions in 57,518 workers in Gujarat, India. Indian J Cancer. 1975;12:126. 2. Epstein JB, Sciubba J, Silverman S. Utility of toluidine blue in oral premalignant lesions and squamous cell carcinoma: Continuing research and implications for clinical practice. Head Neck. 2007;29:948-58. 3. Gupta PC, Mehta FS, Daftary DK, et al. Incidence rates of oral cancer and natural history of oral precancerous lesions in a 10-year follow-up study of Indian Viallagers. Community Dent Oral Epidemiol. 1980;8:287-333. 4. Holmstrup P. Long-term treatment outcome of oral premalignant lesions. Oral Oncol. 2006;42:461. 5. Kaugars GE, Silverman S, Lovas JL, et al. A review of the use of antioxidant supplements in the treatment of human oral leukoplakia. Oral Surg Oral Med Oral Pathol. 1996;81:5-14. 6. Kerr AR, Warnakulasuriya S, Mighell AJ, et al. A systematic review of medical interventions for oral submucous fibrosis and future research opportunities. Oral Dis. 2011;17 (Sup 1):42-57. 7. Mehanna H, Ratty T, Smith J, McConkey CC. Treatment and follow-up of oral dysplasia – a systematic review and meta-analysis. Head and Neck; 2009. pp. 1600-9. 8. Napier SS, Speight PM. Natural history of potentially malignant lesions and conditions: an overview of the literature. J Oral Pathol. 2008;37:1-10.

9. Pitiyage G, Tilakararatne WM, Tavassoli M, Warnakulasuriya S. Molecular markers in oral epithelial dysplasia: a review. J Oral Pathol Med. 2009;38:737-52. 10. Ranganathan K, Mishra G. An overview of classification schemes for oral submucous fibrosis. J Oral Maxiollofac Pathol. 2006;10:55-8. 11. Silverman S, Gorsky M, Lozada F. Oral leukoplakia and malignant transformation. A follow-up study of 257 patients. Cancer. 1984;53:563. 12. Silverman S. Diagnosis and management of leukoplakia and premalignant lesions. Oral Maxillofacial Surg Clin N Amer. 1998;10: 13-23. 13. Speight PM. Update on oral epithelial dysplasia and progression to cancer. Head and Neck Pathol. 2007;1:61-6. 14. Thongprasom K, Carrozzo M, Furness S, Lodi G. Interventions for treating oral lichen planus. Cochrane Database System Rev. 2011; Issue 7. CD001168. 15. Tilakaratne WM, Iqbal Z, Teh MT, Ariyawardana A, et al. Upregulation of HIF-1 alpha in malignant transformation of oral submucous fibrosis. J Oral Pathol Med. 2008; 37:372-7. 16. Tilakaratne WM, Klinikowsky MF, Saku T, Peters TJ, Warnakulasuriya S. Oral submucous fibrosis: Review of aetiology and pathogenesis. Oral Oncology. 2006;42:561-8. 17. Warnakulasuriya S, Johnson NW, van der Waal I. Nomenclature and classification of potentially malignant disorders of the oral mucosa. J Oral Pathol Med. 2007;36:575-80. 18. Warnakulasuriya S, Kovacevic T, Madden P, Coupland VH, Sperandio M, Odell EW, Moller H. Factors predicting malignant transformation in oral potentially malignant disorders among patients accrued over a ten-year period in South East England. J Oral Pathol Med. 2011;40:677-83. 19. Warnakulasuriya S, Reibel J, Bouguot J, Dabelsteen E. Oral epithelial dysplasia classification systems: predictive value, utility, weaknesses and scope for improvement. J Oral Pathol Med. 2008;37:127-33.

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8. “Current management of oral submucous fibrosis is unsatisfactory”. Explain the reasons and what research may be needed in this area. 9. Discuss the prognostic factors for oral leukoplakia. 10. How would screening for OPMDs help in reducing the incidence and mortality from oral cancer?

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Chapter

13 Oral Cancer Saman Warnakulasuriya

Chapter Outline Global Epidemiology • Incidence • Prevalence • Mortality • Survival Risk Factors Clinical Presentation Metastsis • Regional Spread Staging Investigations that Aid Diagnosis Pathology • Histopathological Features of OSCC

• Pathological Grading • Features of Metastasis • Carcinoma in situ • Early Invasion Pathological Subtypes of OSCC Molecular Pathology Prognosis of OSCC Treatment Screening and Prevention Self-assessment Questions

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INTRODUCTION

GLOBAL EPIDEMIOLOGY Incidence Oral and pharyngeal cancer, grouped together is the sixth most common cancer in the world. The annual estimated incidence is around 275,000 for oral and 130,300 for oropharyngeal cancers; two-thirds of these cases occurring in developing countries. There is a wide geographical variation (approximately 20 fold) in the incidence of this cancer. Highest incidence rates for cancers of the lip are reported in white populations in Canada, Australia and Southern Europe (e.g. Spain). For example, more than 50 percent of oral cancers in Australians are located on the lip. Lip cancer is rare in nonwhite populations. For intraoral cancers (excluding lip) the areas characterized by high incidence rates are found in the South and South-East Asia (e.g. Pakistan, India, Sri Lanka, Taiwan), in the Pacific regions (e.g. Papua New Guinea, Melanesia),

ORAL CANCER

The majority of oral and oropharyngeal cancers considered in this chapter comprise a very heterogeneous group of neoplasms commonly referred to as “oral cancer”. These consist of cancers arising from the lining mucosa from various anatomical sites mainly of the lip, tongue and mouth (oral cavity) [ICD-10 C00, C02-06] and that of oropharynx consisting of base of tongue (posterior third), soft palate and uvula, tonsils, tonsillar fossa and pillars and posterior walls of the pharynx that can be seen through the oral cavity [ICD-10: C01, C09-C10]. Cancers of the salivary glands [C0708], pyriform sinus [C12] and other pharyngeal sites (naso- and hypopharynx) [C11 and 13] are excluded from this title and would not be discussed here. More than 90 percent of oral malignancies are squamous cell carcinomas. Oral cancer is a serious and growing problem in many parts of the globe. In the past few decades, there has been a significant age shift and a disproportionate number of young people are presenting with oral cancer. The large majority of oral cancers have similar risk factors, and the disease is preventable.

Fig. 13.1: High incidence regions for oral cancer

some parts of Western (e.g. France) and Eastern Europe (e.g. Hungary, Slovakia and Slovenia) and parts of Latin America (e.g. Brazil, Puerto Alegre) (Fig. 13.1). Data illustrated in Figures 13.2A to C is based on Cancer Incidence in Five Continents (ninth volume) which has become the recognized reference source on the incidence of cancer in populations around the world and refers to latest data covering the period 1998-2002. The relative frequency of a cancer is given as a percent of all cancers. In countries such as Sri Lanka, India and Pakistan where oral cancer is the most common cancer in men, it may contribute up to 25 percent of all new cases of cancer in a country. Where the disease is uncommon such as in the United Kingdom, USA or in Japan, oral cancer accounts for ~3 percent of all cancers. In epidemiological terms the incidence rates (the number of new cases per 100,000 people in a given year) is a more accurate way of recording the frequency. The age-standardized incidence rates are high in several of the high incidence countries (e.g. India, Hungary, Brazil, Taiwan and PNG). The latest reported for India (2006-2008) is around 19 per 100,000 of the population. Males have a higher incidence, and male to female ratio is currently about 2:1. The reported sex differences are attributable to heavier indulgence in risk habits (tobacco and alcohol) by men. As for other cancers of the head and neck, the age-specific incidence rates increase with

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A

B Figs 13.2A and B: Age-standardized (world) incidence (per 100,000) and standard errors for (A) Lip; (B) Mouth

302

age, being highest for older groups, the majority of cases occur in people aged 50 and over. The mean age range reported in many countries is around 56 to 62 years of age. Figures 13.3A and B illustrates age and gender profile from

two countries one with a high and the other with a low incidence. Oral cancer in young people has received considerable attention in the past two decades as the incidences of the disease have increased by many folds in younger age

13 ORAL CANCER

C Fig. 13.2C: Tongue cancer in high incidence countries and regions (Incidence data collected by cancer registries worldwide and published in CI5 (Cancer Incidence in Five Continents) Volume IX. IARC 2007)

groups. In many cancer registry data sources about 6 percent of oral cancers occur in younger people under the age of 40 years.

Prevalence The prevalence of a particular cancer can be defined as the number of persons in a defined population who have been diagnosed with that type of cancer, and who are still alive at a given point of time. This aspect of epidemiology is of particular relevance when discussing people living with cancer. In the world, there is close to a three quarter of a million people who previously had oral cancer and are alive 5 years after diagnosis. The proportion alive at 5 years is lower in middle and low income countries. When discussing the epidemiology of oral cancer it is important to focus on the incidence of disease and to standardize the data to the World Population.

Mortality For most countries age adjusted death rates from oral cancer have been estimated at 3.0-4.0 per

100,000 men and 1.5-2.0 per 100,000 for women. SEER data for USA reports mortality rates of 3.8 per 100,000 men and 1.4 per 100,000 in women based on patients who died in 2005-2009. Mortality rates for black men (5.7) are higher than for other races (white or Hispanic). Oral cancer mortality among French women has risen in the past 20 years. In 2000, rates stood at 4.7 per 100,000 an annual percentage change of +1.73 percent noted between 1980 and 2000. India ranks fourth for mortality in the world and approximately has highest rates in S. Asia. Among young people there has been a small but steady increase in mortality rates in most Western countries. This is particularly noted for the oropharynx in the US populations. Among Scottish males deaths from oropharyngeal cancer has shown the highest increase in the recent years compared to all other cancers.

Survival Survival following any treatment is the primary concern for cancer patients. If a person survives five years following treatment it is considered

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A

B Figs 13.3A and B: Age and gender profile for oral cancer from two countries, (A) Sri Lanka; (B) UK

304

that the disease has been cured and therefore five years survival is a valid statistic. This is measured in two ways, as either overall survival (OS) or disease-specific survival (DSS). Most oral cancer patients are elderly and they can die of other causes and may have a life expectancy less than 5 years. For this reason OS is lower than DFS. Overall survival is relatively easy to measure where national statistics are available. The estimation of disease-free survival (DFS)

requires accurate follow up data. Survival should be stratified by site and the best outcome is for cancers of the lip with over 90 percent of patients surviving five years and the worst is for pharynx. For most countries, overall 5-year survival rates for cancers of the tongue and oral cavity range from 45 percent to 72 percent, the mean is around 50 percent. In the USA overall 5-year survival has in recent years improved to 61.5 percent and within Europe varies from

13

Author

Year

Loree

1990

Shingaki

1995

Chen

1999

Center/Country

No patients

% DFS (5 years)

% OS (5 years)

US#

398

57

Nigata, Japan

61*

87

80

Taiwan

183

36

Pathak

2005

Mumbai, India**

511

57

Aksu

2006

Istanbul, Turkey

61

49

46

Koo

2006

Seoul, S. Korea

127

76

71

Kessler

2008

Germany

128

83

69

Rogers

2008

UK

489

74

56

Walvekar

2009

Mumbai, India**

642

53

ORAL CANCER

ƒ Table 13.1 Survival following primary Surgery for oral cancer

DFS – Disease-free survival; OS – Overall survival * Stages 1 & 2 only **Advanced OSCC also treated with adjunct radiotherapy when indicated # Memorial Sloan Kettering, USA

Fig. 13.4: Five-year disease-free survival reported for oral cancer cases treated at the Tata Memorial Cancer Hospital, India in 1990s

38 to 46 percent. Table 13.1 shows reported data on overall and disease-free 5-year survival from several large series treated by surgery alone. Figure 13.4 shows 5-year disease-free survival reported from a major cancer center in India for their cases treated in 1990s. In general, prognosis decreases with advanced disease and increasing inaccessibility of the tumor. For both cancer of the tongue and oral cavity, women have higher survival rates than men. TNM (Tumor, Node, Metastasis) stage at presentation significantly affects 5-year survival, the presence of cervical metastasis

reduces survival up to 50 percent. For mobile tongue 5-year survival for stage 1 disease is 80 percent while for stage 1V survival drops to 15 percent. As for most cancers, survival is better for affluent groups and younger compared to older patients. Despite important advances in the approaches to treat oral cancer the survival rates for oral cancer in many countries have not shown any improvement over the past 5 decades. Poor survival is at least in part due to failure to detect small lesions and potentially malignant lesions early (Chapter 12). High throughput centers such as the Regional Maxillofacial Unit in Liverpool, UK and the Slone Memorial Hospital in US have reported improvement in survival over time in their follow-up cohorts. For surviving patients improvements in techniques of reconstruction also have helped in rehabilitation and improved quality of life. Many patients who are successfully treated for oral cancer have to cope with the devastating consequences of their treatment. These may affect the patient’s appearance and function, e.g. eating, drinking, swallowing and speaking. These residual defects may lead to other problems such as depression and nutritional deficiency. Quality of life issues are therefore especially important for this group of patients.

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306

RISK FACTORS Oral cancer to a large extent is a self-induced disease. In order to plan preventive measures it is important to understand the risk factors associated with the disease. The major risk factors are well known and are briefly described below, there are excellent reviews on this subject. There are some emerging risk factors for oral cancer that the dentists should be aware of, and some controversies related to the etiology of this disease that needs clarification.

Major Risk Factors – Tobacco, Alcohol and Betel (Areca Nut) Quid Major risk factors for oral cancer are cigarette smoking, alcohol misuse and betel-quid chewing. There are several key epidemiological studies from many countries that confirm the associated risk with these three life-styles. Tobacco use is reported as a major risk factor both for the oral cavity and oropharynx. Numerous independent investigations in the past several decades have confirmed a strong association between oral SCC and tobacco smoking. These data come from numerous case-control and cohort studies. In countries in which epidemiological studies have been conducted, it is clear that oral cancer risk is higher among smokers. A meta-analysis reported 12 studies that estimated oral cancer risk in the USA, Uruguay, Italy, Sweden, India, China, Taiwan and Korea. The reported pooled cancer risk estimate was 3.43 times higher in smokers compared with non-smokers (95% CI: 2.37, 4.94). The attributable risk is close to 70 percent in men and approximately 25 percent for both sexes combined. It is evident that oral cancer risk is related to both intensity and duration of tobacco smoking. Thus, the risk of oral cavity cancer increases with the average daily consumption, duration of consumption and lifetime cumulative consumption of tobacco smoked. The differential risk between non-smokers and heavy smokers, and the steady progression of risk with increasing amount smoked both provide sufficient evidence for tobacco as a major risk factor for oral cancer. The proportion of smokers (~85%) among patients with oral SCC is nearly 3 to

4 times greater than the general population. Furthermore most studies show an inverse relation with age when starting to smoke. These risks are also increased synergistically with alcohol consumption. However, among nondrinkers, cigarette smoking was associated with an increased risk of 2.13 (95% CI: 1.52, 2.98) confirming an independent association with tobacco use. Smokeless tobacco (ST) use and its association with oral SCC has been the subject of several studies. Most tobacco products consumed in Asia and Africa are unregulated and are often of the smokeless variety. Products such as gutka (tobacco, areca nut), mishri (powdered tobacco, i.e. rubbed on the gums), Gudakhu (tobacco and molasses), Khaini (tobacco and lime), Naswar (tobacco, ash and lime), Zarda (boiled and dried tobacco colored with dyes), Shammah (tobacco, ash and lime), Chimo (tobacco and sodium bicarbonate and ashes from Mamon tree-used in Venezuela), Maras (sun-dried powdered tobacco mixed with ash of wood) and Toombak (tobacco and sodium bicarbonate used in the Sudan) are strong risk factors for oral SCC. Cancers associated with these products tend to occur more often in the vestibular, gingival and buccal mucosae, as a result of placement of noncombustible carcinogenic substances in direct and prolonged contact with these areas. In many European and US studies the risks for oral and oropharyngeal cancers are similar for cigarette and cigar smokers. Smoking bidi (hand-rolled and consisting of flaked tobacco rolled in temburni leaf ) is a common practice in India and Sri Lanka. A meta-analysis has shown that the risk of cancer associated with bidi smoking is about 3 times higher compared with cigarettes. Tobacco smoke contains between 2000 and 4000 substances, around 60 of which are identified carcinogens. Among these there are 11 human carcinogens. Some substances generated by tobacco smoke that are recognized carcinogens include polyaromatic hydrocarbons (e.g. Benzo(a)pyrene), heterocyclic hydrocarbons, tobacco-specific nitrosamines (TSNAs), aromatic amines, aldehydes, phenolic compounds, metals and metal compounds.

advisable. The most frequently consumed alcoholic beverage in a population is likely to be associated with highest risk for that given population. Ethanol is metabolized to acetaldehyde by alcohol dehydrogenase, releasing multiple free radicals. Although investigations that attempt to implicate alcohol alone as the main causative agent of oral SCC have yielded largely conflicting results, the correlation of alcohol with increased risk for oral SCC is indisputable. The major clinical significance of alcohol consumption seems to be its ability to potentiate the carcinogenic effect of tobacco. The effect is at least addictive and may be multiplicative in individuals with heavy alcohol consumption or at sites with the highest levels of alcohol exposure. Although the underlying mechanisms for this association are poorly understood, some proposed mechanisms include: • Dehydration effects of alcohol render the mucosa more susceptible to the carcinogens in tobacco. • Alcohol activates carcinogens present in tobacco by a cytochrome p450-2E1dependent mechanism. • Release of acetaldehyde and free radicals within the oral mucosa from local as well as hepatic metabolism of ethanol. Deposition of acetaldehyde protein adducts has recently been demonstrated in human SCC tissues among heavy alcohol users. Joint effect of tobacco and alcohol consumption: Epidemiological studies that have examined the combined role of alcohol and tobacco specifically for oral cavity cancers indicate that the joint effect of alcohol and tobacco is multiplicative or greater than multiplicative in most studies. The population-attributable risk of oral cavity cancer related to the combined consumption of the two carcinogens is around 75 percent and those who smoke and drink could have their risk multiplied by 4.78 compared to non-users. Betel quid is carcinogenic to humans. In parts of South and South East Asia and in Melanesia oral cancer is of high incidence and in these populations betel quid use is recognized as a risk factor for this high incidence of oral cancer. A recent evaluation by the International Agency for Research on Cancer (IARC) in 2004

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Tobacco smoke also contains tumor promoters (phenolics), cocarcinogens and free radicals. Most of the compounds are thought to exert their carcinogenic effects through classical genotoxic mechanisms e.g. by the formation and persistence of DNA adducts with consequent mutations. Carcinogens from smoking that are released into the saliva tend to pool in the lower anatomic areas of the mouth and could account for the frequent occurrence of oral SCC along the lateral-ventral tongue and floor of the mouth. The striking variations in oral SCC sites and incidence seen among different regional, cultural and demographic groups are largely attributable to differences in the use and mode of delivery of tobacco. Alcohol use is the second independent major risk factor for the development of oral cancer and ethanol is classified by the International Agency for Research on Cancer as a human carcinogen. A large number of cohort and case control studies provide strong evidence that the consumption of alcohol is an independent risk factor for oral and pharyngeal cancers. The population-attributable risk of oral cavity cancer for alcohol consumption alone does not exceed 20 percent, and is lower compared to smoking. Doubling the consumption of alcohol above recommended levels increases the risk for oral and oropharyngeal cancers two to three times, compared with the risk of non-drinkers. The risk of oral cancer increases with the number of alcoholic drinks consumed per day in a dose dependent fashion. The risk is multiplicative with the combined use of alcohol and tobacco. Some population groups with inherited defects in metabolism of alcohol may have the inability to breakdown acetaldehyde (the carcinogenic metabolite of alcohol) and may be at increased risk. Oral biofilms (bacteria) assist in metabolism of alcohol to acetaldehyde and poor oral hygiene in alcoholics may potentially increase the risk of oral cancer. There is a controversy as to what type of alcoholic drink mostly causes mouth cancer. It is not clear whether the alcohol concentration in beverages or the quantity drunk contributes to estimates of risk. There is no clear evidence that specific alcoholic drinks, i.e. spirit, wine or beer, have different effects on oral cancer. Substitution of the type of drink is not therefore

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concluded that areca nut, the main ingredient used in betel quid or commercially packaged as pan masala, are carcinogenic to humans. Moreover, chewing betel quid without tobacco has recently been shown to elevate the risks of various oral precancerous lesions and conditions. Cancers of the oral cavity arise in locations (mostly buccal and mandibular groves) where betel quid and areca nut are kept for long periods. Mechanisms of action and chemicals in areca nut responsible for carcinogenicity have been ascertained in recent studies. Endogenous nitrosation has been observed in the saliva of betel quid chewers with consequent production of carcinogenic nitrosamines. Reactive oxygen species generation in buccal cells due to autooxidation of polyphenols in areca nut enhanced by slaked lime an ingredient in BQ has been reported. However, areca nut remains the carcinogenic agent in betel quid and pan masala products. The estimated elevated risks from these different agents and exposures (among smokers, regular users of alcohol and betel quid; adjusted for each other) compared to non-users are reported consistently from many populations. The elevated risks are confirmed by several meta-analysis or systematic reviews providing proof of significant risks of these life-styles for oral cavity cancers. In the United Kingdom there is evidence that the rising incidence of oral cancer noted in the past two decades, especially affecting younger people, is associated with increased intake of alcohol

rather than tobacco use. The synergistic effects on the carcinogenic potency of tobacco in oral cancer by alcohol consumption and/or betel quid are well documented (Fig. 13.5).

Emerging Risk Factors Human papillomavirus infection There is sufficient evidence based on recent studies (mostly conducted in US) that infection with human papillomavirus (HPA) (subtypes 16 and 18) is a risk factor particularly for the oropharynx (posterior tongue, tonsil and the (visible) part of pharynx in continuity with the oral cavity). A meta-analysis of published studies on the prevalence of HPV in SCC in Head and Neck Cancers was found to be around 25 percent; the prevalence of HPV in oropharyngeal carcinomas (35.6%) was higher than in oral cancers (23.5%). The etiological role of HPV in cervical cancer has been well established and new data confirm that a proportion of oral and particularly oropharyngeal cancers can be attributed to HPV infection and seropositive status (particularly among young subjects with no tobacco or alcohol history). Patients with HPV infected tumors tend to be younger and have an overall better survival.

Immunosuppression Lip cancer is reported to be increased following kidney transplantation and may be associated with the use of immunosuppressive agents (azathioprine and cyclosporine). Extended use

Fig. 13.5: Graphs showing the dose dependant nature of tobacco, alcohol and betel quid observed in many studies

Diet and Nutrition There is accumulating evidence that indicates a positive correlation between low intake of fresh vegetables and fruits and an increased risk of oral cancer. An estimated 50 percent reduction in risk for oral cancer is noted among people who consume an adequate daily amount of fresh fruits and vegetables. Excess weight contributes to the increased incidence of many cancers, and may adversely affect quality of life for cancer survivors, which may worsen prognosis for several cancers. However, no data exist for oral cancer.

Mate Drinking Mate is an infusion of the herb Ilex para­ guariensis, cultivated throughout South America. In Argentina, Uruguay, Paraguay and southern Brazil, it is normally drunk very hot through a metal straw. The role of mate drinking in increasing the risk of cancer of the oral cavity is supported by several epidemiological studies conducted in South America that adjusted for other risks. A recent meta-analysis estimated an increased risk (OR of 2.11, 95% CI:1.39, 3.19) confirming this association. The role of mate when drunk very hot is not proven but the high temperature of this beverage could act as a cofactor by causing chronic irritation to the exposed oral mucosa.

Socioeconomic Status Oral cancer is seen more often in people from lower socioeconomic groups and living in deprived areas. A higher prevalence of smoking, alcohol use and poor diet in these groups was thought to account for this unequal distribution. However, new research suggests that lower socioeconomic status (measured by various ways: occupation, income or education)

is a significant risk factor for oral cancer independent of life style behavior.

Controversial Factors with Limited or no Evidence Ethnicity and race

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of immunosuppressive agents (azathioprine) during the management of inflammatory bowel disorders (Crohn’s disease) may also increase the risk of tongue cancer. There is no strong evidence to support that immunosuppression in HIV seropositive individuals increases the risk for oral cancer (see below).

It has been speculated that susceptibility to oral cancer from tobacco and alcohol use may differ by race and ethnicity. Oral cancer incidence rates vary considerably across racial/ethnic groups in the globe. South Asians have higher rates of oral cancer than people from most other countries and black men (in US) have higher rates than whites for oropharyngeal cancer. The Mexican-American population (Hispanics) also has higher rates of oral cancer than US whites. Nutritional differences, smoking patterns (bidi smoking in Asians), difference in amounts smoked or alcohol drunk and the 2 way and 3 way interaction of betel quid chewing with smoking and alcohol rather than genetic factors may play a role in these observed variations in populations and high incidence in some ethnic and racial groups.

Oral Hygiene and Dentition Although poor oral hygiene and poor dentition (faulty restorations, sharp teeth and ill-fitting dentures) have been implicated in a few epidemiological studies. It is not clear whether confounding by tobacco and alcohol have been addressed in these studies. It is likely that chronic irritation from dental factors may facilitate mucosal entry of carcinogens, so this may act as a cofactor in high-risk individuals only. Oral microbes (together with biofilms) may also be a factor in chronic alcohol users as the same microbes facilitate the metabolism of ethanol to acetaldehyde (a potent carcinogen) in the oral cavity.

Indoor Air Pollution Studies from Germany and Brazil have reported increased risks for head and neck and upperdigestive tract cancers (including oral) from indoor air pollution due to daily exposure to fossil fuels from stove heating (with oil, coal,

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or wood) and from use of a wood stoves for cooking. Volatile carcinogenic compounds formed during the cooking processes have been attributed to excess mortality from oral cancer among regular cooks.

Heredity and Familial Risk There is no evidence to suggest that oral cancer is more common among families that have an increased risk for other cancers. Oral cancers have not been reported in hereditary cancer syndromes such as Li-Fraumeni syndrome (breast cancer), Familial adenomatous polyposis (colon cancer), Familial retinoblastoma (retinoblastoma and sarcomas), Peutz-Jeghers syndrome (colorectal, breast and ovarian cancers), Gorlin syndrome (basal cell skin cancer), Multiple endocrine neoplasia (MEN2) (medullary thyroid cancer), Ataxia telangectasia (AT) (lymphoma), Bloom syndrome (solid tumors) or xeroderma pigmentosum (XP) (skin cancer) or in Fanconi anemia (acute myeloid leukemia). The only exceptions are Cowden syndrome (with few reported cases of head and neck cancer) and dyskeratosis congenita, a rare genetic disorder that may present with oral white lesions in young people that have a risk of transformation to cancer. Though oral cancer is rare in people with these disorders, if they have been diagnosed with oral keratosis they fall into a high risk group and should be under the care of a specialist for surveillance. So far, inherited polymorphisms that may contribute to genetic predilection specifically to oral cancer have not been demonstrated. ADH polymorphism and aldehyde dehydrogenase genotypes may influence cancer susceptibility as acetaldehyde–the first metabolite of alcohol (the putant carcinogen in alcohol) may accumulate in tissues. Despite lack of a clear hereditary trait for oral cancer, cancer cells (from oral cavity cancers) contain genetic damage due environmental exposure to carcinogens and for this reason oral cancer should be considered a genetic disease.

Marijuana (Cannabis) Smoking 310

Marijuana is the most commonly abused illicit drug in most countries, usually smoked as a joint

or in a pipe. It is also smoked in blunts, which are cigars that have been (partially) emptied of tobacco and refilled with marijuana and possibly combined with tobacco ingredients. An increased risk for head and neck cancer was reported in the US but there is no consistent evidence to implicate cannabis as causing oral cancer. Any causal inference shown could be due to interaction with heavy tobacco use.

Khat (Qat) Chewing Khat (Catha edulis Forsk) is a plant cultivated in territories of Somalia, Ethiopia, Djibouti, South and North Yemen, Madagascar, Tanzania and down to south eastern Africa. Khat leaves are extensively consumed by these populations. So far, no epidemiological studies on oral cancer and khat use have been reported and there is no evidence to link khat chewing with oral cancer. Evidence from experimental studies are also limited and there are no in vivo data to show any carcinogenicity of khat in animal models.

Nicotine Replacement Therapy There is some confusion in the minds of professionals and patients whether any prolonged and chronic use of nicotine replacement therapy (NRT) could have the potential to cause cancer as these agents contain pure nicotine. There is no clear evidence that medicinal nicotine causes cancer. A recent study based on surveillance data among patients with chronic obstructive pulmonary disease in the US found no independent increased risk for any cancer among NRT users. The authors, however, noted that the surveillance time in this study was short (5 years).

HIV Infection Though it was conceived prior to the era of highly potent antiretroviral therapy, that moderate immunosuppression in HIV disease could increase the risk for oral cancer, there is no strong epidemiological evidence based on cohort studies to confirm an association of infection of HIV or of AIDS with oral squamous cell carcinoma. Oropharyngeal cancers with a known infective cause (HPV) may be moderately

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Fig. 13.6: Summary of risk factors for oral cancer

increased in people with HIV disease but the excess risk could also be attributable to tobacco use. However, it is important to note that two different neoplasms are associated with HIV disease, i.e. Kaposi’s sarcoma and lymphomas, but these are normally not listed under the term oral cancer.

Alcohol in Mouthwashes There has been some controversy about the risks of alcohol containing mouthwashes (MW) for the causation of oral cancer. While an earlier study from US distinguished nonalcohol MW from alcohol containing MWs in their study and reported an increased risk for subjects in the latter group, other studies have not considered this distinction in MW use. So far, nine epidemiological studies are available to examine any associated risks: two studies showed significant increases, two studies show nonsignificant elevated risks and four studies indicated non-significant, lower or similar oral cancer risks among mouthwash users (compared to non users). Based on

these reported studies a recent meta-analysis confirmed that there is no excess risk for oral cancer from mouthwash use (with or without ethanol) (OR 1.13; 95% CI 0.89, 1.44). It is likely that mouthwash use in people who developed oral cancer was a measure to mask their tobacco smell or was initiated after the development of symptoms in an attempt to control the disease. Two independent expert groups (FDA and IPRI) have concluded that there is no evidence for linking alcohol containing mouthwashes to oral cancer. Figure 13.6 shows a summary of risk factors that are modifiable to reduce any risk and those with limited or no evidence which should be ignored in terms of disease causation. However, as not all persons who practice these high-risk habits will develop oral SCC, and as oral SCC in rare instances is idiopathic, there must be person-specific genetic characteristics and environmental factors which may either afford protection against the development of oral SCC, or may predispose to or even promote the development of oral SCC.

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13 CLINICAL PRESENTATION Most oral cancers occur in accessible sites and are easily seen. Symptoms of suspected oral cancers are given in Table 13.2. Oral SCC may take various clinical forms. Patients with early stage SCC are often asymptomatic or may present with vague symptoms. An early presentation of oral cancer could be in the form of white and red or red patches of the lining mucosa particularly when associated with nodular appearance, pain, ulceration and induration. Most are painless but persistent pain in a mucosal patch with a benign appearance should raise concern. Most patients present with signs and symptoms when the disease is locally advanced. The majority of oral cancers present as non-healing ulcers or exophytic growths (Figs 13.7 and 13.8). As the tumor grows the central area may become necrotic largely due to poor blood supply and therefore these two features may often be seen in combination (Fig. 13.8). Malignant ulcers have rolled margins especially prominent in tongue and other mobile mucosa (Figs 13.9A and B). On palpation the base and margins of the ulcer would elicit induration and spongy areas may bleed to touch. When examined carefully there is often a leukoplakic or erythroplakic component at the margins of the tumor (Fig. 13.10).

ƒ Table 13.2 Symptoms indicative of oral cancer (NICE Guidelines-UK) • A non-healing ulcer • Persistent discomfort or pain • A persistent white and red or red patch • A lump or thickening • Difficulty chewing or swallowing • Unusual bleeding or numbness in the mouth • Loose teeth for no apparent reason • Difficulty moving the jaw • Speech problems • A lump in the neck

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• Sore throat and earache on same side

Fig. 13.7: Oral squamous cell carcinoma of floor of mouth presenting as a nonhealing ulcer

Fig. 13.8: An exophytic growth on palate, an example of a T4 tumor

As a cancer spreads the mucosa may be fixed to underlying tissues, with loss of tissue mobility. The tongue may loose its mobility and cancers involving the retromolar region may lead to limitation of mouth opening and present with trismus. Tumor infiltration of the inferior alveolar nerve is associated with pain and paraesthesia found in advanced stages (Fig. 13.11). Oral carcinomas appear to favor certain intraoral locations more than others. In most Western countries, the oral tongue is the most commonly reported site for oral cancer (about a third of all oral SCC), followed closely by the floor of the mouth (about a quarter). The lateral tongue and the floor of the mouth comprise more than 60~ percent of the so-called cancerprone locations in the oral cavity. Other common

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Figs 13.9A and B: A new growth on floor of mouth extending to the ventral tongue showing central necrosis and rolled margins of the ulcer

Fig. 13.10: Coexisting leukoplakia at the margin of a tongue carcinoma

Fig. 13.11: Carcinoma of the alveolar mucosa invading adjacent mandibular bone leading to a pathological fracture

locations include the tonsillar pillars and retromolar pad areas (20%), followed by the soft palate. Gingival carcinomas are less common. In striking contrast, the buccal mucosa is the most common location for oral SCC in some other parts of the world (Central and Southeast Asia). The differences in site-specific incidence are likely attributable to cultural differences in the way tobacco and related products are used relative to their mode of delivery (smoking vs chewing). Among alcohol misusers the floor of the mouth appears to be the most affected site for oral SCC. Oropharyngeal cancers may present with difficulty in swallowing (dysphagia), rarely with difficulty with speech, sore throat and earache.

Other clinical presentations of oral cancer include unexpected tooth mobility not associated with periodontal disease or failure of a tooth socket to heal.

METASTASIS Spread of the tumor could occur to regional lymph nodes, underlying or adjacent bone or to distant sites.

Regional Spread About two-thirds of oral SCC particularly those of substantial size, will have clinically detectable metastases to cervical lymph nodes at the time of diagnosis. Enlargement of one or more neck

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nodes with a primary in the mouth may indicate regional metastasis, especially if they feel firm or hard and fixed to the skin or deeper structures. Neck metastasis is more common with advanced stages or high grade of carcinomas. Neck nodes are mostly asymptomatic, but enlarge due to tumor deposition, reactive hyperplasia or cystic changes in the nodes. About 30 percent of neck nodes with metastatic deposits are missed on palpation or by imaging alone but on histopathological examination will show metastatic spread. Furthermore in one study, a fifth of the cases of SCC of the head and neck in which the regional lymph nodes appeared to be free of metastatic growth when examined microscopically, had on molecular analysis evidence to harbor mutations concordant to the primary site. The presence of extracapsular lymph node spread is associated with a highrate of local and regional recurrence, distant metastasis and mortality. The precise group of nodes likely to be affected depends on the location of the primary tumor, but submandibular, then jugulo-digastric or jugulo-omohyoid deep cervical nodes may be involved in an orderly fashion often referred to as levels 1 to 3. Neck metastases are rarely detected at levels 4 to 5, involving the posterior triangle of the neck (Fig. 13.12). Metastatic spread may skip one or more levels of the neck. Extensive cystic changes may be present in a neck node often leading to a misdiagnosis of a branchial cyst. Tonsillar carcinomas may present in the neck as a metastasis without the primary being noticable. When nodal involvement of the neck is suspected the clinician should initiate investigations for an occult primary in clinically inaccessible sites of the mouth and pharynx.

Bone Invasion It is likely that any invasion to the underlying jaws is more common with tumors centered close to the bone surface. Lesions occurring in sites of gingiva, hard palate, buccal mucosa extending to sulci, or tongue extending to floor of mouth may involve bone of the maxilla and/ or the mandible (Fig. 13.11).

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Fig. 13.12: Neck nodes associated with regional metastasis. Most oral cancers metastasize to levels 1 and 2

Distant Metastasis Distant metastases are very rare: some authors have reported metastases in 2 to 9 percent of their patients. Metastatic disease is often associated with extracapsular spread in lymph nodes, or bilateral neck nodes. The most common distant metastases are to the lung, bones or liver.

STAGING Oral and oropharyngeal cancers are classified according to the TNM system (Table 13.3). The clinical staging defines the extent of the disease in terms of anatomic spread and is vital to the development of a treatment plan. It also provides the framework that permits comparison of treatment strategies, outcomes and survival rates. The universally accepted TNM (Tumor, Node, Metastasis) staging system is used worldwide in staging malignant processes. Staging is site-specific to various anatomic organs and for oral cavity ranges from stage I (local disease) to stage IV (disseminated disease).

T–Primary tumor TX

Primary tumor cannot be assessed

TO

No evidence of primary tumor

Tis

Carcinoma in situ

T1

Tumor 2 cm or less in greatest dimension

T2

Tumor more than 2 cm but not more than 4 cm in greatest dimension

T3

Tumor more than 4 cm in greatest dimension

T4a

(Lip) Tumor invades through cortical bone, inferior alveolar nerve, floor of mouth, or skin (chin or nose)

T4a

(Oral cavity) - Tumor invades through cortical bone, into deep/extrinsic muscle of tongue (genioglossus, hyoglossus, palatoglossus, and styloglossus), maxillary sinus, or skin of face

T4b

(Lip and oral cavity) - Tumor invades masticator space, pterygoid plates, or skull base, or encases internal carotid artery

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ƒ Table 13.3 Staging of lip and oral cavity (ICD-O C00, C02-C06) cancers (TNM, 7th Edition)

Note: Superficial erosion alone of bone/tooth socket by gingival primary is not sufficient to classify a tumor as T4

N-Regional lymph nodes NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension

N2

Metastasis as described below:

N3

N2a

Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension

N2b

Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension

N2c

Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension

Metastasis in a lymph node more than 6 cm in greatest dimension

Note: Midline nodes are considered ipsilateral nodes

M-Distant metastasis M0

No distant metastasis

M1

Distant metastasis

Stage grouping based on TNM Stages 1-4C T1 T2 T3 T4a T4b N0 1 2 3 4a 4b N1 3 3 3 4a 4b N2 4a 4a 4a 4a 4b N3 4b 4b 4b 4b 4b If distant metastasis is known (M1) any T any N is staged as Gp 4c

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The most recent (Seventh) edition of the UICC TNM classification is identical to that published by the AJCC. Tumors are stratified into at least 32 (4 x 4 x 2) possible combinations of local tumor spread (T: 1-4b), regional lymph node involvement (N: 0-3) and presence of distant metastases (M: 0-1). For purposes of simplification the 32 possible T, N and M combinations can be reduced to clustered stages: I, II, III and IVa, b, c which are meant to reflect homogeneous survival and interstage discrimination. The cTNM is based on clinical examination as well as ancillary techniques such as imaging. The pathological stage (pTNM), derived from the histopathological examination of the tumor specimen is generally used for decision making on adjuvant treatment and more accurate estimation of prognosis. The present TNM system of classification lacks biological and molecular basis and overall general health and patient-based prognostic factors, such as co-morbidity. The TNM system however, is simple and therefore easy to use and adhere to and more importantly, it is universally accepted.

INVESTIGATIONS THAT AID DIAGNOSIS Physical examination (including endoscopy particularly for tobacco users) is the primary method for diagnosis of oral and oropharyngeal cancers. A diagnostic biopsy is indicated for any mucosal lesion suspected of cancer, particularly for any ulcer or growth that persists for more than 3 weeks following the elimination of local factors. Early tissue diagnosis is the most important. Proper and timely biopsy is critical. An inadequately performed biopsy may complicate patient care and result in delay in the care pathway. Several biopsy techniques are available; the choice of biopsy is based on the size and location of the mass and the experience of the surgeon. Incisional biopsy is preferred and excisional biopsy is indicated only for small, superficial masses (50 percent of oral and >90 percent of oropharyngeal SCCs are moderately differentiated. Increased discrimination is, however, desirable and a panel of pathologists at the World Health Organization (WHO) has recommended that grading by differentiation is supplemented by assessment of the pattern of invasion.

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Pattern of tumor invasion refers to the manner in which cancer infiltrates connective tissue at the tumor/host interphase. It is considered that neoplasia infiltrating in a widely dispersed manner is more aggressive than those growing in a bulky pushing fashion (Figs 13.18, 13.23 to 13.26). Four patterns of tumor invasion have been described: • The type I pattern corresponds to tumors where the constituent cells retain cohesion and are arranged as broad, bands and columns, occasionally bulbous, which tend to penetrate at more or less the same level; this results in a rather defined, although asymmetrical Fig. 13.22: Poorly differentiated carcinoma with a ‘pushing’ or ‘expansive’ advancing front. basaloid appearance

Fig. 13.20: High power view of a poorly differentiated carcinoma

Fig. 13.23: Squamous cell carcinoma showing invasion as cluster of cells and strands

Fig. 13.21: Marked cellular pleomorphism in a poorly differentiated carcinoma with scattered markedly atypical cells and an apoptotic mitosis

Fig. 13.24: Poorly differentiated SCC invading as clusters of cells and strands

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Fig. 13.25: Moderately differentiated squamous cell carcinoma with invasion as single cells and clusters in a myxoid stroma

Fig. 13.26: Invasive front of a moderately differentiated SCC showing a myxoid tumor stroma and some single cell invasion

• The type II pattern is characterized by the arrangement of malignant keratinocytes as islands or sheets, rounded, irregular or spiky, which are asymmetrically distributed and penetrate at different levels; this results in an irregular tumor silhouette. • The type III pattern resembles type II as regards the tumor silhouette, but discohesion in the form of tiny islands and cords that bud off from the larger islands and sheets, extensively affects the advancing front here. • The type IV pattern corresponds to the archetypal non-cohesive tumors wherein the irregular advancing front shows malignant keratinocytes infiltrating as individual units because of loss of intercellular cohesion.

Tumor thickness of early oral cancers has been significantly correlated with cervical node metastases; particularly when the tumor thickness exceeds 5 mm the metastatic rate is higher. Preoperative ultrasonography may accurately measure tumor thickness. Bryne et al select the most ‘worrisome’/ unfavorable’ region of the advancing front for assessment, consider features of both tumor cells and the tumor-host interface and score each feature on a scale of 1 to 4 to give a total malignancy score ranging from 4 to 24 or 28. Keratinization, nuclear aberrations and mitoses are considered in the assessment of the tumor cells whereas the tumor-host interface is assessed in terms of the pattern and level of invasion and the inflammatory cell reaction. Some pathology laboratories now routinely screen for high-risk HPV. Without activation of p16, just the presence of high risk HPV even in the tissues is not that meaningful. A combined triple method to detect causative HPV in oral and OPCs by p16 immunohistochemistry, consensus PCR HPV-DNA and in situ hybridization improves the sensitivity and specificity of detection. Important histopathological features of oral SCC are illustrated in Figures 13.13 to 13.33. Other features in the biopsy that are recorded include desmoplasia, spread of tumor to deep muscle (Fig. 13.27) lymphovascular invasion and peri- and endoneural invasion and invading minor salivary glands (Fig. 13.31). Lack of clearance at the margin is an important prognostic factor (Fig. 13.28).

Features of Metastasis The earliest stage of pathological metastasis is lymphovascular invasion (Figs 13.29 and 13.30), mostly within endothelial lined lymphatic channels referred to as emboli. These emboli would normally be carried to the lymph nodes, the first echelon draining the primary tumor site (Fig 13.12). These emboli would enter the node via the afferent lymphatic vessels, traverse the capsular sinuses (Fig. 13.32) and reach the medullary sinuses. Some of these may remain dormant or may die due to host defence systems. Some survive and form established metastasis and increase in size within the node

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Fig. 13.27: Sarcolemmal spread of SCC

Fig. 13.30: Intravascular spread through a small vein

Fig. 13.28: Inflitrating single cells and small islands and strands of cells reach the surgical excision margin at the bottom of the picture

Fig. 13.31: Islands of carcinoma invading minor

Fig. 13.29: Intravascular spread in a small mucosal lymphatic, a risk factor for developing metastasis

Fig. 13.32: A micrometastasis of SCC in the subcapsular sinus of a lymph node

salivary glands, an aggressive feature

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(Fig. 13.33). Left untreated nodal metastasis will invade the node capsule leading to extracapsular spread (ECS). The presence and extent of ECS is important in postoperative management and prognosis prediction. Lymphovascular invasion of vessels within the mucoperiosteum covering the jaws may lead to bone invasion. For tumors invading jaw bones (Fig. 13.34) two patterns of invasion are recognized; an infiltrative and an erosive form. In the infiltrative pattern, malignant keratinocytes advance into cancellous spaces in small clusters or chords with little osteoclastic activity. This requires portals of entry through the cortex, such as fenestrations on a resorbed alveolar ridge, an incompletely healed extraction socket, or perhaps a periodontal ligament. In the erosive pattern, the neoplasm advances on a broad

Carcinoma In Situ Fig. 13.33: A lymph node replaced by metastatic carcinoma but with no extra nodal spread

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front, with an intervening connective tissue layer and active osteoclasts separate tumor from bone. Several signal pathways initiated by products of the neoplastic keratinocytes themselves are reported to affect osteoclast function, including proteases, cytokines, and growth factors. Two major groups of proteases participate in bone invasion of OSCC: matrix metalloproteinases and cathepsins. Perineural invasion (PNI) is a form of tumor spread exhibited by some oral SCCs that correlates with aggressive behavior. This is a form of metastatic spread similar to but distinct from vascular or lymphatic invasion. The presence of tumor cells within any of the three-layers of the nerve sheath is considered as perineural spread or even penetration of tumor cells within the nerve itself may occur - referred to as intraneural spread. The mechanism of PNI is poorly understood. The perineural space provides a suitable microenvironment for the growth of SCC cells that exhibit neurotropic behavior, probably due to cellular and growth factors that allows their growth along the nerves. Neural extension of an SCC can be demonstrated through a thorough histopathological examination and also by MRI and CT. There is a marked variation in reporting by pathologists, some laboratories use neural staining but under reporting could be frequent.

Fig. 13.34: Carcinoma islands invading bone

The theoretical concept of carcinoma in situ is that malignant transformation has occurred, but invasion is not present. It is not possible to recognize this by visual inspection (clinically). The following is recommended for the diagnosis of carcinoma in situ: full thickness or almost full thickness architectural abnormalities in the viable cellular layers accompanied by pronounced cytologic atypia (Fig. 13.35). Atypical mitotic figures and abnormally superficial mitoses are commonly seen in carcinoma in situ. The concept of, and recognition of, carcinoma in situ requires consideration. At the furthest end of the spectrum there is a critical distinction which has not been adequately considered and, i.e. recognition of when a lesion stops being dysplastic and is actually malignant.

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Fig. 13.36: Early invasion showing microscopic invasion

Fig. 13.35: Carcinoma in situ; marked cellular atypia and architectural changes extend to almost full thickness of the epithelium

Early Invasion The histological criterion which distinguishes cancer from precursor lesions is invasion. The dictionary definition of invade includes the concepts of encroaching upon and penetrating. The earliest stage of invasion recognized by microscopy is designated microinvasive squamous cell carcinoma with a small collection of epithelial islands that penetrate subepithelial (papillary) lamina propria (Fig. 13.36) When unequivocal/submucosal invasion cannot be established, the question of ‘early SCC’ arises. The major problem here is deciding whether or not frank invasion of the lamina propria is present. In diagnostic practice the most frequent problem is judgement about whether the earliest stages of invasion into the lamina propria are present. There is a huge literature on many aspects of invasion, but the problem the diagnostic pathologist has in identifying whether or

not invasion is present has not been adequately addressed. The pathologist’s decision about the presence of invasion involves subjective judgement. The following features are important to recognize invasion developing from dysplastic epithelium, not necessarily in the sequence given, but in an iterative manner, often reassessing a feature in the context of another feature. • Extent of epithelial encroachment • Dysplasia, particularly mitotic abnormalities • Features of the basal epithelial layer • Interface between epithelium and lamina propria • Eosinophilia and early keratinization Correlation with features of dysplasia is important. Older texts emphasized loss of basement membrane, but this is not a reliable criterion. However, account should be taken of the interface between epithelium and lamina propria. A very irregular interface with pointed cytoplasmic projections of epithelium is suggestive of malignancy. Loss of a defined basal epithelial layer is important and often cells with characteristics more suggestive of stratum spinosum cells are present at the interface. Host reaction is an underexplored and possibly an important feature. There will be occasions when the pathologist is unable to arrive at a decision as to whether or not invasion is present. If the findings in the surface epithelium justify a diagnosis of carcinoma in situ this should be communicated to the clinician.

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13 PATHOLOGICAL SUBTYPES OF ORAL

Basaloid Squamous Cell Carcinoma

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Mostly arise in the posterior part of the oral cavity. Large lobules of basaloid areas are noted, packed with tumor cells with a high nuclear to cytoplasmic ratio.

SQUAMOUS CELL CARCINOMA

Over 90 percent of oral carcinomas are conventional squamous type and resemble squamous epithelium except in a small proportion of anaplastic tumors. Other histological subtypes are encountered. Of these, verrucous carcinoma is particularly common in Asia. These subtypes are described below:

Verrucous Carcinoma Favors older individuals, particularly tobacco users (chewers and cigar/bedi smokers). An exophytic or papillary appearance (rather than infiltrative) should raise the possibility of verrucous carcinoma. It’s a slow growing tumor spreading laterally, is more indolent than that of convential SCC and lacks cellular atypia. The epithelium is highly acanthotic breaking into finger like projections with pathognomically broad bulbous rete ridges, with a pushing margin rather than an infiltrative one. Host response is dense, and tumor remains superficial without extending to muscle, but with time may transform to a more clinicopathological SCC.

Carcinoma Cuniculatum Often involves gingival tissues and appears as a warty mass often loosening teeth. Deep keratin filled crypts are found on the superficial margins and the tumor invades on a broad pushing front and forms histologically characteristic tube-like columns.

Papillary Squamous Cell Carcinoma Takes an exophytic and papillary form, often in elderly and speculated to be HPV positive. Papillary growth pattern is clear on histology, much basaloid, and minimal or no invasion is observed. These tumors are often p53 positive.

Adenosquamous Carcinoma

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Glandular structures either duct-like or acinar structures are seen with the squamous tumor. Largely aneuploid, and known to metastasise early.

Spindle Cell Carcinoma These clinically appear as exophytic, ulcerative or polypoid lesions and is an unusual variant of SCC that frequently recur and metastasise. These neoplasms occur most frequently on the lower lip, tongue, and alveolar ridge. Mean survival time is short and often under 2 years. Histopathologic features include foci of SCC or several epithelial dysplasia, malignant dysplastic spindle cells and cellular atypia is marked. Transition between these cell compartments may be found with prominent intercellular spaces, atypical tumor giant cells, abundant mitotic figures and necrosis. These tumor cells stain positive with anti-pan cytokeratins (AE1/AE3) and are negative for the mesenchymal markers.

Giant Cell Carcinoma This is an infrequently observed feature though laryngeal giant cell carcinomas are reported. The pathological features include numerous focal, bizarre giant cells, with multiple nuclei and prominent nuecleoli interspread within SCC. There could be associated neutrophils and cellular debris. Immunohistochemistry with cytokeratins helps in characterization of these tumors of their epithelial origin. Clinical significance of various types is not fully established except that verrucous and papillary carcinoma may pose a better prognosis and basaloid and adenosquamous types have a poorer prognosis than conventional SCC.

MOLECULAR PATHOLOGY The application of molecular biology techniques to assess the tumor biology of oral SCC has produced a wealth of information on disruption of normal functions and regulation, i.e. responsible for initiation and progression of cancer. It is beyond the scope of this chapter to

clinical setting. Though rapid progress has been made in our understanding of molecular biology of oral SCC none of these genetic alterations are used as tumor markers at the moment. Most researchers now believe it is unlikely that any one molecular event determines tumor evolution and that the complex interaction among genes and proteins may contribute to carcinogenesis. Thus complete behavior of a tumor cannot be ascertained through the analysis of a single tumor marker and it is likely that these markers need to be combined to evolve diagnostic paradigms. The introduction of anti-EGFR and anti-m-TOR therapies for head and neck cancer are the first of the novel biological treatment modalities available for clinical use.

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discuss the voluminous literature on genetics of oral cancer. A short summary of some important events is given below. Loss of heterozygosity at chromosomes 3p, 9p and 17p appear to occur in early stages of carcinogenesis and in oral epithelial dysplasias. Any alterations at 11q, 4q and of chromosome occur later in the process. Presumably if a cancer associated gene is in an area of allelic loss, this would make the host more susceptible. In the past three decades studies have identified many established and candidate genes in oral SCC. There are several putative tumor suppressor genes involved in oral SCC, but the most important so far appear to be TP53, p16INK4A, p14ARF NOTCH1 and the retinoblastoma gene. Among these a high incidence of mutant or upregulated p53 in oral SCC has been mostly reported and correlated with prognosis. P16, retinoblastoma (Rb) and TP53 are major interconnected important pathways frequently perturbed in oral SCC. Aberration of these genes causes deregulation of the cell cycle causing increased cell proliferation. The ability to proliferate continuously, without undergoing senescence is one of the hallmarks of cancer. Loss of cell cycle checkpoint control appears to promote further genetic instability. Tumor growth markers that have been studied include epidermal growth factor receptor family (EGFR), MYC, CCND1 which encodes cyclin D1. These genes are mutated, deleted, amplified or over expressed in a majority of oral and oropharyngeal cancers. EGFR overexpression has been reported in many studies, and once activated, EGFR stimulates a number of downstream molecules including Ras/Raf/ MAPK and STAT3. Another key pathway is PI3K/AKT/mTOR. Both contribute to malignant potential of oral SCC. Among betel quid users ras mutations are particularly prevalent. Alterations of TP53 have commonly been found in oral cancer, but its prognostic value is inconclusive. A meta-analysis found there is large heterogeneity observed across published studies. Recent studies, by immunostaining found Nuclear Stat 3 and p-mTOR played a significant roles in OSCC prognosis. Many markers examined in oral SCC appear to provide little or no definitive prognostic or predictive information that can be used in a

PROGNOSIS OF ORAL SQUAMOUS CELL CARCINOMA Tumor size and nodal status are the most significant clinical prognostic factors for oral SCC. For early tumors, tumor thickness has been found to be a reliable prognostic marker for subclinical nodal metstasis, local recurrence and survival. Histopathologically assessed features of the surgical resection specimen and nodal pathology continue to provide information, i.e. central to determining the postoperative treatment needs and prognosis for an individual patient. Factors of significance are listed in Table 13.4.

TREATMENT Surgery is the most well established mode of initial definitive treatment for a majority of oral cancers, with a longstanding history of being the accepted method of treatment for well over a century. Introduction of ionizing radiation, following the discovery of radium, became an important means of non-surgical treatment of oral cancer. However, in the majority of patients with advanced cancer radiotherapy is employed in conjunction with surgery, most often offered as postoperative treatment. Chemotherapy in the management of oral carcinoma was considered palliative in the 1950’s, 60’s and 70’s but with the introduction of Cis-platinum, clinical trials of induction chemotherapy demonstrated that a good response to chemotherapy was observed

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ƒ Table 13.4 Factors influencing prognosis of oral SCC* Clinical • T stage • Nodal status • Tumor grade Pathology • Histological grade (differentiation) • Pattern of tumor invasion • Lymphovascular and perineural invasion • Sialadenotrophism • Tumor thickness; 4 mm or less vs 9 mm or more • Bone invasion • Margin clearance • HPV infection • High proliferation index (Ki 67)/rapid doubling time • Extracapsular spread of nodal disease *Of those listed some may not have a direct impact on the management at present but may have a significant role in determining the treatment in the future

in a significant number of patients. Unlike other sites in the head and neck area, the response to induction chemotherapy did not translate into long-term control of primary oral squamous cell carcinomas. Targeted therapies with EGFR inhibitors are an active area of investigation at this time. Immunotherapy and gene therapy are also areas of research where further work needs to be done. The initial treatment approaches for patients with oral cancer include: 1. Primary surgery with or without postoperative radiotherapy or chemoradiation, 2. Non-surgical strategies, i.e. primary radiotherapy either by itself or combined with chemotherapy. Radiotherapy is typically now administered postoperatively. Chemotherapy can be given: a. Before surgery (induction/neoadjuvantwhen treatment is administered before primary therapy, i.e it is used to shrink a tumor prior to surgery or radiation) b. After surgery (adjuvant-therapy, i.e. administered after the primary treatment)

c. At the same time as radiotherapy (concomitant–also referred to as chemoradiotherapy) d. Alternating with radiotherapy. Newer approaches include targeted agents directed against epidermal growth factor receptor (EGFR) or anti mTOR reported for other tumors. In many countries, patients with stages I and II disease who have excellent outcome are most optimally treated with only one treatment modality (surgery). No randomized trial has been conducted to clarify whether surgery or radiotherapy would give a better outcome. Moreover, there have been no trials comparing different surgical modalities of the primary tumor. A substantial proportion of patients present with more locally-advanced stage (stages III and IV) disease, many patients with advanced stages are also primarily treated with curatively intended surgery and are then referred for postoperative radiotherapy or chemoradiation. The most commonly employed surgical approaches for resection of primary oral cancer are peroral, mandibulotomy, lower cheek flap approach, visor flap or Weber-Ferguson flap approach. Involvement of bone in cases of OSCC has a major influence on functional outcome and dramatically impacts the patients’ quality of life. In patients with very early invasion of alveolar bone by cancers of gum marginal mandibulectomy is sufficient. Segmental mandibulectomy is considered necessary when there is gross invasion of cancellous bone by oral cancer. For advanced cancers the choice between primary surgical or non-surgical treatment strategies is often dependent on the site of the primary tumor and functional outcomes of treatment. Classic radical neck dissection – removal of all cervical lymph nodes from levels 1 to 5 combined with adjacent structures with resultant postoperative morbidity is only reserved for advanced neck disease. Selective neck dissection is now preferred. For early stage tumors (T1) with clinically negative neck (N0) there is a controversy over the management of cervical lymph nodes, regarding elective neck dissection. There are no universally accepted guidelines for the treatment of clinically negative nodes in early stage SCCs and the use of elective neck dissection in such cases remains unresolved.

Chemotherapy plays an important role in the treatment of locally advanced HNSCC either as concomitant chemoradiotherapy (CT-RT) or as induction chemotherapy. A major advance in the treatment of this stage of disease has been the introduction of concomitant CT-RT. There is some evidence that concomitant radio/chemotherapy is better than radiotherapy alone. There are over 80 trials on the use of chemotherapeutic agents but the information is limited or missing in many reports to extract meaningful outcome data. Cisplatin is the most common chemotherapy agent used, other platins used include carboplatin mostly in combination with 5-FU. The use of methotrexate, bleomycin, vincristine and cyclophosphamide is also reported. Based on a Cochrane analysis use of concomitant chemoradiotherapy is an effective treatment for oral cavity and oropharyngeal cancer and the addition of docetaxel (T) to the regimes containing cisplatin and 5-FU (PF) is associated with further reduction in mortality. There may be additional benefit in the use of induction TPF regimen prior to concomitant chemotherapy with TPF. The epidermal growth factor receptor (EGFR) has been identified as an important gene target for cancer therapy. Inhibition of the EGFR using monoclonal antibodies (MAbs) directed against the external ligand binding domain or small molecule tyrosine kinase inhibitors has been extensively studied in the recent years. Based on promising preclinical studies on the interaction between EGFR inhibitors and ionizing radiation a number of prospective clinical investigations on molecular targeted therapies have been launched for KRAS wild type tumors. Among the EGFR inhibitors, cetuximab (erbitux) is an immunoglobulin G1 (1gG1) monoclonal antibody (MAb) that inhibits ligand binding to the EGFR and can stimulate antibodydependent cell-mediated cytoxity. Rapamycin analogs, including everolimus, temsirolimus, and ridaforolimus, are small molecules that selectively inhibit mTOR activity are currently used in clinical trials for other solid cancers and may be appropriate for treating oral carcinomas. Local relapse after resection of a primary SCC is easily explained, when tumor is detected in the surgical margin and thus residual

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Along with surgery, radiotherapy plays a key role in the management of early stage and locally advanced head and neck squamouscell carcinomas (HNSCC) either alone or more frequently combined with surgery and/ or chemotherapy. Radiotherapy (RT) plays a key role in the management of these locally advanced stages. In recent years, the techniques for external-beam radiation with the intended purpose of delivering more radiation to the tumor while sparing normal tissues and adjacent vulnerable organs have evolved. Its results remain relatively poor in advanced cases. Several approaches have been developed to improve its efficacy while maintaining acceptable toxicities. In the last decades, altered fractionation has been one of the tools shown to improve the efficacy of RT. The objective of altered fractionated RT is to increase the dose intensity of RT by delivering a high total dose in an overall time as short as possible. Mainly two types of altered fractionation regimens have been tested, i.e. accelerated and/or hyperfractionationed RT. Accelerated fractionation radiotherapy (AFRT) was designed to increase the dose intensity usually by delivering 2 (or 3) fractions daily in order to decrease the overall treatment time. This acceleration aimed to reduce tumor cell repopulation between sessions to allow better local control probability. The latter was developed to overcome tumor cell repopulation during the course of therapy. Further variations exist. These include continuous hyperfractionated accelerated radiotherapy (CHART), two and three-dimensional conformal radiation therapy (2DRT and 3 DCRT), intensity modulated radiotherapy (IMRT) and imageguided radiotherapy. A Cochrane review found altered fraction radiotherapy is associated with an improvement in overall survival and local regional control. The benefit may be greater with hyperfractionated regimens rather than accelerated regimens. Proton beam therapy is less commonly used. Hyperfractionated radiotherapy (HFRT) was designed to improve effectiveness by delivering 2 (or 3) fractions daily with a markedly reduced dose per fraction (1.1-1.2 Gy), which in turn could reduce late toxicity and allow to increase the total dose.

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tumor is likely to remain in the patient, but the pathobiology is more complex in cases where the margins are histologically tumorfree. Molecular studies indicate that there are two different mechanisms responsible in these cases. First, small clusters of residual tumor cells that are undetectable on routine histopathological examination (known as minimal residual cancer: MRC) proliferate and this forms the basis of recurring cancer. A second cause of relapse is an undetected field of preneoplastic cells that is struck by additional genetic hits leading to invasive cancer. It is likely that within this field, that can be over 7 cm in diameter, a second primary carcinoma could emerge. Oral and Oropharyngeal cancer is a devastating disease which has wide-ranging effects on the patient, due to the disease process and its surgical and non-surgical management (Table 13.5). Though acute effects of radiotherapy settle in four to six weeks after therapy some permanent late effects and toxicity remain. A patient’s General Medical Practitioner and the General Dental Practitioner

should be aware of the significance of these treatment effects on the poor quality of life, physical and functional changes, psychological effects and aim to provide practical advice in the management of surviving patients or those living with cancer.

SCREENING AND PREVENTION It is well established that the treatment of early stage oral cancers (Figs 13.37 to 13.39) achieves higher survival rates with less attendant morbidity than that at present where far too many patients present with late stage disease (Fig. 13.40). Therefore screening for early stage oral cancers is advocated. Several large population screening programs from SE Asia and smaller studies from England and Japan

ƒ Table 13.5 Complications following therapy • Appearance • Eating and swallowing (PEG feeding) • Employment issues • Fatigue • Psychosocial distress

Fig. 13.37: A small T1 cancer of the gum adjacent to a mobile molar tooth. Rolled margins of this non-healing cancer indicates malignancy

• Sexuality • Shoulder dysfunction • Speech and voice alterations • Osteoradionecrosis (for those treated with radiotherapy) • Dental status due to tooth loss • Root caries • Trismus • Painful mucositis • Excessive mucous production • Taste disturbances

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• Xerostomia

Fig. 13.38: A superficial ulcer on the lateral margin of tongue

Fig. 13.40: An advanced tumor on the floor of the mouth

were reported during the period 1980 to 2000. One randomized control trial on screening for oral cancer conducted in India has demonstrated a significant mortality reduction in tobacco users. However, for low risk populations, there is insufficient evidence to support population screening. Some of the problems include the relative rarity of the disease, a lack of knowledge of the natural history of the disease, disagreement over disease management and the lack of evidence on the efficacy and cost effectiveness of different screening methods. In a high incidence country high risk groups may be targeted for screening. Opportunistic oral mucosal examinations in dental practices reduce the cost of screening and could be an

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Fig. 13.39: A deeply infiltrative cancer on the floor of mouth

effective model for countries with health care systems that support regular dental attendance. The concept underpinning screening is also based on the premise that earlier detection of the asymptomatic phases of oral precancer will allow modification of risky behaviors and to attempt other clinical interventions to prevent cancer. To prevent cancers of the oral cavity it is important to recognize the major risk factors that are appropriate for the population. There is now clear evidence on established and modifiable risk factors (Figure 13.5). Any intervention should be based on good scientific evidence. It is important to take into consideration the difficulties in behavioral modification that requires multisectorial approaches. There is good evidence to suggest that cessation of tobacco use leads to reduced risk of oral SCC though it may take up to 10 years to reach the low risk status of never users. Most adult smokers would like to quit, and effective therapies are now available. Tobacco dependency requires targeted therapies and those with oral precursor lesions constitute a special group who need assistance for quitting tobacco use. The main role of oral health professionals is to stimulate quit attempts among their patients using brief interventions and when appropriate to refer to cessation clinics for further treatment of tobacco dependence. Methods of tobacco interventions are discussed in a later Chapter 24. HPV vaccines (Cervarix and Gadasil) are now available. These are not therapeutic but are expected to offer protection against cervical cancer when given to young adolescent women. Results are waiting to confirm their efficacy to reduce cancer incidence in young adult women with prior exposure to HPV, or for infections in other organs other than the cervix, such as oral cavity or oropharynx.

ACKNOWLEDGMENTS I thank Elsevier Ltd to republish Figures 13.1 and 13.2 and Wiley Blackwell for reuse of Figures 13.35 and 13.36. Figure 13.3A was kindly supplied by Dr Anura Ariyawardana of James Cook University, Queensland, Australia.

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1. Explain why there is much global variation in the incidence of oral cancer. 2. What novel risk factors may be considered causative in subjects who are not exposed to the major risk factors? 3. Outline different clinical and biological characteristics of HPV–negative and HPVpositive tongue and oropharyngeal cancers. 4. Why is staging important and how would you apply TNM staging to a given tumor? 5. Explain the significance of special investigations that you would you carry–out prior to treatment planning. 6. What pathological features would you consider in assessing the prognosis of a squamous cell carcinoma? 7. What microscopic features enable the identification of variants of squamous cell carcinomas? 8. What are the features of early invasion? 9. Discuss the spread of a squamous cell carcinoma.

10. How would our understanding of the molecular alterations of oral cancer contribute to any improvement for early diagnosis and management?

SUGGESTED READING 1. Leemans CR, Braakhuis BJM, Brakehoff RH. The molecular biology of head and neck cancer. Nature Reviews Cancer. 2011;11:9-22. 2. Rogers SN, Brown, Woolgar JA, et al. Survival following primary surgery for oral cancer. Oral Oncology. 2009;45:201-11. 3. Barnes L, Eveson JW, Reichart P, Sidransky D. The Pathology and Genetics of Head and Neck Tumors (World Health Organization Classification of Tumors). IARC Press. 2005. 4. Warnakulasuriya S. Global epidemiology of oral and oropharyngeal cancer. Oral Oncology. 2009;45:309-16. 5. Warnakulasuriya S. Squamous cell carcinoma and precursor lesion: Prevention. Periodontol 2000. 2011;57(1):38-50.

Chapter

14 Recurrent Oral Ulceration Saman Warnakulasuriya

Chapter Outline Introduction and Classification Recurrent Aphthous Ulceration/Recurrent Aphthous Stomatitis • Clinical Aspects • Etiology Systemic Diseases Associated with Recurrent Oral Ulceration • Behçet’s Disease • Immunobullos and Systemic Diseases with ROU • Anemia and Vitamin Deficiencies • GI Tract Diseases • HIV-associated ROU

Chronic Ulcerative Stomatitis Syndromes Associated with ROU Drug-induced Recurrent Oral Ulceration Management • Topical Agents • Systemic Therapy • Systemic Corticosteroids • Pentoxifylline • Colchicine • Azathioprine • Thalidomide • Levamisole Self-assessment Questions

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14 InTRODUCTIOn AnD CLASSIfICATIOn Recurrent oral ulceration (ROU) is regarded as the most common disorder affecting the oral mucosa. Aphthous ulcers constitute the largest group of ROU, occurring in about 20 percent of the general population. A distinction should be made of the ulcers of aphthous type recurrent aphthous ulcers (RAU) from those other ROUs secondary to systemic disease or due to other causes. The diagnosis and management of different categories of ROU would be considered in this chapter. A classification is shown in Table 14.1. It is also prudent to distinguish an ulcer from an erosion. An ulcer is a break in skin or mucous membrane with loss of surface tissue, and disintegration of epithelial tissue. ƒ Table 14.1 Classification of oral ulcers related to cause Condition/cause

Examples

Recurrent aphthous Minor ulceration (stomatitis) Major Herpetiform Behçet’s disease Secondary to hematinic deficiency (Anemia)

Vitamin B12 folate Iron

Secondary to other hematological cause

neutropenia Cyclic neutropenia Pancytopenia Leukemia

Secondary to GI tract Ulcerative colitis disease Crohn’s disease Celiac disease Secondary to a dermatological condition

Erythema multiforme Pemphigus Mucous membrane pemphigoid Erosive lichen planus Dermatitis herpetiformis Linear IgA disease

Secondary to conLupus erythematosus nective tissue disease Reiter’s syndrome

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Secondary to immune deficiency

HIV disease

Secondary to drug therapy

nonsteroidal anti-inflammatory agents Chemotherapy

In contrast, an erosion is the superficial destruction of the epithelial covering of the mucosa by inflammation or trauma.

RECURREnT APHTHOUS ULCERATIOn/RECURREnT APHTHOUS STOMATITIS Recurrent oral ulcers of aphthous type RAU are also referred to as recurrent aphthous stomatitis (RAS). “Aphthous stomatitis” has been used interchangeably with “aphthous ulcers” and may be more accurate terminology. “Aphthous” is derived from the Greek word “aphtha” which means an ulcer. Episodic recurrences are its main characteristic feature. The frequency of recurrence varies between patients. Synonyms now mostly in disuse are: • Mikulicz’ aphthae • Sutton’s disease • Periadenitis mucosa necrotica recurrence • Canker sores.

Clinical Aspects A history of RAU varies from 5 to 60 percent among adults in different populations and at a given time 20 percent may report they suffer from aphthae. RAU is more common in women. Ulceration commences usually in the second decade of life. All races are affected though reportedly it is more common in North America and less frequent in Arabia. The disease is predominant in children of higher socioeconomic status. RAU is uncommon in patients who smoke: quitting smoking seems to initiate the disease in older groups of patients. The diagnosis of RAU is based upon a history of regular recurrence of oral ulcers and the presence of compatible clinical lesions (Figs 14.1 and 14.2). These ulcers, which usually occur on the nonkeratinized oral mucosa, can cause considerable pain and may interfere with eating, speaking and swallowing. For 24 to 48 hours preceding the appearance of an ulcer, most patients have a prodromal sign— pricking or burning sensation in the affected area. RAU usually occur on the nonkeratinized oral mucosa, including the lips, the buccal mucosa, the floor of the mouth, the soft palate and the ventral surface of the tongue. Regions of

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Fig. 14.2: A major aphthous ulcer in the soft palate and oropharynx. Note: Its size is exceeding 10 mm in the longest diameter

B

C Figs 14.1A to C: Examples of minor RAU: (A and B) Minor ulcers on lower lip and tongue in the same subject; (C) A crop of minor aphthous ulcers in buccal mucosa and soft palate. Note: Small size, pale color with surrounding erythema

keratinized oral mucosa, such as the hard palate, the gums and the dorsal surface of the tongue, are uncommon locations. Histopathological and serological findings are neither diagnostic nor exclusionary. A biopsy is therefore not undertaken except in rare circumstances when

RECURREnT ORAL ULCERATIOn

A

a major aphthous ulcer (without an established history of recurrence) may mimic cancer. The patient should be evaluated thoroughly to assess the presence of micronutrient deficiencies or other associated systemic/dermatological diseases, such as Behçet’s, Reiter’s syndrome, erythema multiforme, celiac disease, Crohn’s disease, ulcerative colitis or erosive lichen planus and classified accordingly (Table 14.1). Pemphigus vulgaris (see Chapter 15) may mimic RAU at the initial presentation but a clear note should be made that in untreated pemphigus oral ulceration is persistent. A diagnosis of RAU is made for a patient with a history of recurrent oral ulceration, in the absence of any systemic disease or hematinic deficiencies that contribute to oral ulceration. Box 14.1: Recurrent aphthous ulcers Key features helpful in diagnosis • Present as crops of ulcers that recur • no evidence of systemic disease; patient is otherwise well. Therefore, requires hematinic and immunological investigations • Classified by their size and time taken for healing: as minor, major or herpetiform • More common in teenagers and young adults • In older subjects ROU are likely to be secondary to a systemic cause and should not be assumed to be RAU.

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Box 14.2: Recurrent aphthous ulcers Key features on etiopathogenesis • Is multifactorial • Some have genetic predisposition • Bacterial or viral etiology is unlikely • Immunopathogenesis involving a cellmediated immune response mechanism is most likely • Involves generation of T-lymphocytes, interleukins and tumor necrosis factor • Cross reactivity with streptococcal antigens has been proposed.

Recurrent aphthae are classified into three groups: 1. Minor. 2. Major. 3. Herpetiform. The classification is not clearly defined. It is based upon variation in the clinical presentation. The criteria used in distinguishing between the three forms of recurrent aphthae are: their size, number, localization and duration of the lesion. • Minor type is the most common form encountered (80%). It is characterized by one or more round or oval, well-demarcated, painful ulcers of the nonkeratinized mucosa (Fig. 14.1). They have a depressed base covered with yellowish slough and surrounded by an erythematous margin. Normally selflimiting in nature (healing is spontaneous) they occur most frequently in the second and third decade of life. • Major aphthae are larger in size (>10 mm in size), deep and take longer to heal (3 weeks to several months) (Fig. 14.2). The major form occurs less often. • The herpetiform ulcers are the least common. These are small pin-head ulcers (Fig. 14.3) but may coalesce to form a large ulcer. The characteristics of each are summarized in Table 14.2. Some may have mixed crops both of minor and major types or minor ulcers bordering on major type (Fig. 14.4). A small group with severe RAU (e.g. more than 3 episodes of ulcers per month or is rarely ulcer free) could be regarded as having atypical or complex apthosis.

Fig. 14.3: Herpetiform recurrent oral ulceration

Fig. 14.4: Minor aphthous ulcers bordering on the size of major ulcers

Etiology No single cause has been identified as causative and the etiology to date is largely unknown. RAU occur mostly in otherwise healthy people. Onset later in life suggests the possibility of an underlying cause. The most likely factors precipitating aphthous ulcers are local trauma and stress. In people susceptible to the disease trauma may often initiate RAU. Injury to the oral mucosa may result from accidental selfbiting, dental procedures, toothbrush bristles and sharp-edged foods. Stress is often linked to exacerbation of oral ulcers in susceptible individuals. This association has remained controversial due to inconsistent evidence. However, emotional and environmental stress may precede the first-time an aphthous ulcer

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Features

Minor

Major

Herpetiform

Size of ulcers

Less than 10 mm in diameter

Over 10 mm in diameter

0.5–2 mm in diameter

Shape

Oval, well demarcated

Usually oval, poorly defined margin

Round and well-defined; may coalesce to form an irregular outline

Color

yellow/gray base with thin erythematous border

yellow/gray base

yellow with marked periulcer erythema

Duration

4–7 days

1–2 months

4–14 days

Site

Most, nonkeratinized oral mucosae—labial and buccal mucosae in particular

Most, nonkeratinized oral mucoase—soft palate and fauces

nonkeratinized oral mucosa— but most often ventral surface of tongue, anterior labial sulci and soft palate

Ulcer number

1–5

2–3

10–100

Healing

no scarring

Heal with scarring

no scarring

Peak age of onset

5–20 years

10–20 years

10–30 years

manifests and is involved in a significant proportion of recurrent episodes. Early studies by Thomas Lehner have indicated that RAU is an acquired autoimmune disorder that may manifest in a variety of clinical presentations. Recently cross-reactivity between a 65 kDa heat shock protein (HSP) of microbes and a 60 kDa human mitochondrial HSP resulting in generation of autoreactive T cell response primed to a homologous peptide has been reported. The underlying pathology of RAU is thus due to immune dysregulation, resulting in a cellular cytotoxic assault upon oral mucosal cells. An increase in T-helper cells (CD4+ cells) and a decrease in T-suppressor cells (CD8+ cells) may accompany RAU during periods of disease exacerbation and normalize during remission. The presence of activated gamma/delta T-lymphocytes in the periphery of ulcers indicates that RAU may result from an activated cell-mediated response. Interleukines and tumor necrosis factor (TNF) are involved in immunopathogenesis of the disease. New research indicates a subset of RAU patients showing a partial lack in the NK cell numbers.

RECURREnT ORAL ULCERATIOn

ƒ Table 14.2 Main characteristics of minor, major and herpetiform ulceration

Microorganisms acting as antigenic stimuli in the genesis of antibodies that cross-react with oral keratinocytes have been speculated in the causation of RAU. Several microbes Streptococcus sanguis, Smitis and Soralis have been suggested as causative, as well as Helicobacter pylori that have been detected in RAU biopsies when examined by polymerase chain reaction (PCR). Food allergies occasionally underlie RAU. Where a relationship to the menstrual cycle is noted, a cyclical pattern can be demonstrated. No studies so far have identified a clear hormonal cause. Some people have a well-established fami-lial basis for RAU. However, evidence for a genetic predisposition is not strong. Patients with family history of RAU may develop the disease earlier and more severely than those with no family history. Forty to fifty percent of first-degree relatives of patients with RAU may have the condition. RAU may have a polygenic inheritance with a variable penetrance that makes it difficult to confirm familial nature of the disease.

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Fig. 14.5: Oral ulcers in herpes gingivostomatitis in a child

Fig. 14.6: Pemphigus vulgaris with multiple widespread oral ulceration

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15). In such cases ROU is secondary in nature and many would present with dermatological disorders. In cases when the presentation is unusual of ROU and the history is vague, a biopsy may be helpful in defining the diagnosis. These cases present a diagnostic challenge. The clinical, histological and serological evaluation is often necessary to rule out many similar conditions: Primary (or recurrent) herpetic gingivostomatitis (Fig. 14.5), Behçet’s syndrome, Sweet’s syndrome, pemphigus vulgaris (Fig. 14.6) ulcerative lichen planus (Fig. 14.7), mucous membrane pemphigoid (Fig. 14.8), erythema multiforme (Fig. 14.9), and herpangina (Fig. 14.10). A minority patients with cyclical neutropenia

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Fig. 14.7: Ulcerative lichen affecting buccal mucosa with a history of recurrent episodes. Pathogno- monic feature is keratotic striae seen at the margins of the ulcer

Fig. 14.8: Mucous membrane pemphigoid presenting as desquamative gingivitis. Ulcers may be found elsewhere in the oral cavity

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Fig. 14.10: Herpangina affecting soft palate

present with ‘aphthous-type’ ulceration which occurs at intervals (often monthly), reflecting their neutropenic status. In patients who appear to present with atypical forms of RAU in later life it is advisable to assay antibodies against desmoglein 3 or to send a fresh specimen for direct immunofluorescence studies to exclude pemphigus vulgaris. These conditions should be considered prior to initiating therapies appropriate for a diagnosis of RAU. Systemic diseases involving hematological, and nutritional deficiencies have been associated with recurrent oral ulcers. Oral ulcers have been reported in patients with cyclic neutropenia, hypogammaglobulinemia and agranulocytosis. These are discussed in detail in Chapter 20. Among hematological diseases a history of chronic anemia, myeloproliferative disorders or leukemia may be associated with oral ulceration.

Anemia and Vitamin Deficiencies

Fig. 14.9: Erythema multiforme ulceration affecting lips and labial mucosa. Crusting is a classical feature

ROU may be associated with anemia commonly resulting from iron, folate, vitamin B12 deficiencies or due to chronic blood loss. These conditions should be excluded prior to the diagnosis of RAU or treated in primary care. In patients with ROU (mimicking RAU) it is important to check for a history of anemia, evidence of blood loss, heavy menstrual periods, hemorrhoids or a vegetarian diet. General signs and symptoms of anemia may be present: lethargy, fatigue, shortness of breath,

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koilonychia, and difficulty in swallowing. Oral signs and symptoms include pallor of mucosa, depapillation of tongue and angular cheilitis in addition to ROU. Investigations should include a full blood count and serum micronutrient estimations (see Chapter 22). ROU may be present even before overt anemia develops and therefore the hemoglobin estimate may be normal in such cases. Measurement of serum ferritin, folate levels in serum and RBC and serum B12 estimates are therefore required. Deficiencies of B1, B2 and B6 are also rarely reported as predisposing to ROU. Appropriate supplementation should be undertaken and hematological parameters monitored to ensure any deficiency is corrected.

GI Tract Diseases A small cohort of patients initially presenting with RAU may on investigation be found to have these GI tract disorders. Patients with inflammatory bowel disease may develop ROU. GI tract diseases of significance are: • Crohn’s disease • Ulcerative colitis • Coeliac disease. In these GI tract disorders, whether the link to ROU is related to immunologic mechanisms or nutritional deficiencies resulting from malabsorption is unknown. Patients with ulcerative colitis may present with pyostomatitis vegetans and the diagnosis needs to be confirmed by biopsy. Histology reveals a significant eosinophil response, and formation of intraepithelial miliary microabscesses.

HIV-associated ROU

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ROU is common in patients with HIV disease. HIV-seropositive patients with CD4+ lymphocyte counts below 200 cells/mm3 are more likely to have recurrent major aphthae. In HIV-infected individuals, these ulcers occur more frequently, last longer and produce more painful symptoms than in immunocompetent persons. Oral biopsy of an ulcer is required for prolonged nonhealing ulcers in order to exclude the possibility of deep fungal infections (e.g. CMV-associated disease). The management is different to RAU, for example, thalidomide

Fig. 14.11: Chronic ulcerative stomatitis affecting dorsal tongue

therapy is beneficial and is discussed later in this chapter.

CHROnIC ULCERATIVE STOMATITIS This is an immunologically mediated often recalcitrant condition that produces chronic painful oral ulceration. Tongue (Fig. 14.11) and gingivae are the most common affected sites. It is difficult to diagnose clinically or histologically and fairly refractory to therapy. Direct immunofluorescence studies reveal a unique pattern of IgG immunoglobin deposition (binding) to nuclei of oral keratinocytes, mostly seen in the basal areas of the epithelium. The condition may represent a variant of Crohn’s disease (regional ulcerative enteritis) as such is resistant to local therapy. High dose steroid therapy, mycophenolate mofetil may be tried. The literature indicates hydroxychloroquine (plaquenil) may be helpful. For this reason its important to distinguish CUS from other ROU as the condition is nonresponsive to steroids.

SynDROMES ASSOCIATED wITH ROU Other systemic conditions/syndromes associated with ROU include MAGIC (mouth and genital ulcers with inflamed cartilage) syndrome, FAPA syndrome (periodic fever, aphthous ulcers, pharyngitis and cervical adenitis) and Sweets’ syndrome (fever and leukocytosis, recurrent skin eruptions, particularly localized to dorsal hands or upper neck and aphthous-like oral ulcers, arthritis

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DRUG-InDUCED RECURREnT ORAL ULCERATIOn Antineoplastic medications cause ulcerative stomatitis in a majority of patients receiving therapy for acute or chronic leukemia. The likely mechanism is accelerated detachment of oral epithelial cells. Antineoplastic drugs associated with stomatitits include methotrexate, 5-fluorouracil, doxorubicin, melphalan and hydroxyurea. Predicting which patients are most likely to manifest stomatitis is not possible. Several studies reported well circumscribed, single or multiple ovoid-shaped oral ulcers resembling either aphthous stomatitis or herpetic lesions located mostly on nonkeratinized mucosa. Also noted in patients receiving mTOR inhibitor therapy for advanced cancers. Sometimes the effect is local such as placement of an aspirin tablet or cetiprin. Other examples of medications causing ROU include antimicrobials (sulfonamides and tetracyclins, didanosine, foscarnet), griseofulvin, nonsteroidal anti-inflammatory drugs (e.g. indomethacin, salicylates, gold salts, naproxen), D-penicillamine, barbiturates, phenytoin and quinidine. Cardiovascular medications including antihypertensives can cause oral ulceration—e.g. Captopril. More recently elderly patients on nicorandil (on doses above 20 mg/day) given for the treatment of unstable angina has attracted attention of specialist centres due to a flux of patients with ROU caused by this medication. A recent study has reported the visual assessment of photographs of nicorandil-associated lesions by 60 dermatologists and the outcome was that most regarded these ulcers as nonaphthous in appearance. They have some similarities with major aphthous ulcers in that they are large and have a protracted healing time, but they tend to lack the yellow base and erythematous halo that are usually associated with aphthous ulcers. These drug-induced ulcers have a punched out appearance which is not seen in aphthous

Fig. 14.12: A drug-induced ulcer (caused by nicorandil) with an aphthous like appearance. Note: Absence of erythema in the margins of the ulcer

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and myalgia). Stevens Johnson syndrome (SJS) referred to earlier-results in wide-spread superficial oral ulceration with involvement of other mucosal sites and skin eruptions.

ulceration. Most cases of nicorandil-induced ulceration that have had biopsies of their lesions carried out demonstrated nonspecific ulceration. Some drug-induced ulcerative lesions may mimic erythema multiforme like lesions particularly in SJS, pemphigus/pemphigoid like reactions or present as nonspecific RAU like ulcers (Fig. 14.12). Drugs associated with or causing SJS include all forms of sulfonamides, trimethoprim-sulfamethoxazole, nonsteroidal anti-inflammatory agents, penicillins, anticonvulsants such as barbiturates and carbamazepine, valproic acid, allopruinol and terbinafine. The cytotoxic T-cell response in EM/SJS is presumably against keratinocytes expressing drug antigens. Thus a complete drug history at the initial assessment is essential in formulating a differential diagnosis of ROU.

MAnAGEMEnT Therapy for recurrent aphthous ulcers (RAU) should concern pain relief, promotion of healing and to reduce recurrence. At the outset the roles of stress and trauma should be assessed. Before initiating medications for RAU, clinicians should determine whether well-recognized causes are contributing to the disease, in which case the presenting disorder will not be classified as RAU. Screening tests for allergies and nutritional deficiencies should be performed. Skin-patch tests for allergies to food

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additives, flavoring agents and essential oils may be helpful. A gluten-free diet has shown success in reducing ROU episodes both in the presence and in the absence of celiac disease. Hematologic testing (see Chapter 22) should be considered in patients with a history of ROU since patients with nutritional deficiencies respond well to replacement therapy. Once these initial tests have excluded any underlying disorder the group with RAU may be managed to help their symptoms. The therapy of RAU involves both an empirical as well as a scientific approach. The primary goals of therapy for RAU are relief of pain to reduce intensity of pain, reduction of ulcer duration, and restoration of normal oral function. Secondary goals include reduction in the frequency and severity of recurrences and maintenance of remission. There are few double-blind, placebo-controlled trial of drugs (topical or systemic) used in the treatment of RAU but only few have shown any significant benefit.

Topical Agents For minor RAU viscous lidocaine (2%) provides symptomatic relief. Utility of both antibiotic (e.g. tetracycline) and antiseptic (e.g. chlorhexidine) mouthwashes have been studied in the management of RAU. These agents tend to help in healing thus reducing the duration of ulcers. The time required for healing of aphthous ulcers has been correlated with the ability of antimicrobial mouthwashes to reduce the population of oral mucosal flora. Topical corticosteroids (Table 14.3) are usually prescribed for patients with RAU but only a few of these therapies have been tested in a randomized placebo-controlled trial. An appropriate topical corticosteroid is selected based on the size of the ulcers (minor or major) as well as the severity of symptoms that are present. Minor aphthae should be treated with low-to-mid-potency agents. Major lesions that may affect most parts of the mouth including keratinized mucosa need to be treated with mid-to-high potency agents (Table 14.3). Most cases benefit by regular topical use of steroids (combined with antiseptic and pain relieving mouth rinses) but few atypical cases, particularly

among adults, may fail to respond to local therapy. Topical corticosteroid use in patients with RAU is intended to limit the inflammatory process associated with the formation of aphthae. Corticosteroids may act directly on T lymphocytes or alter the response of effectors cells to precipitants of immunopathogenesis. Topical corticosteroids of benefit are given in Table 14.3 and the appropriate steroid strength should be selected as needed. Only two double-blind, placebo-controlled trials have evaluated the efficacy of topical corticosteroids for RAU. These trials tested the application of betamethasone gel or beclomethasone aerosol spray to ulcers four times daily for four to six weeks. In both trials there were significant reductions, compared with placebo, in ulcer duration and pain severity. No-changes in the frequency of RAU were noticed. Two nonplacebo controlled trials found no significant differences between triamcinolone ointment or betamethasone tablets and adhesive vehicles and orabase in the frequency and duration of severe RAU. A single-blind, placebocontrolled trial involving fluocinonide ointment was performed in patients with minor and ƒ Table 14.3 Topical corticosteroids for use with RAU • Triamcinolone acetonide 0.1 percent paste applied with a dry finger to lesional sites after meals 4 times daily • Soluble prednisolone tablets, 5 mg dissolved in 15 mL of water and used as a mouthrinse 3 times daily • Betamethasone sodium phosphate (500 mcg dissolved in 10 of water) used as a mouthrinse up to 3 times daily • fluticasone propionate spray (50 mcg per puff ), directed to affected areas up to 3–4 times daily • Beclometasone spray (100 mcg per puff ), sprayed 3–4 times daily on affected sites • Clobetasol ointment (0.05%) 2 mL applied to painful areas 3–4 times daily • fluticasone cream (0.05%) applied to painful sites 3–4 times daily • fluticasone spray (50 µg; 2 puffs 4 times daily)

existing lesions are not controlled with topical agents, a specialist opinion needs to be sought to consider alternative systemic therapies. Major RAU and nonhealing ROU may benefit by an intralesional corticosteroid injection and this approach should be tried prior to commencing systemic drugs.

Systemic Therapy Systemic agents used in the past are listed in Table 14.4. In general these agents are only for second line of treatment when topical therapies have failed and reserved for complex or atypical RAU. Primary outcomes expected of systemic therapy include: • Control of pain by reducing inflammation • Reducing episode duration by promoting healing of ulcers • Reducing episode frequency of RAU.

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major RAU. Flucinonide ointment significantly reduced ulcer duration, but ulcer frequency and subjective improvement were the same as for adhesive vehicle (orabase). It is possible to cause hypothalamicpituitary-adrenal axis suppression with use of high potency corticosteroids. Potential absorption of the drug should be evaluated by the estimation of serum cortisol levels on a regular basis. Secondary opportunistic fungal infection may occur during therapy and all patients should be assessed for any raised candidal counts in the oral cavity and appropriately treated with antifungals. Mandatory screening procedures for patients on long term topical steroid therapies is recommended. Nonresponse to therapy should be evaluated by ascertaining patients’ compliance and also that the local agent is reaching the target areas. Nonsteroidal topical agents are also available. One such preparation is amlexanox (aphthasol) available as a 5 percent topical oral paste that has been developed for treatment of RAS. This drug has been approved by the FDA for RAS. It has anti-inflammatory properties and has been shown to accelerate healing of RAS. A recent double-blind study demonstrated its effectiveness in reducing ulcer erythema, pain, and lesional size. Topical medications, such as antimicrobial mouthwashes and topical corticosteroids and other adhesive agents, can achieve the primary goals but have not been shown to alter recurrence or remission rates. All therapies are palliative, and none result in permanent remission. Intralesional injections of long acting corticosteroids are often effective in patients with lesions that are refractory to topical corticosteroids. When

Systemic Corticosteroids Systemic administration of steroids is reserved for the treatment of severe or recalcitrant disease when frequent recurrences of RAU are reported or when a patient is never ulcer-free. A low dose systemic corticosteroid, for example prednisolone 30 mg/day for a couple of weeks, then reducing by 5 mg/day to titrate to a final dose of 5 mg/day or every other day until remission have been advocated. In the author’s experience longer term management on systemic steroids is rarely effective for RAU without causing serious side effects. At doses tolerated, those patients with more severe forms of atypical ulcers develop frequent crops needing to raise the dose of prednisolone too often.

Box 14.3: Therapy for RAU Key features helpful in management • Topical and intralesional corticosteroids are the standard therapies effective in a majority of patients • Various systemic therapies are based on mostly open arm trials conducted on small number of cases • The therapeutic ladder for severe aphthous ulceration ranges from topical and systemic steroid therapy through pentoxifylline, colchicine, azathioprine to oral thalidomide therapy • when potent therapies are prescribed careful steps are needed to prevent pregnancy (e.g. thalidomide) and monitoring for neuropathy (colchicines and thalidomide) or liver toxicity (azathioprine) • A steroid screen should be undertaken regularly for those on both topical and systemic steroids.

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ƒ Table 14.4 Systemic drugs used in clinical trials Immunomodulatory/anti-inflammatory

Antimicrobials • Subantimicrobial doxycycline (20 mg BD) • Tetracycline (250 mg dissolved in 10 mL water; QDS)

Supplements • Longovital (herbal + vitamin) • Longovital (herbal alone) • Propolis (500 mg OD) • Vitamin B12 • Multivitamin

Alternative therapy

Prophylaxis with colchicine has been reported in several case series by authors who reported a favorable effect of this agent on patients with RAU. One RCT using colchicine (0.5 mg three times/day) compared to placebo failed to demonstrate a significant effect. Several possible mechanisms of action of the drug are discussed: it prevents recruitment of polymorphonuclear cells, interferes with their microtubular function and causes an inhibitory effect on the expression of adhesion molecules preventing the migration of white blood cells across blood vessel walls. The dose recommended is 1.5 mg/day, but it is prudent to start with a lower dose. Colchicine blood levels should be examined and toxic symptoms like myopathy and neuropathy should be regularly monitored, preferably at 3 monthly intervals. It may have potential adverse effects on male fertility when given long term to young males, and therefore sperm analysis is recommended, and the reproductive potential of treated patients carefully monitored. Most patients tolerate colchicine well, except for GI symptoms and experience a marked decrease in the frequency of oral ulceration and it is easy to use.

• Camelthorn • Homeopathy Source: Adapted from Cochrane Database of Systematic Reviews 2005; Issue 3

Several recent reports have detailed the effectiveness of other systemic agents useful to treat oral aphthae that are nonresponsive to local steriods. These reports are all open label trials of steroid sparing agents tried on small numbers of patients.

Pentoxifylline This is a medicine which is used in peripheral vascular disease. Results from one RCT run for 60-day suggested pentoxifylline (300 mg, 3 times/day) may have some benefit in the treatment of RAU, but the benefit is limited.

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Colchicine

Azathioprine Azathioprine, and mycophenolate mofetil have been reported to benefit patients with recalcitrant disease. Continued therapy is required to maintain the remission. Azathioprine given orally at a dose of 1 mg/kg is well tolerated but before instituting therapy selection of those who are able to metabolize the drug by performing a TPMT assay is recommended. Those with enzyme levels above 7 are usually able to tolerate this agent. Liver and hematological toxicity should be assessed with regular full blood counts and liver function tests to assess serum levels of liver transaminases. If the level of GGT or AST are more than doubled it is generally ill advised to continue therapy. The British Association of Dermatologists (BAD) has recently issued guidelines on use of azathioprine. Mycophenolate mofetil has fewer adverse side

Thalidomide Thalidomide given per orally has recently been used for patients with major RAU or atypical ulcers in HIV seropositive subjects. NO RCTs are reported. Mechanism of action is not clear but believed to involve a decrease in inflammatory mediators, particularly tumor necrosis factor (TNF)-α and Fas-ligand. Thalidomide has been shown to selectively suppress NF-(Kappa) β activation induced by inflammatory mediators. Atypical major oral ulcers are highly angiogenic. Thalidomide may act to heal by inhibiting angiogenesis and promoting re-epithelialization. Open-label trials suggest that it is highly effective, and may result in an increase in the lymphocyte count and a decrease in the C-reactive protein level. Induction with 100 to 200 mg daily at bedtime results in improvement in 90 percent of the patients who are able to tolerate the drug. Most units however, recommend the lower dose for ROU of 50 mg a day. Toxicity commonly associated with thalidomide use includes drowsiness, headache, weight gain, amenorrhea and dizziness. Patients should be counseled on the risk of birth defects and those in childbearing ages advised to use two simultaneous forms of effective birth control starting at least 4 weeks before starting therapy and a pregnancy test performed before starting treatment. Drowsiness and dizziness may persist during the initial stages of therapy. Thalidomide neuropathy, usually sensory, and often associated with proximal weakness may limit the ability of patients to continue thalidomide on a long-term basis. Neuropathy may be reversible, but there are patients whose neuropathy has progressed despite stopping the drug. Nerve conduction (EMG) studies should be performed at the onset of therapy and

periodically to screen for evidence of toxicity by checking for sensory responses. The nerve responses of superficial peroneal and sural nerves in both lower legs are evaluated by EMG for thalidomide monitoring. Antithrombotic prophylaxis for patients on thalidomide has been discussed but rarely indicated at the lower maintenance dose. For reasons of toxicity topical thalidomide therapy has been advocated recently with some short term success. Thalidomide is a potent teratogen and accordingly a strict program to prevent the chance of pregnancy in patients exposed to the drug should be initiated at onset and regularly monitored by the responsible physician. Unfortunately the response to thalidomide is not durable in most patients therefore longterm, low-dose maintenance therapy may be necessary.

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effects than azathioprine but its efficacy is less well-known. Mycophenolate mofetil is administered orally in a dose of 2 to 3 g daily. It is generally well tolerated, but gastrointestinal side-effects may limit its use in some patients. They are both slow acting and it may take at least 6 to 8 weeks to start to see the benefits.

Levamisole Levamisole is an immunopotentiating agent that has demonstrated the ability to normalize the CD4+ cell/CD8+ cell ratio and improve symptoms in RAU patients. Correction of T-suppressorcell deficiency may reduce the inflammatory response resulting from cellular immunity and promote resolution of aphthae. Seven placebocontrolled clinical trials assessed the efficacy and safety levamisole in patients with RAU. Four of the studies showed a reduction in the frequency and duration of aphthous ulcers during levamisole treatment with ulcer recurrences decreasing by half in up to 43 percent of patients. In six trials a complete absence of ulcers was found at the conclusion of the study in 16 of 144 patients receiving levamisole. Levamisole was well tolerated in a majority of the patients. The most frequent adverse effects were dysgeusia (21%) and nausea (16%).

Other Therapies Other therapies that have been used in open trials include cromoglycic acid, bio-quinine, and zinc sulphate. No RCTs are published on these agents.

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Longovital a herbal-based vitamin/mineral preparation has been reported to provide benefit but the evidence is limited. Some benefit is reported by trying out toothpaste without sodium lauryl sulfate, antibacterial mouthwashes to reduce secondary infection and avoidance of foods that trigger or exacerbate the ulcers. Further trials are needed to ascertain these claims. Future trials should assess any reduction in: the median pain score, ulcer size, number of ulcers, total number of ulcer episodes and ulcer-free periods.

SELf-ASSESSMEnT QUESTIOnS 1. Give a classification of recurrent oral ulceration. 2. How would you distinguish RAU from other recurrent oral ulcers? 3. Explain the features that differentiate the three types of RAU. 4. Write an appraisal of etiopathogenesis of RAU. 5. What outcomes do you expect when initiating treatment for RAU? How do you assess treatment success?

6. What systemic treatments are available for RAU that do not respond to topical steroids? Explain the mechanisms of action. 7. During an initial consultation how would you eliminate systemic disease as a cause of ROU? 8. How would you monitor a patient given corticosteroid therapy at frequent intervals to treat complex aphthosis?

SUGGESTED READInG 1. Baccaglini L, et al. Urban legends: recurrent aphthous stomatitis. Oral Dis. 2011;17:755-70. 2. Eisen D, Lynch DP. Selecting topical and systemic agents for recurrent aphthous stomatitis. Cutis. 2001;68:201-6. 3. Escudier M, Began J, Scully C. Behcet’s disease. Oral Dis. 2006;12:78-84. 4. Jurge S, Kuffer R, Scully C, Porter SR. Recurrent aphthous stomatitis. Oral Diseases. 2006;12:1-21. 5. Mignogna MD, Fortuna G, Leuci S. Oral pemphigus. Minerva Stomatol. 2009;58:501-18. 6. Porter SR, Hegarty A, Kaliakatsou F, Hodgson T, Scully C. Recurrent aphthous stomatitis. Clinics in Dermatology. 2000;18:569-78.

Chapter

15 Vesiculobullous Disorders Paula Farthing

Chapter Outline Diseases Characterized by Intraepithelial Separation • Pemphigus Vulgaris • Paraneoplastic Pemphigus • Pemphigus Foliaceous • IgA Pemphigus Diseases Characterized by Subepithelial Separation • Bullous Pemphigoid • Mucous Membrane Pemphigoid • Epidermolysis Bullosa • Epidermolysis Bullosa Aquisita • Dermatitis Herpetiformis

Linear IgA Disease Angina Bullosa Hemorrhagica Erythema Multiforme • Erythema Multiforme Minor • Erythema Multiforme Major Steven-Johnson Syndrome Toxic Epidermolysis Necrosis Syndrome Herpes Associated Erythema Multiforme Self-assessment Questions

OrAl MEDIcInE AnD PAtHOlOgy: A guIDE tO DIAgnOsIs AnD MAnAgEMEnt

15 IntrODuctIOn Vesiculobullous disorders are characterized by the formation of fluid filled blisters which usually burst to leave areas of erosion or ulceration. In addition to the oral mucosa, they may affect other mucous membranes including genital, conjunctival, esophageal and laryngeal and many also affect the skin. In broad terms, there are two main causes: infective and autoimmune. The infective causes are almost all viral and most are caused by members of the Herpes family, e.g. herpes simplex and zoster. These are outlined in detail in Chapter 16 and will not be considered further here. The others are usually the result of autoantibody production against components of the epithelium and basement membrane, so called type 2 hypersensitivity reactions. Much work over recent years has been directed at identifying the antigens which are targeted by the autoantibodies. Broadly, they fall into two groups: those which target desmosomes, the structures which hold epithelial cells together and those which target hemidesmosomes and components of the basement membrane, which bind the epithelium to the underlying connective tissue. This research has lead not only to an increased understanding of epithelial and basement membrane structure but also has started to explain the differing clinical presentations of these diseases. ƒ Table 15.1 Vesiculobullous disorders classified by the level of separation

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Intraepithelial separation

Subepithelial separation

Pemphigus vulgaris

Bullous pemphigoid

Pemphigus foliaceus

Mucous membrane pemphigoid

Paraneoplastic pemphigus

cicatricial or ocular pemphigoid

IgA pemphigus

linear IgA Disease Dermatitis herpetiformis Epidermolysis bullosa acquisita

Fig. 15.1: Widespread erosions and ulceration affecting the buccal mucosa in a patient with pemphigus vulgaris

Vesiculobullous disorders may be classified according to the level of separation within the mucosa (Table 15.1): a. Intraepithelial separation b. Subepithelial separation. This separation is the result of which structures of the oral mucosa are targeted (Fig. 15.1). Intraepithelial separation occurs when autoantibodies target components of the desmosomes and subepithelial separation, when they target hemidesmosomes and basement membrane components.

DIsEAsEs cHArActErIzED By IntrAEPItHElIAl sEPArAtIOn Pemphigus Pemphigus is a group of autoimmune mediated disorders characterized by autoantibodies targeting the desmosomes. They are potentially life threatening and prior to the introduction of systemic glucocorticosteroids were often fatal. The most common variant affecting the oral mucosa is pemphigus vulgaris.

Pemphigus Vulgaris Pemphigus vulgaris is a relatively rare disorder that affects between 1 to 9 per 1×106 of the population. Unlike most autoimmune diseases, it appears to affect men and women equally and occurs most commonly in third to fifth decades.

Clinical Features Pemphigus vulgaris usually affects the oral mucosa initially (up to 70% cases) and lesions affect the posterior buccal mucosa, the gingivae and palate most commonly although any area may be affected. Initial lesions are flaccid, fragile vesicles or bullae but these easily rupture to leave ragged erosions which may ulcerate. Both the free and attached gingivae may be affected and appear fiery red and show desquamation. This condition is referred to as desquamative gingivitis but is not specific to pemphigus vulgaris and is also seen in lichen planus and mucous membrane pemphigoid. Indeed several studies have shown it is more common in the latter conditions. Patients with pemphigus vulgaris often complain of pain and difficulty with eating as well as a history that lesions develop following trauma. Lesions of pemphigus vulgaris may be restricted to the oral mucosa but sometimes affect the larynx and pharynx and with time almost always spread to involve the skin. Skin lesions are characterized by flaccid, fragile bullae which may occur anywhere on the body. Initially they tend to affect the head and neck but then spread to the trunk and flexor areas of the limbs. They often rupture to leave painful erosions and ulcers. Without treatment the disease is fatal usually due to loss of fluids and secondary infection.

other vesiculobullous disorders and to confirm the presence of autoantibodies in the tissues as well as the blood. It is important to biopsy peri-lesional rather than lesional tissue and either send it fresh to the laboratory or freeze it immediately. Blood should be placed in a plain tube and allowed to clot. Immunofluorescent tests detect autoantibodies in the tissues (direct immunofluorescence) and in the serum (indirect immunofluorescence) but they can only be carried out on fresh tissue as fixation destroys the antigens they detect. The basis of the test is that anti-human antibodies raised in mice against the Fc (tail) portion of human IgG, IgA, IgM and C3 (complement), are reacted with the patient’s biopsy. These anti-human antibodies have been tagged with a fluorescent dye which can be identified by fluorescent microscopy. In a patient with pemphigus vulgaris a characteristic fish scale pattern of IgG and C3 is seen surrounding the cells of the prickle cell layer (Fig. 15.2). In indirect immunofluorescence the basis of the test is the same except that monkey esophagus or fresh normal oral mucosa is incubated with the patient’s serum prior to the addition of the antihuman antibody. Although the immunofluorescence test can localize the antibodies to either the desmosomes or subepithelial components, other tests are necessary to identify the antigens more precisely. These include immunoblotting, enzyme linked immunoabsorbant assay and

15 VEsIculOBullOus DIsOrDErs

Higher incidences are seen in particular races such as Ashkenazi Jews (up to 32 per 1×106) and in individuals of Mediterranean and South east Asian origin. This genetic predisposition appears to be related to human leukocyte antigen (HLA) Class II phenotype as is common with many autoimmune diseases. In Ashkenazi Jews those with HLA-DRw4 particularly DRB1 (*0402 and *0401) alleles are susceptible and in white caucasians, Pakistani and Japanese patients, the rare HLA-DQB1 (*0503) allele confers susceptibility.

Diagnosis Diagnosis is made on the basis of history and examination, biopsy and blood tests. Biopsy is necessary to distinguish the condition from

Fig. 15.2: Deposition of Igg around the periphery of cells in the prickle cell layer, so-called fish scale pattern in a patient with pemphigus vulgaris

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immuno precipitation. These tests are not usually used on a routine basis to confirm diagnosis as they require specialist laboratory techniques. Their basis is that they use epithelial cell lysates or recombinant proteins which are then reacted with the patient’s serum.

Histopathology The oral mucosa shows evidence of a bullae and loss of adhesion between epithelial cells in the prickle cell layer. This occurs just above the basal cell layer and the separation is termed acantholysis. The epithelial cells appear rounded, sometimes forming groups or individual cells in the bullae. These cells are known as Tzank cells and before the advent of

A

B

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Figs 15.3A and B: H and E stained section of mucosa from a patient with pemphigus vulgaris. Note: the intraepithelial separation with the basal cells remaining attached to the basement membrane

immunofluorescent testing were important in the diagnosis. The basal cells remain attached to the basement membrane and have been likened to a row of tombstones. There may be a mild inflammatory infiltrate in the lamina propria. (Figs 15.3A and B) In more advanced cases the superficial epithelium may have been lost leaving only the basal cells although often there may be total loss of the epithelium resulting ulceration. In these cases diagnosis is difficult or impossible explaining why it is important to biopsy perilesional tissue. The diagnosis is almost always confirmed by immunofluorescence tests.

Pathogenesis Pemphigus vulgaris is the result of circulating autoantibodies produced against components of the desmosomes (Fig. 15.4). Desmogleins are cadherin-like proteins which cross the intercellular space between adjacent epithelial cells and almost all patients have antibodies to desmoglein 3 (Dsg3) and some in addition, against desmoglein1 (Dsg1). A small subset have antibodies to the α 9-acetylcholine receptor. The antigens targeted by the antibodies in any given patient correlate to the distribution and severity of the disease. Patients with antibodies against Dsg3 have lesions predominantly affecting the oral mucosa with few skin lesions. In contrast patients with antibodies against Dsg1 have predominantly skin lesions but in this case, the separation is towards the top of the prickle cell layer- resulting in pemphigus foliaceous. Patients with both Dsg1 and 3 antibodies have both mucosal and skin lesions. This distribution is the result of differing proportions and distribution of Dsg 1 and 3 in oral mucosa and skin. Almost all the antibodies are IgG in class and in active disease they are IgG4. However, IgA antibodies are present in a rare variant— IgA pemphigus. There is a considerable amount of evidence to show that these antibodies are the cause of the disease. Levels of circulating autoantibodies correlate with disease severity and purified antibodies from patients with pemphigus vulgaris cause the disease when injected into mice. However the mechanisms which result in separation are not clear although

15 VEsIculOBullOus DIsOrDErs Fig. 15.4: structure of a desmosome, hemidesmosome and basement membrane zone in stratified squamous epithelium. Dsg = desmoglein, Dsc = desmocollins

it has been postulated to involve release of proteases and proinflammatory cytokines from keratinocytes. Complement fixation occurs in almost all cases but is thought to amplify the disease rather than playing an essential role since acantholysis still occurs in complement depleted mice. The trigger for the development of pemphigus is not known but it has long been postulated that cell-mediated immunity may be involved. The production of antibodies by B-cells is controlled by CD4 positive T-cells and T-cells autoreactive against Dsg3 have been detected in patients with pemphigus. However, these cells are also found in healthy individuals but in disease it may an imbalance between autoreactive Th2-type T cells and regulatory Th1 cells which is important since the later are only rarely detected in disease.

Management Following diagnosis, the mainstay of treatment is immunosuppression. For localized oral lesions, topical or intralesional corticosteroids may be used but for more severe disease

systemic corticosteroids are necessary and indeed this is the mainstay of treatment. Steroid sparing agents such as dapsone, azothiaprine and methotrexate are useful to reduce steroid dosage. Levels of Dsg3 and 1 antibodies correlate with disease severity and measuring the titers of each against the clinical symptoms can be useful in delivering minimum dosages to control symptoms. In some patients the initial high doses of steroids are sufficient to keep the disease under control and with time can be reduced. Indeed, some patients undergo complete remission and the proportion of these increases with time. In others, however, longterm steroids are necessary to keep the disease under control. A positive long-term response appears to be related to the initial severity and extent of the disease as well as early response to treatment. Other forms of treatment which have been used include plasmapheresis and the use of intravenous immunoglobulins. For steroidresistant pemphigus vulgaris the monoclonal anti-CD20 antibody, rituximab used as a single agent has been shown to be an effective therapy.

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Box 15.1: Pemphigus Key features useful in diagnosis • rare, 3rd-5th decade, M=F, HlA-Drw4 association and Ashkanazi Jews • Widespread erosions and intraepithelial bullae affecting the oral cavity and/or skin • Autoimmune disease: Autoantibodies against desmoglein in desmosomes, detected by immunofluorescence • Diagnosis by biopsy of paralesional tissue and blood tests • Managed by corticosteroids and steroid sparing agents: Azothiaprine.

Paraneoplastic Pemphigus Paraneoplastic pemphigus is a rare form of pemphigus which, as its name suggests, occurs in association with underlying malignant disease. In a high proportion of cases this is hematological in origin and includes lymphomas and leukemia. Nonhematological causes include adenocarcinoma, squamous cell carcinoma and sarcomas. It has been suggested the disease is renamed paraneoplastic autoimmune multiorgan syndrome because of the multitude of clinical features and disease associations.

Clinical Features In most cases, the clinical features resemble those of pemphigus vulgaris and include vesicles and bullae and widespread erosions and ulcerations. Mucosal lesions are an almost constant feature and may involve multiple sites including the naso- and oropharynx, conjunctiva and anogenital region. The skin is often also affected with blisters on the upper trunk, head and neck and extremities. Some lesions appear lichenoid and are composed small red flat topped papules particularly in children but in other cases, target lesions resembling erythema multiforme or graft versus host disease may be evident. The disease can occur at any age and there is no gender predilection. However, because of the association with malignancy the average age is in the 7th decade.

Histopathology and Pathogenesis 350

The histopathological features often resemble those of pemphigus vulgaris and show

intraepithelial acantholysis and bullae formation with deposition of IgG and C3 in an intercellular distribution evident on direct immunofluorescence. In some cases the lesions may in addition resemble pemphigoid with subepithelial separation and these also show IgG and C3 deposition at the basement membrane zone. Others appear lichenoid with a dense band like inflammatory infiltrate in the upper lamina propria. This variety in the histopathological features is reflected in the antigens targeted in paraneoplastic pemphigus. These include Dsg1 and 3, desmoplakin which is an intracellular component of desmosomes as well as envoplakin and periplakin (Fig. 15.4) Some antibodies also target components of the hemidesmosomes including BPA1 and plectin. The reasons for this widespread autoantibody development are not clear but as in pemphigus, it presumably reflects problems with immune regulation.

Management The disease is often fatal and may be difficult to control. Patients often die from the mucosal and skin lesions rather than the underlying malignancy. This is particularly true with low-grade malignant disease. Hig-dose corticosteroids are often used initially with the introduction of steroid sparing agents later. Immunosuppression remains the mainstay of treatment. Box 15.2: Paraneoplastic pemphigus Key features useful in diagnosis • similar clinical and histological features to pemphigus vulgaris • Associated with underlying malignant disease • Often fatal.

Other Variants of Pemphigus Pemphigus Foliaceous This rare variant usually only affects the skin and is characterized by IgG autoantibodies against Dsg1 which is expressed predominantly in the upper part of the prickle cell layer in the epidermis but at very low levels in the oral

IgA Pemphigus IgA pemphigus is characterized by deposition of IgA antibodies around the surface of keratinocytes in the prickle cells layer. Histologically, numerous intraepithelial bullae are seen filled with neutrophils. Two clinical forms of the disease are recognized SPD or subcorneal pustular dermatosis, and intraepidermal neutrophilic IgA dermatosis (IEN). Lesions are characterized by pustules forming annular patterns on the skin. Mucosal lesions may be present and show widespread ulceration. The target is desmocollins in SPD type but more heterogenous antibodies are present in IEN type.

DIsEAsEs cHArActErIzED By suBEPItHElIAl sEPArAtIOn There are a number of immune-mediated conditions in which autoantibodies are directed against components of the basement membrane zone. This interaction leads to separation of the entire thickness of the epithelium from the underlying connective tissue resulting in a subepithelial bullae. These conditions differ from one another in the antigens that are targeted in the basement membrane zone and this in part explains their differing clinical presentations. They are listed in Table 15.2.

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mucosa. Acantholysis and bullae formation occurs in the upper rather than the lower prickle cell layer of the epidermis and the disease is less severe than pemphigus vulgaris. Skin lesions appear scattered and scaly and may resemble psoriasis. Bullae formation is not obvious clinically and the oral cavity is rarely involved. Patients are managed by corticosteroids.

Bullous Pemphigoid Clinical Features Bullous pemphigoid is the most common subepithelial, blistering disorder affecting the skin and oral lesions are uncommon (10–20% cases). Patients are often elderly and the incidence rises in patients over the age of 60 years. It is characterized by rather tense bullae which

ƒ Table 15.2 Diseases characterized by subepithelial separation Disease

Direct immunofluorescence

Indirect immunofluorescence

Antigen targeted

Bullous pemphigoid

linear Igg and c3 basement membrane zone

circulating Igg in 90% cases

BP180 and BP230

Mucous membrane pemphigoid—oral lesions only

linear Igg and c3 basement membrane zone

low-levels: Igg 18% patients

α6chain of α6β4 integrin

Ocular/cicatricial pemphigoid

linear Igg and c3 at basement membrane zone some cases IgA

low-levels circulating Igg β4 chain of α6β4 7% patients integrin

Mucous membrane and skin pemphigoid

linear Igg/IgA/c3

circulating Igg/A in 80% cases

BP180 and BP230

linear IgA disease

linear IgA at basement membrane zone

circulating IgA high proportion

BP180 and BP230 and unknown antigens

Dermatitis herpetiformis

granular IgA basement membrane zone

none

epidermal transgluataminase 3,

Epidermolysis bullosa aquisita

linear Igg and c3 basemment membrane zone. IgA 10%

circulating Igg 50%

type VII collagen and others unknown

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appear to affect the lower abdomen particularly as well as the inner aspects of the thighs. Because the bullae involve the entire thickness of the epithelium they are less fragile than those of pemphigus vulgaris. Oral lesions are similarly characterized by tense bullae which may affect any area of the mucosa. They rupture to form ulcers.

Histopathology and Pathogenesis Histologically, the lesions are characterized by separation of the entire thickness of the epidermis from the underlying dermis. Typically, accumulations of eosinophils are seen at the tips of the dermal papillae and there is variable inflammation. Direct immunofluorescence shows linear deposition of IgG and C3 at the basement membrane zone in almost all cases. Unlike pemphigus it is difficult to detect circulating autoantibodies using indirect immunofluorescence. The sensitivity of the technique can be increased by using salt-split skin. This results in separation of the epidermis from the dermis through the basement membrane thus exposing more antigens. When this is carried out circulating autoantibodies are found in almost 90 percent of cases. Almost all patients with bullous pemphigoid have autoantibodies directed against two components of the basement membrane zone, so called BP230 and BP180. These were originally identified using immunoprecipitation but they are now recognized as components of the hemi-desmosomes which attach the epithelial cells to the basement membrane. (Fig. 15.4). BP230 is an intracellular component of the hemidesmosome but BP180 is a transmembrane molecule which extends into the lamina lucida where it interacts with laminin 5. BP180 is now known to be Type XVII collagen. As with pemphigus, there is considerable evidence to show that the autoantibodies are responsible for the disease. This includes the observation that the disease can be caused when antibodies are injected into neonatal mice.

Management Topical or systemic corticosteroids are the mainstay of treatment. Severe disease is treated with systemic corticosteroids together with steroid sparing agents such as azathioprine. Occasionally, methotrexate may be used in patients who are unresponsive to steroids. More mild cases are treated topically. Most cases resolve within 2 to 5 years. Box 15.3: Bullous pemphigoid Key features useful in diagnosis • Affects skin>mucosa, elderly patients, tense subepithelial bullae and ulcers • Autoimmune antibodies against hemidesmosomes- antigens (BP230 and BP180) • subepithelial blisters • Management: corticosteroids and steroid sparing agents.

Mucous Membrane Pemphigoid Mucous membrane pemphigoid is a condition that affects the mucous membranes. It was originally known as benign mucous membrane pemphigoid but it is a disease which may carry significant morbidity and the benign suffix has been dropped. Mucous membrane pemphigoid is heterogeneous not only in its severity and the mucous membranes affected, but also by the antibodies which target different molecules in the hemidesmosomes and basement membrane. Several clinical variants have now been recognized.

Clinical Features Patients are usually middle-aged or elderly females in the 5th and 6th decades. The lesions present as tense fluid-filled bullae which may rupture to give widespread ulcers and erosions. In the oral cavity any area may be affected but lesions on the hard and soft palate, buccal mucosa and gingivae are common. (Fig. 15.5). The latter presentation is usually one of desquamative gingivitis. Lesions may

these patients show linear IgG and low levels of circulating autoantibodies.

Fig. 15.5: clinical picture of pemphigoid. Note: the blister formation and erosions affecting the gingivae

be induced by trauma—the so-called Nikolsky sign but this is not specific to pemphigoid and may also be seen in pemphigus. Patients often complain they have difficulty in eating and drinking and that their mucosa is ‘peeling.’ The lesions heal slowly and sometimes lead to scarring. Lesions can spread to the naso-and oropharynx and may result in extreme difficulties with eating and drinking. Problems may arise with scarring and the formation of strictures in severe cases. In some patients, the mucous membranes of the genitalia and rarely the anus are affected. The conjunctiva is commonly affected and initial lesions are characterized by recurrent conjunctivitis which may last for many years. With the development of blisters, the patient may develop symblepharon (fusion of the bulbar and palprebal conjunctiva), inverted eyelashes as well as corneal scarring. This may lead to blindness and is a serious complication. Some patients develop skin lesions but this tends to be only a small proportion. The lesions resemble those of bullous pemphigoid and typically affect the trunk and head and neck.

Mucous membrane and skin pemphigoid: These patients have antibodies against BP180 and 230 antigens. Another variant is recognized which is characterized by antibodies laminin 5 (also known as epiligrin) which binds to BP180 as well as collagen VII. This variant may be associated with an increased risk of internal malignancy.

VEsIculOBullOus DIsOrDErs

Ocular/cicatricial pemphigoid: These patients are characterized by ocular lesions and show IgG antibodies against the β4 integrin subunit. Another group may show IgA antibodies against a 45KD antigen as yet uncharacterized.

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Histology Lesions are characterized by subepithelial separation and in the early stages may be associated by very little inflammation in the underlying lamina propria (Fig. 15.6). Occasional accumulations of neutrophils may seen together with eosinophils but the characteristic eosinophil accumulation seen in bullous pemphigoid is not obvious. In more established lesions accumulations of chronic inflammatory cells including plasma cells may be evident. Direct immunofluorescence may show deposition of IgG, IgM, IgA or C3 at the basement membrane zone in a linear deposition (Fig. 15.7). Circulating autoantibodies are not often seen but as with bullous pemphigoid the sensitivity of indirect immunofluorescence tests may be increased by using salt-split skin.

Variants There are a number of variants recognized depending on the sites affected and also the antibodies identified. The oral variant or oral pemphigoid as its name suggests is characterized by oral lesions only. This group have antibodies against the α6 chain of the α4β6 integrin (Fig. 15.4). On direct immunofluorescence,

Fig. 15.6: subepithelial separation in mucous membrane pemphigoid. the entire thickness of the epithelium has separated from the connective tissue

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Box 15.4: Mucous membrane pemphigoid

Fig. 15.7: Direct immunofluorescence in pemphigoid. note the linear deposition of Igg at the basement membrane zone

Epidermolysis Bullosa Pathogenesis There is considerable evidence that binding of autoantibodies to the hemidesmosomes and the basement membrane zone causes separation. The disease may be transferred passively by injection of antibodies in neonatal animals and these also cause disease in mucosa in organ culture. Blister formation appears to require complement activation and the presence of neutrophils as it does not occur in complement or neutrophil deficient mice. In addition it is thought that proteases may be important.

Management

354

Key features useful in diagnosis • Elderly, 6–7th decade, variable severity and manifestations • subepithelial bullae and erosions affecting mucous membranes • Antibodies against hemidesmosomes and basement membrane zone: BP180, α4β6 integrin, epiligrin • Cicatricial pemphigoid: Affects eyes—may lead to scarring and blindness • low levels circulating antibodies • Managed by topical or systemic corticosteroids.

The mainstay of treatment is corticosteroids and they bring the disease under control very quickly when taken systemically. However, patients with oral lesions may be controlled by topical steroids or sometimes intralesional steroid injections thus avoiding the serious side effects. Before deciding on the appropriate course of treatment, it is important to determine the severity of the disease. Generally, if only the oral mucous membranes are affected then topical steroids should be given. Patients with disease that affects more than one mucosal site are more high-risk and systemic steroids are advocated whilst those with any evidence of ocular lesions should be referred immediately for an ophthalmologist opinion.

Epidermolysis bullosa are a group of disorders characterized by blistering of the skin and occasionally the mucous membranes. One group are inherited and are the result of genetic mutations in components of desmosomes, basement membrane or keratinocytes. They may be divided into simple, junctional and dystrophic types. The simple type is the result of mutations in keratins—intracellular components of keratinocytes. Junctional types show mutations in laminin and the dystrophic forms have mutations in Type VII collagen or in the β4 subunit of the α6β4 integrin. These forms all show evidence of an inherited pattern

Epidermolysis Bullosa Aquisita Epidermolysis bullosa aquisita is an acquired type of epidermolysis bullosa and unlike the inherited types usually although not always affects older individuals. Patients suffer from repeated and chronic subepithelial blistering which affects the skin and the oral mucous membrane in up to 50 percent of cases. It is relatively rare and accounts for about 5 percent of all cases of patients with antibodies against the basement membrane zone.

Clinical Features It appears heterogeneous and some cases resemble the dystrophic form of inherited

Box 15.5: Epidermolysis bullosa aquisita

Fig. 15.8: Mucosal lesion in epidermolysis bullosa aquisita. Note: the ulceration and erythema on the tongue

epidermolysis aquisita. This may be because the autoantibodies target the same molecule which is mutated in the hereditary forms—Type VII collagen. Inflammatory and noninflammatory forms have been recognized. In the latter the skin is extremely fragile and trauma induces blisters and erosions. This may result in atrophy and the formation of milia. In patients with inflammatory type disease, it may be difficult to distinguish the condition from bullous pemphigoid and in these patients the flexural surfaces of the extremities are involved. The mucous membranes are also particularly affected (Fig. 15.8).

Histology Histological changes include subepidermal separation which may or may not be associated with an inflammatory infiltrate in the underlying dermis. Direct immunofluorescence shows linear IgG and C3 deposition in the basement membrane zone and immunoelectron microscopy shows this is deposited in the sublamina densa region. Circulating autoantibodies are also present in the disease and are deposited on the dermal side of salt split skin. In less than 10 percent of cases, there may be deposition of IgA at the basement membrane zone.

Management Patients are usually treated with high-dose corticosteroids but often the results are short

Key features useful in diagnosis • Acquired subepithelial fragile blisters, affecting skin and mucosa • Wide age range • Antibodies against type VII collagen • Managment: High dose corticosteroids.

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lived and the disease may return. As a result, management can be challenging. Other adjunctive therapies include dapsone and colchicine as well as methotrexate. Patients should be advised to avoid trauma, if possible and avoid eating hard foods.

Dermatitis Herpetiformis This disease was first described by Louis Duhring in the late 19th century and it is characterized by an intensely itchy skin rash. In recent years, it has been recognized that the disease is associated with celiac disease although in many patients this may be subclinical.

Clinical Features Patients are often young and the most common age at presentation is between 20 to 40 years although it may occur at any age. The lesions are characterized by vesicle or occasionally bullae formation which may become eroded or crusted. They may be grouped together, hence the term herpetiformis. They are intensely pruritic and in some patients are characterized by prodromal burning and stinging. The flexor surfaces are usually affected but the face, hairline and neck may also be involved. The oral cavity is rarely affected. Almost all patients have celiac disease: gluten sensitive enteropathy. There is a genetic basis for the disease and patients have an increased incidence of HLA-A1, HLA-B8 and HLA-DR3 haplotypes.

Histopathology Neutrophils and eosinophils accumulate at the tips of the dermal papillae immediately beneath the epidermis and this is associated with subepidermal separation and blister formation. Direct immunofluorescence shows deposits of IgA and sometimes C3 in a granular fashion at

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the basement membrane zone. This may also be seen in perilesional skin.

Pathogenesis There is now evidence that the disease is the result of autoantibody to epidermal transglutaminase 3, an enzyme involved in keratinocyte differentiation. It is postulated that patients with a high gluten diet and a genetic predisposition to gluten sensitivity produce IgA antibodies against epidermal transglutaminase 3 and these are deposited at the dermal epidermal junction. Neutrophils are attracted and cause the damage possibly by the release of inflammatory mediators.

Management Patients may be treated with dapsone or sulfapyridine and relief is usually rapid. They should also be advised to change their diet and avoid wheat products. If successful this will obviate the need for drugs but some patients find the diet difficult to tolerate. Box 15.6: Dermatitis herpetiformis Key features useful in diagnosis • Affects young 20–40 years • Associated with celiac disease: gluten sensitive enteropathy • Itchy rash on flexor surfaces, face and neck, oral cavity rarely affected • Autoantibodies to transglutaminase 3 • Managed by dapsone or sulfapyradine and a gluten-free diet.

or perioral region. Similar lesions are seen in the adult form but these affect the elbows, knees and buttocks predominantly. Mucosal involvement may be seen in up to 80 percent of patients with both forms of the disease. Oral lesions have been documented and these may appear as vesicles and bullae, erosions, white patches or striations resembling lichen planus. Desquamative gingivitis or erythema may be evident. In a few cases, oral involvement may be the only oral manifestation of the disease and in these cases diagnosis is difficult. There appears to be a genetic component as the disease is associated with HLA-B8 and HLADR3 phenotypes.

Histopathology Subepidermal blister formation is usually seen associated with accumulations of neutrophils at the basement membrane zone particularly at the tips of the dermal papillae. Direct and indirect immunofluorescence shows linear deposition of IgA at the basement membrane zone.

Pathogenesis The antigens targeted by the autoantibodies have not been clearly defined but using salt split skin binding occurs on the epidermal side in 80 percent of children and 30 percent of adults and in some cases bind to both the epidermal and dermal side. It is thought there are multiple antigens and some may be related to BP180 (Type XVII collagen) as well as BP230. The trigger for the disease is not known but there is evidence it may be drug related in some few cases.

Management lInEAr IgA DIsEAsE

356

This rare disease is characterized as its name suggests by linear deposits of IgA at the basement membrane zone in the skin and the mucous membranes. It occurs in two main forms—Linear IgA disease of childhood and Adult Linear IgA disease. Linear IgA disease of childhood usually affects children below the age of five years and is characterized by papules or vesiculobullous eruptions which may occur around the anus

Diagnosis is established by biopsy and detection of autoantibodies. Most cases respond to dapsone or sulfapyridine. Box 15.7: Linear IgA Key features useful in diagnosis • two forms affecting children and adults • subepithelial separation and bullae with linear IgA deposition basement membrane zone • Affects skin and mucosa in 80% • Managed by dapsone or sulfapyridine

ErytHEMA MultIFOrME

This disorder is characterized by blood filled blisters on the oral mucosa which burst to form erosions that usually heal within a week. Unlike the other disorders considered in this chapter, they are not the result of autoantibodies against components of either the desmosomes, hemidesmosomes or basement membrane zone. It will be considered here since it forms part of the differential diagnosis of vesiculobullous lesions of the oral mucosa.

Erythema multiforme encompasses a range of clinical presentations which vary in severity but all are characterized by lesions which affect the mucosa and/or skin. Over the years, several attempts have been made to classify the different variants and currently, erythema multiforme minor (EM minor), erythema multiforme major (EM major), Stevens-Johnson syndrome (SJS) and toxic epidermolysis necrosis syndrome (TENS) are recognized as part of the spectrum of erythema multiforme.

Clinical Features Patients complain of blood filled blisters which arise rapidly, burst and then heal within one to two weeks. They commonly affect the soft palate although any oral site may be affected. The patients do not have a history of blood disorders or mucosal blistering disorders. The lesions are usually solitary and may occur infrequently or with a pattern consistent for that patient. They often arise after meal times and may be associated with a burning sensation. Patients are usually middle aged or elderly.

Histopathology This shows a subepithelial blister which is usually blood filled. There may be a mild inflammatory infiltrate in the lamina propria. If the blisters have burst the features are those of non-specific ulceration.

Clinical Features

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AngInA BullOsA HEMOrrHAgIcA

Erythema multiforme affects young individuals in the 20 to 40 age group and there appears to be a slight male predilection. Skin lesions are typically targeted in appearance and comprise a flat central red area surrounded by concentric edematous rings. They are usually less than 3 cm in diameter and are well defined (Fig. 15.9). Occasional lesions may be raised and in more severe cases, there may be evidence of bullae formation and lesions may become confluent. The extensor surfaces of the extremities are most often affected and lesions are usually symmetrical. Oral lesions are characterized by macules and blood-filled blisters which usually burst to form widespread erosions and ulceration. The lesions particularly affect the anterior parts of the mouth and the lips which become swollen and blood

Management It is important to exclude autoimmune causes of subepithelial blistering and blood dyscrasias by the appropriate tests including biopsy. Once the diagnosis is established patients should be reassured and treatment may include the use of anti-inflammatory or antibacterial mouth rinses. Box 15.8: Angina bullosa hemorrhagica Key features useful in diagnosis • Blood filled blisters affecting palate, heal within a week • Etiology unknown • Exclude autoimmune causes and reassurance.

Fig. 15.9: target lesion in erythema multiforme on the shins

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esophagus, larynx, genitals and eyes. There is widespread ulceration and usually typical target lesions are present on the skin. Like EM minor this form of the disease may also be recurrent.

stEVEns-JOHnsOn synDrOME

Fig. 15.10: Mucosal lesions in erythema multiforme. Note: the blood encrusted lips and widespread ulceration of the anterior parts of the mouth

tOxIc EPIDErMOlysIs nEcrOsIs synDrOME

encrusted (Fig. 15.10). Other mucosal surfaces may be affected and show widespread erosions and ulcers. Attacks usually last for between 10 to 20 days and the majority are single episode. However, in about 25 percent of cases the disease is recurrent with a rate of one or two per year. Most cases resolve within 10 years but the range of duration is very large and some cases are intractable.

This is a rare variant also known as Lyells disease. Its relationship to erythema multiforme is unclear but it is almost always drug induced. TENS is characterized by widespread detachment of the epidermis from the dermis affecting almost all the skin as well as loss of oral epithelium and widespread ulceration.

Erythema Multiforme Minor

Etiology

As its name suggests this variant is usually mild and by definition, only affects one mucous membrane—usually the oral cavity. The skin is also affected and usually typical target lesions are present on the extensor surfaces of the arms and legs. In some cases, there is evidence of fever and malaise but the disease is usually self limiting. However, it may become recurrent and very severe with widespread oral ulceration although the lips tend to be spared. There is evidence that EM minor is closely linked to EM major. In cases of recurrent EM minor the disease may become more severe with each progressive attack and may affect other mucosal sites.

Erythema multiforme has been linked to a large number of environmental triggers including viruses, bacteria, immune reactions, drugs and foodstuffs. However there appears to be a genetic predisposition and there is an association with certain HLA phenotypes. This is particularly true of recurrent cases which are associated with HLADQ3. Viruses are an important trigger and herpes simplex infection has been implicated in up to 70 percent of recurrent cases. Other viruses such as coxsackie, influenza and hepatitis viruses have also been reported to act as a trigger as well as a number of bacteria including streptococci, mycoplasma, ricketsia, tuberculosis and salmonella. Indeed, the number of reports showing an association with microorganisms and erythema multiforme is very large and the same is true for drugs. Sulfonamides, cephalosporins and nonsteroidal anti-inflammatory drugs have also

Erythema Multiforme Major 358

This is a very severe form of erythema multiforme and the eyes, larynx, pharynx, genitals, oral cavity and skin are all affected. Patients may complain of a flu-like illness up to 3 weeks before the onset with headache, malaise, fever, arthralgias and myalgias. Skin lesions may be atypical and flat rather than raised. Ocular lesions may resemble those of pemphigoid and patients may complain of dry eyes.

This clinical variant affects not only the oral cavity but also other mucosal sites including the

HErPEs AssOcIAtED ErytHEMA MultIFOrME There is increasing evidence that a preceding herpes infection may trigger a significant proportion of cases of both single episode and recurrent EM and these are known as herpes associated erythema multiforme (HAEM). The evidence for this association comes from the significant number of patients who report a preceding herpes infection 1 to 2 weeks before the episode of EM. Even in those patients who do not report such an association, the antiviral drug aciclovir is often effective. There have been several studies designed to determine whether herpes simplex virus (HSV) is present in lesions of EM. Although there is wide variability, HSV has been detected in the region of 60 percent of cases.

Histopathology The histological appearances are very variable and diagnosis may be difficult. There is often both sub- and intraepithelial bullae formation and the epithelium is edematous and shows evidence of necrosis. This is associated with an infiltrate of T-lymphocytes and mononuclear cells in the upper dermis or lamina propria and these may extend into the epithelium and obscure the basement membrane zone. Immunofluorescence shows granular C3 deposition in basement membrane zone and around blood vessels. The extent of the inflammatory infiltrate is variable and appears to be greater in cases precipitated by herpes than those caused by drugs.

Pathogenesis It was originally thought that EM is the result of a type 3 hypersensitivity reaction, i.e. an antibody/antigen reaction in localized blood vessels causes the destruction. However, there is increasing evidence that in some cases the disease is the result of a cell mediated immune reaction. In HAEM, it is thought the HSV-DNA fragments in epithelial cells trigger the disease. T-cells reactive to HSV DNA have been identified and these produce IFN-γ. This cytokine amplifies the immune response and recruits additional T-cells to the area which result in cell mediated tissue damage. In drug associated lesions, it is thought that drug metabolites initiate the disease and that the destruction is not cell mediated but rather mediated by cytokines. The infiltrate which is usually sparse produces TNF-α rather than IFN-γ and this cytokine may induce apoptosis of epithelial cells directly. However, the detailed mechanisms of the damage still remain to be determined.

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been implicated as well as others too numerous to mention. Despite the large number of reported triggers there does appear to be an association between the nature of the trigger and the severity of the response. Viruses tend to trigger EM minor and major whereas drugs tend to trigger Stevens- Johnson syndrome and TENS. However, this association is not exclusive and a small but significant number of cases of EM minor and major are triggered by drugs and conversely, some cases of SJS are triggered by viruses.

Box 15.9: Erythema multiforme Key features useful in diagnosis • spectrum of presentations from mild to severe affecting skin and mucosa • EM minor and major affects skin and one or more mucosal sites respectively • target lesions and blood encrusted lips and ulceration • Triggered by viruses: Herpes, bacteria, drugs and foodstuffs • EM minor and major associated with herpes, stevens-Johnson syndrome with drugs • May be recurrent, manage with aciclovir.

Management Diagnosis can be difficult and in most cases is made on clinical features alone without the use of biopsy. In single episode disease lesions may resolve within two to three weeks and supportive care is the mainstay of treatment. In recurrent cases which are associated with herpes, aciclovir may be used either as a short course at the onset of symptoms or as a prophylaxis over a longer time period. Patients with severe symptoms

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may require hospitalization and supportive care. The use of steroids is controversial but may be used in patients with SJS and TENS as well as EM Minor.

sElF-AssEssMEnt quEstIOns 1. Provide a classification for immunobullous disorders. 2. Describe the clinicopathological features of pemphigus. 3. Describe the clinicopathological features of mucous membrane pemphigoid. 4. Give an account of paraneoplastic immunobullous disease. 5. Describe the role of immunochemistry in the diagnosis of immunobullous disorders. 6. Describe the clinicopathological findings in epidermolysis bullosa. 7. Describe the clinicopathological features of erythema multiforme.

8. Describe the clinicopathological features of angina bullosa hemorrhagica. 9. Describe, using examples, the treatment of immunobullous disease. 10. Give an account of the target antigens affected in immunobullous disease.

suggEstED rEADIng 1. Mignogna MD, Fortuna G, Leuci S. Oral pemphigus. Minerva Stomatol. 2009;98:501-18. 2. Schifter M, Yeoh SC, Coleman H, Georgiou A. Oral mucosal diseases: the inflammatory dermatoses. Aust Dent J. 2010;5:23-38. 3. Schmidt E, Zillikens D. Pemphigoid diseases. Lancet. 2013;381:320-32. 4. Sticherling M. Erfurt-Berge C. Autoimmune blistering diseases of the skin. Autoimmun Rev. 2012:11;226-30.

Chapter

16

Infections of the Oral Mucosa Lakshman Samaranayake, Nipuna Parahitiyawa

Chapter Outline Fungal Infections of the Oral Mucosa Oral Candidiasis • Pseudomembranous Candidiasis • Erythematous (Atrophic) Candidiasis • Hyperplastic Candidiasis (Candidal Leukoplakia) Candida-associated Lesions • Candida-associated Denture Stomatitis • Angular Stomatitis (Perleche, Angular Cheilitis) • Median Rhomboid Glossitis • Linear Gingival Erythema Candidiasis and Immunocompromised Hosts Oral Candidiasis in HIV Disease • Laboratory Diagnosis Exotic Fungal Infections of the Oral Mucosa • Aspergillosis • Blastomycosis • Coccidioidomycosis • Cryptococcosis • Fusariosis • Geotrichosis • Histoplasmosis • Mucormycosis (Zygomycosis; Phycomycosis) • Paracoccidioidomycosis (South American Blastomycosis) • Penicilliosis • Sporotrichosis Oral Viral Infections • Primary Herpes Simplex Infection: Herpetic Stomatitis (HHV-1, HHV-2)

• Secondary Herpes Simplex Infection: Herpes Labialis (HHV-1, HHV-2) • Herpetic Dermatitis and Herpetic Whitlow (HHV-1 and HHV-2) • Laboratory Diagnosis of Herpetic Infection • Direct Examination and PCR Technology • Varicella and Zoster (HHV-3) • Chickenpox • Shingles (Zoster) • Epstein-Barr Virus (Human Herpesvirus 4) • Infectious Mononucleosis • Chronic, Persistent or Reactivated EBV Infection • Burkitt’s Lymphoma • Nasopharyngeal Carcinoma • Hairy Leukoplakia • Cytomegalovirus (Human Herpesvirus 5; HHV-5) • Coxsackie Virus Infections • Paramyxovirus Infections • Human Papilloma-virus Infections Bacterial Infections of the Oral Mucosa • Tuberculosis of the Oral Mucosa • Syphilis • Gonorrhea • Other Bacterial Infections Parasitic Infections of the Oral Mucosa • Mucocutaneous Leishmaniasis Self-assessment Questions

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16 INTRODuCTION The oral mucosa, which covers a significant pro­ portion of the oral cavity, is affected by a number of infectious diseases. The majority of these are of fungal (candidal) and viral origin and are similar to infections seen in other superficial mucosal surfaces of the body, such as the vagina although the unique oral environment laced with saliva may alter the lesion presentation and appearance. In this section, fungal infections are discus­ sed first with greater emphasis on candidal infection, followed by viral infections and bacterial infections. Mucosal infections other than those caused by viruses are uncommon in otherwise healthy people. However, with the increasing numbers of immunocompromised patient populations such as those with HIV, these infections are also on the rise, and therefore deserve attention of the dentist in diagnosing and managing those (Fig. 16.1).

FuNGAL INFECTIONS OF THE ORAL MuCOSA Oral candidiasis (syn. Oral candidosis): • Primary oral candidiases • Secondary oral candidiases

Candida associated lesions: a. Candida­associated denture stomatitis b. Angular cheilitis or angular stomatitis c. Median rhomboid glossitis d. Linear gingival erythema.

ORAL CANDIDIASIS Oral candidiasis or candidosis is used as an umbrella term to describe infections mainly caused by the yeasts belonging to the genus Candida. (Fig. 16.2). Although Candida albi­ cans is the main etiological agent, non­albicans species do cause infection, often in the immu­ nocompromised. All forms of oral candidiasis are considered to be opportunistic infections, and the epithet ‘disease of the diseased’ has been applied to these infections, which are seen mainly in the ‘very young, the very old and the very sick’ (Table 16.1). It is important to note that, particularly in the developing countries, oral candidiasis is the third most common pre­ senting complaint of HIV infected patients. Oral candidiases can be classified as follows: 1. Primary oral candidiases: Localized candidal infections present only in the oral and perio­ ral tissues. 2. Secondary oral candidiases: Candidal infec­ tions that manifest in a generalized manner

Fig. 16.1: Infections of the oral mucosa

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Predisposing factor

Mechanism or effects on host

Physiological

Old age, infancy, or pregnancy that associate with altered host immunity, hyposalivation, etc.

Local trauma

Mucosal irritation, poor denture hygiene

Malnutrition

High-carbohydrate diet, iron, foliate and vitamin B12 deficiencies

Broadspectrum antibiotics

Altered oral microbiology

Corticosteroids

Steroid inhalers, systemic steroids suppressing oral immunity

Immune defects

HIV infection, AIDS, thymic aplasia

Endocrine disorders

Hypoendocrine states (e.g. hypothyroidism, Addison’s disease)

Malignancies

Including blood disorders e.g. acute leukemia, agranulocytosis that impairs host’s immunity

Hyposalivation

Autoimmune disease: Sjögren’s syndrome; acquired: head and neck irradiation, medication including cytotoxic drug therapy

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ƒ Table 16.1 Factors that predispose the host to oral candidiasis

only. Antifungal therapy alone will not cure these diseases and underlying cofactors that perpetuate the disease need to be evaluated and eradicated for disease resolution. These variants include: • Candida­associated denture stomatitis • Angular cheilitis or angular stomatitis • Median rhomboid glossitis • Linear gingival erythema (the microbiologic etiology is not conclusive). Fig. 16.2: Blastospores (yeast phase) and hyphae (filamentous phase) of Candida albicans

both in the oral cavity and on other mucous and cutaneous surfaces (systemic mucocu­ taneous candidal infections). These are due to rare disorders (except perhaps in can­ didiasis of human immunodeficiency virus (HIV) infection) such as thymic aplasia and chronic endocrine diseases.

Pseudomembranous Candidiasis Pseudomembranous candidiasis, classically termed ‘thrush’ (Fig. 16.3), is an acute infection but may persist intermittently for many months

The classic triad of (either primary or secondary) oral candidiases is: • Pseudomembranous variant • Erythematous (atrophic) variant • Hyperplastic variant. In addition there are a number of other Candida­associated lesions where the etiology is multifactorial. These are primary oral candidiases restricted to the oral cavity

Fig. 16.3: Pseudomembranous candidiasis (thrush) in a HIV-infected young adult (Note: The fungal invasion of gingival crevice)

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or even years in patients using corticosteroids topically or by aerosol, in HIV­infected individu­ als, and in other immunocompromised patients. It may also be seen in neonates and in the termi­ nally ill, particularly in association with serious underlying conditions such as leukemia.

Clinical Features The lesions are characterized by white mem­ branes on the surface of the oral mucosa, tongue and elsewhere. These develop to form confluent plaques that resemble milk curds and can be wiped off to reveal a raw, erythematous and sometimes bleeding base. Hence, some consider pseudomembranous and the erythe­ matous variants a continuum and a single entity (i.e. two stages of the same disease).

Microbiology and Pathology The white patches consist of necrotic material and desquamated parakeratotic epithelium, penetrated by yeast cells and hyphae which invade as far as the stratum spinosum. Oropharyngeal thrush may sometimes spread into the adjacent mucosa, particularly that of the upper respiratory tract and the esophagus. The combination of oral and esophageal candidiasis is particularly prevalent in HIV disease. Hence, it is necessary to investigate the underlying immune status of the host when this is encountered.

Management

Clinical Features The clinical presentation is of one or more asymptomatic erythematous areas, generally on the dorsum of the tongue, palate or buccal mucosa. Lesions on the dorsum of the tongue present as depapillated areas; red areas are often seen on the palate in HIV disease. There can be associated angular stomatitis, especially in Candida­associated denture stomatitis.

This consists of topical antifungal preparations, mainly containing the polyene drugs nystatin and amphotericin, given as lozenges or pastilles. In recalcitrant cases fluconazole may be prescribed as second line treatment. Investigate for any underlying systemic disease (e.g. HIV disease) prior to discharging the patient.

Microbiology

Erythematous (Atrophic) Candidiasis

Topical antifungal treatment, mainly nystatin and amphotericin, is given as lozenges or pastilles. Azole group agents, such as oral fluconazole tablets, are useful in HIV disease. Investigate for underlying pathology (e.g. HIV disease).

Erythematous candidiasis is a poorly understood condition associated with corticosteroids, topical or systemic broad­spectrum antibiotics, or HIV disease. It may arise as a consequence

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of acute pseudomembranous candidiasis when the pseudomembranes are shed, or may develop de novo. Erythematous candidiasis of the palate is a common Candida­associated lesion frequently observed in elderly people wearing full dentures (Candida­associated denture stomatitis; see below) (Fig. 16.4).

Not much is known of the role of yeasts in this condition, although antifungal therapy leads to resolution of the lesions.

Management

The lesions in hyperplastic candidiasis present as chronic, discrete raised areas that vary from small, palpable, translucent, whitish areas to large, dense, opaque plaques hard and rough to the touch (plaque­like lesions). Homogeneous areas or speckled areas that do not rub off (nodular lesions) can also be seen. The lesions are often asymptomatic and usually occur on the inside surface of one or both cheeks (retrocommissural area) (Fig. 16.5). Oral cancer may supervene in 9 to 40 percent of cases of hyperplastic candidiasis, as compared with the 2 to 6 percent risk of malignant transformation cited for other oral white patches, e.g. Oral leukoplakia. Therefore, patients with recalcitrant hyperplastic candidal lesions resistant to therapy should be kept under regular surveillance (see chapter 12).

Microbiology and Histopathology Parakeratosis and epithelial hyperplasia occur, with candidal invasion restricted to the upper layers of the epithelium. The condition has been associated in a minority with iron and folate deficiencies and with defective cell­mediated immunity. Biopsy is important as the condition is potentially malignant and shows varying degrees of dysplasia.

Fig. 16.5: Classic appearance of chronic hyperplastic candidiasis on the commissures of the mouth

Management Topical antifungal treatment, mainly nystatin and amphotericin, is given as lozenges or pastilles. Azole group agents, such as oral fluconazole tablets, may help resolve chronic infections. Following successful antifungal treatment the grade of dysplasia may drop by at least one stage. Because of the possibility of malignant transformation, patients should be followed up if the condition is chronic.

CaNdida-ASSOCIATED LESIONS Candida-associated Denture Stomatitis Candida­associated denture stomatitis, also called denture sore mouth or chronic atrophic candidiasis, is one of the most common ailments in wearers of full dentures; in some areas such as Scandinavia 60 percent of wearers over 60 years old were reported to suffer from the condition. It is also associated with patients wearing orthodontic appliances or obturators for cleft palate. The characteristic presenting signs are erythema and edema of the mucosa that is in contact with the fitting surface of the upper denture. The mucosa below the lower dentures is hardly ever involved.

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Hyperplastic Candidiasis (Candidal Leukoplakia)

Clinical Features The patient may occasionally experience slight soreness but is usually free from symptoms; the only presenting complaint is sometimes an associated angular stomatitis. Depending on the severity of inflammation, the lesions may appear as: • Pinpoint erythema of the denture-bearing mucosa (Newton’s type 1) • Diffuse and confluent erythema and edema of the denture­bearing mucosa (Newton’s type 2) (Fig. 16.6) • Papillary hyperplasia and inflammation, commonly involving the central part of the hard palate and the alveolar ridge (Newton’s type 3).

Etiology • Local factors: Poor denture hygiene, illfitting dentures, traumatic dentures,

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• A diet with a low content of fermentable carbohydrates • Polyene antifungals – nystatin (1;100000 units, 1 mL QDS for 10 days), amphotericin (lozenges, pastilles, etc.) 10 mg qds for 7 days • Miconozole gel applied the fitting surface of the denture.

Angular Stomatitis (Perleche, Angular Cheilitis)

Fig. 16.6: Candida-associated dentures stomatitis. Classic appearance showing edematous and erythematous denture bearing mucosa of the hard palate

carbohydrate­rich diets, xerostomia (e.g. Sjögren’s syn-drome). • Systemic factors: Iron and folate deficiency, diabetes mellitus, immune defects.

Microbiology and Histopathology It is generally considered to be due to accumulation of plaque biofilms with yeasts and bacteria on the fitting surface of the denture and the underlying mucosa. In the papillary hyperplastic variety, Candida species do not invade the epithelium. Other etiological factors, such as mechanical irritation or an allergic reaction to the denture base material (though rare) need to be excluded in persistent cases.

Management

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The condition is treated by: • Scrupulous denture hygiene and removal of dentures at night (these measures alone, without antifungals, are adequate in the majority of cases) • Regular disinfection of dentures by steeping them in sodium hypochlorite or chlorhexidine to eradicate the reservoir of candidal hyphae adhering to the prosthesis • Review of the denture fitness to relieve trauma, if any

The lesions of angular stomatitis are seen in one or both angles of the mouth (Figures 16.1 and 16.5), especially as a complication of Candida­ associated denture stomatitis.

Clinical Features Characterized by soreness, erythema and fissuring, this condition is commonly associated with denture­induced stomatitis. Both yeasts and bacteria (especially Staphylococcus aureus) are involved as interacting predisposing factors. However, angular stomatitis is very occasionally an isolated initial sign of anemia or vitamin deficiency, such as vitamin B12 deficiency, and resolves when the underlying disease has been treated. The condition is also seen in HIV­ associated disease.

Microbiology Candida spp. are present with or without co­ infection with Staphylococcus aureus. The presence of yellow crusting may indicate staphylococcal infection.

Treatment Elimination of the intraoral reservoir of infection in patients with concurrent denture stomatitis is essential for successful resolution. Other measures include adjustment of vertical dimension of the dentures to prevent saliva drooling, and moisture at the angles of the mouth (note: moist body surfaces encourage the growth of Candida). Topical antifungal therapy with nystatin, amphotericin B or miconazole (miconazole

in the pathogenesis, and lesions resolve after antifungal therapy in some cases, it is likely that other cofactors such as oral hygiene play an equally important role.

Median Rhomboid Glossitis

A few patients have chronic candidiasis from an early age, sometimes with a definable immune defect, e.g. chronic mucocutaneous candidiasis. Candidal infections in these patients are seen in the oral mucosa, skin and other body parts. These secondary oral candidal infections have increased recently because of the high prevalence of attenuated immune response, consequent to diseases such as HIV infection, hematological malignancy and treatment proto­ cols, including aggressive cytotoxic therapy.

Midline glossitis, or glossal central papillary atro­ phy, is characterized by an area of papillary atro­ phy which is elliptical or rhomboid in shape and symmetrically placed centrally at the midline of the tongue, anterior to the circumvallate papil­ lae (Fig. 16.7). Occasionally, median rhomboid glossitis presents with a hyperplastic exophytic or even lobulated appearance. In addition to fungal infection a number of predisposing cofac­ tors, including smoking, steroid inhalation and remnants of the tubrculum impar, have been proposed. The patients are often worried about the appearance and cancer­phobic. In this event reassurance is essential.

Linear Gingival Erythema This condition, defined as a localized or genera­ lized erythematous band extending along the gingival margins (between adjacent gingival papillae), was first described in HIV­infected individuals; it is however not confined to the latter group. Although Candida are implicated

CANDIDIASIS AND IMMuNOCOMPROMISED HOSTS

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has both antifungal and anti­staphylococcal activity and is useful for mixed infections); anti­staphylococcal preparations (dictated by microbiological investigation) include fusidic acid and neomycin/chlorhexidine. Investigate also for possible underlying disease: iron or vitamin B12 deficiency; HIV infection.

ORAL CANDIDIASIS IN HIV DISEASE Candidal infections, with oral thrush and esophagitis as frequent or recurrent clinical manifestations, are the most common oppor­ tunistic infections encountered in acquired immune deficiency syndrome (AIDS). It has also been shown that the occurrence of an otherwise unexpected mycoses (typically oral candidiasis) in an HIV­infected individual is a poor prognos­ tic indicator of the subsequent development of full-blown AIDS. However, in HIV-infected pop­ ulations on antiretroviral therapy, the incidence of oral candidiasis has significantly declined.

Laboratory Diagnosis Confirmation of diagnosis requires sending a swab and/or a smear from a Candida suspected lesion to a microbiological laboratory. The microbiologist can give a colony count from a mouth rinse made of 10 mL of saline.

ExOTIC FuNGAL INFECTIONS OF THE ORAL MuCOSA

Fig. 16.7: Median rhomboid glossitis. The classic rhomboid, erythematous lesion

The infections that are dealt below are often termed as deep mycoses. These affect the tissues beyond the mucosal layers and often present as a part of systemic affection. Therefore, it

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is important to search for systemic signs and symptoms take a deep biopsy when oral lesions are detected (Table 16.2).

Aspergillosis Aspergillosis has been reported as second only to candidiasis as the most prevalent oppor­ tunistic mycotic infection. It is also the second most frequent orofacial fungal infection in those receiving cancer chemotherapy. Aspergillus spe­ cies are filamentous saprophytes that live in soil and decaying vegetation and the most common pathogen of the species is Aspergillus fumiga­ tus. Human infections are also caused by less

common, Aspergillus flavus, Aspergillus glaucis, Aspergillus terrus and Aspergillus niger. Asper­ gillosis may present as three clinical variants, namely: (i) saprophytic, superficial infection without invasion; (ii) allergic, as a hypersensi­ tivity reaction; and (iii) invasive, infection into viable tissue. Aspergillosis is generally contracted through inhalation of spores, leading to both upper and lower respiratory tract infection­ bronchopulmonary aspergillosis. Infections may then spread to brain, bone or endocardium. Paranasal sinuses, larynx the eyes, ears and oral cavity may be involved in primary aspergillosis.

ƒ Table 16.2 uncommon systemic mycoses and their oral manifestations Disease and representative Main sites affected agent

Major oral manifestations

Aspergillosis Aspergillus fumigatus

Paranasal sinuses; rarely tongue, soft palate

Plaque formation and intense local uncommon pain in oral lesions

Blastomycosis (North American) Blastomyces dermatitidis

Tongue, oral mucosa, gingivae, lip, mandibular bone

ulceration, sessile projections, indurated swellings, actinomycosislike draining abscesses

Rare

Coccidioidomycosis Coccidioides immitis

Nasolabial folds, skin

Verrucous granulomas resembling carcinomas

Very rare

Cryptococcosisa Cryptococcus neoformans

Gingiva, hard and soft Violaceous colored nodules or palate, mucosa, tonsil- granulations, swellings, ulcers lar pillar

Geotrichosis Geotrichum candidum

Oral mucosa

Similar to acute pseudomembranes uncommon of candidosis

Histoplasmosisb Histoplama capsulatum Histoplasma duboisii

Oral mucosa, tongue, plate, gingival, periapical area

Nodular, indurated or granular masses or tissue destruction with bone erosion

Mucormycosis Mucor species

Extension from maxil- Sloughing ulcers with gray eschar lary sinus through pal- and exposed bone (especially maxilla); unilateral facial pain ate into the mouth

Common

Paracoccidioidomycosis (South American Blastomycosis) Paracoccidioides brasiliensis

Hard and soft palate, gingiva, tongue

Papules or vesicles leading to ulcers; extensive local destruction

Common

Sporotrichosis Sporotrichum schenckii

Oral mucosa

Erythematous, ulcerative lesions leading to granuloma, or papillomas

uncommon

a AIDS-associated oral lesions have been described

b May present to the dentist with initial oral manifestations

Frequency of oral affection

uncommon

40 percent

The potential for transmission of apsergillosis from humans­to­humans is low.

Orofacial aspergillosis may affect the paranasal sinuses, nasal cavity, oral mucosa and underlying structures as well as the skin of the face. A. fumigatus is the usual agent of sinus aspergillosis, whereas A. flavus is more common in invasive lesions in immunosuppressed individuals. Orofacial aspergillosis appears to be relatively common in patients undergoing treatment for malignancies of the blood and blood­forming organs. In general, the lesions are yellow or black in color, with a necrotic ulcerated base, typically located on the palate or posterior tongue. The hyphal elements of the fungus may invade the oral mucosa and penetrate the walls of small to medium­sized arteries and veins, producing thrombosis, infarction and necrosis finally leading to systemic spread. Aspergilloma of the maxillary antrum is not uncommon, presenting in a healthy host as a hyphal ball in chronically obstructed sinus.

Diagnosis and Management Main differential diagnoses are from mucor and pseudomonas oral infection. Bone erosion can be more easily detected by NMR or CT imaging and the diagnosis confirmed by periodic acid schiff stained smear; immunostains may be of help. Systemic amphotericin B is the choice antimycotic, if the superficial infections do not resolve within 72 hours of other antifungals ketoconazole or clotrimazole therapy.

Blastomycosis Although becoming more prevalent due to the HIV pandemic, blastomycosis is a relatively uncommon fungal disease. Blastomycosis is a deep mycotic infection, caused by Blastomyces dermatitidis, found mainly in North America particularly in rural Mississippi, Ohio and Missouri river basins as well as the Great Lakes region. In humans, blastomycosis presents as either: pulmonary, disseminated or localized cutaneous lesions. As in aspergillosis the fungal

Oral Considerations Oral lesions may arise through disseminated blastomycosis. Oral blastomycosis is uncom­ mon and may present as single or multiple ulcerations, sessile projections, and granu­ lomatous or verrucous lesions. In a study of 40 patients with blastomycosis, a quarter demonstrated oral or nasal lesions and in another, seven of ten patients had nonspecific oral ulcerations in addition to systemic disease.

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Oral Considerations

spores are found in the soil and may initiate the disease when inhaled. Transmission of blasto­ mycosis from human­to­humans is unlikely and has not been reported.

Diagnosis and Management Diagnosis is based on biopsy, smear or culture. Amphotericin B, ketoconazole, miconazole and itraconazole are all effective.

Coccidioidomycosis This condition is mainly seen in South West United States, Mexico, Central America and some parts of South America. The disease is caused by inhalation of Coccidioides immitis spores found in soil. Antibodies to the fungus are found in 90 percent of the population of these endemic areas. The illness is typically an acute pulmonary disease and fever, sometimes with erythema nodosum or erythema multi­ forme. Chronic pulmonary disease is less common. Disseminated coccidioidomycosis is seen in pregnant women, immigrant workers and immunocompromised individuals. Oral manifestations are almost always secondary to lung involvement. Transmission of cocci­ dioidomycosis from human­to­humans is unlikely and has not been reported.

Oral Considerations Oral lesions are rare and manifest as verrucous lesions with underlying infection of the jaw.

Diagnosis and Management Diagnosis is by history and examination sup­ ported by histology. Coccidioidin skin test

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of choice and can be supplemented with fluconozole.

Fusariosis Fusarium species were once considered as harmless, saprophytic, filamentous fungi liv­ ing in soil. They, however, are now emerging as pathogens due to the high prevalence of compromised patients in the community. Fusa­ riosis is the disseminated form of the disease. The disease is highly unlikely to be transmitted from human­to­humans.

Oral Considerations Human fusarium infections may present as local, focally invasive or disseminated disease. Oral infections are rare and usually present as secondary lesions of disseminated disease where they have been described as black, necrotic ulcers occurring mainly on the palate. As these lesions are similar in appearance to those of aspergillosis and mucormycosis, definitive diagnosis should be made by histology and cultural techniques.

Diagnosis and Management The management depends on the degree of invasion and the status of the patient. Superficial infections reportedly respond to local treatment; however, disseminated infections have a very poor prognosis. The infection can be managed by ketoconazole or voriconazole given for a prolonged period.

Geotrichosis

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Geotrichum candidum is usually saprophytic but occasionally causes opportunistic infection in man. The fungus has been isolated from the skin, sputum and faeces and is carried in the alimentary tract of some individuals. Infections have been described in the bronchi, lung, mouth and intestine. Bronchial geotrichosis is the most commonly recognized form of the disease and is characterized by a persistent cough, the production of gelatinous sputum and absence of fever. Disseminated infections are seen in debilitated patients or in those receiving

severity of the disease in AIDS patients is greater when CD4 count is below 200 cells/cm2.

Oral Considerations

Diagnosis and Management

The oral lesions of geotrichosis are indistin­ guishable clinically from those of acute pseudomembranous candidiasis (thrush) and the reported low incidence of the disease may be due to such misdiagnosis. Other reports indicate that the clinical appearance as edematous and erythematous gingivae and ulcerations. In one study, it was the second­most common oral yeast isolated from patients with hematologic malignancies suffering from stomatitis.

Diagnosis is confirmed by microscopy, culture and serology. Amphotericin B is the first choice drug, whilst fluconazole and itraconazole are alternatives. Relapse rates may be high as 80 percent for patients not placed on mainte­ nance regimens following initial treatment with amphotericin B.

Diagnosis and Management

The term mucormycosis refers to a distinctive group of diseases caused by ubiquitous, saprophytic fungi of the order Mucorales. The organisms are common inhabitants of soil and may be found in the nasal cavities of healthy individuals. Infection arises by inhalation of spores that are deposited in pulmonary alveoli. Other modes of infection include contamination of traumatized tissues and direct inoculation. The infection may present in different anatomic sites; especifically the paranasal, rhino­ orbital, rhinocerebral, cerebral pulmonary and gastrointestinal areas. It can also appear in the soft tissues of the extremities or as disseminated disease. The fungus preferentially erodes arteries, resulting in thrombosis with subsequent necrosis of the surrounding tissues. The host response is suppurative rather than granulomatous although chronic forms of mucormycosis occasionally occur. The infection is often associated with acidosis due to diabetes, diarrhea, or uraemia. Diabetic acidosis was considered to be the predisposing condition in 50 to 70 percent of the reported patients with mucormycosis prior to the HIV pandemic. More recently it is commonly seen associated with HIV infection and AIDS. Other predisposing conditions are blood dyscrasis, malignant disease, hepatitis, burns, malnutrition, irradiation, tuberculosis, and the administration of corticosteroids and immunosuppressive drugs. Mucormycosis is highly unlikely to be transmitted from human­ to­humans.

Diagnosis is confirmed by histology and culture. Nystatin may be effective for localized oral lesions, whilst systemic infections respond well to itraconazole therapy.

Histoplasmosis Histoplasma capsulatum, a dimorphic fungus is endemic in Mississippi and Ohio river valleys and found in Latin America, India the Far East and in Australia. The organisms are found, especially in bird and bat feces. Infection ensues when microconidiae or hyphae are inhaled into the lung and develop into yeast or when old foci of infection are reactivated. AIDS patients are particularly at risk due to impairment of cellular immunity. Clinical presentations include acute and chronic pulmonary cutaneous histoplasmosis, with or without disseminated disease. The latter is particularly common in immunocom­ promised persons. Histoplasmosis is unlikely to be transmitted from human­to­humans.

Oral Considerations Oral lesions are mostly chronic with nodular, indurated or granular masses and ulceration; tissue destruction with bone erosion. Up to 40 to 50 percent case with systemic histoplasmosis presents with oral lesions. The major oral sites affected are the mucosa, tongue, palate, gingivae and the periapical region of teeth. The

Mucormycosis (Zygomycosis; Phycomycosis)

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immunosuppressive drugs. Geotrichosis can­ not be transmitted from human­to­humans.

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Symptoms involving the oral, cranial and facial structures account for about 60 percent of all cases. Oral ulcerations and sinusitis and/or facial cellulitis have been described in mucormycosis. The mortality from mucor­ mycosis is high, 50 to 100 percent, and there is little doubt that the fulminating nature of the infection, late diagnosis, and lack of rational therapy account for the poor prognosis. Other important symptoms include blood­tinged nasal discharge, unilateral facial pain or numbness. Occasionally, the most significant presenting symptom is necrotic ulceration or sloughing of the maxillary or palatal mucosa.

Diagnosis and Management Diagnosis is confirmed by smear and histo­ logical demonstration of tissue invasion by hyphae. MRI may show thickening of the mucosa with patchy destruction of the antral walls in sinus infection. Management of mucor­ mycosis comprises of, (i) detection of acidosis or other predisposing factors (ii) antifungal therapy using amphotericin B, and (iii) surgical debridement.

Paracoccidioidomycosis (South American Blastomycosis) South American blastomycosis caused by Para­ coccidioides brasiliensis is a chronic granulo­ matous disease which primarily infects the lungs and then disseminates to form ulcerative granulomas of the oral and nasal mucosa or other organ systems. This infection cannot be transmitted from human­to­humans. Lymph nodes are commonly involved in mucormycosis and local extension to skin or systemic involvement of multiple organs may occur. The disease is restricted to South and Central America, especially Brazil. The source of the infection is thought to be soil and vegetative material and is acquired by direct inhalation or by direct contact. Infection is present 10 times more commonly in males that females, especially in the 20 to 40 year­old age group. Clinical cases of South American blastomycosis can be classified in one of three categories:

pulmonary, mucocutaneous, lymphangitis or disseminated.

Oral Considerations The oral manifestations of this fungal infection are common and may present in all three forms of the disease. Primary infection of the mouth or gastrointestinal tract is thought to be rare and hence oral lesions are mainly secondary. In the mucocutaneous form of the disease the oral lesions may be the most apparent presenting symptom. The lesions appear initially as small papules or vesicles, which then ulcerate and appear as shallow ulcers with a rolled edge and a white exudative base studded with small hemorrhagic dots. The lesions have a granulo­ matous appearance and spread slowly, causing extensive local destruction. Pain is not usually a feature of early lesions but may become severe as the disease progresses, leading to cachexia as a result of acute pain on eating. In severe cases, infection may extend into bone, leading to perforation of the hard palate. Gross fibrosis and scarring may occur as a result of attempted healing. Lesions have been described in almost all parts of the mouth and pharynx including the hard and soft palates, gingiva, tongue and tonsils. Infections in the gingival and periodontal tissues may lead to loosening and loss of teeth. Infiltration of the oral tissues, especially the lips and cheeks, may severely reduce facial mobility and radically inhibit movement of the mandible. The face may become grossly swollen, and the mouth held open with a constant escape of saliva at the angles. Regional lymph nodes draining the areas involved enlarge and often suppurate with the formation of sinus tracts. The fluid which drains from the sinuses contains numerous fungal cells.

Diagnosis and Management Diagnosis is confirmed by histology and culture. Sulphonamide or amphotericin B, alone or in combination, is the treatment of choice. The doses used and length of administration are matters for expert clinical judgment in individual cases. Ketoconazole has been successfully used in the management of paracoccidioidomycosis.

Penicilliosis

Oral Considerations Skin lesions are usually located on the face, trunk and extremities. The most common skin lesions are papules often with a central necrotic umbilication with or without subcutaneous abscesses that may ulcerate. Intraorally the lesions may be seen as papules, as erosions or shallow ulcers of varying size covered with yellow necrotic slough. The palate, gingiva, labial mucosa, tongue and oropharynx are the most common sites involved.

Diagnosis and Management Diagnosis is confirmed by histology and culture. Although itraconazole is extremely effective against P. marneffei infection, initial treatment is usually amphotericin B followed by oral itraconazole up to 10 weeks. As relapse is common, long­term maintenance therapy with itraconazole is recommended.

Sporotrichosis Sporotrichosis is a chronic nodular subcutaneous mycotic disease with a worldwide distribu­ tion, but is most frequently found in Central

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Penicillium marneffei is a yeast­like fungus and cause disease—penicilliosis, in the normal host, as well as in immunosuppressed patients, but significantly, it has now become a major opportunistic pathogen in HIV­infected patients in Indochina, particularly Northern Thailand. Imported cases of P. marneffei infections have been reported from Australia, France, Italy, Netherlands, UK and United States. Humanto­human transmission of penicilliosis is highly unlikely. P. marneffei infection may either be dis­ seminated or focal in patients who are otherwise healthy, but in HIV disease dis­ seminated infection is the norm. The clinical and histological appearances of focal infection strongly resemble tuberculosis. Fungaemia may be present in systemic disease together with skin affections, reticuloendothelial system, lung and gut. Patients usually present with non-specific symptoms of fever, anemia and weight loss.

America, Brazil and Mexico. The causative agent is Sporotrichum schenckii, a fungus found in moss, soil and rotting wood, with the result that such persons as agricultural workers, florists and miners have a higher incidence of the infection than the general population. Sporotrichosis is highly unlikely to be transmitted from human­ to­humans. Sporotrichum schenckii gains access to the subcutaneous tissues via traumatic lesions, and proliferation of the fungus leads to the appearance of a nodule or small ulcer as soon as five days or as long as six months after inoculation. The nodule becomes a bubo, which may change color from pink to purple then ulcerate. The common site of the primary lesions is the finger, although the face can also be involved. After several weeks or months the initial lesion tends to heal with scarring, as new buboes develop in other areas. The regional lymph nodes become infected and the spread of the fungus can be recognized by the inflammation of the lymph vessels draining the initial lesion. The infection usually becomes chronic and locally destructive or may disseminate to the skin, oral mucosa, bone and other organs.

Oral Considerations The oral manifestations of sporotrichosis may be primary, which is rare, or secondary as a result of dissemination from the skin or lung. The lesions are initially erythematous, ulcerative and suppurative and eventually become granulomatous, vegetative or papillo­ matous. The oral lesions are usually painful and the regional lymph nodes are hard and enlarged. The mucosal lesions usually heal without residual scarring. Oral sporotrichosis may resemble aphthous ulcers, lichen planus, secondary cutaneous leishmaniasis. On rare occasions the nose and sinuses may be involved with extension of infection to the orbit.

Diagnosis and Management Diagnosis is confirmed by histology and culture. Amphotericin B is the most effective drug for treating relapsed lymphocutaneous sporotrichosis or the pulmonary and disse­ minated forms of the disease. Itraconazole is an alternative.

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Box 16.1: Oral fungal infections Key features useful in diagnosis • Most common oral mucosal infection is candidiasis • Candidiasis is usually seen in `the very young, the very old and the very sick’ • Candidiasis could be primary (restricted only to the oral mucosa) or secondary (as a part of widespread systemic affection) • Most oral fungal infections (80–90 %) are caused by Candida albicans • Primary candidiasis is often due to an underlying predisposing factor such as a poorly fitting denture • The classic triad of oral candidiasis are pseudomembranous (most common), erythematous and hyperplastic (least common) variants • Pseudomembranous candidiasis is characterized by easily wiped off, creamy white, curd-like patches on protected sites of oral mucosa, such as in sulcal areas with low salivary flow and tongue movement • A Gram stain of the pseudomembrane shows necrotic epithelial tissue held together by matted filamentous elements of Candida, with or without polymorphonuclear leukocytes • Erythematous lesions are usually seen as red patches over palatal (mostly posterior) mucosa, and as depapillated areas of the tongue • Hyperplastic lesions are discrete raised plaques often seen in retrocommissural area, that cannot be wiped off (compare pseudomembranous variant) • Candidiasis in immunocompromised patients may take a more widespread form with contiguous lesions of erythematous and pseudomembranous variants (multifocal candidiasis) on the mucosa, and represents a more widespread affection • Oral lesions of deep mycotic lesions are rare and often present as nodules or necrotic ulcerations and they are almost exclusively found in patients with compromised immune systems • Differential diagnosis of a chronic oral ulcer in compromised patients should include rare mycoses such as histoplasmosis and cryptococcosis.

ORAL VIRAL INFECTIONS The vast majority of virus infections of the oral mucosa are due to the herpes group of viruses. Of some 80 known herpesviruses eight are human pathogens of which herpes simplex virus causes a contagious infection with a large reservoir in the general population. Occasionally other viruses, such as coxsackieviruses, papillo­ maviruses and paramyxoviruses (which cause measles and mumps), may manifest with oral symptoms.

Primary Herpes Simplex Infection: Herpetic Stomatitis (HHV-1, HHV-2)

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Herpetic stomatitis is the most common viral infection to affect the mouth; it is caused by human herpesviruses 1 and 2 (HHV­1, HHV­2). The incubation period is about 5 days and the virus is transmitted by contact with skin lesions or infected saliva. Children may carry the virus

asymptomatically, or as convalescent carriers, in saliva for several months, but the virus is rarely isolated from adults once the primary lesion heals. The early­childhood infection is usually subclinical, frequently dismissed as ‘teething’, but if the infection occurs in adults the symptoms are obvious and severe. In countries with high standards of hygiene, there is an increasing frequency of adults presenting with primary herpes.

Clinical Features In the initial stages there is mild to severe fever and enlarged lymph nodes, with pain in the mouth and throat; then a variable number of vesicles develop haphazardly on the oral mucosa, the tongue and gingivae. These vesicles rupture quickly to form small round or irregular superficial ulcers with erythematous haloes and grayish­yellow bases. The gingivae are inflamed and the infection may be confused with acute

Secondary Herpes Simplex Infection: Herpes Labialis (HHV-1, HHV-2) About one­third of the patients who have had primary infection develop herpes labialis (cold sore) in later life as a result of reactivation of the latent virus, which usually resides in the trigeminal ganglion. The stimulus for reactiva­ tion could be: • Stress • Trauma • Exposure to sunlight • Menstruation • Debilitating disease. The lesion develops at the mucocutaneous junction of the lip or on the skin adjacent to the nostrils. Characteristically the lesions are preceded, some 24 hours before, by a pre­ monitory sign of itching, prickling or a burning sensation. Blisters then develop, enlarge, coalesce, rupture, become encrusted and heal within 10 to 14 days. Intraoral recurrent herpetic infections are infrequent; they involve the hard palate, alveolar ridges and gingiva. These lesions develop in a similar manner to those of the lips, and appear as a cluster of small, shallow ulcers with red, irregular margins. Pain is not a common feature and the intraoral lesions may or may not recur intermittently for years.

Herpetic Dermatitis and Herpetic Whitlow (HHV-1 and HHV-2) Primary herpetic dermatitis is localized and characterized by pruritus, burning and pain. Multiple vesicles appear, persist for 4 to 5 days and burst, with resultant crusting scabs which heal within 2 to 3 weeks. Dentists who escaped exposure in childhood may contract herpetic dermatitis from patients who have either primary or secondary herpes. Infection may take the form of a herpetic whitlow on the finger,

resulting in an intensely painful lesion. Herpetic whitlow may recur, but less frequently than the perioral infection.

Laboratory Diagnosis of Herpetic Infection It is useful to establish definitive diagnosis of the lesion through laboratory tests. These include viral isolation in tissue culture, cytological examination, direct fluorescent antibody tests, serological assays and DNA detection by PCR based methodology.

Direct Examination and PCR Technology

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necrotizing ulcerative gingivitis (ANUG) of bacterial origin. In some, ANUG may develop secondary to primary herpetic stomatitis. The mouth is sore and eating and swallowing may be difficult. The lesions resolve without scarring within 5 to 10 days. Intraoral viral shedding may persist for several weeks after clinical resolution.

Smears of lesions stained with monoclonal fluorescent antisera to herpes simplex virus type 1 or 2 (HHV­1 or ­2) provide specific and rapid diagnosis. Although PCR based techniques have superseded antibody based cytology, the former is more expensive and not readily available as yet.

Culture Herpes simplex virus is readily isolated from samples of oral lesions in a variety of tissue culture systems. Appropriate transport media should however, be used when sending samples for virology tests.

Serology In primary infection a fourfold or greater increase in antibody titer between the acute and convalescent sera is indicative of recent infection with herpes simplex virus. The dem­ onstration of immunoglobulin M (IgM) anti­ bodies by immunofluorescence techniques in a single sample can also be used in diagnosis.

Management Moderate to severe primary herpetic stomatitis is treated with oral and topical aciclovir, together with symptomatic measures. However, the use of aciclovir in recurrent herpetic infections should be limited to immunocompromised patients and those who have a past history of severe, extensive or frequently recurring

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lesions. The patients should apply the drug before vesicles form to obtain the best results. For those not responding to topical applications a low prophylactic dose of acyclovir may assist to prevent recurrent infections.

Varicella and Zoster (HHV-3) Primary infection with the varicella­zoster virus causes chickenpox. Zoster or shingles is the secondary (synonym: post­primary, reactiva­ tion) infection due to the reactivation of the virus hiding in the latent form in sensory ganglia.

Chickenpox Chickenpox is a common infectious disease and is usually contracted in childhood.

Oral Manifestations Before the typical skin rash develops, lesions may be found in the mouth, especially on the hard palate, pillars of the fauces and uvula, although any area of the oral mucosa may be involved. The characteristic skin rash, which is centripetal, and progresses from macular to papular, vesicular and pustular forms before scabbing, helps to differentiate chickenpox from other causes of oral ulceration. The oral lesions consist of small ulcers surrounded by an area of erythema. The vesicles are quickly ruptured in the mouth and therefore rarely noticed. The lesions may be painful in adults, but children rarely complain of discomfort.

Shingles (Zoster) Shingles is a localized eruption due to the reactivation of the herpes zoster virus. It involves an area of skin supplied by one or more sensory ganglia in which the virus is residing. In some 10 percent of cases zoster reflects an underlying immune­deficiency state, possibly a neoplasm such as lymphoma or HIV disease.

Oral Manifestations

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The trigeminal nerve is affected in about 15 percent of cases, with the ophthalmic, maxil­ lary and mandibular divisions involved in that

order of precedence. The lesions of shingles may be found on the skin, on the oral mucosa, or both. Severe localized oral pain often precedes the rash and mimics the pain of toothache. The most common intraoral sites affected are the anterior half of the tongue, the soft palate and the cheek. The vesicles break down intraorally within a few hours to give very painful ulcerated areas with a yellowish­gray surface and ery­ thematous borders. The oral lesions heal more quickly than the skin lesions and rarely scar. Laboratory diagnosis of chickenpox and shingles. The clinical presentation is characteristic, but in unusual circumstances the disease can be confirmed in the laboratory by submitting: • Vesicle fluid for electron microscopy and virus isolation • Smears from an ulcer for immunofluores­ cence • Acute or convalescent sera to test for the presence of specific IgM antibodies by immunofluorescence. • PCR based assays.

Management Chickenpox is self­limiting; but an effective vaccine is available to prevent infection. For zoster, high­dose aciclovir (800 mg five times daily) should be prescribed as soon as possible, especially in immunocompromised patients.

Epstein–Barr Virus (Human Herpesvirus 4) Epstein-barr virus (EBV) is widespread in hu­ mans, and most adults have antibody to the virus. The virus persists in latent form within lymphocytes after primary infection (lympho­ trophic, unlike HSV and varicella-zoster virus, which are neurotrophic). The genome resides in a latent form in B cells; latent EBV infection is common in the population. It is the etiological agent of a number of diseases: • Infectious mononucleosis (glandular fever) • Burkitt’s lymphoma and other B-cell lymphomas • Nasopharyngeal carcinoma (especially in southern Chinese populations)

developed countries, primary infection is usually delayed to adolescence or young adulthood.

Infectious Mononucleosis

Diagnosis

An acute infection affecting lymphoid tissue throughout the body, infectious mononucleosis is commonly seen in teenagers, with a peak incidence at 15 to 20 years of age. The organism responsible—EBV, is present in saliva and is postulated to be transmitted during kissing— hence it is called the ‘kissing disease’.

As EBV cannot be easily propagated in culture, serological diagnosis is common: • Indirect immunofluorescence is used to detect EBV­specific immunoglobulin M (IgM): The antibody is directed against both the capsid antigen and a non­capsid early antigen • Hematology: A blood film is useful for dem­ onstrating atypical lymphocytosis in infec­ tious mononucleosis • Heterophile antibody (non­specific): Infec­ tious mononucleosis is characterized by the appearance of heterophile (hetero: other, phile: liking) antibodies in the patient’s serum, which agglutinate sheep or horse red blood cells. This property is made use of in the Paul-Bunnell diagnostic test.

Incubation Period Incubation is 4 to 7 weeks; possibly shorter (10– 40 days) in young children.

Signs and Symptoms These include low­grade fever with generalized lymphadenopathy and abnormal lymphocytes in the blood (note that a similar illness, glan­ dular fever­like syndrome, develops during the first fortnight after infection with human immunodeficiency virus (HIV)). Fever, tonsil­ litis and fatigue are common, and many patients have splenomegaly. Lymphocytosis is a characteristic feature, hence the term ‘mono­ nucleosis’; some 10 percent of the lymphocytes are atypical, with enlarged misshapen nuclei and increased cytoplasm.

Chronic, Persistent or Reactivated EBV Infection This may take many clinical forms and is less common than acute mononucleosis, described above. The syndrome is characterized by persistent fatigue, with or without physical or laboratory findings.

Epidemiology The virus is ubiquitous and humans are its only known host. Spread of EBV is via respiratory secretions, primarily through oral contact. Those from lower socioeconomic classes are exposed to EBV at an early age and typically develop asymptomatic infections, while in higher socioeconomic classes, particularly in

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• Oral hairy leukoplakia • Post-transplant lymphoproliferative diseases.

Treatment Infectious mononucleosis is generally mild and self­limiting, hence therapy is usually sympto­ matic.

Burkitt’s Lymphoma Burkitt’s lymphoma is a highly malignant tumor which spreads rapidly, with widespread metastases; it is particularly common in African children. The disease is especially common in areas of Africa with endemic malaria. Hence, it is thought that the effect of the malarial parasite on the reticuloendothelial system could cause an abnormal response to infection with EBV. Under these conditions the EBV may become frankly oncogenic, producing a malignant transformation in lymphoid tissue (lymphoma) instead of the benign proliferation seen in infectious mononucleosis.

Nasopharyngeal Carcinoma A tumor with a remarkable geographic and probably racial distribution, it is particularly common among the southern Chinese. EBV DNA is regularly present in the malignant epithelial cells of the tumor.

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transplant recipients often have local and disseminated CMV disease. The route of CMV transmission is not clear.

Diagnosis and Treatment Diagnosis is by viral isolation in human embryonic fibroblast tissue cultures; it is confirmed using immunofluorescence and DNA hybridization. There are no proven regimens for therapy and prevention of CMV infections.

Oral Manifestations of Other Herpesviruses (HHV-6 to HHV-8) Other herpesvirus infections are generally of minor consequence, except for Kaposi’s sarcoma caused by HHV­8.

Coxsackie Virus Infections Two diseases caused by group A coxsackie viruses produce oral signs and symptoms: • Hand, foot and mouth disease, caused mainly by coxsackie virus A16 and, less commonly, by types A4, A5, A9 or A10 • Herpangina, caused by coxsackie viruses A2, A4, A5, A6 and A8.

Oral Manifestations of Herpangina This febrile disease is characterized by sore throat, dysphagia, anorexia and occasionally a stiff neck. Accompanying oral signs and symptoms are small, papulovesicular lesions about 1 to 2 mm in diameter, with a grayish­ white surface surrounded by red areolae, especially in the palate. The disease lasts for about 3 to 4 days, the fever abates and the oral lesions heal promptly.

Paramyxovirus Infections

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Measles, mumps, parainfluenza and res­ piratory syncytial viruses are categorized as paramyxoviruses. Of these, measles and mumps are of concern in dentistry as they commonly manifest with oral signs or symptoms. Measles is discussed in Chapter 10; mumps is described later under salivary gland infections.

Diagnosis

Papillomavirus is a DNA virus and there are more than 80 serogroups. Some are associated with mucosal and skin malignancies than others. It has been found that nearly 40 percent of the adult population carry the virus in the oral mucosal surfaces, suggesting that mouth is a reservoir of the virus. Serotypes 16 and 18, which are the etiological agents of cervical cancer in women, are also linked to oral cancers.

Tuberculosis lesions are best diagnosed through histological examination of an oral biopsy.

Box 16.2: Oral viral infections Key features useful in diagnosis • Herpes simplex lesions present as painful shallow ulcers over the oral mucosa often associated with fever • In secondary herpes simplex infections (reactivation) there is often a preceding history of exposure to trigger factors such as exposure to sun, stress, and menstruation • Itching sensation of a focal area is usually a prodromal symptom of herpetic labialis • Intraoral lesions precede the generalized rash in chickenpox, but the maculopapular lesions may not be easily noticed due to bursting of the papule • EBV and CMV manifest as pharyngitis with associated lymphadenopathy and fever with generalized malaise.

BACTERIAL INFECTIONS OF THE ORAL MuCOSA • • • • •

Tuberculosis Syphilis Gonorrhea Streptococcal infections Actinomycosis.

Tuberculosis of the Oral Mucosa Mycobacterium tuberculosis and, rarely other mycobacterial species can cause chronic granulomatous lesions of the oral mucosa. It has been noted primarily in patients affected by HIV infection. Lesions could be primary or secondary (secondary to active pulmonary tuberculosis). Chronic, deep, irregular and painful ulcers on the lateral surfaces of the tongue are a common feature of primary tuberculosis, while secondary lesions are indurated painful ulcers.

Syphilis Syphilis has regained prominence as a sexually transmitted disease as a result of increasing high­risk sexual behavior across populations in the world. Oral syphilis may therefore be the presenting feature of a wide spectrum of sexually transmitted diseases including HIV. The disease is caused by a bacteria Treponema pallidum. Because the presentation of different stages of syphilis is highly varied, it is often called the ‘great imitator’ of diseases.

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Human Papillomavirus Infections

Primary Syphilis The chancre is the defining lesion of primary syphilis. It is not as common as genital lesions occurring in some 10 percent of the cases. Transmission is primarily due to orogenital or oroanal contact and rarely through kissing. Lips and the tongues are the common sites affected. The ulcers are usually deep, with a red, purple, or brown base and an irregular raised border. The lesions usually heal within about five weeks. Regional lymph node enlargement is a common feature during the early phase of the infection. Due to its painless nature the chancres may go unnoticed or mistaken for other solitary ulcerations on the oral mucosa. The lesions contain live organisms and are considered highly infectious.

Diagnosis The detailed analysis of the sexual/social lifestyle including the details about sexual partners is necessary to arrive at a presumptive diagnosis. The early laboratory diagnosis may be difficult because the first line of non specific tests (Rapid Plasma Reagin, RPR and Venereal Disease Reference Laboratory, VDRL) take time to become positive. The specific tests for IgG antibodies to T. pallidum become positive before VDRL and RRP tests, and thus should be carried out when a diagnosis of primary disease is likely. Although the lesions are full of live tre­ ponemes, which can be demonstrated through

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dark field microscopy, it is generally not recom­ mended to do so for the risk of nosocomial trans­ mission and the confusion with the treponemes of the normal oral flora (T. denticola, T. pectino­ vorum and T. vincentii).

Secondary Syphilis Oral lesions in secondary syphilis is the result of blood­borne spread of Treponema pallidum. Unlike primary syphilis, the oral manifestations are more varied and can be extensive. Nearly one­third of the patients with secondary syphilis may have oral lesions. Mucosal patches are the most common lesion found on the oral mucosa. These are usually distributed over the tonsils, soft palate, tongue and cheek (Fig. 16.8). Regional lymph node enlargement is a common feature and they tend to have a rubbery consistency. The grayish surface of the lesions are easily removable and contains numerous spirocheates. Therefore, the lesions themselves are infectious. Coalescence of these lesions lead to serpiginous lesions termed as ‘snail tract ulcers’. Sometimes snail tract ulcers occur de novo as well. These lesions heal spontaneously within 2 to 6 weeks and recurrences are seen in about 25 percent of the patients. However, unrelated antimicrobial treatment can expedite the healing of these lesions. In addition to the maculopapular and mucosal patches, nodular necrotic lesions can

be seen on the oral mucosa (lues maligna). These necrotic lesions are associated with systemic symptoms like fever, headache and myalgia and are common among patients who are also infected with HIV. The nodular lesions are commonly seen on the oral mucosa and may mimic malignant lesions.

Diagnosis Although T. pallidum can usually be detected on the surface of erosions or ulcers by darkfield microscopy, it is best avoided for the reasons mentioned above. The histopathological features of secondary syphilis vary. However, perivascular infiltrates with a preponderance of plasma cells are a major feature.

Tertiary Syphilis Approximately one­third of patients with untreated secondary syphilis progress into a much more systemic form of the disease called tertiary syphilis. The characteristic lesion of this stage of the disease is the formation of gumma. Inside the oral cavity gummata are commonly seen on the hard palate .The lesions start as small, midline, pale, raised and painless area. Ulcerations follow and rapid progression to large necrotic zone with exposure of bone is a common feature. The palate may get perforated into the nasal cavity. Unlike in the primary and secondary disease no treponemes could be found in gummata. More rarely, interstitial glossitis which manifest as atrophy of filiform and fungiform papillae develops. These lesions lead syphilitic leukoplakia and are thought increase the development of oral squamous carcinoma.

Diagnosis

Fig. 16.8: Mucosal patches of secondary syphilis

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Histological examination of the gummata characteristically show endarteritis obliterans, necrosis with epithelioid and giant cells and a plasma cell infiltrates. At this stage, the nonspecific tests (VDRL and RPR) may not be positive; the most reliable serological test is FTA which might remain positive long after the treatment is finished.

Gonorrhea

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Oral gonococcal infections principally affect the tonsillar surfaces and the oropharynx, but gingivostomatitis is also common. The causative organism is Neisseria gonorrhoeae, a Gram­ negative diplococcus. The clinical presentation varies from mild erythema to deep ulcers covered by a pseudomembrane. The disease is often transmitted sexually through orogenital contact and thus is common among the sexual active persons and can affect the male and female alike. It often coincides with the genital infections and isolated oral infections are rare. Moreover, transmission of pharyngeal infection to other sites is also uncommon. Disseminated gonococcal infection occurs particularly in patients with complement deficiency, particularly the membrane attack complex (C5b, C6, C7, C8, and C9).

cosa

Box 16.3: Oral bacterial infections Key features useful in diagnosis • The typical lesion in primary syphilis is a chancre; a deep reddish purple painless ulcer with raised edges (differential diagnosis includes carcinoma and tuberculous ulcer) • Oral chancres are uncommon and demands a high degree of suspicion • Chancres are full of live treponemes but interpretation of direct smears may be difficult as commensal treponemes can affect the interpretation of the findings • Secondary syphilis lesions present as mucosal patches over the oral mucosa with associated lymphadenopathy • Coalescence of these lesions lead to serpiginous lesions termed as `snail tract ulcers` • Lues maligna is a type of nodular lesion found over the palatal surfaces in secondary syphilis • Tertiary syphilis is a more systemic form of disease and characterized by the formation of gummata • Gummata are common over the palatal surface and have a nodular appearance • Left unattended these lesions can become necrotic leading to widespread palatal perforations.

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increased human movement has resulted in cases reported sporadically in more than 90 countries of the world. There are more than 20 species of the parasite that affects humans. Four species known as the Viannia subgroup (L. braziliensis, L. amazonensis, L. panamensis, and L. guyanensis) cause the mucocutaneous lesions. The disease is transmitted through the bite of sand flies, Phlebotomus and Lutzomyia. The most common presentation of mucocu­ taneous leishmaniasis is persistent nasal con­ gestion and erosive erythematous ulcers can be seen around the nares and lips in advanced cases. In more severe cases palatal ulceration, gingival edema, and periodontitis develops. Eventually, progressive destruction mucosa, and cartilaginous facial and upper airway struc­ tures, resulting in secondary infection, disfigu­ ration and airway obstruction.

Diagnosis Biopsy and demonstration of intracellular amastigotes are required for diagnosis. Histo­ logical examination of the biopsy material or touch smears from lesions may only show few parasites. However, specimens commonly reveal granulomatous reaction.

Myiasis Oral myiasis often associated with severe underlying immunocompromised status such as neutropenia and malignancies. Malignant ulcers can be infested with fly eggs and they are hatched into larval forms which may be visible at the time of examination.

Treatment Therapy with ivermectin and manual removal of the larvae is the standard mode of treatment but the lesions are very difficult to eradicate unless the underlying condition is treated.

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Box 16.4: Oral parasitic infections Key features useful in diagnosis • Mucocutaneous leishmaniasis may present as lip nodules, often represent a part of a more widespread disease. • In more advanced cases there can be erosive erythematous ulcers seen around the nares.

SELF-ASSESSMENT quESTIONS 1. Provide a classification for candidal lesions of the oral cavity. 2. Discuss the importance in ‘in toto’ assessment of a dental patient in relation to the diagnosis of candidal and other fungal infections. 3. List the predisposing factors for the develop­ ment of oral candidiasis together with examples of the situation in which they may occur. 4. Describe the orofacial presentation of human herpes virus infection. 5. List the common bacterial infections of the oral cavity and describe their clinical presentation. 6. Discuss the interpretation of laboratory tests in the diagnosis of the different stages of syphilis. 7. Discuss the relevance of a direct smear in the diagnosis of viral infections of the oral mucosa. 8. Give an account of parasitic infections of the oral mucosa. 9. List the oral manifestations associated with systemic viral infections. 10. List the (i) common and (ii) uncommon infectious diseases that may cause oral ulceration.

SuGGESTED READING 1. Samaranayake LP. Essential Microbiology for Dentistry, 3rd edn. Edinburgh: Churchill Livingstone Elsevier; 2006. 2. Scully C, de Almeida OP. Orofacial manifestations of the systemic mycoses. J Oral Pathol Med. 1992;21:289-94.

Chapter

17 Connective Tissue Diseases Richard J Cook

Chapter Outline Soft Tissue Conditions • Systemic Lupus Erythematosis (SLE) • Antiphospholipid (Hughes) Syndrome • Systemic Sclerosis or Scleroderma • Dermatomyositis and Polymyositis Group of Conditions Mixed Connective Tissue Disease • Sjögren’s Syndrome

Systemic Vasculitis Raynaud’s Disease and Phenomenon Hard Tissue Disorders/Arthritides • Osteoarthritis • Rheumatoid Arthritis Self-assessment Questions

ORAL MEDiCinE AnD PAtHOLOGy: A GuiDE tO DiAGnOSiS AnD MAnAGEMEnt

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Autoimmune and connective tissue disorders represent a group of conditions in which the humoral and cell based immune defense system has malfunctioned and recognized host tissue and cell structures as hostile. Accordingly, the patterns of disease can be specific but more often are a mixture of common and less common symptoms and signs requiring interpretation and judgment to establish a diagnosis. Connective tissue disorders are characterized by a series of signs and symptoms linked (to variable extents) by a common etiology of multiple autoantibody production, immune complex deposition and vasculitis, causing joint, soft tissue and muscle pain with inflammation. The most classical hard tissue condition a rheumatologist would manage is rheumatoid arthritis. In terms of the soft tissue conditions, the three classic conditions a rheumatologist might consider in this group are: 1. Systemic lupus erythematosus (SLE) (and the discoid/DLE variant). 2. The poly and dermatomyositis groups of conditions. 3. The systemic sclerosis group. Such conditions are regarded as nonorgan specific. In contrast, organ specific conditions feature an autoantibody targeted at a specific tissue or cell function, e.g. pemphigus, pemphigoid, myasthenia gravis, pernicious anemia and Grave’s type hyperthyroidism. These conditions will not be considered further here (See Chapter 15). A patient with an autoimmune disease is most likely to be female, the more prevalent tissue types in the group being HLA B8, B51 (Behçet’s) DR3 and DR4 (rheumatoid). Autoantibodies may well be detectable in the serum, which can be indicative of the condition, but rarely diagnostic, without additional clinical evidence. Circulating autoantibodies may be detectable in clinically uninvolved relatives too, but a family history is common in these conditions. In general terms, the disease group is managed by immunomodulatory drugs. While it is convenient to consider these diseases as separate entities in descriptive

Fig. 17.1: Complex mixes of autoimmune conditions—overlaps and mixed patterns are common and some of the more common overlaps are shown here. SySc: Systemic sp sclerosis; PM and DM: Poly and dermatomyositis; SLE: Systemic lupus erythematosus; SjSy: Sjögren’s syndrome; RhA: Rheumatoid arthritis; MCt: Mixed connective tissue disease; OS: Overlap syndrome. Readers should note these are illustrative: Many more overlaps occur—particularly between right and left side—as if the diagram was a continuum arranged around a cylinder

terms, they have many symptoms, signs and investigation results in common, leading to the concept of “overlap syndrome” or “mixed connective tissue disease”—which includes common elements of two or more of these conditions (Fig. 17.1). Of additional interest to oral care practitioners are the hard tissue rheumatological disorders, classically rheumatoid arthritis and its variants, sharing the same fundamental etiopathological mechanism but typically manifesting in joint damage. These conditions all have a common link as potential primary causes of secondary oro-ocular and genital dryness, i.e. Sjögren’s syndrome—discussed in Chapter 11. The terminology designating primary/secondary is currently under revision.

SOft tiSSuE COnDitiOnS Systemic Lupus Erythematosus Systemic lupus erythematosus can present with a host of symptoms, being a multisystem disorder, and consequently is the most common

Genetic

infection

increased incidence in HLA-B8 and DR3 Also 25% concordance for SLE between identical twins suggesting a heritable predisposition viral agents are thought most likely agents to be able to trigger such an immunologic condition

Drugs

immunological

Gender

female gender predominance

connective tissue disorder, characterized by elevated serum autoantibodies against elements of the cell nucleus—the ANAs, in particular the double-stranded DNA autoantibody (Table 17.1). Lupus can be subdivided into the systemic, drug related and benign discoid forms. The title “lupus” refers to tissue damage as resembling “wolf bites” and erythematosus describes the red lesions—particularly butterfly rash over the nasal and malar regions, induced by bright artificial and sunlight UV sensitivity.

Epidemiology With a peak incidence in women in their third and fourth decades, approximately 0.1 percent of the western population are said to be affected, with a predilection for those with African heritage.

Etiology Unsurprisingly in a multifactorial condition this remains obscure, but a series of factors have

been identified as likely agents (risks or risk factors) for developing lupus (Table 17.1).

Signs and Symptoms The majority of SLE symptoms are driven by the immune complex deposition associated vasculitis and the condition can vary in severity, from minor symptoms to life-threatening organ involvement (particularly renal). In small vessels, immune complexes lodge and fix, whereas in larger vessels, more active complexes bind to vessel wall ligands (and can precipitate in large vessel wall microcirculations too) to exert their proinflammatory effects and establish patterns of inflammation, capable of irritating and subsequently obstructing vessels as endothelium and flow both degenerate. A flitting asymmetrical polyarthralgia (painful joints) is one of the most common symptoms. Unlike rheumatoid arthritis, joint swelling and damage is very rare in pure lupus. The definitive butterfly rash, fanning out onto the cheeks from across the nasal bridge, reflects a solar sensitive cutaneous vasculitis— but is not always present (Figs 17.2A and B). Nonspecific features such as recurrent fevers, low mood, and a general sense of ill health may dominate the clinical presentation although many features may present (Table 17.2). The benign variant: Discoid lupus may only involve orocutaneous epithelial tissue. Typically a solar sensitive, patchy, crusting lupine rash arises in exposed skin, which can develop to include scarring, depapillation in hairy skin, and later pigmentation, along with a lichen like, reticular hyperkeratotic lesion in the oral mucosa, which can also erode and settle leaving postinflammatory pigmentation (Fig. 17.2)— often the buccal epithelium. Joint pains are often the only other complaint. A diagnostic biopsy may show a perivascular rather than purely subepithelial inflammatory infiltrate— helping to discriminating it from lichen planus. Serological investigations are usually negative but elevated serum ANAs are noted in the majority and other immune markers may be weakly positive only. It is considered unlikely for DLE to herald SLE development in most cases, and is best controlled with topical steroid preparations.

17 seases

ƒ Table 17.1 Etiological factors in development of lupus

385

ORAL MEDiCinE AnD PAtHOLOGy: A GuiDE tO DiAGnOSiS AnD MAnAGEMEnt

17

386

A

B

Figs 17.2A and B: Lupus features. (A) typical photosensitive lupus rash across nasal bridge and into cheeks; (B) intraoral lesions forming discoid erosions and pigment deposition at sites of former inflammatory processes

Diagnostic Investigations

Immunological findings in lupus:

In lupus, a chronic disease (normochromic, normocytic) anemia pattern is often seen on blood film. Consumption of inflammatory mediators during active flares produces a low complement level, leukopenia and thrombocytopenia, typically with a raised ESR but unaltered CRP. The classic autoantibody detectable is the antidouble-stranded DNA (dsDNA) which may be regarded as diagnostic for SLE—but is only positive in approximately 50 percent of cases. Rheumatoid factor is positive in approximately 25 percent of cases and anticardiolipin antibodies are detectable in 30 to 40 percent of patients too. A biopsy of involved tissue may (inconsistently) show a vasculitis pattern—of importance in an oral biopsy of suspected Lichen planus— which can alter the diagnosis to discoid lupus instead. Basement membrane thickening, acanthosis and epithelial thinning with inconsistent grainy immunofluorescence against immunoglobulins, and complement at the basement membrane and perivascularly, are present both in normal and lesion/peri-lesional immunofluorescence biopsies.

• ANA+ve ~90 percent cases • Anti-DNA—especially dsDNA—positive • Rheumatoid factor positive ~30 percent cases • Anti-RNA antibody +ve • Anti-Smith antibody positive (highly specific but not sensitive for SLE) • Positive LE cell preparation (neutrophil/ macrophage containing phagocytosed nuclear material (Hematoxylin body) indicating cell damage. • Elevated ESR and γ globulins • False positive syphilis serology (VDRL test) (useful to discriminate from rheumatoid) The American College of Rheumatology defines a diagnosis of lupus as having at least four of the main criteria found both in Table 17.2, and the immunological features listed.

Therapies Lupus management is usually proportionate to the signs, symptoms and degree of disease activity at the time which can characteristically flare and remit over years. Nonsteroidal

17

Common > 75% cases

Frequent 50–75% cases

Less common 60 minutes

low dependence

Degree of dependence

Set the quit date.

Step 4: Quit Date On the quit date, ideally, the patient will be released from the dental practice as a former smoker. It may be worthwhile to give each individual patient a written recommendation for the use of nicotine replacement therapy for the following three months. Confirm or redefine the replacements that have been identified. Give the patient a written recommendation on nicotine replacement therapy on the basis of both his and her smoking behavior and degree of nicotine dependence.

Arrange Experience reveals that smokers have to make several attempts to quit smoking before staying Box 24.2: Care models for dental settings Key features in management • Following a level of care model, tobacco use pre vention and cessation (TUPAC) in the dental treatment setting occurs in brief interventions over repeated visits. • All patients visiting a dental practice have to be asked about tobacco use on a regular basis. • With all tobacco users, the readiness to quit has to be assessed. • Brief Motivational Interviewing (BMI) appears to be suitable for use during brief interventions for tobacco use prevention and cessation in dental practices. • With all tobacco users willing to quit either referral to tobacco use cessation specialists or in-house support (behavioral support and pharmacother apy) has to be arranged. • evidence-based guidelines indicate counseling and pharmacotherapy when used in combination are more effective in improving quit rates (Box 24.3) than either alone.

a former smoker. Of the patients who initially succeed in kicking the habit, 50 to 60 percent will suffer a relapse within the next year. Even though there are at present no evidence-based methods for preventing relapses, the dental practice team can continue to offer support during their patients’ repeated attempts to quit smoking. Alternatively, the patients can be referred at this time to tobacco use cessation specialists, their family doctors, pharmacists or psychotherapists.

Pharmacotherapy for Tobacco Use Cessation Nicotine Replacement Therapy The symptoms of nicotine withdrawal can substantially hamper a person’s success to quit smoking. The most common symptoms of nicotine withdrawal are reported to be headache, gastrointestinal complaints, sleeping disorders, depression and increased appetite. Withdrawal usually occurs shortly after the person has smoked his or her last cigarette and occasionally lasts for several days or a few weeks. Withdrawal symptoms can be significantly reduced by pharmacotherapy, e.g. with the replacement of nicotine. It can help former smokers to resist their withdrawal symptoms and to carry out the replacements instead as planned. Nicotine replacement therapy (NRT) is shown to increase success rates by roughly 100 percent. Additionally, research on NRT consistently revealed that comparable success rates were achieved with the use of nicotine gum, nicotine sublingual tablets or lozenges, or nicotine patches. If there are no medical contraindications for the patient, NRT products can be used without restrictions. Nevertheless, some reservations remain for pregnant women and patients with cardiovascular conditions. Literature suggests, however, that the benefits of NRT for smoking cessation may outweight the detrimental effects from the continued use of tobacco. Significant success rates from the use of NRT will be achieved when the appropriate product is selected adjusted to: 1. The degree of nicotine dependency and 2. The individual smoking behavior (Table 24.1).

24 ssation

On the basis of the answers to these questions, the patients can be divided into four groups: extremely dependent, very dependent, moderately dependent and slightly dependent. The answer showing the greatest dependency indicates the overall dependency.

547

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24

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In general, patients with “high” or “very high” nicotine dependence are advised to take combinations of NRT. Furthermore, NRT should be used for the entire duration of the therapy (3 months), while the nicotine dose will be reduced every month as suggested by the manufacturer.

Bupropion SR Sustained-release Bupropion (Bupropion SR) is a non-nicotine-containing drug used for tobacco use cessation therapy (Zyban®, Wellbutrin®, GlaxoSmithKline, USA). With Bupropion, the neuronal uptake of catecholamines will be selectively inhibited in the central nervous system. Consequently, catecholamine levels will increase in certain areas of the brain resulting in the reduction of nicotine withdrawal symptoms. The manufacturer recommends that Bupropion SR is prescribed for the duration of seven weeks. In order to reach therapeutic levels, Bupropion SR will have to be taken for two weeks. Tobacco use should be ceased only after therapeutic levels have been established. During the first week, it is recommended that 150 mg of Bupropion SR is taken per day. After one week, 150 mg will be taken twice daily for the duration of six weeks. The efficacy of Bupropion SR either alone or in combination with other nicotine replacement therapy options was evaluated with nondepressed cigarette smokers in placebocontrolled double-blind trials. The abstinence rates for the use of Bupropion SR alone was 23.1 percent following 12 months after the quit date, and 35.5 percent following 12 months when Bupropion SR was used in combination with nicotine replacement therapy. The most common side effects of Bupropion have been described as insomnia, headaches, and dry mouth. Prior to prescription, it has to be noted that the simultaneous use of psychotropic drugs or cortisone should be avoided. Further contraindications exist in patients with a history of bulimia, anorexia nervosa, and in those who experience epilepsy. Pregnant women are to be advised not to take Bupropion SR, since its safety during pregnancy has not been studied in clinical trials.

Box 24.3: Pharmacotherapy for tobacco addiction Key features of evidence-based management • Nictotine replacement therapy (NRT) is the most common medication used to assist tobacco cessation. • NRT is available in several formulations: transdermal patch, nicotine gum, lozenge, nasal spray and inhaler. • NRT agents can be combined to obtain a better outcome. • Medications that can be prescribed via a GP practice includes bupropion and varenicline. • Several second–line therapies are also available for those who relapse following treatment.

Varenicline Varenicline has been specifically developed for smoking cessation therapy (Chantix®, Champix®, Pfizer Inc. USA). Varenicline connects as a partial agonist with a high affinity to the α4β2nicotinic acetylcholine receptors in the central nervous system. Subsequently, the binding of nicotine will be blocked resulting in the elimination of its addictive effect. Additionally, the binding of Varenicline sufficiently reduces the symptoms of craving and withdrawal. Varenicline prescription is recommended for the duration of three months and may be extended if necessary by a subsequent three months. In order to reach therapeutic blood plasma levels, 1mg of Varenicline will be taken per day for the duration of one week. Only thereafter, tobacco use should be ceased. After one week, 1mg will be taken twice daily for the duration of 11 weeks. Five clinical studies involving a total of approximately 4300 patients, mostly heavy, long-term smokers have shown significantly greater success rate following one year after quit date with Varenicline (14.4–23%) and placebo (3.9–10.3%). When taking Varenicline for the duration of six months, one-year success rates of 43.6 percent have been reached. The most common side effects of Varenicline include dizziness, insomnia, indigestion and vomiting. Patients with renal insufficiency and

Advanced Care Some smokers eventually relapse while receiving treatment or after quitting for a period of time. Their powerful addiction requires intensive treatment. When first-line treatments have failed or are not tolerated, second-line agents are available for use in addiction specialist centers. These include nortriptiline—a tricyclic antidepressent agent and clonidine—an antihypertensive. These may have adverse side effects and should be used under appropriate settings. New medications and nicotine vaccines are also being tried as Phase II trials. New agents include monoamine type B (MAO-B) inhibitors —for example, selegiline, cannabinoid receptor 1 (CB1). These agents are currently under investigation in specialist centers.

DeTeRMINANTS OF BehAVIOR ChANGe The readiness to accomplish behavior change is often described by the so-called transtheoretical model, according to which a person trying to change his or her behavior passes four different stages: pre-contemplation (“lack of awareness”), contemplation (“gaining of awareness”), preparation (“getting ready”) and action (“implementation”). A suitable model for behavioral support in tobacco use cessation would help patients to move from one stage to the next. However, when asked about their readiness to quit smoking, tobacco users frequently respond that they want to quit “sometime” but that this time has not come yet: there would be certain things to be accomplish first, such as to take a final exam or to recover from an emotional trauma. In many ambivalent cases, smokers have learned or created these excuses to continuously justify their tobacco consumption. Behind this attitude, however, there may the fear of failure to quit, an unpleasant memory of a failed past attempt, or a concern about gaining weight. During the kind of skillful counseling, excuses of this kind can be identified in a nonoffensive way. Possibly, the counselor will be able to touch on them without triggering resistance on the part of the smoker.

Fear to Relapse

24

The fear to relapse is a considerable issue in tobacco use cessation counseling. Many smokers have a significant concern to fail quitting and they often lack self-efficacy. Former smokers frequently report that they successfully quit because they “believed in themselves” and “believed they would make it”. It was this belief, many say, which was the key to their success. Through appropriate counseling, self-efficacy can be strengthened, and readiness to quit may be increased. Furthermore, nicotine dependency should be put into perspective: the possible failure to quit smoking should not be interpreted as a weakness, but rather as a function of high nicotine dependency.

ssation

pregnancy are not recommended for treatment with Varenicline.

Fear to Gain Weight The concern to gain weight after quitting smoking is a second important issue. In a clinical trial performed in the US. with 5,887 smokers aged 35 to 60, an average weight gain of 9.7 kg was recorded over a period of five years which is significantly higher than the 5.3 kg generally estimated amount of gain in nonsmokers during the same period. Since the body’s metabolism in smokers is increased by regular tobacco consumption, Box 24.4: Quit rates Key features on reported outcomes • The quit rates of smokers without any professional help is found to be 10–11 percent • Success rates achieved by smoking cessation counseling are generally dependent on the amount of counseling time: 1–3 minutes (14.0%), 4–30 minutes (18.8%), 31–90 minutes (26.5%) and >90 minutes (28.4%), respectively • Pharmacotherapy has shown to significantly increase tobacco use cessation quit rates • Nicotine replacement therapy (NRT) is shown to increase success rates by roughly 100 percent • Reported one-year abstinence are: Nicotine Replacement Therapy (NRT): 20–25 percent, Bupropin SR: 23.1 percent, Varenicline (3 months): 23 percent, and Varenicline (6 months): 43.6 percent.

549

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smokers generally burn up more calories. Conversely, nicotine withdrawal is shown to lower metabolism. Following nicotine withdrawal, therefore, the energy will be stored as body weight even if the individual stays on the same diet. It may be appropriate for the counsellor at this point to mention that pharmacotherapy, e.g. the administration of nicotine substitutes, may lessen weight gain effectively.

BARRIeRS TO Be OVeRCOMe By The DeNTAl TeAM We know that most tobacco users are aware of their unhealthy habit. A closer look at the questions of what types of health problems caused by tobacco are generally known, however, reveals that the detrimental effects of tobacco use on the oral mucosa and the periodontal tissues are still substantially underestimated. In the interest of public health, therefore, the dental practice team has to perform an important task—namely, mentioning and discussing the consequences of tobacco use on oral health with all their patients—in addition to assessing their oral hygiene. It is not always easy to integrate this kind of patient briefing into the everyday work of a dental practice. As mentioned above, additionally, a number of tobacco users feel as they remain under social pressure to quit tobacco. Moreover, many patients have visited their dentists on numerous occasions in recent years without members from the dental team addressing the topic of tobacco use, mentioning the consequences for oral health, and assessing the patient’s willingness to quit. As a consequence, however, of the scientific knowledge attained over the past 5 to 10 years, the dental practice team was yet assigned an active role in promoting smoking prevention and cessation among their patients. Reported barriers and obstacles to integrating smoking cessation programs into the daily routine of the dental practice may be listed as: 1. Too little time, 2. Financial considerations,

3. 4. 5. 6.

Lack of interest on the part of the patients, Respect for the freedom of the individual, Too little experience in “giving good advice” Fear of losing patients.

In the future these barriers ought to be overcome via appropriate training of dental personnel.

Overcoming Barriers in Practice On the basis of significant evidence on the recovery of both the oral mucosa and the periodontal tissue following tobacco use cessation the task has been emerged in dentistry to deliver brief interventions and provide counseling for patients who ought to quit tobacco use. Even though success rates from dental counseling are limited at a first glance, it has been found that the support from oral health professionals is yet comparable to that from physicians and psychotherapists. There are several barriers, however, constituting a complex of issues for the dental practice, e.g. the lack of possibilities to charge either patients or insurance companies for such counseling, or the lack of training in tobacco use cessation counseling in the curricula of oral health professionals. Considering the relatively small amount of time for brief interventions (5 minutes each) and for tobacco use cessation counseling (up to 4 session of 15 minutes each), however, these efforts appear to be justified in the longer perspective and may serve not only a benefit for one single individual but have a public health impact to achieve better oral health for all.

SelF-ASSeSSMeNT QUeSTIONS 1. Describe the nature of the ‘tobacco use disease’. 2. What are the abstinence rates of smokers who try to quit without professional support? How could this be improved? 3. Describe the level of care model for tobacco use prevention and cessation in the dental practice. 4. “When asked about their readiness to quit smoking, tobacco users often reply that

6.

7.

8.

SUGGeSTeD ReADING 1. Casella G, Caponnetto P, Polosa R. Therapeutic advances in the treatment of nicotine addiction: present and future. Ther Adv Chronic Dis. 2010;1:95-106. 2. Davis, et al. Education of tobacco use prevention and cessation for dental professionals: a paradigm shift. Int Dent J. 2010;60:60-72.

3. Fagerstrom. Measuring degree of physical dependence to tobacco smoking with reference to individualization of treatment. Addict Behav. 1978;3:235-41. 4. Fiore, et al. Treating Tobacco Use and Dependence: Update. Clinical Practice Guideline. Rockville, MD: US Department of Health and Human Services. Public Health Service; 2008. 5. Miller and Rollnick. Motivational Interviewing. New York: Guilford Press; 2002. 6. Needleman, et al. Improving the effectiveness of tobacco use cessation (TUC). Int Dent J. 2010;60:50-9. 7. Ramseier CA and Suvan JE. Health behavior change in the dental practice. Ames, Iowa: Wiley-Blackwell; 2010. 8. Ramseier, et al. Consensus report: 2nd European workshop on tobacco use prevention and cessation for oral health professionals. Int Dent J. 2010;60:3-6. 9. Rollnick, et al. Helping smokers make decisions: the enhancement of brief intervention for general medical practice. Patient education and counseling. 1997;31:191-203. 9. Warnakulasuriya, et al. Oral health risks of tobacco use and effects of cessation. Int Dent J. 2010;60:7-30.

24 ssation

5.

they wish to quit smoking but there are significant barriers to do so at the present time”. Comment on their reply and possible responses by a health professional. Describe the application of “Brief Motivational Interviewing” for tobacco use cessation in the dental practice. What are the four steps enlisted in the StepBy-Step protocol for tobacco use cessation in the dental practice? Concerning pharmacotherapy: what are the common side effects of Nicotine Replacement Therapy (NRT) and precautions needed in prescribing Bupropion SR and Varenicline? Explain the reasons for better success rates achieved in tertiary care facilities compared to primary care.

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Index Page numbers followed by f refer to figure and t refer to table

A Abfraction 21 Abnormal blood clotting 491t Abrasion 20 Abscesses of periodontium 57t Acanthotic stratified squamous epithelium 182f Acetazolamide 490 Acinar atrophy 225f cell vacuolation 227f Acinic cell carcinoma 236, 243, 245f, 246 Acquired abnormalities of teeth 19 immune deficiency syndrome 367, 435, 446 Acromegaly 232 Actinic keratosis 269 Actinobacillus actinomycetemcomitans 94 Actinomyces europaeus 94 israelii 211, 381 naeslundii 66 radingae 94 turicensis 94 viscosus 66 Actinomycosis 94, 211, 379 Activated partial thromboplastin time 490 Activation of protease-activated receptors 69 Acute and chronic maxillary sinusitis 207 sinusitis 210 pseudomembranous candidiasis 277 pulpitis 43f and pulp abscess 42 suppurative parotitis 223f sialadenitis 222 Addison’s disease 443 Adenocarcinoma 236

Adenoid cystic carcinomas 217, 236, 248, 250, 250f, 251f Adenomatoid odontogenic tumor 125, 134, 134f-136f Adenomatous polyposis 12 Adenosquamous carcinoma 324 Adipose tumors 195 Adrenocorticotropic hormone 443 Advanced glycation endproducts 73 tumor on floor of mouth 329f Aggregatibacter actinomycetemcomitans 66 Aggressive fibromatosis 188 periodontitis 57t, 62, 64f, 66 Alanine transaminase 497 transferase 497 Albers-Schonberg disease 176 Albumin 498 Alcohol 306 Alkaline phosphatise 497 Alveolar ostetitis 97, 98 rhabdomyosarcoma 197 ridge keratosis 278 Ameloblastic carcinoma 125, 150, 151, 151f fibrodentinoma 125, 136 fibrodentinosarcoma 155, 156 fibroma 125, 136, 137f, 138, 138f fibro-odontoma 125, 138, 138f, 139 fibro-odontosarcoma 156 fibrosarcoma 125, 154 Ameloblastoma 125, 126, 126f, 127f, 131 solid 128f Amelogenesis imperfecta 2, 3f Amyloidosis 441, 442, 442f, 447 Anemia 337, 481 Anesthesia dolorosa 404 Aneurysmal bone cyst 116, 117f Angina bullosa hemorrhagica 357

Angiosarcoma 191 Angiotensin converting enzyme 500 Angular cheilitis 362, 363, 366, 430f, 447 stomatitis 233f, 362, 363, 366 Ankylosed TM joint 425f Ankylosing spondylitis 423f Anodontia 12 Anomalies of teeth 1 Anticoagulation therapy 492 Anticonvulsant drugs 504 Antineutrophil cytoplasm antibodies 394, 505t cytoplasmic antibody test 504 Antinuclear antibody 503, 503t Antiphospholipid syndrome 389 Antiretroviral therapy 447 Antral polyps 212f pseudocyst 212 Antrochoanal polyps 212, 213 Antroliths 213 Apically repositioned flap 80 Aplasia 222 Apoptotic mitosis 319f Appearance of dentinal tubules 40f proliferative verrucous leukoplakia 277f Applications of cone beam computed tomography 525 sialoendoscopy 539 sialography 537 Areca nut 306 Arthritides 394 Arthrocentesis 419 Aspartate transferase 497 Aspergillosis 210, 211f, 368 Aspergillus 368 flavus 368 fumigatus 210, 368 glaucis 368 niger 368 terrus 368

Oral Medicine and PathOlOgy: a guide tO diagnOsis and ManageMent 554

Assessment of dental caries 45, 46 Atrophic candidiasis 364 mucosa 263f oral lichen planus 287f Atubular dentinoid 142 Atypical cells 319f facial pain 407 odontalgia 407 Autoimmune disorders 232 Azathioprine 342, 433, 507

B Bacillus Calmette-Guérin 435 Bacterial infections 381 infections of oral mucosa 379 Bacteroides forsythus 65 infection 96 Basal cell adenocarcinoma 236 adenoma 236, 241, 243 carcinoma 109 syndrome 109 skin cancer 310 Basal layer of dental lamina 128 Basaloid squamous cell carcinoma 324 Basic cementum structure 35 dentine structure 30 enamel structure 28 periodontal examination 53 Basophils 486 Behçet’s disease 336, 456, 457f, 458 syndrome 336, 456 Benign and malignant tumors 186 cementoblastoma 148, 149 epithelial tumors 236 neoplasms 235 sensory trigeminal neuropathy 234 tumors 125 of maxillary sinuses 213 Bilateral antral pseudocysts 212f parotid gland swelling 438f swellings 232f Bilirubin 497 Biology of human dentinal tubule 38f

Bisphosphonate associated osteonecrosis 84, 88 of jaw 85f-87f related osteonecrosis of jaws 84 Blastomyces dermatitidis 368, 369 Blastomycosis 211, 369 Blastospores 363f Blood cells 493 clotting cascade 490 film 479 glucose measurement 495 in joint 416 Bone invasion 314 profile serological markers 499t regeneration 81 Botryoid cyst 113f odontogenic cyst 112 Botulinum toxin injection 406 Bouchard’s node 395 Branchial cleft cyst 119 Breast cancer 310 British Association of Dermatologists 342 Budd-Chiari syndrome 389 Bullous lichen planus affective gums 288f pemphigoid 346, 351, 352 Burkitt’s lymphoma 377 Burning mouth syndrome 408

C Café-au-lait spots 165 Calcification of falx cerebri 110f Calcifying cystic odontogenic tumor 125, 141, 142f, 143, 144 epithelial odontogenic tumor 125, 132, 132f, 133f, 134 Caldwell-Luc operation 209 Campylobacter rectus 65 Canalicular adenoma 236, 241, 243f Cancer 497 Candida albicans 86, 363f, 374 associated denture stomatitis 362-365, 366f Candidal leukoplakia 365 on lateral tongue 279f Candidiasis 367, 447 Canker sores 332 Cannabis smoking 310

Carbamazepine 424, 483 Carcinoma cuniculatum 324 ex-pleomorphic adenoma 236, 256, 257 in situ 322, 323 of alveolar mucosa 313f of head 497 Carcinosarcoma 236 Caries indices 47 of cementum 35, 36f of dentine 30 of enamel 28 Carious destruction of dentine 33f secondary dentine 35f Cartilage forming tumors 201 Cathepsin C deficiency in Papillon Lefevre syndrome 15 Causes of anemia 481 osteonecrosis 91 Celiac disease 338, 433, 434, 434f, 505 Cell gingivitis 61 lineages 187t volume 483 Cementoblastoma 125, 148f Cemento-osseous dysplasias 158 Cemento-ossifying fibromas 161, 167, 168f, 169f, 199 Central giant cell granuloma 175, 176, 176f Cervical lymph node 220 lymphoepithelial cyst 119 Charcot-Leydun crystals 210 Chediak-Higashi syndrome 15 Chemical injury 277 Cherubism 173 Chest pain 438 Chickenpox 376 Chlorpromazine 504 Chondroma 201, 201f Chondrosarcoma 201, 201f Choriomeningitis viruses 228 Chorioretinitis 457 Chronic diffuse sclerosing osteomyelitis 163 facial pain 400 graft verus host disease 289 hyperplastic candidiasis 448 pulpitis 43, 44f

Coronary heart disease 73 Corpusular hemoglobin and concentration 485 Cotton wool appearance 175f Cough 438 Coxsackie virus infections 378 Craniofacial fibrous dysplasia 158, 164 C-reactive protein 73, 499 Crigler-Najjar syndromes 497 Crohn’s disease 309, 338, 427, 428f, 429, 429f, 430 regional ulcerative enteritis 338 Crown lengthening 80 Cryptococcosis 211, 370 Cryptococcus neoformans 211, 368, 370 Curettes 78 Cyclosporine 433 Cylindrical cell papilloma 215, 215f Cystadenocarcinoma 236 Cystic hygroma 121 Cysts of oral and maxillofacial region 100 Cytokines 69 Cytomegalovirus 228, 378 Cytoplasm of neutrophils 505t

D Dapsone and sulfamethoxypyridazine 508 Decayed-missing-filled index 47 Deep carious lesion in dentine 43f venous thrombosis 492 Definitions of oral leukoplakia 269t Degenerative disease 423 Dental abrasion 20f attrition 19f caries 25, 511f vaccines 47 floss 75 fluorosis 5 follicle 146 fraud 473 fusion 18f injury 472 negligence and dental malpractice 474 occlusion 415 papilla 146 Dentigerous cyst 104, 104f-105f, 127f

Dentine dysplasia 6t, 8, 9, 9f Dentinogenesis imperfecta 6, 7, 8f Dentinogenic ghost cell tumor 125, 143, 143f, 144 Dentoalveolar trauma 525 Denture-induced fibroepithelial hyperplasia 182 Deoxyribonucleic acid 454 Dermal analog tumor 243f Dermatitis herpetiformis 351, 355, 356 Dermatomyositis 233, 234, 384f, 392, 393 Dermoid cyst 119, 119f, 120f Desmoid tumor 188 Desmoplastic ameloblastoma 129f Desquamative gingivitis 61, 288, 288f Detection of dental caries 45 Developmental abnormalities of cementum 11 dentine 6, 10 enamel 2, 10 eruption of teeth 13 number of teeth 12 cysts of foregut origin 121, 121f Diabetes 72 mellitus 232 Diagnosis of herpetic infection 375 oral and maxillofacial diseases 509 Diffuse chronic sclerosing osteomyelitis 96 large B-cell lymphoma 236 sclerosing osteomyelitis 96 Digital subtraction sialography 538f Dipstick urine testing 501, 501t Direct immunofluorescence in pemphigoid 354f Discoid lupus erythematosus 269, 277, 454, 455f Diseases grading system for oral submucous fibrosis 296t of maxillary antrum 206 subepithelial separation 351t Disk displacement with reduction 412 Disorders of hemoglobin 481 temporomandibular joint 419

index

idiopathic facial pain 406 inflammatory cells 43f obstructive sialadenitis and sialolithiasis 224 osteomyelitis 94 pain 403 pancreatitis 232 periapical granuloma 44f periodontitis 56t, 60, 62f, 66 pulpitis 43, 43f recurrent multifocal osteomyelitis 95, 96 renal failure 232 sclerosing osteomyelitis 95 sialadenitis 225f tendoperiostitis 97 ulcerative stomatitis 338 Cicatricial pemphigoid 353, 354 Classification of bone 86t chronic pain 403t oral ulcers related to cause 332t periodontal diseases 56t Clear cell carcinoma 236 odontogenic carcinoma 125, 152, 153, 153f Cleidocranial dysplasia 12f, 14 Cluster headaches 405 Coccidioides immitis 368 Coccidioidomycosis 369 Colchicine 342 Colon cancer 310 Comedonecrosis 255f Community periodontal index of treatment 53 Condensing osteitis 97 Conditions affecting TMJ 417t with sialosis 232t Condylar hyperplasia 420 Cone beam computed tomography 522 Congenital cytomegalovirus infection 228 cytomegalovirus of parotid gland 228f Connective tissue diseases 383, 452 disorders 504t Conspicuous perineural invasion 251f Constituents of saliva 262 Conventional cemento-ossifying fibroma 158, 167, 170

555

Oral Medicine and PathOlOgy: a guide tO diagnOsis and ManageMent 556

Disseminated intravascular coagulation 490 Distant metastasis 314 Disturbance of bite 413 Dog tapeworm 122 Down syndrome 13, 17 Doxycycline 483 Drug induced lupus 387 recurrent oral ulceration 339 Dry eyes 422 socket 97 Duct atresia 222 dilatation 225f Ductal papillomas 236 Dynamics of carious process 40 Dysplastic dentine 142, 143 Dyspnea 438

E Early oral submucous fibrosis 296f Echinococcus granulosus 122 Ectopia 222 Ehlers-Danlos syndrome 7, 10, 10f, 14 Electrical conductance measurements 45 Empirical treatments for oral lichen planus 291t Enamel hypoplasia of permanent lower central incisors 5f pearl 16f Encephalotrigeminal angiomatosis 190 Endodontics 525 Endomysial antibodies 505 Endoscopic sinus surgery 209 Environmental enamel hypoplasia 4 hypoplasia 5f Enzyme linked immunosorbent assay 503 Eosinophilic polyhedral cells 197f Eosinophils 486 Epidemiology of periodontal disease 51 Epidermal growth factor receptor 326 Epidermoid cyst 119, 120f Epidermolysis bullosa 354 acquisita 346, 351, 354, 355, 355f

Epithelial cell rest of Malassez 128 dysplasia 271 graded 274f myoepithelial carcinoma 236, 253, 254f, 255 Epstein-Barr infection 216 viruses 228, 376, 448 Erosion 20 Eruption cyst 106, 106f, 107f Erythema multiforme 357-359 Erythematous candidiasis 364, 364f, 447 of tongue 447f variant 363 Erythrocyte sedimentation rate 492 Erythroleukoplakia 269, 276, 281f Erythromycin 483 Erythroplakia 269, 281, 282 Established gingival lesion 68 Esthesioneuroblastoma 219 Ewing’s sarcoma 202 Exotic fungal infections of oral mucosa 367 Extensive punctuate sialectasis 224f External root resorption 21, 22, 22f Extracellular matrix 295 Extractable nuclear antigen test 390, 504 Extraglandular manifestations of Sjögren’s syndrome 234t Extranodal marginal zone-B cell lymphoma 236 Extravasation mucocele 228, 229f Extrinsic staining 23

F Facial arthromyalgia 406 injury 472 nerve palsy 250 trauma 525 Failure of eruption of teeth 14 Familial adenomatous polyposis 14f, 310 amyloid polyneuropathy 441 florid cemento-osseous dysplasia 163 gigantiform cementoma 158, 163

hypophosphatemic vitamin D resistant rickets 9f retinoblastoma 310 Fiberoptic transillumination 45 Fibrinolytic alveolitis 97 Fibrocellular stroma 169f Fibrocemento-osseous dysplasias 172 neoplasms 158 Fibroepithelial polyp 181, 182f Fibromatosis 188 Fibro-odontosarcoma 125, 155 Fibrosarcoma 188 Fibrous dysplasia 158, 164, 164f-166f epulis 180, 180f histiocytoma 189 lesions 181 stroma without odontogenic ectomesenchyme 125 tumors 187 Fissure caries 28 Florid cemento-osseous dysplasia 158, 159, 161, 162f, 163 osseous dysplasia 96 Flucloxacillin 483 Fluorescence 45 Fluorosis 6f Focal cemento-osseous dysplasia 158-161 epithelial hyperplasia 184, 184f sclerosing osteomyelitis 97 Foliaceus 346 Fordyce’s granules 287 Foregut duplication cyst 121 Forensic ballistics 463 dental extensions 475 dentistry 462-464 odontology 463 method of identification 467 toxicology 463 Formulating treatment plan 58t Fracture dislocation of left condyle with vertical collapse 420f Frictional keratosis 277 Frusemide 490 Fungal infections of maxillary sinuses 210, 211 oral mucosa 362 Fungiform 214 Fusobacterium nucleatum 65

Gallstones 497 Gammaglutamyl transferase 498 Gardner’s syndrome 198, 459, 459f, 460 Gastrointestinal choristomal cysts 121 diseases 427 Gemination 17 Genes 4t, 6t Genetic disorders 57 Geotrichosis 370 Geotrichum candidum 368 Ghost cell odontogenic carcinoma 125, 153, 154 GI tract diseases 338 Giant cell carcinoma 324 epulis 181, 182f granuloma 182f Gingival abscess 57t cyst of adults 111, 112 newborn 111, 111f diseases 56t Gingivectomy 81 Gingivitis 59, 59f, 60, 66 Glandular odontogenic cyst 113, 114f Glassy eosinophilic cytoplasm 448f Global epidemiology 301 Glomerular filtration rate 495t Glomerulonephritis 234 Glucosyltransferases 48 Glycosylated hemoglobin 495 Goldblatt syndrome 7 Gonorrhea 379, 381 Gorlin-Goltz syndrome 107, 310 Grading of OSF 295 Granular basophilic cells 245f cell tumor 192, 193f hyperplasia with erythema of palate 440f Granulomatous diseases 435 lesions in labial mucosa 429f Grocott stain 211f Ground glass appearance 176 Growth and anatomy of maxillary sinuses 207

Guided bone regeneration 81 tissue regeneration 81

H Haemophilus influenzae 208 Hairy leukoplakia 277, 280f, 378 Hallerman-Treiff syndrome 12 Hand-Schüller-Christian syndrome 202 Hard skin 389 tissue disorders 394 Head and neck squamous-cell carcinomas 327 Heart 442 Heat shock protein 335 Heberden’s node 395 Heck’s disease 184, 184f, 185f Helicobacter pylori 335 Hemangiomas 190, 190f, 191f, 202 Hemifacial microsomia 13, 419 Hemoglobin 479 molecule 480f Hemorrhagic bone cyst 117 Hepatitis 234 Hereditary 158 Heredity 310 Herpes associated erythema multiforme 359 erythema multiforme 359 labialis 375 simplex infection 375, 502 virus 359, 456 Herpetic dermatitis 375 stomatitis 374 whitlow 375 Herpetiform ulceration 335t Heterotopia 222 Heterotopic gastrointestinal cysts 121 High grade mucoepidermoid carcinoma 247f Histoplasma capsulatum 371 duboisii 368 HIV associated lymphoepithelial cysts 227 ROU 338 salivary gland disease 227 sialadenitis 228f

infection 310 related periodontal disease 448 Hodgkin’s lymphoma 236 Host derived inflammatory mediators 69 Hughes syndrome 389 Human immunodeficiency virus 363, 377, 446 leukocyte antigen 347, 494 papilloma virus 183, 214, 216, 379, 450 Hydralazine 504 Hyperalgesia 402 Hyperbaric oxygen 90 Hypercellular stroma 137f Hyperdontia 12 Hyperfractionated radiotherapy 327 Hyperplastic candidiasis 365 stratified squamous epithelium 184f variant 363 Hypertrophy of serous acinar cells 232f Hypodontia 12, 13f Hypomaturation type amelogenesis imperfecta 3f Hypomineralized amelogenesis imperfecta 3f Hypoplastic amelogenesis imperfecta 3f hypomineralized amelogenesis imperfecta 3f

index

G

I Ilex paraguariensis 309 Immune reconstitution inflammatory syndrome 451, 452f thrombocytopenic purpura 490 Immunobullous disease 336 Implant dentistry 525 Incisive canal cyst 114 Indoor air pollution 309 Infantile osteomyelitis 94, 95 Infections of oral mucosa 361, 362f Infectious disease 498 mononucleosis 377 Infective disease 222 TMJ disorders 421

557

Oral Medicine and PathOlOgy: a guide tO diagnOsis and ManageMent 558

Inflamed parotid gland 223f Inflammatory bowel disease 427 disease 222, 422 of jaw bones 92 disorders of jaws necrosis 83 Initial gingival lesion 67 Inorganic component of saliva 262t Intensity modulated radiotherapy 89 Interdigitation of teeth 415 Internal root resorption 21, 22 Interobserver agreement in epithelial dysplasia 274t Interproximal caries 28 Interstitial fibrosis 225f lymphoid infiltrate 227f nephritis 234 Intraductal papilloma 236 Intraoral human papilloma virus infection 451f Intrinsic discoloration of teeth 23, 23f Inverted ductal papilloma 236 papilloma 214, 215f Iodine containing drugs 232 Ipsilateral open bite 420 Iridocyclitis 457

J Jaffe-Lichtenstein syndrome 158, 165 Jaw bones 470 realignment 420 Joint 442 dislocation 412 disorders 412 noises 412 washout 419 Juvenile aggressive cemento-ossifying fibroma 158, 170 parotitis 224 psammomatoid cemento-ossifying fibroma 170, 171, 172f, 173 ossifying fibroma 167 trabecular cemento-ossifying fibroma 170, 170f, 171, 171f

K Kaposi’s sarcoma 191, 192f, 227, 448, 459f, 450f, 452f Keratocyst 136 Keratocystic odontogenic tumor 107, 125, 136, 151 Kidneys 442 Klinefelter’s syndrome 17 Koilonychia 460

L Labial gland biopsy 266f Langerhans cell 203f histiocytosis 202, 203f Langhans giant cells 437 Large cell carcinoma 236 dentigerous cyst 515f, 528f facial swelling 223f pleomorphic adenoma of submandibular gland 236f cells 255f Lateral periodontal cyst 103, 112, 113f Leaf fibroma 182 Leathery appearance of oral submucous fibrosis 295f Leiomyomas 196 Leiomyosarcoma 196, 197f Leukemia 488 inhibitory factor 70 Leukocyte 485 adhesion molecule deficiencies 15 Leukoedema 277 of buccal mucosa 278f Leukokeratosis nicotina 277 Leukopenia 387 Leukoplakia 269 of tongue 271f Levamisole 343 Levels of aggregatibacter actinomycetemcomitans 57t Lichen planus 269, 277, 289 Lichenoid dysplasia 274, 275f reaction 277 Li-Fraumeni syndrome 310 Light fluorescence 45 Linear gingival erythema 361, 362, 367 IgA disease 356 Lipoma 195, 196f Lipopolysaccharide 69

Liposarcomas 196 Lithium 504 Liver 442 function tests 497, 498t Lobulated and fissured tongue 263f Low grade cribriform cystadenocarcinoma 236 power of Warthin’s tumor 240f Lower jaw and palatal multiple osteomas 459f Lupus disease 387t Lymphadenoma 236 Lymphangioma 190, 191f Lymphocytes 487 Lymphocytic infiltration 227f Lymphoepithelial carcinoma 236 sialadenitis 232, 234, 235f Lymphopenia 387

M Macrodontia 15 Maffucci’s syndrome 201 Malignant ameloblastoma 125, 149, 150, 150f epithelial tumors 236 fibrous histiocytoma 189 melanomas 218, 243 peripheral nerve sheath tumor 195 spindle cell tumor 197f transformation 293, 297 in odontogenic cysts 114 in oral leukoplakia 272t tumors 125, 529 of maxillary antrum 216 of maxillary sinus 216 Mandibular canal 470 Manifestation of systemic disease 57t Manual toothbrush 75 Marble bone disease 176 Marijuana smoking 310 Matrix metalloproteinases 70, 101, 107 Maxillary alveolar bone 523f sinus 210f, 219, 470 adenoid cystic carcinoma 217 malignant melanoma 218 McCune-Albright syndrome 158, 165

Mucormycosis 371 Mucosal lesions in erythema multiforme 358f patches of secondary syphilis 380f Mucous membrane 353 pemphigoid 346, 352, 354 Mucus retention cysts 229 Multinucleate giant cells 437 Multiplanar display of maxillofacial skeleton 522f Multiple unerupted supernumerary teeth 12f Mumps 226 Muscle tumors 196 Myalgic pain 406 Myasthenia gravis 234 Mycobacterium tuberculosis 379, 435 Myelodysplastic syndromes 488 Myeloma 203 Myiasis 382 Myoepithelial carcinoma 236 cells 254f Myoepithelioma 236 Myofacial pain 406, 417 Myofibroma 187, 188f Myofibromatosis 187 Myofibrosarcoma 188 Myxoid stroma 194f, 320f tumor stroma 320f

N Nance-Horan syndrome 12 Nasolabial cyst 115, 116f Nasopalatine cyst 114, 115f duct cyst 114, 513f Nasopharyngeal carcinoma 377 Natural killer lymphocyte 503, 503f Necrotizing periodontal diseases 57t sialometaplasia 230, 231f stomatitis 449f ulcerative gingivitis 57t, 61, 78, 448 periodontitis 57t, 448, 449f vasculitis 394 Neoplastic disease 423 odontogenic epithelium 137f salivary disorders 235

Neural tumors 192 Neuralgia inducing cavitational osteonecrosis 91 Neurilemmoma 194 Neuroectodermal tumor 202 Neuroendocrine carcinoma 219 Neurofibroma 193 Neuromas of men syndrome 194 Neuropathic pain 403 Nevoid basal cell carcinoma syndrome 107, 109, 110f, 136 Nicotine dependence test 546t replacement therapy 310, 547 Nikolsky sign 353 Nocturnal bruxism 411 Nodular fasciitis 185 Noncaseating epithelioid granulomas 225f Nonerosive arthritis 234 Nonhealing ulcer 312f Non-Hodgkin’s lymphoma 234, 449, 450f Non-metallic restorations 469 Non-neoplastic salivary disorders 222 Nonodontogenic cysts 114 Nonplaque induced gingivitis 56t Nonsyndromic amelogenesis imperfecta 2 dentinogenesis imperfecta 7

index

Mean cell volume 484, 485 corpuscular hemoglobin and concentration 485 Measurement of interincisal opening 414 Median rhomboid glossitis 362, 363, 367, 367f Medicolegal aspects of facial injuries 473 Melanocyte stimulating hormone 443 Melkersson-Rosenthal syndrome 429, 431 Mendelian disorders 10 syndromes 10, 14, 15, 17 Mental foramen 470 Metallic restorations 469 Metastasizing ameloblastoma 125, 149 pleomorphic adenoma 236 Metastatic tumors 204 Methyldopa 504 Microdontia 15 Mikulicz’ aphthae 332 Mild dysplasia 272 epithelial dysplasia 274f Miliary TB 436 Missing teeth 469 Mitosoid bodies 184 Mixed connective tissue disease 384f, 393 Moderate dysplasia 273 epithelial dysplasia 274f Modes of inheritance 6t Molar incisor hypomineralization 5 Monocytes 487 associated with systemic vasculitis 505t Monostotic fibrous dysplasia 158, 164 Morsicatio buccarum 277 Moth eaten appearance 93 Mucinous adenocarcinoma 236 Mucoceles 212, 228, 230 pseudocyst 212 Mucocutaneous leishmaniasis 381 Mucoepidermoid carcinoma 236, 246-248 Mucogingival surgery 81

O Obstructed submandibular gland 225f Occlusal radiography 512 trauma 57 Ocular pemphigoid 353 Oculocardiofacial dental syndrome 18f Odentogenic keratocyst 108f Odontoameloblastoma 125 Odontogenic carcinomas 125 cyst 101 lining 152 epithelium with mature 125 odontogenic ectomesenchyme 125 fibroma 125, 144, 145, 145f gingival epithelial hamartoma 129 keratocyst 101, 107, 109, 109f, 136

559

Oral Medicine and PathOlOgy: a guide tO diagnOsis and ManageMent 560

myxofibroma 125 myxoma 125, 145, 147f, 148 sarcomas 125 tumors 124, 125 Odontology 463 Odontoma 139, 140f, 141 Old theory of periodontitis 51 Ollier’s disease 201 Oncocytic carcinoma 236 papilloma 215, 215f Oncocytoma 236 Oral alimentary tract cyst 121 bacterial infections 381 cancer 300, 311f candidiasis 362 in HIV disease 367 epithelial dysplasia 275f, 318f focal mucinosis 186 fungal infections 374 hairy leukoplakia 377, 448, 448f hygiene and dentition 309 instruction 54, 58 leukoplakia 280f, 282 lichen planus 286, 290f lichenoid contact lesions 289 lesion 289, 289f lymphoepithelial cyst 118, 119f manifestations of herpangina 378 herpesviruses 378 systemic disease 426 parasitic infections 382 potentially malignant disorders 269, 270t squamous cell carcinoma of floor of mouth 312f submucous fibrosis 269, 293, 294 tuberculosis 436f, 437f ulcers 505 viral infections 374, 379 Organic component of saliva 262t Orifice of parotid gland 537f Orofacial digital syndrome 12 granulomatosis 429, 429f, 430, 430f, 431f Orthokeratinized odontogenic cyst 110, 110f stratified squamous epithelium 110f

Osteoarthritis 394, 396 Osteoarthrosis 423 Osteoblastoma 199 Osteochemonecrosis 84, 86, 88 with bisphosphonates 88 Osteochondroma 199 Osteogenesis imperfecta 7 Osteoma 198 Osteomalacia 499t Osteomyelitis 92 of jaw bones 93 Osteonecrosis 84 of jaws 84 Osteopetrosis 14f, 176 Osteoradionecrosis 89, 524f of jaws 91 Osteosarcoma 199, 200f Osteosclerosis of calvarium 14 Ovarian cancer 310 insufficiency 232 Overlap syndrome 384f

P Packed cell volume 483 Paget’s disease 163, 174, 174f, 175, 175f, 395 of bone 149, 499t Pain 401, 411 Palpation of joint 413 masseter and temporalis 414 temporalis muscles for tenderness and muscle spasm 414f Pancreatitis 234 Panoramic radiography 513 Papillary hyperplasia 183f of palate 183 squamous cell carcinoma 324 Paracoccidioides brasiliensis 368, 372 Paracoccidioidomycosis 368, 372 Paradental cyst 103, 104, 104f Paramyxovirus infections 378 Paraneoplastic pemphigus 350 Parasitic cysts 121 infections of oral mucosa 381 Parenchymal lung involvement 234 Parotid gland mumps 227f Patchy chronic inflammatory infiltration 225f

Paterson-Brown-Kelly syndrome 460 Pathergy test 336 Pathogenesis of iris 451 Pathology of dental caries of enamel 31t Pemphigus 346, 350 foliaceous 350 vulgaris 288, 346, 346f-348f Penicillin 490 Penicilliosis 373 Penicillium marneffei 373 Pentoxifylline 342 Peptostreptococcus micros 65 Periadenitis mucosa necrotica recurrence 332 Periapical cemental dysplasia 158, 159, 159f, 160 cemento-osseous dysplasia 158 inflammation of teeth 44 radiography 510 Pericoronal abscess 57t Perineural invasion 322 Periodic acid-Schiff stain 34f Periodontal abscess 57t diseases 50, 51, 60 explorer 78 flap surgery 80 health 66 instruments 78 ligament 146 surgery 58 systemic interface 72 Periodontitis 60 with endodontic lesions 57t Periostitis ossificans 95 Peripheral ameloblastoma 129f giant cell granuloma 181 Peritubular dentinogenesis 38f Pernicious anemia 234, 494 Persistent orofacial pain 407 Peutz-Jegher’s syndrome 310, 460, 460f Phenotypes in amelogenesis imperfecta 2t dentinogenesis imperfecta 6t nonsyndromic amelogenesis imperfecta 4t Photo-stimulable phosphor plate 517 Phycomycosis 371 Pindborg’s tumor 132, 133

Primordial cyst 136 Procainamide 504 Prognosis of oral squamous cell carcinoma 325 Proliferative periostitis 95 verrucous leukoplakia 276 Properties of saliva 262t Prostaglandins 70 Pseudomembranous candidiasis 363, 363f, 447 Pseudostratified columnar ciliated epithelium 118 Pterygoid hamulus 470 Pulmonary embolism 492 Pulp and pulp reaction 42 polyp 44f tissue periodic acid-Schiff staining 35f Pulpodentinal complex to caries progression 37 Pyogenic granuloma 180, 181f, 185 Pyostomatitis vegetans 432f

Q Quantitative laser 45

R Radicular cyst 101, 101, 102f, 103f Radiotherapy-associated osteonecrosis 89 Rampant caries 41 Rashes of systemic lupus erythematosus 234 Raynaud’s disease and phenomenon 394 phenomenon 389, 390 syndrome 234 Readiness scale 544f Recurrent aphthous stomatitis 332, 434f ulceration 332, 339 ulcers 333, 334 hypoxia of Raynaud’s phenomenon 391f oral ulceration 331, 332 parotitis 224 Red blood cell count 484 cell 482f distribution width 485

Reduced platelet numbers 489 salivary secretion 264t Regional odontodysplasia 11, 215f Regular prophylaxis 79 Remnants of Hertwig’s root sheath 128 Removal of salivary tissue 266f Renal calculi 234 tubular acidosis 234 Replaced flap 80 Residual cyst 103 Restriction of opening 412 Retention mucoceles 229 Reticular lichen planus 286f Retinal vasculitis 458 Retinoblastoma and sarcomas 310 Retinoid therapy 285f treatment of oral leukoplakia 285f Rhabdomyoma 196, 197f Rhabdomyosarcomas 197 Rheumatoid arthritis 49, 233, 234, 384f, 395, 396, 397f, 423f joint pannus of condyle 422f Roles of forensic odontologist 463 Root canal therapy 469 surface caries 35 debridement 54, 58, 64, 76, 77, 81 Rothmund-Thomson syndrome 12

index

Pinpoint erythema of denturebearing mucosa 365 Pit caries 28 Plaque induced gingivitis 56t Plasma and interstitial fluid 496 Platelets 489 Pleomorphic adenoma 235, 236, 239 of right parotid gland 530f epidermoid and mucous cells 247f fibrosarcoma 189 sarcoma 189 Plexiform neurofibroma 194f Ploidy status of oral leukoplakia 275 Plummer-Vinson syndrome 460 Polyarteritis nodosa 233 Polycythemia 484 Polymerase chain reaction 214 Polymorphous low-grade adenocarcinoma 236, 251, 252f, 253 Polyostotic fibrous dysplasia 158, 165 with endocrinopathy 158, 165 with pigmentation 158, 165 Porphyria 483 Porphyromonas gingivalis 57t, 64, 66 Positive ANA test 503t Positron emission tomography 416 Postherpetic neuralgia 405 Postirradiation sialadenitis 226 Postnatal infection 378 Postsurgical maxillary cyst 118 Post-transplant lymphoproliferative diseases 377 Potassium 496 Potentially malignant disorders 268, 269t Pregnancy gingivitis 61 Prevotella intermedia 65, 66 Primary biliary 234 cirrhosis 233 chronic osteomyelitis 96 herpes simplex infection 374 intraosseous squamous cell carcinoma 125, 151 oral candidiases 362 polycythemia 484 Sjögren’s syndrome 233 syphilis 379

S Saliva 261 Salivary calculi 226 duct carcinoma 236, 254, 255f, 256f gland 438 disorders 221 duct 226f inclusion disease 228 inclusions in parotid lymph node 222f secretion 261 Salmonella 421 Sample collection for hematological 507t

561

Oral Medicine and PathOlOgy: a guide tO diagnOsis and ManageMent 562

Sarcoidosis 437, 438, 438f, 442f Sarcomas 219 Scaling and root planing 77, 81 Schilling test 494 Schneiderian papillomas 214, 216 Schwann cells 192, 194, 194f Scleroderma 389 Sebaceous adenoma 236 carcinoma 236 cyst 535f lymphadenocarcinoma 236 Secondary oral candidiases 362 polycythemia 484 Sjögren’s syndrome 233t syphilis 380 Sentinel node 317 Serological in connective tissue disorders 388t tests for measuring iron status 493t Serous acinar cells 245f Severe dysplasia 273 Sexual offenses 474 Sharpey’s fibers 36 Sialadenoma papilliferum 236 Sialadenosis 231, 232f of parotid gland 232f Sialoblastoma 236 Sialoendoscopy 539 Sialogram of parotid gland 265f recurrent juvenile sialadenitis 224f Sialography 537, 539 Sialo-odontogenic cyst 113 Sialosis 231, 232f Sicca syndrome 233 Sickle cell anemia 482 disease 482, 483f scaler 78 Sideropenic dysphagia 269 Simple bone cyst 117 Single tufted toothbrush 75, 75f Sinonasal neuroendocrine tumors 219 undifferentiated carcinoma 219, 220 Sistrunk procedure 120

Sjögren’s syndrome 49, 223, 227, 232-234, 235f, 264, 265, 366, 392, 393, 408, 422, 504, 534, 538f Skeletal muscle 187 Skin 442 graft 277 pemphigoid 353 Skull radiography 515 Small cell carcinoma 219, 236 neuroendocrine carcinoma 220 Smooth muscle 187 muscle actin 187 surface caries 28 Socioeconomic status 309 Sodium 496 potassium pump 496 Soft tissue and bone tumors 179 shadow of cyst 106f tumors 180 Solitary bone cyst 117, 118f disease 202 South American blastomycosis 372 Spindle cell carcinoma 324 Sporotrichosis 373 Sporotrichum schenckii 368, 373 Squamous cell carcinoma 217, 236, 281f, 318f, 319f of right tongue 530f cell papilloma 184f odontogenic tumor 131, 131f, 132f papillomas 183 Staging of kidney damage 495t lip and oral cavity 315t Staphylococcus aureus 92, 94, 208, 223, 366, 421 Stevens-Johnson syndrome 357, 358 Stratified squamous epithelium 186f nonkeratinized epithelium 102f, 113f parakeratinized epithelium 109f

Strawberry gingival hyperplasia 440f gingivitis 440 Streptococcal infections 379 Streptococcus mitis 66 mutans 27, 47 pneumoniae 208 sanguis 66, 335 sobrinus 48 Striking vascular hyperemia 227f Structure of desmosome 349f Sturge-Weber syndrome 190 Subcapsular sinus of lymph node 321f Subepithelial infiltrate of chronic inflammatory cells 290f Submandibular duct 225f gland 514f Submucous fibrosis 269 Subtypes of oral squamous cell carcinoma 324 Sulfonamides 483, 490 Sulfamethoxypyridazine 507 Supernumerary teeth 525 Surgery for oral cancer 305t Surgical ciliated cyst of maxilla 118, 118f Sutton’s disease 332 Sweet’s syndrome 336 Symptoms of oral cancer 312t polycythemia vera 484 TMJ disease 414 Syndromic amelogenesis imperfecta 4 dentinogenesis imperfecta 7 Synovitis-acne-pustulosis-hyperostosis-osteomyelitis 96 Syphilis 269, 379 Systemic corticosteroids 341 disease 202 of interest 290 with recurrent oral ulceration 336 drugs in oral medicine 506t lupus erythematosus 233, 384, 384f, 452, 453, 503 sclerosis 233, 389, 392 vasculitides 394

Taenia solium 121 Talon cusp 16f Tannerella forsythia 65, 66 Taurodontism 17, 17f T-cell-mediated epidermal cell cytotoxicity 455 Temporomandibular disorder 406 joint 411, 470 disorders 410 Tertiary syphilis 380 Tests of clotting function 488 Folate status 495t liver function 497 thyroid function 500t Thalassemia 482 Thalidomide 343 Theories of periodontitis 51 Thrombocytopenia 387 Thyroglossal duct cyst 120, 121f Thyroid antibody tests 500 function tests 500 peroxidase antibody 500 stimulating hormone 500 Thyrotropin releasing hormone 500 Tissue inhibitors of metalloproteinases 71 transglutaminase antibodies 505 TMJ pain 411, 412 Tobacco specific nitrosamines 306 use cessation 543, 547 disease 542 prevention 541 Tooth discoloration and staining 23 injuries 473 Toxic epidermolysis necrosis syndrome 357, 358 Transcutaneous electrical nerve stimulation 419

Transport protein transthyretin 441 Transverse section of fractured coronal dentine 40f Traumatic bone cyst 117 neuroma 185 Treatment of HIV 451 periodontal disease 74 Treponema pallidum 380 Tricho-osseous-dental syndrome 17 Tricho-rhino-phalangeal syndrome 12 Tricyclic antidepressants 483 Trigeminal neuralgia 403 Tsunami identifications 464 Tuberculosis 379, 435 of oral mucosa 379 Tuberculous ulcers 436 Tumor like lesions 180 necrosis factor 70, 335, 433 of bone 202 of maxillary antrum 213 Turner hypoplasia 5, 5f Types of gingivitis 61 Typical hand signs of rheumatoid 397f heliotrope rash of dermatomyositis 392f

U Ulcerative colitis 338, 431, 432 oral lichen planus 288f, 293f Ultrasonic instruments 78, 79 Uncommon systemic mycoses 368t Unicameral bone cyst 117 Unicystic ameloblastoma 130f Urea and creatinine 496 electrolytes 495 Use of tongue spatula 414

V Variants of pemphigus 350 Vascular lesions 185 pain 405 tumors 190 Verruciform xanthoma 186, 187f Verrucous carcinoma 218, 324 Vesiculobullous disorders 345, 346t Viral diseases 226 infections of salivary glands 228 Vitamin B12 493 and folate 493 deficiency 494 von Recklinghausen’s disease 193 Vulgaris 346

index

T

W Waldenström’s macroglobulinemia 234 Warthin’s tumor 236, 239-241 Wegener’s granulomatosis 217, 394, 439, 440, 440f Wharton’s duct 225 White blood cell 485, 487f, 488 cell count 486, 486t sponge nevus 277, 278 WHO classification of odontogenic tumors 125t tumors of salivary glands 2005 236t Worse prognosis 276t

X Xerostomia 260, 263, 328

Y Yttrium-aluminium-garnet 88

laser

Z Zygomycosis 371

563

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