Pathology of the Head and Neck

Antonio Cardesa · Pieter J. Slootweg (Eds.)Pathology of the Head and Neck

Antonio Cardesa · Pieter J. Slootweg (Eds.)Pathologyof the Head and NeckWith 249 Figures in 308 separate Illustrationsand 17 Tables123

Professor Dr. Antonio CardesaDepartment of Pathological AnatomyHospital ClinicUniversity of BarcelonaVillarroel 17008036 BarcelonaSpainProfessor Pieter J. SlootwegDepartment of PathologyUniversity Medical Center St. RadboudP.O. Box 91016500 HB NijmegenThe NetherlandsLibrary of Congress Control Number: 2006922731ISBN-10 3-540-30628-5 Springer Berlin Heidelberg New YorkISBN-13 978-3-540-30628-3 Springer Berlin Heidelberg New YorkThis work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned,specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproductionon microfilms or in any other way and storage in data banks. Duplication of this publication or parts thereof ispermitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version,and permission for use must always be obtained from Springer-Verlag. Violations are liable for prosecutionunder German Copyright Law.Springer is a part of Springer Science+Business Mediaspringer.com© Springer-Verlag Berlin Heidelberg 2006Printed in GermanyThe use of general descriptive names, trademarks, etc. in this publication does not imply, even in the absence ofa specific statement, that such names are exempt from the relevant protective laws and regulations and thereoffree for general use.Product liability: the publishers cannot guarantee the accuracy of any information about dosage and applicationcontained in this book. In every individual case the user must check such information by consulting therelevant literature.Editor: Gabriele Schröder, HeidelbergDesk Editor: Ellen Blasig, HeidelbergProduction: LE-T E X, Jelonek, Schmidt & Vöckler GbR, LeipzigTypesetting: Satz-Druck-Service, LeimenCover: Frido Steinen-Broo, eStudio Calamar, SpainPrinted on acid-free paper 24/3100/YL 5 4 3 2 1 0

ToGerhard Seifert and to Leslie Michaels,great pioneers of Head and Neck Pathologyin Europe and founding membersof the Working Groupon Head and Neck Pathologyof the European Society of Pathology.

ForewordPathology of the Head and Neck is an easy soundingtitle for a complex subject matter. This title stands for anaccumulation of diverse diseases occurring in differentorgans whose relationship to each other consists in thefact that they are located between the base of the skulland the thoracic aperture. One reason for assemblingall these different organs under the title “Pathology ofthe Head and Neck” is that the proximity of the organsof the head and neck region makes it difficult for thesurgical pathologist to focus on one of these organs andneglect the pathology of others, which are only a centimetreapart. A second reason, however, is that the upperdigestive tract and the upper respiratory tract, whichmeet in the larynx, have some basic diseases in common,notably squamous cell carcinoma. Thus pathologyof the head and neck is both an arbitrary compilation ofdiseases and, at least to some extent, a group of diseaseentities with a common morphological and pathogenetictrunk.The past years have seen remarkable advances inmany fields of pathology, including that of the head andneck. There is a need for a book that integrates surgicalpathology with molecular genetics, epidemiology, clinicalbehaviour and biology. This book provides a comprehensivedescription of the manifold aspects of themorphology and pathology of the organs of the headand neck region. These description, as comprehensive asthey may be, also show that there are some areas of thepathology of the head and neck that remain an unexploredworld. Examples include the never-ending problemof prognostication of tumour diseases, the pathogeneticsignificance of tumour precursor lesions andthe validation of appropriate sets of tumour markers asmeaningful predictors of malignancy.The editors of the book, Professor Antonio Cardesaand Professor Pieter Slootweg, are leading experts inthe field of the pathology of the head and neck. As suchthey are the main members of the Working Group onPathology of the Head and Neck of the European Societyof Pathology, one of the first European working groupsto be founded under the auspices of the European Societyof Pathology. In this multi-author book the expertiseof outstanding experts on the pathology of the headand neck in Europe is reflected. The chapters are characterisedby the desire to correlate pathology with allnecessary information on clinical features, epidemiology,pathogenesis and molecular genetics. The authors ofthese chapters have not attempted to be encyclopaedic,but rather have aimed at providing concise, yet adequateknowledge. They are therefore to be warmly commendedfor providing us with an excellent book, which willprove useful to surgical pathologists involved in the pathologyof the head and neck.Kiel, GermanyMarch 2006Günter Klöppel

Contents IXPrefaceThis book was initially conceived as a unitary group ofchapters on “Pathology of the Head and Neck”, to bepublished in German within the series of volumes ofRemmele’s Textbook of Pathology. From the outset, theeditorial approach was to concentrate on pathologicalentities that are either unique to or quite characteristic ofthe head and neck. At the same time, we strove to avoidas much as possible unnecessary details on systemicdiseases that, although involving the head and neckregion, have their main focus of activity in other organs.Thus, “Pathology of the Head and Neck” encompassesthe wide range of diseases encountered in the complexanatomic region extending proximally from the frontalsinuses, orbits, roof of the sphenoidal sinuses and clivusto distally the upper borders of the sternal manubrium,clavicles and first ribs. This includes the eyes, ears , upperaerodigestive tract, salivary glands, dental apparatus,thyroid and parathyroid glands, as well as all theepithelial, fibrous, fatty, muscular, vascular, lymphoid,cartilaginous, osseous and neural tissues or structuresrelated to them.The contents have been divided into ten chapters. Thefirst covers the spectrum of precursor and neoplasticlesions of the squamous epithelium. It is followed bychapters devoted to the nasal cavities and paranasalsinuses, oral cavity, maxillofacial skeleton and teeth,salivary glands, nasopharynx and Waldeyer`s ring,larynx and hypopharynx, ear and temporal bone,neck and neck dissection, as well as eye and ocularadnexa. The pathology of the thyroid and parathyroidglands and lymph nodes is covered in greater detailelsewhere.Since the authors selected for writing the differentchapters are international experts and members of theWorking Group on Head and Neck Pathology of theEuropean Society of Pathology, the chief editors of theseries, Prof. Wolfgang Remmele, Prof. Hans Kreipe andProf. Günter Klöppel, accepted that all manuscriptsshould be in English. After the original texts had beensubmitted, it became clear to the editors and publisherthat, in addition to their translation to fit into Remmele’sTextbook, the work warranted publication in Englishas a separate book. Therefore, we want to thank the chiefeditors and the publisher Springer for their stimulatingsupport and trust. We add our special thanks to the authorswho produced such an excellent work, as well as tothose secretaries, photographers and others who helpedthem.Finally, we should like to express our wish that thisbook on “Pathology of the Head and Neck”, the firstever written as a joint project by a Working Group of theEuropean Society of Pathology, could serve as an examplefor new books written by other Working Groups.Barcelona, SpainNijmegen, The NetherlandsMarch 2006Prof. Antonio CardesaProf. Pieter J. Slootweg

Contents1 Benign and Potentially MalignantLesions of the Squamous Epitheliumand Squamous Cell Carcinoma . . . . 1N. Gale, N. Zidar1.1 Squamous Cell Papillomaand Related Lesions . . . . . . . . . . . . . 21.1.1 Squamous Cell Papilloma, Verruca Vulgaris,Condyloma Acuminatumand Focal Epithelial Hyperplasia . . . . . 21.1.2 Laryngeal Papillomatosis . . . . . . . . . 31.2 Squamous Intraepithelial Lesions (SILS) 41.2.1 General Considerations . . . . . . . . . . 41.2.2 Terminological Problems . . . . . . . . . 41.2.3 Aetiology . . . . . . . . . . . . . . . . . . . 51.2.3.1 Oral Cavity and Oropharyn . . . . . . . . . 51.2.3.2 Larynx . . . . . . . . . . . . . . . . . . . . 51.2.4 Clinical Featuresand Macroscopic Appearances . . . . . . . 61.2.4.1 Oral and Oropharyngeal Leukoplakia,Proliferative Verrucous Leukoplakiaand Erythroplakia . . . . . . . . . . . . . . 61.2.4.2 Laryngeal and HypopharyngealLeukoplakia and Chronic Laryngitis . . . 71.2.5 Histological Classifications . . . . . . . . . 81.2.5.1 WHO Dysplasia System . . . . . . . . . . 81.2.5.2 The Ljubljana Classification . . . . . . . . 91.2.5.3 Comparison Betweenthe Ljubljana Classificationand WHO 2005 Classification . . . . . . . 111.2.6 Biomarkers Related to Malignant Potentialof SILs Recognised by Auxiliaryand Advanced Molecular Methods . . . . . 121.2.7 Treatment and Prognosis . . . . . . . . . . 121.2.7.1 Oral Cavity and Oropharynx . . . . . . . . 121.2.7.2 Larynx . . . . . . . . . . . . . . . . . . . . . 131.3 Invasive Squamous Cell Carcinoma . . . . 131.3.1 Microinvasive SquamousCell Carcinoma . . . . . . . . . . . . . . . 131.3.2 Conventional SquamousCell Carcinoma . . . . . . . . . . . . . . . 131.3.2.1 Aetiology . . . . . . . . . . . . . . . . . . . 141.3.2.2 Pathologic Features . . . . . . . . . . . . . 141.3.2.3 Grading . . . . . . . . . . . . . . . . . . . . 141.3.2.4 Invasive Front . . . . . . . . . . . . . . . . 151.3.2.5 Stromal Reaction . . . . . . . . . . . . . . 151.3.2.6 Differential Diagnosis . . . . . . . . . . . . 151.3.2.7 Treatment and Prognosis . . . . . . . . . . 151.3.3 Spindle Cell Carcinoma . . . . . . . . . . . 161.3.3.1 Aetiology . . . . . . . . . . . . . . . . . . . 161.3.3.2 Pathologic Features . . . . . . . . . . . . . 161.3.3.3 Differential Diagnosis . . . . . . . . . . . . 171.3.3.4 Treatment and Prognosis . . . . . . . . . . 171.3.4 Verrucous Carcinoma . . . . . . . . . . . . 171.3.4.1 Aetiology . . . . . . . . . . . . . . . . . . . 171.3.4.2 Pathologic Features . . . . . . . . . . . . . 181.3.4.3 Differential Diagnosis . . . . . . . . . . . . 181.3.4.4 Treatment . . . . . . . . . . . . . . . . . . . 181.3.4.5 Prognosis . . . . . . . . . . . . . . . . . . . 191.3.5 Papillary Squamous Cell Carcinoma . . . . 191.3.5.1 Aetiology . . . . . . . . . . . . . . . . . . . 191.3.5.2 Pathologic Features . . . . . . . . . . . . . 191.3.5.3 Differential Diagnosis . . . . . . . . . . . . 201.3.5.4 Treatment and Prognosis . . . . . . . . . . 201.3.6 Basaloid Squamous Cell Carcinoma . . . . 201.3.6.1 Aetiology . . . . . . . . . . . . . . . . . . . 201.3.6.2 Pathologic Features . . . . . . . . . . . . . 201.3.6.3 Differential Diagnosis . . . . . . . . . . . . 211.3.6.4 Treatment and Prognosis . . . . . . . . . . 211.3.7 Adenoid Squamous Cell Carcinoma . . . . 221.3.7.1 Pathologic Features . . . . . . . . . . . . . 221.3.7.2 Differential Diagnosis . . . . . . . . . . . . 221.3.7.3 Treatment and Prognosis . . . . . . . . . . 221.3.8 Adenosquamous Carcinoma . . . . . . . . 231.3.8.1 Aetiology . . . . . . . . . . . . . . . . . . . 231.3.8.2 Pathologic Features . . . . . . . . . . . . . 231.3.8.3 Differential Diagnosis . . . . . . . . . . . . 231.3.8.4 Treatment and Prognosis . . . . . . . . . . 241.3.9 Lymphoepithelial Carcinoma . . . . . . . 241.3.9.1 Aetiology . . . . . . . . . . . . . . . . . . . 241.3.9.2 Pathologic Features . . . . . . . . . . . . . 241.3.9.3 Differential Diagnosis . . . . . . . . . . . . 251.3.9.4 Treatment and Prognosis . . . . . . . . . . 251.4 Second Primary Tumours . . . . . . . . . . 251.5 Tumour Spread and Metastasising . . . . 251.5.1 Invasion of Lymphaticand Blood Vessels . . . . . . . . . . . . . . 26

XIIContents1.5.2 Perineural Invasion . . . . . . . . . . . . . 261.5.3 Regional Lymph Node Metastases . . . . . 261.5.3.1 Extracapsular Spreadin Lymph Node Metastases . . . . . . . . . 261.5.3.2 Metastases in the Soft Tissueof the Neck . . . . . . . . . . . . . . . . . . 271.5.4 Distant Metastasis . . . . . . . . . . . . . . 271.5.5 Micrometastasis . . . . . . . . . . . . . . . 271.6 Molecular Pathologyof Squamous Cell Carcinoma . . . . . . . 281.6.1 Detecting Tumour Cells . . . . . . . . . . 281.6.2 Clonal Analysis . . . . . . . . . . . . . . . 281.6.3 Assessment of Riskfor Malignant Progression . . . . . . . . . 291.6.4 DNA/RNA Profilingin Predicting Metastatic Disease . . . . . . 29References . . . . . . . . . . . . . . . . . . 292 Nasal Cavityand Paranasal Sinuses . . . . . . . . . . 39A. Cardesa, L. Alos2.1 Introduction . . . . . . . . . . . . . . . . . . 402.1.1 Embryology . . . . . . . . . . . . . . . . . . 402.1.2 Anatomy . . . . . . . . . . . . . . . . . . . . 402.1.3 Histology . . . . . . . . . . . . . . . . . . . . 402.2. Acute and Chronic Rhinosinusitis . . . . . 402.2.1 Viral Infections (Common Cold) . . . . . . 402.2.2 Bacterial Infections . . . . . . . . . . . . . . 402.2.3 Allergic Rhinitis . . . . . . . . . . . . . . . 402.2.4 Atrophic Rhinitis . . . . . . . . . . . . . . . 412.2.5 Hypertrophic Rhinitis . . . . . . . . . . . . 412.2.6 Non-Suppurative Chronic Sinusitis . . . . 412.3 Sinonasal Polyps . . . . . . . . . . . . . . . 412.3.1 Allergic Polyposis . . . . . . . . . . . . . . . 412.3.2 Polyposis in Mucoviscidosis . . . . . . . . . 412.3.3 Polyposis in Immotile Cilia Syndromeand in Kartagener’s Syndrome . . . . . . . 412.3.4 Antrochoanal Polyps . . . . . . . . . . . . . 412.4 Sinonasal Hamartomatousand Teratoid Lesions . . . . . . . . . . . . . 422.4.1 Hamartomas . . . . . . . . . . . . . . . . . 422.4.2 Teratoid Lesions . . . . . . . . . . . . . . . 422.5 Pseudotumours . . . . . . . . . . . . . . . . 432.5.1 Mucocele . . . . . . . . . . . . . . . . . . . . 432.5.2 Organising Haematoma . . . . . . . . . . . 432.5.3 Amyloidosis . . . . . . . . . . . . . . . . . . 432.5.4 Myospherulosis . . . . . . . . . . . . . . . . 432.5.5 Eosinophilic Angiocentric Fibrosis . . . . 432.5.6 Heterotopic Brain Tissue . . . . . . . . . . 432.6 Fungal Diseases . . . . . . . . . . . . . . . . 442.6.1 Aspergillosis . . . . . . . . . . . . . . . . . 442.6.2 Mucormycosis . . . . . . . . . . . . . . . . . 442.6.3 Rhinosporidiosis . . . . . . . . . . . . . . . 442.7 HIV-Related Infections . . . . . . . . . . . 442.8 Mid-Facial NecrotisingGranulomatous Lesions . . . . . . . . . . . 452.8.1 Wegener’s Granulomatosis . . . . . . . . . 452.8.2 Lepromatous Leprosy . . . . . . . . . . . . 452.8.3 Tuberculosis . . . . . . . . . . . . . . . . . . 452.8.4 Sarcoidosis . . . . . . . . . . . . . . . . . . . 452.8.5 Rhinoscleroma . . . . . . . . . . . . . . . . 452.8.6 Leishmaniasis . . . . . . . . . . . . . . . . . 452.8.7 Cocaine Abuse . . . . . . . . . . . . . . . . 462.8.8 Local Steroid Injections . . . . . . . . . . . 462.9 Benign Epithelial Neoplasms . . . . . . . . 462.9.1 Sinonasal Papillomas . . . . . . . . . . . . . 462.9.1.1 Squamous Cell Papilloma . . . . . . . . . . 462.9.1.2 Exophytic Papilloma . . . . . . . . . . . . . 462.9.1.3 Inverted Papilloma . . . . . . . . . . . . . . 462.9.1.4 Oncocytic Papilloma . . . . . . . . . . . . . 472.9.2 Salivary-Type Adenomas . . . . . . . . . . 482.9.3 Pituitary Adenomas . . . . . . . . . . . . . 482.10 Benign SinonasalSoft Tissue Neoplasms . . . . . . . . . . . . 482.10.1 Haemangiomas . . . . . . . . . . . . . . . . 482.10.2 Haemangiopericytoma . . . . . . . . . . . . 482.10.3 Solitary Fibrous Tumour . . . . . . . . . . . 482.10.4 Desmoid Fibromatosis . . . . . . . . . . . . 492.10.5 Fibrous Histiocytoma . . . . . . . . . . . . 492.10.6 Leiomyoma . . . . . . . . . . . . . . . . . . 492.10.7 Schwannoma and Neurofibroma . . . . . . 492.10.8 Meningioma . . . . . . . . . . . . . . . . . . 502.10.9 Paraganglioma . . . . . . . . . . . . . . . . 502.10.10 Juvenile Angiofibroma . . . . . . . . . . . . 502.11 Malignant Sinonasal Tumours . . . . . . . 502.11.1 Keratinising SquamousCell Carcinoma . . . . . . . . . . . . . . . . 512.11.2 Cylindrical Cell Carcinoma . . . . . . . . . 522.11.3 SinonasalUndifferentiated Carcinoma . . . . . . . . 532.11.4 Small Cell (Neuroendocrine)Carcinoma . . . . . . . . . . . . . . . . . . . 542.11.5 Primary SinonasalNasopharyngeal-TypeUndifferentiated Carcinoma . . . . . . . . 542.11.6 Malignant Melanoma . . . . . . . . . . . . 552.11.7 Olfactory Neuroblastoma . . . . . . . . . . 572.11.8 Primitive Neuroectodermal Tumour . . . . 582.11.9 High-Grade SinonasalAdenocarcinomas . . . . . . . . . . . . . . 582.11.9.1 Intestinal-TypeAdenocarcinoma . . . . . . . . . . . . . . . 582.11.9.2 Salivary-Type High-GradeAdenocarcinoma . . . . . . . . . . . . . . . 60

ContentsXIII2.11.10 Low-Grade SinonasalAdenocarcinomas . . . . . . . . . . . . . . . 602.11.10.1 Non-Salivary-TypeLow-Grade Adenocarcinomas . . . . . . . 602.11.10.2 Salivary-TypeLow-Grade Adenocarcinomas . . . . . . . 612.11.11 Sinonasal Malignant Lymphomas . . . . . 612.11.12 Extramedullary Plasmacytoma . . . . . . 622.11.13 Fibrosarcoma . . . . . . . . . . . . . . . . . 622.11.14 Malignant Fibrous Histiocytoma . . . . . 632.11.15 Leiomyosarcoma . . . . . . . . . . . . . . . 632.11.16 Rhabdomyosarcoma . . . . . . . . . . . . . 632.11.17 Malignant PeripheralNerve Sheath Tumour . . . . . . . . . . . . 632.11.18 Teratocarcinosarcoma . . . . . . . . . . . . 63References . . . . . . . . . . . . . . . . . . 643 Oral Cavity . . . . . . . . . . . . . . . . . 72J.W. Eveson3.1 Embryonic Rests and Heterotopias . . . . 723.1.1 Fordyce Granules/Spots . . . . . . . . . . . 723.1.2 Juxtaoral Organ of Chievitz . . . . . . . . 723.2. Vesiculo-Bullous Diseases . . . . . . . . . 723.2.1 Herpes Simplex Infections . . . . . . . . . 723.2.2 Chickenpox and Herpes Zoster . . . . . . 733.2.3 Hand-Foot-and-Mouth Disease . . . . . . 733.2.4 Herpangina . . . . . . . . . . . . . . . . . . 743.2.5 Pemphigus Vulgaris . . . . . . . . . . . . . 743.2.6 Pemphigus Vegetans . . . . . . . . . . . . . 743.2.7 Paraneoplastic Pemphigus . . . . . . . . . 753.2.8 Mucous Membrane Pemphigoid . . . . . . 753.2.9 Dermatitis Herpetiformis . . . . . . . . . 763.2.10 Linear IgA Disease . . . . . . . . . . . . . . 763.2.11 Erythema Multiforme . . . . . . . . . . . . 773.3 Ulcerative Lesions . . . . . . . . . . . . . . 773.3.1 Aphthous Stomatitis(Recurrent Aphthous Ulceration) . . . . . 773.3.2 Behçet Disease . . . . . . . . . . . . . . . . 783.3.3 Reiter Disease . . . . . . . . . . . . . . . . 783.3.4 Median Rhomboid Glossitis . . . . . . . . 783.3.5 Eosinophilic Ulcer(Traumatic Ulcerative Granulomawith Stromal Eosinophilia) . . . . . . . . . 793.3.6 Acute NecrotisingUlcerative Gingivitis . . . . . . . . . . . . . 793.3.7 Wegener’s Granulomatosis . . . . . . . . . 803.3.8 Tuberculosis . . . . . . . . . . . . . . . . . 813.4 White Lesions . . . . . . . . . . . . . . . . 813.4.1 Candidosis . . . . . . . . . . . . . . . . . . 813.4.2 Lichen Planus . . . . . . . . . . . . . . . . . 823.4.3 Lupus Erythematosus . . . . . . . . . . . . 833.4.4 Oral Epithelial Naevi . . . . . . . . . . . . 843.4.5 Smoker’s Keratosis . . . . . . . . . . . . . . 843.4.6 Stomatitis Nicotina . . . . . . . . . . . . . 843.4.7 Hairy Tongue . . . . . . . . . . . . . . . . . 853.4.8 Hairy Leukoplakia . . . . . . . . . . . . . . 853.4.9 Geographic Tongue . . . . . . . . . . . . . 853.4.10 Frictional Keratosis . . . . . . . . . . . . . 863.5 Pigmentations . . . . . . . . . . . . . . . . 863.5.1 Amalgam Tattoo . . . . . . . . . . . . . . . 863.5.2 Localised Melanotic Pigmentation . . . . 863.5.2.1 Oral Melanotic Macules . . . . . . . . . . . 863.5.2.2 Melanoacanthoma . . . . . . . . . . . . . . 873.5.2.3 Pigmented Naevi . . . . . . . . . . . . . . . 873.5.3 Premalignant Oral Melanosesand Oral Melanoma . . . . . . . . . . . . . 873.5.4 Addison Disease . . . . . . . . . . . . . . . 883.5.5 Peutz Jeghers Syndrome . . . . . . . . . . . 893.5.6 Racial Pigmentation . . . . . . . . . . . . . 893.5.7 Laugier Hunziker Syndrome . . . . . . . . 893.5.8 Smoker’s Melanosis . . . . . . . . . . . . . 893.5.9 Drug-AssociatedOral Pigmentation . . . . . . . . . . . . . 903.6 Hyperplastic Lesions . . . . . . . . . . . . 903.6.1 Fibrous Hyperplasias . . . . . . . . . . . . 903.6.2 Papillary Hyperplasia . . . . . . . . . . . . 903.6.3 Generalised GingivalFibrous Hyperplasia . . . . . . . . . . . . . 913.6.4 Crohn’s Disease . . . . . . . . . . . . . . . 913.6.5 Orofacial Granulomatosis . . . . . . . . . 923.6.6 Chronic Marginal Gingivitisand Localised GingivalFibrous Hyperplasia . . . . . . . . . . . . . 923.6.7 Peripheral Giant Cell Granuloma(Giant Cell Epulis) . . . . . . . . . . . . . . 933.6.8 Pyogenic Granuloma . . . . . . . . . . . . 933.6.9 Pulse (Vegetable) Granuloma . . . . . . . 933.7 Benign Tumoursand Pseudotumours . . . . . . . . . . . . . 943.7.1 Giant Cell Fibroma . . . . . . . . . . . . . 943.7.2 Lingual Thyroid . . . . . . . . . . . . . . . 943.7.3 Verruciform Xanthoma . . . . . . . . . . . 953.7.4 Haemangiomas . . . . . . . . . . . . . . . . 953.7.5 Lymphangioma . . . . . . . . . . . . . . . . 953.7.6 Benign Nerve Sheath Tumours . . . . . . . 953.7.6.1 Neurofibroma . . . . . . . . . . . . . . . . 963.7.6.2 Schwannoma . . . . . . . . . . . . . . . . . 963.7.6.3 Neurofibromatosis . . . . . . . . . . . . . . 963.7.6.4 Multiple Neuromasin Endocrine Neoplasia Syndrome . . . . 963.7.7 Granular Cell Tumour(Granular Cell Myoblastoma) . . . . . . . 963.8 Squamous Cell Carcinoma . . . . . . . . . 963.8.1 Introduction . . . . . . . . . . . . . . . . . 963.8.2 Clinical Features . . . . . . . . . . . . . . . 973.8.2.1 Buccal Mucosa . . . . . . . . . . . . . . . . 973.8.2.2 Tongue . . . . . . . . . . . . . . . . . . . . 973.8.2.3 Floor of Mouth . . . . . . . . . . . . . . . . 97

XIVContents3.8.2.4 Gingiva and Alveolar Ridge . . . . . . . . 973.8.2.5 Hard Palate . . . . . . . . . . . . . . . . . . 983.8.2.6 Retromolar Trigone . . . . . . . . . . . . . 983.8.3 Staging . . . . . . . . . . . . . . . . . . . . 98References . . . . . . . . . . . . . . . . . . 984 Maxillofacial Skeletonand Teeth . . . . . . . . . . . . . . . . . 104P.J. Slootweg4.1 Introduction . . . . . . . . . . . . . . . . 1044.1.1 Embryology . . . . . . . . . . . . . . . . 1044.1.2 Tooth Development . . . . . . . . . . . . 1044.2 Inflammatory Diseasesof the Maxillofacial Bones . . . . . . . . 1044.3 Cysts of the Jaws . . . . . . . . . . . . . . 1054.3.1 Odontogenic Cysts –Inflammatory w . . . . . . . . . . . . . . 1054.3.1.1 Radicular Cyst . . . . . . . . . . . . . . . 1054.3.1.2 Paradental Cyst . . . . . . . . . . . . . . 1064.3.2 Odontogenic Cysts –Developmental . . . . . . . . . . . . . . . 1064.3.2.1 Dentigerous Cyst . . . . . . . . . . . . . . 1064.3.2.2 Lateral Periodontal Cyst . . . . . . . . . 1074.3.2.3 Glandular Odontogenic Cyst . . . . . . . 1074.3.2.4 Odontogenic Keratocyst . . . . . . . . . 1074.3.2.5 Gingival Cyst . . . . . . . . . . . . . . . . 1084.3.3 Non-Odontogenic Cysts . . . . . . . . . 1094.3.3.1 Nasopalatine Duct Cyst . . . . . . . . . . 1094.3.3.2 Nasolabial Cyst . . . . . . . . . . . . . . . 1094.3.3.3 Surgical Ciliated Cyst . . . . . . . . . . . 1094.3.4 Pseudocysts . . . . . . . . . . . . . . . . . 1094.3.4.1 Solitary Bone Cyst . . . . . . . . . . . . . 1094.3.4.2 Focal Bone Marrow Defect . . . . . . . . 1094.4 Odontogenic Tumours . . . . . . . . . . 1094.4.1 Odontogenic Tumours –Epithelial . . . . . . . . . . . . . . . . . . 1104.4.1.1 Ameloblastoma . . . . . . . . . . . . . . . 1104.4.1.2 Calcifying EpithelialOdontogenic Tumour . . . . . . . . . . . 1124.4.1.3 Adenomatoid Odontogenic Tumour . . 1124.4.1.4 Squamous Odontogenic Tumour . . . . 1134.4.2 Odontogenic Tumours –Mesenchymal . . . . . . . . . . . . . . . . 1144.4.2.1 Odontogenic Myxoma . . . . . . . . . . . 1144.4.2.2 Odontogenic Fibroma . . . . . . . . . . . 1154.4.2.3 Cementoblastoma . . . . . . . . . . . . . 1164.4.3 Odontogenic Tumours –Mixed Epithelial and Mesenchymal . . . 1174.4.3.1 Ameloblastic Fibroma . . . . . . . . . . . 1174.4.3.2 Ameloblastic Fibro-Odontoma . . . . . . 1174.4.3.3 Odontoma – Complex Type . . . . . . . 1184.4.3.4 Odontoma – Compound Type . . . . . . 1184.4.3.5 Odonto-Ameloblastoma . . . . . . . . . 1184.4.3.6 Calcifying Odontogenic Cyst . . . . . . 1184.4.4 Odontogenic Tumours –Malignant . . . . . . . . . . . . . . . . . . 1194.4.4.1 Malignant Ameloblastoma . . . . . . . . 1194.4.4.2 Ameloblastic Carcinoma . . . . . . . . . 1194.4.4.3 Primary Intraosseous Carcinoma . . . . 1194.4.4.4 Clear Cell Odontogenic Carcinoma . . . 1204.4.4.5 Malignant Epithelial OdontogenicGhost Cell Tumour . . . . . . . . . . . . 1204.4.4.6 Odontogenic Sarcoma . . . . . . . . . . . 1204.5 Fibro-Osseous Lesions . . . . . . . . . . 1214.5.1 Fibrous Dysplasia . . . . . . . . . . . . . 1214.5.2 Ossifying Fibroma . . . . . . . . . . . . . 1214.5.3 Osseous Dysplasia . . . . . . . . . . . . . 1234.6 Giant Cell Lesions . . . . . . . . . . . . . 1244.6.1 Central Giant Cell Granuloma . . . . . . 1244.6.2 Cherubism . . . . . . . . . . . . . . . . . 1244.7 Neoplastic Lesionsof the Maxillofacial Bones,Non-Odontogenic . . . . . . . . . . . . . 1254.7.1 Osteoma . . . . . . . . . . . . . . . . . . . 1254.7.2 Chordoma . . . . . . . . . . . . . . . . . . 1254.7.3 Melanotic Neuroectodermal Tumourof Infancy . . . . . . . . . . . . . . . . . . 126References . . . . . . . . . . . . . . . . . . 1265 Major and MinorSalivary Glands . . . . . . . . . . . . . 132S. Di Palma, R.H.W. Simpson,A. Skalova, I. Leivo5.1 Introduction . . . . . . . . . . . . . . . . . 1325.1.1 Normal Salivary Glands . . . . . . . . . . 1325.1.2 Developmental Disorders . . . . . . . . . . 1325.2 Obstructive Disorders . . . . . . . . . . . . 1325.2.1 Mucus Escape Reaction . . . . . . . . . . . 1325.2.2 Chronic Sclerosing Sialadenitisof the Submandibular Gland(Küttner Tumour) . . . . . . . . . . . . . . 1335.3. Infections . . . . . . . . . . . . . . . . . . . 1335.3.1 Bacteria, Fungi . . . . . . . . . . . . . . . . 1335.3.2 Viruses . . . . . . . . . . . . . . . . . . . . 1335.4 Miscellaneous InflammatoryDisorders . . . . . . . . . . . . . . . . . . . 1335.5 Miscellaneous Non-InflammatoryDisorders . . . . . . . . . . . . . . . . . . . 1335.5.1 Necrotising Sialometaplasia(Salivary Gland Infarction) . . . . . . . . . 1335.5.2 Sialadenosis . . . . . . . . . . . . . . . . . . 1335.5.3 Adenomatoid Hyperplasiaof Mucous Salivary Glands . . . . . . . . . 1345.5.4 Irradiation Changes . . . . . . . . . . . . . 134

ContentsXV5.5.5 Tissue ChangesFollowing Fine Needle Aspiration . . . . . 1345.6 Oncocytic Lesions . . . . . . . . . . . . . . 1345.6.1 Focal and Diffuse Oncocytosis . . . . . . . 1345.6.2 Ductal Oncocytosis . . . . . . . . . . . . . 1345.6.3 Multifocal NodularOncocytic Hyperplasia . . . . . . . . . . . 1355.7 Cysts . . . . . . . . . . . . . . . . . . . . . . 1355.7.1 Salivary PolycysticDysgenetic Disease . . . . . . . . . . . . . . 1355.7.2 Mucoceles . . . . . . . . . . . . . . . . . . . 1355.7.3 Simple Salivary Duct Cysts . . . . . . . . . 1355.7.4 Lymphoepithelial Cystic Lesions . . . . . . 1355.7.4.1 Benign Lymphoepithelial Cyst . . . . . . . 1355.7.4.2 Cystic Lymphoid Hyperplasiaof AIDS . . . . . . . . . . . . . . . . . . . . 1365.7.5 Sclerosing Polycystic Sialadenopathy(Sclerosing Polycystic Adenosis) . . . . . . 1365.7.6 Other Cysts . . . . . . . . . . . . . . . . . . 1375.8 Benign Tumours . . . . . . . . . . . . . . . 1375.8.1 Pleomorphic Adenoma . . . . . . . . . . . 1375.8.1.1 Salivary Gland Anlage Tumour(“Congenital Pleomorphic Adenoma”) . . 1405.8.2 Benign Myoepithelioma . . . . . . . . . . . 1405.8.3 Basal Cell Adenoma . . . . . . . . . . . . . 1415.8.4 Warthin’s Tumour . . . . . . . . . . . . . . 1425.8.5 Oncocytoma . . . . . . . . . . . . . . . . . 1435.8.6 Canalicular Adenoma . . . . . . . . . . . . 1435.8.7 Sebaceous Adenoma . . . . . . . . . . . . . 1445.8.8 Sebaceous Lymphadenoma . . . . . . . . . 1445.8.9 Ductal Papilloma . . . . . . . . . . . . . . . 1445.8.10 Cystadenoma . . . . . . . . . . . . . . . . . 1445.9 Malignant Epithelial Tumours . . . . . . . 1445.9.1 Acinic Cell Carcinoma . . . . . . . . . . . 1445.9.2 Mucoepidermoid Carcinoma . . . . . . . . 1465.9.3 Adenoid Cystic Carcinoma . . . . . . . . . 1475.9.4 Polymorphous Low-GradeAdenocarcinoma . . . . . . . . . . . . . . . 1485.9.4.1 Cribriform Adenocarcinomaof the Tongue . . . . . . . . . . . . . . . . . 1495.9.5 Epithelial-Myoepithelial Carcinoma . . . 1505.9.6 Hyalinising Clear Cell Carcinoma . . . . 1515.9.7 Basal Cell Adenocarcinoma . . . . . . . . 1515.9.8 Myoepithelial Carcinoma(Malignant Myoepithelioma) . . . . . . . . 1525.9.9 Salivary Duct Carcinoma . . . . . . . . . . 1545.9.10 Oncocytic Carcinoma . . . . . . . . . . . . 1555.9.11 Malignancy in Pleomorphic AdenomaMalignant Mixed Tumour . . . . . . . . . 1565.9.11.1 Carcinoma(True Malignant Mixed Tumour)Ex Pleomorphic Adenoma . . . . . . . . . 1565.9.11.2 CarcinosarcomaEx Pleomorphic Adenoma . . . . . . . . . 1575.9.11.3 Metastasising Pleomorphic Adenoma . . . 1575.9.12 Sebaceous Carcinoma . . . . . . . . . . . . 1585.9.13 Lymphoepithelial Carcinoma . . . . . . . 1585.9.14 Small Cell Carcinoma . . . . . . . . . . . . 1585.9.15 Higher Grade Change in Carcinomas . . . 1595.9.16 Metastatic Malignancies . . . . . . . . . . 1595.10 Hybrid Carcinoma . . . . . . . . . . . . . . 1605.11 Endodermal Sinus Tumour . . . . . . . . . 1605.12 Sialoblastoma . . . . . . . . . . . . . . . . . 1605.13 Alterations in Gene Expressionand Molecular Derangementsin Salivary Gland Carcinoma . . . . . . . . 1605.13.1 PredominantlyMyoepithelial Malignancies . . . . . . . . . 1615.13.2 PredominantlyEpithelial Malignancies . . . . . . . . . . . 1615.14 Benign and MalignantLymphoid Infiltrates . . . . . . . . . . . . . 1625.14.1 Non-AutoimmuneLymphoid Infiltrates . . . . . . . . . . . . . 1625.14.2 Benign AutoimmuneLymphoid Infiltrates . . . . . . . . . . . . . 1625.14.3 Malignant Lymphoma . . . . . . . . . . . . 1635.15 Other Tumours . . . . . . . . . . . . . . . . 1635.16 Unclassified Tumours . . . . . . . . . . . . 163References . . . . . . . . . . . . . . . . . . . 1646 Nasopharynxand Waldeyer’s Ring . . . . . . . . . . . 171S. Regauer6.1 Embryological Developmentof the Nasopharynxand Waldeyer’s Ring . . . . . . . . . . . . . 1726.2 Nasopharynx . . . . . . . . . . . . . . . . . 1736.2.1 Anatomy and Histology . . . . . . . . . . . 1736.2.2 Congenital DevelopmentalAnomalies . . . . . . . . . . . . . . . . . . 1736.2.2.1 NasopharyngealBranchial Cleft Cysts . . . . . . . . . . . . 1736.2.2.2 Tornwaldt’s Cyst . . . . . . . . . . . . . . . 1736.2.2.3 Rathke’s Cleft Cyst/Ectopic Pituitary Tissue . . . . . . . . . . . 1746.2.2.4 Craniopharyngioma . . . . . . . . . . . . . 1746.2.2.5 Heterotopic Brain Tissue/Encephalocele . . . . . . . . . . . . . . . . 1746.2.3 Congenital Tumours . . . . . . . . . . . . . 1746.2.3.1 Salivary Gland Anlage Tumour . . . . . . 1756.2.3.2 Hairy Polyp . . . . . . . . . . . . . . . . . . 1756.2.3.3 Congenital NasopharyngealTeratoma . . . . . . . . . . . . . . . . . . . 1756.2.4 Benign Tumoursand Tumour-Like Lesions . . . . . . . . . 175

XVIContents6.2.4.1 Nasopharyngeal Angiofibroma . . . . . . 1756.2.4.2 Respiratory EpithelialAdenomatoid Hamartoma . . . . . . . . . 1786.2.4.3 Nasopharyngeal Inverted Papilloma . . . 1786.2.4.4 Solitary Fibrous Tumour . . . . . . . . . . 1796.2.4.5 Paraganglioma . . . . . . . . . . . . . . . . 1796.2.4.6 Meningioma . . . . . . . . . . . . . . . . . 1796.2.4.7 Glandular Retention Cysts . . . . . . . . . 1796.2.5 Nasopharyngeal Carcinoma . . . . . . . . 1806.2.5.1 Non-Keratinising NasopharyngealCarcinoma . . . . . . . . . . . . . . . . . . 1806.2.5.2 Keratinising NasopharyngealCarcinoma . . . . . . . . . . . . . . . . . . . 1826.2.6 Nasopharyngeal Adenocarcinoma . . . . . 1826.2.6.1 Salivary Gland-Type Adenocarcinomaof the Nasopharynx . . . . . . . . . . . . . 1826.2.6.2 Papillary Adenocarcinomaof the Nasopharynx . . . . . . . . . . . . . 1826.2.7 Malignant Non-Epithelial Tumoursof the Nasopharynx . . . . . . . . . . . . . 1836.2.7.1 Chordoma . . . . . . . . . . . . . . . . . . . 1836.2.7.2 Sarcoma . . . . . . . . . . . . . . . . . . . . 1836.3 Waldeyer’s Ring . . . . . . . . . . . . . . . 1836.3.1 Anatomy and Histologyof Waldeyer’s Ring . . . . . . . . . . . . . . 1836.3.2 Congenital Anomaliesof Waldeyer’s Ring . . . . . . . . . . . . . . 1846.3.3 Tonsillitis . . . . . . . . . . . . . . . . . . . 1846.3.3.1 Bacterial Tonsillitis . . . . . . . . . . . . . 1846.3.3.2 Viral Tonsillitis . . . . . . . . . . . . . . . 1856.3.4 Benign Tumoursof Waldeyer’s Ring . . . . . . . . . . . . . . 1876.3.4.1 Squamous Papilloma . . . . . . . . . . . . 1876.3.4.2 Lymphangiomatous Tonsillar Polyp . . . . 1876.3.5 Carcinomasof Waldeyer’s Ring . . . . . . . . . . . . . . 1876.3.6 Malignant Lymphomasof Waldeyer’s Ring . . . . . . . . . . . . . . 1896.3.6.1 Mantle Cell Lymphoma . . . . . . . . . . . 1896.3.6.2 Extranodal Marginal Zone B-CellLymphoma of Mucosa-AssociatedLymphoid Tissue . . . . . . . . . . . . . . . 1906.3.6.3 Extranodal NK/T-Cell Lymphoma,Nasal Type . . . . . . . . . . . . . . . . . . 1906.3.6.4 Hodgkin’s Lymphoma . . . . . . . . . . . . 1906.3.6.5 Extramedullary Plasmacytoma . . . . . . 1906.3.7 Systemic DiseaseAffecting Waldeyer’s Ring . . . . . . . . . 190References . . . . . . . . . . . . . . . . . . 1917 Larynx and Hypopharynx . . . . . . . 196N. Gale, A. Cardesa, N. Zidar7.1 Summary of Anatomy,Histology and Embryology . . . . . . . . . 1987.2 Laryngocele, Cysts, Heterotopia . . . . . . 1997.2.1 General Considerations . . . . . . . . . . . 1997.2.2 Laryngocele . . . . . . . . . . . . . . . . . . 1997.2.3 Sacccular Cyst . . . . . . . . . . . . . . . . 1997.2.4 Ductal Cyst . . . . . . . . . . . . . . . . . . 1997.2.5 Oncocytic Cyst . . . . . . . . . . . . . . . . 2007.2.6 Zenker’s Hypopharyngeal Diverticle . . . 2017.2.7 Aberrant Thyroid Tissue . . . . . . . . . . 2017.2.8 Tracheopathia Osteochondroplastica . . . 2027.3 Inflammatory Lesions . . . . . . . . . . . . 2027.3.1 Acute Infections . . . . . . . . . . . . . . . 2027.3.1.1 Epiglottitis . . . . . . . . . . . . . . . . . . 2027.3.1.2 Laryngotracheobronchitis . . . . . . . . . 2027.3.1.3 Diphtheria . . . . . . . . . . . . . . . . . . 2027.3.2 Chronic Infections . . . . . . . . . . . . . . 2027.3.2.1 Tuberculosis . . . . . . . . . . . . . . . . . 2027.3.2.2 Fungal Infections . . . . . . . . . . . . . . 2037.3.2.3 Other Rare Infections . . . . . . . . . . . . 2037.3.3 Non-Infectious InflammatoryLesions . . . . . . . . . . . . . . . . . . . . . 2037.3.3.1 Wegener’s Granulomatosis . . . . . . . . . 2037.3.3.2 Sarcoidosis . . . . . . . . . . . . . . . . . . 2047.3.3.3 Rheumatoid Arthritis . . . . . . . . . . . . 2047.3.3.4 Relapsing Polychondritis . . . . . . . . . . 2057.3.3.5 Gout . . . . . . . . . . . . . . . . . . . . . . 2067.3.3.6 Teflon Granuloma . . . . . . . . . . . . . . 2067.3.3.7 Idiopathic SubglotticLaryngeal Stenosis . . . . . . . . . . . . . . 2067.3.3.8 Angioneurotic Oedema . . . . . . . . . . . 2077.4 Degenerative Lesions . . . . . . . . . . . . 2077.4.1 OculopharyngealMuscular Dystrophy . . . . . . . . . . . . . 2077.5 Pseudotumours . . . . . . . . . . . . . . . . 2077.5.1 Exudative Lesions of Reinke’s Space . . . . 2077.5.1.1 Reinke’s Oedema . . . . . . . . . . . . . . . 2087.5.1.2 Vocal Cord Polyp and Nodule . . . . . . . 2087.5.2 Contact Ulcer and Granuloma,Intubation Granuloma . . . . . . . . . . . 2107.5.3 Necrotising Sialometaplasia . . . . . . . . 2117.5.4 Metaplastic Elastic CartilaginousNodules . . . . . . . . . . . . . . . . . . . . 2117.5.5 Amyloidosis . . . . . . . . . . . . . . . . . . 2117.5.6 Sinus Histiocytosiswith Massive Lymphadenopathyand Other Rare Pseudotumours . . . . . . 2127.5.7 Inflammatory MyofibroblasticTumour . . . . . . . . . . . . . . . . . . . . 2137.6 Benign Neoplasms . . . . . . . . . . . . . . 2147.6.1 Squamous Cell Papilloma . . . . . . . . . . 2147.6.2 Salivary Gland-Type Tumours . . . . . . . 2147.6.2.1 Pleomorphic Adenoma . . . . . . . . . . . 2147.6.2.2 Oncocytoma . . . . . . . . . . . . . . . . . 2147.6.3 Haemangioma(Neonatal and Adult Types) . . . . . . . . 214

ContentsXVII7.6.4 Paraganglioma . . . . . . . . . . . . . . . . 2157.6.5 Granular Cell Tumour . . . . . . . . . . . 2167.6.6 Chondroma . . . . . . . . . . . . . . . . . . 2177.7 Malignant Neoplasms . . . . . . . . . . . . 2177.7.1 Potentially Malignant (Precancerous)Lesions . . . . . . . . . . . . . . . . . . . . 2177.7.2 Invasive Squamous Cell Carcinoma . . . . 2187.7.2.1 Epidemiology . . . . . . . . . . . . . . . . . 2187.7.2.2 Aetiology . . . . . . . . . . . . . . . . . . . 2187.7.2.3 Anatomic Sites . . . . . . . . . . . . . . . . 2187.7.2.4 Histological Variants . . . . . . . . . . . . 2197.7.2.5 TNM Grading . . . . . . . . . . . . . . . . 2207.7.3 Neuroendocrine Carcinoma . . . . . . . . 2207.7.3.1 Well-DifferentiatedNeuroendocrine Carcinoma(Carcinoid) . . . . . . . . . . . . . . . . . . 2207.7.3.2 Moderately DifferentiatedNeuroendocrine Carcinoma(Atypical Carcinoid) . . . . . . . . . . . . . 2207.7.3.3 Poorly DifferentiatedNeuroendocrine Carcinoma(Small Cell Carcinoma) . . . . . . . . . . . 2217.7.4 Adenocarcinoma . . . . . . . . . . . . . . . 2227.7.4.1 Adenoid Cystic Carcinoma . . . . . . . . . 2227.7.4.2 Mucoepidermoid Carcinoma . . . . . . . . 2227.7.5 Sarcomas . . . . . . . . . . . . . . . . . . . 2237.7.5.1 Chondrosarcoma . . . . . . . . . . . . . . . 2237.7.5.2 Other Sarcomas . . . . . . . . . . . . . . . 2247.7.6 Other Malignant Neoplasms . . . . . . . . 2247.7.6.1 Malignant Lymphoma . . . . . . . . . . . . 2247.7.6.2 Extraosseus (Extramedullary)Plasmacytoma . . . . . . . . . . . . . . . . 2247.7.6.3 Primary Mucosal Melanoma . . . . . . . . 2257.7.6.4 Metastases to the Larynx . . . . . . . . . . 225References . . . . . . . . . . . . . . . . . . . 2268 Ear and Temporal Bone . . . . . . . . . 234L. Michaels8.1 Summary of Embryology,Anatomy and Histology . . . . . . . . . . . 2368.1.1 Embryology . . . . . . . . . . . . . . . . . . 2368.1.2 Anatomy . . . . . . . . . . . . . . . . . . . . 2368.1.3 Histology . . . . . . . . . . . . . . . . . . . 2378.2 External Ear and Auditory Canal . . . . . 2378.2.1 Inflammatory and Metabolic Lesions . . . 2378.2.1.1 Diffuse External Otitis . . . . . . . . . . . . 2378.2.1.2 Perichondritis . . . . . . . . . . . . . . . . 2378.2.1.3 Malignant Otitis Externa . . . . . . . . . . 2378.2.1.4 Relapsing Polychondritis . . . . . . . . . . 2388.2.1.5 Gout . . . . . . . . . . . . . . . . . . . . . . 2388.2.1.6 Ochronosis . . . . . . . . . . . . . . . . . . 2388.2.2 Pseudocystic and Cystic Lesions . . . . . . 2388.2.2.1 Idiopathic PseudocysticChondromalacia . . . . . . . . . . . . . . . 2388.2.2.2 First Branchial Cleft Cyst . . . . . . . . . . 2388.2.3 Tumour-Like Lesions . . . . . . . . . . . . 2398.2.3.1 Chondrodermatitis Nodularis Helicis . . . 2398.2.3.2 Keratosis Obturans and Cholesteatomaof External Canal . . . . . . . . . . . . . . 2398.2.3.3 Keratin Granuloma . . . . . . . . . . . . . 2398.2.3.4 Angiolymphoid Hyperplasiawith Eosinophiliaand Kimura’s Disease . . . . . . . . . . . . 2398.2.3.5 Accessory Tragus . . . . . . . . . . . . . . 2408.2.3.6 Keloid . . . . . . . . . . . . . . . . . . . . . 2408.2.4 Benign Neoplasms . . . . . . . . . . . . . . 2408.2.4.1 Adenoma of Ceruminal Glands . . . . . . 2408.2.4.2 Pleomorphic Adenomaof Ceruminal Glands . . . . . . . . . . . . 2418.2.4.3 Syringocystadenoma Papilliferumof Ceruminal Glands . . . . . . . . . . . . 2418.2.4.4 Bony Lesions . . . . . . . . . . . . . . . . . 2418.2.5 Malignant Neoplasms . . . . . . . . . . . . 2428.2.5.1 Adenocarcinomaof Ceruminal Glands . . . . . . . . . . . . 2428.2.5.2 Adenoid Cystic Carcinomaof Ceruminal Glands . . . . . . . . . . . . 2428.2.5.3 Basal Cell Carcinoma . . . . . . . . . . . . 2428.2.5.4 Squamous Cell Carcinoma . . . . . . . . . 2438.2.5.5 Melanotic Neoplasms . . . . . . . . . . . . 2438.3 Middle Ear and Mastoid . . . . . . . . . . 2448.3.1 Inflammatory Lesions . . . . . . . . . . . . 2448.3.1.1 Acute and Chronic Otitis Media . . . . . . 2448.3.1.2 Cholesteatoma . . . . . . . . . . . . . . . . 2448.3.1.3 Unusual Inflammatory Lesions . . . . . . 2478.3.2 Neoplasms and LesionsResembling Neoplasms . . . . . . . . . . . 2478.3.2.1 Choristoma(Salivary Gland, Glialand Sebaceous Types) . . . . . . . . . . . . 2478.3.2.2 Adenoma . . . . . . . . . . . . . . . . . . . 2478.3.2.3 Papillary Tumours . . . . . . . . . . . . . . 2488.3.2.4 Jugulotympanic Paraganglioma . . . . . . 2498.3.2.5 Squamous Carcinoma . . . . . . . . . . . . 2508.3.2.6 Meningioma . . . . . . . . . . . . . . . . . 2518.3.2.7 Rhabdomyosarcoma . . . . . . . . . . . . . 2518.3.2.8 Metastatic Carcinoma . . . . . . . . . . . . 2528.4 Inner Ear . . . . . . . . . . . . . . . . . . . 2528.4.1 Bony Labyrinth . . . . . . . . . . . . . . . . 2528.4.1.1 Otosclerosis . . . . . . . . . . . . . . . . . . 2528.4.1.2 Paget’s Disease . . . . . . . . . . . . . . . . 2538.4.1.3 Osteogenesis Imperfecta . . . . . . . . . . 2548.4.1.4 Osteopetrosis . . . . . . . . . . . . . . . . . 2548.4.2 Membranous Labyrinthand Cranial Nerves . . . . . . . . . . . . . 2548.4.2.1 Viral, Bacterialand Mycotic Infections . . . . . . . . . . . 2548.4.2.2 Lesions of the Vestibular System . . . . . . 2568.4.2.3 Tumours and Tumour-Like Lesions . . . . 257

XVIIIContents8.4.2.4 Presbyacusis . . . . . . . . . . . . . . . . . 2608.4.2.5 Malformations . . . . . . . . . . . . . . . . 260References . . . . . . . . . . . . . . . . . . . 2609 Cysts and Unknown Primaryand Secondary Tumours of the Neck,and Neck Dissection . . . . . . . . . . . 262M. A Luna, K. Pineda-Daboin9.1 Introduction . . . . . . . . . . . . . . . . . 2649.2. Anatomy . . . . . . . . . . . . . . . . . . . 2649.2.1 Triangles of the Neck . . . . . . . . . . . . 2649.2.2 Lymph Node Regionsof the Neck . . . . . . . . . . . . . . . . . . 2649.3 Cysts of the Neck . . . . . . . . . . . . . . 2649.3.1 Developmental Cysts . . . . . . . . . . . . 2659.3.1.1 Branchial Cleft Cysts,Sinuses and Fistulae . . . . . . . . . . . . . 2659.3.2 Branchiogenic Carcinoma . . . . . . . . . 2679.3.3 Thyroglossal Duct Cystand Ectopic Thyroid . . . . . . . . . . . . . 2689.3.4 Cervical Thymic Cyst . . . . . . . . . . . . 2699.3.5 Cervical Parathyroid Cyst . . . . . . . . . 2709.3.6 Cervical Bronchogenic Cyst . . . . . . . . 2709.3.7 Dermoid Cyst . . . . . . . . . . . . . . . . 2719.3.8 Unclassified Cervical Cyst . . . . . . . . . 2719.3.9 Non-Developmental Cysts . . . . . . . . . 2719.3.9.1 Ranula . . . . . . . . . . . . . . . . . . . . . 2719.3.9.2 Laryngocele . . . . . . . . . . . . . . . . . . 2719.4 Cystic Neoplasms . . . . . . . . . . . . . . 2729.4.1 Cystic Hygromaand Lymphangioma . . . . . . . . . . . . . 2729.4.2 Haemangioma . . . . . . . . . . . . . . . . 2729.4.3 Teratoma . . . . . . . . . . . . . . . . . . . 2729.4.4 Cervical SalivaryGland Cystic Neoplasms . . . . . . . . . . 2739.4.5 Miscellaneous Lesions . . . . . . . . . . . 2739.5 Paraganglioma . . . . . . . . . . . . . . . . 2739.6 Unknown Primaryand Secondary Tumours . . . . . . . . . . 2749.6.1 Definition . . . . . . . . . . . . . . . . . . . 2749.6.2 Clinical Features . . . . . . . . . . . . . . . 2759.6.3 Search for the Primary Tumour . . . . . . 2759.6.4 Common Locationof the Primary Tumour . . . . . . . . . . . 2769.6.5 Histologic Type of Metastasesand Immunohistochemical Features . . . 2769.6.6 Differential Diagnosis . . . . . . . . . . . . 2769.6.7 Treatment and Results . . . . . . . . . . . . 2789.7 Neck Dissection . . . . . . . . . . . . . . . 2789.7.1 Classification of Neck Dissections . . . . . 2789.7.2 Gross Examinationof Neck Dissection Surgical Specimens . . 2799.7.3 Histologic Evaluationof Neck Dissection . . . . . . . . . . . . . . 279References . . . . . . . . . . . . . . . . . . 28010 Eye and Ocular Adnexa . . . . . . . . . 282M.R. Canninga-Van Dijk10.1 Summary of Anatomyand Histology . . . . . . . . . . . . . . . . 28410.1.1 Conjunctiva . . . . . . . . . . . . . . . . . 28410.1.2 Cornea . . . . . . . . . . . . . . . . . . . . 28410.1.3 Intraocular Tissues . . . . . . . . . . . . . 28410.1.4 Optic Nerve . . . . . . . . . . . . . . . . . 28410.1.5 Lacrimal Glandsand Lacrimal Passages . . . . . . . . . . . 28410.1.6 Eyelids . . . . . . . . . . . . . . . . . . . . . 28410.1.7 Orbit . . . . . . . . . . . . . . . . . . . . . . 28510.2 Conjunctiva . . . . . . . . . . . . . . . . . . 28510.2.1 Developmental Anomalies . . . . . . . . . 28510.2.1.1 Dermoid, Dermolipomaand Complex Choristoma . . . . . . . . . 28510.2.2 Cysts . . . . . . . . . . . . . . . . . . . . . . 28510.2.2.1 Inclusion cysts . . . . . . . . . . . . . . . . 28510.2.3 Degeneration . . . . . . . . . . . . . . . . . 28610.2.3.1 Pinguecula and Pterygium . . . . . . . . . 28610.2.4 Inflammatory Processes . . . . . . . . . . 28610.2.4.1 Acute Conjunctivitis . . . . . . . . . . . . 28610.2.4.2 Chronic Non-GranulomatousConjunctivitis . . . . . . . . . . . . . . . . 28710.2.4.3 Granulomatous Conjunctivitis . . . . . . 28710.2.4.4 Ligneous Conjunctivitis . . . . . . . . . . 28710.2.4.5 Chlamydia Trachomatis (TRIC Agent)Infection . . . . . . . . . . . . . . . . . . . 28710.2.5 Dermatologicand Systemic Diseases . . . . . . . . . . . 28810.2.5.1 Keratoconjunctivitis Sicca . . . . . . . . . 28810.2.5.2 Dermatologic Diseases . . . . . . . . . . . 28810.2.5.3 Metabolic Diseases . . . . . . . . . . . . . 28810.2.6 Tumoursand Tumour-Like Conditions . . . . . . . 28810.2.6.1 Epithelial . . . . . . . . . . . . . . . . . . . 28810.2.6.2 Melanocytic . . . . . . . . . . . . . . . . . 29010.2.6.3 Other Neoplasms . . . . . . . . . . . . . . 29110.3 Cornea . . . . . . . . . . . . . . . . . . . . 29210.3.1 Keratitis and Corneal Ulcers . . . . . . . . 29210.3.1.1 Herpes Simplex Keratitis . . . . . . . . . . 29210.3.1.2 Corneal UlcerationDue to Systemic Disease . . . . . . . . . . 29210.3.2 Keratoconus . . . . . . . . . . . . . . . . . 29210.3.3 Hereditary Corneal Dystrophies . . . . . 29310.3.3.1 Epithelial Dystrophies . . . . . . . . . . . 29310.3.3.2 Stromal Dystrophies . . . . . . . . . . . . 29310.3.3.3 Endothelial Dystrophies . . . . . . . . . . 29310.3.4 Failed Previous Grafts . . . . . . . . . . . . 294

ContentsXIX10.4 Intraocular Tissues . . . . . . . . . . . . . 29410.4.1 Developmental Anomalies . . . . . . . . . 29410.4.1.1 Congenital Glaucoma . . . . . . . . . . . . 29410.4.1.2 Retinopathy of Prematurity . . . . . . . . 29410.4.1.3 Persistent Primary HyperplasticVitreous . . . . . . . . . . . . . . . . . . . . 29410.4.1.4 Retinal Dysplasia . . . . . . . . . . . . . . . 29410.4.1.5 Aniridia . . . . . . . . . . . . . . . . . . . . 29410.4.1.6 Congenital Rubella Syndrome . . . . . . . 29410.4.2 Inflammatory Processes . . . . . . . . . . 29510.4.2.1 Acute Inflammation . . . . . . . . . . . . . 29510.4.2.2 Chronic Non-GranulomatousInflammation . . . . . . . . . . . . . . . . 29510.4.2.3 Granulomatous Inflammation . . . . . . . 29510.4.3 Trauma . . . . . . . . . . . . . . . . . . . . 29610.4.4 Degeneration . . . . . . . . . . . . . . . . . 29610.4.4.1 Glaucoma . . . . . . . . . . . . . . . . . . . 29610.4.4.2 Cataracts . . . . . . . . . . . . . . . . . . . 29710.4.4.3 Phtisis Bulbi . . . . . . . . . . . . . . . . . 29810.4.4.4 Retinal Vascular Disease . . . . . . . . . . 29810.4.4.5 Retinal Detachment . . . . . . . . . . . . . 29810.4.4.6 Retinitis Pigmentosa . . . . . . . . . . . . . 29810.4.5 Tumoursand Tumour-Like Conditions . . . . . . . 29810.4.5.1 Melanocytic . . . . . . . . . . . . . . . . . 29810.4.5.2 Lymphoid . . . . . . . . . . . . . . . . . . . 30010.4.5.3 Retinoblastomaand Pseudoretinoblastoma . . . . . . . . . 30010.4.5.4 Glial . . . . . . . . . . . . . . . . . . . . . . 30110.4.5.5 Vascular . . . . . . . . . . . . . . . . . . . . 30110.4.5.6 Other Primary Tumours . . . . . . . . . . 30110.4.5.7 Metastatic Tumours . . . . . . . . . . . . . 30210.5 Optic Nerve . . . . . . . . . . . . . . . . . 30210.5.1 Papilloedema . . . . . . . . . . . . . . . . . 30210.5.2 Optic Neuritis . . . . . . . . . . . . . . . . 30210.5.3 Optic Atrophy . . . . . . . . . . . . . . . . 30210.5.4 Tumours . . . . . . . . . . . . . . . . . . . 30210.5.4.1 Glioma . . . . . . . . . . . . . . . . . . . . 30210.5.4.2 Meningioma . . . . . . . . . . . . . . . . . 30210.6 Lacrimal Glandand Lacrimal Passages . . . . . . . . . . . 30210.6.1 Inflammatory Processes . . . . . . . . . . 30210.6.2 Tumoursand Tumour-Like Conditions . . . . . . . 30310.7 Eyelids . . . . . . . . . . . . . . . . . . . . . 30310.7.1 Cysts . . . . . . . . . . . . . . . . . . . . . . 30310.7.1.1 Dermoid Cyst . . . . . . . . . . . . . . . . 30310.7.1.2 Epidermal Cyst . . . . . . . . . . . . . . . 30310.7.1.3 Hidrocystoma . . . . . . . . . . . . . . . . 30310.7.2 Inflammatory Processes . . . . . . . . . . 30310.7.2.1 Chalazion and Other Ruptured Cysts . . . 30410.7.2.2 Deep Granuloma Annulare . . . . . . . . . 30410.7.2.3 Necrobiotic Xanthogranuloma . . . . . . . 30410.7.3 Amyloidosis . . . . . . . . . . . . . . . . . 30510.7.4 Tumoursand Tumour-Like Conditions . . . . . . . 30510.7.4.1 Xanthelasmata . . . . . . . . . . . . . . . . 30510.8 Orbit . . . . . . . . . . . . . . . . . . . . . . 30510.8.1 Inflammatory Processes . . . . . . . . . . 30510.8.1.1 Dysthyroid Ophthalmopathy . . . . . . . 30510.8.1.2 Cellulitis . . . . . . . . . . . . . . . . . . . 30510.8.1.3 Pseudotumour . . . . . . . . . . . . . . . . 30610.8.2 Tumoursand Tumour-Like Conditions . . . . . . . 30610.8.2.1 Developmental Cysts . . . . . . . . . . . . 30610.8.2.2 Optic Nerveand Meningeal Tumours . . . . . . . . . . 30610.8.2.3 Metastatic Tumours . . . . . . . . . . . . . 307References . . . . . . . . . . . . . . . . . . 307Subject Index . . . . . . . . . . . . . . . 311

List of ContributorsLlucia Alos(e-mail: lalos@clinic.ub.es)Department of Pathological Anatomy,Hospital Clinic, University of Barcelona,Villarroel 170, 08036 Barcelona, SpainM.R. Canninga-Van Dijk(e-mail: m.r.canningavandijk@azu.nl)Department of Pathology,University Medical Centre Utrecht, H04-312,P.O. Box 85500, 3508 GA, Utrecht, The NetherlandsAntonio Cardesa(e-mail: acardesa@clinic.ub.es)Department of Pathological Anatomy,Hospital Clinic, University of Barcelona,Villarroel 170, 08036 Barcelona, SpainSilvana Di Palma(e-mail: silvana.dipalma@royalsurrey.nhs.uk)Department of Histopathology,University of Surrey, Royal Surrey County Hospital,Egerton Road, Guildford, GU2 7XX, UKJohn Wallace Eveson(e-mail: j.w.eveson@bristol.ac.uk)Division of Oral Medicine,Pathology and Microbiology,University of Bristol Dental School,Lower Maudlin Street, Bristol, BS1 2LY, UKAlessandro Franchi(e-mail: franchi@unifi.it)Department of Human Pathology and Oncology,University of Florence,Viale Morgagni 85, 50134 Florence, ItalyNina Gale(e-mail: nina.gale@mf.uni-lj.si)Institute of Pathology, Faculty of Medicine,University of Ljubljana,Korytkova 2, 1000 Ljubljana, SloveniaIlmo Leivo(e-mail: ilmo.leivo@helsinki.fi)Department of Pathology, Haartman Institute,P.O. Box 21 (Haartmaninkatu 3)00014 University of Helsinki, Helsinki, FinlandMario A. Luna(e-mail: mluna@mdanderson.org)Department of Pathology, The University of Texas,M.D. Anderson Cancer Center,1515 Holcombe Blvd, Box 85,Houston, Texas 77030, USALeslie Michaels(e-mail: l.michaels@ucl.ac.uk)Department of Histopathology,Royal Free and UCL Medical School,Rockefeller Building,University Street, London WC1E 6JJ, UKKeyla Pineda-DaboinDepartment of Pathology,Military Hospital “Carlos Arvelo”and Institute of Anatomical Pathology,University Central of Venezuela, Caracas, VenezuelaSigrid Regauer(e-mail: sigrid.regauer@meduni-graz.at)Institute of Pathology,Karl Franzens University of Graz,Auenbruggerplatz 25, 8036 Graz, AustriaRoderick H.W. Simpson(e-mail: roderick.simpson@virgin.net)Department of Histopathology,Church Lane Exeter, EX2 5AD, UKAlena Skalova(e-mail: skalova@fnplzen.cz)Department of Pathology,Medical Faculty Hospital,Dr. E Benese 13, 305 99 Plzen, Czech Republic

XXIIList of ContributorsPieter J. Slootweg(e-mail: p.slootweg@pathol.umcn.nl)Department of Pathology,University Medical Center St. Radboud, HP 437,P.O. Box 9101, 6500 HB Nijmegen, The NetherlandsNina Zidar(e-mail: nina.zidar@mf.uni-lj.si)Institute of Pathology, Faculty of Medicine,University of Ljubljana,Korytkova 2, 1000 Ljubljana, Slovenia

Chapter 1Benign and Potentially Malignant Lesionsof the Squamous Epitheliumand Squamous Cell CarcinomaN. Gale · N. Zidar1Contents1.1 Squamous Cell Papilloma and Related Lesions . . . . . 21.1.1 Squamous Cell Papilloma,Verruca Vulgaris, Condyloma Acuminatumand Focal Epithelial Hyperplasia . . . . . . . . . . . . 21.1.2 Laryngeal Papillomatosis . . . . . . . . . . . . . . . . . 31.2 Squamous Intraepithelial Lesions (SILS) . . . . . . . . 41.2.1 General Considerations . . . . . . . . . . . . . . . . . . 41.2.2 Terminological Problems . . . . . . . . . . . . . . . . . 41.2.3 Aetiology . . . . . . . . . . . . . . . . . . . . . . . . . . . 51.2.3.1 Oral Cavity and Oropharyn . . . . . . . . . . . . . . . . 51.2.3.2 Larynx . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51.2.4 Clinical Featuresand Macroscopic Appearances . . . . . . . . . . . . . . 61.2.4.1 Oral and Oropharyngeal Leukoplakia, ProliferativeVerrucous Leukoplakia and Erythroplakia . . . . . . . 61.2.4.2 Laryngeal and Hypopharyngeal Leukoplakiaand Chronic Laryngitis . . . . . . . . . . . . . . . . . . 71.2.5 Histological Classifications . . . . . . . . . . . . . . . . 81.2.5.1 WHO Dysplasia System . . . . . . . . . . . . . . . . . . 81.2.5.2 The Ljubljana Classification . . . . . . . . . . . . . . . . 91.2.5.3 Comparison Between the Ljubljana Classificationand WHO 2005 Classification . . . . . . . . . . . . . . . 111.2.6 Biomarkers Related to Malignant Potential of SILsRecognised by Auxiliary and Advanced MolecularMethods . . . . . . . . . . . . . . . . . . . . . . . . . . . 121.2.7 Treatment and Prognosis . . . . . . . . . . . . . . . . . 121.2.7.1 Oral Cavity and Oropharynx . . . . . . . . . . . . . . . 121.2.7.2 Larynx . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131.3 Invasive Squamous Cell Carcinoma . . . . . . . . . . . 131.3.1 Microinvasive Squamous Cell Carcinoma . . . . . . . 131.3.2 Conventional Squamous Cell Carcinoma . . . . . . . . 131.3.2.1 Aetiology . . . . . . . . . . . . . . . . . . . . . . . . . . . 141.3.2.2 Pathologic Features . . . . . . . . . . . . . . . . . . . . . 141.3.2.3 Grading . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141.3.2.4 Invasive Front . . . . . . . . . . . . . . . . . . . . . . . . 151.3.2.5 Stromal Reaction . . . . . . . . . . . . . . . . . . . . . . 151.3.2.6 Differential Diagnosis . . . . . . . . . . . . . . . . . . . 151.3.2.7 Treatment and Prognosis . . . . . . . . . . . . . . . . . 151.3.3 Spindle Cell Carcinoma . . . . . . . . . . . . . . . . . . 161.3.3.1 Aetiology . . . . . . . . . . . . . . . . . . . . . . . . . . . 161.3.3.2 Pathologic Features . . . . . . . . . . . . . . . . . . . . . 161.3.3.3 Differential Diagnosis . . . . . . . . . . . . . . . . . . . 171.3.3.4 Treatment and Prognosis . . . . . . . . . . . . . . . . . 171.3.4 Verrucous Carcinoma . . . . . . . . . . . . . . . . . . . 171.3.4.1 Aetiology . . . . . . . . . . . . . . . . . . . . . . . . . . . 171.3.4.2 Pathologic Features . . . . . . . . . . . . . . . . . . . . . 181.3.4.3 Differential Diagnosis . . . . . . . . . . . . . . . . . . 181.3.4.4 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . 181.3.4.5 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . 191.3.5 Papillary Squamous Cell Carcinoma . . . . . . . . . . 191.3.5.1 Aetiology . . . . . . . . . . . . . . . . . . . . . . . . . . 191.3.5.2 Pathologic Features . . . . . . . . . . . . . . . . . . . . 191.3.5.3 Differential Diagnosis . . . . . . . . . . . . . . . . . . 201.3.5.4 Treatment and Prognosis . . . . . . . . . . . . . . . . 201.3.6 Basaloid Squamous Cell Carcinoma . . . . . . . . . . 201.3.6.1 Aetiology . . . . . . . . . . . . . . . . . . . . . . . . . . 201.3.6.2 Pathologic Features . . . . . . . . . . . . . . . . . . . . 201.3.6.3 Differential Diagnosis . . . . . . . . . . . . . . . . . . 211.3.6.4 Treatment and Prognosis . . . . . . . . . . . . . . . . 211.3.7 Adenoid Squamous Cell Carcinoma . . . . . . . . . . 221.3.7.1 Pathologic Features . . . . . . . . . . . . . . . . . . . . 221.3.7.2 Differential Diagnosis . . . . . . . . . . . . . . . . . . 221.3.7.3 Treatment and Prognosis . . . . . . . . . . . . . . . . 221.3.8 Adenosquamous Carcinoma . . . . . . . . . . . . . . 231.3.8.1 Aetiology . . . . . . . . . . . . . . . . . . . . . . . . . . 231.3.8.2 Pathologic Features . . . . . . . . . . . . . . . . . . . . 231.3.8.3 Differential Diagnosis . . . . . . . . . . . . . . . . . . 231.3.8.4 Treatment and Prognosis . . . . . . . . . . . . . . . . 241.3.9 Lymphoepithelial Carcinoma . . . . . . . . . . . . . . 241.3.9.1 Aetiology . . . . . . . . . . . . . . . . . . . . . . . . . . 241.3.9.2 Pathologic Features . . . . . . . . . . . . . . . . . . . . 241.3.9.3 Differential Diagnosis . . . . . . . . . . . . . . . . . . 251.3.9.4 Treatment and Prognosis . . . . . . . . . . . . . . . . 251.4 Second Primary Tumours . . . . . . . . . . . . . . . . 251.5 Tumour Spread and Metastasising . . . . . . . . . . . 251.5.1 Invasion of Lymphatic and Blood Vessels . . . . . . . 261.5.2 Perineural Invasion . . . . . . . . . . . . . . . . . . . . 261.5.3 Regional Lymph Node Metastases . . . . . . . . . . . 261.5.3.1 Extracapsular Spreadin Lymph Node Metastases . . . . . . . . . . . . . . . 261.5.3.2 Metastases in the Soft Tissue of the Neck . . . . . . . 271.5.4 Distant Metastasis . . . . . . . . . . . . . . . . . . . . 271.5.5 Micrometastasis . . . . . . . . . . . . . . . . . . . . . . 271.6 Molecular Pathologyof Squamous Cell Carcinoma . . . . . . . . . . . . . . 281.6.1 Detecting Tumour Cells . . . . . . . . . . . . . . . . . 281.6.2 Clonal Analysis . . . . . . . . . . . . . . . . . . . . . . 281.6.3 Assessment of Risk for Malignant Progression . . . . 291.6.4 DNA/RNA Profilingin Predicting Metastatic Disease . . . . . . . . . . . . 29References . . . . . . . . . . . . . . . . . . . . . . . . . 29

2 N. Gale · N. Zidar11.1 Squamous Cell Papillomaand Related LesionsBenign, exophytic, papillary or verrucous lesions of thesquamous epithelium of the oral cavity, oropharynxand larynx include similar entities such as squamouscell papilloma (SCP), verruca vulgaris (VV), condylomaacuminatum (CA), and focal epithelial hyperplasia(FEH). However, not every papillary lesion in theseareas can be placed into one of the listed categories. Itseems that the majority of lesions are similar variants ofmucosal proliferations, frequently induced by infectionsby human papillomaviruses (HPV). They show more orless overlapping clinical and morphological properties,but different biological behaviour, ranging from ratherinconspicuous to potentially life threatening. Classificationof these changes into infectious (VV, CA, FEH), andneoplastic (SCP), is thought to be rather inconsistent andnot well founded. Papillary lesions, except for laryngealpapillomatosis, generally have a favourable outcome.1.1.1 Squamous Cell Papilloma,Verruca Vulgaris,Condyloma Acuminatumand Focal Epithelial HyperplasiaICD-O:8052/0Squamous cell papilloma, the most frequent papillarylesion of the oral cavity and oropharynx, is usually asingle, pedunculated, white or pink lesion, consisting offinger-like mucosal projections (Fig. 1.1). It may occasionallybe sessile with a granular or verrucous surface.The lesion, usually smaller than 1 cm, grows rapidlyand has predilections for the hard and soft palate andlateral border of the tongue [2, 285]. Multiple sessile lesionsin children are characteristic of VV; they are foundon the lips, palate and gingiva. CAs are usually largerthan SCPs, multiple dome-shaped nodular lesions thatmainly appear on the lips and soft palate. FEHs are characterisedby multiple sessile or elevated papules, usuallydistributed over the buccal, labial and tongue mucosa.Aetiologically, it is extremely difficult to establishtheir accurate relationship to HPV infection due to variationsin tissue samplings, the ethnic and geographic originof patients, and the use of non-molecular vs. molecularmethods for HPV detection with different levelsof sensitivity [285, 374]. However, more than 20 HPVgenotypes have been detected in oral papillary lesions[285]. SCPs are mainly related to HPV genotypes 6 and11 [386], VV to HPV genotypes 2, 4, 6, 11, and 16 [142,244], CA to HPV genotypes 6, 11, 16, and 18 [100, 201]and FEH to HPV genotypes 13 and 32 [285, 286]. Onlya few cases of VV have been described in the larynx.Barnes and co-workers studied a single case and unexpectedlyfound it to contain HPV genotypes 6 and 11 andnot genotypes 2 and 4, which are characteristic of mucosalVV [22]. Other, non-infectious aetiological factorsare not well known for oral papillary lesions (Fig. 1.1).Histologically, SCPs are composed of narrow papillaryprojections of soft fibrous stroma covered by keratoticor parakeratotic squamous epithelium (Fig. 1.2).Koilocytosis, the only visible cytopathic effect ofHPV infection, which is caused by viral replication inthe upper intermediate and superficial zone of the squamousepithelium, is rarely visible in SCPs. VV showssimilar histological features, but peripheral papillaryprojections are usually centrally bend, and koilocytosisand the granular layer are prominent. The characteristicsof CAs are obvious: koilocytosis and bulbous reteridges of the covering epithelium [100, 285]. Koilocytosis,apoptotic bodies and epithelial hyperplasia are significantin FEH [61, 285].In the differential diagnosis of squamous cell oralpapillary lesions, verrucous carcinoma is the most importantconsideration. An evident downgrowth of bulbousepithelial projections favours a diagnosis of verrucouscarcinoma. Oral SCPs in patients with acquired im-Fig. 1.1. Whitish papillary lesion of the palate. Courtesy of Dr. J.Fischinger, Ljubljana, SloveniaFig. 1.2. Oral squamous cell papilloma. Projections of fibrovascularstroma are covered by parakeratotic squamous epithelium

Lesions of Squamous Epithelium Chapter 1 3munodeficiency syndrome (AIDS) may show a certainamount of epithelial atypia. In these cases SCPs have tobe differentiated from squamous cell carcinoma [295].The treatment for SCPs and related papillary lesionsis surgical removal. The infectivity of HPV in SCPs isvery low and recurrence uncommon, except in lesionsassociated with human immunodeficiency virus (HIV)infections. On the other hand, recurrence is more commonin CAs. No special treatment is required for FEHunless the lesions are extensive.1.1.2 Laryngeal PapillomatosisFig. 1.3. Laryngeal papillomatosis. Numerous clusters of papillomasobliterate the laryngeal lumenICD-O:8060/0Laryngeal squamous cell papillomas (LSCPs) are themost frustrating benign lesions in the head and neckregion. Because of their clinical specificities, such asmultiplicity, recurrence and the propensity to spread toadjacent areas, it has been suggested that LSCPs shouldbe renamed recurrent respiratory papillomatosis (RRP)[34, 89, 91, 187].Recurrent respiratory papillomatosis is aetiologicallyrelated to HPV [4, 212, 283, 289, 352]. HPV-6 and -11 are the most frequent genotypes associated with RRP(Fig. 1.4b) [4, 126, 212, 284, 289, 330].Characteristically, LSCPs show a bimodal age distribution:the first peak is before the age of 5 years with nogender predominance; the second peak occurs betweenthe ages of 20 and 40 years with a male to female ratio of3:2 [34, 87, 91, 189, 216].Human papillomavirus transmission in children isassociated with perinatal transmission from an infectedmother to the child [34, 88, 217]. The mode of HPVinfection in adults remains unclear. The reactivationof a latent infection acquired perinatally or a postpartuminfection with orogenital contacts has been suggested[4, 188]. In contrast to RRP, a solitary keratinisingsquamous papilloma or papillary keratosis of adults appearsnot to be associated with viral infection, althoughit may recur or be occasionally associated with malignanttransformation [20].Recurrent respiratory papillomatosis almost invariablyinvolves the larynx, especially the true and false vocalcords, subglottic areas and ventricles [4]. An extralaryngealspread may occur successively to the oral cavity,trachea and bronchi. Although RRP has been traditionallydivided into juvenile and adult groups [87, 189,216, 352], the prevailing opinion has recognised the diseaseas a unified biological entity with differences inclinical courses, caused by HPV genotypes 6 or 11 [28,126, 189, 218, 321]. For children, multiple and extensivegrowth with rapid recurrence after excision is characteristic.The small diameter of the airways in childrenmay cause dangerous or even fatal airway obstruction.The clinical course in adults is usually not so dramatic,although RRP can be aggressive with multiple recurrences[43, 284]. Most children present with dysphoniaand stridor, and less commonly with a chronic cough,recurrent pneumonia, dyspnoea, and acute life-threateningevents [34, 43, 88]. Affected adults present mostlywith dysphonia and hoarseness [43, 181].Grossly, papillomas are exophytic, branching, pedunculateor sessile masses, pink or reddish in colour, witha finely lobulated surface, presenting either singly or inclusters (Fig. 1.3).Histologically, RRP is composed of finger-like projectionsof the squamous epithelium, covering thin fibrovascularcores. A basal and parabasal hyperplasia ofthe squamous epithelium is most frequently seen, usuallyextending up to the mid-portion (Fig. 1.4a). Mitoticfeatures may be prominent within this area. Irregularlyscattered clusters of koilocytes are seen in the upperpart of the epithelium. Epithelial changes, such as mildto moderate nuclear atypia and hyperchromatism, increasednuclear cytoplasmic ratio, increased mitotic activitywith pathological features, and prominent surfacekeratinisation are rarely found in RRP [181].Various lesions with a papillary structure must beconsidered in the differential diagnosis of RRP. In verrucouscarcinomas, the squamous fronds are thicker andare covered by a prominent keratotic layer, bulbous retepegs infiltrate fibrous stroma in a blunt, pushing mannerand koilocytosis is usually absent. The papillary squamouscarcinoma usually shows an architectonic similarityto RRP. In contrast to RRP, papillary structures in thepapillary squamous carcinoma are covered by a clearlyneoplastic epithelium showing invasive growth.The clinical course of RRP is unpredictable, characterisedby periods of active disease and remissions. HPVpresent in apparently normal mucosa serves as a virusreservoir responsible for repeated recurrence of papillo-

4 N. Gale · N. Zidar1An exact and uniform terminology of SILs is a prerequisitefor successful cooperation among pathologists aswell as adequate understanding with clinicians. A considerableoverlapping of clinical and histological termsrelating to SILs has been widely noticed due to inadeaFig. 1.4. Laryngeal papillomatosis. a Branches of laryngeal papillomaare covered with hyperplastic squamous cell epithelium. Numerouskoilocytes are seen in the upper part of the epithelium.bb Positive in situ hybridisation signal for HPV genotypes 6 and 11in an adult laryngeal papillomamas [301, 330]. The presence of RRP in the neonatal periodis a negative prognostic factor with a greater needfor tracheotomy and likelihood of mortality [88]. Onereport on the spontaneous disappearance of the disease,especially during puberty, has not been further supported[4]. Increased histologic changes (atypia of epithelialcells) are reported to be associated with increased severityand recurrence of RRP [75, 288]. Others have suggestedthat the histologic changes of RRP are not a goodpredictor of eventual malignant transformation [133].Malignant transformation occurs mainly in patientswith a history of previous irradiation or heavy smoking[290], and rarely without any predisposing factors[143, 296]. In children, carcinomas preferentially appearin the bronchopulmonary tree, and in adults in the larynx[141]. HPV genotype 11 is assumed to be most frequentlyassociated with malignant transformation ofRRP [70, 206, 218, 290], followed by HPV-16 [92] andHPV-18 [311].The overall mortality rate of patients with RRP rangesfrom 4 to 14% [20], and is mostly causally related toasphyxia, pulmonary complications and cancer development[17, 20, 338].1.2 Squamous Intraepithelial Lesionspression of the whole spectrum of epithelial changesranging from squamous cell hyperplasia to carcinomain situ.It has been widely accepted that the transition fromnormal mucosa to invasive squamous cell carcinoma(SCC) is a comprehensive and multistage process, causallyrelated to a progressive accumulation of geneticchanges leading to the selection of a clonal population oftransformed epithelial cells [144]. Between six and tenindependent genetic events are required for progressionto SCC [300]. In their evolution, some cases of SIL areself-limiting and reversible, some persist, and some ofthem progress to SCC in spite of treatment [78]. Particularinterest has been focused on potentially malignantor risky (precancerous) lesions [48, 181, 200, 223]. Theselesions have been defined as histomorphological changesof the squamous epithelium from which invasive cancerdevelops in a higher percentage than from other epitheliallesions [125, 179, 181, 223]. A fundamental enigmaof potentially malignant lesions remains when andunder what conditions these changes turn to malignantgrowth [180, 223].Various aetiological, clinical, histological and moleculargenetic aspects are significant for the evaluation,adequate treatment and predictive behaviour of SILs,particularly of potentially malignant lesions.1.2.1 General ConsiderationsHistological changes of the squamous epithelium thatoccur in the process of oral, oro- and hypopharyngealand laryngeal carcinogenesis, are cumulatively designatedsquamous intraepithelial lesions (SILs). Theterm SILs has been proposed as an all-embracing ex-1.2.2 Terminological Problems

6 N. Gale · N. Zidar1to increase with the duration of smoking, the quality oftobacco, the practice of deep inhalation and the inabilityto stop smoking, and inversely with the age of the patientat the start of smoking.Additional aetiological factors are: industrial pollution,chronic infections, voice abuse, obstruction of theupper respiratory tract, vitamin deficiency, and hormonaldisturbance [115, 181, 184, 185, 228, 276]. The role ofHPV infection in laryngeal carcinogenesis remains unclarified[331]. The prevalence of HPV infection in laryngealcarcinomas varies significantly among various studies,ranging from 0 to 54.1% [346]. The overall prevalenceof HPV infection in nine studies of SILs [16, 54, 118, 128,136, 137, 219, 281, 302] was found to be 12.4%. However,HPV DNA was also detected in a clinically and histologicallynormal larynx in 12–25% of individuals [267, 302].Definite evidence of an aetiologic role of HPV in SIL, atleast at present, is lacking, and HPV infection in SILs mayrepresent an incidental HPV colonisation rather than trueinfection of the laryngeal mucosa.1.2.4 Clinical Featuresand Macroscopic Appearances1.2.4.1 Oraland Oropharyngeal Leukoplakia,Proliferative VerrucousLeukoplakia and ErythroplakiaBoth oral leukoplakia (OL) and oral erythroplakia (OE)have generally been defined as premalignant lesions,mainly on the basis of their clinical appearance [14, 371].It seems more reasonable to disregard clinically basedpremalignant connotations, especially for OL, withoutknowing the histological features [200, 297, 342]. Therisk of OL becoming malignant is relatively low andquite unpredictable [342]. In contrast, OE is a muchmore worrisome lesion than OL and always requireshistological evaluation.Oral leukoplakia is a clinical diagnosis of exclusion.If any oral white patch can be diagnosed as some othercondition, such as candidiasis, leukoedema, whitesponge naevus, lichen planus, frictional keratosis, nicotinestomatitis, etc. then the lesion should not be considereda case of OL [263]. The white appearance of OLis most often related to an increase in the surface keratinlayer. OL affects approximately 3% of white adults[46]. It is most frequently seen in middle-aged and oldermen with an increasing prevalence with age, reaching8% in men over 70 years [48, 49]. However, recent studiesreported a tendency towards a lower prevalence ofOL, compared with the past, which might be the resultof the massive public health education campaign againsttobacco [314].Fig. 1.5. Leukoplakia of the dorsal tongue. The microscopicdiagnosis was basal and parabasal cell hyperplasia. Courtesyof Dr. J. Fischinger, Ljubljana, SloveniaThe most common sites of lesions are the buccal andalveolar mucosa and the lower lip. Lesions in the floor ofthe mouth, lateral tongue and lower lip more often showepithelial atypia or even malignant growth [263]. A consensushas been attained to divide OL clinically into homogenousand non-homogenous types [14]. The formertype is characterised as a uniform, flat, thin lesion with asmooth or wrinkled surface showing shallow cracks, buta constant texture throughout (Fig 1.5). The latter typeis defined as a predominantly white or white and red lesionthat may be irregularly flat, nodular or exophytic.Nodular lesions have slightly raised rounded, red and/orwhitish excrescences. Exophytic lesions have irregularblunt or sharp projections [14]. The term non-homogenousis applicable to the aspect of both colour (a mixedwhite and red lesion) and texture (exophytic, papillaryor verrucous) of the lesions (Fig. 1.6).With regard to verrucous lesions, there are no reproducibleclinical criteria to distinguish among verrucoushyperplasia, proliferative verrucous hyperplasia andverrucous carcinoma [371]. Any persisting lesion withno apparent aetiology should be considered suspicious[235]. A period of 2–4 weeks seems acceptable to observethe regression or disappearance of the OL after theelimination of possible causative factors. After that timea biopsy is obligatory [371].Proliferative verrucous hyperplasia (PVL) is a specialtype of OL with a proven high risk of becomingmalignant [32, 322]. Initially, it is relatively benignlooking,a homogenous solitary patch that turns graduallyto an exophytic, diffuse or multifocal, progressiveand irreversible lesion [32, 322, 390]. The diagnosisis made retrospectively after evidence of a progressiveclinical course, accompanied by a particulardeterioration in histological changes. Women predominateover men in PVL by 4 to 1, with a mean age atdiagnosis of 62 years [322]. The epidemiology of PVL

Lesions of Squamous Epithelium Chapter 1 7Fig. 1.6. Erythroleukoplakia of the buccal mucosa. The microscopicdiagnosis was atypical hyperplasia. Courtesy of Dr.D. Dovšak, Ljubljana, Sloveniadoes not highlight a particular causal agent and the lesionwould appear to be multifactorial [114, 342]. Therelatively common absence of well-known risk factorsassociated with oral cancer and a preponderance of elderlyfemale patients, may indicate a different pathogenesisof PVL-related, compared with non-PVL-related,cancer [32]. It appears most frequently in the buccalmucosa, followed by the gingiva, tongue, and floorof the mouth [322]. The severity of histologic featurescorrelates with duration of lesion, from benign keratoticlesion to verrucous hyperplasia, and finally, upto one of three forms of SCC: verrucous, conventionalor papillary types [32]. PVL should be considereda possible diagnosis when a specific discrepancy betweenbland histological features and aggressive clinicalcourse is established [114]. Whether verrucous hyperplasiaforms a separate stage in this series of histologicalfeatures shown by PVL is debatable, as thereseems to be considerable histological overlap betweenthis lesion and verrucous carcinoma. Thus, there areno convincing arguments that verrucous hyperplasiais anything other than a variant of verrucous carcinoma[327, 371, 390]. A mean time of 7.7 years was foundfrom the diagnosis of PVL to cancer development in70.3% of patients [322]. The treatment of PVL continuesto be an unsolved problem with high rates of recurrence,since total excision is rarely possible because ofthe widespread growth [32].Oral erythroplakia is much less common than OL.OE occurs most frequently in older men as a red maculaor plaque with a soft, velvety texture, quite sharplydemarcated and regular in coloration. The disease wasfound to have no apparent sex predilection and is mostfrequent in the 6th and 7th decades [319].The floor of the mouth, the ventral and lateral tongue,the retromolar region and the soft palate are the mostfrequently involved sites [47, 263]. OEs that are intermixedwith white areas are called erythroleukoplakia orspeckled mucosa and are believed to behave similarly topure OE. The red appearance of OE may be related toan increase in subepithelial blood vessels, a lack of surfacekeratin and thinness of the epithelium. Prior to aclinical diagnosis of OE numerous entities should be excluded,such as: median rhomboid glossitis, all kinds ofinjuries, infectious and allergic lesions, haemorrhages,vessel tumours, Wegener’s granulomatosis, etc. [47]. AlthoughOE is a rare lesion, it is much more likely to showdysplasia or carcinoma. Shafer and Waldron reviewedtheir biopsy experiences with 65 cases of OE: 51% of casesshowed invasive SCC, 40% were carcinomas in situor severe dysplasia, and the remaining 9% showed mildto moderate dysplasia [319]. In all red lesions of the oralmucosa that do not regress within 2 weeks of the removalof possible aetiological factors, biopsy is, therefore,mandatory.1.2.4.2 Laryngealand HypopharyngealLeukoplakia andChronic LaryngitisSquamous intraepithelial lesions appear mainly alongthe true vocal cords, and rarely in other parts of the larynx,such as the epiglottis. Two-thirds of vocal cord lesionsare bilateral [48, 178, 181]. They can extend overthe free edge of the vocal cord to its subglottic surface.An origin in, or extension along the upper surface of thevocal cord is less common [181, 194]. The commissuresare rarely involved [48]. Hypopharyngeal lesions arerarely found and are poorly defined [364].Laryngeal SILs do not have a single distinctive orcharacteristic clinical appearance and are variously describedas leukoplakia, chronic hyperplastic laryngitisor rarely erythroplakia. A circumscribed thickening ofthe mucosa covered by whitish patches (Fig. 1.7), or anirregularly growing, well-defined warty plaque may beseen. A speckled appearance of lesions can also be present,caused by unequal thickness of the keratin layer.However, the lesions are commonly more diffuse,with a thickened appearance, and occupy a large part ofone or both vocal cords (Fig. 1.8). A few leukoplakic lesionsare ulcerated (6.5%) or combined with erythroplakia(15%) [48]. Leukoplakic lesions, in contrast to erythroplakicones, tend to be well demarcated.The macroscopic features of hypopharyngeal andlaryngeal SILs are not as well defined as their counterpartsin the oral cavity and their relative importance isnot generally accepted. Most patients with SILs presentwith a history of a few months or more of symptoms;an average duration of 7 months has been reported[48]. Symptoms depend on the location and sever-

8 N. Gale · N. Zidar1Fig. 1.7. Leukoplakia of the left vocal cord. The microscopic diagnosiswas squamous cell hyperplasiaTraditional light microscopic examination, in spite ofcertain subjectivity in interpretation, remains the mostreliable method for determining an accurate diagnosisof a SIL. The clinical validity of any histological gradingsystem depends on the degree of accord with the biologicalbehaviour of the lesions. Worldwide, there areno generally accepted criteria for a histological gradingsystem in the head and neck region with regard to severityof SILs and propensity to malignant transformation.It is, therefore, not surprising to find in the literaturemore than 20 classifications of laryngeal SILs [39,125, 150, 180, 181, 242]. The majority of the classificationshave followed similar criteria to those in commonuse for epithelial lesions of the uterine cervix, such asthe dysplasia or cervical intraepithelial neoplasia systems.The World Health Organisation (WHO) has recentlyreadopted the dysplasia system for classifying SILs ofthe oral cavity and larynx [381]. However, due to differentstandpoints concerning this important problem oforal and laryngeal carcinogenesis, the dysplasia systemwas reviewed simultaneously with two additional classifications:the squamous intraepithelial neoplasia systemand the Ljubljana classification [381]. Here, the WHOdysplasia system and the Ljubljana classification will bereviewed.Fig. 1.8. Chronic laryngitis. Both vocal cords are irregularlythickened and covered by whitish plaques. The microscopic diagnosiswas atypical hyperplasiaity of the disease. Patients may complain of fluctuatinghoarseness, throat irritation, sore throat, and/or achronic cough.1.2.5 Histological Classifications1.2.5.1 WHO Dysplasia SystemPrecursor lesions are designated as altered epitheliumwith an increased likelihood of progression to SCC. Thealtered epithelium shows a variety of architectural andcytological changes that have been grouped under theterm dysplasia. The following architectural changes arerequired to diagnose epithelial dysplasia: irregular epithelialstratification, loss of polarity of basal cells, dropshapedrete ridges, increased number of mitoses, superficialmitoses, dyskeratosis and keratin pearls withinrete pegs. The cytological abnormalities of dysplasia are:anisonucleosis, nuclear pleomorphism, anisocytosis,cellular pleomorphism, increased nuclear cytoplasmicratio, atypical mitotic figures, increased number andsize of nucleoli, and hyperchromatism.The dysplasia system includes the following categories:A. Hyperplasia with increased number of cells. Thismay be in the spinous layer (acanthosis) or in thebasal and parabasal cell layer (basal cell hyperplasia).The architecture of the epithelium is preserved, andthere is no cellular atypia.B. Dysplasia with three grades:1. Mild dysplasia: architectural disturbance is limitedto the lower third of the epithelium, accompanied bycytological atypia.2. Moderate dysplasia: architectural disturbance extendsinto the middle third of the epithelium, accompaniedby an upgraded degree of cytological atypia.

Lesions of Squamous Epithelium Chapter 1 93. Severe dysplasia: architectural disturbance is greaterthan two-thirds of the epithelium with associatedcytological atypia or architectural disturbance in themiddle third of the epithelium with sufficient cytologicalatypia to upgrade from moderate to severedysplasia.C. Carcinoma in situ: full or almost full thickness of theepithelium shows architectural disturbance, accompaniedby pronounced cytological atypia. Atypicalmitotic figures and abnormal superficial mitoses arepresent [381].1.2.5.2 The Ljubljana ClassificationThe Ljubljana grading system does not follow the criteriaused for cervical SILs, but was devised to cater for thespecial clinical and histological problems related to laryngealconditions. Briefly, the different aetiology of SILs inthe upper aerodigestive tract in comparison with cervicallesions probably triggers a different pathway of geneticevents from those established in cervical lesions. Additionally,different anatomic specificities, various clinicalapproaches to obtaining adequate biopsy specimens, aswell as different treatment modalities for high-risk lesionsof cervical and upper aerodigestive tract SILs, werethe basis for establishing the Ljubljana classification morethan three decades ago and this was further formulated in1997 by the working group on SILs of the European Societyof Pathology [125, 150, 178, 181, 182, 183, 242].The main feature of the Ljubljana classification is thatit separates the group of lesions with a minimal risk ofprogression to invasive carcinoma, including squamousand basal-parabasal cell hyperplasia on the one hand,and the potentially malignant group, i.e. those lesionsmore likely to progress to invasive carcinoma (atypicalhyperplasia or risky epithelium), on the other. Carcinomain situ is considered a separate entity within thespectrum of SILs.The general principles of the classification presented,which hold for all of its grades, are the following: theepithelium is generally thickened, although in a minorityof cases the epithelium may show areas of diminishedthickness, but even these cases show basal-parabasal cellhyperplasia; the basement membrane is generally preservedat all grades, with no definite evidence of evenminimal invasion. The presence of a surface keratin layer,which is often present in all grades of SIL, is of no importancein this classification.Group of Reactive Lesions with a Minimal Riskof Progression to Invasive CarcinomaSquamous (simple) hyperplasia is a benign hyperplasticprocess with retention of the normal architectural andcytological pattern of the squamous epithelium.Fig. 1.9. Squamous cell hyperplasia. Thickened epithelium showsincreased prickle cell layer, the basal layer remains unchangedThe epithelium is thickened as a result of an increasedprickle cell layer. The cells of the basal and parabasalregion, which comprise one to three layers, remainunchanged. There is no cellular atypia; infrequent, regularmitoses are seen in the basal layer (Fig. 1.9).Basal and parabasal cell hyperplasia (abnormal hyperplasia)can be defined as a benign augmentation ofbasal and parabasal cells in the lower part of the epitheliallayer while the upper part, containing regular pricklecells, remains unchanged.Stratification of the laryngeal squamous epithelium,characterised by its layered construction, is seen asa smooth transition from an epithelial layer composedof basal cells that are aligned perpendicular to the basementmembrane to the more superficial part in whichthe prickle cells are orientated horizontal to the basementmembrane. Thickened epithelium consists of anincreased number of basal and parabasal cells occupyingup to one-half or occasionally slightly more of the entireepithelium. These cells do not show significant nuclearchanges and are aligned perpendicularly with preservationof normal polarity and organisation. Basal andparabasal cells contain moderately enlarged nuclei anduniformly distributed chromatin, slightly more cytoplasmthan those of the basal layer and, in addition, fewor no intercellular prickles or bridges. Rare, regular mitosesmay be seen, always located in or near the basal layer.Less than 5% of epithelial cells show characteristics of

10 N. Gale · N. Zidar1Fig. 1.10. Basal and parabasal cell hyperplasia. Augmented cellsof the basal and parabasal cell layer extend up to the midportionof the epithelium. Occasional mitoses are seen in the lower part ofthe epitheliumadyskeratosis, a premature and abnormal keratinisationof individual cells or groups of cells that have no pricklesand strongly eosinophilic cytoplasm (Fig. 1.10).Group of Potentially Malignant LesionsAtypical hyperplasia (risky epithelium), considered tobe a potentially malignant lesion, i.e. a lesion with adefinitely increased risk of progressing to invasive carcinoma,is characterised by preservation of stratificationin the epithelium, by alterations of epithelial cells withmild to moderate degrees of cytological atypia occupyingthe lower half or more of the epithelial thickness,and by increased mitotic activity.Stratification is still preserved in the epithelium.There is an increased number of epithelial cells that arefrequently orientated perpendicular to the basementmembrane. The nuclei of many of them show mild tomoderate changes of atypia, such as: enlargement, irregularcontours, and marked variations in staining intensitywith frequent hyperchromaticity; nucleoli are increasedin number and size, showing enhanced stainingcharacteristics. The nuclear/cytoplasmic ratio is generallyincreased. This type of epithelial cell may occupy thelower half, or more of the entire epithelial thickness. Mitosesare moderately increased. They are usually foundin the lower two-thirds of the epithelium, although theymay occasionally appear at a higher level. Mitoses arerarely, if ever, abnormal. Dyskeratotic cells are frequentwithin the entire epithelium. Apoptotic cells may bepresent; they are smaller in size and with hyaline eosinophiliccytoplasm and conspicuous nuclear chromatinbFig. 1.11. a Atypical hyperplasia. Augmented epithelial cellsshowing mild to moderate grades of atypia, preserved stratificationand some regular mitoses. b Augmented epithelial cells withincreased nuclear/cytoplasmic ratio and some regular mitoses.The cells are aligned perpendicularly to the basement membranecondensation or nuclei crumbled into smaller fragments(Fig. 1.11). Two subdivisions of atypical hyperplasia arerecognised: (a) The more frequent “basal cell type” withno intercellular prickles and no cytoplasmic eosinophilia,and the cells aligned perpendicularly or at an acuteangle to the basement membrane, and (b) The less frequent“spinous cell type” (analogous to so-called “keratinisingdysplasia” by Crissman and Zarbo [79]) withintercellular prickles and increased cytoplasmic eosino-

Lesions of Squamous Epithelium Chapter 1 11five per high power field. Abnormal mitoses are frequentlyseen. Hyaline bodies and dyskeratotic cellsare present, often in high numbers (Fig. 1.12).In CIS, as in atypical hyperplasia, the lesion may fallwithin one or the other of the two subdivisions of atypicalhyperplasia:a) Basal cell type with no intercellular prickles and nocytoplasmic eosinophilia;b) Spinous cell type with intercellular prickles and increasedcytoplasmic eosinophilia [125, 150, 242].Fig. 1.12. Carcinoma in situ. The lesion shows loss of stratification,malignant cells with increased mitotic activity replace theentire epithelial thicknessphilia. The cells may be aligned horizontal to the basementmembrane.Group of Actually Malignant LesionsThe term squamous cell carcinoma in situ (CIS) is reservedfor lesions showing the features of carcinomawithout invasion. Three distinct morphologic characteristicsare usually present:a) Loss of stratification or maturation of the epitheliumas a whole; however, the surface of the epitheliummay be covered by one or at most a few layers of compressed,horizontally stratified, and sometimes keratinisedcells.b) Epithelial cells may show all the cytologic characteristicsof invasive squamous cell carcinoma.c) Mitotic figures are usually markedly increasedthroughout the whole epithelium, often more thanIn the differential diagnosis of SILs, regenerative changesof the squamous epithelium after trauma, inflammationor irradiation therapy may simulate various cytoarchitecturaldisturbances resembling different gradesof SILs.Clinical data are always of considerable help in distinguishingdifferent grades of SILs from regenerativeprocesses in which epithelial abnormalities are generallyless pronounced than in atypical hyperplasia or CIS,and atypical mitoses are almost never present.1.2.5.3 Comparison Betweenthe Ljubljana Classificationand WHO 2005 ClassificationComparing the two classifications, one should be awarethat there is no simple relationship and overlapping betweenthe WHO 2005 and the Ljubljana classifications(Table 1.1).The group of the so-called benign lesions, includingsquamous and basal-parabasal cell (abnormal) hyperplasiais comparable in both classifications. Disagreementstarts with the presumption of the WHO 2005 classification[381] that each grade of the whole series of dysplasiais considered to be a precursor or potentially malignantlesion. Histologically, however, there are some similaritiesbetween the basal and parabasal cell hyperplasiaof the Ljubljana classification and the mild dysplasiaof the WHO 2005 [381]. Mild dysplasia, in contrast tobasal and parabasal cell hyperplasia, was classified asthe initial grade within a potentially malignant group,Table 1.1. Comparison between two classifications of squamous intraepithelial lesions: WHO 2005 and Ljubljana classification [381]WHO dysplasia systemHyperplasia*Mild dysplasiaModerate dysplasiaSevere dysplasiaCarcinoma in situLjubljana classification of squamous intraepithelial lesionsSquamous cell hyperplasiaHyperplasia of basal and parabasal cell layersAtypical hyperplasia – risky epitheliumCarcinoma in situ*Hyperplasia may be in the spinous and/or in the basal/parabasal cell layers

12 N. Gale · N. Zidar1whereas in the Ljubljana classification, basal-parabasalhyperplasia is considered a benign lesion with a minimumrisk of malignant transformation. Atypical hyperplasiaof the Ljubljana classification is similar to moderatedysplasia, but also partially includes severe dysplasia.The analogy is, thus, only approximate [150]. Carcinomain situ is equal to the carcinoma in situ of the WHO2005 classification. However, some cases of severe dysplasiawould fall into the category of carcinoma in situof the Ljubljana classification, and the analogy is againonly approximate [150].The Ljubljana classification was devised to satisfythe specific clinical and histological requirements ofthe diagnosis of SILs in the regions of the upper aerodigestivetract where common aetiological, clinical andmorphological aspects are found. Recently, the Ljubljanaclassification has also been successfully applied tooral SILs, which share the same aetiology, and similarclinical and histological specificities with laryngeal lesions[225].Over the many years in practical use, it has beenfound to be more precise for daily diagnostic work thanother grading systems and provides data that have beenshown to be closely correlated with the biological behaviourof the lesions [125].1.2.6 Biomarkers Related to MalignantPotential of SILs Recognisedby Auxiliary and AdvancedMolecular MethodsA genetic progression model with specific genetic alterationsfor different stages of laryngeal SILs has increasedthe possibilities of recognising potential biomarkers incorrelation with histopathologic changes that mightsignal a stage of carcinogenesis from initiation to invasivegrowth [60]. This model has revealed that bothoncogenes and tumour suppressor genes are involvedin tumour progression with a distinct order of progressionstarting with loss of heterozygosity (LOH) at 9p21and 3p21 as the earliest detectable events, followed by17p13 loss. Additional genetic alterations, which tend tooccur in severe dysplasia (atypical hyperplasia), or evenin SCC, are cyclin D1 amplification, pTEN inactivation,and LOH at 11q13, 13q21, 14q32, 6p, 8q, 4q27, and 10q23 [60, 117]. For some chromosomal areas involved thetarget genes have been recognised, such as tumour suppressorgenes p16 at 9p21, p53 at 17p13, and cyclin D1oncogene at 11q13 [60, 117, 381].A similar genetic basis, associated with histopathologicalstages, has been designed for oral carcinogenesis,based on LOH, gene mutations and telomerase reactivation[231]. Recent approaches to identifying geneticchanges as predictors of malignancy risk for low gradeoral dysplasia show that LOH at 3p and 9p could serveas an initial screening marker for the cancer risk of earlylesions [306]. Additionally, telomerase reactivation hasbeen shown to be an early event of laryngeal and oralcarcinogenesis, already detectable at the stage of atypicalhyperplasia in 75% and 43% respectively. However, forprogression towards invasive SCC other genetic eventsseem to be necessary [225, 226].Special attention has been recently devoted to moleculargenetic studies of potentially malignant lesions inan attempt to establish their risk of progression more reliablythan static conventional histological diagnosis enables.In terms of prognostic value, genetic events suchas LOH of 3p, 9p21 and 17q 13 and DNA aneuploidy areconsidered a substantial risk of malignant transformation[344, 381].Predictive factors of different grades of SILs inhead and neck carcinogenesis have also been widelystudied at the level of abnormal protein expressionof the oncogenes and tumour suppressor genesinvolved. Overexpression of p16, p21waf1, p27, p53,epidermal growth factor receptor (EGFR), and cyclinD1 proteins have been examined in an attempt to increasediagnostic sensitivity and predictive values ofSILs [12, 64, 102, 127, 156, 162, 169, 199, 251, 255, 282,363, 369].Additionally, various proliferation and differentiationmarkers, including keratins and carbohydrate antigens,are widely used as predictive factors for determiningthe biological behaviour of oral and laryngealSILs [297]. The detection of proliferative activity, suchas the counting of nucleolar organiser regions (Ag-NORs) and immunohistochemical labelling for proliferatingcell nuclear antigen (PCNA) and Ki-67 antigenare useful adjuncts to light microscopy and may providepredictive information on the clinical outcome ofSILs in the larynx and oral cavity [73, 129, 181, 251, 279,357, 394].The expression of lectins and cytokeratins, particularlythose of low molecular weight, has been shown tobe a good marker of epithelial maturation in normal andpathologic conditions, and may thus facilitate a moreprecise evaluation of SIL [152, 182, 229, 365].1.2.7 Treatment and Prognosis1.2.7.1 Oral Cavity and OropharynxSurgical excision, performed either classically witha cold knife or a CO 2 laser, is the treatment of choicefor oral SILs. However, in highly suspicious lesions asin OE on the floor of the mouth, an incisional biopsy isalways the preferred method for establishing a microscopicdiagnosis. Surgical treatment is only the beginningof therapy for such lesions; the long-term follow-

Lesions of Squamous Epithelium Chapter 1 13up and avoidance of exposure to known risk factors isimportant due to the risk of malignant transformation[47, 263, 334]. Recurrences of high-risk SILs are not infrequentevents, being reported in 18% of lesions thathad been excised with free surgical margins [366]. If thesize or other clinical obstacles make surgical treatmentof oral SILs difficult, various antioxidants, such as betacaroteneand the retinoids, are most commonly used forchemoprevention [191].The occurrence of the higher grades (moderate andsevere dysplasia, atypical hyperplasia) of oral SILs isconsidered the most important risk of SCC development.The reported frequency of malignant transformationof OL ranges from 3.1% [373] to 17.5% [323]. Severallocations of OL, together with histological abnormalities,are linked with higher malignant transformation.The floor of the mouth is, thus, the highest risk site, followedby the tongue and lip [319].The clinical appearance of non-homogenous or speckledOL may correlate with the likelihood that the lesionwill show epithelial changes or malignant transformation.In a study by Silverman and Gorsky the overall malignanttransformation of OL was 17.5%, for the homogenousform only 6.6%, and for speckled OL 23.4%. Aspecial subtype of OL, PVL, was found to develop SCCin 70.3% of patients [322]. Compared with OL, OE hassignificantly worse biological behaviour, with 51% proceedingto malignant transformation [319].1.2.7.2 LarynxThe main task of the pathologist dealing with laryngealSILs is to separate non-risky or a minimally riskyfrom risky changes. Patients with benign hyperplasticlesions (simple and basal-parabasal hyperplasia) donot require such a close follow-up after excisional biopsiesas those with atypical hyperplasia and CIS, althoughelimination of known detrimental influencesis advised [125, 150]. Diagnosis of atypical hyperplasiain laryngeal lesions requires close follow-up and oftenrepeated histological assessment to detect any possiblepersistence or progression of the disease [125, 150, 178,181]. Patients with CIS may require more extensive surgicaltreatment or radiotherapy, although this is controversial[79, 181, 254, 299, 336].The histopathologic degree of severity of laryngealSILs is still used as the most reliable predictive factor[39, 125, 150, 178, 181, 239]. The frequency of subsequentmalignant alteration markedly increases fromsquamous (simple) and basal-parabasal (abnormal) hyperplasia(0.9%), compared with atypical hyperplasia(11 %) [150]. Barnes’s review of the literature shows thatthe risk of SCCs developing in mild, moderate and severelaryngeal dysplasia ranges from 5.5% to 22.5% and28.4% respectively [20].1.3 Invasive Squamous Cell Carcinoma1.3.1 Microinvasive SquamousCell CarcinomaICD-O:8076/3Microinvasive squamous cell carcinoma (SCC) is a SCCwith invasion beyond the epithelial basement membrane,extending into the superficial stroma. There is little consensusamong pathologists on the maximum depth ofinvasion in microinvasive SCCs, but it generally rangesfrom 0.5 mm [20] to 2 mm [77]. The depth of invasionmust be measured from the basement membrane of theadjacent (non-neoplastic) surface epithelium, because ofthe great variations in epithelial thickness.Microinvasive SCC is a biologically malignant lesioncapable of gaining access to lymphatic and blood vessels,which may result in metastases. However, metastasesare rare in microinvasive SCCs and the prognosisis excellent. Studies on SCCs of the floor of the mouthhave shown that there is little or even no metastatic potentialfor SCCs penetrating less than 2 mm beyond thebasement membrane, and a substantially higher risk ofmetastases in more deeply invasive SCCs at this site [74,77, 246]. The prognosis is also excellent in microinvasiveSCCs of the laryngeal glottis because of the poor lymphaticand vascular network in this location. Some authorshave therefore recommended more conservativetreatment of these lesions, such as endoscopic removal,with a careful follow-up [80, 308, 341].The reliable diagnosis of microinvasive SCC can onlybe made with certainty if the whole lesion is examined.It should not be made in small, tangentially cut biopsyspecimens.1.3.2 Conventional SquamousCell CarcinomaICD-O:8070/3Squamous cell carcinoma (SCC) is a malignant epithelialtumour with evidence of squamous differentiationsuch as intercellular bridges and keratin formation. Itoriginates from the surface squamous epithelium, orfrom ciliated respiratory epithelium that has undergonesquamous metaplasia [242].Squamous cell carcinoma of the head and neck is thesixth most prevalent cancer worldwide, accounting for5% of all new cancers, with a global annual incidenceof 500,000 [42]. The vast majority of SCCs are the conventionaltype of SCC, accounting for more than 90%of cases. The remaining cases belong to the variants ofSCC, which will be discussed later in this chapter.Squamous cell carcinoma of the head and neck occursmost frequently in the oral cavity and lip, in the

14 N. Gale · N. Zidar1a b cFig. 1.13. a Well-differentiated squamous cell carcinoma. b Moderatelydifferentiated squamous cell carcinoma. c Poorly differentiatedsquamous cell carcinomaoropharynx, larynx and hypopharynx. Less frequently,it arises in the nasopharynx, nasal cavities and paranasalsinuses. The predilection sites in the oral cavityare the lateral tongue and floor of the mouth. Inthe oropharynx, the most commonly involved sites arethe base of the tongue and the tonsils. In the larynx,there are geographic differences in the topographicdistribution, the glottis being the most frequent locationin some countries, and the supraglottis in others[20, 117].1.3.2.1 AetiologySmoking and alcohol abuse are the greatest risk factorsfor the development of SCCs of the head and neck. Muchattention has been paid to the possible role of viral infection,particularly the Epstein-Barr virus (EBV), andthe human papillomavirus (HPV), in the pathogenesisof the head and neck carcinoma.The EBV is aetiopathogenetically strongly related tonasopharyngeal carcinomas [265], and to rare cases oflymphoepithelial carcinoma of the salivary glands [153,160]. HPV has been aetiologically linked to SCCs of thetonsil [97, 214]. Apart from tonsillar SCC and nasopharyngealSCC, it appears that EBV and HPV play little, ifany, role in the pathogenesis of SCCs in other locationsin the head and neck [93, 153, 227, 392].1.3.2.2 Pathologic FeaturesThe macroscopic appearance of invasive SCCs is variable,and includes flat lesions with a well-defined, raisededge, polypoid exophytic and papillary lesions, as wellas endophytic infiltrative lesions. The surface of the tumouris frequently ulcerated.Microscopically, SCCs are characterised by an invasivegrowth and evidence of squamous differentiation.Invasive growth is manifested by interruption of thebasement membrane and the growth of islands, cords,or single (dyscohesive) tumour cells in the subepithelialstroma; large tumours may invade deeper structures,i.e. muscle, cartilage and bone. Perineural invasion andinvasion of lymphatic and blood vessels may be presentand are reliable proof of invasive cancer. Squamousdifferentiation is demonstrated by intercellular bridgesand/or keratinisation, with keratin pearl formation.Immunohistochemically, SCCs express epithelialmarkers, such as cytokeratins and epithelial membraneantigen (EMA). The patterns of expression of cytokeratinsubtypes are related to the degree of SCC differentiationand to the degree of keratinisation [229].The pattern of cytokeratin expression in low-gradeSCCs is similar to that observed in non-neoplastic squamousepithelium, and is characterised by medium andhigh molecular weight cytokeratins, and the lack of expressionof the low molecular weight cytokeratins. HighgradeSCCs tend to lose the expression of medium andhigh molecular weight cytokeratins and express low molecularweight cytokeratins [229].Of the various cytokeratin subtypes, cytokeratins 8,18 and 19, recognised by the antibody CAM5.2, couldbe used as an indicator of malignant transformation.In a study by Mallofré et al., 40% of SCCs were positivefor CAM5.2, but it was never positive in non-neoplasticsquamous epithelium [229]. In poorly differentiatedSCCs, expression of vimentin may appear [367].

Lesions of Squamous Epithelium Chapter 1 151.3.2.3 GradingSquamous cell carcinomas are traditionally graded intowell-, moderately, and poorly differentiated SCC. Thecriteria for grading are: the degree of differentiation,nuclear pleomorphism and mitotic activity. Well-differentiatedSCCs closely resemble normal squamousepithelium and contain varying proportions of large,differentiated keratinocyte-like squamous cells, andsmall basal-type cells, which are usually located at theperiphery of the tumour islands. There are intercellularbridges and usually full keratinisation; mitoses arescanty (Fig. 1.13a). Moderately differentiated SCCs exhibitmore nuclear pleomorphism and more mitoses, includingabnormal mitoses; there is usually less keratinisation(Fig. 1.13b). In poorly differentiated SCCs, basaltypecells predominate, with a high mitotic rate, includingabnormal mitoses, barely discernible intercellularbridges and minimal, if any, keratinisation (Fig. 1.13c).Although keratinisation is more likely to be present inwell- or moderately differentiated SCCs, it should not beconsidered an important histological criterion for gradingSCCs.1.3.2.4 Invasive FrontTumour growth at the invasive front (tumour–host interface)shows an expansive pattern, an infiltrative pattern,or both. An expansive growth pattern is characterisedby large tumour islands with well-defined pushingmargins, whereas an infiltrative pattern is characterisedby small scattered irregular cords or single tumour cells,with poorly defined infiltrating margins. It has beendemonstrated that the growth pattern at the invasivefront has prognostic implications: an infiltrative patternis associated with a more aggressive course and poorerprognosis than an expansive pattern [57, 58, 76, 382].1.3.2.5 Stromal ReactionInvasive SCCs are almost always associated with a desmoplasticstromal reaction, which consists of proliferationof myofibroblasts, excessive deposition of extracellularmatrix and neovascularisation [63, 94, 221]. Inour experience, desmoplastic stromal reaction is presentonly in invasive SCCs and never in SILs, regardlessof their grade, and may be considered as an additionalmarker of invasion [395, 396].Desmoplastic stromal reaction tends to be pronouncedin well- and moderately differentiated SCCsand weak or absent in poorly differentiated SCCs and inlymphoepithelial carcinomas. The intensity of desmoplasiais inversely related to the density of stromal lymphocyticinfiltration. In SCCs with marked desmoplasia,lymphocytic infiltration is focal and scarce, whileintense lymphocytic infiltration is found in SCCs withlittle or no desmoplasia.1.3.2.6 Differential DiagnosisThe diagnosis of SCC must be confirmed by a biopsy,which must be taken from the clinically most suspiciousarea, avoiding the central necrotic area. In well-oriented,adequate biopsy samples, the diagnosis does usuallynot present a diagnostic problem, as evidence of invasivegrowth and of squamous differentiation is easily found.However, well-differentiated SCCs must be distinguishedfrom verrucous carcinomas and papillary SCCs,as well as from benign conditions, such as pseudoepitheliomatoushyperplasia. Verrucous carcinomas lack atypia,which are always present in SCCs. Papillary SCCs arecharacterised by papillae formation. which is not theprevailing feature in conventional SCCs.Pseudoepitheliomatous hyperplasia is a benign conditionassociated with granular cell tumours, mycoticinfection or tuberculosis. It consists of deep irregulartongues and rete pegs, but there are no abnormal mitosesor atypia, as in SCCs. Identifying the associated condition(granular cell tumour or infection) may be helpfulin establishing the diagnosis of pseudoepitheliomatoushyperplasia.Poorly differentiated SCCs must be differentiatedfrom malignant melanomas, malignant lymphomas,neuroendocrine carcinomas, adenocarcinomas, and adenosquamouscarcinomas. The correct diagnosis is bestachieved by the use of appropriate immunohistochemistryand special stains for the demonstration of mucinproduction.Malignant melanomas are distinguished from SCCsby the expression of S-100, HMB-45 and melan-A. Neuroendocrinecarcinomas express neuroendocrine markers(synaptophysin, chromogranin) and do not show evidenceof squamous differentiation, while SCCs do notexpress neuroendocrine markers. Malignant lymphomasare differentiated from SCCs by the presence of leukocytecommon antigen, and markers of B- or T-celldifferentiation. Adenocarcinomas and adenosquamouscarcinomas can be distinguished from SCCs by the presenceof glands and mucin secretion within the tumourcells.1.3.2.7 Treatment and PrognosisSquamous cell carcinomas of the head and neck havean overall death risk of 40% [328]. The most importantprognostic factor is the TNM stage based on the size ofthe primary tumour, the presence of regional lymphnode metastases, and distant metastases [332].

16 N. Gale · N. Zidar1a b cFig. 1.14. Spindle cell carcinoma. a Squamous cell carcinoma inassociation with pleomorphic spindle cells. b Pure spindle cellcomponent: pleomorphic cells with large hyperchromatic nuclei. cPositive staining for cytokeratin in spindle cellsAdditional important prognostic features are: localisationand depth of the tumour [74, 77, 130, 233, 246],presence of extracapsular spread in lymph node metastases[85, 109, 155, 335], and pattern of tumour growth atthe invasive front [57, 58, 76, 382].The prognostic value of some other parameters, i.e.differentiation of the tumour [166, 280, 376] and DNAploidy [23, 98, 350, 378], is controversial.The treatment of choice is complete excision of thetumour. For small tumours at some locations, such asthe glottic larynx, the primary treatment is radiation. Inlarge tumours, surgery is usually followed by radiotherapy.Patients with advanced, unresectable tumours, withor without metastases, are treated by concurrent chemotherapyand radiotherapy [117].giving rise to both epithelial and mesenchymal components[66, 354].1.3.3.1 AetiologySimilar to conventional SCCs, SpCCs have been aetiologicallyrelated to cigarette smoking and alcohol consumption[356]. It has been suggested that SpCCs maydevelop after radiation exposure; however, some authorsbelieve that this is not a major aetiologic factor [356].The reported incidence of radiation-induced SpCCs ofthe head and neck is between 7.7 and 9.1%; they developafter a latent period of 1.2 to 16 years after radiation exposure[210, 356].1.3.3 Spindle Cell CarcinomaICD-O:8074/3Spindle cell carcinoma (SpCC) is a biphasic tumourcomposed of conventional SCC and a malignant spindlecell component. Synonyms for SpCC are sarcomatoidcarcinoma, carcinosarcoma, collision tumour and pseudosarcoma.It has been described in various sites of the body includingthe upper and lower respiratory tract, breast,skin, urogenital and gastrointestinal tracts, and salivaryglands [31]. In the head and neck, SpCC occurs most frequentlyin the larynx [36, 108, 213, 356] and oral cavity[13, 96, 304], followed by the skin, tonsils, sinonasaltract and the pharynx [13, 375].The histogenesis of this tumour is controversial, butthere is mounting evidence that SpCC is a monoclonalneoplasm originating from a non-committed stem cell1.3.3.2 Pathologic FeaturesMacroscopically, SpCCs are usually exophytic polypoidor pedunculated tumours, with frequent surface ulceration.Less often, SpCCs manifest as sessile, endophyticor ulcero-infiltrative tumours [31, 356].Microscopically, SpCCs consist of a SCC componentand a spindle cell component. The former is representedby in situ carcinoma or by an invasive SCC, and is oftensmall, requiring multiple sections for demonstration(Fig. 1.14a) [210].The spindle cell component usually forms the bulkof the tumour. Spindle cells are often pleomorphic, withlarge hyperchromatic nuclei, prominent nucleoli, andnumerous mitoses (Fig. 1.14b). They are arranged in fasciclesor whorls and can assume many histologic patterns,the most common being that of a malignant fibroushistiocytoma or fibrosarcoma [213, 356]. Foci of

Lesions of Squamous Epithelium Chapter 1 17osteosarcomatous, chondrosarcomatous, or rhabdosarcomatousdifferentiation may be present, particularlyin patients who had been previously treated by radiotherapy[203, 213, 356]. Sometimes, only spindle cellsare present; in such cases, a SpCC can be mistaken fora true sarcoma.However, occasional cases of SpCC may be less cellular,closely resembling a reactive fibroblastic proliferationand can thus be mistaken for a pseudosarcomatousreaction in a SCC or for radiation-induced stromalatypia [13].Metastases usually contain SCCs alone or both SCCand spindle cell components, and rarely, only a spindlecell component [205, 232, 340].Electron microscopy has revealed evidence of epithelialdifferentiation in spindle cells, such as desmosomesand tonofilaments [33, 151, 349, 391].Immunohistochemically, tumour cells in SpCC oftenexpress epithelial and mesenchymal markers; moreover,keratin and vimentin coexpression has been observedon individual tumour cells [241, 391]. Cytokeratin expressioncan be demonstrated in spindle cells in 40–85.7% of cases (Fig. 1.14c), depending on the number ofantikeratin antibodies used [96, 241, 329, 349, 360, 391].The most sensitive/reliable epithelial (keratin) markersfor SpCC seem to be keratin (AE1/AE3, K1) K1, K18 andepithelial membrane antigen (EMA) [356].Spindle cells always express vimentin and often othermesenchymal filaments, such as myogenic markers(smooth muscle actin, muscle specific actin, desmin).The presence of S-100 protein has been reported in rarecases of SpCC [356]. SpCCs do not express glial-fibrillaryacid protein (GFAP), chromogranin or HMB-45[356]. p63 has been recently suggested as an alternativeepithelial marker in SpCCs [213a].1.3.3.3 Differential DiagnosisThe diagnosis of a SpCC is based on the demonstrationof an invasive or in situ SCC and a malignant spindle cellcomponent. However, when a SCC component cannotbe demonstrated, the diagnosis is more difficult, and theSpCC must be distinguished from a number of benignand malignant processes, such as spindle cell sarcomas,nodular fasciitis, inflammatory myofibroblastic tumourand malignant melanoma.In the head and neck, true sarcomas (with the exclusionof chondrosarcomas) and benign mesenchymal tumoursare very rare; if present, they are usually locatedin deep structures [356]. It is therefore a general viewthat in the mucosa of the upper aerodigestive tract a malignantspindle cell tumour is probably a SpCC and nota sarcoma.Negative reaction for S-100 protein and HMB45 helpsto distinguish SpCCs from malignant melanomas [96].1.3.3.4 Treatmentand PrognosisWide surgical excision, alone or with radical neckdissection is the most successful treatment for SpCC.Radiation therapy is generally considered less effective.The prognosis is similar to that for conventionalSCCs and depends on the location of the tumour and thestage: glottic SpCCs have a good prognosis, while SpCCsin the oral cavity and paranasal sinuses behave more aggressively[29, 31]. Prognostic significance has been alsosuggested for the gross appearance of the tumour, i.e.polypoid lesions having a better prognosis than flat ulcerativetumours [375].The reported 5-year survival is between 63 and94%; the overall lethality of the tumour is 30–34% [29,356].1.3.4 Verrucous CarcinomaICD-O:8051/3Verrucous carcinoma (VC; Ackerman’s tumour) is avariant of well-differentiated SCC that was originallydescribed by Ackerman in 1948 [5]. It is characterisedby an exophytic warty growth that is slowly but locallyinvasive and can cause extensive local destruction if leftuntreated. It rarely, if ever, metastasises.The majority of VCs (75%) occurs in the oral cavityand 15% in the larynx. In the oral cavity, the buccal mucosaand gingiva are most frequently involved, and inthe larynx, the most frequent site of occurrence is thevocal cords. It rarely occurs in other locations in thehead and neck, such as the nasal cavity, sinonasal tractand nasopharynx. It has been also described elsewherein the body, i.e. the skin, anus, genitalia, urinary bladderand oesophagus [339].1.3.4.1 AetiologyVerrucous carcinomas have been aetiologically relatedto the use of chewing tobacco or snuff. The habitualchewing of “pan”, a mixture of betel leaf, lime, betelnuts and tobacco has been implicated in the high incidenceof VC of the oral cavity in India [197]. However,tobacco usage is not a reasonable explanation for VC inthe skin, genitourinary tract and other non-aerodigestivesites [107].A possible aetiologic factor is also human papillomavirus(HPV), as HPV types 16 and 18, and rarely 6 and11, have been found in some, but not all cases of VC [52,56, 116, 172, 190].

18 N. Gale · N. Zidar1Fig. 1.15. Verrucous carcinoma. a Projectionsand invaginations lined by thick, welldifferentiatedsquamous epithelium withmarked surface keratinisation, invading thestroma with well-defined pushing margins.b Squamous epithelial cells are large andlack the usual cytologic criteria of malignancy.There are numerous dyskeratotic cellsab1.3.4.2 Pathologic FeaturesMacroscopically, VC usually presents as a large, broadbased exophytic tumour with a white keratotic andwarty surface. On the cut surface, it is firm or hard, tanto white, and may show keratin-filled surface clefts. It isusually large by the time of diagnosis, measuring up to10 cm in its greatest dimension.Microscopically, VCs consist of thickened clubshapedfiliform projections lined with thick, well-differentiatedsquamous epithelium with marked surface keratinisation(“church-spire” keratosis). The squamousepithelial cells in VCs are large [71] and lack the usualcytologic criteria of malignancy. Mitoses are rare, andare only observed in the suprabasal layer; there are noabnormal mitoses. VCs invade the subjacent stromawith well-defined pushing rather than infiltrative borders(Fig. 1.15). A lymphoplasmacytic inflammatory responseis common in the stroma.Hybrid (mixed) tumours also exist composed of VCand conventional well-differentiated SCC; the reportedincidence for the oral cavity and the larynx is 20 and10% [274] respectively. It is important to recognise suchhybrid tumours as foci of conventional SCC in an otherwisetypical VC indicate a potential for metastasis. Orvidaset al. reported that a patient with a hybrid carcinomaof the larynx died of the disease [274]. Patients with hybridcarcinomas must be treated aggressively as if theyhad conventional SCCs [274].Verrucous carcinoma is characterised by a high frequencyof initial misdiagnosis; Orvidas et al. reporteda series of 53 laryngeal VCs; 16 out of 31 patients(52%) had received an incorrect diagnosis of a benignlesion [274]. This emphasises the need for close cooperationbetween the pathologist and the clinician in orderto establish the diagnosis of VC. An adequate, fullthicknessbiopsy specimen must be taken when a cliniciansuspects a VC [274]; moreover, multiple biopsiesmay be needed to rule out a conventional SCC componentin a VC.1.3.4.3 Differential DiagnosisDifferential diagnosis includes verrucous hyperplasia,well-differentiated SCC, papillary SCC, and squamouspapilloma.Invasion below the level of the basal cell layer of theneighbouring normal squamous epithelium distinguishesVC from verrucous hyperplasia. Whether this feature,however, adequately discriminates between VC and verrucoushyperplasia is debatable, as verrucous hyperplasiacould be an exophytic form of VC as well [327].Lack of atypia helps to rule out the conventional SCCand papillary SCC. The VC also lacks the well-formed,wide papillary fronds of a squamous cell papilloma.An additional feature supporting the diagnosis ofa VC is the enlarged spinous cells by morphometricalanalysis [71].1.3.4.4 TreatmentVerrucous carcinoma may be treated by excision (by laseror surgery), and by radiotherapy. It appears that surgeryis a more effective treatment for VC [236, 274]. Hagenet al. reported a 92.4% cure rate for primary surgeryin patients with laryngeal VC [145]. In contrast, Ferlitoand Recher reported a 29% cure rate for radiotherapy inlaryngeal VC [107]. Other studies have shown a 46–57%rate of failure for primary radiation therapy in VCs [224,243, 353].Furthermore, early reports suggested anaplastictransformation following radiotherapy [95, 107, 145,

Lesions of Squamous Epithelium Chapter 1 19Fig. 1.16. Papillary squamous cell carcinoma.a Tumour consists of papillae with acentral fibrovascular core, covered by neoplasticsquamous epithelium. b The coveringepithelium is composed of pleomorphic cellsresembling carcinoma in situMacroscopically, PSCCs present as papillary, friableand soft tumours, ranging in size from 2 mm to 4 cm.The main histologic feature of PSCCs is the papillarygrowth pattern that comprises the majority of the tumour(Fig. 1.16a). Papillae consist of a central fibrovascularcore covered by neoplastic squamous epithelium.The covering epithelium may be composed of immaturebasaloid cells or may be more pleomorphic, resemblingcarcinoma in situ (Fig. 1.16b). It is usually non-keratinisingor minimally keratinising.Multiple lesions can be found, consisting either of invasivePSCCs or mucosal papillary hyperplasia. Stromalinvasion is often difficult to demonstrate in biopsy specimens,and sometimes additional biopsies are needed tomake the diagnosis of an invasive PSCC. A dense lymab278, 287, 309]. However, recent studies do not supportthis notion. It appears that some of the reported cases oftransformation of VC to SCC after radiotherapy were ofmixed (hybrid) tumours. Moreover, similar transformationcan also occur after surgical treatment of VC [237,240, 275, 353]. Radiotherapy is now believed to be an appropriatemode of treatment for oral VC [177] and laryngealVC [275].1.3.4.5 PrognosisIn his original report, Ackerman noted metastasis in theregional lymph node in only one of the 31 patients, andno distant spread was observed in his series [5]. Furtherstudies confirmed his observation that pure VCs do notmetastasise [107, 274]; cases of VC with metastases werereally a hybrid carcinoma that had not been detected atinitial biopsy.Verrucous carcinomas therefore have a good prognosis;the overall 5-year survival rate is 77% [196]. It is importantto recognise hybrid tumours, as foci of a conventionalSCC in a VC indicate the potential for metastasis.Orvidas et al. reported that a patient with a hybridcarcinoma of the larynx died of the disease [274]. Patientswith hybrid carcinomas must be treated aggressivelyas if they had a conventional SCC [274].1.3.5 Papillary Squamous Cell CarcinomaICD-O:8052/3Papillary squamous cell carcinoma (PSCC) is an uncommonvariant of SCC originally described by Crissman etal. in 1988 [75]. Its main characteristics are a papillarygrowth pattern and a good prognosis.In the head and neck, PSCCs show a predilection forthe oropharynx, hypopharynx, larynx, and the sinonasaltract [75, 99, 110, 161, 343, 355]. They also occur inother parts of the body, such as the skin [15], uterine cervix[292], conjunctiva [215], and thymus [209].1.3.5.1 AetiologyIt has been postulated that human papillomavirus(HPV) infection might be an important aetiologic factorin PSCCs, similar to squamous papillomas [343]. However,the reported prevalence of HPV infection in PSCCsvaries from 0 [75] to 48% [30, 343] and does not differsignificantly from the reported overall prevalence ofHPV infection in head and neck SCCs [238]. Therefore,the significance of HPV infection in the pathogenesis ofPSCCs remains unclear.1.3.5.2 Pathologic Features

20 N. Gale · N. Zidar1phoplasmacellular infiltration is usually present in thestroma at the base of the carcinoma, but is scarce withinthe papillae. If no stromal invasion is found, the lesionis called papillary atypical hyperplasia, PSCC in situ, ornon-invasive PSCC [328].1.3.5.3 Differential DiagnosisDifferential diagnosis includes squamous papilloma,VC, and SCC with an exophytic or fungating pattern.Papillomas and VCs share with PSCCs similar architecture,but PSCCs are differentiated from both VCs andpapillomas by the presence of atypia of the squamousepithelium covering the papillae. The differentiationbetween exophytic and papillary SCCs can be more difficultas the histologic criteria for the diagnosis of exophyticSCCs are not clearly defined [30, 355].1.3.5.4 Treatment and PrognosisTreatment of PSCCs is similar to that of conventionalSCCs. Patients with PSCCs are generally believed to havea better prognosis than those with conventional SCCs,although reports in the literature are controversial [343,355]. It appears that, because of a relatively small numberof cases published in the literature, PSCCs possiblyremain the least understood of the several variants ofSCC of the head and neck [30].1.3.6 Basaloid Squamous Cell CarcinomaICD-O:8083/3A basaloid squamous cell carcinoma ( BSCC) is a poorlydifferentiated SCC composed of basaloid cells and squamouscell carcinoma, characterised by an aggressive clinicalcourse. It was first described by Wain et al. in 1986[372]. It has a predilection for the upper aerodigestivetract, but also occurs in other locations such as the uterinecervix [140], oesophagus [202], lung [51], and anus [90].In the upper aerodigestive tract, BSCC shows a predilectionfor the hypopharynx (pyriform sinus), base ofthe tongue, and supraglottic larynx [195, 293]; it has alsobeen described in the oropharynx [195, 293], oral cavity[69, 72, 159] and trachea [277, 312]. The suggested precursorof the BSCC is a totipotent primitive cell locatedin the basal cell layer of the surface epithelium, or withinthe seromucinous glands [293, 372].1.3.6.1 AetiologyTobacco and alcohol use are strong risk factors for thedevelopment of BSCCs [19].1.3.6.2 Pathologic FeaturesMacroscopically, the tumour usually appears as a white,firm, poorly defined, exophytic, polypoid, and centrallyulcerated mass with peripheral submucosal infiltration[21].Microscopically, BSCCs are composed of small, closelypacked basaloid cells, with hyperchromatic nuclei withor without nucleoli, and scant cytoplasm (Fig. 1.17a).The tumour grows in a solid pattern with a lobular configuration,with a frequent peripheral palisading of nuclei.Large central necroses of the comedo type are frequent.Distinctive features of BSCCs that are not foundin conventional SCCs are small cystic spaces containingpara aminosalicylate (PAS)- and Alcian blue-positivematerial and focal stromal hyalinisation [19, 372].BSCCs are always associated with an SCC component,which can present either as an in situ or invasiveSCC. The invasive SCC is usually located superficially,and is typically well- to moderately differentiated.It may also present as focal squamous differentiationwithin the basaloid tumour islands. The transition betweenthe squamous cells and the basaloid cells is oftenabrupt (Fig. 1.17b), or there may be a narrow zone oftransition.If there is extensive ulceration, only dysplastic changesmay be identifiable in the intact surface epithelium[19, 21]. Rarely, BSCCs exhibit a malignant spindle cellcomponent [21, 250]. Metastases may demonstrate basaloidcarcinoma, squamous carcinoma, or both [21].By electron microscopy, desmosomes and tonofilamentswere demonstrated in basaloid cells and in squamouscells. There were no neurosecretory granules,myofilaments or secretory granules [154, 372].Immunohistochemically, BSCCs express keratin andepithelial membrane antigen, but the percentage of positivecells varies among different reports. It is advised touse a cocktail of keratin antibodies (i.e. CAM 5.2, AE-1-AE3) to avoid false-negative results [21]. Some casesexpress carcinoembryonic antigen and neuron-specificenolase [19, 195, 318], while expression of S-100 protein,vimentin and muscle-specific actin varied amongdifferent reports. Vimentin was negative in some studies[69, 195], while Barnes et al. [21] described positivestaining in the majority of basaloid cells, with a peculiarpattern of staining, forming a delicate perinuclear rim.Varying results have also been reported for S-100 immunoreactivity.Some authors described focal immunoreactivityin a few cases [19, 21], while others did not findany S-100-positive tumour cells [69, 195, 248]. However,most cases displayed numerous S-100-positive dendriticcells intermingled with the tumour cells [9, 21, 195,248]. BSCCs do not express chromogranin, synaptophysinand GFAP [19, 21, 195].

Lesions of Squamous Epithelium Chapter 1 21Fig. 1.17. Basaloid squamous cell carcinoma.a Closely packed basaloid cells with hyperchromaticnuclei and scant cytoplasm,with focal peripheral palisading of nuclei.b Abrupt transition between squamous andbasaloid cells. c Focal squamous differentiationin adenoid cystic carcinoma. Courtesyof Dr. Pieter J. Slootwegabc1.3.6.3 Differential DiagnosisDifferential diagnosis includes neuroendocrine carcinoma,adenoid cystic carcinoma, adenocarcinoma andadenosquamous carcinoma.Neuroendocrine carcinomas express various neuroendocrinemarkers that help to distinguish neuroendocrinecarcinomas from BSCCs. However, as 60–75%of cases of BSCC have been reported to express neurone-specificenolase [19, 65, 318] the application of otherneuroendocrine markers, including chromogranin,CD56, and synaptophysin, is advised [19, 65].Adenoid cystic carcinomas, especially the solid variant,may resemble BSCCs but adenoid cystic carcinomasrarely show squamous differentiation (Fig. 1.17C). Immunohistochemistrymay also be helpful: tumour cellsin adenoid cystic carcinomas express S-100 protein andvimentin, while tumour cells in BSCCs usually do notexpress either of the two markers [21, 195].Adenocarcinomas and adenosquamous carcinomascan be distinguished from BSCCs by the presenceof gland formation and mucin secretion within the tumourcells.1.3.6.4 Treatment and PrognosisA BSCC is an aggressive, rapidly growing tumour characterisedby an advanced stage at the time of diagnosis anda poor prognosis. Metastases to the regional lymph nodeshave been reported in two-thirds of patients [19, 195, 277,293], and distant metastases involving lungs, bone, skinand brain in 37–50% of patients [19, 195, 293].It is generally believed that BSCCs are more aggressivethan conventional SCCs [103, 108, 195, 372, 377].However, some studies indicate that BSCCs exhibit behavioursimilar to that of high-grade conventional SCCsof the head and neck [19, 134, 222, 376].The treatment of choice is radical surgical excisionand, because of early regional lymph node and distantvisceral metastases, radical neck dissection and supplementaryradio- and chemotherapy [21, 372, 375].

22 N. Gale · N. Zidar1aFig. 1.18. Adenoid squamous cell carcinoma. a Islands of squamouscell carcinoma with pseudoglandular (adenoid) structuresbdue to acantholysis of neoplastic cells. b Anastomosing spaces andchannels mimicking an angiosarcoma.1.3.7 Adenoid Squamous Cell CarcinomaICD-O:8075/3Adenoid squamous cell carcinoma ( adenoid SCC) is anuncommon histopathologic type of SCC that was firstrecognised by Lever in 1947 [211]. It resembles an ordinarySCC, but because of the acantholysis of malignantsquamous cells, pseudoluminae are formed, creatingthe appearance of glandular differentiation. There is noevidence of true glandular differentiation or mucin production.Adenoid SCC has been referred to by a variety ofnames such as pseudoglandular SCC, acantholytic SCC,SCC with gland-like features and adenoacanthoma.In the head and neck it arises most frequently in theskin (especially in sun-exposed areas) [259, 260], andless frequently in mucosal sites of the upper aerodigestivetract, including the lip, oral cavity, tongue and nasopharynx[27, 37, 105, 135, 173, 348, 375, 388].1.3.7.1 Pathologic FeaturesAdenoid SCCs are composed of islands and cords ofkeratinising SCC; because of the acantholysis of neoplasticcells, pseudoglandular (adenoid) structuresare formed that have central lumina containing detachedacantholytic neoplastic cells, necrotic debris,or they may be empty (Fig. 1.18a). The conventionalsquamous cell carcinoma component is nearly alwayspresent.Acantholysis may lead to the formation of anastomosingspaces and channels, thus mimicking an angiosarcoma(Fig. 1.18b). This variant of adenoid SCC istermed pseudovascular adenoid SCC or angiosarcomalikeSCC, and has been reported in the skin of the headand neck [260], as well as in other organs, such as breastand lungs [18].Immunohistochemically, adenoid SCCs are positivefor epithelial markers, such as cytokeratins and epithelialmembrane antigen (EMA); it may also express carcinoembryonicantigen (CEA) and vimentin [105].Ultrastructural analysis revealed hemidesmosomesand attached tonofilaments, with no glandular features,thus supporting the squamous origin of the adenoidSCC [388].1.3.7.2 Differential DiagnosisAdenoid SCCs must be differentiated from adenocarcinomas,particularly adenoid cystic carcinomas, adenosquamouscarcinomas, and mucoepidermoid carcinomas.This is best achieved by demonstrating that thereis no true gland formation and that stains for mucin arenegative in adenoid SCCs.Differential diagnosis also includes angiosarcoma,but immunohistochemistry helps to distinguish betweenthe two tumours. Angiosarcomas typically expressvascular antigens (CD31, CD34, von Willebrandfactor) that are negative in adenoid SCCs. Cytokeratin,however, may also be positive in some angiosarcomas[139].1.3.7.3 Treatment and PrognosisTreatment and prognosis are similar to those for adenoidSCCs and conventional SCCs. Some authors, however,believe that adenoid SCCs have aggressive behaviour

Lesions of Squamous Epithelium Chapter 1 23and a worse prognosis than conventional SCCs [27, 105,348, 388], but the number of patients reported so far istoo small to draw firm conclusions [328].1.3.8 Adenosquamous CarcinomaICD-O:8560/3Adenosquamous carcinoma (ASC) is a rare malignantepithelial tumour characterised by the presenceof both SCC and adenocarcinoma, and aggressive behaviour.It occurs in various sites, such as the pancreas[68], lung [262], uterine cervix [132], prostate[310], stomach [44] and breast [305]. In the head andneck, it was first reported by Gerughty et al. [131] whodescribed a series of 10 patients with nasal, oral andlaryngeal ASC.Since then, over 150 cases of ASC of the head andneck have been reported; the most frequent site of occurrenceis the larynx [8, 83, 124, 192], followed by thenose and paranasal sinuses [8, 245], oral cavity [8, 192,258, 317, 385], upper lip [234], nasopharynx [234], oropharynx[234] and hypopharnyx [83, 234, 313].The histogenesis of the ASC has not yet been completelyelucidated. Some authors have suggested that itoriginates from the salivary and/or mucoserous glands[131] while others favour a surface epithelial derivationor a combined glandular and surface epithelial derivation[83]. However, it is becoming increasingly acceptedthat the basal cells of the surface squamous epithelium,which are capable of divergent differentiation, arethe sole origin of ASCs [8, 258, 264, 317].1.3.8.1 AetiologyAetiology has not been defined, but cigarette smokingand alcohol consumption probably play an importantrole in the pathogenesis of ASCs, similar to other typesof SCC in the upper aerodigestive tract [8, 131, 192].1.3.8.2 Pathologic FeaturesAdenosquamous carcinomas do not differ macroscopicallyfrom conventional SCCs. Microscopically, they arecharacterised by the presence of both adenocarcinomaand SCC. The two components occur in close proximity,but are generally distinct and separate, and are notclosely intermingled as in the mucoepidermoid carcinoma.The SCC component can present either as an in situor as an invasive SCC, manifesting intercellular bridges,keratin pearl formation or dyskeratosis. The adenocarcinomatouscomponent is usually located in the deeperparts of the tumour; it consists of tubular, alveolar orductular structures (Fig. 1.19).Fig. 1.19. Adenosquamous carcinoma: squamous cell carcinomain situ and the adenocarcinomatous component in the deeper partof the tumour. The two components are in close proximity, thoughseparateThe presence of intracytoplasmic mucin can be demonstratedby special techniques, such as PAS, Alcianblue and Mayer mucicarmine. Necroses and mitoses arecommon [8, 192].Immunohistochemistry has demonstrated positivestaining for cytokeratins with high molecular weightin both the SCC and the adenocarcinomatous components,and positive staining for carcinoembryonic antigen(CEA) and cytokeratins with low molecular weightin the adenocarcinomatous component [8, 234].By electron microscopy, features of both squamousand adenocarcinomatous differentiation have beendemonstrated [41, 164].1.3.8.3 Differential DiagnosisDifferential diagnosis includes mucoepidermoid carcinoma,adenoid SCC, conventional SCC invading thenormal salivary glands, and necrotising sialometaplasia.It is important to differentiate ASCs from mucoepidermoidcarcinomas because ASCs have a worse prognosisthan mucoepidermoid carcinomas [131, 192, 313].The histopathologic features favouring the diagnosis ofASC are: separate and distinct areas of SCC and adeno-

24 N. Gale · N. Zidar1Fig. 1.20. Nasopharyngeal carcinoma.a Islands of poorly differentiated carcinomabeneath the surface epithelium, with denselymphocytic infiltration of the stroma.b In situ hybridisation reveals Epstein-Barrvirus RNA transcripts in the nuclei of all tumourcellsabcarcinomatous components, and the involvement of thesurface epithelium exhibiting atypical hyperplasia, carcinomain situ, or invasive SCC.The presence of mucin in true glandular spaces helpsto distinguish ASCs from adenoid SCCs.Conventional SCCs invading or entrapping the normalsalivary or mucoserous glands can be confused withASC, especially in small biopsy specimens. In such cases,preservation of lobular gland architecture and lack ofsignificant atypia are observed, helping to distinguishconventional SCCs from ASCs.Finally, ASCs must be differentiated from necrotisingsialometaplasia, which is a benign condition. The histopathologicfeatures suggesting the diagnosis of necrotisingsialometaplasia are: surface ulceration, localisationin minor salivary glands, lobular architecture, partialnecrosis of the salivary gland, and squamous metaplasiaof the salivary ducts.ICD-O:8082/3Lymphoepithelial carcinoma (LEC) is a poorly differentiatedSCC or undifferentiated carcinoma, associatedwith dense lymphocytic stromal infiltration. It ismorphologically indistinguishable from nasopharyngealcarcinoma type 3 (WHO classification) [381]. Itwas originally described in the nasopharynx in 1921by Regaud and Reverchon [294], and independently bySchmincke [315]. Synonyms for LEC include lymphoepithelioma,nasopharyngeal-type carcinoma, Regaudand Schmincke-type lymphoepithelioma, and undifferentiatedcarcinoma. The specific features of the nasopharyngealcarcinoma are extensively discussed inChap. 6.Apart from the nasopharynx, it rarely occurs in otherlocations in the head and neck, such as the oropharynx,salivary glands, tonsils, tongue, soft palate, uvula,floor of the mouth, sinonasal tract, larynx and hypopharynx[67, 93, 120, 227, 392], as well as elsewherein the body including the lung, urinary bladder, uterinecervix, breast, skin and stomach [113].1.3.8.4 Treatment and PrognosisThe ASC has a more aggressive course than the conventionalSCC [131, 258, 313], with a tendency toward earlylymph node metastases, frequent local recurrences, andoccasional dissemination [192]. The reported 5-yearsurvival rate is between 13 and 25% [124, 131, 192].The treatment of choice is radical surgical excision.Irradiation alone has had poor results [124, 192, 313].Some reports indicate that radical surgery combinedwith irradiation may improve the survival rate [6].1.3.9.1 AetiologyNasopharyngeal carcinomas are aetiopathogeneticallyassociated with the Epstein-Barr virus (EBV; Fig. 1.20b)[265]. Apart from nasopharyngeal carcinomas, EBV hasbeen also implicated in the pathogenesis of LECs of thesalivary glands, as well as undifferentiated carcinomasof the stomach, lung and thymus [153, 160]. In contrast,it seems that EBV plays little, if any role in the pathogenesisof LEC in other locations in the head and neck [93,153, 227, 392].1.3.9 Lymphoepithelial Carcinoma1.3.9.2 Pathologic FeaturesThe LEC is composed of small clusters or aggregates(Schmincke pattern) or large syncytial masses (Regaudpattern) of cells. Tumour cells have oval or round ve-

Lesions of Squamous Epithelium Chapter 1 25sicular nuclei, and one to three prominent nucleoli(Fig. 1.20a). The cytoplasm is sparse and poorly defined.Normal and abnormal mitoses may be numerous. Necrosesmay be present.The LEC may exist in two histological forms: asa pure LEC and as a mixed form, composed of bothLEC and conventional SCC; such a mixture has beenobserved both in primary and metastatic tumours[227].The stroma in LECs is densely infiltrated by T lymphocytes;stromal inflammatory infiltration may alsocontain plasma cells, follicular dendritic cells and eosinophils.1.3.9.3 Differential DiagnosisDifferential diagnosis includes malignant lymphoma,in particular diffuse large B-cell lymphoma, as well asmalignant melanoma and rhabdomyosarcoma. Differentiationis achieved by the use of appropriate immunohistochemicalstaining. The vast majority ofLECs are positive for cytokeratin and negative for leukocytecommon antigen as well as other lymphocyteantigens. Cytokeratin positivity has been reported inrare lymphomas [123], but leukocyte common antigenpositivity in the tumour cells of LECs has not yet beenreported. A negative reaction to S-100, HMB-45 andmelan-A helps to differentiate LECs from malignantmelanomas.1.3.9.4 Treatment and PrognosisLymphoepithelial carcinomas are more aggressive thanconventional SCCs, with a higher incidence of cervicallymph node metastases, and a propensity for distant metastases,mostly to the lung, liver and bones [93, 227]. Ina series of 34 patients with LECs, 76% of patients hadlymph node metastases at the time of diagnosis, and36% had distant metastases [93].The LEC is a radiosensitive tumour and radiotherapyis an appropriate initial therapy for patients withLECs. Surgical treatment should be reserved for patientswith persistent disease after completing radiotherapy.In those patients adjuvant chemotherapy is also recommendedin an attempt to decrease the rate of distant metastases[93].1.4 Second Primary TumoursPatients with SCCs of the upper aerodigestive tract areat high risk of developing a second primary tumour(SPT) at a separate anatomic site from the index (first)tumour. The SPT is synchronous if it is diagnosedwithin 6 months after the index tumour, or metachronousif it is diagnosed more than 6 months after theindex tumour. Synchronous tumours are simultaneousif they are discovered at the same time as the index tumour.The median prevalence of SPT in patients with an indextumour in the upper aerodigestive tract is 9% [149,291, 337]. The site of the SPT is affected by the site ofthe index tumour. In patients with an index tumour inthe oral cavity, pharynx and oesophagus, the SPT tendsto arise in the same location. In patients with index tumoursin the larynx, the SPT tends to be located in thelungs [174].The risk of developing an SPT closely correlates withthe use of tobacco and alcohol abuse, and is more thandoubled in patients who smoke and drink comparedwith those who do not smoke and drink [207]. Moreover,there is a direct dose-dependent relationship betweentobacco and alcohol exposure and the risk of SPT.It is now accepted that long-term exposure to tobaccoand/or alcohol causes extensive and diffuse DNA changesleading to widespread genetic damage or “field cancerisation”of the whole respiratory tract and the upper digestivetract [324].The prognosis for patients with SPTs is poor, beingworse for synchronous SPTs than for metachronous tumours.They generally present with a more advanced Tstage, and have a much lower 5-year survival than theindex tumour [291].It is therefore imperative for a panendoscopy to beperformed at the time of diagnosis of the index tumour,not only as a part of the staging procedure, but also tolook for an SPT [291].1.5 Tumour Spread and MetastasisSquamous cell carcinomas may spread directly to contiguousstructures, as well as via lymphatic and bloodvessels, giving rise to regional lymph node and distantmetastases, or metastases along the nerves. The behaviourand spread of SCCs are affected by various factors,the most important being the site of the primarytumour. This has been attributed to the rich vascularand lymphatic network in certain areas, such as thebase of the tongue, where metastatic rates are significantlyhigher than for similar-sized tumours on theoral tongue. Similarly, poorly vascularised areas, suchas the glottis, are associated with a lower rate of metastases[106].Other factors important for the spread and behaviourof SCCs include the size and the differentiationof the tumour, as well as poorly defined factors of thehost, i.e. the immune status and genetic susceptibility[130].

26 N. Gale · N. Zidar1associated with an increased risk of local recurrence, regionallymph node metastases and decreased survival[101, 233, 333, 383].1.5.3 Regional Lymph Node MetastasesFig. 1.21. Tumour emboli in a lymph vessel and vein1.5.1 Invasion of Lymphaticand Blood VesselsExperimental studies have shown that metastatic progressionis initiated by local invasion: select tumourcells are released from the tumour where they gain entryto the lymphatic system or circulation, mainly via theproduction of tumour-derived proteolytic enzymes andangiogenic factors [220].Cancer cells commonly invade thin-walled lymphaticvessels, capillaries and veins (Fig. 1.21), whereas thickerwalledarterioles and arteries are relatively resistant. Theappearance of vascular invasion should not be consideredsynonymous with metastasis, because most of thetumour cells that enter the lymphatic system and circulationare destroyed [1]. However, the penetration of tumourcells in the lymphatic and blood vessels is associatedwith a high probability of regional lymph nodeand distant metastases. Furthermore, it allows the tumourto spread beyond the apparent margins. The presenceof vascular invasion is therefore associated withan increased incidence of recurrence and poor survival[383].1.5.2 Perineural InvasionIn perineural invasion, the tumour cells enter the perineuralspace and spread both proximally and distallyalong the nerve fibre. Even though a perineural spreadof more than 2 cm is unusual, the travelling of tumourcells up to 12 cm away from the primary tumour sitealong the perineural space has been described [101,370].Patients with perineural invasion may be asymptomatic,or may experience pain and paresthesia [40]. It appearsthat perineural invasion is a poor prognostic sign,Squamous cell carcinomas of the head and neck havea high tendency to metastasise to the regional lymphnodes. The localisation and frequency of the lymph nodemetastases depend upon the site and size of the primarytumour. Large metastases can be detected clinically byexamination or using ultrasound or radiographic methods.Smaller metastases evade clinical detection, but aredetected by light microscopy [111].Routine analysis of neck dissection specimens is usuallylimited to the examination of a few sections of eachnode stained by haematoxylin-eosin. During such routineanalysis, small metastases can easily be missed. Ithas been demonstrated that with more sensitive techniques,nodal metastases can be detected in 8–20% ofpatients in whom metastases had not been found duringroutine histologic examination [11, 146, 147]. The mostcommonly used sensitive techniques for the detection ofsmall metastases are serial section light microscopy, immunohistochemistryand molecular analysis [130, 273,307, 379].The prognostic significance of lymph node metastaseshas been extensively studied. Metastasis in thelymph nodes is the most significant adverse prognosticfactor in head and neck SCCs. The 5-year survival is decreasedby approximately 50% in patients with lymphnode metastases compared with patients without nodalinvolvement [10, 25, 320]. The number and size of positivenodes, their level in the neck and the presence ofextracapsular spread are the most important prognosticparameters for nodal status [10, 85, 109, 230].1.5.3.1 Extracapsular Spreadin Lymph Node MetastasesCancer cells initially lodge in the marginal sinus, andthen extend throughout the lymph node. Metastasesmay be confined to the lymph node, or may penetrate thecapsule and infiltrate the perinodal tissue; this patternof growth has been referred to as extracapsular spread(ECS). Extracapsular spread is further divided into macroscopicand microscopic ECS [62]; macroscopic ECS isevident to the naked eye during the laboratory dissectionof the surgical specimen and is later confirmed byhistological assessment. It usually involves not only theperinodal fibro-adipose tissue, but also the surroundingstructures. Microscopic ECS is only evident on histologicexamination and is usually limited to the adjacentperinodal fibro-adipose tissue.

Lesions of Squamous Epithelium Chapter 1 27Extracapsular spread is a significant predictor ofboth regional recurrence and the development of distantmetastases resulting in decreased survival [109, 155, 175,335, 337]. In some studies, ECS has been shown as a betterpredictor than the resection margins. It has thereforebeen suggested that ECS should be incorporated into thestaging system for surgically managed patients [380].Some studies, on the contrary, have not confirmed theindependent prognostic significance of extracapsularspread [230, 280].1.5.3.2 Metastases in the Soft Tissueof the NeckIn some patients, an SCC in the soft tissue of the neck isfound, with no evidence of lymph nodes being present.These soft tissue metastases may be the result of eithertotal effacement of a lymph node by the SCC, or extralymphaticspread of the SCC [176].It has been shown that the presence of soft tissue metastasesis associated with an aggressive clinical courseand poor survival [176, 368]. In a study of 155 patients,survival was significantly shorter for patients with softtissue metastases than those without nodal metastasesand those with nodal metastases without extracapsularspread; it was similar to that for patients with lymphnode metastases with extracapsular spread [176].1.5.4 Distant MetastasisDistant metastases in patients with head and neck cancerare usually defined as metastases below the clavicle,and may be the result of lymphogenic or haematogenousspread. Lymphogenic spread results in distant lymphnode metastases; the most commonly affected distantnodes are the mediastinal, axillary and inguinal nodes[7]. Haematogenous spread results in distant metastases,most commonly to the lung, liver and bones, followed bythe skin and brain [84, 157, 198, 208, 337, 362, 387]. Metastaseshave been also described in the small intestine[384], spleen [3] and the cavernous sinus [362].Distant metastases in head and neck SCCs are infrequent,but may occur in the late stages of the disease,with the reported incidence between 3 and 8.5%[337, 387]. Postmortem studies have shown a higher incidenceof distant metastases, ranging from 24 to 57%[266, 325, 393].The incidence of distant metastases depends on thesite of the primary tumour, as well as the initial size ofthe tumour and the presence of nodal metastases [59,198, 253]. The highest incidence of distant metastaseshas been reported in hypopharyngeal SCCs, followed bythe SCCs of the tongue [198].Most distant metastases become clinically apparent2 years after diagnosis of the initial tumour. The averagesurvival once distant metastases are diagnosed rangesbetween 4 and 7 months [208].1.5.5 MicrometastasisMicrometastasis is defined as a microscopic deposit ofmalignant cells, smaller than 2–3 mm, that are segregatedspatially from the primary tumour [193]. The fateof micrometastases is uncertain; the majority of themare probably destined for destruction or dormancy, andonly a small percentage of circulating tumour cells surviveand initiate a metastatic focus [1].The fundamental characteristic of micrometastasisis the absence of a specific blood supply. Micrometastasesare thus dependent on passive diffusion for oxygenand nutrient supply. Experimental studies haveshown that without new blood vessel formation (neoangiogenesis),the growth of tumour cells is limited to2–3 mm and may remain dormant for months or evenyears. During dormancy, the proliferation is balancedby an equivalent rate of cell death by apoptosis. Afterinduction of neoangiogenesis, apoptosis is significantlyreduced, but the proliferation rate remains unchanged,and the growth of the clinically overt metastasiscan occur because of the increased survival of thetumour cells [158].Micrometastases can be detected anywhere in thebody, but most frequently in the lymph nodes, in thesurgical margins, in the blood and in bone marrow[112]. Their detection can be accomplished by serial sectioninglight microscopy, immunohistochemistry, and/or molecular analysis [35, 112, 130, 146].The clinical and prognostic implication of micrometastasesis still uncertain. It has been suggested that residualmicrometastatic tumour cells may increase therisk of tumour recurrence, thus resulting in failure ofthe primary treatment. Furthermore, the presence of tumourcells in the blood and/or bone marrow may be anindicator of a generalised disease with possible disseminationto many organs [163]. Several studies have demonstratedthat lymph node micrometastases are associatedwith a high risk of recurrence and poor survivalin patients with carcinoma of the breast, oesophagus,stomach, colon and lung [163], but few studies have beenfocused on the clinical significance of micrometastasesin SCCs of the head and neck [112, 379].It appears that the detection of micrometastases isa promising approach that might enable us to identifycandidates for adjuvant treatment strategies [163]. However,further studies are needed to define more preciselythe clinical implication of micrometastases, as well asthe most appropriate method for their detection.

28 N. Gale · N. Zidar11.6 Molecular Pathologyof Squamous Cell CarcinomaMalignant tumours arise clonally from transformedcells that have undergone specific genetic alterations intumour suppressor genes and proto-oncogenes [117], aswell as telomerase re-activation [225, 226, 256]. Loss ofchromosomal region 9p21 is the most common geneticchange in head and neck carcinogenesis with consequentinactivation of the p16 gene [168, 169]. A frequentevent is also mutation of the p53 gene located at 17p13;it occurs in approximately 50% of patients with SCCsof the head and neck [255, 257, 270]. Loss of retinoblastomagene (Rb1) expression is seen in less than 20% ofcases, although LOH at 13q14 is present in 60% or moreof SCCs, suggesting the existence of (an)other tumoursuppressor gene(s) neighbouring Rb1 [256].The activation of oncogenes also occurs, such as cyclinD1 amplification, which has been described in one-thirdof patients with SCCs of the head and neck, and is associatedwith advanced disease [167, 272]. Amplification ofother oncogenes, e.g. c-myc and epidermal growth factorreceptor, has also been described in 6–25% of patientswith SCCs of the head and neck [119, 121, 269], while rasmutations probably do not play a significant role in thedevelopment of head and neck SCCs [119].Molecular pathology has significantly deepened ourinsight into genetic alterations occurring in and beingprobably responsible for cancer development. Moreover,it offers the opportunity for tissue characterisation, i.e.detection of tumour cells, distinction between multipleprimary tumours and metastatic disease, and the risk ofprogression of premalignant lesions, going beyond morphologicaltechniques that have been used in pathologyuntil now. The question remains, however, whetherthere is any practical impact of these new techniques regardingdiagnosis, prognosis and management.1.6.1 Detecting Tumour CellsThe introduction of methods more sensitive than histologyfor detecting tumour cells in surgical margins andlymph nodes could be helpful in obtaining better treatmentresults for patients with SCCs of the head and neck[53, 261, 361]. Their application, however, requires somecritical remarks.First, if histology is inadequate for reliable margin assessment,a lot of cases of SCC of the head and neck thathave been classified as tumour-free after surgery by thismethod should nevertheless show recurrence at the sitefrom which the tumour was removed.Secondly, the usefulness of molecular detection of tumourcells in lymph nodes should be demonstrated bytransferring patients from the histopathologically assessedN0 stage to the N+ stage. Merely detecting additionalpositive nodes in patients already classified as N+is of debatable value.In the third place, genetically altered cells are not alwaystumour cells. The whole epithelial lining of the upperaerodigestive tract bears the genetic burden of thecarcinogenetic agents that cause SCCs and, therefore,these cells could have arisen independently from the invasivetumour [50, 268].Also, there is no uniformity as to what constitutesa positive or negative surgical margin [26]. There is abroad spectrum of histological appearance betweennormal epithelium and fully developed SCC. If geneticallyaltered cells are found in areas free of tumour butwith atypical hyperplasia (severe dysplasia), molecularpathology does not provide any information comparedwith conventional microscopical examination.In a recently published study, the value of molecularpathology was compared with traditional histology inthe assessment of surgical margins and neck nodes in patientswith SCCs of the head and neck [326]. It was foundthat from patients with microscopically positive margins,22% had recurrence at the primary site. In contrast, of thecases with histologically tumour-free margins, only 4%showed recurrence of the tumour at the primary site. Theauthors concluded that conventional histology adequatelyidentifies patients with SCCs of the head and neck atrisk of local recurrence, leaving only very limited roomfor improvement using more sophisticated methods.Regarding the neck, local recurrence was observedin 12 out of 107 cases in which a previous neck dissectionwas reported to be tumour-free. These neck recurrencescould be due to the presence of micrometastasesnot detected by microscopy and improved methods fordetecting them may reduce this number. However, it isstill uncertain whether micrometastatic disease has thesame clinical significance as metastatic disease detectedby conventional methods [104].The authors concluded that the added clinical valueof molecular pathology over histology in detecting tumourcells in surgical margins in SCCs of the head andneck does not justify the effort. For lymph nodes, suchan added value is still under discussion [326].1.6.2 Clonal AnalysisPatients with SCCs of the head and neck are at risk of thedevelopment of multiple primary SCCs, not only in thehead and neck region, but also in the lung. Therefore, itis not always clear whether a patient who has multiplelesions either synchronically or metachronically suffersfrom one single disseminated disease or from multipleprimary cancers. If all tumour deposits show SCC, histologycannot distinguish between both possibilitieswhereas both situations require different treatment approaches.If histologically similar tumours differ geneti-

Lesions of Squamous Epithelium Chapter 1 29cally, molecular pathology could be decisive in makingthe distinction. Such a clonal marker should be differentin different tumours and not subject to alterations duringtumour progression and metastasis. The p53 genemeets these requirements; other markers such as lossof heterozygosity analysis are less stable [271, 347, 358,359]. Only in tumours lying close to each other p53 mutationanalysis may be unreliable as separate tumoursdeveloping within a single neoplastic field may have thesame p53 mutation [50]. This, however, does not detractfrom the main value of p53 gene analysis as a tool to distinguishbetween lung lesions as distant metastasis fromSCCs of the head and neck or second primary cancer inthe lung.1.6.3 Assessment of Riskof Malignant ProgressionSquamous cell carcinomas of the head and neck may bepreceded by premalignant alterations showing epithelialchanges of varying degrees. Molecular pathology hasbeen shown to be helpful in identifying lesions at riskof further malignant progression. Chromosomal lossesat loci 3p and 9p have been shown to occur in mucosallesions that subsequently turned into cancer, but as notall of the lesions with these genetic alterations progress,other changes also play a role: additional chromosomallosses, chromosomal polysomies and p53 protein expression[204, 306]. Also, suprabasal expression of p53protein and the presence of cells with abnormal DNAcontent predict malignant transformation, even in theabsence of overt morphologic epithelial alterations [82,344].1.6.4 DNA/RNA Profilingin Predicting Metastatic DiseaseDNA alterations and RNA expression profiles could beuseful in distinguishing between patients with SCCs ofthe head and neck with and without lymph node metastasis,thus diminishing the number of elective neck dissectionsin N0 patients. Data on this issue are just beginningto appear. Their application in patient managementlies in the future [81, 148].References1. Abati A, Liotta LA (1996) Looking forward in diagnostic pathology.The molecular superhighway. Cancer 78:1–32. Abbey LM, Page DG, Sawyer DR (1980) The clinical and histopathologicfeatures of a series of 464 oral squamous cellpapillomas. Oral Surg Oral Med Oral Pathol 49:419–4283. Abramson AL, Parisier SC, Zamansky MJ, Sulka M (1971)Distant metastases from carcinoma of the larynx. Laryngoscope81:1503–15114. Abramson AL, Steinberg BM, Winkler B (1987) Laryngealpapillomatosis: clinical, histopathologic and molecular studies.Laryngoscope 97:678–6855. Ackerman LV (1948) Verrucous carcinoma of the oral cavity.Surgery 23:670–6786. Aden KK, Niehans G, Adams GL, Abdel-Fattah HM (1988)Adenosquamous carcinoma of the larynx and hypopharynxwith five new case presentations. Trans Am Laryngol Assoc109:216–2217. Alavi S, Namazie A, Sercarz JA, Wang MB, Blackwell KE(1999) Distant lymphatic metastasis from head and neck cancer.Ann Otol Laryngol 108:860–8638. Alos L, Castillo M, Nadal A, Caballero M, Mallofre C, PalacinA, Cardesa A (2004) Adenosquamous carcinoma of thehead and neck: criteria for diagnosis in a study of 12 cases.Histopathology 44:1–109. Altavilla G, Mannara GM, Rinaldo A, Ferlito A (1999) Basaloidsquamous cell carcinoma of oral cavity and oropharynx.ORL J Otorhinolaryngol Relat Spec 61:169–17310. Alvi A, Johnson JT (1996) Extracapsular spread in the clinicallynegative neck (N0): implications and outcome. OtolaryngolHead Neck Surg 114:65–7011. Ambrosch P, Bricbeck U (1996) Detection of nodal micrometastasisin head and neck cancer by serial sectioning and immunostaining.Oncology 10:1221–122612. Ambrosch P, Schlott T, Hilmes D, Ruschenburg I (2001) p16alterations and retinoblastoma protein expression in squamouscell carcinoma and neighboring dysplasia from the upperaerodigestive tract. Virchows Arch 438:343–34913. Ansari-Lari MA, Hoque MO, Califano J, Westra WH (2002)Immunohistochemical p53 expression patterns in sarcomatoidcarcinomas of the upper respiratory tract. Am J SurgPathol 26:1024–103114. Axell T, Pindborg JJ, Smith CJ, van der Waal I (1996) Oralwhite lesions with special reference to precancerous and tobacco-relatedlesions: conclusions of an international symposiumheld in Uppsala, Sweden, May 18–21 1994. InternationalCollaborative Group on Oral White Lesions. J OralPathol Med 25:49–5415. Azorin D, Rodriguez-Peralto JL, Garcia-Garcia E, SalamancaJ (2003) Cutaneous papillary squamous cell carcinoma.Report of three new cases and review of the literature. VirchowsArch 442:298–30216. Azzimonti B, Hertel L, Aluffi P, Pia F, Monga G, Zocchi M,Landolfo S, Gariglio M (1999) Demonstration of multipleHPV types in laryngeal premalignant lesions using polymerasechain reaction and immunohistochemistry. J MedVirol 59:110–11617. Balažic J, Mašera A, Poljak M (1997) Sudden death caused bylaryngeal papillomatosis. Acta Otolaryngol 527:111–11318. Banerjee SS, Eyden BP, Wells S, McWilliam LJ, Harris M(1992) Pseudoangiosarcomatous carcinoma – a clinicopathologicalstudy of 7 cases. Histopathology 21:13–2319. Banks ER, Frierson HF, Mills SE, George E, Zarbo RJ, SwansonPE (1992) Basaloid squamous cell carcinoma of the headand neck. Am J Surg Pathol 16:939–94620. Barnes L (2001) Diseases of the larynx, hypopharynx, andesophagus. In: Barnes’ surgical pathology of the head andneck, 2nd edn. Dekker, New York, pp 128–23721. Barnes L, Ferlito A, Altavilla G, MacMillan C, Rinaldo A,Doglioni C (1996) Basaloid squamous cell carcinoma of thehead and neck: clinicopathologic features and differential diagnosis.Ann Otol Rhinol Laryngol 105:75–8222. Barnes L, Yunis EJ, Krebs FJ III, Sonmez-Alpan E (1991) Verrucavulgaris of the larynx. Demonstration of human papillomavirustypes 6/11 by in situ hybridization. Arch PatholLab Med 115:895–89923. Barona de Guzman R, Martorell MA, Basterra J, ArmengotM, Montoro A, Montoro J (1993) Analysis of DNA content insupraglottic epidermoid carcinoma. Otolaryngol Head NeckSurg 108:706–71024. Barrett AW, Kingsmill VJ, Speight PM (1998) The frequencyof fungal infection in biopsies of oral mucosal lesions. OralDis 4:26–31

30 N. Gale · N. Zidar125. Barzan L, Talamini R (1996) Analysis of prognostic factorsfor recurrence after neck dissection. Arch Otolaryngol HeadNeck Surg 122:1299–130226. Batsakis JG (1999) Review article. Surgical excision margins.A pathologist’s perspective. Adv Anat Pathol 3:140–14827. Batsakis JG, Huser J (1990) Squamous carcinomas withglandlike (adenoid) features. Ann Otol Rhinol Laryngol99:87–8828. Batsakis JG, Raymond AK, Rice DH (1983) The pathology ofhead and neck tumors: papillomas of the upper aerodigestivetracts. Head Neck Surg 5:332–34429. Batsakis JG, Rice DH, Howard DR (1982) The pathology ofhead and neck tumors: spindle cell lesions (sarcomatoid carcinomas,nodular fasciitis and fibrosarcoma) of the aerodigestivetracts. Head Neck Surg 4:499–51330. Batsakis JG, Suarez P (2000) Papillary squamous carcinomas:will the real one please stand up? Adv Anat Pathol 7:2–831. Batsakis JG, Suarez P (2000) Sarcomatoid carcinomas of theupper aerodigestive tract. Adv Anat Pathol 7:282–29332. Batsakis JG, Suarez P, el-Naggar AK (1999) Proliferativeverrucous leukoplakia and its related lesions. Oral Oncol35:354–35933. Battifora H (1976) Spindle cell carcinoma: ultrastructuralevidence of squamous origin and collagen production by tumorcells. Cancer 37:2275–228234. Bauman NM, Smith RJ (1996) Recurrent respiratory papillomatosis.Pediatr Clin North Am 43:1385–140135. Becker MT, Shores CG, Yu KK, Yarbrough WG (2004) Molecularassay to detect metastatic head and neck squamouscell carcinoma. Arch Otolaryngol Head Neck Surg 130:21–2736. Berthelet E, Shenouda G, Black MJ, Picariello M, Rochon L(1994) Sarcomatoid carcinoma of the head and neck. Am JSurg 168:455–45837. Blackburn TK, Macpherson D, Conroy B (1999) Primary adenoidsquamous cell carcinoma of the upper lip associatedwith locoregional metastasis: a case report and review of theliterature. J Oral Maxillofac Surg 57:612–61638. Blackwell KE, Calcaterra TC, Fu YS (1995) Laryngeal dysplasia:epidemiology and treatment outcome. Ann Otol RhinolLaryngol 104:596–60239. Blackwell KE, Fu YS, Calcaterra TC (1995) Laryngeal dysplasia.A clinicopathologic study. Cancer 75:457–46340. Boerman RH, Maasen EM, Joonsten J, Kaanders HAM,Marres AM, van Overbeeke J, De Wilde P (1999) Trigeminalneuropathy secondary to perineural invasion of head andneck carcinomas. Neurology 53:213–21741. Bombi JA, Riverola A, Bordas JM, Cardesa A (1991) Adenosquamouscarcinoma of the esophagus. A case report. PatholRes Pract 187:514–51942. Boring CC, Squires TS, Tong T (1991) Cancer statistics, 1991.CA Cancer J Clin 41:19–3643. Boston M, Derkay CS (2003) Recurrent respiratory papillomatosis.Clin Pulm Med 10:10–1644. Boswell JT, Helwig EB (1965) Squamous cell carcinoma andadenoacanthoma of the stomach. A clinicopathologic study.Cancer 18:181–19245. Bouda M, Gorgoulis VG, Kastrinakis NG, Giannoudis A,Tsoli E, Danassi-Afentaki D, Foukas P, Kyroudi A, LaskarisG, Herrington CS, Kittas C (2000) “High risk” HPV typesare frequently detected in potentially malignant and malignantoral lesions, but not in normal oral mucosa. Mod Pathol13:644–65346. Bouquot JE (1994) Oral leukoplakia and erythroplakia: a reviewand update. Pract Periodontics Aesthet Dent 6:9–1747. Bouquot JE, Ephros H (1995) Erythroplakia: the dangerousred mucosa. Pract Periodontics Aesthet Dent 7:59–6748. Bouquot JE, Gnepp DR (1991) Laryngeal precancer: a reviewof the literature, commentary, and comparison with oral leukoplakia.Head Neck 13:488–49749. Bouquot JE, Gorlin RJ (1986) Leukoplakia, lichen planus,and other oral keratoses in 23,616 white Americans over theage of 35 years. Oral Surg Oral Med Oral Pathol 61:373–38150. Braakhuis BJM, Tabor MP, Leemans CR, Waal I van der,Snow GB, Brakenhoff RH (2002) Second primary tumoursand field cancerization in oral and oropharyngeal cancer:molecular techniques provide new insights and definitions.Head Neck 24:198–20651. Brambilla E, Moro D, Veale D, Brichon PY, Stoebner P, ParamelleB, Brambilla C (1992) Basal cell (basaloid) carcinomaof the lung: a new morphologic and phenotypic entity withseparate prognostic significance. Hum Pathol 23:993–100352. Brandsma JL, Steinberg BM, Abramson AL, Winkler B (1986)Presence of human papillomavirus type 16 related sequencesin verrucous carcinoma of the larynx. Cancer Res 46:2185–218853. Brennan JA, Mao L, Hruban RH, Boyle JO, Eby YJ, KochWM, Goodman SN, Sidransky D (1995) Molecular assessmentof histopathological staging in squamous-cell carcinomaof the head and neck. N Eng J Med 332:429–43554. Brito H, Vassallo J, Altemani A (2000). Detection of humanpapillomavirus in laryngeal squamous dysplasia and carcinoma.An in situ hybridization and signal amplificationstudy. Acta Otolaryngol 120:540–54455. Browson RC, Chang JC (1987) Exposure to alcohol and tobaccoand the risk of laryngeal cancer. Arch Environ Health42:192–19656. Bryan RL, Bevan IS, Crocker J, Young LS (1990) Detection ofHPV 6 and 11 in tumors of the upper respiratory tract usingthe polymerase chain reaction. Clin Otolaryngol 15:177–18057. Bryne M (1998) Is the invasive front of an oral carcinoma themost important area for prognostication? Oral Dis 4:70–7758. Bryne M, Jenssen N, Boysen M (1995) Histologic gradingin the deep invasive front of T1 and T2 glottic squamouscell carcinomas has high prognostic value. Virchows Arch427:277–28159. Calhoun KH, Fulmer P, Weiss R, Hokanson JA (1994) Distantmetastases from head and neck squamous cell carcinomas.Laryngoscope 104:1199–120560. Califano J, van der Riet P, Westra W, Nawroz H, ClaymanG, Piantadosi S, Corio R, Lee D, Greenberg B, Koch W, SidranskyD (1996) Genetic progression model for head andneck cancer: implications for field cancerization. Cancer Res56:2488–249261. Carlos R, Sedano HO (1994) Multifocal papilloma virus epithelialhyperplasia. Oral Surg Oral Med Oral Pathol 77:631–63562. Carter RL, Barr LC, O’Brien CJ, Soo KC, Shaw HK (1985)Transcapsular spread of metastatic squamous cell carcinomafrom cervical lymph nodes. Am J Surg 150:495–49963. Cazorla M, Hernandez L, Nadal A, Balbin M, Lopez JM, VizosoF, Fernandez PL, Iwata K, Cardesa A, Lopez-Otin C,Campo E (1998) Collagenase-3 expression is associated withadvanced local invasion in human squamous cell carcinomasof the larynx. J Pathol 186:144–15064. Chen YK, Hsue SS, Lin LM (2003) Immunohistochemicaldemonstration of p63 in DMBA-induced hamster buccalpouch squamous cell carcinogenesis Oral Dis 9:235–24065. Cho KJ, Jang JJ, Lee SS, Zo JI (2000) Basaloid squamous carcinomaof the oesophagus: a distinct neoplasm with multipotentialdifferentiation. Histopathology 36:331–34066. Choi HR, Sturgis EM, Rosenthal DI, Luna MA, Batsakis JG,El-Naggar AK (2003) Sarcomatoid carcinoma of the headand neck. Molecular evidence for evolution and progressionfrom conventional squamous cell carcinoma. Am J SurgPathol 27:1216–122067. Chow TL, Chow TK, Lui YH, Sze WM, Yuen NWF, KwokSPY (2002) Lymphoepithelioma-like carcinoma of oral cavity:report of three cases and literature review. Int J Oral MaxillofacSurg 31:212–21868. Cihak RW, Kawashima T, Steer A (1972) Adenoacanthoma(adenosquamous carcinoma) of the pancreas. Cancer29:1133–114069. Coletta RD, Cotrim P, Almeida OP, Alves VAF, WakamatsuA, Vargas PA (2002) Basaloid squamous carcinoma of oralcavity: a histologic and immunohistochemical study. OralOncol 38:723–729

Lesions of Squamous Epithelium Chapter 1 3170. Cook JR, Hill DA, Humphrey PA, Pfeifer JD, El-Mofty SK(2000) Squamous cell carcinoma arising in recurrent respiratorypapillomatosis with pulmonary involvement: emergingcommon pattern of clinical features and human papillomavirusserotype association. Mod Pathol 13:914–91871. Cooper JR, Hellquist H, Michaels L (1992) Image analysis inthe discrimination of verrucous carcinoma and squamouspapilloma. J Pathol 166:383–38772. Coppola D, Catalano E, Tang CK, Elfenbein IB, Harwick R,Mohr R (1993) Basaloid squamous cell carcinoma of floor ofmouth. Cancer 72:2299–230573. Cör A, Gale N, Kambič V (1997) Quantitative pathology oflaryngeal epithelial hyperplastic lesions. Acta Otolaryngol527:57–6174. Crissman JD, Gluckman JL, Whitely J, Quernelle D (1980)Squamous cell carcinoma of the floor of the mouth. HeadNeck Surg 3:2–775. Crissman JD, Kessis T, Shah KV, Fu YS, Stoler MH, Zarbo RJ,Weiss MA (1988) Squamous papillary neoplasia of the adultupper aerodigestive tract. Hum Pathol 19:1387–139676. Crissman JD, Liu MY, Gluckman J, Cummings G (1984).Prognostic value of histopathologic parameters in squamouscell carcinoma of the oropharynx. Cancer 54:2995–300177. Crissman JD, Sakr WA (2001) Squamous neoplasia of the upperaerodigestive tract. In: Pilch BZ (ed) Head and neck surgicalpathology. Lippincott Williams & Wilkins, Philadelphia,pp 34–5278. Crissman JD, Visscher DW, Sakr W (1993) Premalignant lesionsof the upper aerodigestive tract: pathologic classification.J Cell Biochem 17:49–5679. Crissman JD, Zarbo RJ (1989) Dysplasia, in situ carcinoma,and progression to invasive squamous cell carcinoma of theupper aerodigestive tract. Am J Surg Pathol 13:5–1680. Crissman JD, Zarbo RJ, Drozdowicz S, Jacobs J, Ahmad K,Weaver A (1988) Carcinoma in situ and microinvasive squamouscarcinoma of the laryngeal glottis. Arch OtolaryngolHead Neck Surg 114:299–30781. Cromer A, Carles A, Millon R, Ganguli G, Chalmel F, LemaireF, Young J, Dembélé D, Thibault C, Muller D, Poch O,Abecassis J, Wasylyk B (2004) Identification of genes associatedwith tumorigenesis and metastatic potential of hypopharyngealcancer by microarray analysis. Oncogene23:2484–249882. Cruz IB, Snijders PJF, Meijer CJ, Braakhuis BJ, Snow GB,Walboomers JM, van der Waal I (1998) P53 expression abovethe basal cell layer in oral mucosa is an early event of malignanttransformation and has predictive value for developingoral squamous cell carcinoma. J Pathol 184:360–36883. Damiani JM, Damiani KK, Hauck K, Hyams VJ (1981) Mucoepidermoid-adenosquamouscarcinoma of the larynx andhypopharynx: a report of 21 cases and a review of the literature.Otolaryngol Head Neck Surg 89:235–24384. De Bree R, Mehta DM, Snow GB, Quak JJ (2001) Intracranialmetastases in patients with squamous cell carcinoma of thehead and neck. Otolaryngol Head Neck Surg 124:217–22185. De Carvalho MB (1998) Quantitive analysis of the extent ofextracapsular invasion and its prognostic significance: a prospectivestudy of 170 cases of carcinoma of the larynx andhypopharynx. Head Neck 20:16–2186. De Stefani E, Oreggia F, Rivero S, Fierro L (1992) Hand-rolledcigarette smoking and risk of cancer of the mouth, pharynxand larynx. Cancer 70:679–68287. Derkay CS (2001) Recurrent respiratory papillomatosis. Laryngoscope111:57–6988. Derkay CS, Darrow DH (2000) Recurrent respiratory papillomatosisof the larynx: current diagnosis and treatment.Otolaryngol Clin North Am 33:1127–114289. Derkay CS, Rimell FL, Thompson JW (1998) Recurrent respiratorypapillomatosis. Head Neck 20:418–42490. Dougherty BG, Evans HL (1985) Carcinoma of the anal canal:a study of 79 cases. Am J Clin Pathol 83:159–16491. Doyle DJ, Gianoli GJ, Espinola T, Miller RH (1994) Recurrentrespiratory papillomatosis: juvenile versus adult forms.Laryngoscope 104:523–52792. Doyle DJ, Henderson LA, LeJeune FE Jr, Miller RH (1994)Changes in human papillomavirus typing of recurrent respiratorypapillomatosis progressing to malignant neoplasm.Arch Otolaryngol Head Neck Surg 120:1273–127693. Dubey P, Ha CS, Ang KK, El-Naggar AK, Knapp C, ByersRM, Morrison WH (1998) Nonnasopharyngeal lymphoepitheliomaof the head and neck. Cancer 82:1556–156294. Dvorak HF (1986) Tumors: wounds that do not heal. N EnglJ Med 315:1650–165995. Edstrom S, Johansson SL, Lindstrom J, Sandin I (1987) Verrucoussquamous cell carcinoma of the larynx: evidence forincreased metastatic potential after irradiation. OtolaryngolHead Neck Surg 97:381–38496. Ellis GL, Langloss JM, Heffner DK, Hyams VJ (1987) Spindle-cellcarcinoma of the aerodigestive tract. An immunohistochemicalanalysis of 21 cases. Am J Surg Pathol 11:335–34297. El-Mofty SK, Lu DW (2003) Prevalence of human papillomavirustype 16 DNA in squamous cell carcinoma of the palatinetonsil, and not the oral cavity, in young patients: a distinctclinicopathologic and molecular disease entity. Am JSurg Pathol 27:1463–147098. El-Naggar AK, Dinh M, Tucker S, Luna MA, Goepfert H, HsuP, Batsakis JG (1996) Genotypic analysis of primary head andneck squamous carcinoma by combined fluorescence in situhybridization and DNA flow cytometry. Am J Clin Pathol105:102–10899. Ereño C, Lopez JI, Sanchez JM, Bilbao FJ (2001) Papillarysquamous cell carcinoma of the larynx. J Laryngol Otol115:164–166100. Eversole LR, Laipis PJ, Merrell P, Choi E (1987) Demonstrationof human papillomavirus DNA in oral condyloma acuminatum.J Oral Pathol 16:266–272101. Fagan JJ, Collins B, Barnes L, D’Amico F, Myers EN, JohnsonJT (1998) Perineural invasion in squamous cell carcinomaof the head and neck. Arch Otolaryngol Head Neck Surg124:637–640102. Faridoni-Laurens L, Bosq J, Janot F, Vayssade M, Le BihanML, Kaghad M, Caput D, Benard J, Ahomadegbe JC (2001)P73 expression in basal layers of head and neck squamous epithelium:a role in differentiation and carcinogenesis in concertwith p53 and p63? Oncogene 20:5302–5312103. Ferlito A, Altavilla G, Rinaldo A, Doglioni C (1997) Basaloidsquamous cell carcinoma of the larynx and hypopharynx.Ann Otol Rhinol Laryngol 106:1024–1035104. Ferlito A, Devaney KO, Devaney SL, Rinaldo A, Carbone A(1999) Clinicopathological consultation. Micrometastases:have they an impact on prognosis? Ann Otol Rhinol Laryngol108:1185–1189105. Ferlito A, Devaney KO, Rinaldo A, Milroy CM, Carbone A(1996) Clinicopathological consultation. Mucosal adenoidsquamous cell carcinoma of the head and neck. Ann OtolRhinol Laryngol 105:409–413106. Ferlito A, Partridge M, Brennan J, Hamakawa H (2001)Lymph node micrometastasis in the head and neck cancer: areview. Acta Otolaryngol 121:660–665107. Ferlito A, Recher G (1980) Ackerman’s tumor (verrucous carcinoma)of the larynx: a clinicopathologic study of 77 cases.Cancer 46:1617–1630108. Ferlito A, Rinaldo A, Devaney KO, Devaney SL, Milroy CM(1998) Impact of phenotype on treatment and prognosis oflaryngeal malignancies. J Laryngol Otol 112:710–714109. Ferlito A, Rinaldo A, Devaney KO, MacLennan K, Myers JN,Petruzzelli GJ, Shaha AR, Genden EM, Johnson JT, de CarvalhoMB, Myers EN (2002) Prognostic significance of microscopicand macroscopic extracapsular spread from metastatictumor in the cervical lymph nodes. Oral Oncol 38:747–751110. Ferlito A, Rinaldo A, Devaney KO, Putzi MT (1999) Papillarysquamous cell carcinoma versus verrucous squamouscell carcinoma of the head and neck. Ann Otol Rhinol Laryngol108:318–322111. Ferlito A, Rinaldo A, Robbins KT, Leemans CR, Shah JP, ShahaAR, Andersen PE, Kowalski LP, Pellitteri PK, ClaymanGL, Rogers SN, Medina JE, Byers RM (2003) Changing con-

32 N. Gale · N. Zidar1cepts in the surgical management of the cervical node metastasis.Oral Oncol 39:429–435112. Ferlito A, Shaha AR, Silver CE, Rinaldo A, Mondin V (2001)Incidence and sites of distant metastases from head and neckcancer. ORL J Otorhinolaryngol Relat Spec 63:202–207113. Ferlito A, Weiss CM, Rinaldo A, Carbone A, Devaney KO,MacMillan C, Barnes L (1997) Clinicopathologic consultation.Lymphoepithelial carcinoma of the larynx, hypopharynxand trachea. Ann Otol Rhinol Laryngol 106:437–444114. Fettig A, Pogrel MA, Silverman S Jr, Bramanti TE, Da CostaM, Regezi JA (2000) Proliferative verrucous leukoplakia ofthe gingiva. Oral Surg Oral Med Oral Pathol Oral Radiol Endod90:723–730115. Fiorella R, Di Nicola V, Resta L (1997) Epidemiological andclinical relief on hyperplastic lesions of the larynx. Acta OtolaryngolSuppl 527:77–81116. Fliss DM, Noble-Topham SE, McLachlin CM, Freeman JL,Noyek AM, van Nostrand AWP, Hartwick WJ (1994) Laryngealverrucous carcinoma: a clinicopathologic study and detectionof human papillomavirus using polymerase chain reaction.Laryngoscope 104:146–152117. Forastiere A, Koch W, Trotti A, Sidransky D (2001) Head andneck cancer. N Engl J Med 345:1890–1900118. Fouret P, Dabit D, Sibony M, Alili D, Commo F, Saint-GuilyJL, Callard P (1995) Expression of p53 protein related to thepresence of human papillomavirus infection in precancer lesionsof the larynx. Am J Pathol 146:599–604119. Fracchiolla NS, Pignataro L, Capaccio P, Trecca D, BoletiniA, Ottaviani A, Polli E, Maiolo AT, Neri A (1995) Multiplegenetic lesions in laryngeal squamous cell carcinomas. Cancer75:1292–1301120. Frank DK, Cheron F, Cho H, DiConstanzo D, Sclafani AP(1995) Nonnasopharyngeal lymphoepitheliomas (undifferentiatedcarcinomas) of the upper aerodigestive tract. AnnOtol Rhinol Laryngol 104:305–310121. Freier K, Joos S, Flechtenmacher C, Devens F, Benner A,Bosch FX, Lichter P, Hofele C (2003) Tissue microarray analysisreveals site-specific prevalence of oncogene amplificationsin head and neck squamous cell carcinoma. Cancer Res63:1179–1182122. Friedmann I, Ferlito A (1993) Precursors of squamous cellcarcinoma. In: Ferlito’s neoplasms of the larynx. ChurchillLivingstone, Edinburgh, pp 97–111123. Frierson HF, Bellafiore FJ, Gaffey MJ, McCary WS, Innes DJ,Williams ME (1994) Cytokeratin in anaplastic cell large celllymphoma. Mod Pathol 7:317–321124. Fujino K, Ito J, Kanaji M, Shiomi Y, Saiga T (1995) Adenosquamouscarcinoma of the larynx. Am J Otolaryngol16:115–118125. Gale N, Kambič V, Michaels L, Cardesa A, Hellquist H, ZidarN, Poljak M (2000) The Ljubljana classification: a practicalstrategy for the diagnosis of laryngeal precancerous lesions.Adv Anat Pathol 7:240–251126. Gale N, Poljak M, Kambič V, Ferluga D, Fischinger J (1994)Laryngeal papillomatosis: molecular, histopathological, andclinical evaluation. Virchows Arch 425:291–295127. Gale N, Zidar N, Kambič V, Poljak M, Cör A (1997) Epidermalgrowth factor receptor, c-erbB-2 and p53 overexpressionsin epithelial hyperplastic lesions of the larynx. ActaOtolaryngol 527:105–110128. Gallo O, Bianchi S, Giannini A, Boccuzzi S, Calzolari A,Fini-Storchi O (1994) Lack of detection of human papillomavirus(HPV) in transformed laryngeal keratosis by in situ hybridization(ISH) technique. Acta Otolaryngol 114:213–217129. Gallo O, Franchi A, Chiarelli I, Porfirio B, Grande A, SimonettiL, Bocciolini C, Fini-Storchi O (1997) Potential biomarkersin predicting progression of epithelial hyperplasticlesions of the larynx. Acta Otolaryngol Suppl 527:30–38130. Genden EM, Ferlito A, Bradley PJ, Rinaldo A, Scully C (2003)Neck disease and distant metastases. Oral Oncol 39:207–212131. Gerughty RM, Hennigar GR, Brown FM (1968) Adenosquamouscarcinoma of the nasal, oral and laryngeal cavities: aclinicopathologic survey of ten cases. Cancer 22:1140–1155132. Gluckmann A, Cherry CP (1956) Incidence, histology, andresponse to radiation of mixed carcinomas (adenoacanthomas)of the uterine cervix. Cancer 9:971–979133. Go C, Schwartz MR, Donovan DT (2003) Molecular transformationof recurrent respiratory papillomatosis: viraltyping and p53 overexpression. Ann Otol Rhinol Laryngol112:298–302134. Goes FCGD, Oliviera DT, Dorta RG, Nishimoto IN, LandmanG, Kowalski LP (2004) Prognoses of oral basaloid squamouscell carcinoma and squamous cell carcinoma – a comparison.Arch Otolaryngol 130:83–86135. Goldman RL, Klein HZ, Sung M (1977) Adenoid squamouscell carcinoma of the oral cavity: report of the first case arisingin the tongue. Arch Otolaryngol 103:496–498136. Gorgoulis V, Rassidakis G, Karameris A, GiatromanolakiA, Barbatis C, Kittas C (1994) Expression of p53 protein inlaryngeal squamous cell carcinoma and dysplasia: possiblecorrelation with human papillomavirus infection and clinicopathologicalfindings. Virchows Arch 425:481–489137. Gorgoulis VG, Zacharatos P, Kotsinas A, Kyroudi A, RassidakisAN, Ikonomopoulos JA, Barbatis C, Herrington CS,Kittas C (1999) Human papilloma virus (HPV) is possiblyinvolved in laryngeal but not in lung carcinogenesis. HumPathol 30:274–283138. Grasl MCH, Neuwirth-Riedl K, Vutuc C, Horak F, VorbeckF, Banyai M (1990) Risk of vocal cord dysplasia in relationto smoking, alcohol intake and occupation. Eur J Epidemiol6:45–48139. Gray MH, Rosenberg AE, Dickersin GR, Bhan AK (1990) Cytokeratinexpression in epitheloid vascular neoplasms. HumPathol 21:212–217140. Grayson W, Cooper K (2002) A reappraisal of “basaloid carcinoma”of the cervix, and the differential diagnosis of basaloidcervical neoplasms. Adv Anat Pathol 5:290–300141. Green GE, Bauman NM, Smith RJ (2000) Pathogenesis andtreatment of juvenile onset recurrent respiratory papillomatosis.Otolaryngol Clin North Am 33:187–207142. Green TL, Eversole LR, Leider AS (1986) Oral and labial verrucavulgaris: clinical, histologic and immunohistochemicalevaluation. Oral Surg Oral Med Oral Pathol 62:410–416143. Guillou L, Sahli R, Chaubert P, Monnier P, Cuttat JF, CostaJ (1991) Squamous cell carcinoma of the lung in a nonsmoking,nonirradiated patient with juvenile laryngotracheal papillomatosis.Evidence of human papillomavirus-11 DNA inboth carcinoma and papillomas. Am J Surg Pathol 15:891–898144. Ha PK, Califano JA (2002) The molecular biology of laryngealcancer. Otolaryngol Clin North Am 35:993–1012145. Hagen P, Lyons GD, Haindel C (1993) Verrucous carcinomaof the larynx: role of human papillomavirus, radiation, andsurgery. Laryngoscope 103:253–257146. Hamakawa H, Fukizumi M, Bao Y, Sumida T, Onishi A,Tanioka H, Sato H, Yumoto E (1999) Genetic diagnosis ofmicrometastasis based on SCC antigen mRNA in cervicallymph nodes of head and neck cancer. Clin Exp Metastasis17:593–599147. Hamakawa H, Takemura K, Sumida T, Kayahara H, TaniokaH, Sogawa K (2000) Histological study on pN upgrading oforal cancer. Virchows Arch 437:116–121148. Hannen EJM, Macville MVE, Wienk SM, Slootweg PJ, ManniJJ, Hanselaar AGJM, de Wilde PCM (2004) Different chromosomalimbalances in metastasized and nonmetastasizedtongue carcinomas identified by comparative genomic hybridization.Oral Oncol 40:364–371149. Haughey BH, Gates GA, Arkfen CL, Harvey J (1992) Metaanalysisof second tumours in head and neck cancer: the casefor an endoscopic screening protocol. Ann Otol Rhinol Laryngol101:105–112150. Hellquist H, Cardesa A, Gale N, Kambič V, Michaels L (1999)Criteria for grading in the Ljubljana classification of epithelialhyperplastic laryngeal lesions. A study by members ofthe Working group on Epithelial Hyperplastic Laryngeal Lesionsof the European Society of Pathology. Histopathology34:226–233

Lesions of Squamous Epithelium Chapter 1 33151. Hellquist H, Olofsson J (1989) Spindle cell carcinoma of thelarynx. APMIS 97:1103–1113152. Hellquist HB, Olofsson J (1988) Expression of low molecularweight cytokeratin proteins in laryngeal dysplasia. AP-MIS 96:971–978153. Herrmann K, Niedobitek G (2003) Epstein-Barr virus-associatedcarcinomas; facts and fiction. J Pathol 199:140–145154. Hewan-Lowe K, Dardick I (1995) Ultrastructural distinctionof basaloid-squamous carcinoma and adenoid cystic carcinoma.Ultrastruct Pathol 19:371–381155. Hirabayashi H, Koshii K, Uno K, Ohgaki H, Nakasone Y, FujisawaT, Syouno N, Hinohara T, Hirabayashi K (1991) Extracapsularspread of squamous cell carcinoma in neck lymphnodes: prognostic factor of laryngeal cancer. Laryngoscope101:501–506156. Hirai T, Hayashi K, Takumida M, Ueda T, Hirakawa K, YajinK (2003) Reduced expression of p27 is correlated with progressionin precancerous lesions of the larynx. Auris NasusLarynx 30:163–168157. Hoffman GR, Hayter JP (2002) Widespread subcutaneousdistant metastases from a head and neck squamous cell carcinoma.J Oral Maxillofac Surg 60:954–958158. Holmgren L, O’Reilly S, Folkman J (1995) Dormancy of micrometastasis:balanced proliferation and apoptosis in thepresence of angiogenesis. Nat Med 1:149–153159. Ide F, Shimoyama T, Horie N, Kusama K (2002) Basaloidsquamous cell carcinoma of the oral mucosa: new case andreview of 45 cases in the literature. Oral Oncol 38:120–124160. Iezzoni JC, Gaffey MJ, Weiss LM (1995) The role of Epstein-Barr virus in lymphoepithelioma-like carcinomas. Am J ClinPathol 103:308–315161. Ishiyama A, Eversole LR, Ross DA, Raz Y, Kerner MM, FuYS, Blackwell KE, Feneberg R, Bell TS, Calcaterra TC (1994)Papillary squamous neoplasms of the head and neck. Laryngoscope104:1446–1452162. Izawa H, Yonemitsu N, Shin T, Sugihara H (1999) Histopathologicalanalysis of apoptosis, and expression of p53, bcl-2,bax, and Ki-67 in laryngeal squamous cell carcinomas anddysplasia. Auris Nasus Larynx 26:317–330163. Izbicki JR, Pantel K, Hosch SB (2002) Micrometastasis insolid epithelial tumors: impact on surgical oncology. Surgery131:1–5164. Izumi K, Nakajima T, Maeda T, Cheng J, Saku T (1998) Adenosquamouscarcinoma of the tongue – report of a case withhistochemical, immunohistochemical, and ultrastructuralstudy and review of the literature. Oral Surg Oral Med OralPathol Oral Radiol Endod 85:178–184165. Jaber MA, Porter SR, Gilthorpe MS, Bedi R, Scully C (1999)Risk factors for oral epithelial dysplasia – the role of smokingand alcohol. Oral Oncol 35:151–156166. Janot F, Klijanienko J, Russo, Mamet JP, de Braud F, El-NaggarAK, Pignon JP, Luboinski B, Cvitkovic E (1996) Prognosticvalue of clinicopathologic parameters in head and necksquamous carcinoma: a prospective analysis. Br J Cancer73:531–538167. Jares P, Fernández PL, Campo E, Nadal A, Bosch F, Aiza G,Nayach I, Traserra J, Cardesa A (1994) PRAD-1/Cyclin D1gene amplification correlates with messenger RNA overexpressionand tumor progression in human laryngeal carcinomas.Cancer Res 54:4813–4817168. Jares P, Fernández PL, Nadal A, Cazorla M, Hernández L,Pinyol M, Hernández S, Traserra J, Cardesa A, Campo E(1997) p16MTS1/CDK4I mutations and concomitant loss ofheterozygosity at 9p21-23 are frequent events in squamouscell carcinoma of the larynx. Oncogene 15:1445–1453169. Jares P, Nadal A, Fernandez PL, Pinyol M, Hernandez L, CazorlaM, Hernandez S, Bea S, Cardesa A, Campo E (1999)Disregulation of p16MTS1/CDK4I protein and mRNA expressionis associated with gene alterations in squamous-cellcarcinoma of the larynx. Int J Cancer 81:705–711170. Johnson NW, Ranasinghe AW, Warnakulasuriya KA (1993)Potentially malignant lesions and conditions of the mouthand oropharynx: natural history-cellular and molecularmarkers of risk. Eur J Cancer Prev 2:31–51171. Johnson NW, Warnakulasuriy S, Tavassoli M (1996) Hereditaryand environmental risk factors; clinical and laboratoryrisk matters for head and neck, especially oral, cancer andprecancer. Eur J Cancer Prev 5:5–17172. Johnson TL, Plieth DA, Crissman JD, Sarkar FH (1991) HPVdetection by polymerase chain reaction (PCR) in verrucouslesions of the upper aerodigestive tract. Mod Pathol 4:461–463173. Jones AC, Freedman PD, Kerpel SM (1993) Oral adenoidsquamous cell carcinoma: a report of three cases and reviewof the literature. J Oral Maxillofac Surg 51:676–681174. Jones AS, Morar P, Phillips DE, Field JK, Husband D, HelliwellTR (1994) Second primary tumours in patients withhead and neck cancer. Cancer 95:1343–1352175. Jose J, Coatesworth AP, MacLennan K (2003) Cervical metastasesin upper aerodigestive tract squamous cell carcinoma:histopathologic analysis and reporting. Head Neck25:194–197176. Jose J, Moor JW, Coatesworth AP, Johnston C, MacLennanK (2004) Soft tissue deposits in neck dissections of patientswith head and neck squamous cell carcinoma. Arch OtolaryngolHead Neck Surg 130:157–160177. Jyotirmayi R, Sankaranarayanan R, Varghese C, Jacob R,Krishnan Nair M (1997) Radiotherapy in the treatment ofverrucous carcinoma of the oral cavity. Oral Oncol 33:124–128178. Kambič V (1978) Difficulties in management of vocal cordprecancerous lesions. J Laryngol Otol 92:305–315179. Kambič V (1997) Epithelial hyperplastic lesions – a challengingtopic in laryngology. Acta Otolaryngol 527:7–11180. Kambič V, Gale N (1986) Significance of keratosis and dyskeratosisfor classifying hyperplastic aberrations of laryngealmucosa. Am J Otolaryngol 7:323–333181. Kambič V, Gale N (1995) Epithelial hyperplastic lesions ofthe larynx. Elsevier, Amsterdam, pp 1–265182. Kambič V, Gale N, Ferluga D (1992) Laryngeal hyperplasticlesions, follow-up study and application of lectins and anticytokeratinsfor their evaluation. Pathol Res Pract 188:1067–1077183. Kambič V, Lenart I (1971) Our classification of hyperplasia ofthe laryngeal epithelium from the prognostic point of view. JFr Otorhinolaryngol Audiophonol Chir Maxillofac 20:1145–1150184. Kambič V, Radšel Z, Gale N (1989) Alterations in the laryngealmucosa after exposure to asbestos. Br J Ind Med 46:717–723185. Kambič V, Radšel Z, Preželj J, Žargi M (1984) The role oftestosterone in laryngeal carcinogenesis. Am J Otolaryngol5:344–349186. Kansky AA, Poljak M, Seme K, Kocjan BJ, Gale N, Luzar B,Golouh R (2003) Human papillomavirus DNA in oral squamouscell carcinomas and normal oral mucosa. Acta Virol47:11–16187. Kashima H, Mounts P, Leventhal B, Hruban RH (1993) Sitesof predilection in recurrent respiratory papillomatosis. AnnOtol Rhinol Laryngol 102:580–583188. Kashima HK, Mounts P, Shah K (1996) Recurrent respiratorypapillomatosis. Obstet Gynecol Clin North Am 23:699–706189. Kashima HK, Shah F, Lyles A, Glackin R, Muhammad N,Turner L, Van Zandt S, Whitt S, Shah K (1992) A comparisonof risk factors in juvenile-onset and adult-onset recurrent respiratorypapillomatosis. Laryngoscope 102:9–13190. Kasperbauer JL, O’Halloran GL, Espy MJ, Smith TF, LewisJE (1993) Polymerase chain reaction (PCR) identification ofhuman papillomavirus (HPV) DNA in verrucous carcinomaof the larynx. Laryngoscope 103:416–420191. Kaugars GE, Silverman S Jr, Lovas JG, Thompson JS, BrandtRB, Singh VN (1996) Use of antioxidant supplements in thetreatment of human oral leukoplakia. Oral Surg Oral MedOral Pathol Oral Radiol Endod 81:5–14192. Keelawat S, Liu CZ, Roehm PC, Barnes L (2002) Adenosquamouscarcinoma of the upper aerodigestive tract: a clinicopathologicstudy of 12 cases and review of the literature. AmJ Otolaryngol 23:160–168

34 N. Gale · N. Zidar1193. Kell MR, Winter DC, O’Sullivan GC, Shanaha F, RedmondHP (2000) Biological behaviour and clinical implications ofmicrometastasis. Br J Surg 87:1629–1639194. Kleinsasser O (1988) Tumors of the larynx and hypopharynx.Thieme, Stuttgart, pp 61–123195. Klijanienko J, El-Naggar A, Ponzio-Prion A, Marandas P,Micheau C, Caillaud JM (1993) Basaloid squamous carcinomaof the head and neck. Immunohistochemical comparisonwith adenoid cystic carcinoma and squamous cell carcinoma.Arch Otolaryngol Head Neck Surg 119:887–890196. Koch BB, Trask DK, Hoffman HT, Karnell LH, Robinson RA,Zhen W, Menck HR (2001) National survey of head and neckverrucous carcinoma: pattern of presentation, care, and outcome.Cancer 92:110–120197. Kolbusz RV, Goldberg LH (1994) Verrucous carcinoma of theoral cavity. Int J Dermatol 33:618–622198. Kotwall C, Sako K, Razack MS, Rao U, Bakamjian V, SheddDP (1987) Metastatic patterns in squamous cell cancer of thehead and neck. Am J Surg 154:439–442199. Krecicki T, Jelen M, Zalesska-Krecicka M, Szkudlarek T, SzajowskiK (1999) Immunohistochemically stained markers(p53, PCNA, bcl-2) in dysplastic lesions of the larynx. CancerLett 143:23–28200. Küffer R, Lombardi T (2002) Premalignant lesions of the oralmucosa. A discussion about the place of oral intraepithelialneoplasia (OIN). Oral Oncol 38:125–130201. Kui LL, Xiu HZ, Ning LY (2003) Condyloma acuminatumand human papilloma virus infection in the oral mucosa ofchildren. Pediatr Dent 25:149–153202. Lam KY, Law S, Luk JM, Wong J (2001) Oesophageal basaloidsquamous cell carcinoma: a unique clinicopathological entitywith telomerase activity as a prognostic indicator. J Pathol195:435–442203. Lambert PR, Ward PH, Berci G (1980) Pseudosarcoma ofthe larynx: a comprehensive analysis. Arch Otolaryngol106:700–708204. Lee JJ, Hong WK, Hittelman WN, Mao L, Lotan R, Shin DM,Benner SE, Xu XC, Lee JS, Papadimitrakopolou VM, GeyerC, Perez C, Martin JW, El-Naggar AK, Lippman SM (2000)Predicting cancer development in oral leukoplakia: ten yearsof translational research. Clin Cancer Res 6:1702–1710205. Leifer C, Miller AS, Putong PB, Min BH (1974) Spindle cellcarcinoma of oral mucosa: a light and electron microscopicstudy of apparent sarcomatous metastasis to cervical lymphnodes. Cancer 34:597–605206. Lele SM, Pou AM, Ventura K, Gatalica Z, Payne D (2002)Molecular events in the progression of recurrent respiratorypapillomatosis to carcinoma. Arch Pathol Lab Med 126:1184–1188207. León X, Quer M, Diez S, Orús C, López-Pousa A, Burgués J(1998) Second neoplasm in patients with head and neck cancer.Head Neck 21:204–210208. León X, Quer M, Orús C, del Prado Venegas M, López M(2000) Distant metastases in head and neck cancer patientswho achieved loco-regional control. Head Neck 22:680–688209. Leong AS, Brown JH (1984) Malignant transformation in athymic cyst. Am J Surg Pathol 8:471–475210. Leventon GS, Evans HL (1981) Sarcomatoid squamous cellcarcinoma of the mucous membranes of the head and neck: aclinicopathologic study of 20 cases. Cancer 48:994–1003211. Lever WF (1947) Adenoacanthoma of sweat glands: carcinomaof sweat glands with glandular and epidermal elements.Report of 4 cases. Arch Dermatol Syphilol 56:157–171212. Levi JE, Delcelo R, Alberti VN, Torloni H, Villa LL (1989)Human papillomavirus DNA in respiratory papillomatosisdetected by in situ hybridization and the polymerase chainreaction. Am J Pathol 135:1179–1184213. Lewis JE, Olsen KD, Sebo TJ (1997) Spindle cell carcinomaof the larynx: review of 26 cases including DNA content andimmunohistochemistry. Hum Pathol 28:664–673213a. Lewis Jr JS, Ritter JH, El-Mofty S (2005) Alternative epithelialmarkers in sarcomatoid carcinomas of the head and neck,lung and bladder – p63, MOC-31, and TT-F1. Modern Pathology18:1471–1481214. Li W, Thompson CH, O’Brien CJ, McNeil EB, Scolyer RA,Cossart YE, Veness MJ, Walker DM, Morgan GJ, Rose BR(2003) Human papillomavirus positivity predicts favourableoutcome for squamous carcinoma of the tonsil. Int J Cancer106:553–558215. Li WW, Pettit TH, Zakka KA (1980) Intraocular invasion bypapillary squamous cell carcinoma of the conjunctiva. Am JOphthalmol 90:697–701216. Lindeberg H, Elbrond O (1989) Laryngeal papillomas: clinicalaspects in a series of 231 patients. Clin Otolaryngol14:333–342217. Lindeberg H, Elbrond O (1990) Laryngeal papillomas: theepidemiology in a Danish subpopulation 1965–1984. ClinOtolaryngol 15:125–131218. Lindeberg H, Elbrond O (1991) Malignant tumours in patientswith a history of multiple laryngeal papillomas: thesignificance of irradiation. Clin Otolaryngol 16:149–151219. Lindeberg H, Krogdahl A (1997) Laryngeal dysplasia and thehuman papillomavirus. Clin Otolaryngol 22:382–386220. Liotta LA (1992) Cancer cell invasion and metastasis. Sci Am266:54–59; 62–63221. Liotta LA, Rao CN, Barsky SH (1983) Tumor invasion andthe extracellular matrix. Lab Invest 49:636–649222. Luna MA, El Naggar A, Parichatikanond P, Weber SR, BatsakisJG (1990) Basaloid squamous carcinoma of the upperaerodigestive tract. Clinicopathologic and DNA flow cytometricanalysis. Cancer 66:537–542223. Luna MA, Pineda-Daboin K (2001) Upper aerodigestivetract. In: Henson and Albores-Savedra’s Pathology of incipientneoplasia, 3rd edn. Oxford, New York, pp 57–85224. Lundgren JAV, van Nostrand AWP, Harwood AR, Cullen RJ,Bryce DP (1986) Verrucous carcinoma (Ackermans’s tumor)of the larynx: diagnostic and therapeutic considerations.Head Neck Surg 9:19–26225. Luzar B, Poljak M, Marin IJ, Eberlinc A, Klopčič U, Gale N(2004) Human telomerase catalytic subunit gene re-expressionis an early event in oral carcinogenesis. Histopathology45:13–19226. Luzar B, Poljak M, Marin IJ, Gale N (2003) Telomerase reactivationis an early event in laryngeal carcinogenesis. ModPathol 16:841–848227. MacMillan C, Kapadia SB, Finkelstein SD, Nalesnik MA,Barnes L (1996) Lymphoepithelial carcinoma of the larynxand hypopharynx: study of eight cases with relationship toEpstein-Barr virus and p53 gene alterations, and review ofthe literature. Hum Pathol 27:1172–1179228. Maier H, Tisch M (1997) Epidemiology of laryngeal cancer:results of the Heidelberg case-control study. Acta OtolaryngolSuppl 527:160–164229. Mallofré C, Cardesa A, Campo E, Condom E, Palacin A, Garin-ChesaP, Traserra J (1993) Expression of cytokeratins insquamous cell carcinomas of the larynx: immunohistochemicalanalysis and correlation with prognostic factors. PatholRes Pract 189:275–282230. Mamelle G, Pampurik J, Luboinski B, Lancar R, Lusinchi A,Bosq J (1994) Lymph node prognostic factors in head andneck squamous cell carcinomas. Am J Surg 168:494–498231. Mao L (1997) Leukoplakia: molecular understanding of premalignantlesions and implications for clinical management.Mol Med Today 3:442–448232. Martin MR, Kahn LB (1977) So-called pseudosarcoma ofthe esophagus: nodal metastases of the spindle cell element.Arch Pathol Lab Med 101:604–609233. Martinez-Gimeno C, Rodriguez EM, Villa CN, Varela CL(1995) Squamous carcinoma of the oral cavity: a clinicopathologicscoring system for evaluating risk of cervical lymphnode metastasis. Laryngoscope 105:107–114234. Martinez-Madrigal E, Baden E, Casiraghi O, Micheau C(1991) Oral and pharyngeal adenosquamous carcinoma. Areport of four cases with immunohistochemical studies. EurArch Otorhinolaryngol 248:255–258235. Mashberg A, Samit A (1995) Early diagnosis of asymptomaticoral and oropharyngeal squamous cancers. CA Cancer JClin 45:328–351

Lesions of Squamous Epithelium Chapter 1 35236. McCaffrey TV, Witte M, Ferguson MT (1998) Verrucous carcinomaof the larynx. Ann Otol Rhinol Laryngol 107:391–395237. McDonalds JS, Crissman JD, Gluckman JL (1982) Verrucouscarcinoma of the oral cavity. Head Neck Surg 5:22–28238. McKaig RG, Baric RS, Olshan AF (1998) Human papillomavirusand head and neck cancer. Epidemiology and molecularbiology. Head Neck 20:250–265239. McLaren KM, Burnett RA, Goodland JR, Howatson SR,Lang S, Lee FD, Lessells AM, Ogston S, Robertson AJ, SimpsonJG, Smith GD, Tavadia HB, Walker F; The Scottish PathologyConsistency Group (2000) Consistency of histopathologicalreporting of laryngeal dysplasia. Histopathology37:460–463240. Medina JE, Dichtel W (1984) Verrucous carcinoma of thehead and neck. Arch Otolaryngol 110:437–440241. Meijer JW, Ramaekers FC, Manni JJ, Slooff JJ, AldeweireldtJ, Vooys GP (1988) Intermediate filament proteins in spindlecell carcinoma of the larynx and tongue. Acta Otolaryngol106:306–313242. Michaels L, Hellquist HB (2001) Ear, nose and throat histopathology,2nd edn. Springer, London, pp 15–51243. Milford CA, O’Flynn PE (1991) Management of verrucouscarcinoma of the larynx. Clin Otolaryngol 16:160–162244. Miller CS, White DK, Royse DD (1993) In situ hybridizationanalysis of human papillomavirus in orofacial lesions using aconsensus biotinylated probe. Am J Dermatopathol 15:256–259245. Minić AJ, Stajčić Z (1994) Adenosquamous carcinoma ofthe inferior turbinate: a case report. J Oral Maxillofac Surg52:764–767246. Mohit-Tabatabai MA, Sobel HJ, Rush BF, Mashberg A (1986)Relation of thickness of floor of mouth stage-I and stage-IIcancers to regional metastases. Am J Surg 152:351–353247. Moreno-Lopez LA, Esparza-Gomez GC, Gonzalez-NavarroA, Cerero-Lapiedra R, Gonzalez-Hernandez MJ, Dominguez-RojasV (2000) Risk of oral cancer associated with tobaccosmoking, alcohol consumption and oral hygiene: acase-control study in Madrid, Spain. Oral Oncol 36:170–174248. Morice WG, Ferreiro JA (1998) Distinction of basaloid squamouscell carcinoma from adenoid cystic and small cell undifferentiatedcarcinoma by immunohistochemistry. HumPathol 29:609–612249. Műller KM, Krohn RB (1980) Smoking habits and their relationshipto precancerous lesions of the larynx. J Cancer ResClin Oncol 96:211–217250. Muller S, Barnes L (1995) Basaloid squamous cell carcinomaof the head and neck with a spindle cell component. An unusualhistologic variant. Arch Pathol Lab Med 119:181–182251. Munck-Wikland E, Edström S, Jungmark E, KuylenstiernaR, Lindholm J, Auer G (1994) Nuclear DNA content, proliferating-cellnuclear antigen (PCNA) and p53 immunostainingin predicting progression of laryngeal cancer in situ lesions.Int J Cancer 56:95–99252. Muscat JE, Wynder EL (1992) Tobacco, alcohol, asbestos,and occupational risk factors for laryngeal cancer. Cancer69:2244–2251253. Myers EN, Alvi N (1996) Management of the carcinoma ofthe supraglottic larynx: evolution, current concepts, and futuretrends. Laryngoscope 106:559–567254. Myssiorek D, Vambutas A, Abramson AL (1994) Carcinomain situ of the glottic larynx. Laryngoscope 104:463–467255. Nadal A, Campo E, Pinto J, Mallofre C, Palacin A, Arias C,Traserra J, Cardesa A (1995) p53 expression in normal, dysplastic,and neoplastic laryngeal epithelium. Absence of acorrelation with prognostic factors. J Pathol 175:181–188256. Nadal A, Cardesa A (2003) Molecular biology of laryngealsquamous cell carcinoma. Virchows Arch 442:1–7257. Nadal A, Jares P, Cazorla M, Fernández PL, Sanjuan X,Hernández L, Pinyol M, Aldea M, Mallofré C, Muntané J,Traserra J, Campo E, Cardesa A (1997) p21WAF1/Cip1 expressionis associated with cell differentiation but not withp53 mutations in squamous cell carcinomas of the larynx. JPathol 183:156–163258. Napier SS, Gormley JS, Newlands C, Ramsay-Baggs P (1995)Adenosquamous carcinoma. A rare neoplasm with an aggressivecourse. Oral Surg Oral Med Oral Pathol Oral RadiolEndod 79:607–611259. Nappi O, Pettinato G, Wick MR (1989) Adenoid (acantholytic)squamous cell carcinoma of the skin. J Cutan Pathol16:114–121260. Nappi O, Wick MR, Pettinato G, Ghiselli RW, Swanson PE(1992) Pseudovascular adenoid squamous cell carcinoma ofthe skin. A neoplasm that may be mistaken for angiosarcoma.Am J Surg Pathol 16:429–438261. Nathan CAO, Sanders K, Abreo FW, Nassar R, Glass J (2000)Correlation of p53 and the proto-oncogene eIF4E in larynxcancers: prognostic implications. Cancer Res 60:3599–3604262. Naunheim KS, Taylor JR, Skosey C, Hoffman PC, FergusonMK, Golomb HM, Little AG (1987) Adenosquamous lungcarcinoma, clinical characteristics, treatment and prognosis.Ann Thorac Surg 44:462–466263. Neville BW, Day TA (2002) Oral cancer and precancerous lesions.CA Cancer J Clin 52:195–215264. Newman J, Antonakopoulos GN, Darnton J, Matthews HR(1992) The ultrastructure of oesophageal carcinoma: multidirectionaldifferentiation. A transmission microscope studyof 43 cases. J Pathol 167:192–198265. Niedobitek G, Hansmann ML, Herbst H, Young LS, DienemannD, Hartmann CA et al. (1991) Epstein-Barr-virus andcarcinomas – undifferentiated carcinomas but not squamous-cellcarcinomas of the nasopharynx are regularly associatedwith the virus. J Pathol 165:17–24266. Nishijima W, Takooda S, Tokita N, Takayama S, Sakura M(1993) Analyses of distant metastases in squamous cell carcinomaof the head and neck and lesions above the clavicles atautopsy. Arch Otolaryngol Head Neck Surg 119:65–68267. Nunez DA, Astley SM, Lewis FA, Wells M (1994) Humanpapilloma viruses: a study of their prevalence in the normallarynx. J Laryngol Otol 108:319–320268. Oijen MCGT van, Leppers vd Straat FGJ, Tilanus MGJ, SlootwegPJ (2000) The origin of multiple squamous cell carcinomasin the aerodigestive tract. Cancer 88:884–893269. Oijen MG van, Rijksen G, ten Broek FW, Slootweg PJ (1998)Increased expression of epidermal growth factor receptors innormal epithelium adjacent to head and neck carcinomas independentof tobacco and alcohol abuse. Oral Dis 4:4–8270. Oijen MGCT van, Slootweg PJ (2000) Gain-of-function mutationsin the tumor suppressor gene p53. Clin Cancer Res6:2138–2145271. Oijen MGCT van, Slootweg PJ (2000) Review. Oral field cancerization.Carcinogen-induced independent events or micrometastaticdeposits? Cancer Epidemiol Biomarkers Prev9:249–256272. Oijen MGCT van, Tilanus MG, Medema RH, Slootweg PJ(1998) Expression of p21 (Waf1/Cip1) in head and neck cancerin relation to proliferation, differentiation, p53 status. JOral Pathol Med 27:367–375273. Onishi A, Nakashiro K, Mihara M, Sumida T, Kawamata H,Shintani S, Aida T, Tachikawa T, Kamakawa H (2004) Basicand clinical studies on quantitative analysis of lymph nodemicrometastasis in oral cancer. Oncol Rep 11:33–39274. Orvidas LJ, Kerry DK, Lewis JE, Suman VJ (1998) Verrucouscarcinoma of the larynx. Head Neck 20:197–203275. O’Sullivan B, Warde P, Keane T, Irish J, Cummings B, PayneD (1995) Outcome following radiotherapy in verrucous carcinomaof the larynx. Int J Radiat Oncol Biol Phys 32:611–617276. Parnes SM (1990) Asbestos and cancer of the larynx: is therea relationship? Laryngoscope 100:254–261277. Paulino AFG, Singh B, Shah JP, Huvos AG (2000) Basaloidsquamous cell carcinoma of the head and neck. Laryngoscope110:1479–1482278. Perez CA, Kraus FT, Evans JC, Powers WE (1966) Anaplastictransformation in verrucous carcinoma of the oral cavity afterradiation therapy. Radiology 86:108–115279. Piattelli A, Rubini C, Fioroni M, Iezzi G, Santinelli A (2002)Prevalence of p53, bcl-2, and Ki-67 immunoreactivity and

36 N. Gale · N. Zidar1of apoptosis in normal oral epithelium and in premalignantand malignant lesions of the oral cavity. J Oral MaxillofacSurg 60:532–540280. Pinsolle J, Pinsolle V, Majoufre C, Duroux S, Demeaux H, SiberchicotF (1997) Prognostic value of histologic findings inneck dissections for squamous cell carcinoma. Arch OtolaryngolHead Neck Surg 123:145–148281. Poljak M, Gale N, Kambič V (1997) Human papilloma viruses:a study of their prevalence in the epithelial hyperplasticlesions of the larynx. Acta Otolaryngol Suppl 527:66–69282. Poljak M, Gale N, Kambič V, Ferluga D, Fischinger J (1996)Overexpression of p53 protein in benign and malignant laryngealepithelial lesions. Anticancer Res 16:1947–1951283. Poljak M, Seme K, Gale N (1998) Detection of human papillomavirusesin tissue specimens. Adv Anat Pathol 5:216–234284. Pou AM, Rimell FL, Jordan JA, Shoemaker DL, Johnson JT,Barua P, Post JC, Ehrlich GD (1995) Adult respiratory papillomatosis:human papillomavirus type and viral coinfectionsas predictors of prognosis. Ann Otol Rhinol Laryngol104:758–762285. Praetorius F (1997) HPV-associated diseases of oral mucosa.Clin Dermatol 15:399–413286. Premoli-De-Percoco G, Cisternas JP, Ramirez JL, Galindo I(1993) Focal epithelial hyperplasia: human-papillomavirusinduceddisease with a genetic predisposition in a Venezuelanfamily. Hum Genet 91:386–388287. Proffitt SD, Spooner TR, Kosek JC (1970) Origin of undifferentiatedneoplasm from verrucous epidermal carcinoma oforal cavity following irradiation. Cancer 26:389–393288. Quick CA, Foucar E, Dehner LP (1979) Frequency and significanceof epithelial atypia in laryngeal papillomatosis. Laryngoscope89:550–560289. Quiney RE, Wells M, Lewis FA, Terry RM, Michaels L, CroftCB (1989) Laryngeal papillomatosis: correlation between severityof disease and presence of HPV 6 and 11 detected by insitu DNA hybridisation. J Clin Pathol 42:694–698290. Rady PL, Schnadig VJ, Weiss RL, Hughes TK, Tyring SK(1998) Malignant transformation of recurrent respiratorypapillomatosis associated with integrated human papillomavirustype 11 DNA and mutation of p53. Laryngoscope108:735–740291. Rafferty MA, O’Dwyer TP (2001) Secondary primary malignanciesin head and neck squamous cell carcinoma. J LaryngolOtol 115:988–991292. Randall ME, Andersen WA, Mills SE, Kim JA (1986) Papillarysquamous cell carcinoma of uterine cervix: a clinicopathologicstudy of nine cases. Int J Gynecol Pathol 5:1–10293. Raslan WF, Barnes L, Krause JR, Contis L, Killeen R, KapadiaSB (1994) Basaloid squamous cell carcinoma of the headand neck: a clinicopathologic and flow cytometric study of 10new cases with review of the English literature. Am J Otolaryngol15:204–211294. Regaud C, Reverchon L (1921) Sur un cas d’epithelioma epidermoidedeveloppé dans le massif maxillaire supérieureétendu aux ligaments de la face, aux cavaties buccale, nasaleet orbitaire ainsi que aux ganglions du cou guéri par la radiothérapie.Rev Laryngol Otol Rhinol (Bord) 42:369–378295. Regezi JA, Sciubba JJ, Jordan RCK (2003) Oral pathology.Clinical pathologic correlations, 4th edn. Saunders, St. Louis,pp 143–156296. Rehberg E, Kleinsasser O (1999) Malignant transformationin non-irradiated juvenile laryngeal papillomatosis. EurArch Otorhinolaryngol 256:450–454297. Reibel J (2003) Prognosis of oral pre-malignant lesions: significanceof clinical, histopathological, and molecular biologicalcharacteristics. Crit Rev Oral Biol Med 14:47–62298. Reichart PA (2001) Identification of risk groups for oral precancerand cancer and preventive measures. Clin Oral Investig5:207–213299. Reid BC, Winn DM, Morse DE, Pendrys DG (2000) Headand neck in situ carcinoma: incidence, trends, and survival.Oral Oncol 36:414–420300. Renan MJ (1993) How many mutations are required for tumorigenesis?Implications from human cancer data. MolCarcinog 7:139–146301. Rihkanen H, Aaltonen LM, Syrjanen SM (1993) Human papillomavirusin laryngeal papillomas and in adjacent normalepithelium. Clin Otolaryngol 18:470–474302. Rihkanen H, Peltomaa J, Syrjänen S (1994) Prevalence of humanpapillomavirus DNA in vocal cords without laryngealpapillomas. Acta Otolaryngol 114:348–351303. Rindum JL, Stenderup A, Holmstrup P (1994) Identificationof Candida albicans types related to healthy and pathologicaloral mucosa. J Oral Pathol Med 23:406–411304. Rizzardi C, Frezzini C, Maglione M, Tirelli G, Melato M(2003) A look at the biology of spindle cell squamous carcinomaof the oral cavity: report of a case. J Oral MaxillofacSurg 61:264–268305. Rosen PP, Ernsberger D (1987) Low-grade adenosquamouscarcinoma. A variant of metaplastic mammary carcinoma.Am J Surg Pathol 11:351–358306. Rosin MP, Cheng X, Poh C, Lam WL, Huang Y, Lovas J, BereanK, Epstein JB, Priddy R, Le ND, Zhang L (2000) Use of allelicloss to predict malignant risk for low-grade oral epithelialdysplasia. Clin Cancer Res 6:357–362307. Ross GL, Soutar DS, MacDonald DG, Shoaib T, Camilleri IG,Robertson AG (2004) Improved staging of cervical metastasesin clinically node-negative patients with head and necksquamous cell carcinoma. Ann Surg Oncol 11:213–218308. Rotfield RE, Myers EN, Johnson JT (1991) Carcinoma in situand microinvasive squamous cell carcinoma of the vocalcord. Ann Otol Rhinol Laryngol 100:793–796309. Ryan RE, de Santo LW, Devine KD, Weiland LH (1977) Verrucouscarcinoma of the larynx. Laryngoscope 87:1989–1994310. Saito R, Davis BK, Ollapathy EP (1984) Adenosquamous carcinomaof the prostate. Hum Pathol 15:87–89311. Sakakura A, Yamamoto Y, Takasaki T, Makimoto K, NakamuraM, Takahashi H (1996) Recurrent laryngeal papillomatosisdeveloping into laryngeal carcinoma with human papillomavirus (HPV) type 18: a case report. J Laryngol Otol110:75–77312. Saltarelli MG, Fleming MV, Wenig BM, Gal AA, MansourKA, Travis WD (1995) Primary basaloid squamous cell carcinomaof the trachea. Am J Clin Pathol 104:594–598313. Sanderson RJ, Rivron PR, Wallace WA (1991) Adenosquamouscarcinoma of the hypopharynx. J Laryngol Otol105:678–680314. Scheifele C, Reichart PA, Dietrich T (2003) Low prevalence oforal leukoplakia in a representative sample of the US population.Oral Oncol 39:619–625315. Schmincke A (1921) Über lympho-epitheliale Geschwülste.Beitr Pathol Anat 68:161–170316. Sciubba JJ (1995) Oral leukoplakia. Crit Rev Oral Biol Med6:147–160317. Scully C, Porter SR, Speight PM, Eveson JW, Gale D (1999)Adenosquamous carcinoma of the mouth: a rare variant ofsquamous cell carcinoma. Int J Oral Maxillofac Surg 28:125–128318. Seidman JD, Berman JJ, Yost BA, Iseri OA (1991) Basaloidsquamous carcinoma of the hypopharynx and larynx associatedwith second primary tumors. Cancer 68:1545–1549319. Shafer WG, Waldron CA (1975) Erythroplakia of the oralcavity. Cancer 36:1021–1028320. Shah JP (1990) Patterns of cervical lymph node metastasesfrom squamous carcinomas of the upper aerodigestive tract.Am J Surg 160:405–409321. Shah KV, Stern WF, Shah FK, Bishai D, Kashima HK (1998)Risk factors for juvenile onset recurrent respiratory papillomatosis.Pediatr Infect Dis J 17:372–376322. Silverman S Jr, Gorsky M (1997) Proliferative verrucous leukoplakia:a follow-up study of 54 cases. Oral Surg Oral MedOral Pathol Oral Radiol Endod 84:154–157323. Silverman S Jr, Gorsky M, Lozada F (1984) Oral leukoplakiaand malignant transformation. A follow-up study of 257 patients.Cancer 53:563–568

Lesions of Squamous Epithelium Chapter 1 37324. Slaughter DP, Southwick HW, Smejkal W (1953) “Field cancerization”in oral stratified squamous epithelium: clinicalimplication of multicentric origin. Cancer 6:963–968325. Slootweg PJ, Hordijk GJ, Koole R (1996) Autopsy findings inpatients with head and neck squamous cell cancer and theirtherapeutic relevance. Oral Oncol Eur J Cancer 32B:413–415326. Slootweg PJ, Hordijk GJ, Schade Y, Es RJJ van, Koole R (2002)Treatment failure and margin status in head and neck cancer.A critical view on the potential value of molecular pathology.Oral Oncol 38:500–503327. Slootweg PJ, Muller H (1983) Verrucous hyperplasia or verrucouscarcinoma. An analysis of 27 patients. J MaxillofacSurg 11:13–19328. Slootweg PJ, Richardson M (2001) Squamous cell carcinomaof the upper aerodigestive system. In: Gnepp DR (ed) Diagnosticsurgical pathology of the head and neck. Saunders,Philadelphia, pp 19–78329. Slootweg PJ, Roholl PJM, Müller H et al. (1987) Spindle cellcarcinoma of the oral cavity and larynx. Immunohistochemicalaspects. J Craniomaxfac Surg 17:234–236330. Smith EM, Pignatari SS, Gray SD, Haugen TH, Turek LP(1993) Human papillomavirus infection in papillomas andnondiseased respiratory sites of patients with recurrent respiratorypapillomatosis using the polymerase chain reaction.Arch Otolaryngol Head Neck Surg 119:554–557331. Smith EM, Summersgill KF, Allen J, Hoffman HT, Mc-Culloch T, Turek LP, Haugen TH (2000) Human papillomavirusand risk of laryngeal cancer. Ann Otol Rhinol Laryngol109:1069–1076332. Sobin LH, Wittekind C (2002) TNM: classification of malignanttumours, 6th edn. Wiley, New York333. Soo KC, Carter RL, O‘Brien CJ, Barr L, Bliss JM, Shaw HJ(1986) Prognostic implication of perineural spread in squamouscarcinomas of the head and neck. Laryngoscope96:1145–1148334. Sood S, O’Hara J, Quraishi HS (2002) The significance of oralleukoplakia. Curr Opin Otolaryngol Head Neck Surg 10:80–84335. Souglu Y, Erdamar B, Katircioglu OS, Karatay MC, Sunay T(2002) Extracapsular spread in ipsilateral neck and contralateralneck metastases in laryngeal cancer. Ann Otol RhinolLaryngol 111:447–454336. Spayne JA,Warde P, O‘Sullivan B, Payne D, Liu FF, WaldronJ, Gullane PJ, Cummings BJ (2001) Carcinoma in situ of theglottic larynx: results of the treatment with radiation therapy.Int J Radiat Oncol Biol Phys 49:1235–1238337. Spector JG, Sessions DG, Haughey BH, Chao KSC, SimpsonJ, Al Mofty S, Perez CA (2001) Delayed regional metastases,distant metastases, and second primary malignancies insquamous cell carcinomas of the larynx and hypopharynx.Laryngoscope 111:1079–1087338. Sperry K (1994) Lethal asphyxiating juvenile laryngeal papillomatosis.Am J Forensic Med Pathol 15:146–150339. Spiro RH (1998) Verrucous carcinoma, then and now. Am JSurg 176:393–397340. Staley CJ, Ujiki GT, Yokoo H (1977) “Pseudocarcinoma” ofthe larynx: independent metastasis of carcinomatous andsarcomatous elements. Arch Otolaryngol 94:458–465341. Stutsman AC, McGavran MH (1971) Ultraconservative managementof superficially invasive epidermoid carcinoma ofthe true vocal cord. Ann Otol Rhinol Laryngol 80:506–512342. Suarez P, Batsakis JG, el-Naggar AK (1998) Leukoplakia: stilla gallimaufry or is progress being made? A review. Adv AnatPathol 5:137–155343. Suarez PA, Adler-Storthz K, Luna MA, El-Naggar AK, Abdul-KarimFW, Batsakis JG (2000) Papillary squamous cellcarcinoma of the upper aerodigestive tract: a clinicopathologicand molecular study. Head Neck 22:60–368344. Sudbo J, Kildal W, Risberg B, Koppang HS, Danielsen HE,Reith A (2001) DNA content as a prognostic marker in patientswith oral leukoplakia. N Engl J Med 344:1270–1278345. Sugiyama M, Bhawal UK, Dohmen T, Ono S, Miyauchi M,Ishikawa T (2003) Detection of human papillomavirus-16and HPV-18 DNA in normal, dysplastic, and malignant oralepithelium. Oral Surg Oral Med Oral Pathol Oral Radiol Endod95:594–600346. Syrjänen K, Syrjänen S (2000) Papillomavirus infections inhuman pathology. Wiley, Chichester, pp 1–615347. Tabor MP, Houten VMM van, Kummer JA, Vosjan MJWD,Vlasblom R, Snow GB, Leemans CR, Braakhuis BJM, BrakenhoffRH (2002) Discordance of genetic alterations betweenprimary head and neck tumors and corresponding metastasesassociated with mutational status of the TP53gene. GenesChromosomes Cancer 33:168–177348. Takagi M, Sakota Y, Takayama S, Ishikawa G (1977) Adenoidsquamous cell carcinoma of the oral mucosa. Report of twoautopsy cases. Cancer 40:2250–2255349. Takata T, Ito H, Ogawa I, Miyaguchi M, Iljuhin N, Nikai H(1991) Spindle cell squamous carcinoma of the oral region.An immunohistochemical and ultrastructural study on thehistogenesis and differential diagnosis with a clinicopathologicanalysis of six cases. Virchows Arch 419:177–182350. Takes RP, Baatenburg de Jong RJ, van Blommestein R, HermansJ, van Krieken HHJM, Cornelisse CJ (2002) DNA ploidystatus as a prognostic marker and predictor of lymph nodemetastasis in laryngeal carcinoma. Ann Otol Rhinol Laryngol111:1015–1020351. Tavani A, Negri E, Franceschi S, Barbone F, La Vecchia C(1994) Attributable risk for laryngeal cancer in northern Italy.Cancer Epidemiol Biomarkers Prev 3:121–125352. Terry RM, Lewis FA, Robertson S, Blythe D, Wells M (1989)Juvenile and adult laryngeal papillomata: classification by insituhybridization for human papillomavirus. Clin Otolaryngol14:135–139353. Tharp ME, Shidnia H (1995) Radiotherapy in the treatmentof verrucous carcinoma of the head and neck. Laryngoscope105:391–396354. Thompson L, Chang B, Barsky SH (1996) Monoclonal originsof malignant mixed tumors (carcinosarcomas). Evidence fora divergent histogenesis. Am J Surg Pathol 20:277–285355. Thompson LDR, Wenig BM, Heffner DK, Gnepp DR (1999)Exophytic and papillary squamous cell carcinomas of thelarynx: a clinicopathologic series of 104 cases. OtolaryngolHead Neck Surg 120:718–724356. Thompson LDR, Wieneke JA, Miettinen M, Heffner DK(2002) Spindle cell (sarcomatoid) carcinomas of the larynx:a clinicopathologic study of 187 cases. Am J Surg Pathol26:153–170357. Thomson PJ, Soames JV, Booth C, O’Shea JA (2002) Epithelialcell proliferative activity and oral cancer progression. CellProlif 1:110–120358. Tjebbes GWA, Kreijveld PA, Tilanus MGJ, Hordijk GJ, SlootwegPJ (2002) P53 tumor suppressor gene mutations in laryngealcancer and in recurrent disease following radiation therapy.Oral Oncol 38:296–300359. Tjebbes GWA, Leppers FGJ, Hordijk GJ, Tilanus MGJ, SlootwegPJ (1999) p53 tumor suppressor gene as a clonal markerin head and neck squamous cell carcinoma. p53 mutationsin primary tumor and matched lymph node metastases. OralOncol 35:384–389360. Toda S, Yonemitsu N, Miyabara S, Sugihara H, Maehara N(1989) Polypoid squamous cell carcinoma of the larynx. Animmunohistochemical study for ras p21 and cytokeratin.Pathol Res Pract 185:860–866361. Toorn PP van der, Veltman JA, Bot FJ, de Jong JM, ManniJJ, Ramaekers FC, Hopman AH (2001) Mapping of resectionmargins of oral cancer for p53 overexpression and chromosomeinstability to detect residual (pre)malignant cells. JPathol 193:66–72362. Traserra J, Comas J, Conde C, Cuchi A, Cardesa A (1990)Metastatic involvement of the cavernous sinus from primarypharyngolaryngeal tumors. Head Neck 12:426–429363. Uhlman DL, Adams G, Knapp D, Aeppli MM, Niehans G(1996) Immunohistochemical staining for markers of futureneoplastic progression in the larynx. Cancer Res 56:2199–2205364. Uzcudun AE, Bravo Fernández P, Sánchez JJ, García GrandeA, Rabanal Retolaza I, González Baron M, Gavilán Bouzas J(2001) Clinical features of pharyngeal cancer: a retrospective

38 N. Gale · N. Zidar1study of 258 consecutive patients. J Laryngol Otol 115:112–118365. Vaidya MM, Sawant SS, Borges AM, Ogale SB, Bhisey AN(1998) Cytokeratin expression in precancerous lesions of thehuman oral cavity. Oral Oncol 34:261–264366. Vedtofte P, Holmstrup P, Hjorting-Hansen E, Pindborg JJ(1987) Surgical treatment of premalignant lesions of the oralmucosa. Int J Oral Maxillofac Surg 16:656–664367. Velden LA van der, Schaafsma HE, Manni JJ, Ruiter DJ, RamaekersFCS, Kuijpers W (1997) Cytokeratin expression innormal epithelium and squamous cell carcinomas of the larynx.Eur Arch Otorhinolaryngol 254:376–383368. Violaris NS, O’Neill D, Helliwell TR, Caslin AW, Roland NJ,Jones AS (1994) Soft tissue cervical metastases of squamouscarcinoma of the head and neck. Clin Otolaryngol 19:394–399369. Volavšek M, Bračko M, Gale N (2003) Distribution and prognosticsignificance of cell cycle proteins in squamous carcinomaof the larynx, hypopharynx and adjacent epithelial hyperplasticlesions. J Laryngol Otol 117:286–293370. Vural E, Hutcheson J, Korourian S, Kechelava S, Hanna E(2000) Correlation of neural cell adhesion molecules withperineural spread of squamous cell carcinoma of the headand neck. Otolaryngol Head Neck Surg 122:717–720371. Waal I van der, Schepman KP, van der Meij EH, Smeele LE(1997) Oral leukoplakia: a clinicopathological review. OralOncol 33:291–301372. Wain SL, Kier R, Volmer RT, Bossen EH (1986) Basaloidsquamouscarcinoma of the tongue, hypopharynx, and larynx.Report of 10 cases. Hum Pathol 17:1158–1166373. Waldron CA, Shafer WG. Leukoplakia revisited (1975) Aclinicopathologic study 3256 oral leukoplakias. Cancer36:1386–1392374. Ward KA, Napier SS, Winter PC, Maw RD, Dinsmore WW(1995) Detection of human papilloma virus DNA sequencesin oral squamous cell papillomas by the polymerase chain reaction.Oral Surg Oral Med Oral Pathol Oral Radiol Endod80:63–66375. Wenig BM (2002) Squamous cell carcinoma of the upperaerodigestive tract: precursors and problematic variants.Mod Pathol 15:229–254376. Wiernik G, Millard PR, Haybittle JL (1991) The predictivevalue of histological classification into degrees of differentiationof squamous cell carcinoma of the larynx and hypopharynxcompared with the survival of patients. Histopathology19:411–417377. Winzenburg SM, Niehans GA, George E, Daly K, Adams GL(1997) Basaloid squamous carcinoma: a clinical comparisonof two histologic types with poorly differentiated squamouscell carcinoma. Otolaryngol Head Neck Surg 119:471–475378. Wolf GT, Fisher SG, Truelson JM, Beals TF (1994) DNA contentand regional metastases in patients with advanced laryngealsquamous carcinoma. Laryngoscope 104:479–483379. Woolgar JA (1999) Micrometastasis in oral/oropharyngealsquamous cell carcinoma: incidence, histopathological featuresand clinical implications. Br J Oral Maxillofac Surg37:181–186380. Woolgar JA, Rogers SN, Lowe D, Brown JS, Vaughan ED(2003) Cervical lymph node metastasis in oral cancer: theimportance of even microscopic extracapsular spread. OralOncol 39:130–137381. World Health Organization Classification of Tumours (2005)Pathology and genetics of tumours of the head and neck.IARC, Lyon382. Yilmaz T, Hoşal AŞ, Gedikoğlu G, Kaya S (1999) Prognosticsignificance of histopathological parameters in cancer of thelarynx. Eur Arch Otorhinolaryngol 256:139–144383. Yilmaz T, Hoşal AS, Gedikoĝlu G, Őnerci M, Gürsel B (1998)Prognostic significance of vascular and perineural invasionin cancer of the larynx. Am J Otolaryngol 19:83–88384. Yoshihara T, Yamamura Y (1997) An unusual case of laryngealcarcinoma metastasizing to the small intestine. J LaryngolOtol 111:575–577385. Yoshimura Y, Mishima K, Obara S, Yoshimura H, MaruyamaR (2003) Clinical characteristics of oral adenosquamous carcinoma:report of a case and an analysis of the reported Japanesecases. Oral Oncol 39:309–315386. Young SK, Min KW (1991) In situ DNA hybridization analysisof oral papillomas, leukoplakias, and carcinomas forhuman papillomavirus. Oral Surg Oral Med Oral Pathol71:726–729387. Yucel OT, Yilmaz T, Unal OF, Turan E (1999) Distant metastasesin laryngeal squamous cell carcinoma. J Exp Clin CancerRes 18:285–288388. Zaatari GS, Santoianni RA (1986) Adenoid squamous cellcarcinoma of the nasopharynx and neck region. Arch PatholLab Med 110:542–546389. Zain RB (2001) Cultural and dietary risk factors of oral cancerand precancer – a brief overview. Oral Oncol 37:205–210390. Zakrzewska JM, Lopes V, Speight P, Hopper C (1996) Proliferativeverrucous leukoplakia: a report of ten cases. OralSurg Oral Med Oral Pathol Oral Radiol Endod 82:396–401391. Zarbo RJ, Crissman JD, Venkat H, Weiss MA (1986) Spindle-cellcarcinoma of the upper aerodigestive tract mucosa.An immunohistochemical and ultrastructural study of 18 biphasictumors and comparison with seven monophasic spindle-celltumors. Am J Surg Pathol 10:741–753392. Zbären P, Borisch B, Lang H, Greiner R (1997) Undifferentiatedcarcinoma of nasopharyngeal type of the laryngopharyngealregion. Otolaryngol Head Neck Surg 117:688–693393. Zbären P, Lehmann W (1987) Frequency and sites of distantmetastases in head and neck squamous cell carcinoma. Ananalysis of 101 cases at autopsy. Arch Otolaryngol Head NeckSurg 11:762–764394. Zidar N, Gale N, Cör A, Kambič V (1996) Expression of Ki-67 antigen and proliferative cell nuclear antigen in benignand malignant epithelial lesions of the larynx. J LaryngolOtol 110:440–445395. Zidar N, Gale N, Kambič V, Fischinger J (2001) Expression oftenascin and fibronectin in benign epithelial hyperplastic lesionsand squamous carcinoma of the larynx. Anticancer Res21:451–454396. Zidar N, Gale N, Kambič V, Fischinger J (2002) Proliferationof myofibroblasts in the stroma of epithelial hyperplasticlesions and squamous carcinoma of the larynx. Oncology62:381–385

Chapter 2Nasal Cavityand Paranasal SinusesA. Cardesa · L. Alos · A. Franchi2Contents2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . 402.1.1 Embryology . . . . . . . . . . . . . . . . . . . . . . . 402.1.2 Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . 402.1.3 Histology . . . . . . . . . . . . . . . . . . . . . . . . . 402.2. Acute and Chronic Rhinosinusitis . . . . . . . . . . 402.2.1 Viral Infections (Common Cold) . . . . . . . . . . . 402.2.2 Bacterial Infections . . . . . . . . . . . . . . . . . . . 402.2.3 Allergic Rhinitis . . . . . . . . . . . . . . . . . . . . . 402.2.4 Atrophic Rhinitis . . . . . . . . . . . . . . . . . . . . 412.2.5 Hypertrophic Rhinitis . . . . . . . . . . . . . . . . . 412.2.6 Non-Suppurative Chronic Sinusitis . . . . . . . . . . 412.3 Sinonasal Polyps . . . . . . . . . . . . . . . . . . . . . 412.3.1 Allergic Polyposis . . . . . . . . . . . . . . . . . . . . 412.3.2 Polyposis in Mucoviscidosis . . . . . . . . . . . . . . 412.3.3 Polyposis in Immotile Cilia Syndromeand in Kartagener’s Syndrome . . . . . . . . . . . . . 412.3.4 Antrochoanal Polyps . . . . . . . . . . . . . . . . . . . 412.4 Sinonasal Hamartomatousand Teratoid Lesions . . . . . . . . . . . . . . . . . . 422.4.1 Hamartomas . . . . . . . . . . . . . . . . . . . . . . . 422.4.2 Teratoid Lesions . . . . . . . . . . . . . . . . . . . . . 422.5 Pseudotumours . . . . . . . . . . . . . . . . . . . . . 432.5.1 Mucocele . . . . . . . . . . . . . . . . . . . . . . . . . 432.5.2 Organising Haematoma . . . . . . . . . . . . . . . . 432.5.3 Amyloidosis . . . . . . . . . . . . . . . . . . . . . . . 432.5.4 Myospherulosis . . . . . . . . . . . . . . . . . . . . . 432.5.5 Eosinophilic Angiocentric Fibrosis . . . . . . . . . . 432.5.6 Heterotopic Brain Tissue . . . . . . . . . . . . . . . . 432.6 Fungal Diseases . . . . . . . . . . . . . . . . . . . . . 442.6.1 Aspergillosis . . . . . . . . . . . . . . . . . . . . . . . 442.6.2 Mucormycosis . . . . . . . . . . . . . . . . . . . . . . 442.6.3 Rhinosporidiosis . . . . . . . . . . . . . . . . . . . . 442.7 HIV-Related Infections . . . . . . . . . . . . . . . . . 442.8 Mid-Facial Necrotising Granulomatous Lesions . . 452.8.1 Wegener’s Granulomatosis . . . . . . . . . . . . . . . 452.8.2 Lepromatous Leprosy . . . . . . . . . . . . . . . . . . 452.8.3 Tuberculosis . . . . . . . . . . . . . . . . . . . . . . . 452.8.4 Sarcoidosis . . . . . . . . . . . . . . . . . . . . . . . . 452.8.5 Rhinoscleroma . . . . . . . . . . . . . . . . . . . . . . 452.8.6 Leishmaniasis . . . . . . . . . . . . . . . . . . . . . . 452.8.7 Cocaine Abuse . . . . . . . . . . . . . . . . . . . . . . 462.8.8 Local Steroid Injections . . . . . . . . . . . . . . . . 462.9 Benign Epithelial Neoplasms . . . . . . . . . . . . . 462.9.1 Sinonasal Papillomas . . . . . . . . . . . . . . . . . . 462.9.1.1 Squamous Cell Papilloma . . . . . . . . . . . . . . . 462.9.1.2 Exophytic Papilloma . . . . . . . . . . . . . . . . . . 462.9.1.3 Inverted Papilloma . . . . . . . . . . . . . . . . . . . 462.9.1.4 Oncocytic Papilloma . . . . . . . . . . . . . . . . . . 472.9.2 Salivary-Type Adenomas . . . . . . . . . . . . . . . . 482.9.3 Pituitary Adenomas . . . . . . . . . . . . . . . . . . . 482.10 Benign Sinonasal Soft Tissue Neoplasms . . . . . . 482.10.1 Haemangiomas . . . . . . . . . . . . . . . . . . . . . 482.10.2 Haemangiopericytoma . . . . . . . . . . . . . . . . . 482.10.3 Solitary Fibrous Tumour . . . . . . . . . . . . . . . . 482.10.4 Desmoid Fibromatosis . . . . . . . . . . . . . . . . . 492.10.5 Fibrous Histiocytoma . . . . . . . . . . . . . . . . . . 492.10.6 Leiomyoma . . . . . . . . . . . . . . . . . . . . . . . . 492.10.7 Schwannoma and Neurofibroma . . . . . . . . . . . 492.10.8 Meningioma . . . . . . . . . . . . . . . . . . . . . . . 502.10.9 Paraganglioma . . . . . . . . . . . . . . . . . . . . . . 502.10.10 Juvenile Angiofibroma . . . . . . . . . . . . . . . . . 502.11 Malignant Sinonasal Tumours . . . . . . . . . . . . 502.11.1 Keratinising Squamous Cell Carcinoma . . . . . . . 512.11.2 Cylindrical Cell Carcinoma . . . . . . . . . . . . . . 522.11.3 Sinonasal Undifferentiated Carcinoma . . . . . . . . 532.11.4 Small Cell (Neuroendocrine) Carcinoma . . . . . . 542.11.5 Primary Sinonasal Nasopharyngeal-TypeUndifferentiated Carcinoma . . . . . . . . . . . . . . 542.11.6 Malignant Melanoma . . . . . . . . . . . . . . . . . . 552.11.7 Olfactory Neuroblastoma . . . . . . . . . . . . . . . 572.11.8 Primitive Neuroectodermal Tumour . . . . . . . . . 582.11.9 High-Grade Sinonasal Adenocarcinomas . . . . . . 582.11.9.1 Intestinal-Type Adenocarcinoma . . . . . . . . . . . 582.11.9.2 Salivary-Type High-Grade Adenocarcinoma . . . . 602.11.10 Low-Grade Sinonasal Adenocarcinomas . . . . . . 602.11.10.1 Non-Salivary-TypeLow-Grade Adenocarcinomas . . . . . . . . . . . . . 602.11.10.2 Salivary-TypeLow-Grade Adenocarcinomas . . . . . . . . . . . . . 612.11.11 Sinonasal Malignant Lymphomas . . . . . . . . . . . 612.11.12 Extramedullary Plasmacytoma . . . . . . . . . . . . 622.11.13 Fibrosarcoma . . . . . . . . . . . . . . . . . . . . . . 622.11.14 Malignant Fibrous Histiocytoma . . . . . . . . . . . 632.11.15 Leiomyosarcoma . . . . . . . . . . . . . . . . . . . . 632.11.16 Rhabdomyosarcoma . . . . . . . . . . . . . . . . . . 632.11.17 Malignant Peripheral Nerve Sheath Tumour . . . . 632.11.18 Teratocarcinosarcoma . . . . . . . . . . . . . . . . . . 63References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

40 A. Cardesa · L. Alos · A. Franchi22.1 Introduction2.1.1 EmbryologyThe midface, or area between the upper lip and forehead,develops at between 4 and 8 weeks’ gestation [219]. Thefrontal prominence forms during the 4th postovulatoryweek and gives rise to the superior and middle portionsof the face. The maxillary and nasal swellings form beneaththe frontal prominence. At the end of the 4th weeksurface thickening of the nasal swellings forms the nasalplacodes, which are of ectodermal origin and give riseto the epithelial lining of the nasal cavity and paranasalsinuses. The placodes invaginate, producing the nasalpits that become the anterior choanae (nostrils) and,less superficially, the primitive posterior choanae. Themedial nasal and frontal processes give rise to the nasalseptum, frontal bones, nasal bones, ethmoid sinus complexesand upper incisors. The lateral nasal and maxillaryprocesses fuse to form the philtrum and columella.The cartilaginous nasal capsule forms deep to the nasaland frontal bones from the chondrocranium (skull base)during the 7th and 8th postovulatory weeks. The paranasalsinuses develop from the lateral nasal walls at the6th foetal week, and their growth continues after birth,throughout childhood and adolescence.2.1.2 AnatomyThe nasal cavities are separated by the nasal septum,and limited by a roof, which is formed by the cribriformplate of the ethmoid, and a floor, which is formed by thehard palate [261]. The lateral walls have three turbinatesor conchae, and three horizontal spaces, or meatus, oneach side. The nasolacrimal duct opens in the inferiormeatus, whereas the middle meatus receives drainagefrom the frontal, anterior ethmoid and maxillary sinuses.Below the superior turbinate is the sphenoethmoidrecess, with the openings of the sphenoid and posteriorethmoid sinuses. Each nasal cavity communicates posteriorlywith the nasopharynx through the choanae.The paranasal sinuses are a group of cavities within thecorresponding craniofacial bones (maxilla, sphenoid,ethmoid and frontal) that communicate with the nasalcavities through an ostium.2.1.3 HistologyThe nasal vestibule and skin share a similar histology.At the level of the limen nasi, the keratinising squamousepithelium gradually changes first to cuboidal or columnarepithelium, and then to ciliated respiratory-type epithelium,which lines most of the nasal cavity and all theparanasal sinuses, with the exception of the roof [261].Numerous goblet cells are interspersed in the respiratory-typeepithelium. The lamina propria contains severalseromucous glands, lymphocytes, monocytes, anda well-developed vascular network, particularly evidentin the inferior and middle turbinate. The olfactory epitheliumis predominantly made of columnar non-ciliatedsustentacular cells, with scattered bipolar sensoryneurons and basal cells.2.2 Acute and Chronic Rhinosinusitis2.2.1 Viral Infections (Common Cold)Infectious rhinitis is typically viral and is often referredto as the “common cold”. It is more common in childrenthan in adults, and the most frequently identified agentsare rhinovirus, myxovirus, coronavirus and adenovirus[67, 271]. Swelling of the mucosa may cause obstructionof a sinus ostium, with subsequent secondary bacterialinfection (acute bacterial sinusitis). The histologic findingsinclude marked oedema and a non-specific mixedinflammatory infiltrate of the lamina propria.2.2.2 Bacterial InfectionsBacterial rhinosinusitis usually follows a viral infectionor allergic rhinitis, and the most commonly involvedagents are Streptococcus pneumoniae, Haemophilusinfluenzae and Moraxella catarrhalis [11, 34]. A denseinflammatory infiltrate mainly made of neutrophils occupiesthe lamina propria. Acute bacterial rhinosinusitisusually resolves with antibiotic therapy. Complicationsare rare and include contiguous infectious involvementof the orbit or central nervous system.2.2.3 Allergic RhinitisAllergic rhinitis (hay fever) is part of an inherited syndrome,which may also manifest as atopic eczema andasthma. In allergic rhinitis, airborne particles, such asgrass pollens, moulds and animal allergens, are depositedon the nasal mucosa giving rise to acute and chronicreactions. Allergens combine with the IgE antibodiesproduced by the plasma cells of the nasal mucosa,which are avidly bound to the Fc-epsilon receptors onmast cells. This triggers degranulation of mast cells andreleases the inflammatory mediators of the type I hypersensitivityreaction, causing rhinorrhoea and nasal obstruction.Microscopically, the nasal mucosa shows numerouseosinophils, abundant plasma and in some casesan increased number of mast cells. There is goblet cell

Nasal Cavity and Paranasal Sinuses Chapter 2 41hyperplasia of the respiratory epithelium and the basementmembrane, which is destroyed in the acute phase,appears considerably thickened in the chronic phase.2.2.4 Atrophic RhinitisAtrophic rhinitis is a chronic inflammation of the nasalmucosa of unknown aetiology characterised by progressivenasal mucosal atrophy and by a thick, dense secretion,with a foetid smell and crusting [178]. Multiplefactors may be involved in the pathogenesis, includingchronic bacterial infections and nutritional deficiencies.Its incidence has markedly decreased in the last century,and nowadays most cases are secondary to trauma,surgery, granulomatous diseases, infection and radiationexposure [178]. Histologically, there is non-specificchronic inflammatory infiltrate, squamous metaplasiaof the surface epithelium and of glandular excretoryducts, and atrophy of mucoserous glands [1, 69].2.2.5 Hypertrophic RhinitisThis term is applied to a condition of unknown aetiology,characterised by thickening of the sinonasal mucosaresulting from chronic inflammatory diseases [28, 71].Frequently, these patients have undergone several sinusoperations, each time with limited success and subsequentrecurrence. Recurrent nasal polyposis is often associated.2.2.6 Non-Suppurative Chronic SinusitisChronic sinusitis is a complex, multifactorial disorderresulting from persistent acute inflammation or repeatedepisodes of acute or subacute sinusitis. There are usuallypredisposing factors like small sinus ostia, repeatedepisodes of common cold, allergy or acute sinusitisdetermining obstruction of the sinus ostia, reductionof ciliary activity (immotile cilia syndrome) and cysticfibrosis. The mucosal changes observed are variableand include basement membrane thickening, goblet cellhyperplasia, oedema of varying extent, inflammation(mostly lymphocytes and plasma cells) and polypoidchange of the mucosa [242].Allergic sinonasal polyps consist largely of myxoidoedematous tissue with pseudocysts containing eosinophilicproteinaceous fluid and infiltrates of inflammatorycells [115]. They are covered by respiratoryepithelium with variable ulceration, goblet cellhyperplasia, squamous metaplasia and thickening ofthe basement membranes. Seromucous glands andmucin-containing cysts may also occur. They arisemost frequently in the ethmoidal region and the upperpart of the nasal cavity. Allergic polyps usually exhibitheavy infiltration by eosinophils (Fig. 2.1a), markedthickening of the basement membranes and gobletcell hyperplasia. Most sinonasal polyps are of allergicorigin. Epithelial dysplasia is present in a few cases.Granulomas may be present in polyps treated withintranasal injection, application of steroids or otheroily medications. Atypical fibroblasts with abundantcytoplasm, poorly defined cell borders and large pleomorphicnuclei are present in a small proportion ofcases [183]. These atypical cells occur individuallyand are more frequently found close to blood vessels(Fig. 2.1b) or near the epithelial surface. Such stromalatypia is a reactive phenomenon and it should not beconfused with sarcoma.2.3.2 Polyposis in MucoviscidosisNasal polyps in mucoviscidosis show cystic glands filledwith inspissated mucoid material and thickening of thebasement membranes that surround the glands [22,189]. Some other polyps are of infective or chemical aetiology.The histological appearances of nasal polyps donot always correlate well with their aetiology.2.3.3 Polyposisin Immotile Cilia Syndromeand Kartagener’s SyndromeImmobile cilia syndrome (or primary ciliary dyskinesia)is a genetic disease affecting ciliary movementand resulting in respiratory infections and male infertility.Situs inversus may be associated ( Kartagener’ssyndrome). About 15% of patients develop nasal polypshistologically indistinguishable from other nasalpolyps. Ultrastructural analysis of nasal biopsies isneeded to identify the alterations in the architecture ofthe cilium [177].2.3 Sinonasal Polyps2.3.1 Allergic Polyposis2.3.4 Antrochoanal PolypsAntrochoanal polyps are polyps that arise in themaxillary antrum and extend into the middle meatusprojecting posteriorly through the ipsilateral choana[106]. Antrochoanal polyps typically have prominentfibrous stroma surrounding thick-walled blood vessels

42 A. Cardesa · L. Alos · A. Franchi2aabFig. 2.1. a Allergic polyp with marked oedema of the stroma andheavy infiltration by eosinophils. b Atypical fibroblasts in an inflammatoryallergic polyp: enlarged fibroblasts with bizarre nucleiand occasional prominent nucleoli appear interspersed in granulationtissuebFig. 2.2 a Respiratory epithelial adenomatoid hamartoma: glandular-likespaces lined by respiratory epithelium and supportedby fibrous stroma. b Glandular hamartoma: abundant nodular aggregatesof modified seromucous glands supported by slightly oedematousstroma[7]. In addition, scattered, enlarged, stromal cells withhyperchromatic nuclei are not an uncommon findingin this type of polyp [235]. Those polyps that arisein the maxillary antrum and extend into the middlemeatus projecting anteriorly are known as antronasalpolyps.2.4 Sinonasal Hamartomatousand Teratoid Lesions2.4.1 HamartomasSinonasal hamartomas are benign polypoid lesions inwhich well-developed branching glands and/or stromawith variable participation of different mesenchymalcomponents are present [266]. These lesions may resultfrom an exuberant hyperplastic reaction within thecontext of an inflammatory polyp. When the glands aremainly covered by ciliated respiratory epithelium the lesionis termed “ respiratory epithelial adenomatoid hamartoma”(Fig. 2.2a). If the glandular component consistsof seromucous glands they are known as “glandularhamartomas” (Fig. 2.2b). “Mesenchymal hamartomas”show predominance of skeletal muscle or of other mesenchymalelements.2.4.2 Teratoid LesionsDermoid cysts of the nose constitute 5.5–12% of thoseof the head and neck region. More than half are detectedin children 6 years old or less, and approximately athird are present at birth. They occur most commonlyin the bridge of the nose and always in the midline [33,63, 88, 254, 278]. Dermoid cysts are lined with maturekeratinising squamous epithelium and contain appendagesof the skin in the cyst wall, but no endoderm.The lumen is filled with cheesy, yellow-white material.

Nasal Cavity and Paranasal Sinuses Chapter 2 43This lesion is differentiated from the very rare sinonasalteratoma by the limited variety of tissue types andthe absence of endodermal components [100]. Epidermalinclusion cysts do not contain adnexa. Dermoidcysts of the nose should also be distinguished from encephalocele.We are unaware of hairy polyps occurringin the nose.2.5 Pseudotumours2.5.1 MucoceleMucocele is a cyst filled with mucus that develops withina sinus cavity as the result of occlusion of the ostium.Most commonly it is due to infection, but may also resultfrom trauma or be congenital [109]. Retained secretionscause expansion of the sinus and bone erosion. Themost common sites of occurrence are the frontal and thesphenoidal sinuses. The cyst is lined by respiratory epitheliumthat shows prominent goblet-cell hyperplasia[158, 184]. Expansion of the cyst may cause atrophy andmetaplasia of the epithelium.2.5.2 Organising HaematomaOrganising haematoma, also known as “ cholesterolgranuloma” or “rhinitis caseosa”, is in most cases the resultof occult submucosal haemorrhage in the maxillarysinus due to external trauma or tooth extraction [147].Resolution of the haematoma produces the formation ofcholesterol granulomas and fibrosis, simulating a foreignbody reaction.2.5.4 MyospherulosisMyospherulosis is characterised by the presence of cystlikespaces lined by flattened histiocytes and containingclusters of brownish spherules resembling fungi [198,217, 230]. They lie loosely or within sacs formed by thinrefractile membranes. The brownish spherules do notstain with PAS or Gomori methanamine silver and theirmorphology does not correspond to any known fungus[228]. They are found within fibrous granulation tissue,which may show a foreign body reaction. The lesion isusually found in patients who have had previous operations[145]. It is now recognised that the spherules areextravasated red cells that have been altered by interactionwith traumatised fat or petrolatum-based ointmentsand gauzes used in surgical procedures.2.5.5 Eosinophilic Angiocentric FibrosisEosinophilic angiocentric fibrosis is a rare, chronic, benign,idiopathic condition of the upper respiratory tractoccurring predominantly in adult women [214, 248].Initially, the histologic picture is characterised by nonnecrotisingeosinophilic vasculitis involving capillariesand venules of the sinonasal mucosa, accompanied by aninflammatory infiltrate with lymphocytes, plasma cells,histiocytes and occasional neutrophils [214]. In late lesionsthere is a characteristic obliterative perivascularonion-skin fibrosis, while the inflammatory infiltrate isless dense and eosinophils predominate [214]. The differentialdiagnosis includes reactive processes of the sinonasalmucosa, like Wegener’s granulomatosis, Churg-Strauss syndrome, Kimura disease, and angiolymphoidhyperplasia with eosinophilia.2.5.3 AmyloidosisIsolated amyloid deposition in the sinonasal mucosa isa rare event, with about 20 cases reported in the English-languageliterature [180, 258]. Grossly, the lesionappears as a friable tumour-like mass, with a tendencyto bleed. Histologically, there is a deposition of intenselyeosinophilic material in the stroma, around blood vesselsand around ducts of the mucoserous glands, whichis often associated with diffuse chronic inflammationand foreign body granulomatous reaction. Amyloidstains orange with Congo red, and showed apple greenbirefringence under polarised light examination. Immunohistochemistrymay help to identify the type ofamyloid deposition.2.5.6 Heterotopic Brain TissueThis lesion mostly occurs in young children, usually theresult of a congenital abnormality related to a variant ofmeningoencephalocele [136, 196]. Commonly used synonymsare glial heterotopia and nasal glioma, althoughthe latter is a misnomer. The lesion mainly arises at thebase of the nose or in the upper part of the nasal cavity,and grossly may be polypoid. Histologically, it is mostlycomposed of a mixture of astrocytes, glial fibres andfibrous connective tissue. Multinucleated glial cells arefrequently found. Some glial cells can have large nucleiresembling nerve cells. Immunostaining for glial fibrillaryacidic protein is a helpful diagnostic adjunct. A fewtrue nerve cells or even ependymal elements can rarelybe identified. Mitoses are not found.

44 A. Cardesa · L. Alos · A. Franchi2aPAS or Gomori methanamine silver the fungi appearas dichotomously branching septate hyphae 6–8 mwide. Aspergillosis may occur as a non-invasive diseasein which a mass of fungal hyphae (fungal ball) is presentin a sinus (Fig. 2.3a). Invasive aspergillosis is seenmore often in immunocompromised patients, associatedwith destructive inflammation of the sinonasaltissues [223]. The disease may also occur as an allergicmucinous sinusitis in which the sinuses contain massesof inspissated mucus with abundant eosinophils, Charcot-Leydencrystals (Fig. 2.3b), necrotic cell debris andscarce fungal hyphae (Fig. 2.3c) [137, 172]. The sinusmucosa shows inflammatory changes without fungalinvasion.b2.6.2 MucormycosisMucormycosis is caused by fungi of the class Zygomycetesand order Mucorales [73]. The most common speciescausing sinonasal infection are Rhizopus arrhizusand Rhizopus oryzae. In sections stained with PAS orGomori methanamine silver the fungi are seen as nonseptatehyphae measuring 10- to 20-m wide, usuallybranching at right angles. Infection is usually opportunisticand causes rapidly progressive disease in poorlycontrolled diabetics and immunocompromised patients.The fungus has a tendency to invade blood vessels causingthrombosis; the affected tissues may exhibit coagulativenecrosis and haemorrhage.cFig. 2.3. a Sinonasal aspergilloma: densely packed branching hyphaeof aspergillus forming a fungal ball. (Gomori’s methenaminesilver). b Sinonasal allergic mucinosis: dense aggregates of eosinophilicleukocytes distributed between pools of mucin. At the centre,one Charcot-Leyden crystal. c Allergic fungal sinusitis: scarcefungal hyphae found after diligent search in a lake of mucin (Gomori’smethenamine silver)2.6 Fungal Diseases2.6.1 AspergillosisAspergillosis is caused by Aspergillus fumigatus, Aspergillusniger and other species. In sections stained with2.6.3 RhinosporidiosisRhinosporidiosis is caused by the endosporulatingfungus Rhinosporidium seeberi. The lesions are polypoidand occur principally in the nasal cavity [21, 161].They are characterised by the presence of thick-walledsporangia measuring 50–350 m in diameter and containingnumerous mucicarminophilic spores. They areassociated with a heavy chronic inflammatory reactionwith occasional foci of suppuration and foreign body giantcell reaction.2.7 HIV-Related InfectionsSinonasal infections are frequently observed in HIV patients,are often asymptomatic and tend to be recurrentor refractory [281]. They are due to various pathogensincluding cytomegalovirus [164], Staphylococcus aureus,fungi (Aspergillus) [170] and parasites (Microsporidium,Cryptosporidium) [66].

Nasal Cavity and Paranasal Sinuses Chapter 2 452.8 Mid-Facial NecrotisingGranulomatous LesionsTuberculosis of head and neck occurs infrequently andinvolvement of the nose is rare, representing in mostcases a secondary event to pulmonary involvement[231]. In most cases there is a polyp of the nasal septumor an ulcerated granular lesion. Presence of intracranialextension may lead to a clinical diagnosis of malignancy[19]. Microscopically, there are caseating giant cellgranulomas in which acid-fast bacilli may occasionallybe identified. The definitive diagnosis is made by isolatingMycobacterium tuberculosis from tissue removedduring biopsy.2.8.1 Wegener’s GranulomatosisWegener’s granulomatosis is an immunologically mediatedinflammatory disease characterised by granulomatousvasculitis of the upper and lower respiratorytracts together with glomerulonephritis. Variable degreesof disseminated vasculitis involving both smallarteries and veins may also occur. The lesions in theupper respiratory tract are ulcerative and destructiveand occur mainly in the nasal cavity and paranasalsinuses. The hallmarks of Wegener’s granulomatosisare the presence of geographic necrosis surrounded bypalisaded histiocytes, granulomas and scattered giantcells, vasculitis with fibrinoid necrosis or infiltrationof vessel walls by inflammatory cells, neutrophilic microabscessesand a mixed inflammatory infiltrate withvariable fibrosis [57, 165]. Stains for acid fast bacilli andfungi are negative. There is no cytological atypia. Theclassic histological features of Wegener granulomatosisare not present in many biopsy specimens. Repeatbiopsies and clinical correlations are often essential forearly diagnosis. The disease may be restricted to theupper respiratory tract in the early stages. A high percentageof patients develop c-ANCA. More details areto be found in Chap. 3.2.8.2 Lepromatous LeprosyLepromatous leprosy is the most frequent form of thistype of disease involving the nasal cavity [101]. It ischaracterised by nodular masses of foamy macrophages(lepra cells) in which large numbers of acid fast bacilli(Mycobacterium leprae) are demonstrable by the modifiedZiehl-Neelsen method. Tuberculoid leprosy is characterisedby non-caseating granulomas and the indeterminatevariant by a non-specific chronic inflammatoryreaction; acid fast bacilli are seldom demonstrable inthese types.2.8.3 Tuberculosis2.8.4 SarcoidosisSarcoidosis is a chronic multisystem granulomatousdisorder that has a predilection for pulmonary and upperrespiratory tract mucosa. The sinonasal mucosais rarely involved, and most patients have generaliseddisease [143]. Discrete non-caseating granulomatacomposed predominantly of epithelioid histiocyteswith multinucleated giant cells and a peripheral rim oflymphocytes are present in the mucosa. Stains for acidfastbacilli are negative. The differential diagnosis includesother granulomatous disorders, like tuberculosis,leprosy, Wegener’s granulomatosis and cholesterolgranuloma [57].2.8.5 RhinoscleromaRhinoscleroma is caused by Klebsiella rhinoscleromatis[21], a capsulated gram-negative bacillus. Largenodular tumour-like masses are found in the nasalcavity and less often in other parts of the upper respiratorytract. They contain large macrophages withabundant clear or vacuolated cytoplasm (Mikuliczcells). The causative organism may be identified bythe Warthin-Starry staining method or by immunostainingfor the Klebsiella capsular antigen. Thereis heavy infiltration by chronic inflammatory cells,mainly plasma cells showing numerous Russell bodies.2.8.6 LeishmaniasisLeishmaniasis of the nasal region, when seen in Mediterraneancountries, is mostly in the form of an “orientalsore” caused by Leishmania tropica. In Central and SouthAmerica it is mostly seen in the form of mucocutaneousleishmaniasis caused by Leishmania braziliensis [153,197]. The protozoan parasite is seen in the cytoplasmof histiocytes or extracellularly, measures 1.5–3.0 m inits maximum dimension and has a nucleus and a rodshapedkinetoplast that stains positively with Giemsa.The kinetoplast is more readily identified in Giemsastainedsmears of exudates or scrapings than in paraffinsections. The lesions, commonly found in the nasal mucosaand facial skin, are associated with chronic inflammatoryreaction and granuloma formation. They are ingeneral circumscribed and self-involutive in the case ofthe “oriental sore” and markedly destructive in mucocutaneousleishmaniasis.

46 A. Cardesa · L. Alos · A. Franchi22.8.7 Cocaine AbuseCocaine abuse may be associated with severe nasalnecrotising inflammation [225]. Endoscopically, there isatrophy of the inferior and middle turbinates and ulcerationof the nasal septum. Histologically, areas of acuteand chronic inflammation are found; however, vasculitisis minimal or absent and granulomas may be present.The lesion may be confused with Wegener’s granulomatosis.2.8.8 Local Steroid InjectionsA granulomatous lesion of the nasal mucous membraneshas been observed in patients treated with injections ofsteroid preparations [272]. There is a central deposition ofamorphous material bordered by histiocytes and foreignbody giant cells. Occasional particles of birefringent crystallinematerial may be present. Special stains should beperformed to exclude the presence of micro-organisms.2.9 Benign Epithelial Neoplasms2.9.1 Sinonasal PapillomasSinonasal papillomas may be divided into squamous cellpapillomas of the nasal vestibule and schneiderian papillomasof the nasal cavity and paranasal sinuses [121].The first are covered by epithelium of the skin surface.The latter are lined by well-differentiated respiratoryepithelium (referred to as the schneiderian membrane)and comprise three histopathological types: exophytic,inverted and oncocytic. The histopathological featuresthat clearly differentiate between the three types of schneiderianpapillomas have been well documented [173].Human papilloma virus (HPV) types 6 and 11 are involvedin the pathogenesis of exophytic papillomas, butnot in the other two variants of schneiderian papillomas[35, 89, 128]. All oncocytic papillomas examined havebeen HPV-negative [35, 128, 221].2.9.1.1 Squamous Cell PapillomaICD-O:8052/0Squamous cell papillomas are located in the nasal vestibuleand are formed by keratinising stratified squamousepithelium of the skin surface [122]. They are exophyticand consist of a thickened layer of differentiated squamousepithelium, without evidence of atypia or mitoses,which is supported by arborescent stalks of fibrovascularstroma. Varying degrees of keratinisation are presentand either hyperkeratosis, parakeratosis or both may beseen. They are benign, rarely recur after simple excision.Its main differential diagnosis is the exophytic schneiderianpapilloma.2.9.1.2 Exophytic PapillomaICD-O:8121/0Exophytic papilloma, also known as “everted” or “fungiform”papilloma, is a single, warty tumour measuringup to 1.5 cm in diameter, arising most frequentlyat the nasal septum and only very rarely in the lateralnasal walls or in paranasal sinuses [122]. Males are predominantlyaffected. Patients tend to be younger thanwith other types of schneiderian papilloma. Exophyticpapillomas are almost always unilateral [54]. No side ispreferred and bilaterality is exceptional. The tumour iscomposed of branching papillary structures, with papillaecovered by stratified non-keratinising squamousepithelium, admixed with intermediate or transitionalcells and with ciliated respiratory epithelium that containsinterspersed mucin-secreting cells. Koilocytosisis not infrequently found in the squamous epithelium.Seromucinous glands are abundantly found when theunderlying submucosa is removed.The two main differential diagnoses are invertedpapilloma and oncocytic papilloma. Neither the invaginatedpattern of growth of inverted papillomas nor theoncocytic columnar epithelium of oncocytic papillomasare found in exophytic papillomas [173]. Cylindrical cellcarcinoma can be easily ruled out by the lack of atypiaand invasion. Wide surgical excision is the best choiceof treatment to avoid recurrences. Recurrences occur inabout 20–40% of cases, which is less than in invertedpapillomas. Malignant transformation almost never occursin exophytic papillomas.2.9.1.3 Inverted PapillomaICD-O:8121/0Inverted papilloma is the most common type of schneiderianpapilloma. This lesion occurs almost exclusivelyin the lateral wall of the nasal cavity and in the paranasalsinuses, although on rare occasions it may alsoarise on the nasal septum [226]. Grossly, they frequentlyhave a polypoid appearance, but they differ from nasalpolyps of the common type by their histological features.Inverted papillomas are composed of invaginatingcrypts, cords and nests covered by non-keratinisingsquamous epithelium, which alternates with columnarciliated respiratory epithelium and with intermediate ortransitional epithelium (Fig. 2.4a). This newly formedduct system is similar to the embryonic developmentof the nasal mucosa [240]. The multilayered epitheliumtypically contains mucous cells and mucin-filled micro-

Nasal Cavity and Paranasal Sinuses Chapter 2 47cysts. The invagination of the mucosa may result in thepresence of apparently discontinuous cell masses lyingdeep to the epithelial surface, but the basement membraneis intact and may be shown in continuity with thatof the surface epithelium [226]. An inverted growth isthe hallmark of inverted papilloma, but varying degreesof papillary growth may be seen at the surface [54]. Thesurface is characteristically lined by a respiratory typeof epithelium; nevertheless, foci of surface keratinisationare occasionally present [122]. A few regular mitosesmay be found in the basal and parabasal layers. Althoughthe nuclei may show mild nuclear irregularitiesand hyperchromatism, no disturbances of the cellularpolarity are found. An abundant and oedematous connectivetissue stroma is a common feature of invertedpapillomas. It usually contains macrophages and neutrophils,but eosinophils may also be present. This inflammatoryinfiltrate may also be present between theepithelial cells, within the dilated lumens of invaginatedcrypts, and within the numerous microcysts that usuallyoccur in the respiratory epithelium. Seromucinousglands are absent, but branching gland ducts are oftenpresent. The tumour grows by extension to involve thecontiguous sinonasal epithelium.If treated only by local surgical excision, recurrenceoccurs in up 75% of cases. Therefore, lateral rhinotomyand medial maxillectomy are advisable for tumours ofthe lateral nasal wall [236]. Carcinoma develops in about10–15% of inverted papillomas [122, 211, 236]. Carcinomamay coexist with inverted papilloma at the initialpresentation or originate subsequently [122, 273].According to the experience of Michaels and Hellquist[171], carcinoma does not usually develop in the courseof recurrences of inverted papilloma. In the presenceof severe atypia or marked keratinisation in an invertedpapilloma malignant transformation is always suspected(Fig. 2.4b). In these instances the entire specimenshould be thoroughly examined to exclude an associatedcarcinoma. Most associated carcinomas are squamous[204], although other types may also occur such asverrucous carcinoma [192].2.9.1.4 Oncocytic PapillomaabFig. 2.4. a Inverted papilloma: prominent invaginating cryptslined by hyperplastic respiratory epithelium are supported by oedematousconnective tissue. b Squamous cell carcinoma ex invertedpapilloma: remnants of benign invaginating crypts are seen betweeninvasive cords of squamous epitheliumICD-O:8121/1Oncocytic papilloma, also known as “columnar” or “cylindric”cell papilloma [226], is the least common type ofschneiderian papilloma. It constitutes less than 5% of allsinonasal papillomas [18, 122, 173, 262]. Both sexes areequally affected. Bilaterality has not been documented.Tumours are in general small, although occasionally mayreach various centimetre measurements in their greatestdimension. They are composed of exophytic frondsand endophytic invaginations lined by pseudostratifiedor multilayered columnar cells with prominent oncocyticfeatures. The cells have uniform hyperchromaticnuclei and abundant eosinophilic, occasionally granular,cytoplasm that contains abundant mitochondriaand stains for the mitochondrial enzyme cytochromeC oxidase [59]. Goblet cells are not found. Cilia may beoccasionally encountered on the superficial epitheliallayer. Intraepithelial microcysts containing mucin andneutrophils are usually present. These microcysts arelarger than the similar structures also seen in invertedpapilloma. The tumour resembles inverted papilloma inits sites of occurrence, the lateral wall of the nasal cavityand the maxillary antrum. The rate of recurrence isconsidered to be 36%, which is lower than in invertedpapilloma. The low frequency of this tumour makes itdifficult to evaluate its true malignant potential, whichseems to be similar to that of inverted papilloma [262].Atypical hyperplasia and carcinoma in situ changescan be occasionally found (Fig. 2.5). Surgical excisionwith wide margins is the treatment of choice. Invasivesquamous cell carcinoma, high-grade mucoepidermoid

48 A. Cardesa · L. Alos · A. Franchi2carcinoma and undifferentiated carcinoma have beenreported in association with oncocytic papilloma [18,122, 135, 265, 274].2.9.2 Salivary-Type AdenomasPleomorphic adenoma is the most frequent benign glandulartumour of the sinonasal region. Most arise on thenasal septum and the rest on the lateral nasal wall orturbinates. Origin in the maxillary antrum is rare. Therecurrence rate of sinonasal pleomorphic adenoma ismuch lower than for its counterpart in the major salivaryglands [56, 109]. Rare examples of sinonasal oncocytoma,myoepithelioma and basal cell adenoma havebeen reported [27, 55, 103, 277], as well as one case ofsinonasal myoepithelioma transformed into myoepithelialcarcinoma after various recurrences [9].2.9.3 Pituitary AdenomasThe rare pituitary adenomas of the sinonasal region arein most instances extensions from intrasellar tumours.Very unusually, they arise from ectopic pituitary tissueas tumours from the sphenoid sinus or the nasal cavity.Histologically, they are similar to tumours within thesella [61, 151].2.10 Benign SinonasalSoft Tissue Neoplasms2.10.1 HaemangiomasHaemangiomas of the upper respiratory tract may be ofthe capillary, cavernous or venous types [90]. The mostcommon type is the capillary haemangioma whichconsists of lobules of blood-filled capillaries separatedby loose connective tissue. The lesion should be distinguishedfrom granulation tissue and from the vascularectasias found in Rendu-Weber-Osler disease.2.10.2 Haemangiopericytoma(Glomangiopericytoma)ICD-O:9150/1Haemangiopericytoma is characterised by the proliferationof oval, polyhedral or spindle-shaped cells enmeshedby collagen type IV fibres and arranged around vascularchannels that are lined by a single layer of endothelialcells. The tumour contains numerous thin-walled bloodvessels and the tumour cells, typically arranged aroundthe blood vessels, are of uniform size with regular ovalFig. 2.5. Oncocytic papilloma with atypical cells: papillary stalkscovered by columnar cells with frequent atypical nuclei and oncocyticcytoplasm-forming microcystsor elongated nuclei and pale cytoplasm (Fig. 2.6). Thecells may also be arranged in short, haphazard fasciclesor in sheets of closely packed cells containing compressedcapillaries. Areas of poor cellularity, myxoid change andfibrosis are not uncommon. The tumour cells are entirelysituated outside the capillaries, which are lined by a singlelayer or normal-looking endothelium. This feature, wellshown by reticulin staining or by anti-collagen IV antibodies,helps to distinguish the tumour from angiosarcoma.The distinction from other well-vascularised mesenchymaltumours is usually made by exclusion. Haemangiopericytomasof the nasal cavity are generally lessaggressive than those occurring elsewhere. They exhibit amore orderly structure with minimal mitotic activity, buttend to recur after removal and may rarely metastasise[249]. Muscle-specific actin is focally positive in tumourcells. The term glomangiopericytoma has been recentlyproposed for this entity [267a].2.10.3 Solitary Fibrous TumourICD-O:8815/0Solitary fibrous tumour of the nose, paranasal sinusesand nasopharynx is in most instances a benign fibroblasticproliferation with variable cellularity and vascularity(Fig. 2.7) having features identical to those ofsolitary fibrous tumour of the pleura [8, 168, 279]. Itsmain differential diagnoses are sinonasal haemangiopericytomaand nasopharyngeal angiofibroma.2.10.4 Desmoid FibromatosisICD-O:8821/1Desmoid fibromatoses are a group of non-metastasisingunencapsulated fibrous tissue proliferations that have a

Nasal Cavity and Paranasal Sinuses Chapter 2 49tendency towards local invasion and recurrence, whichrarely arise in the sinonasal mucosa [96]. They compriseinterlacing fascicles of bland spindle-shaped fibroblasts,in a collagenous or myxoid background. The main differentialdiagnoses are fibrosarcoma and reactive fibrosis.Desmoid fibromatosis of the sinonasal tract showslower recurrence rates than desmoid fibromatoses arisingin other locations.2.10.5 Fibrous HistiocytomaICD-O:8830/0Benign fibrous histiocytoma presents as a yellow-tan noduleor polyp, most commonly causing nasal obstruction orbleeding [201]. It is composed of spindle-shaped cells producinga storiform pattern admixed with histiocytic cellsand multinucleated giant cells. Distinction from other benignsinonasal spindle cell proliferations is largely basedon the immunohistochemical findings. Benign fibroushistiocytomas may recur if incompletely excised.Fig. 2.6. Haemangiopericytoma: interconnected thin-walledblood vessels surrounded by uniform spindle-shaped cells withoval or elongated nuclei2.10.6 LeiomyomaICD-O:8890/0Sinonasal leiomyoma is a rare tumour occurring inadults, preferentially involving the nasal cavities, withnon-specific symptoms of nasal obstruction [91]. Itsmorphologic and immunohistochemical profile is identicalto that of leiomyomas of other sites. It has been postulatedthat they may originate from blood vessel walls.Distinction from sinonasal leiomyosarcoma is basedon the absence of atypia and mitoses. Huang and Antonescuhave proposed separating a category of smoothmuscle tumours of uncertain malignant potential, characterisedby the presence of 1–4 mitotic figures/10 highpower fields, that tend to pursue a more aggressive behaviourthan leiomyomas [119].2.10.7 Schwannoma and NeurofibromaICD-O:9560/0, 9540/0About 4% of schwannomas of the head and neck regionarise in the sinonasal tract [202]. They usually presentas polypoid lesions involving the nasal cavity and/ora paranasal sinus, with non-specific symptoms of obstruction,compression, or extension in the surroundingstructures [202]. Histologically, the tumour is composedof elongated wavy-shaped monomorphic spindle cells,with eosinophilic cytoplasm and oval nucleus. Antonitype A and type B areas usually coexist within the lesion,and nuclear palisading may be present. Focal degenerativenuclear atypia has been described [108], whilemitotic activity is absent to low. A consistently reportedFig. 2.7. Solitary fibrous tumour: fibroblastic proliferation, collagenproduction and dilated blood vessels. Identical features to thepleural counterpartfeature of sinonasal schwannomas is the lack of tumourencapsulation that determines an apparently infiltrativegrowth pattern [36, 108]. Immunohistochemically,sinonasal schwannoma is intensely reactive for S-100protein [108]. The differential diagnosis includes otherspindle cell lesions of the sinonasal mucosa, like juvenileangiofibroma, solitary fibrous tumour and leiomyoma.Particular care should be taken when evaluating cellularschwannomas with a predominance of Antoni typeA areas, which should not be confused with malignantspindle cell neoplasms, like fibrosarcoma, leiomyosarcoma,malignant peripheral nerve sheath tumour, andspindle cell melanoma.Neurofibromas of the sinonasal mucosa are usuallynot associated with the Von Recklinghausen syndrome,and appear as unencapsulated lesions composed of a mixtureof Schwann cells and fibroblasts embedded in a predominantlymyxoid stroma [117, 202]. Due to the overlappingof the histologic features, it may be difficult to differ-

50 A. Cardesa · L. Alos · A. Franchisinuses. Histologically, they are similar to paragangliomaselsewhere [12, 98, 187].22.10.10 Juvenile AngiofibromaabFig. 2.8. Juvenile angiofibroma. a Polypoid mass of white-redcut surface and rubbery consistency. b Vascular elements embeddedin fibrous tissue showing intravascular microembolisation, atreatment modality prior to surgeryentiate neurofibromas from schwannomas of the sinonasalmucosa. Neurofibromas should also be distinguishedfrom myxomas, which are S-100 protein-negative.2.10.8 MeningiomaICD-O:9530/0Meningiomas of the sinonasal tract may extend directlyfrom the central nervous system or arise from ectopicextracranial tissue. Although always rare, they are morecommonly seen in the orbit, ear and skin of the head andneck than in the sinonasal tract. Histologically, they aresimilar to meningiomas elsewhere, the meningothelialtype being the most frequent. Sinonasal meningiomastend to occur in younger patients than intracranial meningiomas[118, 203].2.10.9 ParagangliomaICD-O:8680/1There are few reports on nasal paragangliomas. The tumoursoriginate in the middle turbinates and ethmoidICD-O:9160/0Juvenile nasopharyngeal angiofibroma arises in theconfluence of the posterolateral nasal wall and thelateral nasopharynx and occurs almost exclusively inmales during adolescence [90, 125]. The tumour is sessileor polypoid (Fig. 2.8a) and is histologically benign,but has a tendency to recur and is locally destructive,causing pressure necrosis of adjacent soft tissue andbone. It may occasionally extend into paranasal sinuses,orbit and cranial fossae. It is composed of vascular andfibrous elements in varying proportions. The vessels inthe superficial portions of the tumour are mainly gapingcapillaries that may become compressed with increasingstromal fibrosis. Thick-walled vessels withoutelastic membranes and with irregular, incomplete orabsent muscle coats and focal intimal thickenings areusually present in the deeper portions of the tumour.These vessels resemble those normally seen in the submucosaof the nasal conchae. The vascular elements areembedded in fibrous tissue, which varies in cellularityand collagenisation. Stellate fibroblast-like cells are oftenpresent close to the blood vessels. The fibroblasticcells of nasopharyngeal angiofibroma are stronglypositive for testosterone receptors [120]. Ultrastructurally,the nuclei of angiofibroma contain characteristicdense granules [251]. Occasionally, the fibroblasts mayexhibit cytologic atypia, and some of these cells maybe multinucleated, but mitosis is rare. Mast cells maybe numerous. There may be focal thrombosis, haemorrhageand chronic inflammatory reaction. With theadvent of preoperative selective embolisation, iatrogenicemboli (Fig. 2.8b) are increasingly encounteredin resected specimens [232]. For more details on thistumour see Chap. 6.2.11 Malignant Sinonasal TumoursMalignant sinonasal tumours represent less than 1% ofall cancers seen in humans and about 3% of all malignanciesof the head and neck region [160]. Despite thelow rate of malignancy arising in the sinonasal tract, agreat variety of histological types of tumours may befound [216, 226]. The use of electron microscopy andmore recent advances in immunohistochemistry andmolecular biology have made it possible to refine thecriteria for their correct recognition.Geographical differences in the relative frequencyof certain histological types of malignant sinonasaltumours may be related to variations in the exposure

Nasal Cavity and Paranasal Sinuses Chapter 2 51Table 2.1. Malignant sinonasal tumours at the Hospital Clinic, University of Barcelona Medical SchoolHistologicaltype of tumourFrequencyn %Menn %Womenn %MeanageAgerangeSquamous cell carcinomaUndifferentiated carcinomaCylindrical cell carcinomaMalignant lymphomaMalignant melanomaHigh-grade adenocarcinomaAdenoid cystic carcinomaLow-grade adenocarcinomaOlfactory neuroblastomaMucoepidermoid carcinomaMalignant fibrous histiocytomaPlasmacytomaRhabdomyosarcomaMalignant schwannomaAdenosquamous carcinomaMyoepithelial carcinomaKaposi’s sarcomaTeratocarcinosarcomaEwing’s sarcoma (PNET)54261919141311107444432221127139.59.57755322221.51110.50.538191515710743333212221–7073797950776440437575755033100100100100–167447346411122––––13027212150233660572525255067––––1006460595969595864365556513057664737762339–8741–8726–849–8956–8916–8122–6928–922–6750–6135–6550–658–5127–7061–7129–6634–40––Total 200 100 137 69 63 31 58 2–92to environmental carcinogens (see epidemiological aspectsSect. 11.1.1). In Table 2.1 the histological types ofmalignant sinonasal tumours diagnosed at the HospitalClinic of the University of Barcelona are presentedin decreasing order of frequency. The most frequenthistological types are: keratinising squamous cell carcinoma,undifferentiated carcinoma, cylindrical cellcarcinoma, malignant lymphoma, malignant melanoma,intestinal-type adenocarcinoma, adenoid cysticcarcinoma, low-grade adenocarcinomas and olfactoryneuroblastoma.A practical way to start classifying malignant sinonasaltumours is to separate them initially into large andsmall cell categories. Among the large cell malignant tumoursthe most common types are: squamous cell carcinoma,cylindrical cell carcinoma, malignant melanoma,intestinal-type adenocarcinoma, and low-grade adenocarcinomas.To the most common small cell tumoursbelong the sinonasal undifferentiated carcinoma, malignantlymphoma, adenoid cystic carcinoma and olfactoryneuroblastoma. Large cell tumours account for approximately75% of the malignant sinonasal tumours and thesmall cell tumours for the remaining 25% [41].For staging of malignant sinonasal tumours the TNMclassification of 2002 and the TNM atlas of 2004 are recommended,since nasal cavity tumours are now included[237, 271a].2.11.1 Keratinising SquamousCell CarcinomaICD-O:8071/3At the nasal vestibule, keratinising squamous cell carcinomais the most common malignancy [130, 167, 245].Due to early recognition and easy access to treatment,they usually have a more favourable prognosis than theircounterpart of the sinonasal region.Sinonasal keratinising squamous cell carcinomarepresents up to 45–50% of the malignant tumours ofthis region in several series [93, 259]. At the HospitalClinic of the University of Barcelona, where non-keratinisingsquamous cell carcinomas (see Sect. 2.11.2on cylindrical cell carcinomas) are grouped separatelyfrom keratinising squamous cell carcinomas, the latteraccount for only 27% of the sinonasal malignancies.They predominate in males and the great majority areseen in patients aged over 50 years. The maxillary antrum,the lateral nasal wall and the sphenoidal sinusesare the most common sites, whereas the frontal andsphenoid sinuses are rarely involved. These tumoursgrow by local extension, infiltrating the neighbouringstructures, but lymph node metastases are rare [215].For neoplasms circumscribed to the nasal cavity the5-year survival is slightly above 50% [30], whereas inneoplasms of the maxillary antrum the 5-year survivalmay be as low as 25% [146].

52 A. Cardesa · L. Alos · A. Franchi2The occupational epidemiology of sinonasal squamouscell carcinoma has been strongly related to exposureto nickel [141, 243, 252, 253] and to a lesser extentto chromium, isopropyl alcohol and radium [218]. As inother territories of the respiratory tract, a definite associationbetween sinonasal squamous cell carcinoma and cigarettesmoking has been documented [26, 146]. Chronicsinonasal inflammation is considered a predisposingfactor. A case of carcinoma of the maxillary antrum afterthorotrast exposure has been reported [97]. Nitrosaminesand to a lesser extent formaldehyde are strong nasal carcinogensin laboratory rodents [44, 155].Keratinising squamous cell carcinomas originate inthe respiratory sinonasal mucosa from areas of pre-existingsquamous metaplasia and manifest the same rangeof histological appearances as those arising in other sites.They are characterised by the proliferation of malignantepithelial cells with squamous differentiation and intercellularbridges. Malignancy is graded according tothe degree of differentiation, cellular pleomorphism andmitotic activity. They are divided into well-differentiated,moderately differentiated and poorly differentiatedforms. Well-differentiated carcinomas are uncommonin this territory and when encountered need to be differentiatedfrom pseudoepitheliomatous types of hyperplasiaand from verrucous carcinoma. Most conventionalkeratinising squamous cell carcinomas of the sinonasaltract present as moderately or poorly differentiatedtumours. Special types, such as verrucous carcinoma[104], spindle cell carcinoma [205, 276], basaloid-squamouscell carcinoma [16, 269] and adenosquamous carcinoma[10, 94] are occasionally found in the sinonasaltract. Regional lymph node involvement is seen in about17% of sinonasal squamous cell carcinomas and distantmetastases in about 1.5% [215].2.11.2 Cylindrical Cell CarcinomaICD-O:8121/3Cylindrical cell carcinoma, also known as non-keratinisingsquamous cell carcinoma, transitional cell carcinomaor schneiderian carcinoma, is a tumour composed of malignantproliferating cells derived from sinonasal respiratory(schneiderian) epithelium. The name cylindrical cellcarcinoma was first coined by Ringertz in 1938 [212] andrecommended as the preferred term by Shanmugaratnamin the WHO classification of 1991 [226].Grossly, the tumours grow in most cases as exophyticmasses showing either a corrugated or a smooth surface.They may arise from the antrum, the lateral nasalwall or the ethmoid, the maxillary antrum beingthe most frequent site [193, 194]. They may occur concomitantlywith other non-neoplastic polypoid formations.Microscopically, cylindrical cell carcinoma iscomposed of papillary fronds (Fig. 2.9a), thick ribbonsand polystratified masses of cells that give rise quiteoften to invaginations of the surface epithelium, whichat low magnification may mimic inverted papilloma.The tumour cells are commonly cylindrical and havea tendency to form palisade arrangements perpendicularto the underlying basement membrane (Fig. 2.9b).The nuclei are atypical and show increased mitotic activity,as well as abnormal mitotic figures. The patternof invasion is usually expansive, being characterised bypushing margins with focal infiltration of the stroma.The basement membrane remains in most cases conspicuous,despite stromal infiltration, which shouldnot be regarded as carcinoma in situ. Foci of squamousmetaplasia, with transition from cylindrical to squamousepithelium, are not uncommon and when extensivethese tumours may be indistinguishable fromsquamous cell carcinoma. This resulted in denominationssuch as “transitional cell carcinoma” and “nonkeratinisingsquamous cell carcinoma”, which may beconfusing. The first because the term transitional hasalso been applied to carcinomas of the lymphoepithelialtype, and the second due to the fact that tumours called“non-keratinising squamous cell carcinoma” also havefoci of keratinisation [267a]. In addition, the term cylindricalcell carcinoma should be preferred to non-keratinisingsquamous cell carcinoma because “pure” cylindricalcell carcinomas, without any squamous cellcomponent, carry a better prognosis than conventionalsquamous cell carcinomas [84]. Very recent observationssuggest a strong etiologic relationship of cylindricalcell carcinoma to high-risk human papillomavirus[69a]. A high proportion of these tumours showmarked immunoreactivity for p16.More aggressive types of carcinoma, such as sinonasalundifferentiated carcinoma (SNUC) or high-gradeadenocarcinoma, may appear occasionally intermingledwith cylindrical cell carcinoma [226]. Two cases of cylindricalcell carcinoma with endodermal sinus-like featureshave been reported [162]. A full examination of theresected specimen is therefore mandatory before labellinga tumour a “pure cylindrical cell carcinoma”.The two main differential diagnoses of cylindricalcell carcinoma are the schneiderian papillomas of theinverted and oncocytic types, especially when they haveconcomitant carcinomatous changes. Both types of papillomalack the atypical cellularity constantly seen in cylindricalcell carcinoma. When schneiderian papillomascoexist with cylindrical cell carcinomas, or with othertypes of carcinoma, the two components usually appeardemarcated from one another although in contiguity.When the invaginating crypts of an inverted papillomaare filled with the cords and ribbons of a keratinisingor non-keratinising squamous cell carcinoma, the lesionrepresents a conventional squamous cell carcinomaarising in an inverted papilloma, which implies a worseprognosis than that of cylindrical cell carcinoma.

Nasal Cavity and Paranasal Sinuses Chapter 2 53abFig. 2.9. Cylindrical cell carcinoma. a Papillary structures coveredby malignant cells with cylindrical cytoplasm and basal nucleiarranged in palisades. b Marked immunoreactivity of the epithelialneoplastic cells for p16, which is related to high-risk HPV2.11.3 Sinonasal UndifferentiatedCarcinomaICD-O:8020/3Sinonasal undifferentiated carcinoma (SNUC) is definedas a high-grade malignant epithelial neoplasm of the nasalcavity and paranasal sinuses, composed of small tomedium-sized cells, lacking evidence of squamous orglandular differentiation and of rosette formation [48,86, 114]. Cigarette smoking [86] and nickel exposure[252] have been associated with SNUC. Epstein-Barr virus(EBV) and the deletion of the retinoblastoma genehave been ruled out as factors involved in the developmentof this tumour [127]. Ionising radiation is anotheraetiologic factor, as radiotherapy either for retinoblastomaor for nasopharyngeal carcinoma has been associatedwith SNUC [127].Sinonasal undifferentiated carcinoma occurs inboth sexes over a wide age range, with a median in the6th decade of life. It commonly originates from theethmoidal region as a large fungating mass. Grossly,the tumours are quite frequently extensive lesions,obstructing the nasal cavity either unilaterallyor bilaterally and invading the adjacent sinonasalstructures (Fig. 2.10a), as well as the orbit, skullbase and the brain. Microscopically, SNUC is composedof small to medium-sized, undifferentiatedcells, which arise via dysplastic changes from the basalcells of the surface epithelium. The cells are polygonalwith distinct borders, showing round to oval, hyperchromaticor vesicular nuclei, with either inconspicuousor slightly prominent nucleoli, surroundedby a moderate amount of either amphophilic or eosinophiliccytoplasm (Fig. 2.10b). Mitotic figures arecommon. The tumour forms nests, cords and sheetsof cells that show frequent areas of central necrosisand tendency to vascular (Fig. 2.10c) and perineuralinvasion. Ultrastructural studies demonstrate poorlyformed desmosomes in quite a number of cells, whilethe presence of tiny bundles of tonofilaments is veryrare. Neurosecretory granules are very rarely found.SNUC are immunoreactive with epithelial markers,such as CAM 5.2 and epithelial membrane antigen(EMA). Variable reactivity can be seen with neuronspecificenolase (NSE), whereas there is negative reactivityfor synaptophysin, chromogranin and otherneuroendocrine markers. SNUC are also negative forEBV [48, 127].The two main differential diagnoses of SNUC aresmall cell (neuroendocrine) carcinoma (SCC) andhigh-grade olfactory neuroblastoma (ONB). All threeentities may share some clinical and light microscopicfeatures. However, SNUC and SCC show a markedimmunoreactivity for cytokeratins that is not seen inONB, and SNUC lacks the neuroendocrine immunoreactivityseen in SCC and ONB. Most lesions categorisedin the past as grade IV ONB are now consideredto be either SNUC or SCC. This is important becauseSNUC and SCC have a worse prognosis than ONB. Inaddition, SNUC needs to be distinguished from otherprimary sinonasal tumours, such as solid adenoid cysticcarcinoma, microcytic malignant melanoma, cylindricalcell carcinoma, primary sinonasal nasopharyngeal-typeundifferentiated carcinoma, lymphoma andothers (Table 2.2).Sinonasal undifferentiated carcinomas are very aggressivetumours. In most instances, the tumour is solarge and the infiltration is so extensive that completesurgical resection cannot be achieved. Radiotherapyand chemotherapy are additional options, either singleor combined. High-dose chemotherapy and autologousbone marrow transplantation have been consideredas a form of treatment [241]. Prognosis of SNUCis dismal, with a median survival of 4 months to 1 year[86, 114]. In our experience survival after 2 years is lessthan 40%.

54 A. Cardesa · L. Alos · A. Franchi2abrequired for diagnosis [176]. Before placing a tumourwithin this category, a differential diagnosis of a primarytumour from the lung must be ruled out.This type of tumour has been well documented invarious head and neck territories, mainly in the parotidgland and in the larynx. In the sinonasal tract, wherethey are distinctly uncommon, small cell neuroendocrinecarcinomas have been less precisely characterised,and so far no unanimous consensus has been reachedwith regard to the way they have to be separated fromother small cell tumours, either round or undifferentiated,occurring in this region [51, 132, 151, 191, 208, 210,229, 264]. Table 2.2 provides the current criteria mostwidely accepted for their recognition.Small cell neuroendocrine carcinoma of the sinonasalregion is considered to derive from cells with neuroendocrinedifferentiation occasionally found in the seromucousglands. In some cases the tumour grows surroundingthe seromucous glands of the lamina propria,as if it were originating from them. They give rise tonests, cords and sheets of small, undifferentiated cells,with moulded nuclei and scanty cytoplasm. Immunohistochemistryexhibits a positive reaction for low molecularweight cytokeratins and EMA, as well as variablepositivity for neuron-specific enolase, Leu-7, CD56, synaptophysinand chromogranin. At least two neuroendocrinemarkers should demonstrate positivity [199]. Diligentsearching and expert hands usually demonstrateneurosecretory granules by electron microscopy.Although its prognosis seems to be somewhat betterthan that of SNUC, or for similar tumours of the lung,small cell neuroendocrine carcinoma is a high-grademalignancy. Treatment should be a combination of surgeryand radiotherapy, plus chemotherapy.cFig. 2.10. Sinonasal undifferentiated carcinoma (SNUC) a Extensiveneoplastic growth invading ethmoid, orbit and sphenoid atthe left and also the right ethmoid. Courtesy of Prof. J. Traserra,Barcelona, Spain. b Nests of small to intermediate epithelial cellsshowing markedly atypical nuclei and areas of necrosis. c Frequentfoci of intra-vascular invasion2.11.4 Small Cell (Neuroendocrine)CarcinomaICD-O:8041/3This is a high-grade malignant epithelial tumour withhistological features similar to small cell carcinoma ofthe lung [226]. Variable degrees of neuroendocrine differentiationmay be demonstrable by electron microscopyor immunohistochemistry, but have not always been2.11.5 Primary SinonasalNasopharyngeal-TypeUndifferentiated CarcinomaICD-O:8082/3Although nasopharyngeal carcinoma (NPC), alsoknown as lymphoepithelioma, almost invariably arisesin the nasopharynx, “bona fide” primary sinonasal nasopharyngeal-typeundifferentiated carcinomas (PSN-PC) have recently been reported [127]. Due to the undifferentiatedappearance of cells in NPC and PSNPC,these tumours may be lumped together with SNUC ifunaware of their differences [48, 80, 127]. SNUC doesnot arise in the nasopharynx, but bulky lesions mayextend into this region. Also, NPC may extend fromthe nasopharynx into the sinonasal region. The distinctionbetween these tumours can generally be madeon purely histological grounds, since SNUC lacks thelymphoplasmacytic cell infiltrate seen in most casesof NPC and PSNPC. Immunohistochemistry and in

Nasal Cavity and Paranasal Sinuses Chapter 2 55Table 2.2. Sinonasal undifferentiated tumors. Immunohistochemistry and genetics.CK NSE S-100 CG SYN NF EBV L MIC-2 t11;22AmplN-mycSNUC + ± – – – – – – – – –SCC + + – ± + – – – – – –PSNPC + – – – – – + – – – –SNML – – – – – – + + – – –PNET – + + ± + – – – + + –ONB – + (+) + + + – – – – –MNB – + – + + + – – – – +SNUC sinonasal undifferentiated carcinoma, SCC small cell (neuroendocrine) carcinoma, PSNPC primary sinonasal nasopharyngealtypecarcinoma, SNML sinonasal malignant lymphoma, PNET primitive neuroectodermal tumour, ONB olfactory neuroblastoma,MNB metastatic neuroblastoma, CK cytokeratin, NSE neuronal specific enolase, S-100 Protein S-100, CG chromogranin, SYN synaptophysin,NF neurofilaments, EBV Epstein-Barr virus, L lymphoma markers, MIC-2 CD99, t(11;22) EWS-FLI1, Ampl amplification, (+)positive only in sustentacular cellssitu hybridisation are of great help in difficult cases.All three, NPC, PSNPC, and SNUC, react positively forlow molecular weight cytokeratins and EMA. In contrast,NPC and PSNPC are positive for EBV, whereasSNUC is negative. Until very recently, confusion ofNPC and PSNPC with SNUC has led to the belief thatsome SNUC were related to EBV. The sharp distinctionof these entities is crucial because NPC and PSNPChave a better prognosis and are more responsive to radiationtherapy than SNUC.2.11.6 Malignant MelanomaICD-O:8720/3Sinonasal melanomas represent between 0.5 and 1.5% ofall melanomas [25, 82, 157] and between 3 and 20% ofsinonasal malignant neoplasms [25, 74]. They most frequentlydevelop after the fifth decade of life [25, 42, 250]and seem to originate from melanocytes present in themucosa of the respiratory tract [25, 58, 275]. In our experience,it is not uncommon to see melanomas arising in anarea of squamous metaplasia . In contrast to Caucasians,black Africans often show visible pigmentation at sitescorresponding with the common locations of intranasalmelanomas, of which they have a higher incidence [148].Although there is not a significant sex predilection, menseem to be affected more than women [25, 29, 42]. Thesigns and symptoms of presentation of sinonasal melanomasare not specific. Epistaxis and nasal obstruction arefrequent when located in the nasal cavity.Grossly sinonasal malignant melanomas are eitherpigmented (black-brown) or non-pigmented (pink-tan)lesions. In the nasal cavity, they commonly arise in theanterior portion (Fig. 2.11a) of the septum and presentas tan-brown polypoid formations, with occasional ulceratedand hemorrhagic areas. When arising withinsinuses, they present as extensive and widely infiltrativetumours. The development of an intranasal malignantmelanoma in an inverted papilloma has been reported[99].The histological features of sinonasal melanomasmay be as polymorphic as in their cutaneous counterpart.Metastatic disease needs to be ruled out, beforethey are labelled as primary tumours. Primary melanomasmay be recognised by the presence of junctionalactivity (Fig. 2.11c) or by the finding of an intraepithelialcomponent in the adjacent mucosa; nevertheless,these features are usually lost in advanced stages of thedisease. Histologically, melanomas are composed of mediumto large cells that may be polyhedral, round, fusiform(Fig. 2.11b), pleomorphic, microcytic, or a mixtureof them. Usually, they have finely granular cytoplasmand nuclei with one or more eosinophilic nucleoli. Mitoticactivity is prominent. A rare balloon cell variantwith clear cytoplasm may mimic various types of clearcell tumours (see Chap. 5). Osteocartilaginous differentiationhas also been observed [244]. The cells of sinonasalmelanoma grow in solid, loosely cohesive, storiform,pseudo-alveolar or organoid patterns [25]. Two-thirdsof sinonasal melanomas contain some intracytoplasmicbrown pigment (Fig. 2.11d) [25], which has to be confirmedas melanin by Masson-Fontana or Grimelius silverstains. However, in the sinonasal tract non-pigmentedmelanomas are not uncommon; in our Barcelona seriesup to 40% of the sinonasal melanomas are amelanotic.When melanin is scarce or is not found, diagnosismay be difficult, and special techniques are mandatory.Immunohistochemically, the cells of amelanotic melanomasare negative for cytokeratin and positive for vimentin,S-100 protein and HMB-45 [65, 82, 209], as well asanti-tyrosinase and other newly reported markers [207].Electron microscopy reveals the presence of pre-melanosomesand/or melanosomes.

56 A. Cardesa · L. Alos · A. Franchi2abcdFig. 2.11. Sinonasal malignant melanoma. a Darkly pigmentedpolypoid lesion of the anterior nasal cavity in contiguity with apigmented lesion of nasal skin. Courtesy of Prof. J. Traserra, Barcelona,Spain. b Spindle cell non-pigmented malignant melanocyteswith storiform pattern. c Nests of non-pigmented, invasivemalignant melanocytes arising from metaplastic squamous epitheliumshowing junctional activity. d Pigmented malignant melanocytesunderneath ciliated respiratory epitheliumThe differential diagnosis of amelanotic malignantmelanoma of the sinonasal tract comprises a long list ofentities. Epithelioid melanomas mainly have to be distinguishedfrom non-keratinising squamous cell carcinomas,but also from other large cell carcinomas aswell as from epithelioid malignant schwannomas [76]and from metastases. Microcytic melanoma may mimicSNUC and other small round cell tumours (Table 2.2).Spindle-cell melanoma may be mistaken for a variety ofspindle-cell sarcomas (see Sects. 2.11.13 to 2.11.17).The prognosis and management is related to the peculiarbiology of the tumour. The prognostic significanceof the level of local invasion, as established for cutaneousmelanomas, does not apply to mucosal melanomas becauseof the absence of histological landmarks analogousto the papillary and reticular dermis; nevertheless, inva-

Nasal Cavity and Paranasal Sinuses Chapter 2 57sion deeper than 0.5 mm is associated with decreased survival[25].Although many of the patients do not show initiallymph node involvement or disseminated metastases [25,83, 107] and have stage I disease at the time of initial diagnosis,the prognosis is bad due to a high recurrence rate[250]. This recurrence appears to be related to the multicentricityof the tumours and to the anatomic characteristicsof the region that preclude adequate resection, whichis the treatment of choice [29, 256]. The utility of radiotherapyis controversial, but it can be of use in unresectablecases or to control recurrences [29, 95]. Immunotherapyand chemotherapy are also used for metastatic disease[256]. Five-year survival of sinonasal melanoma is reportedlyunder 35% [29, 250, 256]. The mean survival has notimproved during the past 15 years [32]. In our Barcelonaseries, the 5-year survival rate of 35% is similar to thatof sinonasal squamous cell carcinoma. Patients with primarynasal melanomas had a significantly better 5-yearsurvival rate than patients with melanomas from otherhead and neck sites [154].2.11.7 Olfactory NeuroblastomaICD-O:9522/3Olfactory neuroblastoma (ONB) is defined as a malignanttumour composed of neuroblasts derived from theolfactory membrane [14, 175, 246, 257]. Synonyms includeearly terminology such as esthesioneuroepithelioma,esthesioneurocytoma and esthesioneuroblastoma.The site of origin of ONB is confined to the olfactorymucosa that lines the upper part of the nasal cavity [181].On rare occasions ONB predominantly involves the superioraspect of the cribiform plate and grow as intracranialmasses [15, 186]. Before establishing a diagnosisof the extremely rare entity known as “ectopic” olfactoryneuroblastoma, which implies absence of involvementof the olfactory membrane, other sinonasal small roundcell tumours have to be carefully ruled out (Table 2.2).Olfactory neuroblastoma has a bimodal age distributionwith peaks in the 2nd and 6th decades [70]. Thisclearly differs from adrenal neuroblastoma, with mostcases arising in children under 4 years of age. Both sexesare equally affected. Nasal obstruction, rhinorrhoea andepistaxis are the most common presenting symptoms.Grossly, the tumours are often unilateral, presentingas smooth polypoid or fungating masses of fleshy consistencyand yellow to pink colour (Fig. 2.12a).At low magnification, ONB exhibits one of two mainpatterns of growth [176]. Most often, it presents a lobulararrangement with well-defined groups of tumourcells separated by abundant oedematous stroma. Less frequently,the tumour grows as diffuse sheets of cells withscanty, but highly vascular stroma. The neoplastic neuroblastsare typically small, showing round to oval nucleiwith stippled chromatin, absent or small nucleoli, andminimal cytoplasm. They are commonly separated by aneurofibrillary matrix formed by neuronal cell processesin which axons may be demonstrable by conventionalsilver stains. This background, seen in about 85% ofONBs, is the most helpful diagnostic feature (Fig. 2.12b).The Homer-Wright type of rosettes is quite characteristicof ONB; however, they are less commonly seen. Theyform when the tumour cells surround the neurofibrillarymatrix in collar-like arrangements. Even more rareare the true olfactory Flexner-Wintersteiner type of rosettes,which depict well-defined lumina lined by columnarcells resembling olfactory epithelium. These cells generallyhave basally located nuclei and merge with the adjacentneuroblasts without any intervening basal lamina.Perivascular pseudorosettes, formed by tumour cells arrangedaround capillaries, are of no diagnostic value, forthey may be found in several types of neoplasms.The scheme proposed by Hyams [122] to grade ONBinto four groups carries diagnostic and prognostic implications(Table 2.3). The differential diagnosis of ONBincludes a wide variety of small round cell tumours arisingin the sinonasal region (Table 2.2). Immunohistochemically,ONB shows diffuse positivity for NSE andsynaptophysin, but is less often positive for chromogranin.In tumours with a nesting pattern, sustentacularcells are positive for S-100 protein, but generally negativefor cytokeratin, although in ONB with a nestingpattern a few tumours may exhibit focal staining for lowmolecular weight cytokeratins. They are negative forEMA. Neurofilament protein and other markers of neuraldifferentiation are more often expressed in tumourswith diffuse, sheet-like patterns [53, 87, 246, 268]. Electronmicroscopy shows evidence of neuroblastic differentiation,demonstrating neuritic processes, neurotubulesand membrane-bound dense-core granules [131,159, 247]. The human analogue of achaete-scute gene(HASH1), expressed in immature olfactory neurons,is also expressed in ONB [45]. Conversely, the olfactorymarker protein [182], expressed exclusively in matureolfactory neurons, is not. ONB lacks CD 99 (MIC-2) expression, as well as the t(11;22) translocation characteristicof primary neuroectodermal tumour (PNET)[13, 263]. It also lacks the molecular genetic changes ofsympathetic neuroblastoma, which, in children, may bemetastatic to the sinonasal region.Staging of ONB is based on the Kadish system [129], inwhich stage A disease is confined to the nasal cavity, stageB to the nasal cavity and paranasal sinuses, and stage Cshows local or distant spread beyond the nasal cavity orsinuses. This correlates with prognosis [70]. Necrosis isthe single histological feature that seems to correlate withpoor survival [175]. About two-thirds of recurrences arein the form of local disease, whereas locoregional recurrences,with intracranial extension or involvement ofcervical lymph nodes, represent about 20%, and distant

58 A. Cardesa · L. Alos · A. Franchi2of uniform, small, undifferentiated, primitive neuroectodermalcells (Fig. 2.13a) [149]. The great majorityof these tumours will react strongly with antibodiesagainst the MIC-2 (CD99) protein product (Fig. 2.13b).This marker is of considerable value, but it is by nomeans specific. A growing number of other neoplasmsexpressing this protein have been documented. Amongthese are T-cell lymphomas [263]. The standard translocationt(11; 22) (q24; q12) of PNET [260] results inthe fusion of the EWS-FLI1 genes. The detection of thechimeric transcript by techniques of molecular biologyconfirms the diagnosis [238]. We have seen one exampleof PNET arising from the maxillary antrum [39],which ultrastructurally showed rudimentary neuriticdifferentiation, as well as scanty microtubule formation.This raised the differential diagnostic dilemmaof “ectopic olfactory neuroblastoma”; nevertheless, thetumour cells were positive for MIC-2 and showed thet(11;22)(q24;q12) translocation, findings that are characteristicallynegative in ONB [13].a2.11.9 High-GradeSinonasal Adenocarcinomas2.11.9.1 Intestinal-TypeAdenocarcinomabFig. 2.12. a Olfactory neuroblastoma: polypoid mass of fleshyconsistency and pink colour. b Well-differentiated olfactory neuroblastoma:nests of small round neuroblasts embedded in a neurofibrillarymatrix are surrounded by delicate networks of capillaryblood vesselsmetastases account for the rest [70]. Distant metastasesmainly involve bone and lung [68]. Complete surgical excision,often followed by radiation therapy and/or chemotherapy,seems to be the treatment of choice [14, 179]. Inadvanced ONB, high-dose chemotherapy and autologousbone marrow transplantation has been used [68, 188].2.11.8 PrimitiveNeuroectodermal TumourICD-O:9364/3Approximately 9% of extraosseous Ewing’s sarcoma/primitive neuroectodermal tumour (PNET) arise in thehead and neck region [176]. This tumour is composedICD-O:8144/3This is a tumour with histological features resemblingcolorectal adenocarcinoma [126, 220]. It is considered tooriginate through intestinal metaplasia of the ciliated respiratorycells lining the schneiderian membrane. Thistumour is the most common type of sinonasal adenocarcinoma,representing about 6–13% of malignanciesdeveloping in the sinonasal tract [41, 105, 216]. Metastasisfrom gastrointestinal adenocarcinoma should beruled out before a tumour is labelled as a primary of thisregion. These tumours are strongly associated with exposureto different types of dust, mainly hardwood, butalso softwood dusts, as well as leather dust [4, 5, 47, 102,123, 124, 142]. About 20% of sinonasal intestinal-typeadenocarcinomas seem to be sporadic, without evidenceof exposure to industrial dusts [4].Grossly, they have a fungating appearance with eitherpolypoid or papillary features. Occasionally, they mayhave a gelatinous consistency resembling a mucocele. Themost common location is the ethmoidal region [17]. Histologically,the tumour is mainly composed of columnarmucin-secreting cells and goblet cells [17]. Some well-differentiatedtumours may also contain resorptive cells, argentaffincells and Paneth cells. Endocrine-amphicrineenteric differentiation may occasionally be found [222].Metaplastic and atypical changes have been observed inadjacent pre-neoplastic epithelium [270]. These tumours

Nasal Cavity and Paranasal Sinuses Chapter 2 59Table 2.3. Olfactory neuroblastoma. Hyams Grading Scheme [122].Histologic grades 1 2 3 4Lobular architecture Present Present ± +Mitotic activity Absent Present Prominent MarkedNuclear pleomorphism Absent Moderate Prominent MarkedFibrillary matrix Prominent Moderate Slight AbsentRosettes H-W + H-W + Flexner + AbsentNecrosis Absent Absent Occasional CommonCalcification ± + Absent AbsentH-W Homer-Wright rosettes, + present or absentabFig. 2.13. Primitive neuroectodermal tumour (PNET). a Monotonousproliferation of small, round, undifferentiated cells. bCD99-positive immune reaction at the cellular membranedepict different histological patterns that may be predominantlypapillary, glandular, compact, mucinous or mixed[17, 23]. Papillary tumours mainly consist of elongatedoutgrowths lined by intestinal-type cells with markedlyatypical pseudostratified nuclei (Fig. 2.14a). Althoughmost of them are high-grade tumours, low-grade forms(Fig. 2.14b) mimicking colonic villous adenoma may occasionallyoccur [174]. The glandular pattern resemblescommon-type intestinal adenocarcinoma. Compact orsolid forms show poorly differentiated nests of cells inwhich glandular formation is rarely seen. In the mucinouspattern, more than 50% of the tumour is composedof dilated mucin-filled glands lined by columnar mucin-secretingepithelium, and lakes of mucin containingfragmented epithelial elements (Fig. 2.14c). Other mucinoustumours show mucin-filled cells with the pattern of“signet-ring” cell carcinoma. Various attempts have beenmade to correlate histopathological grading and typingwith clinical behaviour [78, 81, 140].Features such as cytologic atypia, high mitotic rate andareas of necrosis, which are common findings in most intestinal-typeadenocarcinomas, help to distinguish thehigh-grade variants from rare low-grade intestinal-typeadenocarcinomas and from mucoceles. The lack of epidermoidand squamous differentiation separates these tumoursfrom mucoepidermoid and adenosquamous carcinomas.Immunohistochemistry and electron microscopyhave confirmed the enteric differentiation of the tumourcells [24]. These tumours are positive for a wide spectrumof cytokeratin markers, whereas they are only occasionallypositive for carcinoembryonic antigen [166]. Intestinal-typeadenocarcinomas are frequently but not alwayspositive for cytokeratin 7, while most express cytokeratin20 and CDX-2, two markers related to intestinal differentiation[79]. The prognosis for high-grade intestinal-typeadenocarcinoma is poor. Recurrences and subsequentdeeply invasive local growth are frequent; however,lymph node and distant metastases are rare [17, 78,142]. Treatment of choice is complete surgical resectionfollowed by radiotherapy.2.11.9.2 Salivary-TypeHigh-Grade AdenocarcinomasAdenoid Cystic CarcinomaICD-O:8200/3Adenoid cystic carcinoma (see Chap. 5) is the most commonmalignant salivary-type of tumour of the upper

60 A. Cardesa · L. Alos · A. Franchi2aggressive tumour from the seromucous glands of theupper respiratory tract may occasionally occur. We haveseen one example of SDC originating in the maxillaryantrum, in which the characteristic ductal pattern, withcomedo-type necrosis, was only evident in the metastasesto the submandibular lymph nodes. The primarytumour was initially classified as adenocarcinoma nototherwise specified (NOS) due to the absence of convincingdiagnostic features [40]. Carcinoma ex pleomorphicadenoma may also occur in the sinonasal tract [110].ab2.11.10 Low-Grade SinonasalAdenocarcinomasLow-grade adenocarcinomas arising primarily withinthe sinonasal tract are an uncommon and heterogeneousgroup of tumours [23, 113, 139, 150]. Some ofthese neoplasms show apparent histological continuitywith the normal surface epithelium of the sinonasalmucosa, whereas others are of salivary gland origin. Allhave better prognosis and different clinical presentationthan their high-grade counterpart. With the exceptionof the well-differentiated, low-grade, adenocarcinomasof intestinal type, no correlation with occupational activitieshas been found in these tumours.2.11.10.1 Non-Salivary-TypeLow-Grade AdenocarcinomascFig. 2.14. Intestinal-type adenocarcinoma. a Papillary outgrowthof intestinal-like malignant epithelium. Destruction of sinonasalbone at the bottom. b Low-grade variant mimicking villous adenomaof the colon. c Mucinous variant mimicking mucocelerespiratory tract and constitutes 5–10% of all sinonasalmalignancies [43, 105, 206]. It is most common in themaxillary antrum, followed by the nasal cavity [60], althoughethmoid, sphenoid and frontal sinuses may alsobe involved [110, 169, 255].Other Salivary-Type High-Grade AdenocarcinomasWith the exception of adenoid cystic carcinoma, thesetumours are quite rare in the sinonasal region. Althoughmost salivary duct carcinomas (SDCs) arise from themajor salivary glands, the development of this highlyNon-salivary-type low-grade sinonasal adenocarcinomasare a distinctive group of tumours comprising well-differentiatedtubular or papillary structures, or a combinationof both. They are lined by a single layer of cuboidalor columnar cells that display uniform round or ovalnuclei, inconspicuous nucleoli, minimal cytologic atypiaand scarce mitotic figures. They are locally infiltrativeand have a tendency towards local recurrence [113].Different histological patterns may be recognised:papillary, glandular, mucinous, trabecular, cribriformand clear cell. The papillary pattern is characterised bycomplex papillary fronds lined by bland columnar cellsthat may occasionally mimic oncocytic (columnar) cellpapilloma. Quite similar tumours also develop in thenasopharynx [267]. The glandular pattern may simulateadenoma; nevertheless, the presence of closely packedglands, forming back-to-back arrangements, indicatesthe true malignant nature. Mucinous tumours have to bedistinguished from mucoceles and from mucinous adenocarcinomaof intestinal or salivary type [20, 224]. Thetrabecular pattern may resemble acinic cell carcinoma[200]. The cribriform arrangements have to be distinguishedfrom low-grade salivary duct carcinoma of salivaryglands [62]. The clear cell type has to be separatedfrom the salivary-type tumours with clear cells and

Nasal Cavity and Paranasal Sinuses Chapter 2 61Fig. 2.15. Tubulopapillary carcinoma: low-grade proliferation ofcuboidal to columnar epithelial cells forming tubules at the centreand papillae at the surfaceafrom metastatic renal cell carcinoma [31, 280]. A tubulopapillaryvariant has recently been reported (Fig. 2.15)[234] that has to be differentiated from terminal tubulusadenocarcinoma of the nasal seromucous glands [139].2.11.10.2 Salivary-Type Low-GradeAdenocarcinomasMucoepidermoid carcinoma, polymorphous low-gradeadenocarcinoma (Fig. 2.16) and acinic cell carcinomaoriginate only on rare occasions from the seromucousglands of the sinonasal mucosa [43, 110, 150, 190, 200,239]. Most mucoepidermoid carcinomas of the sinonasaltract are low-grade. Some large oncocytic tumoursof the sinonasal tract may behave in a locally aggressivefashion and are better classified as low-grade adenocarcinomas[55, 103, 110]. All these tumours are dealt within detail in Chap. 5 on salivary glands. Their main differentialdiagnoses are other salivary- or non-salivarytypelow-grade adenocarcinomas.2.11.11 Sinonasal Malignant LymphomasMalignant lymphomas of the sinonasal region compriseapproximately 6% of all sinonasal malignancies [134]. Inour Barcelona series, they account for 9.5% (Table 2.1).In western countries, about 50% of sinonasal lymphomasare of B-cell type, whereas the other 50% mostly showedNK/T-cell lineage [38]; nevertheless, other reports pointto more variable rates [3, 72, 77, 85]. Conversely, in orientalpopulations most primary lymphomas of the nasalcavity and nasopharynx are of NK/T cell lineage [49, 50,52, 92, 233].Sinonasal B-cell lymphomas are in general composedof a diffuse proliferation of large lymphoid cells, or of abFig. 2.16. Polymorphous low-grade adenocarcinoma. a CT scanshowing an irregularly nodular lesion destroying the anterior nasalseptum. Courtesy of Prof. J. Traserra, Barcelona, Spain. b Variegatedglandular arrangements composed of tubules with blandcellularity are seen beneath respiratory epitheliumdiffuse mixed pattern of small and large cells. They infiltrateand expand the subepithelial soft tissue and mayextend into the underlying bone. Sinonasal B-cell lymphomaslack epitheliotropism, polymorphous cell infiltrate,angiocentricity, prominent necrosis, and fibrosis.They are usually positive for B-cell markers (CD20and CD79a) and negative for NK/T cell markers. lightchain restriction is seen more often than restriction.They are often negative for EBV markers. Radiotherapyand chemotherapy is the standard treatment for advancedtumours [213].Sinonasal NK/T cell lymphomas were labelled in pastdecades with terms such as “lethal midline granuloma”,“polymorphic reticulosis” and “angiocentric T-cell lymphoma”,among others. Until quite recently, non-B cellsinonasal lymphomas were considered as other forms ofT-cell lymphoma, frequently displaying angiocentricity.Patients may present either with an obstructive massor with mid-facial destructive lesions. Histologically, anangiocentric and angiodestructive infiltrate with extensivenecrosis (Fig. 2.17a) is frequently seen. In NK/T-celllymphoma, cells may be small, medium-sized, large, oranaplastic, and may show a conspicuous admixture of

62 A. Cardesa · L. Alos · A. Franchi2abFig. 2.17. Sinonasal NK/T lymphoma. a Angiocentric infiltrateof atypical lymphocytes with extensive necrotic areas. b Stronglypositive CD56 immunoreactioninflammatory cells. Pseudoepitheliomatous hyperplasiaof the covering epithelium may occur [49]. NK/T celllymphoma is almost always associated with EBV positivity.The most typical immunophenotypes are CD2+,CD56+ (Fig. 2.17b), surface CD3–, and cytoplasmicCD3epsilon+. Most cases are also positive for cytotoxicgranule-associated proteins (granzyme B, TIA-1 andperforin). They are usually negative for other T and NKcellassociated markers. Sinonasal lymphomas demonstratingCD3epsilon+, CD56–, cytotoxic molecule+, andEBV+ are also included within the NK/T category. Thecommonest cytogenetic abnormality found in NK/Tcelllymphoma is the 6q-22-23 deletion [233]. The prognosisof nasal NK/T-cell lymphoma is variable. Some patientsrespond well to therapy and others die of diseasedespite aggressive therapy [52].Sinonasal malignant lymphomas of either B-cell or T-cell derivation need a careful differential diagnosis withother small round cell tumours (Table 2.2) and with extramedullaryplasmacytoma [6, 46], as well as with extramedullarytumours composed of myeloid or lymphoidblasts [133].2.11.12 Extramedullary PlasmacytomaICD-O:9731/3Plasmacytoma of the sinonasal tract appears as a diffuseinfiltration of mature plasma cells of the mucosa;occasionally, tumour cells are less differentiated, anddiagnosis may be difficult on a histologic basis [2, 6, 46,185]. Immunohistochemical staining for CD138 and and chains may be helpful. Full examination of thepatient is required to exclude disseminated disease.2.11.13 FibrosarcomaICD-O:8810/3Fibrosarcoma of the sinonasal tract occurs across awide age range, most commonly causing obstruction orepistaxis. The histologic appearance is that of a spindlecell lesion, with fascicles or bundles of neoplastic cellsintersecting at various angles, sometimes with a herringbonepattern. Most sinonasal fibrosarcomas have alow-grade appearance, with moderate cellularity and alow mitotic rate [111]. In accordance, the behaviour ismore often characterised by repeated local recurrences,while distant metastases are rare. The differentialdiagnosis includes desmoid fibromatosis, leiomyosarcoma,nerve sheath tumours, spindle cell carcinomaand melanoma.2.11.14 Malignant FibrousHistiocytomaICD-O:8830/3Malignant fibrous histiocytoma is a high-grade sarcomaof adulthood histologically consisting of a proliferationof spindle cells arranged in a storiform pattern, intermixedwith atypical pleomorphic, often multinucleatedgiant cells. In the sinonasal tract it presents as a highlyaggressive and destructive lesion, with bone invasionand extension in adjacent structures [201]. Before a diagnosisof malignant fibrous histiocytoma is rendered,other pleomorphic malignant tumours, like leiomyosarcoma,osteosarcoma and sarcomatoid carcinoma shouldbe excluded by means of immunohistochemical or ultrastructuralanalysis.

Nasal Cavity and Paranasal Sinuses Chapter 2 632.11.15 LeiomyosarcomaICD-O:8890/3Leiomyosarcoma of the sinonasal tract is an extremelyrare neoplasm, with identical histological appearanceand immunoprofile to the soft tissue counterpart [91]. Ifthe tumour is limited to the nasal cavity the prognosis isgood, and according to Kuruvilla et al. [144], sinonasalleiomyosarcoma can be regarded as a locally aggressiveneoplasm with limited metastatic potential that shouldbe treated by surgery alone. Distinction from sinonasalleiomyoma is based on mitotic activity and cellularatypia.2.11.16 RhabdomyosarcomaICD-O:8900/3Rhabdomyosarcoma is the most common sinonasal malignancyof the paediatric age, but it is also observed inadults [37, 116]. The most common histologic subtypesare the embryonal and the alveolar [37]. The overall 5-year survival is around 40%; adult age and alveolar subtypeare adverse prognostic factors. Treatment includesa combination of radiotherapy and chemotherapy, withsurgical resection reserved for residual disease. The riskof neck involvement is high.2.11.17 Malignant PeripheralNerve Sheath TumourICD-O:9560/3Malignant peripheral nerve sheath tumour (MPNST) ofthe sinonasal tract is a very rare neoplasm [163] that isprobably under-recognised due to the lack of reproduciblehistologic criteria and to the tendency of these tumoursto be negative for the commonly used immunohistochemicalmarkers of nerve sheath differentiation.Only in some cases can the diagnosis be based on theidentification of a pre-existing neurofibroma. Histologically,MPNST is a moderately to highly cellular spindlecell proliferation, with variable mitotic activity and areasof necrosis. A variant composed of epithelioid cells hasbeen described in the sinonasal cavities (Fig. 2.18) [76].Some tumours may show morphologic and immunohistochemicalfeatures of skeletal muscle differentiationand are designated “malignant triton tumours” [138].2.11.18 TeratocarcinosarcomaICD-O:8980/3The term “ teratocarcinosarcoma” is designated to anunusual entity in which a malignant sinonasal teratomatoustumour also shows features of carcinosarcomaFig. 2.18. Sinonasal malignant epithelioid schwannoma: markedS-100 protein positivity in a large cell malignant neoplasm, mimickingamelanotic melanoma[112]. Patients suffering from this malignancy are exclusivelyadults (age range 18–79 years; mean 60 years) [64,75, 112, 156, 195, 227]. There is a male predominanceand symptoms are non-specific with nasal obstructionand epistaxis produced by a nasal cavity mass (Fig. 2.19a)[112].Histologically, sinonasal teratocarcinosarcoma(SNTCS) comprises a multiplicity of cell types ofvarying maturity (Fig. 2.19b). The epithelial componentincludes keratinising squamous epithelium, pseudostratifiedcolumnar ciliated epithelium and glandularstructures lined by cuboidal and columnar cellsincluding mucus cells. Masses of immature epithelialcells, some containing glycogen or mucin, are frequentlyfound. “Foetal-appearing” clear cell squamousepithelium is a common finding and a very importantdiagnostic clue for some authors [112]. Neuroepithelialelements with rosettes and neuroblastoma-like areasare in most instances present. These epithelial andneuroepithelial elements occur in close relationshipwith each other and with mesenchymal elements, themost prominent of which are immature cells with ovalor elongated nuclei. The mesenchymal cells may exhibitskeletal muscle differentiation with cross striations(Fig. 2.19c). Foci of cartilage, smooth muscle, adiposetissue and fibrovascular tissues may also be present. Inspite of the common occurrence of areas having a varietyof mature tissues, mitotic activity and cytologicalfeatures of malignancy are demonstrable in the undifferentiatedareas of both the epithelial and mesenchymalelements [75].In order to achieve the correct diagnosis of SNTCSa thorough sampling of the specimen is required. Inadequatesampling may lead to mistaken diagnoses ofesthesioneuroblastoma, squamous cell carcinoma, undifferentiatedcarcinoma, adenocarcinoma, malignantcraniopharyngioma, malignant mixed tumour of salivarygland type, mucoepidermoid carcinoma, adeno-

64 A. Cardesa · L. Alos · A. Franchi2baFig. 2.19. Teratocarcinosarcoma. a CT scan showing massive destructiveinfiltration of the nasal cavity and maxillary sinus on theleft. With permission [75] b Cystic spaces filled with mucin arepartly covered by benign columnar epithelium and surrounded bycimmature blastematous tissue. c Immature glands surrounded byblastematous elements at the lower left; presence of immature striatedmuscle, upper right and centresquamous carcinoma and others [105]. In contradistinctionto malignant gonadal teratomas, which arefrequently found in patients at a younger age, sinonasalteratocarcinosarcoma does not contain areas of embryonalcarcinoma, choriocarcinoma or germinoma (seminoma),as seen in many germ cell tumours. This makesa germ cell origin of SNTCS unlikely [112]. The histogenesisof sinonasal teratocarcinosarcoma is debatable.The presence of neural tissue in these neoplasms raisesthe possibility that the origin could be in some wayrelated to the olfactory membrane, or alternatively tothe sinonasal membrane as a whole, since the olfactorymembrane also develops from it [112].Sinonasal teratocarcinosarcomas are locally aggressivetumours, with rapid invasion of soft tissues andbone, and metastasise to regional lymph nodes andsites, such as the lung. The average survival of a patientwith SNTCS is 1.7 years, with 60% of the patientsnot surviving beyond 3 years. The treatment of SNTCSis controversial, but an aggressive initial therapeuticalapproach with a combination of surgical resection, radiotherapyand chemotherapy is usually recommended[112].References1. Abdel-Latif SM, Baheeg SS, Aglan YI, Babin RW, Giltman LI(1987) Chronic atrophic rhinitis with fetor (ozena): a histopathologictreatise. Rhinology 25:117–1202. Abemayor E, Canalis RF, Greenberg P, Wortham DG, RowlandJP, Sun NC (1988) Plasma cell tumors of the head andneck. J Otolaryngol 17:376–3813. Abbondanzo SL, Wenig BM (1995) Non-Hodgkin’s lymphomaof the sinonasal tract. A clinicopathologic and immunophenotypicstudy of 124 cases. Cancer 75:1281–12914. Acheson ED, Cowdell RH, Hadfield E, Macbeth RG (1968)Nasal cancer in woodworkers in the furniture industry. BrMed J 2:587–5965. Acheson ED, Cowdell RH, Jolles B (1970) Nasal cancer in theNorthamptonshire boot and shoe industry. Br Med J 1:385–3936. Aguilera NS, Kapadia SB, Nalesnik MA, Swerdlow SH (1995)Extramedullary plasmacytoma of the head and neck: use ofparaffin sections to assess clonality with in situ hybridization,growth fraction, and the presence of Epstein-Barr virus.Mod Pathol 8:503–5087. Aktas D, Yetiser S, Gerek M, Kurnaz A, Can C, KahramanyolM (1998) Antrochoanal polyps: analysis of 16 cases. Rhinology36:81–858. Alobid I, Alos L, Blanch JL, Benitez P, Bernal-Sprekelsen M,Mullol J (2003) Solitary fibrous tumour of the nasal cavityand paranasal sinuses. Acta Otolaryngol 123:71–749. Alos L, Cardesa A, Bombí JA, Mallofré C, Cuchi A, TraserraJ (1996) Myoepithelial tumours of salivary glands: a clinico-

Nasal Cavity and Paranasal Sinuses Chapter 2 65pathologic, immunohistochemical, ultrastructural and flowcytometricstudy. Semin Diagn Pathol 13:138–14710. Alos L, Castillo M, Nadal A, Caballero M, Mallofre C, PalacinA, Cardesa A (2004) Adenosquamous carcinoma of thehead and neck: criteria for diagnosis in a study of 12 cases.Histopathology 44:1–1011. Anon JB (2003) Acute bacterial rhinosinusitis in pediatricmedicine: current issues in diagnosis and management. PaediatrDrugs 5 [Suppl 1]:25–3312. Apple D, Kreines K (1982) Case report. Cushing’s syndromedue to ectopic ACTH production by a nasal paraganglioma.Am J Med Sci 283:32–3513. Argani P, Perez-Ordonez B, Xiao H, Caruana SM, Huvos AG,Ladanyi M (1998) Olfactory neuroblastoma is not related tothe Ewing family of tumours. Absence of EWS/FLI1 gene fusionand MIC2 expression. Am J Surg Pathol 22:391–39814. Bailey BJ, Barton S (1975) Olfactory neuroblastoma managementand prognosis. Arch Otolaryngol 101:1–515. Banerjee AK, Sharma BS, Vashista RK, Kak VK (1992) Intracranialolfactory neuroblastoma: evidence for olfactory epithelialorigin. J Clin Pathol 45:299–30216. Banks ER, Frierson HF, Mills SE et al. (1992) Basaloid squamouscell carcinoma of the head and neck. A clinicopathologicand immunohistochemical study of 40 cases. Am J SurgPathol 16:939–94617. Barnes L (1986) Intestinal-type adenocarcinoma of the nasalcavity and paranasal sinuses. Am J Surg Pathol 10:192–20218. Barnes L, Bedetti C (1984) Oncocytic Schneiderian papilloma:a reappraisal of cylindrical cell papilloma of the sinonasaltract. Hum Pathol 15:344–35119. Batra K, Chaudhary N, Motwani G, Rai AK (2002) An unusualcase of primary nasal tuberculosis with epistaxis andepilepsy. Ear Nose Throat J 81:842–84420. Batsakis JG (1970) Mucous gland tumors of the nose and paranasalsinuses. Ann Otol Rhinol Laryngol 79:557–56221. Batsakis JG, el-Naggar AK (1992) Rhinoscleroma and rhinosporidiosis.Ann Otol Rhinol Laryngol 101:879–88222. Batsakis JG, el-Naggar AK (1996) Cystic fibrosis and the sinonasaltract. Ann Otol Rhinol Laryngol 105:329–33023. Batsakis JG, Holtz F, Sueper RH (1963) Adenocarcinoma ofthe nasal and paranasal cavities. Arch Otolaryngol 77:625–63324. Batsakis JG, Mackay B, Ordóñez NG (1984) Enteric-type adenocarcinomaof the nasal cavity. An electron microscopicand immunocytochemical study. Cancer 54:855–86025. Batsakis JG, Regezi JA, Solomon AR, Rice DH (1982) The pathologyof head and neck tumors: Mucosal melanomas. HeadNeck Surg 4:404–41826. Beatty CW, Pearson BW, Kern EB (1982) Carcinoma of thenasal septum: experience with 85 cases. Otolaryngol HeadNeck Surg 90:90–9427. Begin LR, Rochon L, Frenkel S (1991) Spindle cell myoepitheliomaof the nasal cavity. Am J Surg Pathol 15:184–19028. Benninger MS, Ferguson BJ, Hadley JA, Hamilos DL, JacobsM, Kennedy DW, Lanza DC, Marple BF, OsguthorpeJD, Stankiewicz JA, Anon J, Denneny J, Emanuel I, LevineH (2003) Adult chronic rhinosinusitis: definitions, diagnosis,epidemiology, and pathophysiology. Otolaryngol Head NeckSurg 129:S1–S3229. Berthelsen A, Andersen AP, Jensen S, Hansen HA (1984) Melanomasof the mucosa in the oral cavity and the upper respiratorypassages. Cancer 54:907–91230. Bosch A, Vallecillo L, Frias Z (1976) Cancer of the nasal cavity.Cancer 37:1458–146331. Brandwein M (2002) Renal cell-like carcinoma of the sinonasaltract. XXIV International Congress of the InternationalAcademy of Pathology. Amsterdam. The Netherlands 2002.Slide Seminar 9, “Unusual Head and Neck Lesions”. Case 632. Brandwein MS, Rothstein A, Lawson W, Bodian C, UrkenML (1997) Sinonasal melanoma. A clinicopathologic studyof 25 cases and literature meta-analysis. Arch OtolaryngolHead Neck Surg 123:290–29633. Brarsman FA (1980) The median nasal sinus and dermoidcyst. Arch Otorhinolaryngol 226:107–11334. Brook I, Frazier EH (2004) Microbiology of recurrent acuterhinosinusitis. Laryngoscope 114:129–13135. Buchwald C, Franzmann MB, Jacobsen GK, Lindeberg H(1995) Human papillomavirus (HPV) in sinonasal papillomas:a study of 78 cases using in situ hybridization and thepolymerase chain reaction. Laryngoscope 105:66–7136. Buob D, Wacrenier A, Chevalier D, Aubert S, Quinchon JF,Gosselin B, Leroy X (2003) Schwannoma of the sinonasaltract: a clinicopathologic and immunohistochemical studyof 5 cases. Arch Pathol Lab Med 127:1196–119937. Callender TA, Weber RS, Janjan N, Benjamin R, Zaher M,Wolf P, el-Naggar A (1995) Rhabdomyosarcoma of the noseand paranasal sinuses in adults and children. OtolaryngolHead Neck Surg 112:252–25738. Campo E, Cardesa A, Alos L, Palacin A, Cobarro J, TraserraJ, Montserrat E (1991) Non-Hodgkin’s lymphomas of nasalcavity and paranasal sinuses. An immunohistochemicalstudy. Am J Clin Pathol 96:184–19039. Cardesa A (1998) Peripheral primitive neuroectodermal tumour,left maxillary sinus. XXII International Congress ofthe International Academy of Pathology. Nice. France 1998.Slide Seminar 18, “Head and Neck Pathology”. Case 1240. Cardesa A (1998) Sinonasal salivary duct carcinoma metastaticto right cervical lymph nodes. XXII InternationalCongress of the International Academy of Pathology. Nice.France 1998. Slide Seminar 18, “Head and Neck Pathology”.Case 641. Cardesa A, Alos L (2002) Special tumours of the head andneck region: characterization of undifferentiated sinonasaltumours. Histopathology 41 [Suppl 2]:473–47742. Cardesa A, Alos LL, Bombi JA, Palacin A, Traserra J (1991) Relativefrequency and diagnoses of sinonasal malignant melanoma(SNMM). Lab Invest 64:63A43. Cardesa A, Bombi JA, Alos L (1993) The classification of tumoursof the minor salivary glands. Arquivos de Patologia,Univ. Coimbra, Portugal 25:75–8544. Cardesa A, Pour P, Haas H, Althoff J, Mohr U (1976) Histogenesisof tumors from the nasal cavities induced by diethylnitrosamine.Cancer 37:346–35545. Carney ME, O’Reilly RC, Sholevar B et al. (1995) Expressionof the human Achaete-scute 1 gene in olfactory neuroblastoma(esthesioneuroblastoma). J Neurooncol 26:35–4346. Castro EB, Lewis JS, Strong EW (1973) Plasmacytoma of paranasalsinuses and nasal cavity. Arch Otolaryngol 97:326–32947. Cecchi F, Buiatti E, Kriebel D, Nastasi L, Santucci M (1980)Adenocarcinoma of the nose and paranasal sinuses in shoemakersand woodworkers in the province of Florence, Italy(1963–77). Br J Ind Med 37:222–22548. Cerilli LA, Holst VA, Brandwein MS, Stoler MH, Mills SE(2001) Sinonasal undifferentiated carcinoma. Immunohistochemicalprofile and lack of EBV association. Am J SurgPathol 25:156–16349. Chan JK (1998) Natural killer cell neoplasms. Anat Pathol3:77–14550. Chan JK, Ng CS, Lau WH, Lo ST (1987) Most nasal/nasopharyngeallymphomas are peripheral T-cell neoplasms. Am JSurg Pathol 11:418–42951. Chaudry MR, Aktar S, Kim DS (1994) Neuroendocrine carcinomaof the ethmoid sinus. Eur Arch Otorhinolaryngol251:461–46352. Cheung MM, Chan JK, Lau WH et al. (1998) Primary non-Hodgkin’s lymphoma of the nose and nasopharynx: clinicalfeatures, tumor immunophenotype, and treatment outcomein 113 patients. J Clin Oncol 16:70–7753. Choi HS, Anderson PJ (1986) Olfactory neuroblastoma: animmuno-electron microscopic study of S-100 protein-positivecell. J Neuropathol Exp Neurol 45:576–58754. Christensen WN, Smith RL (1986) Schneiderian papillomas:a clinicopathologic study of 67 cases. Hum Pathol 17:393–40055. Cohen MA, Batsakis JG (1968) Oncocytic tumors (oncocytomas)of minor salivary glands. Arch Otolaryngol 88:97–99

66 A. Cardesa · L. Alos · A. Franchi256. Compagno J, Wong RT (1977) Intranasal mixed tumours(pleomorphic adenomas). A clinicopathologic study of 40cases. Am J Clin Pathol 68:213–21857. Coup AJ, Hopper IP (1980) Granulomatous lesions in nasalbiopsies. Histopathology 4:293–30858. Cove H (1994) Melanosis, melanocytic hyperplasia, andprimary malignant melanoma of the nasal cavity. Cancer44:1424–143359. Cunningham MJ, Brantley S, Barnes L, Schramm VL (1987)Oncocytic Schneiderian papilloma in a young adult: a rarediagnosis. Otolaryngol Head Neck Surg 97:47–5160. Da-Quan M, Guang-Yan Y (1987) Tumours of the minor salivaryglands. A clinicopathologic study of 243 cases. ActaOtolaryngol (Stockh) 103:325–33161. Davis JM, Weber AL (1980) Pituitary adenoma presenting asa sphenoid sinus lesion. Ann Otol Rhinol Laryngol 89:883–88462. Delgado R, Klimstra D, Albores-Saavedra J (1996) Low gradesalivary duct carcinoma. A distinctive variant with low gradehistology and a predominant intraductal growth pattern.Cancer 78:958–96763. Denoyelle F, Ducroz V, Roger G, Garabedian EN (1997) Nasaldermoid sinus cysts in children. Laryngoscope 107:795–80064. Devgan BK, Devgan M, Gross CW (1978) Teratocarcinomaof the ethmoid sinus: review of literature plus a new case report.Otolaryngol Head Neck Surg 86:689–69565. Drier JK, Swanson PE, Cherwitz DL, Wick MR (1987) S100protein immunoreactivity in poorly differentiated carcinomas.Immunohistochemical comparison with malignantmelanoma. Arch Pathol Lab Med 111:447–45266. Dunand VA, Hammer SM, Rossi R, Poulin M, Albrecht MA,Doweiko JP, DeGirolami PC, Coakley E, Piessens E, WankeCA (1997) Parasitic sinusitis and otitis in patients infectedwith human immunodeficiency virus: report of five casesand review. Clin Infect Dis 25:267–27267. Dykewicz MS (2003) 7. Rhinitis and sinusitis. J Allergy ClinImmunol 111:S520–S52968. Eden BV, Debo RF, Larner JM et al. (1994) Esthesioneuroblastoma.Long term outcome and patterns of failure – theUniversity of Virginia experience. Cancer 73:2556–256269. El-Barbary AE-S, Yassin A, Fouad H, Shennawy ME (1976)Histopathological and histochemical studies in atrophic rhinitis.J Laryngol Otol 84:1103–111169a. El-Mofty SK, Lu DW (2005) Prevalence of high-risk humanpapillomavirus DNA in non-keratinising (cylindrical cell)carcinoma of the sinonasal tract. A distinct clinicopathologicand molecular disease entity. Am J Surg Pathol 29:1367–137270. Elkon D, Hightower SI, Lim ML, Cantrell RW, Constable WC(1979) Esthesioneuroblastoma. Cancer 44:1087–109471. Fang SY, Shen CL (1998) Neuropeptide innervation and neuroendocrinecells in allergic rhinitis and chronic hypertrophicrhinitis. Clin Exp Allergy 28:228–23272. Fellbaum C, Hansmann ML, Lennert K (1989) Malignantlymphomas of the nasal cavity and paranasal sinuses. VirchowsArchiv A Pathol Anat Histopathol 414:399–40573. Ferguson BJ (2000) Mucormycosis of the nose and paranasalsinuses. Otolaryngol Clin North Am 33:349–36574. Fernandez PL, Cardesa A, Alos L (1995) Malignant melanomaof the sinonasal tract. Check Sample. APII. Am J ClinPathol 19:45–5875. Fernandez PL, Cardesa A, Alos L, Pinto J, Traserra J (1995)Sinonasal teratocarcinosarcoma: an unusual neoplasm. PatholRes Pract 191:166–17176. Fernandez PL, Cardesa A, Bombi JA, Palacin A, Traserra J(1993) Malignant sinonasal epithelioid schwannoma. VirchowsArch 423:401–40577. Ferry JA, Sklar J, Zukerberg RL, Harris NL (1991) Nasal lymphoma.A clinicopathologic study with immunophenotypicand genotypic analysis. Am J Surg Pathol 15:268–27978. Franchi A, Gallo O, Santucci M (1999) Clinical relevance ofthe histological classification of sinonasal intestinal-type adenocarcinomas.Hum Pathol 30:1140–114579. Franchi A, Massi D, Palomba A, Biancalani M, Santucci M(2004) CDX-2, cytokeratin 7 and cytokeratin 20 immunohistochemicalexpression in the differential diagnosis of primaryadenocarcinomas of the sinonasal tract. Virchows Arch445:63–6780. Franchi A, Moroni M, Massi D, Paglierani M, Santucci M(2002) Sinonasal undifferentiated carcinoma, nasopharyngeal-typeundifferentiated carcinoma, and keratinizing andnonkeratinizing squamous cell carcinoma express differentcytokeratin patterns. Am J Surg Pathol 26:1597–160481. Franquemont DW, Fechner RE, Mills SE (1991) Histologicclassification of sinonasal intestinal-type adenocarcinoma.Am J Surg Pathol 15:368–37582. Franquemont DW, Mills SE (1991) Sinonasal malignantmelanoma. A clinicopathologic and immunohistochemicalstudy of 14 cases. Am J Clin Pathol 96:689–69783. Freedman HM, DeSanto LW, Devine KD, Weiland LH (1973)Malignant melanoma of the nasal cavity and paranasal sinuses.Arch Otolaryngol 97:322–32584. Friedmann I, Osborn DA (1982) Carcinoma of the surfaceepithelium (including ameloblastoma). In: Friedmann I, OsbornD (eds) Pathology of granulomas and neoplasms of thenose and paranasal sinuses. Churchill Livingstone, Edinburgh,pp 118–13285. Frierson HF Jr, Innes DJ Jr, Mills SE, Wick M (1989) Immunophenotypicanalysis of sinonasal non-Hodgkin’s lymphomas.Human Pathol 20:636–64286. Frierson HF, Mills SE, Fechner RE, Taxy JB, Levine PA(1986) Sinonasal undifferentiated carcinoma. An aggressiveneoplasm derived from Schneiderian epithelium and distinctfrom olfactory neuroblastoma. Am J Surg Pathol 10:771–77987. Frierson HF Jr, Ross GW, Mills SE, Frankfurter A (1990) Olfactoryneuroblastoma. Additional immunohistochemicalcharacterization. Am J Surg Pathol 94:547–55388. Frodel JL, Larrabee WF, Raisis J (1989) The nasal dermoid.Head Neck Surg 101:392–39689. Fu YS, Hoover L, Franklin M, Cheng L, Stoler MH (1992)Human papillomavirus identified by nucleic acid hybridizationin concomitant nasal and genital papillomas. Laryngoscope102:1014–101990. Fu YS, Perzin KH (1974) Non-epithelial tumors of the nasalcavity, paranasal sinuses, and nasopharynx: a clinicopathologicstudy. I. General features and vascular tumors. Cancer33:1275–128891. Fu YS, Perzin KH (1975) Nonepithelial tumors of the nasalcavity, paranasal sinuses, and nasopharynx: a clinicopathologicstudy. IV. Smooth muscle tumors (leiomyoma, leiomyosarcoma)Cancer 35:1300–130892. Gaal K, Sun NCJ, Hernandez AM, Arber DA (2000) SinonasalNK/T-cell lymphomas in the United States. Am J SurgPathol 24:1511–151793. Gadeberg CC, Hjelm-Hansen M, Sögaard H et al. (1984) Malignanttumors of the paranasal sinuses and nasal cavity. Aseries of 180 patients. Acta Radiol Oncol 23:181–18794. Gerughty RM, Hennigar GR, Brown FM (1984) Adenosquamouscarcinoma of the nasal, oral and laryngeal cavities. Aclinicopathologic survey of ten cases. Cancer 22:1140–115595. Ghamrawi KAE, Glennie JM (1974) The value of radiotherapyin the management of malignant melanoma of the nasalcavity. J Laryngol Otol 88:71–7596. Gnepp DR, Henley J, Weiss S, Heffner D (1996) Desmoid fibromatosisof the sinonasal tract and nasopharynx. A clinicopathologicstudy of 25 cases. Cancer 78:2572–257997. Goren AD, Harley N, Eisenbud L, Levin S, Cohen N (1980)Clinical and radiobiologic features of Thorotrast-inducedcarcinoma of the maxillary sinus. A case report. Oral SurgOral Med Oral Pathol 49:237–24298. Gosavi DK, Moidekar AT (1978) Chemodectoma of the noseand sphenoid sinus. J Laryngol Otol 92:813–81699. Gouldesbrough DR, Martin-Hirsch DP, Lannigan F (1992)Intranasal malignant melanoma arising in an inverted papilloma.Histopathology 20:523–526100. Guarisco JL, Butcher RB (1990) Congenital cystic teratoma ofthe maxillary sinus. Otolaryngol Head Neck Surg 103:1035–1038

Nasal Cavity and Paranasal Sinuses Chapter 2 67101. Gupta A, Seiden AM (2003) Nasal leprosy: case study. OtolaryngolHead Neck Surg 129:608–610102. Hadfield EH, Macbeth RG (1971) Adenocarcinoma of ethmoidsin furniture workers. Ann Otol Rhinol Laryngol80:699–703103. Handler SD, Ward PH (1979) Oncocytoma of the maxillarysinus. Laryngoscope 69:372–376104. Hanna GS, Ali MH (1987) Verrucous carcinoma of the nasalseptum. J Laryngol Otol 101:184–187105. Harbo G, Grau C, Bundgaard T, Overgaard M, Elbrond O,Sogaard H, Overgaard J (1997) Cancer of the nasal cavity andparanasal sinuses. A clinico-pathological study of 277 patients.Acta Oncol 36:45–50106. Hardy G (1957) The choanal polyp. Ann Otol Laryngol Rhinol66:306–326107. Harrison DFN (1976) Malignant melanomata arising in the nasalmucous membrane. J Laryngol Otol 90:993–1005108. Hasegawa SL, Mentzel T, Fletcher CD (1997) Schwannomasof the sinonasal tract and nasopharynx. Mod Pathol 10:777–784109. Heffner DK (1983) Problems in pediatric otorhinolaryngicpathology. I. Sinonasal and nasopharyngeal tumors andmasses with myxoid features. Int J Pediatr Otorhinolaryngol5:77–91110. Heffner DK (1991) Sinonasal and laryngeal salivary gland lesions.In: Ellis GL, Auclair PL, Gnepp DR (eds) Surgical pathologyof salivary glands. Saunders, Philadelphia, pp 544–559111. Heffner DK, Gnepp DR (1992) Sinonasal fibrosarcomas, malignantschwannomas, and “Triton” tumors. A clinicopathologicstudy of 67 cases. Cancer 70:1089–1101112. Heffner DK, Hyams VJ (1984) Teratocarcinosarcoma (malignantteratoma?) of the nasal cavity and paranasal sinuses. Cancer53:2140–215113. Heffner DK, Hyams VJ, Hauck KW, Lingeman C (1982) Lowgradeadenocarcinoma of the nasal cavity and paranasal sinuses.Cancer 50:312–322114. Helliwell TR, Yeoh LH, Stell PM (1986) Anaplastic carcinomaof the nose and paranasal sinuses. Light microscopy, immunohistochemistry,and clinical correlation. Cancer 58:2038–2045115. Hellquist HB (1996) Nasal polyps update. Histopathology.Allergy Asthma Proc 17:237–242116. Herrmann BW, Sotelo-Avila C, Eisenbeis JF (2003) Pediatricsinonasal rhabdomyosarcoma: three cases and a review ofthe literature. Am J Otolaryngol 24:174–180117. Hillstrom RP, Zarbo RJ, Jacobs JR (1990) Nerve sheath tumorsof the paranasal sinuses: electron microscopy andhistopathologic diagnosis. Otolaryngol Head Neck Surg102:257–263118. Ho KL (1980) Primary meningioma of the nasal cavity andparanasal sinuses. Cancer 46:1442–1447119. Huang HY, Antonescu CR (2003) Sinonasal smooth musclecell tumors: a clinicopathologic and immunohistochemicalanalysis of 12 cases with emphasis on the low-grade end ofthe spectrum. Arch Pathol Lab Med 127:297–304120. Hwang HC, Mills SE, Patterson K, Gown AM (1998) Expressionof androgen receptors in nasopharyngeal angiofibroma:an immunohistochemical study of 24 cases. Mod Pathol11:1122–1126121. Hyams VJ (1971) Papillomas of the nasal cavity and paranasalsinuses. A clinicopathologic study of 315 cases. Ann OtolRhinol Laryngol 80:192–206122. Hyams VJ, Batsakis JG, Michaels L (1988) Tumors of the upperrespiratory tract and ear. In: Atlas of Tumor Pathology,2nd series. Fascicle 25. Armed Forces Institute of Pathology,Washington, D.C.123. Imbus HR, Dyson WL (1987) A review of nasal cancer in furnituremanufacturing and woodworking in North Carolina,the United States, and other countries. J Occup Med 29:734–740124. Ironside P, Matthews J (1975) Adenocarcinoma of the noseand paranasal sinuses in woodworkers in the state of Victoria,Australia. Cancer 36:1115–1124125. Jacobsson M, Petruson B, Svendsen P, Berthelsen B (1988)Juvenile nasopharyngeal angiofibroma. A report of eighteencases. Acta Otolaryngol 105:132–139126. Jarvi O (1945) Heterotopic tumors with an intestinal mucousmembrane structure in the nasal cavity. Acta Otolaryngol33:471–85127. Jeng YM, Sung MT, Fang CL, Huang HY, Mao TL, Cheng W,Hsiao CH (2002) Sinonasal undifferentiated carcinoma andnasopharyngeal-type undifferentiated carcinoma. Two clinically,biologically, and histopathologically distinct entities.Am J Surg Pathol 26:371–376128. Judd R, Zaki SR, Coffield LM, Evatt BL (1991) Sinonasal papillomasand human papillomavirus: human papillomavirus11 detected in fungiform schneiderian papillomas by insitu hybridization and the polymerase chain reaction. HumPathol 22:550–556129. Kadish S, Goodman M, Wang CC (1976) Olfactory neuroblastoma.A clinical analysis of 17 cases. Cancer 37:1571–1576130. Kagan AR, Nussbaum H, Rao A, Chan P, Gilbert H, Hintz B,Ryoo M, Miles J, Rice D (1981) The management of carcinomaof the nasal vestibule. Head Neck Surg 4:125–128131. Kahn LB (1974) Esthesioneuroblastoma. A light and electronmicroscopic study. Hum Pathol 5:364–371132. Kameya T, Shimosato Y, Adachi I, Abe K, Ebihara S, Ono I(1980) Neuroendocrine carcinoma of the paranasal sinus. Amorphological and endocrinological study. Cancer 45:330–339133. Kapadia SB (1985) Hematologic diseases: malignant lymphomas,leukemias, plasma cell dyscrasias, histiocytosis X, andreactive lymph node lesions. In: Barnes L (ed) Surgical pathologyof the head and neck, vol 2. Dekker, New York134. Kapadia SB, Barnes L, Deutsch M (1981) Non-Hodgkin’slymphoma of the nose and paranasal sinuses: a study of 17cases. Head Neck Surg 3:490–499135. Kapadia SB, Barnes L, Pelzman K, Mirani N, Heffner DK, BedettiC (1993) Carcinoma ex oncocytic Schneiderian (cylindricalcell) papilloma. Am J Otolaryngol 14:332–338136. Karma P, Rasanen O, Karja J (1977) Nasal gliomas. A reviewand report of two cases. Laryngoscope 87:1169–1179137. Katzenstein AL, Sale SR, Greenberger PA (1983) Pathologicfindings in allergic aspergillus sinusitis. A newly recognizedform of sinusitis. Am J Surg Pathol 7:439–443138. Kim ST, Kim CW, Han GC, Park C, Jang IH, Cha HE, ChoiG, Lee HM (2001) Malignant triton tumor of the nasal cavity.Head Neck 23:1075–1078139. Kleinsasser O (1985) Terminal tubulus adenocarcinoma ofthe nasal seromucous glands. A specific entity. Arch Otorhinolaryngol241:183–193140. Kleinsasser O, Schroeder HG (1988) Adenocarcinoma of theinner nose after exposure to wood dust. Morphological findingsand relationships between histopathology and clinicalbehavior in 79 cases. Arch Otorhinolaryngol 245:1–15141. Klein-Szanto AJ, Boysen M, Reith A (1987) Keratin and involucrinin preneoplastic and neoplastic lesions. Distributionin the nasal mucosa of nickel workers. Arch Pathol Lab Med111:1057–1061142. Klintenberg C, Olofsson J, Hellquist H, Sokjer H (1984) Adenocarcinomaof the ethmoid sinuses. A review of 28 caseswith special reference to wood dust exposure. Cancer54:482–488143. Krespi YP, Kuriloff DB, Aner M (1995) Sarcoidosis of the sinonasaltract: a new staging system. Otolaryngol Head NeckSurg 112:221–227144. Kuruvilla A, Wenig BM, Humphrey DM, Heffner DK (1990)Leiomyosarcoma of the sinonasal tract. A clinicopathologicstudy of nine cases. Arch Otolaryngol Head Neck Surg116:1278–1286145. Kyriakos M (1977) Myospherulosis of the paranasal sinuses,nose and middle ear. A possible iatrogenic disease. Am J ClinPathol 67:118–130146. Larsson LG, Martensson G (1972) Maxillary antral cancers.JAMA 219:342–345147. Lee BJ, Park HJ, Heo SC (2003) Organized hematoma of themaxillary sinus. Acta Otolaryngol 123:869–872

68 A. Cardesa · L. Alos · A. Franchi2148. Lewis MG, Martin JAM (1967) Malignant melanoma of the nasalcavity in Ugandan Africans: relationship of ectopic pigmentation.Cancer 20:1699–1705149. Llombart-Bosch A, Terrier-Lacombe J, Peydro-Olaya A,Contesso G (1989) Peripheral neuroectodermal sarcoma ofsoft tissue (peripheral neuroepithelioma): a pathologic studyof ten cases with differential diagnosis regarding other small,round-cell sarcomas. Hum Pathol 20:273–280150. Lloreta J, Serrano S, Corominas JM, Ferrer-Padro E (1995)Polymorphous low-grade adenocarcinoma arising in the nasalcavities with an associated undifferentiated carcinoma.Ultrastruct Pathol 19:365–370151. Lloreta-Trull J, Mackay B, Troncoso P, Ribalta-Farres T,Smith T, Khorana S (1992) Neuroendocrine tumors of thenasal cavity: an ultrastructural study of 24 cases. UltrstructPathol 16: 165–175152. Lloyd RV, Chandler WF, Kovaks K, Ryan N (1986) Ectopicpituitary adenomas with normal anterior pituitary glands.Am J Surg Pathol 108:546–552153. Lohuis PJ, Lipovsky MM, Hoepelman AI, Hordijk GJ, HuizingEH (1997) Leishmania braziliensis presenting as a granulomatouslesion of the nasal septum mucosa. J Laryngol Otol111:973–975154. Loree TR, Mullins AP, Spellman J, North JH Jr, Hicks WLJr (1999) Head and neck mucosal melanoma: a 32-year review.Ear Nose Throat J 78:372–375155. Luce D, Gerin M, Leclerc A, Morcet JF, Brugere J, GoldbergM (1993) Sinonasal cancer and occupational exposureto formaldehyde and other substances. Int J Cancer 53:224–231156. Luna MA (1995) Critical commentary to “Sino nasal teratocarcinosarcoma”.Pathol Res Pract 191:172157. Lund V (1982) Malignant melanoma of the nasal cavity andparanasal sinuses. J Laryngol Otol 96:347–355158. Lund VJ, Milroy CM (1991) Fronto-ethmoidal mucoceles: ahistopathological analysis. J Laryngol Otol 105:921–923159. Mackay B, Luna MA, Butler JJ (1976) Adult neuroblastoma.Electronmicroscopic observations in nine cases. Cancer37:1334–1351160. Majumdar B, Kent S (1983) Malignant neoplasms of the noseand paranasal sinuses. A survey of cases treated in a regionalcentre. Clin Otolaryngol 8:97–102161. Makannavar JH, Chavan SS (2001) Rhinosporidiosis. A clinicopathologicalstudy of 34 cases. Indian J Pathol Microbiol44:17–21162. Manivel C, Wick MR, Dehner LP (1986) Transitional (cylindric)cell carcinoma with endodermal sinus tumor-like featuresof the nasopharynx and paranasal sinuses. Clinicopathologicand immunohistochemical study of two cases.Arch Pathol Lab Med 110:198–202163. Mannan AA, Singh MK, Bahadur S, Hatimota P, SharmaMC (2003) Solitary malignant schwannoma of the nasal cavityand paranasal sinuses: report of two rare cases. Ear NoseThroat J 82:634–646164. Marks SC, Upadhyay S, Crane L (1996) Cytomegalovirus sinusitis.A new manifestation of AIDS. Arch OtolaryngolHead Neck Surg 122:789–791165. McDonald TJ, DeRemee RA, Kern EB, Harrison EG Jr (1974)Nasal manifestations of Wegener’s granulomatosis. Laryngoscope84:2101–2112166. McKinney CD, Mills SE, Franquemont DW (1995) Sinonasalintestinal-type adenocarcinoma. Immunohistochemicalprofile and comparison with colonic adenocarcinoma. ModPathol 8:421–426167. Mendenhall WM, Stringer SP, Cassisi NJ, Mendenhall NP(1999) Squamous cell carcinoma of the nasal vestibule. HeadNeck 21:385–393168. Mentzel T, Bainbridge TC, Katenkamp D (1997) Solitary fibroustumour: clinicopathological, immunohistochemical,and ultrastructural analysis of 12 cases arising in soft tissues,nasal cavity and nasopharynx, urinary bladder and prostate.Virchows Arch 430:445–453169. Mesara BW, Batsakis JG (1966) Glandular tumors of the upperrespiratory tract. A clinicopathologic assessment. ArchSurg 92:872–878170. Meyer RD, Gaultier CR, Yamashita JT, Babapour R, PitchonHE, Wolfe PR (1994) Fungal sinusitis in patients with AIDS:report of 4 cases and review of the literature. Medicine (Baltimore)73:69–78171. Michaels L, Hellquist HB (2001) Ear, nose and throat histopathology.Springer, Berlin Heidelberg New York172. Michaels L, Lloyd G, Phelps P (2000) Origin and spread of allergicfungal disease of the nose and paranasal sinuses. ClinOtolaryngol 25:518–525173. Michaels L, Young M (1995) Histogenesis of papillomas of thenose and paranasal sinuses. Arch Pathol Lab Med 119:821–826174. Mills SE, Fechner RE, Cantrell RW (1982) Aggressive sinonasallesion resembling normal intestinal mucosa. Am J SurgPathol 6:803–809175. Mills SE, Frierson HF (1985) Olfactory neuroblastoma. Aclinicopathologic study of 21 cases. Am J Surg Pathol 9:317–327176. Mills SE, Gaffey MJ, Frierson HF (2000) Tumors of the upperaerodigestive tract and ear. Atlas of tumor pathology.Third Series. Fascicle 26. Armed Forces Institute of Pathology.Washington D.C.177. Min YG, Shin JS, Choi SH, Chi JG, Yoon CJ (1995) Primaryciliary dyskinesia: ultrastructural defects and clinicalfeatures. Rhinology 33:189–193178. Moore EJ, Kern EB (2001) Atrophic rhinitis: a review of 242cases. Am J Rhinol 15:355–361179. Morita A, Ebersold MJ, Olsen KD, Foote RL, Lewis JE, QuastLM (1993) Esthesioneuroblastoma: prognosis and management.Neurosurgery 32:706–715180. Mufarrij AA, Busaba NY, Zaytoun GM, Gallo GR, Feiner HD(1990) Primary localized amyloidosis of the nose and paranasalsinuses. A case report with immunohistochemical observationsand a review of the literature. Am J Surg Pathol14:379–383181. Nakashima T, Kimmelman CP, Snow JB Jr (1984) Structureof human fetal and adult olfactory neuroepithelium. ArchOtolaryngol 110:641–646182. Nakashima T, Kimmelman CP, Snow JB Jr (1985) Olfactorymarker protein in the human olfactory pathway. Arch Otolaryngol111:294–297183. Nakayama M, Wenig BM, Heffner DK (1995) Atypical stromalcells in inflammatory nasal polyps: immunohistochemicaland ultrastructural analysis in defining histogenesis. Laryngoscope105:127–134184. Natvig K, Larsen TE (1978) Mucocele of the paranasal sinuses.A retrospective clinical and histological study. J LaryngolOtol 92:1075–1082185. Navarrete ML, Quesada P, Pellicer M, Ruiz C (1991) Extramedullarynasal plasmacytoma. J Laryngol Otol 105:41–43186. Ng HK, Poon WS, Poon CY, South JR (1988) Intracranial olfactoryneuroblastoma mimicking carcinoma: report of twocases. Histopathology 12:393–403187. Nguyen QA, Gibbs PM, Rice DH (1995) Malignant nasalparaganglioma: a case report and review of the literature.Otolaryngol Head Neck Surg 113:157–161188. O’Connor GT Jr, Drake CR, Johns ME, Cail WS, Winn HR,Niskanen E (1985) Treatment of advanced esthesioneuroblastomawith high-dose chemotherapy and autologous bonemarrow transplantation. A case report. Cancer 55:347–349189. Oppenheimer EH, Rosenstein BJ (1979) Differential pathologyof nasal polyps in cystic fibrosis and atopy. Lab Invest40:455–449190. Ordoñez NG, Batsakis JG (1986) Acinic cell carcinoma of thenasal cavity: electron-optic and immunohistochemical observations.J Laryngol Otol 100:345–349191. Ordóñez NG, Mackay B (1993) Neuroendocrine tumors ofthe nasal cavity. Pathol Annu 28:77–111192. Orvidas LJ, Lewis JE, Olsen KD, Weiner JS (1999) Intranasalverrucous carcinoma; relationship to inverting papillomaand human papillomavirus. Laryngoscope 109:371–375193. Osborn DA (1956) Transitional cell growths of the upper respiratorytract. J Laryngol Otol 70:574–587194. Osborn DA (1970) Nature and behavior of transitional tumorsin the upper respiratory tract. Cancer 25:50–60

Nasal Cavity and Paranasal Sinuses Chapter 2 69195. Pai SA, Naresh KN, Masih K, Ramarao C, Borges AM (1998)Teratocarcinosarcoma of the paranasal sinuses: a clinicopathologicand immunohistochemical study. Hum Pathol 29:718–722196. Patterson K, Kapur S, Chandra RS (1986) “Nasal gliomas”and related brain heterotopias: a pathologist’s perspective.Pediatr Pathol 5:353–362197. Patuano E, Carrat X, Drouet Y, Barnabe D, Vincey P, BerthelotB (1993) Mucocutaneous leishmaniasis in otorhinolaryngology.Ann Otolaryngol Chir Cervicofac 110:415–419198. Paugh DR, Sullivan MJ(1990) Myospherulosis of the paranasalsinuses. Otolaryngol Head Neck Surg 103:117–119199. Perez-Ordoñez B, Caruana SM, Huvos AG, Shah JP (1998)Small cell neuroendocrine carcinoma of the of the nasal cavityand paranasal sinuses. Hum Pathol 29:826–832200. Perzin KH, Cantor JO, Johannessen JV (1981) Acinic cell carcinomaarising in the nasal cavity: report of a case with ultrastructuralobservations. Cancer 47:1818–1822201. Perzin KH, Fu YS (1980) Non-epithelial tumors of the nasalcavity, paranasal sinuses and nasopharynx: a clinico-pathologicstudy. XI. Fibrous histiocytomas. Cancer 45:2616–2626202. Perzin KH, Panyu H, Wechter S (1982) Nonepithelial tumorsof the nasal cavity, paranasal sinuses and nasopharynx.A clinicopathologic study. XII. Schwann cell tumors (neurilemomaneurofibroma, malignant schwannoma). Cancer50:2193–2202203. Perzin KH, Pushparaj N (1984) Nonepithelial tumors of thenasal cavity, paranasal sinuses, and nasopharynx. A clinicopathologicstudy. XIII. Meningiomas. Cancer 54:1860–1869204. Phillips PP, Gustafson RO, Facer GW (1990) The clinical behaviorof inverting papilloma of the nose and paranasal sinuses;report of 112 cases and review of the literature. Laryngoscope100:468–469205. Piscioli F, Aldovini D, Bondi A, Eusebi V (1984) Squamouscell carcinoma with sarcoma-like stroma of the nose and paranasalsinuses: report of two cases. Histopathology 8:633–639206. Pitman KT, Prokopakis EP, Aydogan B, Segas J, Carrau RL,Snyderman CH,Janecka IP, Hanna E, D’Amico F, JohnsonJT (1999) The role of skull base surgery for the treatment ofadenoid cystic carcinoma of the sinonasal tract. Head Neck21:402–407207. Prasad ML, Jungbluth AA, Iversen K, Huvos AG, Busam KL(2001) Expression of melanocytic differentiation markers inmalignant melanomas of the oral and sinonasal mucosa. AmJ Surg Pathol 25:782–787208. Raychowdhuri RN (1965) Oat cell carcinoma and paranasalsinuses. J Laryngol Otol 79:253–255209. Regauer S, Anderhuber W, Richtig E, Schachenreiter J, OttA, Beham A (1998) Primary mucosal melanomas of the nasalcavity and paranasal sinuses. A clinicopathologic analysis of14 cases. APMIS 106:403–404210. Rejowski JE, Campanella RS, Block LJ (1982) Small cell carcinomaof the nose and paranasal sinuses. Otolaryngol HeadNeck Surg 90:516–517211. Ridolfi RL, Liberman PH, Erlandson RA, Moore OS (1977)Schneiderian papillomas; a clinicopathologic study of 30 cases.Am J Surg Pathol 1:43–53212. Ringertz N (1938) Pathology of malignant tumours arising inthe nasal and paranasal cavities and maxilla. Acta OtolaryngolSuppl 27:31–42213. Robbins KT, Fuller LM, Vlasak M et al. (1985) Primary lymphomasof the nasal cavity and paranasal sinuses. Cancer56:814–819214. Roberts PF, McCann BG (1985) Eosinophilic angiocentricfibrosis of the upper respiratory tract: a mucosal variant ofgranuloma faciale? A report of three cases. Histopathology9:1217–1225215. Robin PE, Powell DJ (1980) Regional node involvement anddistant metastases in carcinoma of the nasal cavity and paranasalsinuses. J Laryngol Otol 94:301–309216. Robin PE, Powell DJ, Stassbie JM (1979) Carcinoma of thenasal cavity and paranasal sinuses: incidence and presentationof different histological types. Clin Otolaryngol 4:431–456217. Rosai J (1978) The nature of myospherulosis of the upper respiratorytract. Am J Clin Pathol 69:475–481218. Rousch GC (1979) Epidemiology of cancer of the nose andparanasal sinuses: current concepts. Head Neck Surg 2:3–11219. Sadler TW (1985) Langman’s medical embryology, 5th edn.Williams & Wilkins, Baltimore220. Sanchez-Casis G, Devine KD, Weiland LH (1971) Nasal adenocarcinomasthat closely simulate colonic carcinomas.Cancer 28:714–729221. Sarkar FH, Visscher DW, Kintanar EB, Zarbo RJ, CrissmanJD (1992) Sinonasal schneiderian papillomas: human papillomavirustyping by polymerase chain reaction. Mod Pathol5:329–332222. Schmid KO, Aubock L, Albegger K (1979) Endocrine-amphicrineenteric carcinoma of the nasal mucosa. Virchows ArchA Pathol Anat Histol 383:329–343223. Schwartz S, Thiel E (1997) Clinical presentation of invasiveaspergillosis. Mycoses 40 [Suppl 2]:21–24224. Seifert G (1991) WHO histological typing of salivary glandtumours. Springer, Berlin Heidelberg New York225. Seyer BA, Grist W, Muller S (2002) Aggressive destructivemidfacial lesion from cocaine abuse. Oral Surg Oral MedOral Pathol Oral Radiol Endod 94:465–470226. Shanmugaratnam K (1991) WHO histological typing of tumoursof the upper respiratory tract and ear. Springer, BerlinHeidelberg New York227. Shanmugaratnam K, Kunaratnam N, Chia KB, Chiang GS,Sinniah R (1983) Teratoid carcinosarcoma of the paranasalsinuses. Pathology 15:413–419228. Shimada K, Kobayashi S, Yamadori I, Ohmori M (1988) Myospherulosisin Japan. A report of two cases and an immunohistochemicalinvestigation. Am J Surg Pathol 12:427–432229. Silva EG, Butler JJ, Mackay B, Goepfert H (1982) Neuroblastomasand neuroendocrine carcinomas of the nasal cavity. Aproposed new classification. Cancer 50:2388–2405230. Sindwani R, Cohen JT, Pilch BZ, Metson RB (2003) Myospherulosisfollowing sinus surgery: pathological curiosityor important clinical entity? Laryngoscope 113:1123–1127231. Singhal SK, Dass A, Mohan H, Venkataramana Y (2002) Primarynasal tuberculosis. J Otolaryngol 31:60–62232. Siniluoto TM, Luotonen JP, Tikkakoski TA, Leinonen AS,Jokinen KE (1993) Value of pre-operative embolization insurgery for nasopharyngeal angiofibroma. J Laryngol Otol107:514–521233. Siu LL, Chan V, Chan JK, Wong KF, Liang R, Kwong YL(2000) Consistent patterns of allelic loss in natural killer celllymphoma. Am J Pathol 157:1803–1809234. Skalova A, Cardesa A, Leivo I, Pfaltz M, Ryska A, SimpsonR, Michal M (2003) Sinonasal tubulopapillary low grade adenocarcinoma.Histopathological, immunohistochemical andultrastructural features of a poorly recognized entity. VirchowsArch 443:152–158235. Smith CJ, Echevarria R, McLelland CA (1974) Pseudosarcomatouschanges in antrochoanal polyps. Arch Otolaryngol99:228–230236. Smith O, Gullane PJ (1987) Inverting papilloma of the nose:analysis of 48 patients. J Otolaryngol 16:154–156237. Sobin LH, Wittekind C (2002) UICC TNM classification ofmalignant tumours, 6th edn. Wiley-Liss, New York238. Sorensen PH, Liu XF, Delattre O et al. (1993) Reverse transcriptasePCR amplification of EWS/FLI-1 fusion transcriptsas a diagnostic test for peripheral primitive neuroectodermaltumors of childhood. Diagn Mol Pathol 2:147–157239. Spiro RH, Koss LG, Hajdu SI, Strong EW (1973) Tumors ofminor salivary gland origin: a clinicopathologic study of 492cases. Cancer 31:117–129240. Stammberger H (1983) Neue Aspekte zur Genese des invertiertenPapilloms. Laryngol Rhinol Otol (Stuttg) 62:249–255241. Stewart FM, Lazarus HM, Levine PA, Stewart KA, TabbaraIA, Spaulding CA (1989) High-dose chemotherapy and autologousmarrow transplantation for esthesioneuroblastomaand sinonasal undifferentiated carcinoma. Am J Clin Oncol12:217–221

70 A. Cardesa · L. Alos · A. Franchi2242. Stierna P, Carlsoo B (1990) Histopathological observationsin chronic maxillary sinusitis. Acta Otolaryngol 110:450–458243. Sunderman FW Jr, Morgan LG, Andersen A, Ashley D, ForouharFA (1989) Histopathology of sinonasal and lung cancersin nickel refinery workers. Ann Clin Lab Sci 19:44–50244. Takeshita H, Miwa T, Furukawa M (2002) Osteocartilaginousdifferentiation of mucosal melanoma in the sinonasalcavity. Ann Otol Rhinol Laryngol 111:1112–1115245. Taxy JB (1997) Squamous carcinoma of the nasal vestibule.An analysis of five cases and literature review. Am J ClinPathol 107:698–703246. Taxy JB, Bharani NK, Mills SE, Frierson HF Jr, Gould VE(1986) The spectrum of olfactory neural tumors. A light-microscopic,immunohistochemical and ultrastructural analysis.Am J Surg Pathol 10:687–705247. Taxy JB, Hidvegi DF (1977) Olfactory neuroblastoma: an ultrastructuralstudy. Cancer 39:131–138248. Thompson LD, Heffner DK (2001) Sinonasal tract eosinophilicangiocentric fibrosis. A report of three cases. Am JClin Pathol 115:243–248249. Thompson LD, Miettinen M, Wenig BM (2003) Sinonasaltypehemangiopericytoma: a clinicopathologic and immunophenotypicanalysis of 104 cases showing perivascular myoiddifferentiation. Am J Surg Pathol 27:737–749250. Thompson LD, Wieneke JA, Miettinen M (2003) Sinonasaltract and nasopharyngeal melanomas: a clinicopathologicstudy of 115 cases with a proposed staging system. Am J SurgPathol 27:594–611251. Topilko A, Zakrzewski A, Pichard E, Viron A (1984) Ultrastructuralcytochemistry of intranuclear dense granules innasopharyngeal angiofibroma. Ultrastruct Pathol 6:221–228252. Torjussen W, Haug FM, Andersen I (1978) Concentrationand distribution of heavy metals in nasal mucosa of nickel-exposedworkers and of controls, studied with atomic absorptionspectrophotometric analysis and with Timm’s sulphidesilver method. Acta Otolaryngol 86:449–463253. Torjusen W, Solberg LA, Hogetvit AC (1979) Histopathologicchanges of the nasal mucosa in nickel workers. A pilot study.Cancer 44:963–974254. Torske KR, Benson GS, Warnock G (2001) Dermoid cyst ofthe maxillary sinus. Ann Diagn Pathol 5:172–176255. Tran I, Sidrys J, Horton D et al. (1989) Malignant salivarygland tumors of the paranasal sinuses and nasal cavity. TheUCLA experience. Am J Clin Oncol 12:387–392256. Trapp TK, Fu YS, Calcaterra TC (1987) Melanoma of the nasaland paranasal sinus mucosa. Head Neck Surg 113:1086–1089257. Trojanowski JQ, Lee V, Pillsbury N, Lee S (1982) Neuronalorigin of human esthesioneuroblastoma demonstrated withanti-neurofilament monoclonal antibodies. N Engl J Med307:159–161258. Tsikoudas A, Martin-Hirsch DP, Woodhead CJ (2001) Primarysinonasal amyloidosis. J Laryngol Otol 115:55–56259. Tufano RP, Mokadam NA, Montone KT Weinstein GS, ChalianAA, Wolf PF, Weber RS (1999) Malignant tumors of thenose and paranasal sinuses: hospital of the University ofPennsylvania experience 1990–1997. Am J Rhinol 13:117–123260. Turc-Carel C, Aurias A, Mugneret F, Lizard S, Sidaner I, VolkC, Thiery JP, Olschwang S, Philip I, Berger MP (1988) Chromosomesin Ewing’s sarcoma. I. An evaluation of 85 casesof remarkable consistency of t(11;22)(q24;q12). Cancer GenetCytogenet 32:229–238261. Walike JW (1973) Anatomy of the nasal cavities. OtolaryngolClin North Am 6:609–621262. Ward BE, Fechner RE, Mills SE (1990) Carcinoma arising inoncocytic Schneiderian papilloma. Am J Surg Pathol 14:364–369263. Weidner N, Tjoe J (1994) Immunohistochemical profile ofmonoclonal antibody O13: antibody that recognizes glycoproteinp30/32MIC2 and is useful in diagnosing Ewing’s sarcomaand peripheral neuroepithelioma. Am J Surg Pathol18:486–494264. Weiss MD, deFies HO, Taxy JB, Braine H (1983) Primarysmall cell carcinoma of the paranasal sinuses. Arch Otolaryngol109:341–343265. Weissler MC, Montgomery WW, Montgomery SK, TurnerPA, Joseph MP (1986) Inverted papilloma. Ann Otol RhinolLaryngol 95:215–221266. Wenig BM, Heffner DK (1995) Respiratory epithelial adenomatoidhamartomas of the sinonasal tract and nasopharynx:a clinicopathologic study of 31 cases. Ann Otol Rhinol Laryngol104:639–645267. Wenig BM, Hyams VJ, Heffner DK (1988) Nasopharyngealpapillary adenocarcinoma. A clinicopathologic study of alow-grade carcinoma. Am J Surg Pathol 12:946–953267a. World Health Organization Classification of Tumours (2005)Pathology and genetics of tumours of the head and neck.IARC, Lyon268. Wick MR, Stanley SJ, Swanson PE (1988) Immunohistochemicaldiagnosis of sinonasal melanoma, carcinoma, andneuroblastoma with monoclonal antibodies HMB-45 andantisynaptophysin. Arch Pathol Lab Med 112:616–620269. Wieneke JA, Thompson LD, Wenig BM (1999) Basaloid squamouscell carcinoma of the sinonasal tract. Cancer 85:841–854270. Wilhelmsson B, Hellquist H, Olofsson J, Klintenberg C (1985)Nasal cuboidal metaplasia with dysplasia. Precursor to adenocarcinomain wood-dust exposed workers? Acta Otolaryngol99:641–648271. Winther B, Gwaltney JM Jr, Mygind N, Hendley JO (1998)Viral-induced rhinitis. Am J Rhinol 12:17–20271a. Wittekind C, Greene FL, Hutter RVP, Klimpfinger M, SobinLH (2004) UICC TNM atlas. Illustrated guide to the TNM/pTNM classification of malignant tumours. 5 th edn. Springer,Berlin272. Wolff M (1974) Granulomas in nasal mucous membranes followinglocal steroid injections. Am J Clin Pathol 62:775–782273. Woodson GE, Robbins KT, Michaels L (1985) Inverted papilloma.Considerations in treatment. Arch Otolaryngol111:806–811274. Yang YJ, Abraham JL (1997) Undifferentiated carcinomaarising in oncocytic Schneiderian (cylindrical cell) papilloma.J Oral Maxillofac Surg 55:289–294275. Zak FG, Lawson W (1974) The presence of melanocytes in thenasal cavity. Ann Otol Rhinol Laryngol 83:515–519276. Zarbo RJ, Crissman JD, Venkat H, Weiss MA (1986) Spindlecellcarcinoma of the upper aerodigestive tract mucosa. Am JSurg Pathol 10:741–753277. Zarbo RJ, Ricci A, Kowalczyk PD, Kartun RW, Knibbs DR(1985) Intranasal dermal analogue tumor (membranous basalcell adenoma). Arch Otolaryngol 111:333–337278. Zerris VA, Annino D, Heilman CB (2002) Nasofrontal dermoidsinus cyst: report of two cases. Neurosurgery 51:811–814279. Zukerberg LR, Rosenberg AE, Randolph G, Pilch BZ, GoodmanML (1991) Solitary fibrous tumor of the nasal cavity andparanasal sinuses. Am J Surg Pathol 15:126–130280. Zur KB, Brandwein M, Wang B, Som P Gordon R, Urken ML(2002) Primary description of a new entity; renal cell-likecarcinoma of the nasal cavity. Van Meegeren in the house ofVermeer. Arch Otolaryngol Head Neck Surg 128:441–447281. Zurlo JJ, Feuerstein IM, Lebovics R, Lane HC (1992) Sinusitisin HIV-1 infection. Am J Med 93:157–162

Chapter 3Oral Cavity3J.W. EvesonContents3.1 Embryonic Rests and Heterotopias . . . . . . . . . . . 723.1.1 Fordyce Granules/Spots . . . . . . . . . . . . . . . . . 723.1.2 Juxtaoral Organ of Chievitz . . . . . . . . . . . . . . . 723.2. Vesiculo-Bullous Diseases . . . . . . . . . . . . . . . . 723.2.1 Herpes Simplex Infections . . . . . . . . . . . . . . . . 723.2.2 Chickenpox and Herpes Zoster . . . . . . . . . . . . . 733.2.3 Hand-Foot-and-Mouth Disease . . . . . . . . . . . . . 733.2.4 Herpangina . . . . . . . . . . . . . . . . . . . . . . . . . 743.2.5 Pemphigus Vulgaris . . . . . . . . . . . . . . . . . . . . 743.2.6 Pemphigus Vegetans . . . . . . . . . . . . . . . . . . . 743.2.7 Paraneoplastic Pemphigus . . . . . . . . . . . . . . . . 753.2.8 Mucous Membrane Pemphigoid . . . . . . . . . . . . 753.2.9 Dermatitis Herpetiformis . . . . . . . . . . . . . . . . 763.2.10 Linear IgA Disease . . . . . . . . . . . . . . . . . . . . 763.2.11 Erythema Multiforme . . . . . . . . . . . . . . . . . . 773.3 Ulcerative Lesions . . . . . . . . . . . . . . . . . . . . . 773.3.1 Aphthous Stomatitis(Recurrent Aphthous Ulceration) . . . . . . . . . . . . 773.3.2 Behçet Disease . . . . . . . . . . . . . . . . . . . . . . . 783.3.3 Reiter Disease . . . . . . . . . . . . . . . . . . . . . . . 783.3.4 Median Rhomboid Glossitis . . . . . . . . . . . . . . . 783.3.5 Eosinophilic Ulcer(Traumatic Ulcerative Granulomawith Stromal Eosinophilia) . . . . . . . . . . . . . . . 793.3.6 Acute Necrotising Ulcerative Gingivitis . . . . . . . . 793.3.7 Wegener’s Granulomatosis . . . . . . . . . . . . . . . . 803.3.8 Tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . 813.4 White Lesions . . . . . . . . . . . . . . . . . . . . . . . 813.4.1 Candidosis . . . . . . . . . . . . . . . . . . . . . . . . . 813.4.2 Lichen Planus . . . . . . . . . . . . . . . . . . . . . . . 823.4.3 Lupus Erythematosus . . . . . . . . . . . . . . . . . . . 833.4.4 Oral Epithelial Naevi . . . . . . . . . . . . . . . . . . . 843.4.5 Smoker’s Keratosis . . . . . . . . . . . . . . . . . . . . . 843.4.6 Stomatitis Nicotina . . . . . . . . . . . . . . . . . . . . 843.4.7 Hairy Tongue . . . . . . . . . . . . . . . . . . . . . . . 853.4.8 Hairy Leukoplakia . . . . . . . . . . . . . . . . . . . . 853.4.9 Geographic Tongue . . . . . . . . . . . . . . . . . . . . 853.4.10 Frictional Keratosis . . . . . . . . . . . . . . . . . . . . 863.5 Pigmentations . . . . . . . . . . . . . . . . . . . . . . . 863.5.1 Amalgam Tattoo . . . . . . . . . . . . . . . . . . . . . . 863.5.2 Localised Melanotic Pigmentation . . . . . . . . . . . 863.5.2.1 Oral Melanotic Macules . . . . . . . . . . . . . . . . . 863.5.2.2 Melanoacanthoma . . . . . . . . . . . . . . . . . . . . . 873.5.2.3 Pigmented Naevi . . . . . . . . . . . . . . . . . . . . . 873.5.3 Premalignant Oral Melanosesand Oral Melanoma . . . . . . . . . . . . . . . . . . . . 873.5.4 Addison Disease . . . . . . . . . . . . . . . . . . . . . . 883.5.5 Peutz Jeghers Syndrome . . . . . . . . . . . . . . . . . 893.5.6 Racial Pigmentation . . . . . . . . . . . . . . . . . . . . 893.5.7 Laugier Hunziker Syndrome . . . . . . . . . . . . . . . 893.5.8 Smoker’s Melanosis . . . . . . . . . . . . . . . . . . . . 893.5.9 Drug-Associated Oral Pigmentation . . . . . . . . . . 903.6 Hyperplastic Lesions . . . . . . . . . . . . . . . . . . . 903.6.1 Fibrous Hyperplasias . . . . . . . . . . . . . . . . . . . 903.6.2 Papillary Hyperplasia . . . . . . . . . . . . . . . . . . . 903.6.3 Generalised Gingival Fibrous Hyperplasia . . . . . . 913.6.4 Crohn’s Disease . . . . . . . . . . . . . . . . . . . . . . 913.6.5 Orofacial Granulomatosis . . . . . . . . . . . . . . . . 923.6.6 Chronic Marginal Gingivitisand Localised Gingival Fibrous Hyperplasia . . . . . 923.6.7 Peripheral Giant Cell Granuloma(Giant Cell Epulis) . . . . . . . . . . . . . . . . . . . . 933.6.8 Pyogenic Granuloma . . . . . . . . . . . . . . . . . . . 933.6.9 Pulse (Vegetable) Granuloma . . . . . . . . . . . . . . 933.7 Benign Tumours and Pseudotumours . . . . . . . . . 943.7.1 Giant Cell Fibroma . . . . . . . . . . . . . . . . . . . . 943.7.2 Lingual Thyroid . . . . . . . . . . . . . . . . . . . . . . 943.7.3 Verruciform Xanthoma . . . . . . . . . . . . . . . . . . . 953.7.4 Haemangiomas . . . . . . . . . . . . . . . . . . . . . . . 953.7.5 Lymphangioma . . . . . . . . . . . . . . . . . . . . . . . 953.7.6 Benign Nerve Sheath Tumours . . . . . . . . . . . . . . 953.7.6.1 Neurofibroma . . . . . . . . . . . . . . . . . . . . . . . 963.7.6.2 Schwannoma . . . . . . . . . . . . . . . . . . . . . . . . 963.7.6.3 Neurofibromatosis . . . . . . . . . . . . . . . . . . . . . 963.7.6.4 Multiple Neuromasin Endocrine Neoplasia Syndrome . . . . . . . . . . . 963.7.7 Granular Cell Tumour(Granular Cell Myoblastoma) . . . . . . . . . . . . . . 963.8 Squamous Cell Carcinoma . . . . . . . . . . . . . . . . 963.8.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . 963.8.2 Clinical Features . . . . . . . . . . . . . . . . . . . . . . 973.8.2.1 Buccal Mucosa . . . . . . . . . . . . . . . . . . . . . . . 973.8.2.2 Tongue . . . . . . . . . . . . . . . . . . . . . . . . . . . 973.8.2.3 Floor of Mouth . . . . . . . . . . . . . . . . . . . . . . . 973.8.2.4 Gingiva and Alveolar Ridge . . . . . . . . . . . . . . . 973.8.2.5 Hard Palate . . . . . . . . . . . . . . . . . . . . . . . . . 983.8.2.6 Retromolar Trigone . . . . . . . . . . . . . . . . . . . . 983.8.3 Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . 98References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98

72 J.W. Eveson33.1 Embryonic Restsand Heterotopias3.1.1 Fordyce Granules/SpotsFordyce granules are ectopic sebaceous glands in theoral mucosa [39, 119]. They appear as soft, creamy whiteor yellowish spots or clusters, typically a few millimetresin diameter. They are symmetrically distributedand tend to increase in size and number with age. Themain site is the buccal mucosa, but they may also involvethe vermilion border and labial mucosa, particularly inthe upper lip. More rarely, the tongue, palatoglossal fold,tonsil and other intraoral sites may be affected, and thecondition can then be confused with other lesions. Microscopyshows typical sebaceous glands opening directlyonto the surface by short, keratinised ducts withno associated hair follicles.3.1.2 Juxtaoral Organ of ChievitzChievitz’s organ, or the bucco-temporal organ, isthought to be a vestigial neuroepithelial structure. It hasalso been suggested that the juxtaoral organ is an anlageof the parotid gland, or arises from Schwann cells thathave undergone squamous metaplasia [132]. It has beendemonstrated in neonates and children and can persistinto adult life [16]. The organ is usually found betweenthe temporalis muscle and the bucco-temporal fascia orpterygomandibular raphe, and is usually present bilaterally.It is seen fortuitously, generally in material takenfrom surgical resections, and is important as it can bemisinterpreted as a squamous cell carcinoma. Very rarecases have presented as tumours in the infratemporalfossa [83]. It is usually only a few millimetres in size andmicroscopically forms a multilobulated mass of discretecell nests that resemble squamous epithelium, but do notshow obvious keratinisation. Occasionally, the cells haveclear cytoplasm and form duct-like structures that maycontain mucin-negative colloid. The cell nests are associatedwith nerve fibres, particularly at the periphery, andthis may be mistakenly interpreted as a squamous carcinomawith perineural involvement, or sometimes mucoepidermoidcarcinoma and thyroid carcinoma [103].The central areas of the epithelial cell nests are positivefor cytokeratin 19 and most cell nests are positive forvimentin and weakly positive for epithelial membraneantigen. They are negative for S-100 protein, glial acidicfibrillary protein, and neuroendocrine markers suchas chromogranin, synaptophysin and neurone-specificenolase [132]. A similar appearance to the juxtaoral organhas rarely been described elsewhere in the mouth,including intraosseous locations [47].3.2 Vesiculo-Bullous Diseases3.2.1 Herpes Simplex InfectionsHerpes simplex is a common virus that often causessubclinical infections. It is, however, a cause of seriousand sometimes fatal illnesses in immunocompromisedpatients. In the orofacial tissues, clinically apparent infectionscan be primary or recurrent. The majority ofcases of oral infections are due to Herpes simplex type1, but an increasing proportion is being attributed toHerpes simplex type 2, which is typically more closelyassociated with genital infections. The virus is transmittedby close contact. Although in the past primaryherpes affected children most frequently, in Westernsocieties it is seen increasingly in young and middleagedadults.Primary herpes infection (primary herpetic gingivostomatitis)is characterised by widespread vesicular lesionsof the oral mucosa [183]. Any site may be involved,but the hard palate and the dorsum of the tongue arethe most common locations. The vesicles quickly ruptureto leave shallow, painful, sharply demarcated ulcersthat are 1–2 mm in diameter and have an erythematoushalo. Ulcers frequently coalesce to form more irregularlesions. Gingivitis is a very characteristic feature of primaryherpes. The gingivae are swollen and often strikinglyerythematous, even in the absence of frank ulceration.There is often conspicuous cervical lymphadenopathy,together with mild fever and malaise. Oral lesionsusually resolve spontaneously within 1–2 weeks.About a third of patients infected with Herpes simplex,either clinically or sub-clinically, are susceptible to recurrentinfections.It is uncommon for herpetic lesions to be biopsied(Fig 3.1). In the early stages there is intercellular oedemaand ballooning and vacuolisation of keratinocytesdue to intracellular oedema. This leads to intraepithelialvesiculation. Nuclei become enlarged, and occasionallybasophilic or eosinophilic nuclear inclusions witha clear halo ( Lipschutz bodies) can be identified. Cellsmay fuse to form multinucleated epithelial giant cells.The vesiculation is followed rapidly by epithelial necrosisand breakdown, leading to ulceration and more floridinflammatory infiltration.Herpes simplex virus can persist in a latent form inthe trigeminal ganglion and when re-activated causesrecurrent infections. These are typically seen at themucocutaneous junctions of the mouth or nasal cavity,and involvement of the lips, the most common site,is called herpes labialis. A variety of apparently disparatefactors can trigger re-activation, including thecommon cold (“fever blister”), exposure to sunlight,menstruation, stress and others. There is usually abrief prodromal burning or prickling sensation in the

Oral Cavity Chapter 3 73affected area, followed by the formation of a localisedcluster of vesicles. These rapidly break down, ulcerateand crust. The lesions usually heal spontaneously in1–2 weeks. Occasionally there may be intraoral recurrences,particularly in the hard palate. These may betriggered by local anaesthetic injections. Persistentlyrecurrent intraoral herpes, however, should alwaysraise the possibility of immunosuppression. Atypicaland often very severe forms of intraoral herpes infectionscan be seen in patients who are immunocompromised[21].3.2.2 Chickenpoxand Herpes ZosterFig. 3.1. Primary herpetic stomatitis showing intercellular vacuolationand multinucleated epithelial cellsChickenpox is a highly contagious infection caused bythe herpes virus Varicella zoster. It is typically seen inchildren where it causes crops of pruritic cutaneousvesicles. It is usually transmitted by direct contact andhas an incubation period of 2–3 weeks. The exanthem isfrequently preceded by a slight fever, malaise and mildheadache. The cutaneous lesions start as an itchy macularrash, which progressively becomes vesicular andpustular before breaking down to form focal crustinglesions. They tend to erupt in crops, but lesions at allstages of evolution are frequently present. The back andchest are often the first sites of involvement, but laterlesions appear on the face, neck and limbs. They caninvolve the nose, ears, conjunctiva and genital areas.In the mouth they form small, non-specific, scatteredulcers. The symptoms last from a few days to 2 weeks.In many cases the virus remains latent in dorsal rootganglia.Herpes zoster (shingles) is due to reactivation ofthe Varicella zoster virus. In the orofacial region itis characterised by pain, a vesicular rash and stomatitisin the related dermatome. Unlike herpes labialis,repeated recurrences of zoster are very rare. Occasionallythere is an underlying immunodeficiency.Herpes zoster is a hazard in organ transplant patientsand can be an early complication of haematolymphoidneoplasms and HIV infections. Herpes zoster usuallyaffects adults of middle age or older, but occasionallyinvolves children. The first signs are often pain, irritationor tenderness in one or more divisions of thetrigeminal nerve. The pain may be severe and can bemisinterpreted as toothache, leading to inappropriatedental intervention. Malaise and low-grade feverare common constitutional symptoms. There is usuallya strikingly unilateral, vesicular exanthem restrictedto the affected dermatome. Intraorally, there mayalso be extensive unilateral ulceration in the distributionof the involved nerves. There is usually tender regionallymphadenopathy. The acute phase lasts about7–10 days, but pain may continue until the lesions ulcerateand crust over, which may take several weeks,especially if there is suppuration and subsequent scarring.In these circumstances a significant number ofpatients develop the most unpleasant consequence ofpost-herpetic neuralgia.3.2.3 Hand-Foot-and-Mouth DiseaseThis is a common and usually mild viral infectionthat often causes local clusters of infections amonggroups of young children and is characterised by oralulceration and a vesicular rash on the extremities. Itis caused by a variety of strains of the coxsackie A16virus and is highly infectious. Sporadic cases associatedwith Coxsackie A4–7, A9, A10, B1–B3, and B5have also been reported. It frequently spreads throughclassrooms, schools and local communities in an epidemicmanner. The incubation period is between 3 and10 days. It presents clinically as small, scattered oral ulcersthat often cause few symptoms. Although the initiallesions are vesicular, intact blisters are rarely seen.Unlike primary herpes infections, the gingivae arerarely affected. It is unusual for regional lymph nodesto be involved except in severe cases and constitutionalsymptoms tend to be mild or absent. The cutaneous exanthemconsists of small vesicles or occasionally largerblisters that form mainly around the base of fingers ortoes, but may extend to involve any part of the limb.In some outbreaks, either the mouth or the extremitiesalone may be affected. Although serological investigationscan confirm the diagnosis, due to the relativelymild and transient nature of the disease, this investigationis rarely undertaken. Typically, the condition resolvesspontaneously within a week to 10 days and doesnot recur. However, in some epidemics patients havedeveloped severe complications, including interstitialpneumonitis, myocarditis and encephalitis, resultingin death [36].

74 J.W. Eveson3.2.4 Herpangina3Herpangina is also caused by a variety of group A coxsackieviruses including A1 to 6, 8, 10, and 22. Othercauses include coxsackie group B (strains 1–4), echoviruses,and other enteroviruses [161]. It is highly contagiousand tends to affect young children in the summerand early autumn period. Like hand-foot-and-mouthdisease, it rapidly spreads through close-knit communities,such as schools, and presents with acute pharyngitis,anorexia and dysphagia, with or without cervicallymphadenopathy. Typically, the lesions are restricted tothe soft palate, uvula, anterior pillars of the fauces andpalatine tonsils. They consist of multiple, small vesiclesthat rapidly rupture to form superficial ulcers, whichmay coalesce. In addition, there is often more generalisedoropharyngeal erythema. The condition usuallylasts 1–2 weeks and is treated symptomatically.3.2.5 Pemphigus VulgarisFig. 3.2. Pemphigus vulgaris showing suprabasal clefting and acantholyticcells in an intraepithelial blisterPemphigus vulgaris is an uncommon, but potentiallylethal, mucocutaneous disorder that occasionally alsoinvolves the eyes. It is an autoimmune disease due to circulatingantibodies against the intercellular attachmentsof stratified squamous epithelia [163]. The specific targetappears to be desmoglein 3 [2]. However, 50% of patientswith pemphigus vulgaris also have autoantibodiesto Dsg1, but cases that are predominantly oral have onlyDsg3 antibodies [70]. Associations have been describedbetween pemphigus vulgaris, myasthenia gravis andthymoma and a variety of drugs, including penicillamine,rifampicin and captopril. In addition, some casesare associated with internal malignancies, particularlyof the haematolymphoid system, and the condition isthen termed paraneoplastic pemphigus.Pemphigus is more common in Asians and AshkenaziJews than other races and most patients are in the fourthor fifth decades. The mouth is the most common site ofinitial involvement and remains the only site affected inabout half of patients. The oral features are very variable.It is uncommon to find intact vesicles and most patientspresent with painful, ragged superficial ulcers and areasof boggy and shredded mucosa. The buccal mucosa, gingivaand soft palate are the most common sites. In thetongue the condition may present as deep, non-healingfissures. Fluid from intact or recently ruptured blistersmay contain acantholytic ( Tzanck) cells, although thisis rarely used as a diagnostic measure. The disease maybe relatively mild or even regress, but some cases, particularlythose with extensive cutaneous involvement, maybe fulminant, either as a consequence of the disease itself,or as a complication of medical treatment.Microscopy shows suprabasal clefting of the epitheliumdue to loss of intercellular attachments and acantholysis(Fig 3.2). A single layer of keratinocytes may remainattached to the corium by their hemidesmosomes,but the cells are separated from each other laterally toform a characteristic “tombstone” appearance. The acantholyticcells floating in the vesicular fluid are rounded,with condensed cytoplasm surrounding hyperchromaticnuclei. The vesicles may contain acute and chronicinflammatory cells, and eosinophils may be a conspicuousfeature. In many cases, the roof of the blister is lostduring the biopsy procedure due to a positive Nikolskyphenomenon, but a row of keratinocytes remains adherentto the floor. Direct immunofluorescence on frozentissue shows deposits of IgG and less frequently IgM andIgA in the intercellular junctions, producing a characteristic“chicken wire” appearance.3.2.6 Pemphigus VegetansPemphigus vegetans is considerably less common in themouth than pemphigus vulgaris [15]. It usually presentsclinically as serpiginous ulcers that are most frequent onthe dorsum of the tongue and lips [187]. The lingual lesionsclosely resemble those of erythema migrans. Thepapillomatous, proliferative lesions that characterisecutaneous pemphigus vegetans can sometimes be seenat the angles of the mouth. As in pemphigus vulgaris,drugs, particularly ACE inhibitors, have been invokedas possible causative agents in some cases [12, 137].Microscopically, the epithelium tends to proliferateand become verruciform. Acantholytic cells may not beconspicuous and eosinophil microabscesses are said tobe the most typical histological feature. However, thelesions frequently resemble pyostomatitis vegetans andconventional microscopy may not be diagnostic. Thepresence of typical skin lesions often helps in makingthe diagnosis and it may be differentiated from pyostomatitisby the clinical picture and appropriate immunocytochemicalinvestigations [73].

Oral Cavity Chapter 3 753.2.7 Paraneoplastic PemphigusAlthough an occasional association between pemphigusand malignancy had been recognised for many years, itwas not until 1990 that paraneoplastic pemphigus wasrecognised as a distinct clinical, histological and immunocytochemicalentity [5]. The condition is seenpredominantly in association with B-cell lymphoproliferativedisorders, especially non-Hodgkin lymphoma,chronic lymphocytic leukaemia, Castleman disease,thymoma and Waldenström macroglobulinaemia [92].Less commonly it is associated with non-lymphoid neoplasms,including some carcinomas of the bronchus,breast and pancreas. In some cases showing otherwisetypical features of the disease, no underlying malignancyis found. Paraneoplastic pemphigus is characterisedby the following features:■ Painful mucocutaneous vesiculo-bullous eruptions;■ Histopathologic features of intraepithelial acantholysisand vacuolar interface changes;■ Demonstration of intercellular epithelial IgG and C3,with or without granular linear deposition of complementalong the BMZ;■ Presence of circulating autoantibodies that bind tothe surfaces of stratified squamous epithelia as wellas simple, columnar and transitional epithelia;■ Presence of a characteristic complex of proteins derivedfrom keratinocytes and serum antibodies demonstratedby serum immunoprecipitation. Theseinclude desmoplakins I and II, bullous pemphigoidantigen I, envoplakin and periplakin [92].In addition, paraneoplastic pemphigus tends to be extremelyrefractory to the usual immunosuppressantdrugs used to control pemphigus vulgaris.Paraneoplastic pemphigus is most common betweenthe ages of 45 and 70 years and there appears tobe a male predominance. The mouth is almost alwaysinvolved and oral lesions present as a painful, intractablestomatitis that extends into the oropharynx and oftenbeyond the vermilion borders of the lips. It causesblisters and irregular, ragged ulceration. The buccalmucosa and lips are the most common sites, but almostanywhere in the mouth, oropharynx and nasopharynxcan be involved. About two-thirds of patients haveconjunctival involvement characterised by frequentlysevere pseudomembranous conjunctivitis and symblepharon.Microscopy shows intraepithelial acantholysis withsuprabasal clefting, dyskeratotic keratinocytes, basalcell liquefaction, and epithelial inflammatory cellexocytosis [78]. In many cases, however, the conditioncannot be distinguished from conventional pemphigus[89]. The overall appearances suggest that thereis an overlap between paraneoplastic pemphigus anderythema multiforme. Indirect immunofluorescenceon the transitional epithelium of rat bladder appearsto be a highly specific test for paraneoplastic pemphigus[100].3.2.8 Mucous Membrane PemphigoidMucous membrane pemphigoid is an uncommon, chronicblistering disorder affecting the mouth [186]. Othersites of involvement include the eyes, skin, and mucosaof the nasopharynx, anogenital region, oesophagus andlarynx [32]. It has been defined as a group of putativeautoimmune, chronic inflammatory, subepithelial blisteringdiseases predominantly affecting mucous membranesand characterised by linear deposition of IgG,IgA and C3 along the epithelial basement membrane[33]. It has also been called benign mucous membranepemphigoid and cicatricial pemphigoid. However, it canbe a severely disabling condition, and rarely causes scarringexcept in the eye and oesophagus/larynx, so theseterms are not appropriate.Mucous membrane pemphigoid is more common inwomen than men and most patients are in the 40–60-year age range. The mouth is often the first and onlysite of involvement. Oral lesions can be intact blistersthat may contain clear or sero-sanguinous fluid, erythematouspatches or superficial ulcers. Lesions aremost common on the attached gingiva, usually buccallyand labially, and the palatal mucosa. Less frequentsites include the labial, lingual and buccal mucosae.Ocular lesions are characterised by conjunctival inflammation,ulceration and symblepharon due to fusionof the palpebral and bulbar conjunctivae. Theremay be severe scarring, entropion and blindness. Skinlesions are uncommon and usually involve the scalpand upper torso.Microscopy shows subepithelial blister formationwith clean separation of the full thickness ofthe epithelium from the underlying connective tissue(Fig. 3.3). There is usually a dense mixed inflammatoryinfiltration of the corium. Due to the stronglypositive Nikolsky phenomenon seen in mucous membranepemphigoid, it is very common to receive a biopsyspecimen where most or all of the epithelium hasbeen lost or completely separated from the connectivetissue. The specimen then consists of non-specificallyinflamed connective tissue, which lacks the surfacefibrinous slough that would be more typical of a nonspecificoral ulcer. This type of appearance, though notdiagnostic, is highly suggestive of mucous membranepemphigoid.Direct immunofluorescence on peri-lesional mucosalbiopsies shows continuous deposits of IgG, IgA or C3, eithersingly or in combination, along the basement membranezone (BMZ) in about 80% of cases. When present,these deposits help to distinguish mucous membrane

76 J.W. Eveson3Fig. 3.3. Mucous membrane pemphigoid showing clean subepithelialblisteringFig. 3.4. Dermatitis herpetiformis showing polymorphonuclearleukocytes at the tips of the papillary coriumpemphigoid from several other common oral mucosalinflammatory disorders. For example, lichen planusdoes not have linear immunoglobulin deposits, but haslinear and shaggy deposits of fibrin in the BMZ, and erythemamultiforme has no linear BMZ deposits. However,these deposits do not distinguish mucous membranepemphigoid from bullous pemphigoid, epidermolysisbullosa aquista or linear IgA bullous dermatosis. Suchdistinctions should be made on the basis of clinical findings.Several possible target antigens have been identifiedin the sera of patients with mucous membrane pemphigoid.These include: bullous pemphigoid antigens 1 and2; laminins 5 and 6; type VII collagen and ß4 integrinsubunit [32].3.2.9 Dermatitis HerpetiformisDermatitis herpetiformis is an uncommon, intenselypruritic mucocutaneous disorder related to coeliac diseasethat only occasionally involves the mouth [126].Oral lesions present as areas of erythema and clustersof small, friable vesicles or superficial, painful ulcers.The lesions can involve both keratinised and non-keratinisedmucosa and head and neck cutaneous lesionstend to affect the scalp and periorbital regions. Dermatitisherpetiformis is seen most frequently in teenagersand young adults, particularly males, and there is a predilectionin people of Anglo-Saxon and Scandinavianorigin. There is a strong association between dermatitisherpetiformis and gluten-sensitive enteropathy. TheClass I antigen HLA-B8 is found in the large majorityof patients with both dermatitis herpetiformis and coeliacdisease, and HLA-DR3 is expressed in nearly 95%of patients.Clinically, oral dermatitis herpetiformis presents aspatches of mucosal erythema, clusters of small vesicles,herpetiform ulcers or more extensive areas of non-healingulceration. In conventional gluten-sensitive enteropathyoral ulcers tend to be of the typical minor aphthousstomatitis type.Microscopically, the lesions of dermatitis herpetiformisshow polymorphonuclear leukocyte microabscessesin the tips of the papillary corium (Fig. 3.4). Initially,neutrophils predominate, but as the microabscessesenlarge eosinophils become more conspicuous. The microabscesseseventually fuse to form visible blisters thatfrequently rupture leaving superficial ulcers. Direct immunofluorescenceshows granular deposits of IgA in theBMZ of the dermal papillae, in both affected and adjacentnormal mucosa.3.2.10 Linear IgA diseaseLinear IgA disease is a rather poorly defined heterogeneousgroup of mucocutaneous blistering disordersthat closely resemble mucous membrane pemphigoidclinically and microscopically [160, 191]. Like pemphigoid,the eyes may be involved. Linear IgA diseasein adults has been separated from similar conditionsin childhood such as bullous dermatosis of childhoodand childhood cicatricial pemphigoid. Cutaneous linearIgA disease of adults has a strong association with ahistory of bowel disease. This association is much lessclear in patients with oral lesions. However, patientswith oral linear IgA disease appear to have a higherrisk of severe ocular lesions. Some cases of oral lesionshave been associated with drugs [51]. The conditionis more common in women than men and it usuallypresents as a desquamative gingivitis with, or without,ulceration.Microscopy shows subepithelial vesiculation andfull thickness blister formation. Direct immunofluorescenceshows linear deposition of IgA along the BMZand a low titre of circulating IgA to the BMZ. Althoughsmall amounts of IgG, IgM and C3 may be seen, if these

Oral Cavity Chapter 3 77are present in other than trace amounts mucous membranepemphigoid is a much more likely diagnosis.Linear IgA disease tends to be refractory to systemicsteroids, but it may respond to dapsone or sulphonomides.3.2.11 Erythema MultiformeErythema multiforme is a mucocutaneous inflammatorydisorder, but sometimes the mouth is the only siteof involvement [1, 8]. It can be relatively mild or manifestwith fever, malaise and extensive skin, mucosaland ocular lesions when it is sometimes called StevensJohnson syndrome or erythema multiforme major. Itis thought to be an immunologically mediated disorder,but in many cases no precipitating factor is found.Triggering agents that have been implicated include infectionswith Herpes simplex virus [7] and Mycoplasmapneumoniae [99] and a wide range of drugs includingsulphonamides, anticonvulsants, non-steroidal antiinflammatorymedications and antibiotics. Althoughpatients may suffer a single episode, it is often recurrent.Erythema multiforme is usually seen in young adults(20–40 years) and is more common in males. Oral lesionsmay be the only feature of the disease or cutaneousinvolvement may follow several attacks of oral ulceration.The lips are the most frequently involved siteand typically show swelling and extensive haemorrhagiccrusting. Within the mouth there are usually diffuseerythematous areas and superficial ulcers on the buccalmucosa, floor of the mouth, tongue, soft palate andfauces. It is uncommon for the gingiva to be involvedand this sometimes helps to distinguish erythema multiformefrom primary herpetic gingivostomatitis, wheregingival inflammation is a conspicuous feature. The areasof mucosa involved frequently break down to formpainful, shallow, irregular ulcers on a background ofmore generalised erythema. It is unusual to see intactblisters in the mouth.The classical cutaneous manifestation of erythemamultiforme is the development of so-called target orbull’s eye lesions. These begin as dark red macules, usually1–3 cm in diameter. They become slightly elevatedand develop a characteristic bluish centre. These lesionsare seen most frequently on the hands and lower limbs.In erythema multiforme major there may be ocular andgenital involvement together with constitutional symptoms.A very severe and potentially lethal variant is toxicepidermal necrolysis, when there is widespread cutaneousand mucosal involvement with extensive blisteringand epidermal loss leading to fluid and electrolyte lossand secondary infection.Microscopy shows variable features and early epithelialbreakdown of oral lesions frequently masks anycharacteristic features [25]. In the early lesions there isapoptosis and necrosis of keratinocytes, intercellular oedemaand inflammatory infiltration of the epithelium.This leads to intra- and sub-epithelial vesiculation andultimately loss of the roof of the blister to form an ulcer.There is lymphohistiocytic and polymorphonuclear infiltrationof the superficial corium and the inflammatoryinfiltrate can extend more deeply, often in a perivasculardistribution. Patchy deposits of C3 and IgM maybe found in the walls of blood vessels, but there is nofrank vasculitis and the immune complex depositionappears to be non-specific.3.3 Ulcerative Lesions3.3.1 Aphthous Stomatitis(Recurrent Aphthous Ulceration)This is the most common ulcerative disease of the oralmucosa and can affect as many as 15–20% of the populationat some time in their lives [152]. It is characterisedby persistently recurrent, painful oral ulcers [142, 143,193]. The condition usually starts in early childhoodand typically resolves spontaneously in the late teens orearly adult life. When the condition develops in olderindividuals, predisposing causes such as haematinicdeficiencies or smoking cessation are more likely to beassociated.There are three main clinical forms of the condition:minor, major and herpetiform ulceration, although aminority of patients may show various combinations ofthese types. Minor aphthae are by far the most commonmanifestation (~85%) and are characterised by the formationof one or several superficial ulcers, usually 2–8 mm in diameter with a yellowish-grey, fibrinous floorand an erythematous halo. The ulcers tend to involvethe non-keratinised mucosa such as the lips, buccal mucosa,ventrum of the tongue and floor of the mouth.They usually heal within 7–10 days by regeneration ofthe epithelium across the floor of the ulcer, and withoutscarring. The ulcers frequently recur at regular intervals,typically of 2–3 weeks. Some patients, however,are virtually never ulcer free, as new crops appear beforepre-existing ones have healed. A minority of casesare menstruation-related and the ulcers appear monthlyin the premenstrual week. Major aphthae are less common(~10%) and ulcers can form on both keratinisedand non-keratinised mucosae. The ulcers are usuallysingle but can be several centimetres in diameter andare penetrating. Hence, healing is by secondary intentionand characterised by granulation tissue formationand scarring. In severe cases the scarring following progressiveulceration can be so severe that it causes trismusand microstomia. Herpetiform aphthae are uncommon

78 J.W. Eveson3(~5%) and are characterised by the formation of sometimeshundreds of small (~2 mm), superficial ulcers thatfrequently coalesce and may form on a background ofmore generalised mucosal erythema [154]. Any oral sitemay be involved, but the labial and ventral lingual mucosaeare the sites of predilection.Although most cases of recurrent aphthous stomatitisare idiopathic, a minority are caused, or exacerbated,by deficiencies in iron, vitamin B 12 or folate, and assuch are potentially curable. Haematinic deficienciesare reported to be twice as common in patients withrecurrent aphthous stomatitis compared with controls.The condition is often made worse by emotional stress.Occasional cases are said to be related to gastro-intestinalcomplaints such as coeliac disease, Crohn’s diseaseand ulcerative colitis, but some of the data are conflicting[56, 164]. However, it is likely that in most instancesany associations are secondary to haematinic deficiencies.It is uncommon for recurrent aphthae to be biopsied,except when a major aphtha simulates malignancy [97].Reported early changes include infiltration of the epitheliumby lymphocytes and histiocytes and focal aggregatesof lymphocytes in the superficial corium. Thisis followed by areas of epithelial cell apoptosis, degenerationand necrosis [77]. The epithelium is lost and thesubsequent ulcer is covered by a fibrinous slough, heavilyinfiltrated by polymorphonuclear leukocytes. Moredeeply there is a mononuclear cell infiltration and perivascularcuffing is an inconsistent feature. The conditionappears to be a T-cell mediated immunological response[62] and is thought to be a response to a keratinocyte-associatedantigen that is yet to be identified.3.3.2 Behçet DiseaseThis condition comprises recurrent oral ulceration togetherwith genital ulceration and ocular lesions [56,88, 109]. The ocular lesions include uveitis and retinalvasculitis. Behçet disease, however, is a multisystemdisorder and can show a wide range of clinical manifestations.Features of more generalised disease includeneurological disorders, arthralgia, and vascular, gastrointestinaland renal lesions. The disease is uncommonthe USA and UK, but has a much higher prevalence insoutheast Asia, Japan and the eastern Mediterranean region.There is a strong association with the presence ofHLA*B51 [116].The oral lesions are clinically identical to recurrentaphthae [177]. Patients also have genital or perigenitalcutaneous ulcers and erythema nodosum is common.Microscopically, like recurrent aphthae, the ulcers associatedwith Behçet disease show essentially non-specificfeatures. It has been suggested that perivascular inflammatoryinfiltration into the deeper corium may bemore characteristic of Behçet disease, but the significanceof this observation is questionable.3.3.3 Reiter DiseaseReiter disease comprises non-specific urethritis, arthritisand conjunctivitis, although the conjunctivitis ispresent in less than half of cases. It was initially thoughtto be only sexually transmitted, but many cases appearto result from enteric infections by a variety of organismsincluding Shigella, Salmonella and Campylobactor.The disease is typically seen in young males andshows a strong association with HLA-B27 and has beenreported in HIV-infected individuals [182]. Patients developpainful mono- or polyarticular arthropathy andoccasionally the temporomandibular joint is involved.Patients can have fever, weight loss and CNS involvement,and facial nerve palsy has been described. Cutaneousand mucosal lesions are relatively common. Theskin lesions include macules, vesicles, and pustules onthe hands and feet particularly, and plaque-like hyperkeratoticlesions of the trunk and scalp. Oral lesionsconsist of circinate white or yellowish lesions surroundingmacular areas that are erythematous or superficiallyulcerated. They resemble circinate balanitis and the lesionsof geographical tongue and geographical stomatitis[131]. They are painless and transient and are thereforerarely biopsied. Microscopy shows features similarto those seen in geographical tongue with spongiformpustules focally and diffusely dispersed in the superficialepithelium, but without evidence of psoriasiformhyperplasia.3.3.4 Median Rhomboid GlossitisMedian rhomboid glossitis usually presents as a painless,reddened, sharply demarcated area of depapillationin the centre of the dorsum of the tongue anterior tothe foramen caecum. In some cases the area is nodularor grooved. It was originally thought to be due to thepersistence of the developmental eminence called thetuberculum impar, but now most cases are believed tobe candidal in origin [180, 188]. Predisposing factorsinclude smoking, wearing dentures, diabetes and usingsteroid inhalers. Sometimes there is a “kissing lesion” inthe palate.Microscopy typically shows elongation, branchingand fusion of the rete ridges with mild epithelial atypia(Fig. 3.5). There may be spongiform pustules in theparakeratinised surface layers and evidence of candidalhyphae. Sometimes the epithelial hyperplasia is floridresulting in a pseudoepitheliomatous appearance. Someof these lesions have been misinterpreted as squamous

Oral Cavity Chapter 3 79Fig. 3.5. Median rhomboid glossitis showing extensive epithelialhyperplasia and fusing of rete processesFig. 3.6. Eosinophilic ulcers showing plump histiocytic nucleiand eosinophilscell carcinomas, with significantly adverse clinical consequences[129]. Below the epithelium there is often adense, band-like zone of hyalinisation that is sometimesmistaken for amyloidosis.The lesion often responds to antifungal treatment,but almost invariably recurs if the patient continues tosmoke. There does not appear to be any premalignantpotential and the dorsum of the tongue is a very uncommonsite for oral cancer.3.3.5 Eosinophilic Ulcer(Traumatic Ulcerative Granulomawith Stromal Eosinophilia)So-called eosinophilic ulcers are chronic but selflimitinglesions of a traumatic or reactive nature inwhich there is an intense inflammatory infiltrationwith a prominent eosinophilic component [45]. Despitetheir designation, about a third of these lesionsdo not undergo ulceration. Eosinophilic ulcers areseen most commonly in children and young adultsand are frequently painless. In infants, particularly,the condition has been called Riga-Fede disease[46]. Although these ulcers can be seen anywhere inthe oral mucosa, including the gingiva, they are mostcommon on the tongue and buccal mucosa. About athird of patients have a history of trauma, particularlya crush injury of the lingual muscle due to biting [43].The lesions are usually single and can be several centimetresin diameter. If left, most heal spontaneouslywithin 2 months, and this may be accelerated by incisionalbiopsy. Although recurrence tends to be uncommon,in one report 6 out of 15 cases were recurrentor multiple [43]. On the basis of the clinical andimmunocytochemical features it has been suggestedthat eosinophilic ulcers might be the oral equivalentof primary cutaneous CD30-positive lymphoproliferativedisorders [54].Microscopically, these lesions can be mistaken formalignancy. There is non-specific ulceration with underlyinginflamed granulation tissue (Fig. 3.6). Thereis an associated dense inflammatory infiltrate that extendsdeeply into the underlying muscle. The infiltrateconsists of lymphocytes and plasma cells, macrophages,polymorphonuclear leukocytes and mast cells. Eosinophilsare particularly numerous and they may form microabscesses.Macrophages are frequently conspicuousand can form sheets of cells with poorly demarcated cytoplasm,but large, vesicular nuclei with prominent nucleoliand a high mitotic frequency. These macrophages,together with damaged muscle cells showing sarcolemmalnuclear degeneration and regeneration, can give theerroneous impression of a lymphoma. In addition, theprominent eosinophilic component can lead to a mistakendiagnosis of Langerhans cell histiocytosis. Thiserroneous diagnosis is particularly likely in lesions involvingthe gingiva, where there may be associated resorptionof the underlying bone. Appropriate immunocytochemicalcharacterisation should avoid this confusion.3.3.6 Acute NecrotisingUlcerative GingivitisAcute necrotising ulcerative gingivitis (Vincent disease,trench mouth) is a relatively common oral disease. Althoughit is generally accepted that bacteria play a pivotalrole in the development of the disease, a specific causalagent has not been established. In the past the Gramnegativeanaerobes designated as Treponema vincentiiand Fusobacterium nucleatum were strongly implicatedand Treponema denticola [165] and Prevotella intermediaare some of the current candidate organisms.A wide variety of factors predispose to the developmentof the disease. The most important local factorsare cigarette smoking and poor oral hygiene. General

80 J.W. Eveson3predisposing factors include emotional stress, malnutritionand immunosuppressive disorders. Recently, diabeteshas also been implicated in the aetiology [102]. Thecondition is most common in young adult males and itstarts with painful, punched out and crateriform ulcersdeveloping on and permanently destroying the tips ofthe interdental papillae. It can spread to the marginalgingiva and progress to involve and destroy the underlyingalveolar bone. Lesions sometimes develop in relationto an operculum overlying a partially erupted third molartooth and occasionally they spread into the adjacentbuccal mucosa. There is often severe halitosis and tastedisturbances. Regional lymphadenopathy is common,but constitutional symptoms tend to be relatively mild.It is very uncommon to receive a biopsy specimenfrom patients with active disease, but scrapings from thebase of one of the ulcers typically show numerous polymorphs,fibrin and debris, and suitable staining revealsfusiform and spiral organisms.The acute condition usually responds well to oralmetronidazole or tinidazole.3.3.7 Wegener’s GranulomatosisWegener’s granulomatosis (WG) is an uncommon butdistinctive form of vasculitis characterised in its classicalform by necrotising granulomatous inflammationof the upper and lower respiratory tracts and segmentalnecrotising glomerulonephritis [76]. It is now recognisedthat a wide variety of other organs and tissuesmay be involved. Rarely, a proliferative rather than adestructive response produces tumefactions [65]. Variantsof WG include a limited form, which has few extrapulmonarymanifestations, and a protracted superficialform, which is characterised by lesions restricted to theupper respiratory tract, mucosa and skin for a prolongedperiod, although it may eventually progress to renal involvement[58]. Wegener’s granulomatosis limited tothe respiratory system may respond to antibiotics suchas co-trimoxazole and Staphylococcus aureus has beenimplicated as a triggering agent for this disease, but theevidence remains equivocal [141].Head and neck manifestations, particularly in the sinonasalcomplex, are common and can affect as many as90% of patients at presentation [50] (see Chap. 2). Theyinclude severe rhinorrhoea, sinusitis, otitis media anddestruction of the nasal septum and cartilage to producea saddle-nose deformity. By contrast, oral lesionsare less common and affect only about 5% of patients[69]. They include oral ulceration, delayed healing of extractionwounds, tooth mobility and loss of teeth. Perforationof the palate is usually as a direct extension of sinonasaldisease. Extraorally, head and neck manifestationsinclude swelling and desquamation of the lips, parotidgland enlargement, and cranial nerve palsies.Fig. 3.7. Wegener’s granulomatosis of gingiva showing intenseinflammation, haemorrhage and scattered, small multinucleatedgiant cellsA rare, but particularly characteristic oral feature isso-called strawberry gums, which is considered to bevirtually pathognomonic of Wegener’s granulomatosis[111, 124]. There is a localised or generalised proliferativegingivitis with a mottled, purplish-red granular surface,which resembles an over-ripe strawberry. Diseaselocalised to the gingiva tends to be fairly low-grade. Involvementof the underlying bone, however, may causethe related teeth to loosen or exfoliate.Microscopy of the gingiva shows irregular epithelialhyperplasia with downgrowths of the rete processes intothe underlying corium. The connective tissue shows vascularlakes of extravasated blood and haemosiderin-containingmacrophages and there are neutrophil and eosinophilmicroabscesses, together with a more diffusemixed inflammatory infiltration (Fig. 3.7). Small multinucleatedgiant cells are unevenly distributed in the lesion,and although considered to be characteristic, maybe absent in many levels. Vasculitis is not usually seen,possibly because vessels of sufficient size to show thisfeature are rarely present in gingivectomy specimens. Bycontrast, biopsies of other oral lesions rarely show microabscessesor necrosis. Also, the granulomatous reactioncharacteristic of many other sites is uncommon [42].Investigations of patients with suspected oral WGshould include sinus and chest radiographs, full bloodpicture, erythrocyte sedimentation rate, C-reactive protein,autoantibody profile (including rheumatoid factor)and renal function tests. An important investigationis the titre of antineutrophil cytoplasmic antibody(ANCA), particularly cytoplasmic or cANCA. cANCA isa useful marker of WG and is found in up to 100% of patientswith widespread, active disease [27], but only 60–70% of patients with limited forms of the disease [63].Although cANCA has a very high specificity for WG,it is rarely found in other types of vasculitis [27]. OtherANCA-associated vasculitides include microscopicpolyangiitis and Churg-Strauss syndrome [38], but

Oral Cavity Chapter 3 81these do not affect the mouth. The titre of cANCA maybe related to the severity of the disease and therefore canbe a useful index of prognosis and efficacy of treatment.However, in patients with limited or protracted superficialforms of the disease, the ANCA may be negativefor months or even years so that other clinicopathologicalcriteria should not be ignored when making the diagnosis.3.3.8 TuberculosisOral tuberculosis is rare, but is important as it is usuallya complication of advanced open pulmonary disease[155]. Tuberculosis is becoming increasingly more commonin developed countries. This is partly due to HIVinfections and the fact that multiple drug-resistant mycobacteriaare becoming widespread.The typical lesion is an ulcer, most commonly on themid-dorsum of the tongue and gingiva, but other sitesmay be involved [122]. The ulcer usually has underminededges, which may be stellate, and a pale granularfloor. Occasionally it presents as a non-specific areaof erythema or a chronic fissure [112]. It is painless inits early stages, but may become painful later. There isusually no regional lymph node involvement. The clinicalfeatures are often entirely non-specific and the diagnosisis initially suspected when the microscopy showsmultiple epithelioid granulomas in the corium underlyingan ulcer with undermined margins. The granulomasare usually non-caseating and it is unusual to demonstrateMycobacteria, even using auramine and rhodaminestaining. The organisms may be detected in thesputum (but rarely in the oral lesion) and chest radiographstypically show advanced disease. In patients whoare immunosuppressed, the possibility of atypical mycobacterialinfection needs to be considered.3.4 White Lesions3.4.1 CandidosisOral infections with candidal organisms are very common.The most frequent organism is Candida albicans,a yeast-like fungus [150]. It can cause acute and chronicwhite lesions and atrophic, red lesions. Candidal sporesare present as commensal organisms in the mouths ofas many as 70% of individuals. The infective phase ofthe organism is characterised by the presence of hyphaethat can directly invade oral keratinocytes [31]. A widevariety of factors predispose to infection by candidal organisms,particularly depressed cellular immunity andinhibition of the normal oral flora by broad spectrumantibiotics.Fig. 3.8. Candidal hyphae penetrating the superficial layers (PAS/D stain)Thrush, or acute hyperplastic candidosis, is seenmost commonly in neonates whose immune systemsare still developing and in debilitated patients at the extremesof life. It is also a feature of patients with xerostomiadue to irradiation, Sjögren syndrome and a widevariety of medications, particularly the tricyclic antidepressants.In addition, it is now increasingly becoming afeature of immunosuppressed individuals. Other factorspredisposing to the development of thrush include irondeficiency anaemia, broad spectrum antibiotics and steroidinhalers used for the control of asthma. It is characterisedclinically by the formation of soft, creamy-white,friable plaques that can be easily wiped off to leave underlyingerythematous areas of mucosa. The soft palateand areas protected from friction such as the vestibularreflections are the most common sites.Microscopically, the characteristic plaque of thrushis due to invasion of the superficial epithelial layers bycandidal hyphae and the subsequent proliferative epithelialresponse (Fig 3.8) [26]. The surface epithelium isparakeratinised, oedematous and infiltrated by numerousneutrophils. Candidal hyphae penetrate the epitheliumvertically and extend downwards as far as the glycogen-richlayer. The hyphae may be inconspicuous inH&E sections unless the microscope condenser is loweredto increase their refractility, but they can be readilyvisualised with periodic acid Schiff or Grocott’s silverstains. The epithelium may show hyperplastic but attenuatedrete processes and there is variable but occasionallyflorid acute inflammation of the underlying corium.Denture-induced stomatitis is a variant of atrophiccandidosis. It is typically seen in the hard palate beneatha full or partial dental prosthesis, particularly one constructedfrom acrylic. There is a sharply demarcatedarea of bright red, often boggy erythema limited by theextent of the denture. Occasionally there may be a fewflecks of thrush, but typically there is no plaque formation.Although sometimes referred to as “denture soremouth” the condition rarely causes any symptoms un-

82 J.W. Eveson3less it is associated with angular stomatitis. Microscopyshows intercellular oedema and chronic inflammatoryinfiltration of the corium. Candidal organisms maynot be seen in biopsy specimens, as the fungus tends toproliferate within the microscopic interstices of the denturematerial.Generalised mucosal erythema, often with depapillationof the filiform lingual papillae, can also be a featureof both broad-spectrum antibiotic use and HIV infection.Candidal lesions may present as persistent, adherent,firm white plaques that may be solitary or multiple,particularly in mucocutaneous candidosis syndromes[30]. In the latter, the mouth is often the most severelyaffected site. These lesions are referred to as chronichyperplastic candidosis or candidal leukoplakia. Mostpatients with isolated plaques are men of middle age orolder and the majority smoke cigarettes. The most commonsites of involvement are the dorsum of the tongueand the post-commissural buccal mucosa. The plaquesare often thick with a rough, irregular surface that maybe nodular. In many cases the lesion forms a variegatedred and white patch producing a speckled appearance.Microscopy shows a parakeratinised surface infiltratedby neutrophils forming spongiform pustules. Theepithelium shows downgrowths of blunt or club-shapedrete ridges with thinning of the suprapapillary areas toproduce a psoriasiform appearance. The BMZ may bethickened and prominent and there is variable but oftensevere inflammation in the underlying corium. In somecases there can be conspicuous peri-capillary fibrinousexudation, particularly in the papillary corium. Candidalhyphae may be remarkably sparse and not detectedunless multiple sections and special stains are used.Electron microscopy shows that the hyphae are intracellularparasites that grow within the cytoplasm of the epithelialcells rather than along the intercellular spaces.3.4.2 Lichen PlanusLichen planus is a relatively common chronic inflammatorymucocutaneous disease that can also involve thehair and nails [162]. Although the majority of cases ofcutaneous involvement resolve spontaneously within2–3 years, oral lesions can be remarkably persistent andmany cases never resolve. It can give rise to white lesions,atrophic areas or superficial ulcers (erosions). Theaetiology is unknown, but the histological appearance,which shows T lymphocytes attacking the basal epithelium,suggests an autoimmune mechanism. A wide rangeof drugs can precipitate or exacerbate the disease and asimilar reaction is seen in graft versus host disease.Middle aged or older people are predominantly affectedand the disease is rare in children and young adults.Women account for at least 65% of patients. White lesionsare frequently asymptomatic, but in some patientslichen planus can lead to intractable oral ulceration thatmay persist for decades. The lesions have characteristicclinical appearances and distribution. The most commonform is striae, which are sharply demarcated andform lace-like (reticular) or annular patterns. Thesemay be interspersed with defined, small, elevated papules.The patient may complain that they feel a slight restrictionon opening. Less common types of white lesionsare confluent plaques, which some term homogeneouslichen planus. They are usually well demarcated,raised plaques and are frequently traversed by intersectinggrooves producing a tessellated appearance. The latterappearance is particularly common on the dorsumof the tongue and other sites in long-standing disease.Atrophic areas, with redness due to mucosal thinningbut without ulceration are usually combined with areasof striation. Erosions are shallow, irregular ulcers usuallycovered by a slightly raised, yellowish, fibrinousslough. Very rarely bullae form.Oral lesions of lichen planus are very often symmetrical,sometimes strikingly so, but may be more prominenton one side than another. The most frequently affectedsites are the buccal mucosae, particularly posteriorly,but lesions may extend to the commissures. Thetongue is the next most commonly affected site. The lesionsusually involve the lateral areas of the dorsum bilaterallyor less frequently the centre of the dorsum. Theventrum is a relatively uncommon site. Atrophic lichenplanus often involves the gingiva, but reticular lesionsare relatively uncommon at this site. The lips, sometimesincluding the vermilion border, may be involved,but the palate is rarely affected; lesions of the floor of themouth are exceptional.Sometimes involvement of the gingiva may be thepredominant or only manifestation of lichen planus. Assuch, it needs to be distinguished from a variety of otherinflammatory gingival conditions. The most commonappearance is gingival atrophy and the epithelial thinningleads to a shiny, red, smooth appearance. This isknown clinically as desquamative gingivitis. It is importantto appreciate that desquamative gingivitis is a clinical,descriptive term and not a diagnosis. Diseases otherthan lichen planus that can produce this appearance includemucous membrane pemphigoid, pemphigus anda condition called plasma cell gingivitis that is probablyallergy based. Unlike marginal gingivitis, the inflammationcan extend onto the alveolar mucosa, but in theabsence of secondary plaque accumulation there is usuallysparing of the marginal gingiva and interdental papillae.The condition may be generalised or only patchilydistributed. Also, for unknown reasons, it is rare onthe lingual and palatal gingiva.Clinically, white lesions show parakeratosis or hyperorthokeratosis,sometimes with a prominent granularcell layer [4]. The keratosis may be patchily distrib-

Oral Cavity Chapter 3 83Fig. 3.9. Lichen planus showing basal cell degeneration andCivatte bodiesuted as might be expected in reticular or striated lesions.There is a characteristic band-like lymphohistiocytic infiltratesharply localised to the superficial corium. Occasionally,germinal centres form within the lymphoidinfiltrate. There is often conspicuous basal cell damagewith apoptosis, ballooning degeneration due to intracellularoedema and the formation of colloid (Civatte) bodies(Fig. 3.9). Fibrinogen deposition along the BMZ issometimes a conspicuous feature and there may be pigmentaryincontinence secondary to the basal cell liquefactionand melanophages in the superficial corium. Therete ridge pattern is variable, but the saw-tooth patterntypical of cutaneous lichen planus is relatively uncommonin oral lesions. In lesions from the dorsum of thetongue in particular, the rete processes may be elongatedwith dense inflammatory infiltrates around their tips.Atrophic lesions show conspicuous thinning andflattening of the epithelium, but the characteristic bandlikeinflammatory infiltrate is retained. In ulcerated lesionsthe inflammatory infiltrate contains polymorphonuclearleukocytes and plasma cells and extends into thedeeper corium, often leading to a non-specific appearance.As lichen planus is often treated with topical steroidsit is not uncommon to find infestation of the superficialepithelial layers by candidal hyphae. These may or maynot be associated with spongiform pustules. Some ofthese lesions may also show reactive cytological atypia.A great variety of drugs can cause diseases resembling,or in some cases indistinguishable from, lichenplanus. There may be a history relating the onset of lesionsto the drug administration or exacerbation of previouslyquiescent disease [104, 105]. The oral lesions areoften severely ulcerated and the dorsum of the tongueand palate appear to be sites of predilection. In some patients,there may be a lichenoid reaction in mucosa indirect contact with dental amalgam fillings and occasionallyeven composite filling material and gold restorations.Microscopically, there are no absolute diagnostic criteriadistinguishing lichen planus from lichenoid drugeruptions [104]. It is reported that in lichenoid reactionsthe inflammatory infiltrate is more dense. In addition,it is said to be more likely to show the presence ofplasma cells in the infiltrate, particularly in the leadingedge, and a greater likelihood of germinal follicle formation.In addition, the deep layer of the infiltrate is lessdefined and perivascular inflammatory infiltration extendinginto the deeper corium is seen more frequently.However, many of these features may reflect the moresevere nature of the disease and be related merely to theeffects of ulceration. It is therefore essential to examineareas well away from obvious ulceration when interpretingthese biopsies.3.4.3 Lupus ErythematosusLupus erythematosus is an autoimmune disease ofunknown origin. The two main forms that affect themouth are discoid lupus erythematosus (DLE; chroniccutaneous lupus erythematosus) and systemic lupus erythematosus(SLE). Oral lesions are present in over 20%of patients with SLE.The clinical features of oral DLE closely resemblethose of lichen planus [157]. They typically show a centralarea of atrophic, erythematous or granular mucosawith a surrounding radiating, striated white halo. Thecentral area occasionally ulcerates. Lesions are mostcommon in the centre of the palate and on the labialaspect of the upper lip, but they can be seen elsewherein the mouth. Sometimes there are adjacent “kissinglesions” on the gingiva opposite labial lesions. The lesionsof DLE lack the symmetrical distribution characteristicof oral lichen planus. Patients with SLE may havethe classical photosensitive butterfly rash in the midfaceand show other evidence of a systematised disease. Themucosal lesions may resemble those of DLE or show evidenceof more severe mucositis and non-specific ulceration.Shallow linear ulcers running parallel to the palatalgingiva are sometimes a striking feature.Microscopy shows many similarities to lichen planus[90, 156]. There is either hyperorthokeratosis orhyperparakeratosis. The follicular plugging characteristicof cutaneous lesions has been described in oral lesions,but it is an inconsistent and frequently poorly definedfeature (Fig. 3.10). The rete processes are hyperplasticand can form flame-like downgrowths into the

84 J.W. Eveson3Fig. 3.10. Discoid lupus erythematosus showing irregular focalepithelial hyperplasia and follicular pluggingunderlying corium. This feature is sometimes so floridthat it produces a pseudoepitheliomatous appearance.The slender downgrowths can also show a tendency tofuse with each other producing an appearance simulatingan embedding artefact. Dyskeratotic cells arean occasional feature. There is apoptosis and liquefactiondegeneration of the basal cells, sometimes withCivatte body formation. The BMZ may become hyalinisedand thickened and this is sometimes a notable feature.There is a band-like infiltrate of lymphohistiocyticcells in the superficial corium similar to that seen inlichen planus, but the lower border tends to be less welldefined and the infiltrate often extends into the deepertissues in a perivascular distribution. Reactive folliclesmay form in the lymphoid infiltrate. In cases ofSLE there may be evidence of fibrinoid necrosis in vessels.Direct immunofluorescence of lesional tissue forIgG, IgM or IgA shows a granular deposit in the BMZof about 75% of cases of oral DLE and all cases of SLE.A lupus band test in clinically normal skin or mucosais diagnostic of systemic disease. The presence of C3 orfibrinogen in the BMZ is not specific and is frequentlydemonstrated in lichen planus.3.4.4 Oral Epithelial NaeviNon-pigmented epithelial naevi are rare in the oral cavity.They include white sponge naevus, oral epithelialnaevi and naevi associated with naevus unius lateris.White sponge naevus is an autosomal dominant inheritedtrait characterised by heaped up, sodden, irregularwhite plaques that can affect any part of the oralmucosa and may involve other mucosae including nasal,anal and vaginal (Cannon’s syndrome). Microscopically,there is acanthosis with vacuolated cells in the stratumspinosum producing a basket weave appearanceand irregular, shaggy parakeratosis. It is associated witha novel mutation in the keratin 4 gene [34].Oral epithelial naevus was the term given to distinctivewhite plaques involving the ventral lingual mucosaand floor of the mouth [37]. These were sharply defined,irregularly butterfly shaped and had a uniformly wrinkledsurface. However, a retrospective study of lesions ofthis type in the floor of the mouth suggested there was asubstantial risk of malignant transformation in this lesionand it was renamed sublingual keratosis [94, 139].Since that time there have been no other studies substantiatingthese observations and the status of these lesionsneeds to be re-established.Naevus unius lateris typically involves the skin withunilateral linear, papillary or verrucous lesions, usuallyalong the long axis of a limb or across the trunk.It has uncommonly been associated with oral lesions[74]. These are typically papillary, wart-like proliferationsand have been described on the lips, tongue, buccalmucosa, palate and gingivae, usually on the left. Microscopyshows papilliferous proliferation with non-keratinised,hyperplastic epithelium covering connectivetissue cores that may be patchily inflamed. Similar lesionshave been described in the absence of cutaneouslesions, usually in the midline of the palate.3.4.5 Smoker’s KeratosisKeratosis may be associated with both tobacco-smokingand -chewing. In smoker’s keratosis the lesions appear tobe a result of both thermal and chemical irritation. Theyrarely show significant dysplasia and appear to have alow pre-malignant potential. The affected mucosa mayshow diffuse whitening or more focal lesions and occasionallythey are pigmented and have a slate-blue colour.The epithelium can be hyperplastic or atrophic andis not dysplastic [136]. There is very variable parakeratosisor hyperorthokeratosis. Some cases show focalparakeratotic spikes (“chevrons”). Although suchchevrons were thought to be most characteristic ofsmokeless tobacco-induced keratosis, only a minorityof such lesions show this feature [40]. Pigmentary incontinenceis common and may be florid in darkly pigmentedindividuals. Inflammatory infiltration is usuallyminimal.3.4.6 Stomatitis NicotinaStomatitis nicotina is usually seen in the palates of pipeor cigar smokers and the overwhelming majority of patientsare men [158]. Minor degrees of the condition maybe seen in heavy cigarette smokers. Similar clinical appearanceshave been reported in patients who regularlydrink excessively hot liquids. It is usually painless andasymptomatic. The initial lesion appears to be increased

Oral Cavity Chapter 3 85keratosis of the palate exposed to the smoke. This leadsto obstruction of the ducts of the underlying minor salivaryglands, which then become inflamed. The classicalclinical appearance, therefore, is whitening of the palatalmucosa, which may show tessellated plaque formation.The involved minor glands become swollen andhave red, umbilicated centres.Microscopy shows variable hyperkeratosis, acanthosisand duct dilatation. There is usually no evidence ofepithelial dysplasia. There is variable submucosal chronicinflammation and there may be evidence of pigmentaryincontinence. Keratinisation can extend down thesalivary ducts and there is interstitial inflammation ofthe underlying minor mucous glands.The condition will gradually resolve if the habit isdiscontinued and there appears to be minimal risk ofmalignant transformation. However, affected individualshave an increased risk of developing squamouscell carcinoma in other parts of the mouth, particularlythe floor of the mouth and adjacent ventral lingualmucosa, and the retromolar trigone. Conversely, palatalkeratosis due to “reverse smoking” where the lightedend of a cigarette or cigar is held in the mouth isassociated with the development of carcinomas of thehard or soft palates in a very high number of patientspractising the habit [148].3.4.7 Hairy TongueHairy tongue is due to hyperplasia and elongation ofthe filiform papillae, which form hair-like overgrowthson the dorsum. The filaments can be several millimetreslong. The colour varies from pale brown to intenseblack. The discoloration is due to proliferation ofchromogenic bacteria and fungi. Hairy tongue is usuallyseen in older individuals, and smoking, antisepticmouthwashes, antibiotics and a diet lacking abrasivefoodstuffs are the most common predisposing factors.The dorsum of the tongue may also become blackenedwithout elongation of the filiform papillae byantibiotic mouthwashes such as tetracycline and ironcompounds. Hairy tongue is rarely biopsied. Microscopically,it is characterised by irregular, hyperplasticfiliform papillae showing hyperorthokeratosis or hyperparakeratosiswith numerous bacterial conglomeratesand filamentous organisms in the surface layersand more deeply between fronds of epithelium. It hasbeen shown by immunocytochemical analysis of keratinexpression that in black hairy tongue there is defectivedesquamation of cells in the central column ofthe filiform papillae. This results in the typical highlyelongated, cornified spines that are the characteristicfeature of the condition [110].3.4.8 Hairy LeukoplakiaPatients infected with HIV, particularly homosexualmales, may develop characteristic intraoral white lesions[149]. The lateral margins and underlying ventrum ofthe tongue are the most common sites. The lesion wascalled hairy leukoplakia, but typically it forms painless,vertical, white corrugations that may or may not havea rough or “hairy” surface. Some lesions are flat whiteplaques. Other sites may also be involved, especially thepost-commissural buccal mucosa.Microscopy shows acanthosis and parakeratosis,usually with verruciform, hair-like surface projections[168]. Invasion of the surface epithelium by candidal hyphaeis common. Immediately below the parakeratoticlayer there is a zone of vacuolated and enlarged epithelialcells with intense basophilic, pyknotic nuclei and perinuclearclearing (koilocytes). Epstein-Barr capsid viralantigen and viral particles can be demonstrated in thekoilocytic nuclei [172]. There is usually little or no inflammatoryinfiltration of the epithelium or underlyingcorium. Similar lesions have occasionally been reportedin patients receiving immunosuppressant drugs followingorgan transplantation. The early cases of hairy leukoplakiaassociated with HIV infection showed a veryhigh rate of progression to full-blown AIDS. Lesions canresolve spontaneously and usually respond well to antiviralor anti-retroviral drug treatment; they appear tohave no premalignant potential.3.4.9 Geographic TongueGeographic tongue is a relatively common idiopathiccondition typically characterised by migrating areas ofdepapillation on the dorsum of the tongue [6]. In manycases it is associated with fissuring. There is loss of filiformpapillae often surrounded by a slightly raisedyellowish-white and crenellated margin. These areasof depapillation tend to heal centrally and spread centrifugally.Occasionally, the ventrum is involved and inthat site lesions consist of an area of erythema completelyor partially surrounded by a circinate whitish halo.Identical lesions can occasionally be seen elsewhere inthe mouth and have been called “ectopic geographicaltongue”, although geographical stomatitis or benignmigratory stomatitis would be more appropriate terms[81]. The majority of cases of geographical tongue arepainless, but some patients complain bitterly of sorenessand discomfort, which may or may not be associatedwith specific foods.Geographical tongue is usually obvious clinicallyand is rarely biopsied. However, it has very typical microscopicalfeatures [114]. There is loss of filiform papillaeand typically only a mild chronic inflammatory

86 J.W. Eveson3shredded, often patchily erythematosus white plaqueslimited to areas accessible to chewing. In typical frictionalkeratosis microscopy usually shows a thick orthokeratinisedlayer with a prominent granular cell layer.There is no significant dysplasia and inflammation ofthe underlying corium may be minimal in the absenceof ulceration. In keratosis due to habitual chewing thereis often acanthosis and the surface is usually irregularand parakeratinised. It frequently shows a covering ofadherent basophilic cocci or more dense bacterial conglomerates.Fig. 3.11. Geographical tongue (erythema migrans) showingpolymorphonuclear leukocyte microabscesses in the epithelium3.5 Pigmentationsreaction in the underlying corium. The striking featureis the presence of polymorphonuclear leukocytic microabscessesin the upper stratum spinosum (Fig. 3.11).These spongiform pustules are not pathognomonic ofgeographical tongue and can be seen in oral psoriasis,acute and chronic candidosis, Reiter syndrome and plasmacell gingivostomatosis. Some describe elongation ofthe rete ridges, but this is by no means a consistent observation.However, occasionally there may be psoriasiformhyperplasia in geographical tongue and it may bedifficult or impossible to distinguish from psoriasis. Indeed,geographical tongue and migratory stomatitis are4–5 times more common in patients with psoriasis andsome believe that geographical tongue is the oral homologyof psoriasis [179, 194]. The presence of spongiformpustules in oral biopsies should always promptthe search for candidal hyphae with a PAS or Grocottstain. These are not usually seen in geographical tongueand their presence would make a diagnosis of candidosismuch more likely. Chronic hyperplastic candidosis canalso show psoriasiform hyperplasia, but typically thereis much more florid inflammatory infiltration of the coriumand irregular surface parakeratosis.3.4.10 Frictional KeratosisFrictional keratosis of the oral mucosa is common and isusually a response to low-grade irritation by such causesas sharp edges of teeth or restorations, dental prostheses,abrasive foods, vigorous tooth brushing and playingwind instruments.Clinically, the lesions tend to form diffuse keratoticplaques. In the early stages these are pale and translucentand merge imperceptibly into the surrounding normalmucosa. Later, they become more dense and whiteand may have an irregular, shaggy surface. The habit ofcheek, lip and tongue chewing is a usually characteristicvariant of frictional keratosis. It results in roughened or3.5.1 Amalgam TattooAmalgam tattoo is the most common localised form oforal mucosal pigmentation [23]. Lesions usually formpainless, bluish-black macules, which may be well definedor diffuse, and the most common sites are the gingiva,alveolar mucosa and floor of the mouth. They arecaused by ingress of dental amalgam through a mucosalbreach during a restorative procedure or tooth extractionand can also follow an apicectomy with retrograderoot filling.Microscopy shows dark, refractile particles of amalgamin the corium [44]. These may be coarse, but usuallyform fine, black or brownish granules. These aredeposited along collagen and elastic fibres, and aroundsmall blood vessels, nerves and muscles. About half ofcases show a fibrous and chronic inflammatory reaction,with or without multinucleated foreign body giantcells. Occasionally, there is a granulomatous reaction.3.5.2 Localised Melanotic Pigmentation3.5.2.1 Oral Melanotic MaculesThese benign, ephelis-like pigmented macules are themost common melanocytic lesions of the oral mucosa.They are brownish-blue or black and may be single ormultiple. They are typically well defined and rarelyexceed 6 mm in diameter. They develop during earlyto middle adult life with a mean age at presentation of41 years [22]. There is a female predilection of 2:1. Theyare most frequent in the anterior part of the mouth affectingthe gingiva, buccal mucosa and, most commonly,the labial mucosa. Those involving the vermilion border(labial melanotic macules) often darken in strong sunlightand may cause cosmetic problems. Oral melanoticmacules have been reported following radiotherapy [11],

Oral Cavity Chapter 3 87Fig. 3.12. Melanotic macule showing increased melanotic pigmentationof the basal keratinocytes and melanophages in the superficialcoriumand in HIV infections, probably related to the administrationof retroviral drugs [55].Microscopy shows increased melanotic pigmentationin the basal and occasionally the immediately suprabasalkeratinocytes. There is often pigmentary incontinenceand melanophages in the superficial corium(Fig. 3.12).3.5.2.2 MelanoacanthomaMelanoacanthoma (melanoacanthosis) is a rare, probablyreactive, proliferation of both keratinocytes andmelanocytes [61, 64]. It is seen most commonly in adultblack females, typically involving the labial or buccalmucosa. Lesions may be single or multiple [49] and areusually macular; less frequently, they are slightly raisedor papilliferous. Trauma is thought to be the most likelycause and lesions can regress spontaneously or followingincisional biopsy.Microscopy shows acanthosis and frequently spongiosisthat can be florid. There are strongly Fontana silverstain- and HMB45-positive, dendritic melanocytesextending throughout the full thickness of the epithelium(Fig. 3.13). As a consequence of a partial or completeblock in pigment transfer the keratinocytes in melanoacanthomacontain little or no melanin in spite of theabundance of melanocytes.3.5.2.3 Pigmented NaeviOral melanocytic naevi are much rarer than cutaneouslesions with a prevalence of 0.1% of the general population[75]. The most common sites are the hard palate,buccal mucosa and labial mucosa. Women are affectedtwice as frequently as men and most cases are seen in thethird and fourth decades. They are usually single andFig. 3.13. Melanoacanthoma showing dendritic melanocytes extendingthroughout the epithelial thickness. Inset shows melanocytesstained with Masson-Fontanaform brown, bluish or black macules or sessile papules.Most are less than 6 mm in diameter [24]. Intramucosal(intradermal) naevi account for over half of the casesand junctional or compound naevi are uncommon. Bluenaevi form 25–35% of cases and usually present in thepalate. The large majority are of the common ratherthan the cellular type.3.5.3 Premalignant Oral Melanosesand Oral MelanomaICD-O:8720/3Oral mucosal melanomas are rare and account for about0.5% of oral malignancies [35, 75]. However, they appearto be more common in Japan, India and Africa. Mostarise in adults with a peak incidence between 40 and60 years. Large series show a male predominance. About80% of cases involve the palate and maxillary alveolusand gingivae. About a third of cases are preceded by

88 J.W. Eveson3long-standing areas of oral hyperpigmentation, but theyrarely arise from pre-existing benign melanocytic naevi.The majority of cases are painless in the early stages andform irregular, black or brownish flat, raised or nodularareas that are frequently multicentric. Rarely, they areamelanotic and may be reddish in colour. Nodular areasare usually a feature of more advanced tumours andmay be ulcerated and associated with pain and bleeding.Invasion of the underlying bone is common and teethinvolved may loosen or exfoliate. In most cases there isinvolvement of the cervical lymph nodes at presentationand half of patients have distant metastases.Purely nodular melanomas are relatively rare andmost tumours have a radial growth element similar tothat seen in cutaneous acral lentiginous melanoma togetherwith evidence of upward migration. Oral melanomashave been divided into:1. In situ oral mucosal melanomas;2. Invasive oral mucosa melanomas;3. Mixed in situ and invasive oral mucosal melanomas.Fig. 3.14. In situ melanoma showing atypical melanocytes widelydispersed throughout the epitheliumAbout 15% of oral mucosal melanomas are in situ and30% are invasive [9]. Fifty-five percent of melanomashave a combined pattern. Borderline lesions have beentermed atypical melanocytic proliferations [75].Microscopically, in situ melanomas show an increasein atypical melanocytes. Although these atypical melanocyteshave angular and hyperchromatic nuclei, mitosestend to be sparse. The melanocytes may form aggregatesor be irregularly distributed in a junctional location.The characteristic nested or thequal pattern commonlyseen in cutaneous melanomas is less frequentlyobserved in mucosal lesions. Sometimes the melanocytesare dispersed throughout the epithelium and thismay be combined with a junctional pattern (Fig. 3.14).Sequential biopsies have shown increases in the densityof the junctional atypical melanocytes over time. Atypicalmelanocytes can extend down the excretory ducts ofthe underlying minor salivary glands. However, there isusually no inflammatory response to in situ lesions.The melanocytes present in invasive melanomasshow a variety of cell types including epithelioid, spindleand plasmacytoid. They typically have large, vesicularnuclei with prominent nucleoli. Mitoses may be present,but usually not in large numbers. They are usuallyaggregated into sheets or alveolar groups and less commonlyneurotropic or desmoplastic configurations areseen. About 10% of cases are amelanotic. Over 95% of lesionsare anti S-100 antigen-positive [10] and more specificmarkers include HMB45, Melan-A and antityrosinase[144].Atypical melanocytic proliferation or hyperplasia isthe term used for lesions with equivocal histopathologicalfeatures, but the criteria for inclusion in this categoryare rather ill-defined [176]. These include oral mucosallesions with melanocytes containing angular or hyperchromaticnuclei with very infrequent mitoses. Melanocyticatypia can vary from mild to severe [75].Oral melanomas are much more aggressive than theircutaneous counterparts. The prognosis of oral melanomasis poor with a 5-year survival rate of less than 20%[9], and even Stage I tumours have a 5-year survival rateof less than 50%. The conventional depth of invasionindicators such as Breslow thickness and Clark’s levelstend to be of little value in mucosal melanomas, as manypresent at an advanced stage and most are deeper than4 mm [145]. Histological features associated with a poorprognosis include evidence of vascular invasion, cellularpleomorphism, necrosis and amelanotic tumours [14,75, 123, 145].3.5.4 Addison DiseaseAddison disease is rare with an estimated annual incidenceof 0.8 cases per 100,000 of the population inWestern societies. It is due to bilateral destruction of theadrenal cortex. Formerly, the most common cause wastuberculosis. Most cases now are due to organ-specificauto-immune destruction and opportunistic infectionssuch as histoplasmosis in patients with AIDS. Due tothis, it is likely that the number of patients with Addisondisease will increase significantly. Addison diseasemay be associated with autoimmune polyglandular deficiencytype I (Addison disease, chronic mucocutaneouscandidosis, hypoparathyroidism) and autoimmunepolyglandular deficiency type II (Addison disease, primaryhypothyroidism, primary hypogonadism, insulindependentdiabetes, pernicious anaemia, vitiligo) [130].Clinically, there is usually slowly progressive weakness,lassitude and weight loss. Gastro-intestinal symptomscan include diarrhoea or constipation and anorexia,nausea and vomiting. Postural hypotension is a commonsymptom. An early sign is pigmentation of the skinand oral mucosa secondary to increased adrenocortico-

Oral Cavity Chapter 3 89tropic hormone (ACTH) secretion. Parts of the skin exposedto the sun and areas subjected to trauma or frictionbecome bronzed [85]. There is also increased pigmentationin skin folds and scars. About 10% of patientsalso show areas of vitiligo.Oral pigmentation is variable and where presentranges from light brown to densely black [95]. The gingiva,lateral margins of the tongue, buccal mucosa andlips are the sites of predilection. Microscopy of the areasshows increased melanin predominantly in the basalkeratinocytes.3.5.5 Peutz Jeghers SyndromePeutz Jeghers syndrome (periorifacial lentiginosis)comprises melanotic spots of the face, mouth and lesscommonly the hands and feet, together with intestinalpolyposis. It is inherited as an autosomal dominant traitwith nearly complete penetrance [93], but new mutationsoccur in 40% of cases.There are multiple ephelides on the face and melanoticmacules in the mouth involving the lower labialand buccal mucosa in particular. Lesions are oftenpresent at birth. The facial pigmentation is around themouth, nose and eyes and tends to progressively fadeafter puberty. The mucosal pigmentation persists intoadult life.There are hamartomatous polyps throughout the intestinaltract, but typically these are most numerous inthe small intestine. They can give rise to abdominal painand bleeding and intussusception is a rare complication.The polyps have a low malignant potential, with thosein the colon having the highest risk. Patients also are atincreased risk of malignancy at other sites including theuterus, ovary, pancreas and breast.3.5.6 Racial PigmentationRacial pigmentation is the most common cause of intraoralpigmentation. It is seen predominantly in Blacks,Asians and people of Mediterranean origin, but about5% of Caucasians also have significant intraoral pigmentation.The degree and extent of racial pigmentationis very variable and does not necessarily correlate withthe depth of skin pigmentation. It can vary from lightbrown to almost black and the most commonly involvedsites are the gingiva, palate and buccal mucosa. Sometimeswhen the tongue is involved the only areas affectedare the fungiform papillae, producing an appearanceof spotty pigmentation.Microscopy shows increased melanocytic pigmentationof the basal and, to a much lesser degree, the immediatelysuprabasal keratinocytes. The denser pigmentationis due to increased synthesis of melanin by melanocytes,which are otherwise normal in number and distribution.3.5.7 Laugier Hunziker SyndromeLaugier Hunziker syndrome is an acquired, benignmacular hyperpigmentation of the lips and oral mucosa[118]. It typically starts in early to middle adult life andis more common in women than men. The pigmentationconsists of brownish, circular or linear macules,that may be sharply circumscribed or more diffuse innature, and lesions may coalesce. The lesions are seenmost commonly on the buccal mucosa, lips and thehard and soft palates. Other less frequent sites includethe tongue, gingiva and floor of the mouth. Occasionally,the pharynx and oesophagus are also involved[190]. About half of the cases also have nail involvementin the form of longitudinal pigmented bands inone or more fingers or toes. There are no known systemicassociations.Microscopy shows increased melanotic pigmentationof basal keratinocytes and melanophages in the superficialcorium secondary to pigmentary incontinence. Ultrastructuralstudies show increased numbers of normal-appearingmelanosomes in keratinocytes in thelower epithelial layers [118].3.5.8 Smoker’s MelanosisHeavy smokers can sometimes develop areas of oralhyperpigmentation. It is more common in womenthan men. Although any part of the mouth can beaffected the anterior gingivae are involved most frequently.The lesions vary in colour from light brownto bluish-black and the lesions may be focal or diffuse.Sometimes the overlying mucosa has a somewhatmilky-white appearance, particularly in the buccalmucosa. The condition can slowly resolve if smokingis stopped or reduced [72]. Pigmentation of the softpalate has been reported in a significant number ofpatients with suppurative lung disease and malignancy[117]. Nearly a quarter of patients with confirmedbronchogenic carcinoma show this feature. Most patientshave a long history of cigarette smoking and it ispossible that in many cases these lesions were merelysmoker’s melanosis rather than being related directlyto the pulmonary lesions.Microscopy may show slightly increased melanoticpigmentation of the basal keratinocytes, but the moststriking feature is usually pigmentary incontinence andaccumulation of melanophages in the superficial corium.

90 J.W. Eveson3.5.9 Drug-AssociatedOral Pigmentation3Gingival pigmentation due to heavy metals such asmercury, lead, bismuth, arsenic and others was notrare in the past due to industrial exposure and in somecases therapeutic administration, particularly for thetreatment of syphilis. They caused blue, brown orblack lines close to the gingival margins due to the depositionof sulphides as a result of reactions with productsof the dental plaque. A wide range of drugs cancause more generalised oral pigmentation includingantimalarials, phenothiazines and some contraceptivepills [98]. Drugs used in the treatment of HIV infectionsuch as zidovudine and some antifungals such asketoconazole have also been shown to cause oral pigmentation.3.6 Hyperplastic Lesions3.6.1 Fibrous HyperplasiasThe majority of fibrous and fibroblastic lesions withinthe mouth appear to be reactive rather than neoplastic.They are the most common tumour-like swelling of oralmucosa. Although these lesions are considered to be aresponse to low-grade irritation, the source of such irritationmay not be immediately apparent. Fibroepithelialpolyps tend to form smooth nodules or swellings thatmay be soft or firm and are usually covered by normal,pink mucosa unless ulcerated. The polypoid swellingsmay be sessile or pedunculated.Fibrous overgrowths of the gingiva are a type of epulis(lit. – swelling of the gum). They can arise from theinterdental papilla or gingival margin and tend to affectthe anterior part of the mouth. They can grow to severalcentimetres in diameter. Fibrous epulides are frequentlyassociated with local irritation from dental calculus,sharp edges of restorations or carious teeth. A very characteristicform of hyperplasia is associated with the edgesof loose dentures. Such denture-induced fibrous hyperplasiahas been termed denture granuloma and epulisfissuratum. The rocking backwards and forwards ofthe denture causes extensive overgrowth of fibrous tissueon either side of the edges, or flanges, of the denture.This often leads to the formation of a series of linearfolds of hyperplastic tissue and the base of the groovesso formed is often ulcerated by the denture’s edge. Othercommon sites for fibrous overgrowths are along theocclusal line of the buccal mucosa and lateral border ofthe tongue, and related to spaces where teeth have beenextracted.Microscopically most of these nodules consist of interlacingbundles of sparsely cellular fibrous tissue. TheFig. 3.15. Fibrous epulis showing osseous metaplasiaoverlying epithelium is often hyperplastic with irregularrete processes extending sometimes deeply into the underlyingfibrous tissue. There may be candidal infestationof the superficial epithelium. The degree of inflammatoryinfiltration is very variable, but tends to be mildunless there has been ulceration.The microscopical appearances of fibrous epulidescan differ from fibrous overgrowths seen elsewhere inthe mouth. They typically show much more evidenceof cellular fibroblastic proliferation. These lesions mayconsist predominantly or focally of a vascular stromacontaining plump fibroblasts with large, vesicular nucleiand prominent nucleoli. There can be brisk mitoticactivity. Ulceration is common and the lesions areoften heavily inflamed. Calcifications are common infibrous epulides and there may be florid osseous metaplasiaor dystrophic calcification (Fig. 3.15). Sometimesthe calcified masses are basophilic and they canalso be laminated and resemble cementicles. Such lesionshave been termed “peripheral ossifying fibromas”,but there is no evidence that they are neoplasticor have any relationship with central ossifying fibromas(see Chap. 4). Mineralisation tends to be uncommonin extra-gingival oral fibrous overgrowths.Most fibrous overgrowths respond to conservativesurgical removal, but a minority of fibrous epulides canrecur, sometimes repeatedly.3.6.2 Papillary HyperplasiaPapillary hyperplasia is typically seen in the hard palate.In many cases it is related to dentures as part of theclinical spectrum of denture-induced stomatitis [174].Although Candida albicans is frequently invoked as thecausal agent, in a significant number of cases there is noevidence of fungal infection. The large majority of casesinvolve the hard palate, particularly when this is higharched,but similar lesions are occasionally seen on thedorsum of the tongue. The lesions form painless, nodu-

Oral Cavity Chapter 3 91Fig. 3.16. Papillary hyperplasia of the palate showing long reteprocesses extending into the connective tissue coreslar or papilliferous proliferations. Florid cases have beenreported in immunocompromised patients [151].Microscopy shows nodular, papilliferous hyperplasiaof the epithelium and underlying fibrous connectivetissue (Fig. 3.16). The surface usually shows parakeratosisor less commonly orthokeratosis. There may be evidenceof candidal infestation such as spongiform pustulesor obvious hyphae. The underlying hyperplasticrete ridges often extend into the cores of the papillae, resultingin a striking pseudoepitheliomatous appearance.The corium often contains a dense chronic inflammatorycell infiltrate. The condition then needs to be distinguishedfrom oral papillary plasmacytosis [66].3.6.3 GeneralisedGingival Fibrous HyperplasiaGeneralised fibrous hyperplasia/hypertrophy of thegingiva can be familial or drug-induced.Hereditary gingival fibromatosis is a rare conditionthat is usually inherited as an autosomal dominant trait[20]. It can affect all of the gingiva, often in a symmetricalmanner. It may be associated with hypertrichosis,coarsening of the facial features and neurological problemssuch as epilepsy and mental retardation. The conditionusually first affects adolescents, but occasionallyit can involve the deciduous dentition. The enlargementis usually most conspicuous in the interdental areas andaffects the palatal and lingual gingiva as well as the labialand buccal aspects. The overgrowths may be so floridthat the teeth involved are almost completely buried(pseudo-anodontia). The overgrowths are rounded,smooth, firm and pale-coloured. Treatment is by surgicalremoval of the redundant fibrous tissue (gingivectomy),but the condition often recurs.Drug-associated gingival hypertrophy is seen in abouthalf of patients using the anti-epileptic drug phenytoinfor long-term treatment [1]. Other drugs producing asimilar reaction include cyclosporin (~30% of patients)and calcium channel blockers such as nifedipine, amlodipineand verapamil (~10% patients). The enlargementsmay be generalised or more localised. The anteriorinterdental papillae tend to be the most severely affectedareas, particularly on the labial aspect. The gingivatend to enlarge laterally and this growth pattern mayresult in the formation of vertical clefts between adjacentovergrowths. The normal gingival stippling may beenhanced, producing an orange-peel appearance. Thecondition is exacerbated by poor oral hygiene and meticulousattention to tooth cleaning may help preventthe development of the condition.Microscopy of generalised gingival fibrous hyperplasiatends to be the same irrespective of the cause. Thereis fibrous hypertrophy of the affected gingiva, often containingmyofibroblastic cells. An increase in the amountof myxoid ground substance material is also common.In areas distant from the gingival sulcus there is usuallyno significant inflammatory component. There is oftenelongation and fusing of the rete process of the overlyingepithelium. It is unusual for these lesions to becomeulcerated3.6.4 Crohn’s DiseaseCrohn’s disease is a multisystem disorder characterisedmicroscopically by non-caseating, epithelioid granulomas.Despite extensive investigations the cause remainsunknown. Recently, genetic predisposition has been extensivelyinvestigated and among others, a susceptibilitygene has been identified on chromosome 16q [18].Smoking also appears to play a critical role in some patients[60]. Although an infective aetiology, particularlymycobacterial, has been long suspected, critical proofis lacking [173]. The most likely candidate organism isthe Mycobacterium avium subspecies paratuberculosis[68]. Granulomatous vasculitis, possibly initiated by themeasles virus, has been proposed as a significant factorin the pathogenesis [178]. However, blood vessel involvementmay be a secondary phenomenon rather thana primary event [120]. Patients are usually children andyoung adults and there is a male preponderance. Associationsbetween alterations in the intestinal microfloraare also suspected and a statistically significant associationbetween Crohn’s disease and previous antibioticuse has been proposed [29]. The condition may be madeworse by cigarette smoking [80].Oral lesions are relatively common in patients withCrohn’s disease of the lower gastro-intestinal tract [57,185], but may be the presenting symptoms. They includeswelling of the lips and cheeks (Fig. 3.17), recurrent aphthae,painful, indolent linear ulcers in the vestibular sulci,cobblestone thickening of the buccal mucosa, mucosaltags and hyperplastic, granular gingivitis [138]. Thepalate, tongue and pharynx, including the palatine ton-

92 J.W. Eveson3Fig. 3.17. Crohn’s disease showing unilateral lip swelling with fissuringand peri-oral dermatitisFig. 3.18. Crohn’s disease showing a small, irregular epithelioidgranuloma and patchy chronic inflammationsil, are only rarely involved [19]. Extraorally, there maybe angular stomatitis and vertical fissuring of the lips,and perioral erythema and scaling.Oral lesions may precede, or accompany, bowel symptoms,but in a significant number of cases intestinal diseaseis subclinical. In patients with active bowel diseasethere may be atrophic glossitis secondary to malabsorptionof the haematinics iron, vitamin B 12 or folate.Microscopy of oral lesions typically shows oedemaof the superficial corium with lymphangiectasiaand diffuse and focal aggregates of small lymphocytes.Non-caseating epithelioid granulomas with orwithout multinucleated giant cells are present in about90% of cases [138]. However, granulomas may be smalland poorly formed and may only be present in the underlyingmuscle so that they can be easily missed, especiallyif the biopsy is superficial (Fig. 3.18). Granulomascan also sometimes be seen in the minor salivaryglands. Aggregates of mononuclear cells or granulomasmay be seen bulging into or within the luminaof lymphatics. This feature has been termed endovasalgranulomatous lymphangiitis [128]. Dilated lymphatics,with or without associated granulomas, are characteristicof Crohn’s disease elsewhere in the alimentarytract [120].3.6.5 Orofacial GranulomatosisAs many as 80–90% of patients with orofacial lesionsthat resemble those of Crohn’s disease, both clinicallyand microscopically, have no gastro-intestinal signs orsymptoms and do not develop gut disease [159]. Theterm orofacial granulomatosis (OFG) has been introducedto describe this group of patients [184]. OFG,therefore, is a diagnosis based on the exclusion of othercauses of granulomatous inflammation, particularlysarcoidosis, tuberculosis and other mycobacterial infections,and Crohn’s disease itself. Up to 60% of patientswith OFG are atopic [86] and some patients appear toshow an idiosyncratic intolerance to a variety of foodsor additives, including cinnamonaldehyde, carvone,carnosine, sun yellow, benzoates and monosodium glutamate[169], and to metallic compounds containing cobalt[146]. In many cases there is a partial or completeresolution of symptoms following withdrawal of theprovoking agent.OFG may be part of a spectrum of diseases that includesMelkersson Rosenthal syndrome (MRS) andcheilitis granulomatosa ( Miescher’s syndrome). MRS,in its complete form, is a triad of fissured tongue, labialor facial swelling due to granulomatous inflammation,and facial nerve palsy, which may be the first indicationof the disease [192]. Cheilitis granulomatosa is probablymerely an isolated manifestation of OFG.3.6.6 Chronic Marginal Gingivitisand Localised GingivalFibrous HyperplasiaChronic marginal gingivitis of variable degree is socommon as to be almost universal. It represents a responseof the gingival tissues to accumulation of dentalmicrobial plaque around the teeth. If left untreated theinflammation can become more severe and extend intothe underlying periodontal tissues causing loss of periodontalligament attachment and a pocket develops betweenthe tooth and the overlying gingiva exacerbatingthe tendency for plaque accumulation. Eventually, thereis progressive resorption of the supporting alveolar boneleading to loosening or loss of the tooth.Chronic marginal gingivitis is characterised microscopicallyby mild vascular hyperaemia and densechronic inflammatory infiltration. The crevicular epitheliumis ulcerated and may become hyperplastic withthin, irregular and anastomosing processes extendinginto the gingival connective tissue. There may be consid-

Oral Cavity Chapter 3 93erable intercellular oedema and infiltration of the spongiformspaces by neutrophils, especially in the presenceof gross dental plaque and calculus deposits. Many lymphocytesand plasma cells are present in the inflammatoryinfiltrate and dense, basophilic, granular depositsof extracellular immunoglobulin are common. Russellbodies may be a conspicuous feature. There is variableloss of collagen in areas of severe inflammation. However,in younger patients especially, there may be a proliferativeresponse with extensive formation of new fibroustissue leading to localised areas of fibrous hyperplasia.The enlarged gingiva may prevent effective cleaning ofthe related tooth, predisposing to further plaque accumulationand progressive inflammation. This type of localisedinflammatory gingival hyperplasia is seen muchmore frequently on the buccal or labial aspects of thegingiva than in the palatal or lingual areas. Such overgrowths,although frequently removed as part of a gingivectomyprocedure are not commonly sent for histologicalexamination.3.6.7 Peripheral Giant Cell Granuloma(Giant Cell Epulis)This lesion is found on the gingiva or edentulous alveolusand is thought to originate from elements of the periodontalligament. It is seen across a wide age range, butthe peak incidence is between 30 and 50 years. Lesionstend to affect the area anterior to the permanent molarsand are slightly more frequent in the mandible. The giantcell epulis usually forms a fleshy, bluish swelling thatmay be sessile or broadly pedunculated and the surfaceis often ulcerated. There may be erosion of the underlyingbone or periodontium.Microscopically, there is usually an uninvolved zoneof fibrous tissue between the lesion and the overlying epithelium,but this is lost if there is inflammation or ulceration.The lesion consists of a matrix of plump, spindle-shapedcells with interspersed multinucleated andosteoclast-like giant cells. These can be numerous andmay be confluent, blurring the distinction between eachother and the stromal cells. The multinucleated cellsare large and contain about 10–20 nuclei. There are twotypes: the most common have lightly eosinophilic cytoplasmand large vesicular nuclei with prominent nucleoliwhile the other type has much more densely stainedcytoplasm, and pyknotic and densely haematoxyphilicnuclei. The latter are probably a degenerative form ofthe first type. The multinucleated cells are thought to beformed by fusion of bone marrow-derived mononuclearpre-osteoclasts [84, 101]. The lesion is usually very vascularand giant cells may be seen within the dilated vascularspaces. Red blood cell extravasation and haemosiderindeposition is common. Mitoses can often be seenin stromal and endothelial cells, but this observation hasno bearing on the likely behaviour. Osseous metaplasiaand dystrophic calcification may be present, usually inthe middle or deeper aspects of the lesion.Giant cell epulis is indistinguishable microscopicallyfrom central giant cell granuloma and the brown tumourof hyperparathyroidism. Radiographs should betaken to exclude the possibility of a central bone lesion.If such a lesion is detected, hyperparathyroidism is excludedby assessing serum calcium, phosphate and alkalinephosphatase and measuring parathormone levels ifnecessary.Treatment is usually by conservative surgical excisionwith curettage of the underlying bone, but about 10% ofcases recur. Some cases in children have been treated bydaily administration of calcitonin, delivered either bysubcutaneous injections or nasal spray for up to 1 year.Although the treatment is protracted it appears to be effective[96].3.6.8 Pyogenic GranulomaPyogenic granulomas are most common on the gingivaeand less frequently in other intraoral sites, particularlythe lip and tongue. They form solitary, soft, red and friablenodules that bleed readily. They frequently ulcerateand are covered by a fibrinous slough. Gingival lesionsmay be seen in pregnancy and appear to be a focal exacerbationof pregnancy gingivitis [113]. Pregnancy epulides(“pregnancy tumour”) usually manifest towards theend of the first trimester. They have a strong tendency torecur if removed before parturition and may show partialor complete spontaneous resolution if left followingdelivery. Occasionally, similar lesions are seen in otherparts of the mouth during pregnancy, particularly thedorsum of the tongue, and they are termed granulomagravidarum [52].Microscopically, oral pyogenic granulomas consist ofnumerous large, thin-walled, anastomosing blood vesselsin a loose, oedematous and moderately cellular stroma.Older lesions may show some fibrosis. Inflammationis very variable and can be minimal or absent. However,if the lesion ulcerates there may an intense inflammatoryinfiltration. Foci of papillary endothelial hyperplasiaare an occasional feature.Although excision is usually curative, rare cases canshow repeated recurrences and require more extensivesurgery for their eradication.3.6.9 Pulse (Vegetable) GranulomaThis unusual and uncommon chronic inflammatory lesionof oral tissues has been described under a varietyof terms including chronic periostitis, giant-cell hyalinangiopathy, oral vegetable granuloma and hyaline ring

94 J.W. Eveson3Fig. 3.19. Pulse granuloma showing chronic inflammation andeosinophilic, hyaline rings together with multinucleated foreignbody-typegiant cellsFig. 3.20. Giant cell fibroma showing stellate and angular fibroblastsin collagenous matrixgranuloma [171]. Most cases are seen in the premolar/molar region of the edentulous mandible and the mostcommon complaints are recurrent swelling and tenderness.Fifty-three percent of cases are extraosseous (peripheral)and radiographs often show a poorly definederosion of the underlying alveolar bone. Intraosseous orcentral lesions (42%) show an irregular radiolucent areathat is non-diagnostic. Occasionally, the lesion is foundwithin the fibrous wall of an odontogenic or nasopalatineduct cyst [140].Microscopy shows chronic inflammation and eosinophilic,hyaline rings together with multinucleatedforeign-body-type giant cells (Fig. 3.19). The ringsmay be complete or horse-shoe shaped and may enclosegiant cells, connective tissue and blood vessels.Haemosiderin within the centre of the rings is a frequentfinding. The suggestion that the histologicalappearances are due to thickening and hyalinisationof the walls of blood vessels is not supported by mostobservers. Light and electron microscopical findingssuggest that the rings are the cell walls of vegetableremains, often with collagen attached to their surface[71]. There does not appear to be any evidence thatthese appearances are exclusively due to pulses. Completeexcision is curative.3.7 Benign Tumoursand Pseudotumours3.7.1 Giant Cell FibromaGiant cell fibroma is an unusual but distinctive typeof fibrous overgrowth. It is typically less than 5 mm indiameter and usually presents as a pedunculated polypwith a lobulated surface. Most are seen in the first threedecades of life. Although they can form anywhere in theoral mucosa, about half of cases are seen on the gingiva[79].Microscopically, they consist of interweaving bundlesof collagenous connective tissue with a prominent capillarynetwork that surround stellate or angular fibroblasticgiant cells with large vesicular nuclei (Fig. 3.20). Occasionalcells may have several nuclei. These cells mayhave conspicuous dendritic processes and some containmelanin pigment. The giant cells are positive for vimentin,but negative for S-100, cytokeratin, leukocyte commonantigen and neurofilament [107]. Conservative surgicalexcision is usually curative.3.7.2 Lingual ThyroidEctopic lingual thyroid is a rare developmental anomalydue to failure of the thyroglossal duct to migrate caudallyfrom the foramen caecum [13]. It is seen in femalesabout four times more frequently than males and usuallypresents in middle age. The lingual gland is seen inthe base of the tongue, deep to the foramen caecum. It isoften asymptomatic, but may cause dysphagia, dysphoniaor dyspnoea. Symptoms may coincide with puberty,pregnancy or the menopause due to hyperplasia secondaryto raised levels of thyroid-stimulating hormone. Inaddition, any of the diseases involving the conventionalthyroid gland, including inflammatory conditions, adenomasand carcinomas, can affect the ectopic thyroidtissue.Microscopy typically shows normal thyroid tissue.As many as 70% of patients with lingual thyroid haveno other thyroid tissue present, so it is essential that presurgicalevaluation includes appropriate imaging andassessment of function using 131I or 99mTc pertechnetate.

Oral Cavity Chapter 3 953.7.3 Verruciform XanthomaThis rare but distinctive lesion, first described in 1971[166], forms most commonly in the oral cavity [82,135]. Extraoral locations include the male and femalegenitalia. There is no association with HPV in the vastmajority of cases studied. Verruciform xanthomas areseen at all ages, but are most frequent in the fifth toseventh decades. Incidence is roughly equal betweenthe sexes. They usually present as solitary, painless,discrete nodules that may be the colour of the surroundingmucosa, reddish or pink. They can be sessileor pedunculated and the surface can be domed or flat,and can be keratotic or papilliferous. They usually havesharply defined margins and are typically less than acentimetre in diameter. They do not appear to be relatedto any local irritating factors and most cases areasymptomatic. The gingival margin accounts for 85%of cases. Other common sites include the hard palate,tongue, buccal mucosa and a variety of other intraoralsites.Microscopy typically shows corrugated, hyperplasticepithelium with elongated, broad rete ridges thatextend to a straight, well-defined lower border [127].There are deep clefts within the epithelium that oftencontain keratinised plugs. The surface shows parakeratinisedspikes, which often stain a deep orange colour.There may be secondary candidal infestation ofthe surface keratin layers [125]. The characteristic featureis the presence of vacuolated, foamy xanthomatouscells, which fill the papillary corium. These xanthomacells can occasionally extend into the overlyingepithelium or into the deeper corium. The xanthomacells have been shown to be derived from cells ofmonocyte/macrophage lineage [121].The lesions are entirely benign and recurrence followingeven conservative surgery is very rare.3.7.4 HaemangiomasICD-O:9120/0Haemangiomas are vasoformative tumours that closelyresemble normal vessels. They are amongst the mostcommon soft tissue tumours and about a third of allcases involve the head and neck region. In this locationcongenital or neonatal lesions are relatively uncommonand tend to involve the lips and parotid glands. The majorityof cases are seen in older individuals, and the mostcommon sites are the lips and post-commissural buccalmucosa and the lateral border of the tongue. There is amale predominance of about 2:1. Haemangiomas typicallyform painless, flat or nodular, soft and purplishredlesions. They are usually well circumscribed andmay blanch on pressure. Congenital lesions behave likehamartomas and increase in size in proportion to generalsomatic growth and tend to stabilise in size in earlyadult life. Those presenting in older individuals mayshow slow but progressive growth over several years.Their classification and microscopic aspects are discussedin the section on soft tissue tumours in Chap. 2[3, 48, 53, 170, 175, 181].3.7.5 LymphangiomaICD-O:9170/0Lymphangioma is a benign, cavernous or cystic vascularlesion composed of dilated lymphatic channels.The head and neck region is the most common site ofinvolvement. Many lesions are present at birth or developwithin the first few years of life. There appearsto be no sex predilection. They usually form painlessswellings that are frequently superficial, but some extenddeeply into the surrounding tissues and are illdefined.Oral lesions are seen most commonly in the tongueand lips where they may cause macroglossia and macrocheiliarespectively. Involvement of underlying bonein oral lesions is uncommon [133]. Mucosal lymphangiomasusually have a pale, translucent surface, whichis nodular or bossellated. It is common for black areasto appear in the lesion due to focal areas of haemorrhage.In the neck, the lesions tend to be larger and showmore extensive cystic dilatation. These lymphangiomasare then frequently called cystic lymphangiomas or cystichygromas [91]. Some are associated with Turner syndrome(Monosomy X) [28]. The most common locationsfor cystic hygroma are the posterior triangle, submandibularregion and floor of the mouth. It can extend upwardsto involve the cheek and parotid gland, forwardsinto the anterior triangle or downwards into the mediastinum.Some cystic hygromas are severely disfiguringand they can compromise swallowing or breathing. Theclassification and microscopic aspects of oral lymphangiomasare discussed in Chap. 9.3.7.6 Benign Nerve Sheath TumoursNeurofibroma and schwannoma are the two mostcommon benign tumours of nerve sheath origin. Althoughthey both appear to be derived from Schwanncells they have distinctive clinical and microscopicalfeatures.

96 J.W. Eveson33.7.6.1 NeurofibromaICD-O:9540/0Solitary neurofibromas are relatively uncommon inthe orofacial region and tend to affect people in the20–40 years age group [189]. Most tumours are sporadic,but the possibility of neurofibromatosis type 1should always be considered when dealing with theselesions. They usually form small, painless, expansilesubmucosal nodules. The tongue is the most commonintraoral site, but occasionally they develop onthe inferior dental nerve and appear as a fusiform radiolucentarea along the course of the inferior dentalcanal.3.7.6.2 SchwannomaICD-O:9560/0Schwannoma ( neurilemmoma; neurinoma) is a benignneoplasm of Schwann cell origin. Patients are usuallyin the third or fourth decades and the tumour is morecommon in women than men. Lesions in the mouthtend to form small, painless and slow-growing swellingsand the tongue is the most common site. However,occasional cases can be several centimetres in diameter[41, 87].3.7.6.3 NeurofibromatosisICD-O:9540/0Von Recklinghausen disease or neurofibromatosis type Iis inherited as an autosomal dominant trait and the generesponsible is located on chromosome 17 [153]. It is relativelycommon and affects about 1 in 4,000 births. It isusually diagnosed before the age of 10 years because ofthe characteristic cutaneous lesions and the frequentfamily history.Clinically, it is characterised by cutaneous neurofibromasthat are usually associated with café au lait pigmentationof the skin. Lesions may be focal, but sometimesthere can be thousands of tumours and the conditionis then grossly disfiguring. The lesions are usuallypainless, but itching can be a serious problem. Therecan be overgrowth of bone and associated soft tissueleading to bizarre localised gigantism. Nearly a quarterof cases involve the head and neck, but only about 5% affectthe oral cavity.3.7.6.4 Multiple Neuromasin Endocrine NeoplasiaSyndromeICD-O:9570/0Multiple endocrine neoplasia syndrome type 2B is anautosomal dominant condition characterised by thepresence of mucosal neuromas together with medullarycarcinoma of the thyroid gland and phaeochromocytoma[147]. Nearly 90% of patients with the conditionhave point mutations at codon 918 of the RET proto-oncogene.Clinically, patients often have a Marfanoid habituswith arachnodactyly and a narrow face. Mucosal neuromasare the most consistent feature of the disease andmay be pathognomonic. They tend to form on the lateralmargins and dorsum of the tongue and appear asmultiple, small, painless nodules. These nodules may bethe first indication of the condition. The lips are sometimesenlarged and blubbery. Mucosal neuromas oftenaffect the palpebral conjunctiva and can also involve thesclera.Microscopy shows a partially encapsulated tangledmass of small nerve fibres, often with a thickened perineurium.These nerves lie in a loose fibrous stroma. Thenerves usually stain with S-100 and may stain with epithelialmembrane antigen indicating perineurial differentiation.The mucosal neuromas themselves rarely cause clinicalproblems, but may act as indicators of the more seriousaspects of the syndrome.3.7.7 Granular Cell Tumour(Granular Cell Myoblastoma)ICD-O:9580/0Granular cell tumours are uncommon, but about half ofall cases involve the head and neck region. The tongue,particularly the dorsum, is the most common site. Thepeak incidence is in middle life and 10–20% of cases aremultiple. There is a female predominance of about 2:1.They usually form nondescript, painless swellings, butoccasionally surface candidal infestation causes the lesionto present as a white plaque [59, 108]. See for thislesion also Chap. 7.3.8 Squamous Cell Carcinoma3.8.1 IntroductionSquamous cell carcinomas account for about 90% ofall malignant neoplasms in the mouth and orophar-

Oral Cavity Chapter 3 97ynx. It is important to consider the site of involvementas the epidemiological factors can vary considerably intumours in different intraoral locations. There is typicallya higher frequency in men than women, and thisis attributed to the use of tobacco and alcohol [17]. Ithas been estimated that as many as 75% of cases of oralsquamous cell carcinomas in Western countries and Japancan be ascribed to these factors. Globally, oral canceraccounts for 5% of all malignancies in men and 2%in women [134]. Much higher rates, however, are seen inboth men and women in parts of southeast Asia, wherethey are usually associated with the habitual use of arecanut and tobacco products.3.8.2 Clinical FeaturesDespite the fact that oral tumours frequently causesymptoms, and the mouth can be readily visualisedwith simple equipment, many oral cancers present at arelatively advanced stage where treatment may be disfiguringand prognosis is poor. This is often becausemany patients are elderly and frail and frequently weardental prostheses and are accustomed to minor degreesof oral discomfort. In addition, early lesions may not beregarded as suspicious by the patient or the clinician andmay therefore be treated empirically with antibacterialor antifungal preparations.Any part of the oral mucosa can be the site of developmentof squamous cell carcinomas. The commonoral locations can show wide variations in different geographicalareas depending on the prevalent risk factors.The intraoral subsites include the buccal mucosa,tongue, floor of mouth, upper and lower gingivae andalveolar processes, the hard palate and retromolar trigone.As the clinical presentation can vary according tothe specific sites of involvement, these will be discussedseparately.3.8.2.1 Buccal MucosaThe buccal mucosa extends from the commissureanteriorly to the retromolar trigone posteriorly andfrom the upper and lower vestibular reflections. Themajority of carcinomas arise from the posterior areawhere they are commonly traumatised by the molarteeth. They soon spread into the underlying buccinatormuscle and though insidious initially they may eventuallycause trismus. Bone, however, is generally involvedonly in advanced tumours. Tumours at this site oftenextend posteriorly into the palatoglossal fold and tonsillarfossa. Metastases are most common in the submandibular,submental, parotid and lateral pharyngeallymph nodes.3.8.2.2 TongueThe tongue is the most common oral location of squamouscell carcinoma and can account for half of allcases. The majority affect the middle third of the lateralborder and adjacent ventral surface. The dorsum is avery uncommon site and tumours arising there may beassociated with precursor lesions such as lichen planusand candidal leukoplakia. Lingual tumours are oftenexophytic and ulceration is common. Even clinicallysmall tumours can infiltrate deeply into the underlyingmuscle. With progressive growth tumours becomeindurated and frequently develop characteristic rolled,raised, everted margins. Infiltration of the lingual musculaturemay cause pain, dysphagia and dysphonia.Half of patients have regional lymph node metastasesat presentation. Tumours towards the tip of the tonguedrain to the submental and thence to the jugulo-digastriclymph node, and those located on the dorsum andlateral borders tend to involve the submandibular andjugulo-digastric nodes. Contralateral or bilateral spreadis relatively common, particularly in tumours arisinganteriorly.3.8.2.3 Floor of MouthThe floor of the mouth is a horseshoe-shaped mucosaltrough extending between the lower lingual alveolarmucosa and the ventral lingual mucosa. It isthe second most common site for intraoral squamouscell carcinomas and shows the highest frequency ofsmall and symptomless tumours [115]. Tumours aremost frequent in the anterior segment and tumoursthere tend to spread superficially rather than deeply.Involvement of the submandibular duct can causeobstructive sialadenitis and tumours can also extenddown the duct itself. If the tumour extends to involvethe mandible, there can be spread along the periodontalligament and subperiostally [106]. Lymphatic involvementis early but less frequent than tumours ofthe tongue itself.3.8.2.4 Gingivaand Alveolar RidgeTumours at this site can be exophytic resembling dentalabscesses or epulides, or ulcerated and fixed to theunderlying bone. They account for about 20% of oraltumours. In parts of the USA there is a very high frequencyin women who practise snuff dipping. Relatedteeth are often loosened and there is extension along theperiodontal ligament. On the alveolus tumours can re-

98 J.W. Eveson3semble simple lesions like denture-induced hyperplasiaor denture-related ulceration. The underlying bone maybe eroded or invaded in 50% of patients and regionalmetastases are seen in over half the patients at presentation.3.8.2.5 Hard PalateThis is a relatively uncommon site of involvement exceptin areas where reverse smoking is common [148].Tumours at this site can be exophytic or ulcerative, buttend to spread superficially rather than deeply.3.8.2.6 Retromolar TrigoneTumours from this site spread to the buccal mucosa laterallyand distally involve the tonsillar area. They canpenetrate into the parapharyngeal area and may showextensive spread along the lingual and inferior alveolarnerves. In addition, tumours frequently erode or invadethe adjacent mandible.3.8.3 StagingStaging of oral squamous cell carcinomas is undertakenusing the current TNM Classification [67, 167].References1. Abdollahi M, Radfar MA (2003) A review of drug-inducedoral reactions. J Contemp Dent Pract 4:10–312. Amagai M, Karpati S, Prussick R, Klaus-Kovtun V, StanleyJR (1992) Autoantibodies against the amino-terminal cadherin-likebinding domain of pemphigus vulgaris antigenare pathogenic. J Clin Investig 90:919–9263. Amerigo J, Matilla A, Gonzalez-Campora R, Galera-DavidsonH (1979) Vegetant intravascular hemangioendotheliomaof the skin. Report of 3 cases with a critical pathogeneticstudy. Dermatologica 159:476–4814. Andreasen JO (1968) Oral lichen planus. II. A histologic evaluationof 97 cases. Oral Surg Oral Med Oral Pathol 25:158–1665. Anhalt GJ, Kim SC, Stanley JR, Korman NJ et al. (1990) Paraneoplasticpemphigus. An autoimmune mucocutaneous diseaseassociated with neoplasia. N Engl J Med 320:1729–17356. Assimakopoulos D, Patrikakos G, Fotika C, Elisaf M (2002)Benign migratory glossitis or geographic tongue: an enigmaticoral lesion. Am J Med 113:751–7557. Aurelian L, Ono F, Burnett J (2003) Herpes simplex virus(HSV)-associated erythema multiforme (HAEM): a viraldisease with an autoimmune component. Dermatol OnlineJ 9:18. Ayangco L, Rogers RS III (2003) Oral manifestations of erythemamultiforme. Dermatol Clin 21:195–2059. Barker BF, Carpenter WM, Daniels et al. (1997) Oral mucosalmelanomas: the WESTOP Banff workshop proceedings.Western Society of Teachers of Oral Pathology. Oral SurgOral Med Oral Pathol Oral Radiol Endod 83:672–67910. Barrett AW, Bennett JH, Speight PM (1995) A clinicopathologicaland immunohistochemical analysis of primary oralmucosal melanoma. Eur J Cancer B Oral Oncol 31B:100–10511. Barrett AW, Porter SR, Scully C, Eveson JW, Griffiths MJ(1994) Oral melanotic macules that develop after radiationtherapy. Oral Surg Oral Med Oral Pathol 77:431–43412. Bastiaens MT, Zwan NV, Verschueren GL, Stoof TJ, NieboerC (1994) Three cases of pemphigus vegetans: induction byenalapril – association with internal malignancy. Int J Dermatol33:168–17113. Batsakis JG, El-Naggar AK, Luna MA (1996) Thyroid glandectopias. Ann Otol Rhinol Laryngol 105:996–100014. Batsakis JG, Suarez P (2000) Mucosal melanomas: a review.Adv Anat Pathol 7:167–18015. Becker BA, Gaspari AA (1993) Pemphigus vulgaris and vegetans.Dermatol Clin 11:429–45216. Benateau H, Rigau V, Comoz F, Benchemam Y, Galateau F,Compere JF (2003) Tumour of the juxtaoral organ. Int J OralMaxillofac Surg 32:101–10317. Blot WJ, McLaughlin JK, Winn DM et al. (1988) Smokingand drinking in relation to oral and pharyngeal cancer. CancerRes 48:3282–328718. Bonen DK, Cho JH (2003) The genetics of inflammatorybowel disease. Gastroenterology 124:521–53619. Bozkurt T, Langer M, Fendel K, Lux G (1992) Granulomatoustonsillitis. A rare extraintestinal manifestation of Crohn’sdisease. Dig Dis Sci 37:1127–113020. Bozzo L, Machado MA, de Almeida OP, Lopes MA, ColettaRD (2000) Hereditary gingival fibromatosis: report of threecases. J Clin Pediatr Dent 25:41–4621. Brooke AE, Eveson JW, Luker J, Oakhill A (1999) Oral presentationof a novel variant of herpes simplex infection in agroup of bone marrow transplant patients: a report of fivecases. Br J Dermatol 141:381–36322. Buchner A, Hansen LS (1979) Melanotic macule of the oralmucosa. A clinicopathologic study of 105 cases. Oral SurgOral Med Oral Pathol 48:244–24923. Buchner A, Hansen LS (1980) Amalgam pigmentation (amalgamtattoo) of the oral mucosa. A clinicopathologic study of268 cases. Oral Surg Oral Med Oral Pathol 49:139–14724. Buchner A, Leider AS, Merrell PW, Carpenter WM (1990)Melanocytic nevi of the oral mucosa: a clinicopathologicstudy of 130 cases from northern California. J Oral PatholMed 19:197–20125. Buchner A, Lozada F, Silverman S Jr (1980) Histopathologicspectrum of oral erythema multiforme. Oral Surg Oral MedOral Pathol 49:221–22826. Budtz-Jorgensen E (1990) Histopathology, immunology, andserology of oral yeast infections. Diagnosis of oral candidosis.Acta Odontol Scand 8:37–4327. Burrows NP, Lockwood CM (1995) Antineutrophil cytoplasmicantibodies and their relevance to the dermatologist. Br JDermatol 132:173–18128. Byrne J, Blanc WA, Warburton D, Wigger J (1984) The significanceof cystic hygroma in fetuses. Hum Pathol 15:61–6729. Card T, Logan RF, Rodrigues LC, Wheeler JG (2004) Antibioticuse and the development of Crohn’s disease. Gut 53:246–25030. Cawson RA, Lehner T (1968) Chronic hyperplastic candidiasis– candidal leukoplakia. Br J Dermatol 80:9–1631. Cawson RA, Rajasingham KC (1972) Ultrastructural featuresof the invasive phase of Candida albicans. Br J Dermatol87:435–44332. Chan LS (2001) Mucous membrane pemphigoid. Clin Dermatol19:703–71133. Chan LS, Ahmed AR, Anhalt GJ et al. (2002) The first internationalconsensus on mucous membrane pemphigoid:definition, diagnostic criteria, pathogenic factors, medicaltreatment, and prognostic indicators. Arch Dermatol 2002138:370–37934. Chao SC, Tsai YM, Yang MH, Lee JY (2003) A novel mutationin the keratin 4 gene causing white sponge naevus. Br JDermatol 148:1125–1128

Oral Cavity Chapter 3 9935. Chaudhry AP, Hampel A, Gorlin RJ (1958) Primary malignantmelanoma of the oral cavity: a review of 105 cases. Cancer11:923–92836. Chong CY, Chan KP, Shah VA et al. (2003) Hand, foot andmouth disease in Singapore: a comparison of fatal and nonfatalcases. Acta Paediatr 92:1163–116937. Cooke BED (1956) Leukoplakia buccalis and oral epithelialnaevi: a clinical and histological study. Br Dent J 68:151–17438. Csernok E (2003) Anti-neutrophil cytoplasmic antibodiesand pathogenesis of small vessel vasculitides. AutoimmunRev 2:158–16439. Daley T (1993) Pathology of intraoral sebaceous glands. JOral Pathol Med 22:241–24540. Daniels TE, Hansen LS, Greenspan JS et al. (1992) Histopathologyof smokeless tobacco lesions in professional baseballplayers. Associations with different types of tobacco. OralSurg Oral Med Oral Pathol 73:720–72541. Dayan D, Buchner A, Hirschberg A (1989) Ancient neurilemmoma(Schwannoma) of the oral cavity. J CraniomaxillofacSurg 17:280–28242. Devaney KO, Travis WD, Hoffman G et al. (1990) Interpretationof head and neck biopsies in Wegener’s granulomatosis.A pathologic study of 126 biopsies in 70 patients. Am J SurgPathol 14:555–56443. Doyle JL, Geary W, Baden E (1989) Eosinophilic ulcer. J OralMaxillofac Surg 47:349–35244. Eley BM (1982) Tissue reactions to implanted dental amalgam,including assessment by energy dispersive x-ray microanalysis.J Pathol 138:251–27245. El-Mofty SK, Swanson PE, Wick MR, Miller AS (1993) Eosinophiliculcer of the oral mucosa. Report of 38 new caseswith immunohistochemical observations. Oral Surg OralMed Oral Pathol 75:716–72246. Elzay RP (1983) Traumatic ulcerative granuloma with stromaleosinophilia (Riga-Fede’s disease and traumatic eosinophilicgranuloma). Oral Surg Oral Med Oral Pathol 55:497–50647. Eversole LR, Leider AS (1978) Maxillary intraosseous neuroepithelialstructures resembling those seen in the organ ofChievitz. Oral Surg Oral Med Oral Pathol 46:555–55848. Eveson JW, Lucas RB (1979) Angiolymphoid hyperplasiawith eosinophilia. J Oral Pathol 8:103–10849. Fatahzadeh M, Sirois DA (2002) Multiple intraoral melanoacanthomas:a case report with unusual findings. Oral SurgOral Med Oral Pathol Oral Radiol Endod 94:54–5650. Fauci AS, Wolff SM (1973) Wegener’s granulomatosis: studiesin eighteen patients and a review of the literature. Medicine(Baltimore) 52:535–56151. Femiano F, Scully C, Gombos F (2003) Linear IgA dermatosisinduced by a new angiotensin-converting enzyme inhibitor.Oral Surg Oral Med Oral Pathol Oral Radiol Endod95:169–17352. Fenton JE, Timon CI, McShane DP (1996) Lingual granulomagravidarum. Otolaryngol Head Neck Surg 114:682–68353. Fetsch JF (2002) Endothelioid haemangioma. In: FletcherCDM, Unni KK, Mertens F (eds) Pathology and genetics oftumours of soft tissue and bone. WHO Classification of Tumours.IARC Press, Lyon, pp 159–16054. Ficarra G, Prignano F, Romagnoli P (1997) Traumatic eosinophilicgranuloma of the oral mucosa: a CD30+(Ki-1) lymphoproliferativedisorder? Oral Oncol 33:375–37955. Ficarra G, Shillitoe EJ, Adler-Storthz K et al. (1990) Oral melanoticmacules in patients infected with human immunodeficiencyvirus. Oral Surg Oral Med Oral Pathol 70:748–75556. Field EA, Allan RB (2003) Review article: oral ulceration –aetiopathogenesis, clinical diagnosis and management in thegastrointestinal clinic. Aliment Pharmacol Ther 18:949–96257. Field EA, Tyldesley WR (1989) Oral Crohn’s disease revisited– a 10-year-review. Br J Oral Maxillofac Surg 27:114–12358. Fienberg R (1981) The protracted superficial phenomenon inpathergic (Wegener’s) granulomatosis. Hum Pathol 12:458–46759. Fine SW, Li M (2003) Expression of calretinin and the alphasubunitof inhibin in granular cell tumors. Am J Clin Pathol119:259–26460. Fiocchi C (1998) Inflammatory bowel disease: etiology andpathogenesis. Gastroenterology 115:182–20561. Fornatora ML, Reich RF, Haber S, Solomon F, Freedman PD(2003) Oral melanoacanthoma: a report of 10 cases, review ofthe literature, and immunohistochemical analysis for HMB-45 reactivity. Am J Dermatopathol 25:12–1562. Freysdottir J, Lau S, Fortune F (1999) Gammadelta T cellsin Behcet’s disease (BD) and recurrent aphthous stomatitis(RAS). Clin Exp Immunol 118:451–45763. Fukase S, Ohta N, Inamura K, Kimura Y, Aoyagi M, Koike Y(1994) Diagnostic specificity of anti-neutrophil cytoplasmicantibodies (ANCA) in otorhinolaryngological diseases. ActaOtolaryngol Suppl 511:204–20764. Goode RK, Crawford BE, Callihan MD, Neville BW (1983)Oral melanoacanthoma. Review of the literature and reportof ten cases. Oral Surg Oral Med Oral Pathol 56:622–62865. Goulart RA, Mark EJ, Rosen S (1995) Tumefactions as an extravascularmanifestation of Wegener’s granulomatosis. AmJ Surg Pathol 19:145–15366. Grattan CE, Gentle TA, Basu MK (1992) Oral papillary plasmacytosisresembling candidosis without demonstrable fungusin lesional tissue. Clin Exp Dermatol 17:112–11667. Greene FL, Page DL, Fleming ID, Fritz AG, Balch CM, HallerDG, Morrow M (2002) American Joint Committee on Cancer,Cancer Staging Manual. Springer, New York Berlin Heidelberg68. Greenstein RJ (2003) Is Crohn’s disease caused by a mycobacterium?Comparisons with leprosy, tuberculosis, andJohne’s disease. Lancet Infect Dis 3:507–51469. Handlers JP, Waterman J, Abrams AM, Melrose RJ (1985)Oral features of Wegener’s granulomatosis. Arch Otolaryngol111:267–27070. Harman KE, Seed PT, Gratian MJ, Bhogal BS, ChallacombeSJ, Black MM (2001) The severity of cutaneous and oral pemphigusis related to desmoglein 1 and 3 antibody levels. Br JDermatol 144:775–78071. Harrison JD, Maretin IC (1986) Oral vegetable granuloma:ultrastructural and histological study. J Oral Pathol 15:322-32672. Hedin CA, Pindborg JJ, Axell T (1993) Disappearance ofsmoker’s melanosis after reducing smoking. J Oral PatholMed 22:228–23073. Hegarty AM, Barrett AW, Scully C (2004) Pyostomatitis vegetans.Clin Exp Dermatol 29:1–774. Hickman RE, Eveson JW, Cawson RA (1988) Nevus uniuslateris and intraoral verrucous nevi. Oral Surg Oral MedOral Pathol 66:226–22975. Hicks MJ, Flaitz CM (2000) Oral mucosal melanoma: epidemiologyand pathobiology. Oral Oncol 36:152–16976. Hoffman GS (1994) “Wegener’s granulomatosis”: The pathtravelled since 1931. Medicine 73:325–32977. Honma T, Saito T, Fujioka Y (1985) Possible role of apoptoticcells of the oral epithelium in the pathogenesis of aphthousulceration. Oral Surg Oral Med Oral Pathol 59:379–38778. Horn TD, Anhalt GJ (1992) Histologic features of paraneoplasticpemphigus. Arch Dermatol 128:1091–109579. Houston GD (1982) The giant cell fibroma. A review of 464cases. Oral Surg Oral Med Oral Pathol 53:582–58780. Hume G, Radford-Smith GL (2002) The pathogenesis ofCrohn’s disease in the 21st century. Pathology 34:561–56781. Hume WJ (1975) Geographic stomatitis: a critical review. JDent 3:25–4382. Hume WJ, Smith CJ, Franklin CD (1980) Verruciform xanthoma.Br J Oral Surg 18:157–16183. Ide F, Mishima K, Saito I (2003) Juxtaoral organ of Chievitzpresenting clinically as a tumour. J Clin Pathol 56:789–79084. Itonaga I, Hussein I, Kudo O, Sabokbar A, Watt-Smith S, FergusonD, Athanasou NA (2003) Cellular mechanisms of osteoclastformation and lacunar resorption in giant cell granulomaof the jaw. J Oral Pathol Med 32:224–23185. Jabbour SA (2003) Cutaneous manifestations of endocrinedisorders: a guide for dermatologists. Am J Clin Dermatol4:315–331

100 J.W. Eveson386. James J, Patton DW, Lewis CJ et al. (1986) Oro-facial granulomatosisand clinical atopy. J Oral Med 41:29–3087. Jordan RC, Regezi JA (2003) Oral spindle cell neoplasms: areview of 307 cases. Oral Surg Oral Med Oral Pathol Oral RadiolEndod 95:717–72488. Jorizzo JL, Rogers RS III (1990) Behcet’s disease. J Am AcadDermatol 23:738–74189. Kanitakis J, Wang YZ, Roche P, Cozzani E et al. (1994) Immunohistopathologicalstudy of autoimmune pemphigus.Lack of strictly specific histological and indirect immunofluorescencecriteria for paraneoplastic pemphigus. Dermatology188:282–28590. Karjalainen TK, Tomich CE (1989) A histopathologic studyof oral mucosal lupus erythematosus. Oral Surg Oral MedOral Pathol 67:547–55491. Kennedy TL (1989) Cystic hygroma-lymphangioma: a rareand still unclear entity. Laryngoscope 99:1–1092. Kimyai-Asadi A, Jih MH (2001) Paraneoplastic pemphigus.Int J Dermatol 40:367–37293. Kitagawa S, Townsend BL, Hebert AA (1995) Peutz-Jegherssyndrome. Dermatol Clin 13:127–13394. Kramer IR, El-Labban N, Lee KW (1978) The clinical featuresand risk of malignant transformation in sublingualkeratosis. Br Dent J 144:171–18095. Lamey PJ, Carmichael F, Scully C (1985) Oral pigmentation,Addison’s disease and the results of screening for adrenocorticalinsufficiency. Br Dent J 158:297–29896. Lange J de, Rosenberg AJ, Akker HP van den, Koole R, WirdsJJ, Berg H van den (1999) Treatment of central giant cellgranuloma of the jaw with calcitonin. Int J Oral MaxillofacSurg 28:372–37697. Lehner T (1969) Pathology of recurrent oral ulceration andoral ulceration in Behcet’s syndrome: light, electron and fluorescencemicroscopy. J Pathol 97:481–49498. Lenane P, Powell FC (2000) Oral pigmentation. J Eur AcadDermatol Venereol 14:448–46599. Levy M, Shear NH (1991) Mycoplasma pneumoniae infectionsand Stevens-Johnson syndrome. Report of eight casesand review of the literature. Clin Pediatr (Phila) 30:42–49100. Liu AY, Valenzuela R, Helm TN, Camisa C et al. (1993) Indirectimmunofluorescence on rat bladder transitional epithelium:a test with high specificity for paraneoplastic pemphigus.J Am Acad Dermatol 28:696–699101. Liu B, Yu SF, Li TJ (2003) Multinucleated giant cells in variousforms of giant cell containing lesions of the jaws expressfeatures of osteoclasts. J Oral Pathol Med 32:367–375102. Lopez R, Fernandez O, Jara G, Baelum V (2002) Epidemiologyof necrotizing ulcerative gingival lesions in adolescents. JPeriodontal Res 37:439–444103. Lutman GB (1974) Epithelial nests in intraoral sensory nerveendings simulating perineural invasion in patients with oralcarcinoma. Am J Clin Pathol 61:275–284104. McCartan BE, McCreary CE (1997) Oral lichenoid drugeruptions. Oral Dis 3:58–63105. McCartan BE, McCreary CE, Healy CM (2003) Studies ofdrug-induced lichenoid reactions: criteria for case selection.Oral Dis 9:163–164106. McGregor AD, MacDonald DG (1988) Routes of entry ofsquamous cell carcinoma into the mandible. Head Neck10:294–301107. Magnusson BC, Rasmusson LG (1995) The giant cell fibroma.A review of 103 cases with immunohistochemical findings.Acta Odontol Scand 53:293–296108. Maiorano E, Favia G, Napoli A, Resta L, Ricco R, Viale G,Altini M (2000) Cellular heterogeneity of granular cell tumours:a clue to their nature? J Oral Pathol Med 29:284–290109. Main DM, Chamberlain MA (1992) Clinical differentiationof oral ulceration in Behcet’s disease. Br J Rheumatol 31:767–770110. Manabe M, Lim HW, Winzer M, Loomis CA (1999) Architecturalorganization of filiform papillae in normal and blackhairy tongue epithelium: dissection of differentiation pathwaysin a complex human epithelium according to their patternsof keratin expression. Arch Dermatol 135:177–181111. Manchanda Y, Tejasvi T, Handa R, Ramam M (2003) Strawberrygingiva: a distinctive sign in Wegener’s granulomatosis.J Am Acad Dermatol 49:335–337112. Mani NJ (1985) Tuberculosis initially diagnosed by asymptomaticoral lesions. Report of three cases. J Oral Med 40:39–42113. Manus DA, Sherbert D, Jackson IT (1995) Management considerationsfor the granuloma of pregnancy. Plast ReconstrSurg 95:1045–1050114. Marks R, Radden BG (1981) Geographic tongue: a clinicopathologicalreview. Australas J Dermatol 22:75–79115. Mashberg A, Samit A (1995) Early diagnosis of symptomaticoral and orophayngeal squamous cancers. CA Cancer J Clin45:328–351116. Meador R, Ehrlich G, Von Feldt JM (2002) Behcet’s disease:immunopathologic and therapeutic aspects. Curr RheumatolRep 4:47–54117. Merchant HW, Hayes LE, Ellison LT (1976) Soft-palate pigmentationin lung disease, including cancer. Oral Surg OralMed Oral Pathol 41:726–733118. Mignogna MD, Lo Muzio L, Ruoppo E, Errico M, Amato M,Satriano RA (1999) Oral manifestations of idiopathic lenticularmucocutaneous pigmentation (Laugier-Hunziker syndrome):a clinical, histopathological and ultrastructural reviewof 12 cases. Oral Dis 1999 5:80–86119. Miles AEW (1958) Sebaceous glands in the lip and cheek mucosaof man. Br Dent J 105:235–248120. Mooney EE, Walker J, Hourihane DO (1995) Relation ofgranulomas to lymphatic vessels in Crohn’s disease. J ClinPathol 48:335–338121. Mostafa KA, Takata T, Ogawa I, Ijuhin N, Nikai H (1993)Verruciform xanthoma of the oral mucosa: a clinicopathologicalstudy with immunohistochemical findings relatingto pathogenesis. Virchows Arch A Pathol Anat Histopathol423:243–248122. Murray A, Gardiner DS, McGuiness RJ (1998) Primary mycobacterialinfection of the uvula. J Laryngol Otol 112:1183–1185123. Nandapalan V, Roland NJ, Helliwell TR, Williams EM, HamiltonJW, Jones AS (1998) Mucosal melanoma of the head andneck. Clin Otolaryngol 23:107–116124. Napier SS, Allen JA, Irwin CR, McCluskey DR (1993) Strawberrygums: a clinicopathological manifestation diagnosticof Wegener’s granulomatosis? J Clin Pathol 46:709–712125. Neville BW, Weathers DR (1980) Verruciform xanthoma.Oral Surg Oral Med Oral Pathol 49:429–434126. Nicolas ME, Krause PK, Gibson LE, Murray JA (2003) Dermatitisherpetiformis. Int J Dermatol 42:588–600127. Nowparast B, Howell FV, Rick GM (1981) Verruciform xanthoma.A clinicopathologic review and report of fifty-fourcases. Oral Surg Oral Med Oral Pathol 51:619–625128. Nozicka Z (1985) Endovasal granulomatous lymphangiitisas a pathogenetic factor in cheilitis granulomatosa. J OralPathol 14:363–365129. Ogus HD, Bennett MH (1978) Carcinoma of the dorsum ofthe tongue: a rarity or misdiagnosis. Br J Oral Surg 16:115–124130. Obermayer-Straub P, Manns MP (1998) Autoimmune polyglandularsyndromes. Baillieres Clin Gastroenterol 12:293–315131. O’Keefe E, Braverman IM, Cohen I (1973) Annulus migrans.Identical lesions in pustular psoriasis, Reiter’s syndrome, andgeographic tongue. Arch Dermatol 107:240–244132. Pantanowitz L, Balogh K (2003) Significance of the juxtaoralorgan (of Chievitz). Head Neck 25:400–405133. Park YW, Kim SM, Min BG, Park IW, Lee SK (2002) Lymphangiomainvolving the mandible: immunohistochemical expressionsfor the lymphatic proliferation. J Oral Pathol Med31:280–283134. Parkin DM, Whelan SL, Ferlay J et al. (2003) Cancer incidencein five continents, vol. VIII. IARC Press, Lyon135. Philipsen HP, Reichart PA, Takata T, Ogawa I (2003) Verruciformxanthoma – biological profile of 282 oral lesionsbased on a literature survey with nine new cases from Japan.Oral Oncol 39:325–336

Oral Cavity Chapter 3 101136. Pindborg JJ, Reibel J, Roed-Peterson B, Mehta FS (1980) Tobacco-inducedchanges in oral leukoplakic epithelium. Cancer45:2330–2336137. Pinto GM, Lamarao P, Vale T (1992) Captopril-induced pemphigusvegetans with Charcot-Leyden crystals. Am AcadDermatol 27:281–284138. Plauth M, Jenss H, Meyle J (1991) Oral manifestations ofCrohn’s disease. An analysis of 79 cases. J Clin Gastroenterol13:29–37139. Pogrel MA (1979) Sublingual keratosis and malignant transformation.J Oral Pathol 8:176–178140. Pola JG, de la Cruz, Bustillo F, Gallas M, Leston JS (2003)Pulse granuloma in the wall of an inflammatory radicularcyst. Otolaryngol Head Neck Surg 129:441–442141. Popa ER, Tervaert JW (2003) The relation between Staphylococcusaureus and Wegener’s granulomatosis: currentknowledge and future directions. Intern Med 42:771–780142. Porter SR, Hegarty A, Kaliakatsou F, Hodgson TA, ScullyC (2000) Recurrent aphthous stomatitis. Clin Dermatol18:569–578143. Porter SR, Scully C, Pedersen A (1998) Recurrent aphthousstomatitis. Crit Rev Oral Biol Med 9:306–321144. Prasad ML, Jungbluth AA, Iversen K, Huvos AG, Busam KJ(2001) Expression of melanocytic differentiation markers inmalignant melanomas of the oral and sinonasal mucosa. AmJ Surg Pathol 25:782–787145. Prasad ML, Patel S, Hoshaw-Woodard S et al. (2002) Prognosticfactors for malignant melanoma of the squamous mucosaof the head and neck. Am J Surg Pathol 26:883–928146. Pryce DW, King CM (1990) Orofacial granulomatosis associatedwith delayed hypersensitivity to cobalt. Clin Exp Dermatol15:384–386147. Pujol RM, Matias-Guiu X, Miralles J, Colomer A, de MoragasJM (1997) Multiple idiopathic mucosal neuromas: a minorform of multiple endocrine neoplasia type 2B or a newentity? J Am Acad Dermatol 337:349–352148. Quigley LF, Cobb CM, Hunt EE, Williams P, Schoenfeld S(1964) Reverse smoking and its oral consequences in Caribbeanand South American peoples. J Am Dent Assoc 69:426–442149. Reichart PA, Langford A, Gelderblom HR et al. (1989) Oralhairy leukoplakia: observations in 95 cases and review of theliterature. J Oral Pathol Med 18:410–415150. Reichart PA, Samaranayake LP, Philipsen HP (2000) Pathologyand clinical correlates in oral candidiasis and its variants:a review. Oral Dis 6:85–91151. Reichart PA, Schmidt-Westhausen A, Samaranayake LP,Philipsen HP (1994) Candida-associated palatal papillaryhyperplasia in HIV infection. J Oral Pathol Med 23:403–405152. Rennie JS, Reade PC, Hay KD, Scully C (1985) Recurrentaphthous stomatitis. Br Dent J 159:361–367153. Reynolds RM, Browning GG, Nawroz I, Campbell IW (2003)Von Recklinghausen’s neurofibromatosis: neurofibromatosistype 1. Lancet 361:1552–1554154. Rogers RS III (1997) Recurrent aphthous stomatitis: clinicalcharacteristics and associated systemic disorders. Semin CutanMed Surg 16:278–283155. Sah SP, Raj GA, Bahadur T (1999) Chronic ulceration of thetongue and laryngitis: first clinical sign of asymptomaticpulmonary tuberculosis. J Infect 39:163–164156. Schiodt M (1984) Oral discoid lupus erythematosus. III. Ahistopathologic study of sixty-six patients. Oral Surg OralMed Oral Pathol 57:281–293157. Schiodt M, Halberg P, Hentzer B (1978) A clinical study of32 patients with oral discoid lupus erythematosus. Int J OralSurg 7:85–94158. Schwartz DL (1965) Stomatitis nicotina of the palate; reportof two cases. Oral Surg Oral Med Oral Pathol 20:306–315159. Sciubba JJ, Said-Al-Naief N (2003) Orofacial granulomatosis:presentation, pathology and management of 13 cases. J OralPathol Med 32:576–585160. Scott JE, Ahmed AR (1998) The blistering diseases. Med ClinNorth Am 82:1239–1283161. Scott LA, Stone MS (2003) Viral exanthems. Dermatol OnlineJ 9:4162. Scully C, Beyli M, Ferreiro MC et al. (1998) Update on orallichen planus: etiopathogenesis and management. Crit RevOral Biol Med 9:86–122163. Scully C, Challacombe SJ (2002) Pemphigus vulgaris: updateon etiopathogenesis, oral manifestations, and management.Crit Rev Oral Biol Med 13:397–408164. Sedghizadeh PP, Shuler CF, Allen CM, Beck FM, Kalmar JR(2002) Celiac disease and recurrent aphthous stomatitis: areport and review of the literature. Oral Surg Oral Med OralPathol Oral Radiol Endod 94:474–478165. Sela MN (2001) Role of Treponema denticola in periodontaldiseases. Crit Rev Oral Biol Med 12:399–413166. Shafer WG (1971) Verruciform xanthoma. Oral Surg OralMed Oral Pathol 31:784–789167. Sobin LH, Wittekind C (2002) TNM: classification of malignanttumours, 6th edn. Wiley, New York168. Southam JC, Felix DH, Wray D, Cubie HA (1991) Hairy leukoplakia– a histological study. Histopathology 19:63–67169. Sweatman MC, Tasker R, Warner JO et al. (1986) Oro-facialgranulomatosis. response to elemental diet and provocationby food additives. Clin Allergy 16:331–338170. Sund S, Bang G (1990) Intramuscular hemangioma in theoral region: report of three cases. Oral Surg Oral Med OralPathol 70:765–768171. Talacko AA, Radden BG (1988) Oral pulse granuloma: clinicaland histopathological features. A review of 62 cases. Int JOral Maxillofac Surg 17:343–346172. Thomas JA, Felix DH, Wray D et al. (1991) Epstein-Barr virusgene expression and epithelial cell differentiation in oralhairy leukoplakia. Am J Pathol 139:1369–1380173. Thompson DE (1994) The role of mycobacteria in Crohn’sdisease. J Med Microbiol 41:74–94174. Tucker KM, Heget HS (1976) The incidence of inflammatorypapillary hyperplasia. J Am Dent Assoc 93:610–613175. Tsuboi H, Fujimura T, Katsuoka K (2001) Angiolymphoidhyperplasia with eosinophilia in the oral mucosa. Br J Dermatol145:365–366176. Umeda M, Komatsubara H, Shibuya Y, Yokoo S, Komori T(2002) Premalignant melanocytic dysplasia and malignantmelanoma of the oral mucosa. Oral Oncol 38:714–722177. Verpilleux MP, Bastuji-Garin S, Revuz J (1999) Comparativeanalysis of severe aphthosis and Behcet’s disease: 104 cases.Dermatology 198:247–251178. Wakefield AJ, Sankey EA, Dhillon AP et al. (1991) Granulomatousvasculitis in Crohn’s disease. Gastroenterology100:1279–1287179. Wal N van der, Kwast WA van der, Dijk E van, Waal I van der(1988) Geographic stomatitis and psoriasis. Int J Oral MaxillofacSurg 17:106–109180. Wal N van der, Waal I van der (1986) Candida albicans inmedian rhomboid glossitis. A postmortem study. Int J OralMaxillofac Surg 15:322–325181. Weiss SW, Golblum JR (2001) Benign tumors and tumor-likelesions of blood vessels. In: Enzinger and Weiss’s soft tissuetumors, 4th edn. Mosby, St. Louis, pp 840–843182. Weitzul S, Duvic M (1997) HIV-related psoriasis and Reiter’ssyndrome. Semin Cutan Med Surg 16:213–218183. Whitley RJ (2002) Herpes simplex virus infection. Semin PediatrInfect Dis 13:6–11184. Wiesenfeld D, Ferguson MM, Mitchell DN et al. (1985) Orofacialgranulomatosis – a clinical and pathological analysis.Q J Med 54:101–113185. Williams AJ, Wray D, Ferguson A (1991) The clinical entityof orofacial Crohn’s disease. Q J Med 79:451–458186. Williams DM (1990) Vesiculo-bullous mucocutaneous disease:benign mucous membrane and bullous pemphigoid. JOral Pathol Med 19:16–23187. Woo TY, Solomon AR, Fairley JA (1985) Pemphigus vegetanslimited to the lips and oral mucosa. Arch Dermatol 121:271–272188. Wright BA, Fenwick F (1981) Candidiasis and atrophictongue lesions. Oral Surg Oral Med Oral Pathol 51:55–61

102 J.W. Eveson3189. Wright BA, Jackson D (1980) Neural tumors of the oral cavity.A review of the spectrum of benign and malignant oraltumors of the oral cavity and jaws. Oral Surg Oral Med OralPathol 49:509–522190. Yamamoto O, Yoshinaga K, Asahi M, Murata I (1999) A Laugier-Hunzikersyndrome associated with esophageal melanocytosis.Dermatology 199:162–164191. Yeh SW, Ahmed B, Sami N, Razzaque Ahmed A (2003) Blisteringdisorders: diagnosis and treatment. Dermatol Ther16:214–223192. Zimmer WM, Rogers RS 3rd, Reeve CM, Sheridan PJ (1992)Orofacial manifestations of Melkersson-Rosenthal syndrome.A study of 42 patients and review of 220 cases fromthe literature. Oral Surg Oral Med Oral Pathol 74:610–619193. Zunt SL (2003) Recurrent aphthous stomatitis. DermatolClin 21:33–39194. Zunt SL, Tomich CE (1989) Erythema migrans – a psoriasiformlesion of the oral mucosa. J Dermatol Surg Oncol15:1067–1070

Chapter 4Maxillofacial Skeletonand TeethP.J. Slootweg4Contents4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . 1044.1.1 Embryology . . . . . . . . . . . . . . . . . . . . . . . 1044.1.2 Tooth Development . . . . . . . . . . . . . . . . . . . 1044.2 Inflammatory Diseasesof the Maxillofacial Bones . . . . . . . . . . . . . . . 1044.3 Cysts of the Jaws . . . . . . . . . . . . . . . . . . . . . 1054.3.1 Odontogenic Cysts – Inflammatory . . . . . . . . . 1054.3.1.1 Radicular Cyst . . . . . . . . . . . . . . . . . . . . . . 1054.3.1.2 Paradental Cyst . . . . . . . . . . . . . . . . . . . . . 1064.3.2 Odontogenic Cysts – Developmental . . . . . . . . . 1064.3.2.1 Dentigerous Cyst . . . . . . . . . . . . . . . . . . . . 1064.3.2.2 Lateral Periodontal Cyst . . . . . . . . . . . . . . . . 1074.3.2.3 Glandular Odontogenic Cyst . . . . . . . . . . . . . 1074.3.2.4 Odontogenic Keratocyst . . . . . . . . . . . . . . . . 1074.3.2.5 Gingival Cyst . . . . . . . . . . . . . . . . . . . . . . . 1084.3.3 Non-Odontogenic Cysts . . . . . . . . . . . . . . . . 1094.3.3.1 Nasopalatine Duct Cyst . . . . . . . . . . . . . . . . 1094.3.3.2 Nasolabial Cyst . . . . . . . . . . . . . . . . . . . . . 1094.3.3.3 Surgical Ciliated Cyst . . . . . . . . . . . . . . . . . . 1094.3.4 Pseudocysts . . . . . . . . . . . . . . . . . . . . . . . 1094.3.4.1 Solitary Bone Cyst . . . . . . . . . . . . . . . . . . . . 1094.3.4.2 Focal Bone Marrow Defect . . . . . . . . . . . . . . . 1094.4 Odontogenic Tumours . . . . . . . . . . . . . . . . . 1094.4.1 Odontogenic Tumours – Epithelial . . . . . . . . . . 1104.4.1.1 Ameloblastoma . . . . . . . . . . . . . . . . . . . . . 1104.4.1.2 Calcifying Epithelial Odontogenic Tumour . . . . . 1124.4.1.3 Adenomatoid Odontogenic Tumour . . . . . . . . . 1124.4.1.4 Squamous Odontogenic Tumour . . . . . . . . . . . 1134.4.2 Odontogenic Tumours – Mesenchymal . . . . . . . 1144.4.2.1 Odontogenic Myxoma . . . . . . . . . . . . . . . . . 1144.4.2.2 Odontogenic Fibroma . . . . . . . . . . . . . . . . . . 1154.4.2.3 Cementoblastoma . . . . . . . . . . . . . . . . . . . . 1164.4.3 Odontogenic Tumours –Mixed Epithelial and Mesenchymal . . . . . . . . . 1174.4.3.1 Ameloblastic Fibroma . . . . . . . . . . . . . . . . . 1174.4.3.2 Ameloblastic Fibro-Odontoma . . . . . . . . . . . . 1174.4.3.3 Odontoma – Complex Type . . . . . . . . . . . . . . 1184.4.3.4 Odontoma – Compound Type . . . . . . . . . . . . . 1184.4.3.5 Odonto-Ameloblastoma . . . . . . . . . . . . . . . . 1184.4.3.6 Calcifying Odontogenic Cyst . . . . . . . . . . . . . 1194.4.4 Odontogenic Tumours – Malignant . . . . . . . . . 1194.4.4.1 Malignant Ameloblastoma . . . . . . . . . . . . . . . 1194.4.4.2 Ameloblastic Carcinoma . . . . . . . . . . . . . . . . 1194.4.4.3 Primary Intraosseous Carcinoma . . . . . . . . . . . 1194.4.4.4 Clear Cell Odontogenic Carcinoma . . . . . . . . . . 1204.4.4.5 Malignant Epithelial OdontogenicGhost Cell Tumour . . . . . . . . . . . . . . . . . . . 1204.4.4.6 Odontogenic Sarcoma . . . . . . . . . . . . . . . . . 1204.5 Fibro-Osseous Lesions . . . . . . . . . . . . . . . . . 1214.5.1 Fibrous Dysplasia . . . . . . . . . . . . . . . . . . . . 1214.5.2 Ossifying Fibroma . . . . . . . . . . . . . . . . . . . . 1214.5.3 Osseous Dysplasia . . . . . . . . . . . . . . . . . . . . 1234.6 Giant Cell Lesions . . . . . . . . . . . . . . . . . . . . 1244.6.1 Central Giant Cell Granuloma . . . . . . . . . . . . 1244.6.2 Cherubism . . . . . . . . . . . . . . . . . . . . . . . . 1244.7 Neoplastic Lesions of the Maxillofacial Bones,Non-Odontogenic . . . . . . . . . . . . . . . . . . . . 1254.7.1 Osteoma . . . . . . . . . . . . . . . . . . . . . . . . . 1254.7.2 Chordoma . . . . . . . . . . . . . . . . . . . . . . . . 1254.7.3 Melanotic Neuroectodermal Tumourof Infancy . . . . . . . . . . . . . . . . . . . . . . . . . 126References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126

104 P.J. Slootweg4.1 Introduction4.1.1 Embryology4The maxillofacial skeleton is partly derived from migratedcranial neural crest cells. These cells give riseto most connective tissues in the craniofacial regionincluding the bones of the calvarium, face and jaws.So, the diseases to be discussed in this chapter occurin bones that are formed by mesenchymal cells withan ectodermal/neuroectodermal ancestry – that iswhy they are also known as ectomesenchyme – andare therefore different from bone and cartilage thathave a mesodermal origin elsewhere in the body [145,171].4.1.2 Tooth DevelopmentTeeth develop from epithelial cells from the mucosal liningof the oral cavity and cranial neural crest-derived ectomesenchymalcells. Under the influence of reciprocalinductive events, these cells develop into enamel-formingameloblasts and dentin-producing odontoblasts(Fig. 4.1) [145, 171].While ameloblasts and odontoblasts are depositingenamel and dentin, the epithelium proliferates downwards,thus creating a tube that maps out the form andsize of the root of the teeth. This epithelial cuff is knownas the sheath of Hertwig. Its remnants form a permanentcomponent of the periodontal ligament; they are knownas rests of Malassez and are the source of some cysticjaw lesions (Fig. 4.2). Other epithelial reminiscences oftooth development lie more superficially in the jaw tissues.These are the epithelial rests of Serres, which havetheir origin in the dental lamina.4.2 Inflammatory Diseasesof the Maxillofacial BonesThese include osteomyelitis, which mainly involves themandible. It may occur through extension of infectionof the dental pulp or as a complication after tooth extraction.When seen after irradiation, e.g. for head andneck cancer, it is called osteoradionecrosis.There are five types: acute suppurative osteomyelitis,chronic suppurative osteomyelitis, chronic focal sclerosingosteomyelitis, chronic diffuse sclerosing osteomyelitis,and proliferative periostitis. Acute suppurative osteomyelitisshows bone marrow cavities infiltrated withneutrophils. The bony trabeculae are necrotic. Usually,this form of osteomyelitis evolves into chronic suppurativeosteomyelitis, which also may arise de novo. Besidesbone sequesters surrounded by numerous neutrophilicFig. 4.1. Overview of normal tooth germ lying in its bony crypt.Odontogenic epithelium covers the enamel space from which theenamel is dissolved due to decalcification. An epithelial strandas remnant of the dental lamina can be seen in the fibrous tissuebridging the gap in the bony cryptFig. 4.2. The periodontal ligament connects the root surface(right side) with the bony socket (left side). An epithelial rest ofMalassez is clearly visiblegranulocytes granulation tissue is also present. Sinusesare formed partly lined by squamous epithelium fromthe oral mucosa. In less severe cases, fibrosis and developmentof a chronic inflammatory infiltrate may alsobe seen. Unless the sequestra are removed, the diseasewill not heal.When the inflammation is mild, the jaw bone respondsby bone formation. This form of osteomyelitis isknown as chronic sclerosing, which may be focal as wellas diffuse. Dense sclerotic bone masses are seen togetherwith a bone marrow exhibiting oedema and small fociof lymphocytes and plasma cells. Both focal as well asdiffuse chronic sclerosing osteomyelitis must be distinguishedfrom other bone lesions, especially the fibro-osseousones (see Sect. 4.5).

Maxillofacial Skeleton and Teeth Chapter 4 105Table 4.1. Cysts of the jaws [73]Odontogenic cysts – inflammatoryOdontogenic cysts – developmentalNon-odontogenic cystsPseudocystsRadicular cystResidual cystParadental cystDentigerous cystLateral periodontal cystBotryoid odontogenic cystGlandular odontogenic cystOdontogenic keratocyst (keratocystic odontogenic tumour [181])Gingival cystNasopalatine duct cystNasolabial cystSurgical ciliated cystSolitary bone cystFocal bone marrow defectWhen the inflammation mainly involves the periosteum,the disease is called proliferative periostitis, orcalled periostitis ossificans. Histologically, bony trabeculaethat lie in a linear parallel pattern are seen. The interveningstroma is composed of fibrous connective tissuesparsely infiltrated with lymphocytes and plasmacells.4.3 Cysts of the JawsCysts of the jaws are classified into several categories dependingon histogenesis and aetiology. Those that arisefrom odontogenic epithelium are called odontogenic,those that have their source in other epithelial structuresare known as non-odontogenic. Among the odontogeniccysts, developmental and inflammatory typescan be distinguished [73]. By definition, cysts are linedby epithelium. There are, however, also cavities in thejaw lacking such an epithelial investment that are alsodiscussed under this heading. The various entities arelisted in Table 4.1.4.3.1 Odontogenic Cysts –Inflammatory4.3.1.1 Radicular CystFig. 4.3. Schematic drawing showing a bisected mandible. Left toright: examples of a dentigerous cyst, a lateral periodontal cyst anda radicular cyst (drawing by John de Groot)Radicular cysts are located at the root tips of the teeth(Fig. 4.3). They arise from the epithelial rests of Malassezand are the cysts most frequently seen [34, 146].They are lined by non-keratinising squamous epithelium.This epithelial lining may be thin and atrophicor show elongated rete processes. In many cysts,cholesterol clefts with adjacent giant cells occur. Withinthe cyst epithelium, hyaline bodies of various sizeand shape may be present (Fig. 4.4). The specific natureof these so-called Rushton bodies is unclear [95]. Occasionally,the lining squamous cells are admixed withmucous cells or ciliated cells (Fig. 4.5). Sometimes, thehistologic pattern of the radicular cyst is complicatedby extensive intramural proliferation of squamous epithelialnests of varying size, thus mimicking a squamousodontogenic tumour (see Sect. 4.4.1.4) [187]. Thesame histology may be shown by other jaw cysts, in particularwhen there are extensive inflammatory changes.When a radicular cyst is retained in the jaws afterremoval of the associated tooth, the lesion is called aresidual cyst .When complicated by inflammation, radicular cystsmay cause pain and swelling. However, they may also beasymptomatic and fortuitously detected by radiographicexamination of the dentition.

106 P.J. Slootweg4Fig. 4.4. Epithelial lining of a radicular cyst containing manyRushton bodiesFig. 4.5. Cyst lining composed of squamous as well as mucous epithelium.This can be found in radicular cysts as well as in dentigerousor residual cysts4.3.1.2 Paradental CystThe paradental cyst is located on the lateral side of thetooth at the border between the enamel and root cementum.This cyst is secondary to an inflammatory processin the adjacent periodontal tissues that induces proliferationof neighbouring odontogenic epithelial rests, similarto the pathogenesis of the radicular cyst [88]. Histologically,it resembles the other inflammatory odontogeniccysts, the distinction being made by the specificclinical presentation. It is a rare lesion [128]. Treatmentconsists of excision with or without concomitant extractionof the involved tooth [45].4.3.2 Odontogenic Cysts –Developmental4.3.2.1 Dentigerous CystA dentigerous cyst surrounds the crown of an uneruptedtooth, mostly the maxillary canine or the mandibularthird molar tooth (Fig. 4.3). They are quite common.The cyst wall has a thin epithelial lining that maybe only two to three cells thick. In case of inflammation,the epithelium becomes thicker and will showfeatures similar to the lining of a radicular cyst. Also,mucous-producing cells as well as ciliated cells maybe observed (Fig. 4.6). The connective tissue componentof the cyst wall may be fibrous or fibromyxomatous.The cyst wall may also contain varying amountsof epithelial nests representing remnants of the dentallamina.Radiologically, a lot of jaw diseases associated withunerupted teeth may have an appearance similar to thatof a dentigerous cyst. Histologic examination, however,will be decisive in ruling out these possibilities amongFig. 4.6. Lining of a dentigerous cyst mainly composed of mucouscellswhich keratocyst and unicystic ameloblastoma (seeSects. 4.3.2.4 and 4.4.1.1) are the most prevalent. Moreover,the radiologic picture of the dentigerous cyst maybe mimicked by hyperplasia of the dental follicle, theconnective tissue capsule that surrounds the uneruptedtooth [33].Fibromyxomatous areas in the connective tissue wallof the dentigerous cyst may resemble the odontogenicmyxoma (see Sect. 4.4.2.1). The presence of odontogenicepithelial rests may lead to the erroneous diagnosisof one or another type of epithelial odontogenic tumour[71]. However, identification of the epithelial cyst liningwill rule out these alternatives.In most instances, dentigerous cysts are a fortuitousfinding on oral radiographs. Only when excessively largemay they cause swelling of the involved part of the jaw.If there is inflammation, they will cause pain and swelling.Removal of the cyst wall and the tooth involved willyield a permanent cure.The eruption cyst is a specific type of dentigerous cystlocated in the gingival soft tissues overlying the crown

Maxillofacial Skeleton and Teeth Chapter 4 107of an erupting tooth. Mostly, these cysts are short-lived,rupturing with the progressive eruption of the associatedtooth. They are lined by squamous epithelium that isthickened due to inflammatory changes in the underlyingconnective tissue and thus similar to the lining of aradicular cyst.4.3.2.2 Lateral Periodontal CystLateral periodontal cysts are rare lesions, derived fromodontogenic epithelial remnants, and occurring on thelateral aspect or between the roots of vital teeth (Fig. 4.3)[166]. They are lined by a thin, non-keratinising squamousor cuboidal epithelium with focal, plaque-likethickenings consisting of clear cells that may containglycogen (Fig. 4.7) [150].Lateral periodontal cysts do not cause any symptoms.They are fortuitous findings on radiographs where theypresent as a well-demarcated radiolucency on the lateralsurface of a tooth root. Simple enucleation is adequatetreatment.The botryoid odontogenic cyst represents a multilocularform of the lateral periodontal cyst [54]. Treatmentby curettage is the most appropriate treatment, but recurrencesmay occur [52].Fig. 4.7. Lateral periodontal cyst. The epithelial lining formsplaques consisting of clear cells4.3.2.3 Glandular Odontogenic CystThe glandular odontogenic cyst , also called sialo-odontogeniccyst is a rare cystic lesion characterised by an epitheliallining with cuboidal or columnar cells both at thesurface and lining crypts or cyst-like spaces within thethickness of the epithelium [34, 73].The lining epithelium is partly non-keratinising,squamous and with focal thickenings similar to theplaques in the lateral periodontal cyst and the botryoidodontogenic cyst. There may be a surface layer ofeosinophilic cuboidal or columnar cells that can havecilia and may form papillary projections. Some superficialcells assume an apocrine appearance. Also, mucus-producingcells may be present. Focally, the epitheliumshows areas of increased thickness in which glandularspaces are formed. Moreover, the epithelial cellsmay lie in spherical structures with a whorled appearance(Fig. 4.8).Mucous cells and cuboidal cells with cilia may alsooccur in other jaw cysts, but the latter lack the other epithelialfeatures described above. Mucous cells and nonkeratinisingsquamous epithelium also occur in mucoepidermoidcarcinoma [91, 177]. However, epithelialplaques consisting of clear cells are not a feature of thislatter lesion.The glandular odontogenic cyst most commonly affectsthe body of the mandible and the most prominentFig. 4.8. Epithelial lining of glandular odontogenic cyst showingintraepithelial duct formation and apocrine differentiation at thesurfacesymptom is painless swelling [126]. Treatment may beconservative, but recurrence may occur [48].4.3.2.4 Odontogenic KeratocystOdontogenic keratocyst , formerly also called primordialcyst , is defined by the presence of an epithelial lining notexceeding 10 cell layers in thickness, palisading of thebasal cells, and a parakeratinised, corrugated surface[114].Odontogenic keratocysts are common lesions [147,148, 149]. They show a wide age range with a peak frequencyin the 2nd and 3rd decades, are more commonin males then in females and occur twice as frequently inthe mandible as in the maxilla. Involvement of the gingivalsoft tissues has also been reported [26]. They alsooccur in cases of nevoid basal cell carcinoma syndromeand in patients with Marfan’s syndrome [11, 50, 186].

108 P.J. Slootweg4Fig. 4.9. Epithelial lining of a keratocyst. The basal palisadingand the corrugated parakeratinised surface are unique to this lesion.Moreover, there is a striking parallel between the basal layerand the surfaceFig. 4.10. In the event of inflammation, the epithelial lining of akeratocyst loses its typical pattern to transform into a lattice ofspongiotic squamous epitheliumThe odontogenic keratocyst shows a thin connectivetissue wall lined by stratified squamous epitheliumwith a well-defined basal layer of palisading columnaror cuboidal cells and with a surface of a corrugatedlayer of parakeratin (Fig. 4.9). Mitotic figurescan be identified in parabasilar and midspinous areas[12]. Rushton bodies similar to those seen in radicularcysts may also be present. The underlying cyst wallmay contain tiny daughter cysts and solid epithelialnests. Also, epithelial proliferations similar to ameloblastomahave been reported. Daughter cysts and intramuralepithelial nests are more common in cystsassociated with the nevoid basal cell carcinoma syndrome[185]. When inflamed, the odontogenic keratocystloses its typical histologic features, but showsa non-keratinising stratified epithelium exhibitingspongiosis and elongated rete pegs supported by a connectivetissue containing a mixed inflammatory infiltrate(Fig. 4.10). Rarely, odontogenic keratocysts showdevelopment of epithelial dysplasia and squamous cellcarcinoma [87].Immunohistochemical studies have not yielded dataof diagnostic or prognostic significance [148, 149].Odontogenic keratocysts may also contain mucouscells, melanin-producing cells, dentinoid and intramuralcartilage [12, 74, 86, 105]. Ciliated cells may be seen,but in maxillary cases, they could also be the result of acommunication with the maxillary sinus [122]. In addition,the cyst wall may contain intramural odontogenicepithelial remnants. Occasionally, intraosseous cysts arelined by orthokeratinised epithelium, thus having theappearance of an epidermoid cyst. Such cysts are knownas orthokeratinised odontogenic cysts. Their differentiationfrom the odontogenic keratocyst with parakeratinisationis clinically important as recurrence of orthokeratinisedcysts is rare [188]. Differential diagnosiswith unicystic ameloblastoma (see Sect. 4.4.1.1) maybe difficult. Odontogenic keratocyst exhibits a compactspinous layer and a corrugated superficial parakeratinlayer, and ameloblastoma a spinous layer with intercellularoedema.Keratocysts do not cause symptoms unless concomitantinflammation causes pain and swelling. Radiographsmay reveal extensive uni- or multilocular radiolucentlesions that occupy the major part of the jawwithout having caused any appreciable cortical expansion.When the odontogenic keratocyst forms part ofthe nevoid basal cell carcinoma syndrome, patientsmay show any of the other features of this syndrome[72].Odontogenic keratocysts tend to recur after enucleation[147, 148, 149]. Sometimes, a partial jaw resectionis needed to a provide permanent cure [182]. If associatedwith the nevoid basal cell carcinoma syndrome, thechance of recurrence is even higher [18]. If located in thegingiva, the behaviour of the odontogenic keratocyst isless aggressive [65].As there is sufficient evidence that this lesion actuallyrepresents a cystic neoplasm, the most recent WHOclassification proposes the diagnostic designation keratocysticodontogenic tumour [181].4.3.2.5 Gingival CystGingival cysts are divided in those occurring in adultsand those in infants. They are located in the gingival tissues.Gingival cysts of adults are rarely larger than 1 cmand may be multiple. They are lined by either thin epitheliumof one to three cell layers or thicker and exhibitkeratinisation. Plaques similar to those occurring in thelateral periodontal cyst (see Sect. 4.3.2.2) may be seen[107].

Maxillofacial Skeleton and Teeth Chapter 4 109Gingival cysts of infants occur either singularly ormultiply on the edentulous alveolar ridge of the newborninfant. When occurring at the midline of the palate,they are known as palatal cysts of infants. These tinylesions, usually not larger than 3 mm, disappear spontaneouslywithin a short time. Histologically, they resembleepidermoid cysts [24, 94]. Historically, Epstein’spearls and Bohn’s nodules are terms that have been usedfor these lesions.4.3.3 Non-Odontogenic Cysts4.3.3.1 Nasopalatine Duct CystNasopalatine duct cysts arise within the nasopalatinecanal from epithelial remnants of the nasopalatine duct.Radiologically, they present as radiolucent lesions situatedbetween the roots of both maxillary central incisorteeth. The cyst lining may be pseudostratified columnarciliated epithelium, stratified squamous epithelium,columnar or cuboidal epithelium and combinations ofthese. As surgical treatment comprises emptying thenasopalatine canal, the specimen always includes theartery and nerve that run in this anatomic structure.These are seen within the fibrous cyst wall and formthe most convincing diagnostic feature, as the specificepithelial structures may be obscured by inflammatorychanges. Recurrences are rarely seen, and are probablydue to incomplete removal [168].4.3.3.2 Nasolabial CystNasolabial cysts are located in the soft tissue just lateralto the nose at the buccal aspect of the maxillary alveolarprocess and are thought to arise from the nasolacrimalduct. Non-ciliated pseudostratified columnar epitheliuminterspersed with mucous cells form the epitheliallining. These features may be lost through squamousmetaplasia [180]. Apocrine metaplasia of the cyst lininghas also been reported [83]. Treatment consists ofenucleation.4.3.3.3 Surgical Ciliated CystSurgical ciliated cysts arise from detached portionsof the mucosa that line the maxillary antrum and areburied within the maxillary bone. This may occur aftertrauma or surgical intervention in this area [93]. Mostly,the cyst is an incidental radiographic finding, observedas a well-defined unilocular radiolucency adjacent to themaxillary antrum.The cyst lining is similar to the normal mucosal surfaceof the paranasal cavities: pseudostratified ciliatedcolumnar epithelium with interspersed mucous cells.Treatment consists of simple enucleation.4.3.4 Pseudocysts4.3.4.1 Solitary Bone CystThe solitary bone cyst , also known as traumatic bone cystor simple bone cyst is confined to the mandibular body.Its pathogenesis is ill-understood; a remnant of intraosseoushaemorrhage is the most favoured hypothesis. Radiographsshow a cavity that varies from less than 1 cmin diameter to one that occupies the entire mandibularbody and ramus. At surgical exploration, one encountersa fluid-filled cavity. Material for histologic examinationmay be difficult to obtain as a soft tissue liningof the bony cavity may be entirely absent or very thin.If present, it usually consists only of loose fibrovasculartissue, although it may also contain granulation tissuewith signs of previous haemorrhage such as cholesterolclefts and macrophages loaded with iron pigment [136].Sometimes, this cyst develops simultaneously with a varietyof fibro-osseous cemental lesions [62].4.3.4.2 Focal Bone Marrow DefectThe focal bone marrow defect represents an asymptomaticradiolucent lesion of the jaws that containsnormal hematopoietic and fatty bone marrow. It is alsocalled osteoporotic bone marrow defect . This conditionis mostly seen at the angle of the mandible where it revealsits presence as a radiolucency with more or lesswell-defined borders. Due to the lack of radiographicspecificity, the lesion is usually biopsied. Then, histologicexamination will reveal the presence of normalhematopoietic marrow [141]. Of course, further treatmentis superfluous.4.4 Odontogenic TumoursOdontogenic tumours comprise a group of lesions thathave in common that they arise from the odontogenictissue. They develop from the epithelial part of the toothgerm, the ectomesenchymal part or from both. Theirbehaviour varies from frankly neoplastic, includingmetastatic potential, to non-neoplastic hamartomatous.Some of them may recapitulate normal tooth developmentincluding the formation of dental hard tissues suchas enamel, dentin and cementum [129]. Table 4.2 gives

110 P.J. SlootwegTable 4.2. Odontogenic tumours [73, 181]4EpithelialMesenchymalMixed epithelial and mesenchymalMalignantAmeloblastomaCalcifying epithelial odontogenic tumourAdenomatoid odontogenic tumourSquamous odontogenic tumourOdontogenic myxomaOdontogenic fibromaCementoblastomaAmeloblastic fibromaAmeloblastic fibro-odontomaOdontoma – complex typeOdontoma – compound typeCalcifying odontogenic cyst (calcifying cystic odontogenic tumour/dentinogenic ghost cell tumour [181])Odonto-ameloblastomaMalignant ameloblastomaAmeloblastic carcinomaPrimary intraosseous carcinomaClear cell odontogenic carcinomaMalignant epithelial odontogenic ghost cell tumourOdontogenic sarcomaan overview of the various entities encompassed underthis heading.4.4.1 Odontogenic Tumours –EpithelialEpithelial odontogenic tumours are supposed to bederived from odontogenic epithelium: dental lamina,enamel organ and Hertwig’s root sheath. As there is nocontribution, either proliferative or inductive, from theodontogenic mesenchyme, these lesions do not containdental hard tissues or myxoid tissue resembling the dentalpapilla.4.4.1.1 AmeloblastomaICD-O:9310/0Ameloblastomas closely resemble the epithelial part ofthe tooth germ. They behave aggressively locally, but donot metastasise.It is the most common odontogenic tumour [34] andmay occur at any age, although cases in the first decadeare rare. Maxillary cases are far outnumbered by mandibularones. Rarely, the sinonasal cavities are involved[130, 139].The intraosseous lesions are solid, solid with cysticparts, multicystic or unicystic. In the gingiva, the tumourshave a white fibrous appearance on the cut surface,due to the preponderance of fibrous stroma of lesionsat this site.Ameloblastomas consist of either anastomosing epithelialstrands and fields or discrete epithelial islands.The former pattern is called the plexiform type, the otherthe follicular (Figs 4.11, 4.12). Both may occur withinone and the same lesion [73, 181]. The peripheral cells atthe border with the adjacent fibrous stroma are columnarwith nuclei usually in the apical half of the cell bodyaway from the basement membrane. The cells lying morecentrally are fusiform to polyhedral and loosely connectedto each other through cytoplasmic extensions. Especiallyin the follicular type, an increase in intercellularoedema may cause cysts that coalesce to form the largecavities responsible for the multicystic gross appearanceameloblastomas may show. In the plexiform type, cystformation is usually the result of stromal degeneration.Condensation of collagenous fibres may cause a juxtaepithelialeosinophilic hyaline band. At the peripheryof the lesion, the tumour infiltrates the adjacent cancellousbone. The lower cortical border of the mandible andthe periosteal layer usually expand, but will not be perforated,the periosteum in particular forming a barrier[99]. Spread into soft tissues is highly unusual; whenobserved, it is probably an ameloblastic carcinoma, a lesionto be discussed later on (see Sect. 4.4.4.2). Mitoticfigures may occur within the peripheral columnar aswell as in the stellate reticulum-like cells. In the absenceof cytonuclear atypia and with a normal configuration,they are without prognostic significance.

Maxillofacial Skeleton and Teeth Chapter 4 111Fig. 4.11. Large epithelial areas of loosely structured spindle epitheliumenclosing liquefacting stromal areas are typical of a plexiformameloblastoma. The epithelial cells facing the stroma showpalisadingFig. 4.13. Desmoplastic ameloblastoma consists of denselypacked spindle cells lying in a fibrous stroma. Palisading of peripheralcells is not a conspicuous feature in this type of ameloblastomaFig. 4.12. In cases of follicular ameloblastoma, the tumour consistsof epithelial islands with a loose oedematous centre and a peripheralrim of palisading cells. Liquefaction of their centre resultsin cyst formationFig. 4.14. In unicystic ameloblastoma, the tumour consists ofcyst-lining epithelium that still shows the typical features of ameloblastoma:loose epithelium and a rim of palisading cells facingthe stromaAcanthomatous and granular cell type ameloblastomaare variants of follicular ameloblastoma with squamousmetaplasia and granular cells respectively. If keratinisationis abundant, leading to large cavities filledwith keratin, lesions are called keratoameloblastoma[135]. In these tumours acantholysis may lead to a pseudopapillarylining that characterises the variant calledpapilliferous keratoameloblastoma.The basal cell ( basaloid) ameloblastoma is composedof nests of basaloid cells with a peripheral rim of cuboidalcells and does not display a well-developed, loose oedematouscentre.Desmoplastic ameloblastoma shows a dense collagenousstroma, the epithelial component being reduced tonarrow, compressed strands of epithelium. When thesestrands broaden to form larger islands, a peripheral rimof dark staining cuboidal cells and a compact centre inwhich spindle-shaped epithelial cells assume a whorlingpattern may be discerned (Fig. 4.13). Within the stromalcomponent, active bone formation can be observed[119].Unicystic ameloblastoma represents a cyst that islined by ameloblastomatous epithelium (Fig. 4.14) [115].This epithelium may proliferate to form intraluminalnodules with the architecture of plexiform ameloblastoma.Downward proliferation of this epithelium may leadto infiltration of the fibrous cyst wall by ameloblastomanests. Sometimes, the cyst lining itself lacks any featuresindicative of ameloblastoma, these being confined to intramuralepithelial nests [47]. Inflammatory alterationsmay obscure the specific histologic details to such an extentthat none are left.Ameloblastomas may also contain clear cells as wellas mucous cells [100, 184].Epithelial nests resembling ameloblastoma may befound in calcifying odontogenic cysts and ameloblas-

112 P.J. Slootweg4tic fibromas, lesions to be discussed under the appropriateheadings (Sects. 4.4.3.1 and 4.4.3.6). Also, epithelialnests in the dental follicle that surrounds an impactedtooth and in the wall of odontogenic cysts may mimicameloblastoma. Maxillary ameloblastomas may bemistaken for solid-type adenoid cystic carcinomas (seeChap. 5).Ameloblastomas usually have swelling as the mostprominent symptom. In the maxilla, growth into theparanasal sinuses allows tumours to attain a considerablesize without causing any external deformity. Radiographically,ameloblastoma is a radiolucent lesion that isusually multilocular, the so-called soap bubble appearance,or unilocular with scalloped outlines [130].Sometimes, ameloblastomas present as soft tissueswellings occurring in the tooth-bearing areas of themaxilla or mandible without involvement of the underlyingbone. This peripheral ameloblastoma should not beconfused with intraosseous ameloblastomas that spreadfrom within the jaw into the overlying gingiva [117]. Inthe past, these lesions have also been described as odontogenicgingival epithelial hamartoma [6].Clinically, some variants differ slightly from the prototypicameloblastoma. Desmoplastic ameloblastomaoccurs more often in the anterior parts of both maxillaand mandible than the other types, which favour theposterior mandible [119]. Unicystic ameloblastoma occursat a lower mean age than the other types and oftenhas a radiographic appearance similar to a dentigerouscyst because of its association with an impactedtooth [115].Treatment of ameloblastoma consists of adequate tumourremoval including a margin of uninvolved tissue.For peripheral ameloblastoma simple excision willbe sufficient treatment [47, 115]. For unicystic ameloblastomawith the ameloblastomatous epithelium confinedto the cyst lining, enucleation is adequate therapy,but in cases of intramural proliferation, treatmentshould be the same as for the other ameloblastoma types[133]. When adequately treated, ameloblastomas are notexpected to recur. Adequate removal, however, may bedifficult to realise in maxillary cases that grow posterocranially.In that case, extension into the cranial cavitymay be fatal [103]. In rare instances, metastatic deposits,mainly to the lung, have been observed. Lesions showingthis behaviour are called malignant ameloblastoma(see Sect. 4.4.4.1).4.4.1.2 Calcifying EpithelialOdontogenic TumourICD-O:9340/0The calcifying epithelial odontogenic tumour , alsonamed Pindborg tumour occurs between the 2nd and6th decade and mainly involves the posterior jaw area.Also, cases located at the gingiva may be seen [63,116].The tumour consists of sheets of polygonal cells withample eosinophilic cytoplasm, distinct cell borders andvery conspicuous intercellular bridges. Nuclei are pleomorphicwith prominent nucleoli; cells with giant nucleiand multiple nuclei are also present (Fig. 4.15). Mitoticfigures, however, are absent. Clear cell differentiationmay occur [58]. The epithelial tumour islands as well asthe surrounding stroma frequently contain concentricallylamellated calcifications. The stroma contains eosinophilicmaterial that stains like amyloid (Fig. 4.16)[73, 181]. The presence of bone and cementum in the tumourhas also been reported [155]. There is no encapsulation.The tumour grows into the cancellous spaces ofthe adjacent jaw bone while causing expansion and thinningof the cortical bone.Due to its pronounced nuclear pleomorphism, the tumourmay be mistaken for a high-grade malignant carcinoma;the absence of mitotic figures should preventthis diagnostic error.Swelling is the most common clinical symptom ofthis tumour. Radiographically, the tumour is characterisedby a diffuse mixed radiodense and radiolucent appearance.Quite often, an unerupted tooth lies buriedin the tumour mass. Surgery consists of removal with amargin of uninvolved tissue. Recurrences are occasionallyseen, in particular with the clear cell variant [58].Cases occurring in the extragnathic gingival tissue canbe treated by simple excision as they are less aggressivethan the intraosseous ones [63].Metastatic disease is only seen in cases that combinethe appearance of a calcifying epithelial odontogenic tumourwith the presence of mitotic activity, suggestingmalignant transformation [175]. Mitotic activity has alsobeen seen in combination with perforation of corticalplates and invasion of blood vessels, both also highly unusualfor calcifying epithelial odontogenic tumours [27].Apparently, mitoses in this tumour indicate malignancy.4.4.1.3 AdenomatoidOdontogenic TumourICD-O:9300/0Adenomatoid odontogenic tumour probably representsan odontogenic hamartoma rather than a neoplasm[73, 181]. The lesion is mostly is seen in peoplein their 2nd decade. The anterior maxilla is the favouredsite and the lesion is often associated with animpacted tooth [120]. Grossly, the adenomatoid odontogenictumour is a cyst that embraces the crown ofthe involved tooth.The lesion consists of two different cell populations:spindle-shaped and columnar. The spindle-shapedcells form whorled nodules that may contain drop-

Maxillofacial Skeleton and Teeth Chapter 4 113Fig. 4.15. Nuclear atypia, ample cytoplasm and pronounced intercellularbridging are typical of a calcifying epithelial odontogenictumourFig. 4.17. Areas of small spindle cells and cylindrical cells facingextracellular material characterise the adenomatoid odontogenictumourOdontogenic adenomatoid tumour usually has swellingat the site of a missing tooth as a presenting symptom.Radiographically, this missing tooth is seen surroundedby a radiolucency that may contain multipletiny opaque foci.Treatment consists of simple enucleation.4.4.1.4 SquamousOdontogenic TumourFig. 4.16. Extracellular material staining for amyloid with congored is another characteristic feature of a calcifying epithelialodontogenic tumourlets of eosinophilic material. A lattice of thin epithelialstrands may connect these nodules to each other.The columnar cells line duct-like spaces with a lumeneither empty or containing eosinophilic material andmay form curvilinear opposing rows with interposedeosinophilic material (Fig. 4.17). In the stroma, thereare large aggregates of eosinophilic hyaline material,which is judged to be a dysplastic form of dentin, orcementum, or to be a metaplastic reaction of the stromaltissue [73, 120, 181]. Also, concentrically laminatedcalcified bodies similar to those seen in calcifyingepithelial odontogenic tumours may occur.In some adenomatoid odontogenic tumours, areasof eosinophilic cells with well-defined cell boundariesand prominent intercellular bridges similar to thoseobserved in the calcifying epithelial odontogenic tumourare seen [110]. They do not influence the biologicbehaviour of this tumour and are considered to be partof its histologic spectrum as is the presence of melaninpigment [78, 178].ICD-O:9312/0Squamous odontogenic tumour is a rare lesion thatmainly involves the periodontal tissues. There is nopreference for either sex or jaw area [73, 181].The lesion is composed of islands of well-differentiatedsquamous epithelium surrounded by mature fibrousconnective tissue. There is no cellular atypia.There is spinous differentiation with well-defined intercellularbridges, but keratinisation is unusual. In theepithelial islands, cystic degeneration and calcificationmay occur. Invasion into cancellous bone may be present.The absence of cytonuclear atypia rules out well-differentiatedsquamous cell carcinoma and the absence ofperipheral palisading of columnar cells excludes ameloblastomaas an alternative diagnosis. Sometimes, intramuralepithelial proliferation in jaw cysts may simulatesquamous odontogenic tumour [187].The lesion may cause loosening of the teeth involved.Radiographically, lucent areas are seen. Treatmentconsists of conservative removal of the tumourtissue. Occasionally, more extensive local spread maynecessitate surgical excision with wider margins[142]. Sometimes, multicentric presentation may occur[79].

114 P.J. Slootweg4Fig. 4.18. Odontogenic myxoma is composed of poorly cellularmyxoid material that surrounds pre-existing jaw boneFig. 4.19. Odontogenic fibroma consists of fibrous areas containingepithelial odontogenic nests4.4.2 Odontogenic Tumours –MesenchymalMesenchymal odontogenic tumours are derived fromthe ectomesenchymal part of the tissues that participatein the development of teeth and periodontal tissues.Odontogenic epithelial rests may be part of the histologicpicture they show, but only fortuitously by tumourtissue-engulfed structures. They have no neoplastic orinductive potential.4.4.2.1 Odontogenic MyxomaICD-O:9320/0Odontogenic myxomas usually occur in the 2nd or 3rddecade of life, although cases occurring at a very youngor old age have been reported. It is one of the more commonodontogenic tumours [8].Myxomas consist of rather monotonous cells withmultipolar or bipolar slender cytoplasmic extensionsthat lie in a myxoid stroma. Nuclei vary from round tofusiform in appearance. Binucleated cells and mitoticfigures are present, but scarce (Fig. 4.18). Occasionally,the lesion contains odontogenic epithelial rests.They are a fortuitous finding without any diagnosticor prognostic significance. Myxoma cells are positivefor vimentin and muscle-specific actin, whereas positivityfor S-100 is controversial [82, 102, 169].Myxoma may be mimicked by dental follicle anddental papilla. Both contain myxoid areas [71, 101,165]. Dental papilla tissue can be distinguished frommyxoma by the presence of a peripheral layer of columnarodontoblasts. For both dental papilla and dentalfollicle clinical and radiographic data are decisivein avoiding misinterpretation of myxomatous tissue injaw specimens: in the first case, a tooth germ lies in thejaw area from which the submitted tissue has been takenwhereas in the second case, the tissue sample coveredthe crown area of an impacted tooth.Odontogenic myxomas occur in the maxilla as well asthe mandible and in both anterior and posterior parts.Swelling may be the presenting sign as well as disturbancesin tooth eruption or changes in position of teethalready erupted. In maxillary cases, nasal stuffiness maybe the presenting sign due to tumour growth in nasaland paranasal cavities. Radiographically, lesions show aunilocular or soap-bubble appearance.As the lesion lacks encapsulation, treatment usuallyconsists of excision with a margin of uninvolved tissue[161]. Incidentally, cases with extremely aggressive localgrowth have been reported [35].4.4.2.2 Odontogenic FibromaICD-O:9321/0Odontogenic fibroma is a controversial entity. Uncertaintyexists about the broadness of histologic spectrumthat these lesions may show, and about its distinctionfrom other fibrous jaw lesions [73, 181].Odontogenic fibroma has an age distribution of 9–80 years and occurs predominantly in females [55]. Thelesion is seen within the jaw as well as in the gingiva[32].Odontogenic fibroma consists of fibroblasts lyingin a background of myxoid material intermingled withcollagen fibres that may vary from delicate to coarse.Odontogenic epithelium, either scarce or abundant,may occur (Fig. 4.19). Only rarely is the epithelialcomponent so conspicuous that differentiation betweenodontogenic fibroma and ameloblastoma maybe difficult [66]. This histologic spectrum may expandto include cell-rich myxoid areas, a greater epithelialcomponent and varying amounts of amorphous calcifiedglobules or mineralised collagenous matrix. Tu-

Maxillofacial Skeleton and Teeth Chapter 4 115mours with this more variegated histology have beenreferred to as complex odontogenic fibroma or WHOtypeodontogenic fibroma [73, 181]. Odontogenic fibromamay also contain granular cells. These lesionshave been called granular cell odontogenic fibromasor, alternatively, granular cell ameloblastic fibromas(see Sect. 4.4.3.1). This tumour, however, could alsorepresent a unique entity: central odontogenic granularcell tumour [15, 170]. The granular cells are negativefor epithelial markers and S-100 whereas positivityfor CD68 suggests a histiocytic nature [15, 23].Rarely, this tumour may show atypical histologic featuresincluding mitotic activity and aggressive behaviour[121].There are also lesions that combine the histologic featuresof giant cell granuloma and central odontogenic fibroma[108]. Their aggressive nature suggests that thegiant cell granuloma (see Sect. 4.6.1) component determinesthe clinical behaviour.When odontogenic fibromas show a preponderanceof myxoid material, distinguishing them from odontogenicmyxomas may become problematic. It is probablybest to consider such cases to be myxomas and to treatthem accordingly.Another significant diagnostic problem is the distinctionbetween odontogenic fibroma and desmoplasticfibroma, which is clinically very important, as theformer is benign whereas the latter shows aggressive behaviour[160]. Lesions with features of both odontogenicfibroma and desmoplastic fibroma may occur in patientswith tuberous sclerosis [10].Peripheral odontogenic fibroma should not be confusedwith peripheral ossifying fibroma, a gingival softtissue lesion characterised by the presence of mineralisedmaterial of various appearances, but lacking odontogenicepithelium (see Chap. 3) [69]. Peripheral odontogenicfibroma has also to be distinguished from peripheralameloblastoma, the former lesion lacking ameloblastomatousepithelium. Cases of peripheral odontogenic fibromawith an extensive epithelial component have inthe past been reported with the designation odontogenicepithelial hamartoma [176].All histologic features shown by odontogenic fibromamay also be displayed by the dental follicle [37, 71, 85,165]. In these cases, the radiographic appearance of thelesion, a small radiolucent rim surrounding the crownof a tooth buried within the jaw, will make the distinction.Central odontogenic fibromas may present as localbony expansions of the involved jaw area. Quite often,they are incidental findings on radiographs performedfor other diagnostic purposes: demarcated unilocularradiolucencies located adjacent to the roots of the neighbouringteeth or surrounding an impacted tooth. Peripheralodontogenic fibromas are firm-elastic gingivalswellings.Fig. 4.20. A hard tissue mass firmly connected to the root surfaceof the tooth involved is diagnostic for cementoblastomaTreatment consists of enucleation. Peripheral cases,however, may recur after excision [32].4.4.2.3 CementoblastomaICD-O:9273/0Cementoblastomas are heavily mineralised cementummasses connected to the apical root part of a tooth(Fig. 4.20) [73, 181]. These tumours are most often seenin young adults and show a predilection for males [14].They are composed of a vascular, loose-textured fibroustissue that surrounds coarse trabeculae of basophilicmineralised material bordered by plump cellswith ample cytoplasm and large but not atypical nuclei.Mitotic figures are rare. At the periphery, the mineralisedmaterial may form radiating spikes. Also, osteoclasticgiant cells form part of the histologic spectrum.The hard tissue component is connected with the rootof the involved tooth, which usually shows signs of externalresorption. The sharp border between the tubulardentin of the root and the hard tissue component formsthe hallmark of cementoblastomas (Fig. 4.21).All features of the cementoblastoma may also beshown by the osteoblastoma, except the connection withthe tooth root. Therefore, cases in which this connectioncannot be demonstrated should be diagnosed as osteoblastomaand not cementoblastoma [156].

116 P.J. Slootweg4Fig. 4.21. Higher magnification of Fig. 4.20 shows the continuitybetween the root forming tubular dentin (right side) and the cementalmasses of the cementoblastomaPain is the most common presenting symptom andthe posterior jaw areas are the predilection site. Sometimes,the lesion is attached to multiple neighbouringteeth [156]. Radiographically, the lesion is demarcatedwith a mixed lucent and dense appearance and is continuouswith the partially resorbed root of a tooth. As recurrenceand continued growth are possible, treatmentshould consist of removal of the lesion along with the affectedtooth or teeth, and should also include some adjacentjaw bone [14].4.4.3. Odontogenic Tumours –Mixed Epithelialand MesenchymalMixed odontogenic tumours are composed of both epithelial-derivedand mesenchymal-derived tissues. Thesetumours recapitulate proliferation and differentiation asseen in the developing teeth. Deposition of the dental hardtissues – enamel and dentin – may also occur [73, 174,181]. Lesions with an identical histology can show neoplasticas well as hamartomatous behaviour [118, 153].4.4.3.1 Ameloblastic FibromaICD-O:9330/0Ameloblastic fibroma lacks a hard tissue component,only displaying soft tissues similar to those found in theimmature tooth germ.It is one of the less common lesions [34, 109, 127].Mean age of occurrence is 14.8 years, but cases maybe seen from as young as only 7 weeks up to as old as62 years. Most cases are seen in the posterior mandible[96, 118].The epithelial part of ameloblastic fibroma consistsof branching and anastomosing epithelial strandsthat form knots of varying size. These knots have a peripheralrim of columnar cells that embraces a looselyarranged spindle-shaped epithelium. These epithelialstrands lie in a myxoid cell-rich mesenchyme. Theamount of epithelium may vary among cases and regionallywithin an individual case. There is no formationof dental hard tissues. Mitotic figures, either in epitheliumor mesenchyme, are extremely rare; when easilyfound, they should raise concern about the benign natureof the case.Ameloblastic fibroma may contain granular cells.Whether these lesions should be called granular cell ameloblasticfibroma or granular cell odontogenic fibroma iscontroversial (see also Sect. 4.4.2.2) [118, 170].The epithelial component of ameloblastic fibromaclosely resembles that of ameloblastoma. The stromalcomponent, however, is entirely different: in ameloblastomait is mature fibrous connective tissue whereasin the ameloblastic fibroma it is immature, embryonic,cell-rich myxoid tissue. Areas similar to ameloblasticfibroma may also be observed in the hyperplastic dentalfollicle [71, 165]. The radiographic appearance makesthe distinction; a radiolucent rim surrounding an uneruptedtooth in the case of a dental follicle and an expansiveradiolucent jaw lesion in the case of an ameloblasticfibroma.Most cases of ameloblastic fibroma present as painlessswellings or are discovered due to disturbances intooth eruption. Radiographically, the tumour presentsas a well-demarcated expansive radiolucency, often inconnection with a malpositioned tooth.Treatment consists of enucleation and curettage. Insome cases, recurrence may occur [118]. Sometimes,ameloblastic fibroma may progress to malignancy.These lesions are characterised by increased cellularityand mitotic activity of the mesenchymal componentand therefore known as ameloblastic fibrosarcoma (seeSect. 4.4.4.6) [96].4.4.3.2 AmeloblasticFibro-OdontomaICD-O:9290/0Ameloblastic fibro-odontomas are lesions that combinea soft tissue component, similar to ameloblastic fibroma,with the presence of dentin and enamel. In rare cases,only dentin is formed; those tumours are called ameloblasticfibro-dentinoma (ICD-O:9271/0) [73, 181].

Maxillofacial Skeleton and Teeth Chapter 4 117as those as already mentioned (see Sect. 4.4.3.1). Ameloblasticfibro-odontomas can be distinguished from ameloblastomasby the presence of cellular myxoid tissueand of dentin and enamel.Most cases of ameloblastic fibro-odontoma presentas painless swelling or are discovered due to disturbancesin tooth eruption. Radiographically, the tumourpresents as a well-demarcated expansive radiolucencywith a radiopaque centre. Treatment consistsof enucleation and curettage. Recurrence is rarely seen[46].Fig. 4.22. Ameloblastic fibro-odontoma combines the soft tissueelements of an ameloblastic fibroma with the deposition of thedental hard tissues enamel and dentin. Cavities in the homogeneouseosinophilic dentin contain high-columnar ameloblasts lyingdown enamel matrix (deep purple)Fig. 4.23. Panoramic radiograph showing radiodense mass inconnection with a tooth germ, a picture typical of complex odontomaAmeloblastic fibro-odontomas are rare [34, 127].They occur primarily within the first two decades andhave the posterior jaw areas as sites of predilection, themandible more often involved than the maxilla [118,153].The soft tissue component is identical to that of ameloblasticfibroma. Dentin may be formed either as eosinophilicmineralised material containing tubuli, justas in normal teeth, but it may also form as an homogeneouseosinophilic mass with sparse cells included.It always lies in close association with adjacent epitheliumand forms the scaffold for the deposition of enamelmatrix that is laid down at the epithelial–dentin interfaceby columnar epithelial cells that have reachedtheir terminal differentiation as ameloblasts. The dentalhard tissues are arranged haphazardly without any reminiscenceof the orderly structure characterising normalteeth (Fig. 4.22).Hyperplastic dental follicles may also show focal areaswith the appearance of ameloblastic fibro-odontoma.Differential diagnostic considerations are the same4.4.3.3 Odontoma –Complex TypeICD-O:9282/0Complex odontoma is a lesion composed of a haphazardconglomerate of dental hard tissues. This hamartoma isone of the more common odontogenic lesions [34, 127].The posterior mandible is the favoured site (Fig. 4.23).Ages at which this lesion occurs are difficult to determineas lesions may be present unnoticed for a longtime, the age distribution mentioned reflecting the agewhen the lesion was found rather than the age at whichit formed. This explains the enormous range in age distributionreported: 2–74 years [118].Complex odontomas consist of a usually well-delineatedmass of dental hard tissues in a haphazard arrangement.The bulk of the lesion consists of dentinrecognisable by the presence of tubuli. Enamel plays aminor role, usually confined to small rims in cavities inthe dentin mass. The stroma consists of mature fibrousconnective tissue.Sometimes, odontomas may contain areas identicalto the calcifying odontogenic cyst includingghost cells [22, 61, 80]. Odontoma-like structuresmay also occur in the hyperplastic dental follicle (seeSect. 4.4.2.1).Complex odontomas may reveal their existence bydisturbances in tooth eruption, missing teeth or jawexpansion. Quite often, they are incidental findings onradiographs taken for other purposes. In those cases,an amorphous calcified mass is seen that may be connectedwith the crown of an unerupted tooth. Treatmentconsists of conservative removal. Recurrences arenot seen.4.4.3.4 Odontoma –Compound TypeICD-O:9281/0Compound odontoma is a malformation consistingof tiny teeth that may vary in number from only a fewto numerous. These teeth do not resemble the normal

118 P.J. Slootweg4teeth, but are usually cone-shaped. Histologically, theyshow the normal arrangement of centrally placed fibrovascularpulp tissue surrounded by dentin with an outersurface covered by enamel in the crown area and cementumin the root part.Compound odontoma is one of the more frequentlyencountered odontogenic lesions [34, 127]. Data on ageof occurrence show the same wide range as with complexodontoma: 0.5–73 years of age, which is due to thefact that compound odontomas may also remain unnoticedfor a long time.In contrast with almost all other odontogenic lesionsthat have the posterior mandible as the preferredsite, compound odontomas have a definite predilectionfor the anterior maxilla [118, 153]. They may causeswelling or disturbed tooth eruption. Radiographically,a radiolucency containing multiple tooth-like radiopaquestructures is seen. Treatment consists of enucleationand there is no recurrence.Compound odontomas may contain areas identicalto those of the calcifying odontogenic cyst includingghost cells (see Sect. 4.4.3.6) [22, 61, 80].4.4.3.5 Odonto-AmeloblastomaICD-O:9311/0Odonto-ameloblastoma is a very rare neoplasm thatcombines the features of ameloblastoma and odontoma,including the presence of enamel and dentin [73,181]. The ameloblastoma component determines clinicalpresentation and behaviour. Radiographically, thesoap-bubble appearance of ameloblastoma is combinedwith radiopaque masses due to the odontoma component[97].4.4.3.6 CalcifyingOdontogenic CystFig. 4.24. Calcifying odontogenic cyst closely resembles ameloblastoma,but the presence of large intraepithelial aggregates ofghost cells rules out the latter diagnosisICD-O:9301/0Calcifying odontogenic cysts occur both in the maxillaand in the mandible in equal proportions. They mostcommonly lie intraosseously, but cases in the gingiva arealso seen. The lesion is most commonly found in the 2ndand 3rd decades [19, 20, 173].In its most simple form, calcifying odontogenic cystis a cavity with a fibrous wall and an epithelial lining.This epithelial lining closely mimics that seen in unicysticameloblastoma, but, in addition, there are intraepithelialeosinophilic ghost cells lacking nuclei that mayundergo calcification. Ghost cell masses may also herniatethrough the basal lamina to reach the underlyingstroma where they can act as foreign material and evokea giant cell reaction (Fig. 4.24). In the fibrous stroma adjacentto the basal epithelial cells, homogenous eosinophilicmaterial resembling dentin may be found in varyingamounts. Dentin-like material and ghost cells togethermay form mixed aggregates.To this simple unicystic structure other features maybe added, thus creating different subtypes with differentnames [173].The proliferative calcifying odontogenic cyst showsmultiple intramural daughter cysts with an epitheliallining similar to the main cyst cavity. The solid (neoplastic)calcifying odontogenic cyst has been describedby a variety of other terms: dentinogenic ghost cell tumour,epithelial odontogenic ghost cell tumour, calcifyingghost cell odontogenic tumour, and cystic calcifyingodontogenic tumour [81]. This lesion combines themorphology of an ameloblastoma with intra-epithelialand stromal ghost cells with a dentin-like material.The most recent WHO classification proposes thediagnostic designations calcifying cystic odontogenictumour (ICD-O:9301/0) and dentinogenic ghost celltumour (ICD-O:9302/0) to discern between the cysticand the solid lesion [181].Also, calcifying odontogenic cysts may occur in associationwith other odontogenic tumours, in most instancesameloblastoma and odontoma [124]. All variantsof calcifying odontogenic cyst may show melaninpigment [60, 162].Ghost cells, either intraepithelially or in the stroma,separate calcifying odontogenic cyst from ameloblastoma.The solid variant of calcifying odontogenic cyst issimilar to craniopharyngioma [7, 111].Intraosseous calcifying odontogenic cysts cause bonyexpansion. The peripheral type forms a gingival soft tissueswelling. Radiographically, the lesion shows a lucentappearance when located intraosseously, mostly withvariable amounts of radiopacities. Treatment of the calcifyingodontogenic cyst consists of enucleation in casesof intraosseous location or excision for peripheral ones.

Maxillofacial Skeleton and Teeth Chapter 4 119Recurrences have been documented for both the cysticand the solid variant [124, 143]. If the lesion is combinedwith an ameloblastoma, this latter component dictatesthe most appropriate therapy, which consists of surgicalexcision including a margin of healthy tissue as alreadydiscussed [124].4.4.4 Odontogenic Tumours –MalignantBoth odontogenic epithelium as well as odontogenicmesenchyme may show neoplastic degeneration, causingeither odontogenic carcinomas or odontogenicsarcomas [73, 159, 181]. All entities to be mentionedshow the clinical presentation and course as well as theradiographic appearance of an intraosseous malignanttumour.4.4.4.1 Malignant AmeloblastomaICD-O:9310/3Malignant (metastasising) ameloblastoma is an ameloblastomathat metastasises in spite of an innocuoushistologic appearance. The primary tumour shows nospecific features that are different from ameloblastomasthat do not metastasise. Therefore, this diagnosiscan only be made in retrospect, after the occurrence ofmetastatic deposits. It is thus clinical behaviour and nothistology that justifies a diagnosis of malignant ameloblastoma[181]. This definition profoundly differs fromthat given in the previous WHO classification [73]. Atthat time a malignant ameloblastoma was described asa neoplasm in which the pattern of an ameloblastomais combined with cytological features of malignancy,a definition not based on behaviour but on histology.It is obvious that disparate views on what representsa malignant ameloblastoma can give rise to confusion[41, 159]. It has to be emphasised that to avoid mixingup different entities, the term malignant ameloblastomashould be reserved for metastasising ameloblastomaswhereas the ameloblastomas with atypia shouldbe called ameloblastic carcinomas, a type of lesion tobe discussed in Sect. 4.4.4.2 [104]. Confusion may alsoarise through the use of the term atypical ameloblastomasto denote lesions with a fatal outcome for variousreasons, either metastasis, histologic atypia or relentlesslocal spread [3].Metastatic deposits of malignant ameloblastomas aremostly seen in the lung [76, 77, 159]. Apart from metastasis,malignant ameloblastoma shows no featuresthat are different from conventional ameloblastoma (seeSect. 4.4.1.1).Fig. 4.25. Ameloblastic carcinoma combines the presence of epithelialnests with peripheral palisading and cytonuclear atypia4.4.4.2 Ameloblastic CarcinomaICD-O:9270/3Ameloblastic carcinoma , an entity that has only recentlybeen recognised, is a lesion with the histologicfeatures of both ameloblastoma and squamous cellcarcinoma [42, 181]. This tumour may arise de novoor from a pre-existing benign odontogenic tumour orcyst [159].Most cases of ameloblastic carcinoma occur in themandible [30]. They show a wide age range with a meanof 30.1 years [30].Ameloblastic carcinoma is characterised by cells that,although mimicking the architectural pattern of ameloblastoma,exhibit pronounced cytological atypia andmitotic activity, thus allowing the distinction betweenameloblastic carcinoma and ameloblastoma (Fig. 4.25).Metastatic lesions are described in the lungs and in thelymph nodes [36, 151].4.4.4.3 PrimaryIntraosseous CarcinomaICD-O:9270/3Primary intraosseous carcinoma is a squamous cell carcinomaarising within the jaw, having no initial connectionwith the oral mucosa, and presumably developingfrom residues of the odontogenic epithelium [73, 181].It ranges from well to poorly differentiated [42], mainlyoccurs in the posterior mandible and is more often seenin males [190].The tumour may arise from a still recognisable precursorlesion such as the epithelial lining of an odontogeniccyst [67, 90]. Also, enamel epithelium has beendocumented as a tissue of origin [154].

120 P.J. Slootweg4Fig. 4.26. Clear cell odontogenic carcinoma is characterised byclear cells forming epithelial nestsFig. 4.27. At higher magnification, clear cell odontogenic carcinomais seen to contain clear cells as well as eosinophilic cellsSwelling of the jaw and pain are most often the presentingsigns. Surgery and postoperative radiotherapyseem to provide the best results. The tumour maymetastasise to regional lymph nodes as well as lungs.Prognosis is poor with almost 50% of the patients failingloco-regionally within the first 2 years of followup[190].4.4.4.4 Clear CellOdontogenic CarcinomaICD-O:9341/1Clear cell odontogenic carcinoma was initially reportedas a clear cell odontogenic tumour [56]. As these lesionsnot only behave aggressively locally, but may also metastasise,the currently used diagnostic term clear cellodontogenic carcinoma appears to be more appropriate[43, 75]. The tumour is mostly seen in elderly patients[5].The tumour is composed of cells with clear cytoplasm.These cells form nests and strands, intermingledwith smaller islands of cells with eosinophilic cytoplasm(Figs. 4.26, 4.27). Also, squamous differentiationhas been reported [17]. Cells at the periphery ofthe nests may show palisading. The clear cells stain positivefor glycogen as well as for epithelial markers keratinAE1/AE3, cytokeratin 8/18, cytokeratin 19 and epithelialmembrane antigen (EMA) [89].The anterior mandible appears to be the site of predilection.Metastases are found in lymph nodes as well asin the lungs and the skeleton. Recurrent disease is seenin more than 50% of cases with documented follow-up.Death due to the tumour has also been reported [5, 89].Differential diagnosis includes metastatic renal cellcarcinoma, the clear cell variant of mucoepidermoidcarcinoma, and ameloblastoma with clear cells. Metastaticrenal cell carcinoma may be ruled out on clinicalgrounds. The clear cell variant of muco-epidermoidcarcinoma can be identified with stains for mucin production.Differentiation from ameloblastoma with clearcells may be problematic and it has been proposed thatthese lesions represent the same entity [16]. Clear cellcarcinoma of minor salivary gland origin is another differentialdiagnosis (see Chap. 5).4.4.4.5 Malignant EpithelialOdontogenicGhost Cell TumourICD-O:9270/3Malignant epithelial odontogenic ghost cell tumour ,also called odontogenic ghost cell carcinoma is a tumourthat combines the elements of a benign calcifying odontogeniccyst with a malignant epithelial component.Only a few cases of this tumour have been reported, thusprecluding any conclusions regarding clinicopathologicfeatures. Malignancy has been demonstrated by local aggressivegrowth and distant metastasis [84]. The tumourapparently arises most often from malignant transformationof a pre-existing benign calcifying odontogeniccyst [81].4.4.4.6 Odontogenic SarcomaICD-O:9270/3The WHO discerns between ameloblastic fibrosarcoma ,ameloblastic fibrodentino- and fibro-odontosarcomaand odontogenic carcinosarcoma [73, 181]. The ameloblasticfibrosarcoma consists of malignant connectivetissue admixed with epithelium similar to that seen inan ameloblastoma or ameloblastic fibroma [152]. If thereis also dentin, this is known as an ameloblastic fibrodentinosarcoma, and if there is also enamel, it is called ameloblasticfibro-odontosarcoma . This subclassification hasno prognostic significance [2]. These tumours may arise

Maxillofacial Skeleton and Teeth Chapter 4 121Table 4.3. Fibro-osseous lesions [13, 181]Fibrous dysplasiaOssifying fibromaOsseous dysplasiaConventionalJuvenile trabecularJuvenile psammomatoidPeriapical osseous dysplasiaFocal osseous dysplasiaFlorid osseous dysplasiaFamilial gigantiform cementomade novo or from a pre-existing ameloblastic fibroma orameloblastic fibro-odontoma [98].Those extremely rare lesions that combine carcinomatousand sarcomatous elements, but are recognisableas odontogenic from the epithelial component, resembleameloblastic carcinomas, and have been called odontogeniccarcinosarcoma or odontogenic carcinoma with sarcomatousproliferation [152].4.5 Fibro-Osseous LesionsThe current classification of maxillofacial fibro-osseouslesions includes fibrous dysplasia, ossifying fibroma andosseous dysplasia [13, 158]. Table 4.3 gives an overviewof the various entities in this group.4.5.1 Fibrous DysplasiaFibrous dysplasia is composed of cellular fibrous tissuecontaining trabeculae of woven bone. It occurs in threeclinical subtypes: monostotic, which affects one bone,polyostotic, which affects multiple bones, and Albright’ssyndrome, in which multiple bone lesions are accompaniedby skin hyperpigmentation and endocrine disturbances[13]. Activating missense mutations of the geneencoding the α subunit of the stimulatory G protein area consistent finding in the various forms of fibrous dysplasia[123].Craniofacial fibrous dysplasia is usually of the monostotictype [44]. The disease mostly occurs during thefirst three decades, although cases are occasionally seenat an older age. The maxilla is more often involved thanthe mandible. In the maxilla, fibrous dysplasia may extendby continuity across suture lines to involve adjacentbones [13].Fibrous dysplasia shows replacement of the normalbone by moderately cellular fibrous tissue containingirregularly shaped trabeculae consisting of wovenbone without rimming osteoblasts that fuse with adjacentbone. Jaw lesions may also show lamellar bone(Fig. 4.28). Sometimes, tiny calcified spherules may bepresent [158].Fig. 4.28. In the jaws, fibrous dysplasia may consist of both wovenand lamellar bone, as shown in this photomicrograph takenwith the use of partly polarised light to enhance the collagenousscaffold of the boneFibrous dysplasia has to be distinguished from otherlesions characterised by the combination of fibrous tissueand bone: ossifying fibroma, osseous dysplasia, lowgradeosteosarcoma and sclerosing osteomyelitis. However,none of these is composed of woven bone trabeculaefusing with adjacent uninvolved bone. Ossifying fibromaand osseous dysplasia both show much variety inappearance of mineralised material and stromal cellularity,low-grade osteosarcoma invades through the corticalbone into soft tissues and sclerosing osteomyelitisshows coarse trabeculae of lamellar bone, whereas theintervening stroma is not cellular but oedematous withsprinkled lymphocytes [158].Fibrous dysplasia clinically presents as a painlessswelling of the bone involved. Radiographically, the classicalappearance is described as orange-skin or groundglassradiopacity without defined borders [13]. Usually,fibrous dysplasia is a self-limiting disease. Therefore,treatment is only required if there are problems due tolocal increase in size of the affected bone. Sometimes, anosteosarcoma may arise in fibrous dysplasia [39].4.5.2 Ossifying FibromaICD-O:9262/0, 9274/0Ossifying fibroma , formerly also called cemento-ossifyingfibroma is a well-demarcated lesion composed offibrocellular tissue and mineralised material of varyingappearance. It occurs most often in the 2nd through the4th decades. The lesion shows a predilection for females,is mostly seen in the posterior mandible [13] and mayoccur multifocally [70].Chromosomal abnormalities have been observed inossifying fibromas [31, 49, 138]. Data are still too scarceto determine their pathogenetic significance.

122 P.J. Slootweg4Fig. 4.29. Ossifying fibroma contains both cell-rich and cell-poorareas as well as well-structured bone and amorphous calcified materialFig. 4.31. Juvenile trabecular ossifying fibroma shows slenderbony trabeculae rimmed with osteoblasts that merge with an extremelycellular stromaFig. 4.30. Ossifying fibroma may also contain more smoothlycontoured bony elements, formerly thought to represent cementumFig. 4.32. At higher magnification, the plump osteoblasts thatline the bony trabeculae in juvenile trabecular ossifying fibromaare shown to be a prominent featureOssifying fibroma is composed of fibrous tissue thatmay vary in cellularity from areas with closely packedcells displaying mitotic figures to almost acellular sclerosingparts within one and the same lesion. The mineralisedcomponent may consist of plexiform bone, lamellar boneand acellular mineralised material, sometimes all occurringtogether in one single lesion (Figs 4.29, 4.30).Juvenile psammomatoid and juvenile trabecular ossifyingfibroma are subtypes [40]. Juvenile trabecularossifying fibroma consists of cell-rich fibrous tissuewith bands of cellular osteoid together with slendertrabeculae of plexiform bone lined by a dense rimof enlarged osteoblasts (Figs. 4.31, 4.32). Sometimesthese trabeculae may anastomose to form a lattice.Mitoses are present, especially in the cell-rich areas.Also, multinucleated giant cells, pseudocystic stromaldegeneration and haemorrhages may be present. Dueto its cellularity and mitotic activity, the lesion may beconfused with osteosarcoma. However, atypical cellularfeatures or abnormal mitotic figures are not seen.Moreover, the lesion is demarcated from its surroundings[73, 158, 181].Juvenile psammomatoid ossifying fibroma is characterisedby a fibroblastic stroma containing small ossiclesresembling psammoma bodies, hence its name. Thestroma varies from loose and fibroblastic to intenselycellular. The spherical or curved ossicles are acellularor include sparsely distributed cells (Fig. 4.33). Theyshould not be confused with the cementum-like depositsthat are present in conventional ossifying fibroma.These particles have a smooth contour whereas the ossiclesin juvenile psammomatoid ossifying fibroma hasa peripheral radiating fringe of collagen fibres. Ossiclesmay coalesce to form trabeculae. Sometimes, juvenilepsammomatoid ossifying fibroma contains basophilic,concentrically lamellated particles, as well as irregularthread-like or thorn-like calcified strands in a hyalinisedbackground (Fig. 4.34). Other features such as trabeculaeof woven bone as well as lamellar bone, pseudocysticstromal degeneration and haemorrhages resulting

Maxillofacial Skeleton and Teeth Chapter 4 123Fig. 4.33. Psammomatoid ossicles in a cellular stroma characterisejuvenile psammomatoid ossifying fibroma. A comparison withFig. 4.30 shows that these particles are not as smoothly outlined asthose occurring in conventional ossifying fibromasFig. 4.35. Osseous dysplasia typically lies at the root tip. It consistsof fibrous tissue containing mineralised material of varyingappearanceFig. 4.34. Thread-like calcifications in an eosinophilic matrix arealso often present in juvenile psammomatoid ossifying fibromathe psammomatoid ossicles in juvenile psammomatoidossifying fibroma are clearly different from the acellularspherical real psammoma bodies [172].Clinically, ossifying fibroma causes expansion of thebone involved leading to a palpable swelling. Radiographically,a demarcated lesion is seen that may haveradiodense as well as radiolucent areas depending onthe various contributions of soft and hard tissue componentsto an individual lesion [13].Excision of ossifying fibromas usually yields a permanentcure.in areas similar to an aneurysmal bone cyst, multinucleategiant cells, and mitotic figures can also be observed.Juvenile psammomatoid ossifying fibroma hasthe bony walls of the paranasal sinuses as site of predilection[179].Ossifying fibroma may be confused with fibrous dysplasia.The most important distinguishing feature is thepresence of demarcation and/or encapsulation in ossifyingfibroma as opposed to the merging with its surroundingsas shown by fibrous dysplasia. In addition,the variation in cellularity as well as in appearance ofmineralised material distinguishes ossifying fibromafrom fibrous dysplasia. To distinguish ossifying fibromafrom osseous dysplasia, data on clinical presentationand radiographic appearance are indispensable (seeSect. 4.5.3).Juvenile psammomatoid ossifying fibroma has to bedifferentiated from meningioma with psammoma bodies;immunohistochemistry positive for EMA rules outjuvenile psammomatoid ossifying fibroma. Moreover,4.5.3. Osseous DysplasiaICD-O:9272/0Osseous dysplasia is a pathologic process of unknownaetiology located in the tooth-bearing jaw areas in thevicinity of the tooth apices and is thought to arise fromthe proliferation of periodontal ligament fibroblaststhat may deposit bone as well as cementum. The conditionoccurs in various clinical forms that bear differentnames. However, all have the same histomorphology:cellular fibrous tissue, trabeculae of woven as well aslamellar bone and spherules of cementum-like material(Fig. 4.35). The ratio of fibrous tissue to mineralisedmaterial may vary and it has been shown that these lesionsare initially fibroblastic, but over the course ofseveral years may show increasing degrees of calcification.This variation in ratio of soft tissue to hard tissueis reflected in the radiographic appearance; lesions arepredominantly radiolucent, predominantly radiodenseor mixed.

124 P.J. Slootweg4Fig. 4.36. Central giant cell granuloma shows osteoclast-like giantcells in a loose fibrocellular stroma. Cherubism has an identicalappearanceOsseous dysplasia lacks encapsulation or demarcation,but tends to merge with the adjacent cortical ormedullary bone [13].The several subtypes of osseous dysplasia are distinguishedby clinical and radiological features. Periapicalosseous dysplasia occurs in the anterior mandible andinvolves only a few adjacent teeth. A similar limited lesionoccurring in a posterior jaw quadrant is known asfocal osseous dysplasia [167]. Florid osseous dysplasia isnon-expansile, involves two or more jaw quadrants andoccurs in middle-aged black females [13]. Familial gigantiformcementoma is expansile, involves multiplequadrants and occurs at a young age. This type of osseousdysplasia shows an autosomal dominant inheritancewith variable expression, but sporadic cases without ahistory of familial involvement have also been reported[1, 189]. Simple bone cysts may be seen with florid andfocal osseous dysplasia [59, 62].Osseous dysplasia has to be distinguished from ossifyingfibroma. Osseous dysplasia is a mixed radiolucent-radiodenselesion with ill-defined borders in thetooth-bearing part of the jaws, either localised or occupyinglarge jaw areas depending on the type. In contrast,ossifying fibroma is usually a localised lesion thatexpands the jaw, and is predominantly radiolucent withradiodense areas [164].Osseous dysplasia also has to be differentiated fromsclerosing osteomyelitis [140]. Sclerotic lamellar bonetrabeculae and well-vascularised fibrous tissue withlymphocytes and plasma cells define sclerosing osteomyelitis,whereas cementum-like areas and fibrocellularsoft tissue are lacking [53].The various forms of osseous dysplasia do not requiretreatment unless necessitated by complications such asinfection of sclerotic bone masses, as may occur in floridosseous dysplasia, or facial deformity, as may be seenin familial gigantiform cementoma.4.6 Giant Cell LesionsCentral giant cell granuloma , cherubism and aneurysmalbone cyst all show osteoclast-like giant cells lyingin a fibroblastic background tissue. The fibroblastic tissuemay vary in cellularity from very dense to cell-poor.Mitotic figures may be encountered but are usually notnumerous and not atypical. The giant cells mostly clusterin areas of haemorrhage, but they may also lie moredispersed among the lesion (Fig. 4.36). Bone formation,if present, is usually confined to the periphery of the lesion.Radiologically, all three types of giant cell lesionshave a lucent, quite often multilocular appearance. Multiplegiant cell lesions may occur in association withNoonan’s syndrome as well as with neurofibromatosis[38, 134]. Further discussion will only include giant cellgranuloma and cherubism as they are confined to thejaws.4.6.1 Central Giant Cell GranulomaCentral giant cell granuloma is mostly seen before theage of 30. The lesion is restricted to the jaws, the mandiblebeing more often involved than the maxilla. Its aetiologyis unknown. Lesions with a histologic appearanceidentical to that of the central giant cell granuloma mayoccur in the gingiva and are called giant cell epulis (seeChap. 3). Sometimes, lesions combine the appearanceof a giant cell granuloma with that of an odontogenicfibroma [108].Clinically, central giant cell granuloma manifests itselfas a localised jaw swelling. Radiographically, it is aradiolucent lesion that may be either uni- or multilocular.As the lesion is not encapsulated, removal is sometimesfollowed by recurrence. If there is recurrence, hyperparathyroidismshould be ruled out as the brown tumoursassociated with this latter disease are identical togiant cell granulomas. Also, distinction has to be madebetween giant cell granulomas and true giant cell tumours.There has been much discussion whether giantcell granulomas with more aggressive behaviour thanusually observed could represent a gnathic manifestationof this latter lesion [4, 163].4.6.2 CherubismIn cases of cherubism, two or more jaw quadrants containlesions histologically similar to giant cell granuloma.The disease occurs in young children, often with ahistory of other afflicted family members. The geneticdefect responsible for cherubism has been localised tochromosome 4p16.3 [112].The expansion of the affected jaw areas causes the angelicface leading to the lesion’s designation: cherubism.

Maxillofacial Skeleton and Teeth Chapter 4 125With the onset of puberty, the lesions lose their activityand may mature to fibrous tissue and bone.There may also be a component consisting of immatureodontogenic tissue due to developing tooth germslying within the lesional tissue. This is a fortuitous findingwithout any clinical relevance.4.7 Neoplastic Lesionsof the Maxillofacial Bones,Non-OdontogenicTo be included in the following text, lesions should bemainly confined to the maxillofacial bones.Fig. 4.37. At high magnification, the vacuolated nature of thechordoma cells are clearly visible, as is their epithelial cohesion4.7.1 OsteomaICD-O:9180/0Osteomas are lesions composed of compact lamellarbone with sparse marrow cavities filled with fatty orfibrous tissue. In the maxillofacial skeleton, they mostcommonly occur in the frontal and ethmoid sinus; lessoften, the maxillary antrum and the sphenoid sinus areinvolved [137]. They may also occur in the jaw bones asa manifestation of Gardner’s syndrome [183].Paranasal osteomas as a group are common lesions[92]. Clinically, they cause sinusitis and headache or othersigns of sinonasal disease. Similar bony outgrowths atthe palate or mandible are called tori.4.7.2 ChordomaICD-O:9370/3Chordomas are malignant tumours derived from embryonicremnants of the notochord. The mostly occur ateither the cranial or caudal end of the vertebral column[57]. Chordomas show a slight male predominance; theymay occur at any age [57].Three different types of chordoma are discerned:conventional, chondroid, and dedifferentiated. Conventionalchordoma consists of lobules separated fromeach other by fibrous bands. These lobules containovoid cells with small, dark nuclei and homogeneouseosinophilic cytoplasm. Other cells show large vesicularnuclei and abundant cytoplasm with vacuoles.Sometimes, these cells contain only one single vacuolecausing a signet-ring appearance or vacuoles surroundingthe nucleus: these latter cells represent theso-called physaliphorous cells thought to be pathognomonicfor chordoma. In general, the cell density ismaximal at the periphery of the lobules; more centrally,the cells lose their epithelial cohesion and may lieisolated in an abundant mucoid matrix (Fig. 4.37). Althoughthere may be atypia, mitotic figures are infrequent.The lesion invades adjacent structures. Immunohistochemically,chordoma is characterised by positivityfor S-100 as well as vimentin and a broad varietyof epithelial markers [131].Chondroid chordoma (ICD-O:9371/3) denotes a variantof chordoma that contains cartilaginous areas indistinguishablefrom chondrosarcoma [57]. However,chondrocytic differentiation in chordomas probablyrepresents a focal maturation process [51]. Neitherhas the distinction between conventional and chondroidchordoma any clinical significance [29]. Therefore, it isadvocated that this designation be dropped. Dedifferentiatedchordomas are those lesions that contain areas ofchordoma as well as an additional malignant mesenchymalcomponent that may be a fibrosarcoma, an osteosarcomaor, most likely, a poorly differentiated sarcoma[64].Chordoma has to be distinguished from chondrosarcoma.Positivity for epithelial markers is a consistentfeature in chordomas and is absent in chondrosarcoma[132]. Other look-alikes, such as extraskeletal myxoidchondrosarcoma, myxoid liposarcoma and myxopapillaryependymoma, also lack positivity for epithelialmarkers [28]. Chordoid meningiomas may also mimicchordomas, but there are no physaliphorous cells, noris there positivity for cytokeratins in this meningiomasubtype [125].The differential diagnosis of chordoma should alsoinclude pleomorphic adenoma. Both lesions may showepithelial clusters as well as single cells with vacuolatedcytoplasm lying in a mucoid matrix. Moreover, positivityfor S-100, vimentin, and epithelial markers is displayedby both. Positivity for myoepithelial markers,however, is restricted to pleomorphic adenoma.Chordomas manifest by destroying adjacent structuresresulting in cranial nerve dysfunction. Rarely, theycause a swelling in the neck due to lateral growth. Theirsite precludes radical surgical treatment. Mostly, thera-

126 P.J. Slootweg4Fig. 4.38. Melanotic neuroectodermal tumour of infancy consistsof small dark cells and larger cells with vesicular nuclei. Melaninis usually associated with the latter cell populationpy consists of debulking and irradiation. Five-year survivalrate is approximately 50%. Histologic features relatedwith prognosis have not been identified [29]. Metastaticdisease is unusual [25].4.7.3 Melanotic NeuroectodermalTumour of InfancyICD-O:9363/0Cells derived from the neural crest play a major role inthe formation of the jaws and teeth. These cells are alsothought to be the source from which the melanotic neuroectodermaltumour of infancy develops [106]. Most ofthe lesions occur before the age of 1 year. The majorityof them occur in the anterior maxilla [68].The tumour shows dense fibrous stroma with nestscomposed of two different cell types: centrally placedsmall dark cells without any discernable cytoplasm andperipherally located larger cells with vesicular nucleiand ample cytoplasm with melanin pigment (Fig. 4.38)[9, 68, 113]. Maturation of the small cells to ganglioncells has been reported [144]. Although the cells may beatypical, mitotic figures are rare [9]. Sometimes, a transitionof the large cells to osteoblasts forming tiny bonytrabeculae can be observed [157]. The lesion is not encapsulated.Immunohistochemically, the large cells are positivefor a wide variety of cytokeratins, neuron-specific enolase,S-100, HMB45 and chromogranin. The small cellsshow positivity for CD56, neuron-specific enolase, synaptophysinand chromogranin [9]. This pattern can besummarised as evidence for neural, melanocytic and epithelialdifferentiation. In addition, the large cells havebeen shown to be positive for vimentin [157]. Ultrastructurally,the small cells show neurosecretory granulesand the large cells show melanosomes at differentstages of development [113].Quite often, immature odontogenic tissues form partof the material excised or biopsied, due to the early ageof occurrence and the close association of the tumourwith tooth germs. This should not be mistaken as evidenceof an odontogenic tumour. The highly characteristichistological pattern leaves no room for other differentialdiagnostic considerations.Clinically, melanotic neuroectodermal tumour of infancymanifests as a rapidly growing blue tissue mass,usually at the anterior alveolar maxillary ridge. Radiologically,bone resorption may be seen, although this isdifficult to evaluate in the delicate bony structures of theinfantile maxilla. Tooth germs are displaced and may liewithin the tumour mass. Conservative excision usuallyconstitutes adequate treatment. Recurrences have beendescribed, but metastases are exceptionally rare [113].There are no histological features predicting more aggressivebehaviour [9].References1. Abdelsayed RA, Eversole LR, Singh BS, Scarbrough FE (2001)Gigantiform cementoma: clinicopathologic presentation of 3cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod91:438–4442. Altini M, Thompson SH, Lownie JF, Berezowski BB (1985)Ameloblastic sarcoma of the mandible. J Oral MaxillofacSurg 43:789–7943. Ameerally P, McGurk M, Shaheen O (1996) Atypical ameloblastoma:report of 3 cases and a review of the literature. Br JOral Maxillofac Surg 34:235–2394. Auclair PL, Cuenin P, Kratochvil FJ, Slater LJ, Ellis GL (1988)A clinical and histomorphologic comparison of the centralgiant cell granuloma and the giant cell tumor. Oral Surg OralMed Oral Pathol 66:197–2085. August M, Faquin W, Troulis M, Kaban L (2003) Clear cellodontogenic carcinoma. Evaluation of reported cases. J OralMaxillofac Surg 61:580–6856. Baden E, Moskow BS, Moskow R (1968) Odontogenic gingivalepithelial hamartoma. J Oral Surg 26:702–7147. Badger JV, Gardner DG (1997) The relationship of adamantinomatouscraniopharyngioma to ghost cell ameloblastomaof the jaws: a histopathologic and immunohistochemicalstudy. J Oral Pathol Med 26:349–3558. Barker BF (1999) Odontogenic myxoma. Semin Diagn Pathol16:297–3019. Barrett AW, Morgan M, Ramsay AD, Farthing PM, NewmanL, Speight PM (2002) A clinicopathologic and immunohistochemicalanalysis of melanotic neuroectodermal tumor ofinfancy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod93:688–69810. Barron RP, Kainulainen VT, Forrest CR, Krafchik B, MockD, Sandor GKB (2002) Tuberous sclerosis: clinicopathologicfeatures and review of the literature. J Craniomaxillofac Surg30:361–36611. Brannon RB (1976) The odontogenic keratocyst. A clinicopathologicstudy of 312 cases. I. Clinical features. Oral SurgOral Med Oral Pathol 42:54–7212. Brannon RB (1977) The odontogenic keratocyst. A clinicopathologicstudy of 312 cases. II. Histopathologic features.Oral Surg Oral Med Oral Pathol 43:233–25513. Brannon RB, Fowler CB (2001) Benign fibro-osseous lesions:a review of current concepts. Adv Anat Pathol 8:126–14314. Brannon RB, Fowler CB, Carpenter WM, Corio RL (2002)Cementoblastoma: an innocuous neoplasm? A clinicopathologicstudy of 44 cases and review of the literature with spe-

Maxillofacial Skeleton and Teeth Chapter 4 127cial emphasis on recurrence. Oral Surg Oral Med Oral PatholOral Radiol Endod 93:311–32015. Brannon RB, Goode K, Eversole LR, Carr RF (2002) The centralgranular cell odontogenic tumor: report of 5 new cases.Oral Surg Oral Med Oral Pathol Oral Radiol Endod 94:614–62116. Braunshtein E, Vered M, Taicher S, Buchner A (2003) Clearcell odontogenic carcinoma and clear cell ameloblastoma.A single clinicopathologic entity? A new case and comparativeanalysis of the literature. J Oral Maxillofac Surg 61:1004–101017. Brinck U, Gunawan B, Schulten HJ, Pinzon W, Fischer U,Fuezesi L (2001) Clear cell odontogenic carcinoma with pulmonarymetastases resembling pulmonary meningotheliallikenodules. Virchows Arch 438:412–41718. Browne RM (1971) The odontogenic keratocyst. Histologicalfeatures and their correlation with clinical behavior. Br DentJ 131:249–25919. Buchner A (1991) The central (intraosseous) calcifying odontogeniccyst: an analysis of 215 cases. J Oral Maxillofac Surg49:330–33920. Buchner A, Merrell PW, Hansen LS, Leider AS (1991) Peripheral(extraosseous) calcifying odontogenic cyst. Oral SurgOral Med Oral Pathol 72:265–27021. Buchner A, Hansen LS (1979) The histomorphologic spectrumof the gingival cyst in the adult. Oral Surg Oral MedOral Pathol 48:523–53922. Budnick SD (1976) Compound and complex odontomas.Oral Surg Oral Med Oral Pathol 42:501–50623. Calvo N, Alonso D, Prieto M, Junquera L (2002) Centralodontogenic fibroma granular cell variant: a case report andreview of the literature. J Oral Maxillofac Surg 60:1192–119424. Cataldo E, Berkman MD (1968) Cysts of the oral mucosa innewborns. Am J Dis Child 16:44–4825. Chambers PW, Schwinn CP (1979) Chordoma. A clinicopathologicstudy of metastasis. Am J Clin Pathol 72:765–77626. Chehade A, Daley TD, Wysocki GP, Miller AS (1994) Peripheralodontogenic keratocyst. Oral Surg Oral Med Oral Pathol77:494–49727. Cheng YSL, Wright JM, Walstad WR, Finn MD (2002) Calcifyingepithelial odontogenic tumor showing microscopicfeatures of potential malignant behavior. Oral Surg OralMed Oral Pathol Oral Radiol Endod 93:287–29528. Coffin CM, Swanson PE, Wick MR, Dehner LP (1993) An immunohistochemicalcomparison of chordoma with renal cellcarcinoma, colorectal adenocarcinoma, and myxopapillaryependymoma: a potential diagnostic dilemma in the diminutivebiopsy. Mod Pathol 6:531–53829. Colli B, Al-Mefty O (2001) Chordomas of the craniocervicaljunction: follow-up review and prognostic factors. J Neurosurg95:933–94330. Corio RL, Goldblatt LI, Edwards, PA, Hartman KS (1987)Ameloblastic carcinoma: a clinicopathologic study and assessmentof eight cases. Oral Surg Oral Med Oral Pathol64:570–57631. Dal-Cin PD, Sciot R, Fossion E, Damme B van, Berghe H vanden (1993) Chromosome abnormalities in cementifying fibroma.Cancer Genet Cytogenet 71:170–17232. Daley TD, Wysocki GP (1994) Peripheral odontogenic fibroma.Oral Surg Oral Med Oral Pathol 78:329–33633. Daley TD, Wysocki GP (1995) The small dentigerous cyst.Oral Surg Oral Med Oral Pathol Oral Radiol Endod 79:77–8134. Daley TD, Wysocki GP, Pringle GA (1994) Relative incidenceof odontogenic tumors and oral and jaw cysts in a Canadianpopulation. Oral Surg Oral Med Oral Pathol 77:276–28035. Deron PB, Nikolovski N, Hollander JC den, Spoelstra HA,Knegt PP (1996) Myxoma of the maxilla; a case with extremelyaggressive biologic behavior. Head Neck 18:459–46436. Dhir K, Sciubba J, Tufano RP (2003) Case report. Ameloblasticcarcinoma of the maxilla. Oral Oncol 39:736–74137. Dunlap CL (1999) Odontogenic fibroma. Semin Diagn Pathol16:293–29638. Dunlap C, Neville B, Vickers RA, O’Neil D, Barker B (1989)The Noonan syndrome/cherubism association. Oral SurgOral Med Oral Pathol 67:698–70539. Ebata K, Takeshi U, Tohnai I, Kaneda T (1992) Chondrosarcomaand osteosarcoma arising in polyostotic fibrous dysplasia.J Oral Maxillofac Surg 50:761–76440. El-Mofty SK (2002) Psammomatoid and trabecular juvenileossifying fibroma of the craniofacial skeleton: two distinctclinicopathologic entities. Oral Surg Oral Med Oral PatholOral Radiol Endod 93:296–30441. Elzay RP (1982) Primary intraosseous carcinoma of the jaws.Review and update of odontogenic carcinomas. Oral SurgOral Med Oral Pathol 54:299–30342. Eversole LR (1999) Malignant epithelial odontogenic tumors.Semin Diagn Pathol 16:317–32443. Eversole LR, Duffey DC, Powell NB (1995) Clear cell odontogeniccarcinoma. A clinicopathologic analysis. Arch OtolaryngolHead Neck Surg 121:685–68944. Eversole LR, Sabes WR, Rovin S (1972) Fibrous dysplasia: anosologic problem in the diagnosis of fibro-osseous lesions ofthe jaws. J Oral Pathol 1:180–22045. Fowler CB, Brannon RB (1989) The paradental cyst: a clinicopathologicstudy of six new cases and review of the literature.J Oral Maxillofac Surg 47:243–24846. Friedrich RE, Siegert J, Donath K, Jäkel KT (2001) Recurrentameloblastic fibro-odontoma in a 10-year-old boy. J OralMaxillofac Surg 59:1362–136647. Gardner DG (1996) Some current concepts on the pathologyof ameloblastomas. Oral Surg Oral Med Oral Pathol Oral RadiolEndod 82:660–66948. Gardner DG, Morency R (1993) The glandular odontogeniccyst; a rare lesion that tends to recur. J Can Dent Assoc59:929–93049. Gollin SM, Storto PD, Malone PS, Barnes L, Washington JA,Chidambaram A, Janecka IP (1992) Cytogenetic abnormalitiesin an ossifying fibroma from a patient with bilateral retinoblastoma.Genes Chromosomes Cancer 4:146–15250. Gorlin RJ, Goltz RW (1960) Multiple nevoid basal cell epithelioma,jaw cysts and bifid rib. A syndrome. N Engl J Med262:908–91251. Gottschalk D, Fehn M, Patt S, Saeger W, Kirchner T, AignerT (2001) Matrix gene expression analysis and cellular phenotypingin chordoma reveals focal differentiation pattern ofneoplastic cells mimicking nucleus pulposus development.Am J Pathol 158:1571–157852. Greer RO, Johnson M (1988) Botryoid odontogenic cyst:clinicopathologic analysis of ten cases with three recurrences.J Oral Maxillofac Surg 46:574–57953. Groot RH, Merkesteyn JPR van, Bras J (1996) Diffuse sclerosingosteomyelitis and florid osseous dysplasia. Oral SurgOral Med Oral Pathol Oral Radiol Endod 81:333–34254. Gurol M. Burkes EJ, Jacoway J (1995) Botryoid odontogeniccyst: analysis of 33 cases. J Periodontol 66:1069–107355. Handlers JP, Abrams AM, Melrose RJ, Danfort R (1991) Centralodontogenic fibroma. Clinicopathologic features of 19cases and review of the literature. J Oral Maxillofac Surg49:46–5456. Hansen LS, Eversole LR, Green TL, Powell NB (1985) Clearcell odontogenic tumor – a new histologic variant with aggressivepotential. Head Neck Surg 8:115–12357. Heffelfinger MJ, Dahlin DC, MacCarry CS, Beabout JW(1973) Chordomas and cartilaginous tumors at the skullbase. Cancer 32:410–42058. Hicks MJ, Flaitz CM, Wong ME, McDaniel RK, Cagle PT(1994) Clear cell variant of calcifying epithelial odontogenictumor: case report and review of the literature. Head Neck16:272–27759. Higuchi Y, Nakamura N, Tashiro H (1988) Clinicopathologicstudy of cemento-osseous dysplasia producing cysts of themandible – report of four cases. Oral Surg Oral Med OralPathol 65:339–34260. Hirschberg A, Dayan D, Horowitz I (1987) Dentinogenicghost cell tumor. Int J Oral Maxillofac Surg 16:620–625

128 P.J. Slootweg461. Hirschberg A, Kaplan I, Buchner A (1994) Calcifying odontogeniccyst associated with odontoma: a possible separateentity (odontocalcifying odontogenic cyst). J Oral MaxillofacSurg 52:555–55862. Horner K, Forman GH (1988) Atypical simple bone cysts ofthe jaws. II. A possible association with benign fibro-osseous(cemental) lesions of the jaws. Clin Radiol 39:59–6363. Houston GD, Fowler CB (1997) Extraosseous calcifying epithelialodontogenic tumor. Report of two cases and review ofthe literature. Oral Surg Oral Med Oral Pathol Oral RadiolEndod 83:577–58364. Hruban RH, May M, Marcove RC, Huvos AG (1990) Lumbosacralchordoma with high-grade malignant cartilaginousand spindle cell components. Am J Surg Pathol 14:384–38965. Ide F, Saito I (2003) Letter to the editor. Many faces of odontogenickeratocyst. Oral Oncol 39:204–20566. Ide F, Sakshita H, Kusama K (2002) Ameloblastomatoid, centralodontogenic fibroma: an epithelium-rich variant. J OralPathol Med 31:612–61467. Johnson LM, Sapp JP, McIntire DN (1994) Squamous cellcarcinoma arising in a dentigerous cyst. J Oral MaxillofacSurg 52:987–99068. Kapadia SB, Frisman DM, Hitchcock CL, Popek EJ (1993)Melanotic neuroectodermal tumor of infancy. Clinicopathological,immunohistochemical, and flow cytometric study.Am J Surg Pathol 17:566–57369. Kenney JN, Kaugars GE, Abbey LM (1989) Comparison betweenthe peripheral ossifying fibroma and peripheral odontogenicfibroma. J Oral Maxillofac Surg 47:378–38270. Khanna JN, Andrade NN (1993) Giant ossifying fibroma.Case report on a bimaxillary presentation. Int J Oral MaxillofacSurg 21:233–23571. Kim J, Ellis GL (1993) Dental follicular tissue: misinterpretationas odontogenic tumors. J Oral Maxillofac Surg 51:762–76772. Kimonis VE, Goldstein AM, Pastakia B, Yang ML, Kase R,DiGiovanna JJ, Bale AE, Bale SJ (1997) Clinical manifestationsin 105 patients with nevoid basal cell syndrome. Am JMed Genet 69:299–30873. Kramer IRH, Pindborg JJ, Shear M (1992) Histological typingof odontogenic tumours, 2nd edn. Springer, Berlin HeidelbergNew York, pp 10–4274. Kratochvil FJ, Brannon RB (1993) Cartilage in the walls ofodontogenic keratocysts. J Oral Pathol Med 22:282–28575. Kumar M, Fasanmade A, Barrett AW, Mack G, Newman L,Hyde NC (2003) Metastasising clear cell odontogenic carcinoma:a case report and review of the literature. Oral Oncol39:190–19476. Kunze E, Donath K, Luhr HG, Engelhardt W, DeVivie R(1985) Biology of metastasizing ameloblastoma. Pathol ResPract 180:526–53577. Laughlin EH (1989) Metastasizing ameloblastoma. Cancer64:776–78078. Ledesma CM, Taylor AM, Romero de Leon E, Piedra GarzaM de la, Jaukin PG, Robertson JP (1993) Adenomatoid odontogenictumour with features of calcifying epithelial odontogenictumour. (The so-called combined epithelial odontogenictumour.) Clinico-pathological report of 12 cases. OralOncol Eur J Cancer 29B:221–22479. Leider AS, Jonker LA, Cook HE (1989) Multicentric familialsquamous odontogenic tumor. Oral Surg Oral Med OralPathol 68:175–18180. Levy BA (1973) Ghost cells and odontomas. Oral Surg OralMed Oral Pathol 36:851–85581. Li TJ, Yu SF (2003) Clinicopathologic spectrum of the socalledcalcifying odontogenic cysts. A study of 21 intraosseouscases with reconsideration of the terminology and classification.Am J Surg Pathol 27:372–38482. Lombardi T, Lock C, Samson J, Odell EW (1995) S100, α-smooth muscle actin and cytokeratin 19 immunohistochemistryin odontogenic and soft tissue myxomas. J Clin Pathol48:759–76283. Lopez-Rios F, Lassaletta-Atienza L, Domingo-Carrasco C,Martinez-Tello FJ (1997) Nasolabial cyst: report of a casewith extensive apocrine change. Oral Surg Oral Med OralPathol Oral Radiol Endod 84:404–40684. Lu Y, Mock D, Takata T, Jordan RC (1999) Odontogenic ghostcell carcinoma: report of four new cases and review of the literature.J Oral Pathol Med 28:323–32985. Lukinmaa PL, Hietanen J, Anttinen J, Ahonen P (1990) Contiguousenlarged dental follicles with histologic features resemblingthe WHO type of odontogenic fibroma. Oral SurgOral Med Oral Pathol 70:313–31786. MacLeod RI, Fanibunda KB, Soames JV (1985) A pigmentedodontogenic keratocyst. Br J Oral Maxillofac Surg 23:216–21987. MacLeod RI, Soames JV (1988) Squamous cell carcinoma inan odontogenic keratocyst. Br J Oral Maxillofac Surg 26:52–5788. Magnusson B, Borrman H (1995) The paradental cyst: a clinicopathologicstudy of 26 cases. Swed Dent J 19:1–789. Maiorano E, Altini M, Viale G, Piatelli A, Favia G (2001)Clear cell odontogenic carcinoma. Report of two cases andreview of the literature. Am J Clin Pathol 116:107–11490. Makowski GJ, McGuff S, Sickels JE van (2001) Squamouscell carcinoma in a maxillary odontogenic keratocyst. J OralMaxillofac Surg 59:76–8091. Manojlovic S, Grguveric J, Knezevic G, Kruslin B (1997)Glandular odontogenic cyst: a case report and clinicopathologicanalysis of the relationship to central mucoepidermoidcarcinoma. Head Neck 19:227–23192. Mehta BS, Grewal GS (1963) Osteoma of the paranasal sinusesalong with a case of an orbito-ethmoid osteoma. J LaryngolOtol 77:601–61093. Miller R, Longo J, Houston G (1988) Surgical ciliated cyst ofthe maxilla. J Oral Maxillofac Surg 46:310–32294. Monteleone L, McLellan MS (1964) Epstein’s pearls (Bohn’snodules) of the palate. J Oral Surg 22:301–30495. Morgan PR, Johnson NW (1974) Histological, histochemicaland ultrastructural studies on the nature of hyaline bodies inodontogenic cysts. J Oral Pathol 3:127–14796. Mosby EL, Russell D, Noren S, Barker BF (1998) Ameloblasticfibroma in a 7-week-old infant; a case report and review ofthe literature. J Oral Maxillofac Surg 56:368–37297. Mosqueda-Taylor A, Carlos-Bregni R, Ramirez-Amador V,Palma-Guzman JM, Esquivel-Bonilla D, Hernandez-RojasLA (2002) Odontoameloblastoma. Clinico-pathologic studyof three cases and critical review of the literature. Oral Oncol38:800–80598. Muller S, Parker DC, Kapadia SB, Budnick SD, Barnes L(1995) Ameloblastic fibrosarcoma of the jaws. A clinicopathologicand DNA analysis of five cases and review of the literaturewith discussion of its relationship to ameloblastic fibroma.Oral Surg Oral Med Oral Pathol Oral Radiol Endod79:469–47799. Müller H, Slootweg PJ (1985) The growth characteristics ofmultilocular ameloblastomas. A histological investigationwith some inferences with regard to operative procedures. JMaxillofac Surg 13:224–230100. Müller H, Slootweg PJ (1986) Clear cell differentiation in anameloblastoma. J Maxillofac Surg 14:158–160101. Müller H, Slootweg PJ (1988) A peculiar finding in Le Fort Iosteotomy. J Craniomaxillofac Surg 16:238–239102. Muzio LL, Nocini PF, Favia G, Procaccini M, Mignogna MD(1996) Odontogenic myxoma of the jaws. A clinical, radiologic,immunohistochemical, and ultrastructural study. OralSurg Oral Med Oral Pathol Oral Radiol Endod 82:426–433103. Nastri AL, Wiesenfeld D, Radden BG, Eveson J, Scully C(1995) Maxillary ameloblastoma: a retrospective study of 13cases. Br J Oral Maxillofac Surg 33:28–32104. Newman L, Howells GL, Coghlan KM, DiBase A, WilliamsDM (1995) Malignant ameloblastoma revisited. Br J OralMaxillofac Surg 33:47–50105. Ng KH, Siar CH (2003) Odontogenic keratocyst with dentinoidformation. Oral Surg Oral Med Oral Pathol Oral RadiolEndod 95:601–606106. Nitta T, Endo T, Tsunoda A, Kadota Y, Matsumoto T, Sato K(1995) Melanotic neuroectodermal tumor of infancy: a molecularapproach to diagnosis. J Neurosurg 83:145–148

Maxillofacial Skeleton and Teeth Chapter 4 129107. Nxumalo TN, Shear M (1992) Gingival cysts in adults. J OralPathol Med 21:309–313108. Odell EW, Lombardi T, Barrett AW, Morgan PR, SpeightPM (1997) Hybrid central giant cell granuloma and centralodontogenic fibroma-like lesions of the jaws. Histopathology30:165–171109. Odukoya O (1995) Odontogenic tumors: analysis of 289 Nigeriancases. J Oral Pathol Med 24:454–457110. Okada Y, Mochizuki K, Sigimural M, Noda Y, Mori M (1987)Odontogenic tumor with combined characteristics of adenomatoidodontogenic and calcifying epithelial odontogenictumors. Pathol Res Pract 182:647–657111. Paulus W, Stöckel C, Krauss J, Sörensen N, Roggendorf W(1997) Odontogenic classification of craniopharyngiomas:a clinicopathological study of 54 cases. Histopathology30:172–176112. Petschler M, Stiller M, Hoffmeister B,Witkowski R, Opitz C,Bill JS, Peters H (2003) Klinische und molekulargenetischeBefunde bei Familien mit Cherubismus über 3 Generationen.Mund Kiefer Gesichtschir 7:83–87113. Pettinato G, Manivel C, d’Amore ES, Jaszcz W, Gorlin RJ(1991) Melanotic neuroectodermal tumor of infancy. A reexaminationof a histogenesis problem based on immunohistochemical,flow cytometric, and ultrastructural study of 10cases. Am J Surg Pathol 15:233–245114. Philipsen HP (1956) Om keratocystes (kolesteatomer). I Kaeberne,Tandlaegebladet 60:963–980115. Philipsen HP, Reichart PA (1998) Unicystic ameloblastoma.A review of 193 cases from the literature. Oral Oncol 34:317–325116. Philipsen HP, Reichart PA (2000) Calcifying epithelial odontogenictumour: biological profile based on 181 cases fromthe literature. Oral Oncol 36:17–26117. Philipsen HP, Reichart PA, Nikai H, Takata T, Kudo Y (2001)Peripheral ameloblastoma: biological profile based on 160cases from the literature. Oral Oncol 37:17–27118. Philipsen HP, Reichart PA, Praetorius F (1997) Mixed odontogenictumours and odontomas. Considerations on interrelationship.Review of the literature and presentation of 134cases of odontomas. Oral Oncol 33:86–99119. Philipsen HP, Reichart PA, Takata T (2001) Desmoplasticameloblastoma (including “hybrid” lesion of ameloblastoma).Biological profile based on 100 cases from the literatureand own files. Oral Oncol 37:455–460120. Philipsen HP, Reichart PA, Zhang KH, Nikai AH, Yu QX(1991) Adenomatoid odontogenic tumor: biologic profilebased on 499 cases. J Oral Pathol Med 20:149–158121. Piatelli A, Rubini C, Goteri G, Fioroni M, Maiorano E (2003)Case report. Central granular cell odontogenic tumour. Reportof the first malignant case and review of the literature.Oral Oncol 39:78–82122. Piecuch JF, Eisenberg E, Segal D, Carlson R (1980) Respiratoryepithelium as an integral part of an odontogenic keratocyst:report of a case. J Oral Surg 38:445–447123. Pollandt K, Engels C, Kaiser E, Werner M, Delling G (2001)Gsα gene mutations in monostotic fibrous dysplasia of boneand fibrous dysplasia-like low-grade central osteosarcoma.Virchows Arch 439:170–175124. Praetorius F, Hjorting-Hansen E, Gorlin RJ, Vickers RA(1981) Calcifying odontogenic cyst. Range, variations andneoplastic potential. Acta Odontol Scand 39:227–240125. Radner H, Katenkamp D, Reifenberger G, Deckert M, PietschT, Wiestler OD (2001) New developments in the pathologyof skull base tumors. Virchows Arch 438:321–335126. Ramer M, Montazem A, Lane SL, Lumerman H (1997) Glandularodontogenic cyst. Report of a case and review of the literature.Oral Surg Oral Med Oral Pathol Oral Radiol Endod84:54–57127. Regezi JA, Kerr DA, Courtney RM (1978) Odontogenic tumors:analysis of 706 cases. J Oral Surg 36:771–778128. Reichart PA, Philipsen HP (2003) Entzündliche paradentaleZyste. Bericht von 6 Fällen. Mund Kiefer Gesichtschir 7:171–174129. Reichart PA, Philipsen HP (2003) Revision der WHO-Klassifikationodontogener Tumoren von 1992. Ein Vorschlag.Mund Kiefer Gesichtschir 7:88–93130. Reichart PA, Philipsen HP, Sonner S (1995) Ameloblastoma:biological profile of 3677 cases. Oral Oncol Eur J Cancer31B:86–99131. Rosenberg AE, Brown GA, Bhan AK, Lee JM (1994) Chondroidchordoma – a variant of chordoma. A morphologic andimmunohistochemical study. Am J Clin Pathol 101:36–41132. Rosenberg AE, Nielsen GP, Keel SB, Renard LG, Fitzek, MunzenderJE, Liebsch NJ (1999) Chondrosarcoma of the base ofthe skull: a clinicopathologic study of 200 cases with emphasison its distinction from chordoma. Am J Surg Pathol23:1370–1378133. Rosenstein T, Pogrel MA, Smith RA, Regezi JA (2001) Cysticameloblastoma – behavior and treatment of 21 cases. J OralMaxillofac Surg 59:1311–1316134. Ruggieri M, Pavone V, Polizzi A, Albanese S, Magro G, MerinoM, Duray PH (1999) Unusual form of recurrent giantcell granuloma of the mandible and lower extremities in apatient with neurofibromatosis type 1. Oral Surg Oral MedOral Pathol Oral Radiol Endod 87:67–72135. Saied-Al-Naief NAH, Lumerman H, Ramer M, Kopp W,Kringstein GJ, Persenchino F, Torno R (1997) keratoameloblastomaof the maxilla. A case report and review of the literature.Oral Surg Oral Med Oral Pathol Oral Radiol Endod84:535–539136. Saito Y, Hoshina Y, Nagamine T, Nakajima T, Suzuki M,Hayashi T (1992) Simple bone cyst. A clinical and histopathologicstudy of fifteen cases. Oral Surg Oral Med Oral Pathol74:487–491137. Samy LL, Mostafa H (1971) Osteomata of the nose and paranasalsinuses with a report of twenty-one cases. J LaryngolOtol 85:449–469138. Sawyer JR, Tryka AF, Bell JM, Boop FA (1995) Nonrandomchromosome breakpoints at Xq26 and 2q33 characterize cemento-ossifyingfibromas of the orbit. Cancer 76:1853–1859139. Schafer DR, Thompson LD, Smith BC, Wenig BM (1998) Primaryameloblastoma of the sinonasal tract: a clinicopathologicstudy of 24 cases. Cancer 82:667–674140. Schneider LC, Mesa LM (1990) Differences between floridosseous dysplasia and chronic diffuse sclerosing osteomyelitis.Oral Surg Oral Med Oral Pathol 70:308–312141. Schneider LC, Mesa ML, Fraenkel D (1988) Osteoporoticbone marrow defect: radiographic features and pathogenicfactors. Oral Surg Oral Med Oral Pathol 65:127–129142. Schwartz-Arad D, Lustmann J, Ulmansky M (1990) Squamousodontogenic tumor. Review of the literature and casereport. Int J Oral Maxillofac Surg 19:327–330143. Scott J, Wood GD (1989) Aggressive calcifying odontogeniccyst – a possible variant of ameloblastoma. Br J Oral MaxillofacSurg 27:53–59144. Shah RV, Jambhekhar NA, Rana DN, Raje NS, AlbuqurqueKV, Mistry RC, Desai PB, Advani SH (1994) Melanotic neuroectodermaltumor of infancy: report of a case with ganglionicdifferentiation. J Surg Oncol 55:65–68145. Sharpe PT (2001) Neural crest and tooth morphogenesis.Adv Dent Res 15:4–7146. Shear M (1992) Cysts of the oral regions, 3rd edn. Wright,Oxford, p 6147. Shear M (2002) The aggressive nature of the odontogenickeratocyst: is it a benign cystic neoplasm? I. Clinical and earlyexperimental evidence of aggressive behaviour. Oral Oncol38:219–226148. Shear M (2002) The aggressive nature of the odontogenickeratocyst: is it a benign cystic neoplasm? II. Proliferationand genetic studies. Oral Oncol 38:323–331149. Shear M (2002) The aggressive nature of the odontogenickeratocyst: is it a benign cystic neoplasm? III. Immunocytochemistryof cytokeratin and other epithelial markers. OralOncol 38:407–415150. Shear M, Pindborg JJ (1975) Microscopic features of the lateralperiodontal cyst. Scand J Dent Res 83:103–110

130 P.J. Slootweg4151. Simko EJ, Brannon RB, Eibling DE (1998) Ameloblastic carcinomaof the mandible. Head Neck 20:654–659152. Slater LJ (1999) Odontogenic sarcoma and carcinosarcoma.Semin Diagn Pathol 16:325–332153. Slootweg PJ (1981) An analysis of the interrelationship of themixed odontogenic tumors – ameloblastic fibroma, ameloblasticfibro-odontoma, and the odontomas. Oral Surg OralMed Oral Pathol 51:266–276154. Slootweg PJ (1987) Carcinoma arising from reduced enamelepithelium. J Oral Pathol 16:479–482155. Slootweg PJ (1991) Bone and cementum as stromal featuresin Pindborg tumor. J Oral Pathol Med 20:93–95156. Slootweg PJ (1992) Cementoblastoma and osteoblastoma: acomparison of histologic features. J Oral Pathol Med 21:385–389157. Slootweg PJ (1992) Heterologous tissue elements in melanoticneuroectodermal tumor of infancy. J Oral Pathol Med21:90–92158. Slootweg PJ (1996) Maxillofacial fibro-osseous lesions: classificationand differential diagnosis. Semin Diagn Pathol13:104–112159. Slootweg PJ (2002) Malignant odontogenic tumors; an overview.Mund Kiefer Gesichtschir 6:295–302160. Slootweg PJ, Müller H (1983) Central fibroma of the jaw,odontogenic or desmoplastic. Oral Surg Oral Med OralPathol 56:61–70161. Slootweg PJ, Wittkampf ARM (1986) Myxoma of the jaws.An analysis of 15 cases. J Maxillofac Surg 14:46–52162. Soames JV (1982) A pigmented calcifying odontogenic cyst.Oral Surg Oral Med Oral Pathol 53:395–400163. Stolovitzky JP, Waldron CA, McConnel FMS (1994) Giantcell lesions of the maxilla and paranasal sinuses. Head Neck16:143–148164. Su L, Weathers DR, Waldron CA (1997) Distinguishing featuresof focal cemento-osseous dysplasias and cemento-ossifyingfibromas. II. A clinical and radiologic spectrum of 316cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod84:540–549165. Suarez PA, Batsakis JG, El-Naggar AJ (1996) Pathology consultation.Don’t confuse dental soft tissues with odontogenictumors. Ann Otol Rhinol Laryngol 105:490–494166. Suljak JP, Bohay RN, Wysocki GP (1998) Lateral periodontalcyst: a case report and review of the literature. J Can Dent Assoc64:58–51167. Summerlin DJ, Tomich CE (1994) Focal cemento-osseousdysplasia: a clinicopathologic study of 221 cases. Oral SurgOral Med Oral Pathol 78:611–620168. Swanson KS, Kaugars GE, Gunsolley JC (1991) Nasopalatineduct cyst: an analysis of 334 cases. J Oral Maxillofac Surg49:268–271169. Takahashi H, Fujita S, Okabe H (1991) Immunohistochemicalinvestigation in odontogenic myxoma. J Oral Pathol Med20:114–119170. Takeda Y (1999) Review. Ameloblastic fibroma and relatedlesions: current pathologic concept. Oral Oncol 35:535–540171. Thesleff I, Keränen S, Jernvall J (2001) Enamel knots as signalingcenters linking tooth morphogenesis and odontoblastdifferentiation. Adv Dent Res 15:14–18172. Thompson LD, Gyure KA (2000) Extracranial sinonasal tractmeningiomas: a clinicopathologic study of 30 cases with reviewof the literature. Am J Surg Pathol 24:640–650173. Toida M (1998) So-called calcifying odontogenic cyst: reviewand discussion on the terminology and classification. J OralPathol Med 27:49–52174. Tomich CE (1999) Benign mixed odontogenic tumors. SeminDiagn Pathol 16:308–316175. Venness MJ, Morgan G, Collins AP (2001) Calcifying epithelialodontogenic (Pindborg) tumor with malignant transformationand metastatic spread. Head Neck 23:692–696176. Villiers Slabbert H de, Altini M (1991) Peripheral odontogenicfibroma: a clinicopathologic study. Oral Surg Oral MedOral Pathol 72:86–90177. Waldron CA, Koh ML (1990) Central mucoepidermoid carcinomaof the jaws: report of four cases with analysis of theliterature and discussion of the relationship to mucoepidermoid,sialodontogenic and glandular odontogenic cysts. JOral Maxillofac Surg 48:871–877178. Warter A, George-Diolombi G, Chazal M, Ango A (1990)Melanin in a dentigerous cyst and associated adenomatoidodontogenic tumor. Cancer 66:786–788179. Wenig BM, Vinh TN, Smirniotopoulos JG, Fowler CB, HoustonGD, Heffner DK (1995) Aggressive psammomatoid ossifyingfibromas of the sinonasal region: a clinicopathologicstudy of a distinct group of fibro-osseous lesions. Cancer76:1155–1165180. Wesley RK, Scannel T, Nathan LE (1984) Nasolabial cyst:presentation of a case with a review of the literature. J OralMaxillofac Surg 42:188–192181. World Health Organization Classification of Tumours (2005)Pathology and genetics of tumours of the head and neck.IARC, Lyon182. Williams TP, Connor FA Jr (1994) Surgical managementof the odontogenic keratocyst: aggressive approach. J OralMaxillofac Surg 52:964–966183. Williams SC, Peller PJ (1994) Gardner’s syndrome. Case reportand discussion of the manifestations of the disorder.Clin Nucl Med 19:668–670184. Wilson D, Walker M, Aurora N, Moore S (2001) Ameloblastomawith mucous cell differentiation. Oral Surg Oral MedOral Pathol Oral Radiol Endod 91:576–578185. Woolgar JA, Rippin JW, Browne RM (1987) A comparativehistological study of odontogenic keratocysts in basal cellnaevus syndrome and non-syndrome patients. J Oral Pathol16:75–80186. Woolgar JA, Rippin JW, Browne RM (1987) The odontogenickeratocyst and its occurrence in the nevoid basal cell carcinomasyndrome. Oral Surg Oral Med Oral Pathol 64:727–730187. Wright JM (1979) Squamous odontogenic tumorlike proliferationsin odontogenic cysts. Oral Surg Oral Med Oral Pathol47:354–358188. Wright JM (1981) The odontogenic keratocyst: orthokeratinizedvariant. Oral Surg Oral Med Oral Pathol 51:609–618189. Young SK, Markowitz NR, Sullivan S, Seale TW, Hirschi R(1989) Familial gigantiform cementoma: classification andpresentation of a large pedigree. Oral Surg Oral Med OralPathol 68:740–747190. Zwetyenga N, Pinsolle J, Rivel J, Majoufre-Lefebvre C, FaucherA, Pinsolle V (2001) Primary intraosseous carcinoma ofthe jaws. Arch Otolaryngol Head Neck Surg 127:794–797

Chapter 5Major and MinorSalivary GlandsS. Di Palma · R.H.W. Simpson · A. Skalova · I. Leivo5Contents5.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . 1325.1.1 Normal Salivary Glands . . . . . . . . . . . . . . . . . 1325.1.2 Developmental Disorders . . . . . . . . . . . . . . . . 1325.2 Obstructive Disorders . . . . . . . . . . . . . . . . . . 1325.2.1 Mucus Escape Reaction . . . . . . . . . . . . . . . . . . 1325.2.2 Chronic Sclerosing Sialadenitisof the Submandibular Gland (Küttner Tumour) . . . 1335.3. Infections . . . . . . . . . . . . . . . . . . . . . . . . . . 1335.3.1 Bacteria, Fungi . . . . . . . . . . . . . . . . . . . . . . . 1335.3.2 Viruses . . . . . . . . . . . . . . . . . . . . . . . . . . . 1335.4 Miscellaneous Inflammatory Disorders . . . . . . . . 1335.5 Miscellaneous Non-Inflammatory Disorders . . . . . 1335.5.1 Necrotising Sialometaplasia(Salivary Gland Infarction) . . . . . . . . . . . . . . . 1335.5.2 Sialadenosis . . . . . . . . . . . . . . . . . . . . . . . . 1335.5.3 Adenomatoid Hyperplasiaof Mucous Salivary Glands . . . . . . . . . . . . . . . . 1345.5.4 Irradiation Changes . . . . . . . . . . . . . . . . . . . . 1345.5.5 Tissue ChangesFollowing Fine Needle Aspiration . . . . . . . . . . . 1345.6 Oncocytic Lesions . . . . . . . . . . . . . . . . . . . . . 1345.6.1 Focal and Diffuse Oncocytosis . . . . . . . . . . . . . 1345.6.2 Ductal Oncocytosis . . . . . . . . . . . . . . . . . . . . 1345.6.3 Multifocal Nodular Oncocytic Hyperplasia . . . . . . 1355.7 Cysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1355.7.1 Salivary Polycystic Dysgenetic Disease . . . . . . . . . 1355.7.2 Mucoceles . . . . . . . . . . . . . . . . . . . . . . . . . 1355.7.3 Simple Salivary Duct Cysts . . . . . . . . . . . . . . . 1355.7.4 Lymphoepithelial Cystic Lesions . . . . . . . . . . . . 1355.7.4.1 Benign Lymphoepithelial Cyst . . . . . . . . . . . . . 1355.7.4.2 Cystic Lymphoid Hyperplasia of AIDS . . . . . . . . . 1365.7.5 Sclerosing Polycystic Sialadenopathy(Sclerosing Polycystic Adenosis) . . . . . . . . . . . . 1365.7.6 Other Cysts . . . . . . . . . . . . . . . . . . . . . . . . . 1375.8 Benign Tumours . . . . . . . . . . . . . . . . . . . . . . 1375.8.1 Pleomorphic Adenoma . . . . . . . . . . . . . . . . . . 1375.8.1.1 Salivary Gland Anlage Tumour(“Congenital Pleomorphic Adenoma”) . . . . . . . . . 1405.8.2 Benign Myoepithelioma . . . . . . . . . . . . . . . . . 1405.8.3 Basal Cell Adenoma . . . . . . . . . . . . . . . . . . . . 1415.8.4 Warthin’s Tumour . . . . . . . . . . . . . . . . . . . . . 1425.8.5 Oncocytoma . . . . . . . . . . . . . . . . . . . . . . . . 1435.8.6 Canalicular Adenoma . . . . . . . . . . . . . . . . . . 1435.8.7 Sebaceous Adenoma . . . . . . . . . . . . . . . . . . . 1445.8.8 Sebaceous Lymphadenoma . . . . . . . . . . . . . . . . 1445.8.9 Ductal Papilloma . . . . . . . . . . . . . . . . . . . . . 1445.8.10 Cystadenoma . . . . . . . . . . . . . . . . . . . . . . . . 1445.9 Malignant Epithelial Tumours . . . . . . . . . . . . . 1445.9.1 Acinic Cell Carcinoma . . . . . . . . . . . . . . . . . . 1445.9.2 Mucoepidermoid Carcinoma . . . . . . . . . . . . . . 1465.9.3 Adenoid Cystic Carcinoma . . . . . . . . . . . . . . . 1475.9.4 Polymorphous Low-Grade Adenocarcinoma . . . . . 1485.9.4.1 Cribriform Adenocarcinoma of the Tongue . . . . . . 1495.9.5 Epithelial-Myoepithelial Carcinoma . . . . . . . . . . 1505.9.6 Hyalinising Clear Cell Carcinoma . . . . . . . . . . . 1515.9.7 Basal Cell Adenocarcinoma . . . . . . . . . . . . . . . 1515.9.8 Myoepithelial Carcinoma(Malignant Myoepithelioma) . . . . . . . . . . . . . . 1525.9.9 Salivary Duct Carcinoma . . . . . . . . . . . . . . . . 1545.9.10 Oncocytic Carcinoma . . . . . . . . . . . . . . . . . . 1555.9.11 Malignancy in Pleomorphic AdenomaMalignant Mixed Tumour . . . . . . . . . . . . . . . . 1565.9.11.1 Carcinoma (True Malignant Mixed Tumour)Ex Pleomorphic Adenoma . . . . . . . . . . . . . . . . 1565.9.11.2 Carcinosarcoma Ex Pleomorphic Adenoma . . . . . . 1575.9.11.3 Metastasising Pleomorphic Adenoma . . . . . . . . . 1575.9.12 Sebaceous Carcinoma . . . . . . . . . . . . . . . . . . . 1585.9.13 Lymphoepithelial Carcinoma . . . . . . . . . . . . . . 1585.9.14 Small Cell Carcinoma . . . . . . . . . . . . . . . . . . . 1585.9.15 Higher Grade Change in Carcinomas . . . . . . . . . 1595.9.16 Metastatic Malignancies . . . . . . . . . . . . . . . . . 1595.10 Hybrid Carcinoma . . . . . . . . . . . . . . . . . . . . 1605.11 Endodermal Sinus Tumour . . . . . . . . . . . . . . . 1605.12 Sialoblastoma . . . . . . . . . . . . . . . . . . . . . . . 1605.13 Alterations in Gene Expressionand Molecular Derangementsin Salivary Gland Carcinoma . . . . . . . . . . . . . . 1605.13.1 Predominantly Myoepithelial Malignancies . . . . . . 1615.13.2 Predominantly Epithelial Malignancies . . . . . . . . 1615.14 Benign and Malignant Lymphoid Infiltrates . . . . . 1625.14.1 Non-Autoimmune Lymphoid Infiltrates . . . . . . . . 1625.14.2 Benign Autoimmune Lymphoid Infiltrates . . . . . . 1625.14.3 Malignant Lymphoma . . . . . . . . . . . . . . . . . . 1635.15 Other Tumours . . . . . . . . . . . . . . . . . . . . . . 1635.16 Unclassified Tumours . . . . . . . . . . . . . . . . . . . 163References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164

132 S. Di Palma · R.H.W. Simpson · A. Skalova · I. Leivo5.1 Introduction5.1.1 Normal Salivary Glands5The salivary glands include paired major glands (parotid,submandibular and sublingual) and minor glandsthroughout the upper aerodigestive tract.The cellular component comprises serous and mucousacinar and ductal epithelial cells, myoepithelialcells and connective tissue components (e.g. fat, fibroustissue, nerves and blood vessels). The parotidglands consist of predominantly serous acini, the submandibularglands of mixed, serous and mucous acini,while the sublingual glands contain mainly mucousacini. Minor salivary glands also have mixed serousand mucous acini in varying proportions.Of particular interest are the myoepithelial cells.They are a normal constituent of the major and minorsalivary glands, and are believed to have contractileproperties that assist in the secretion of saliva. Similarcells are also found in the breast, tracheo-bronchialand sweat glands. They are plentiful in the salivaryacini and intercalated ducts, but much less so in thelarger excretory ducts of the major glands. Microscopicexamination shows that myoepithelial cells are thinand spindle-shaped and situated between the basementmembrane and epithelial cells, and ultrastructurallythey are seen to possess a number of cytoplasmicprocesses that extend between and over the acinarand ductal lining cells. They display features of bothsmooth muscle and epithelium, such as numerous microfilamentswith focal densities in the cytoplasmicprocesses, and desmosomes that attach the myoepithelialto the epithelial cells [62]. Similarly, immunohistochemistryshows that myoepithelial cells stainstrongly with alpha smooth muscle actin (SMA), calponin,smooth muscle myosin heavy chain (SMMHC)[164], h-caldesmon [74], S-100 protein [114] as well aswith some cytokeratins (e.g. subtype 14). Maspin, p63[8, 166] and CD 10 [143, 183] have recently been describedas markers of breast myoepithelial cells, andmay have a role in identifying their salivary equivalents.Preliminary studies show that p63 may well havepractical value [166]. Scattered nests of sebaceous cellscan be seen in normal parotid and minor salivaryglands [62].Serial sectioning has shown an average of 20 lymphnodes within each parotid [67], and they may be affectedby inflammatory processes and neoplasms, bothprimary and metastatic. Their presence may hamperhistologic evaluation of parotid gland lesions [6].Fig. 5.1. Extravasation mucocele (mucous escape reaction): mucin-filledcavity lined with granulation tissue and macrophages5.1.2 Developmental DisordersAgenesis, aplasia, hypoplasia and atresia of the mainducts are all extremely rare. In contrast, intra-parotidnodal heterotopias are very common [129], and epithelialtumours may arise from them [175]. Extranodalheterotopia is rare, and can be subdivided into high(involvement of the ear, pituitary, mandible, etc.) or lowforms (lower neck, thyroid).Accessory parotid glands comprising salivary tissueseparate from the main gland, adjacent to Stenson’sduct, are found in 20% of people.5.2 Obstructive Disorders5.2.1 Mucus Escape ReactionThis forms an extravasation mucocele, which is definedas the pooling of mucus in the connective tissue in a cavitynot lined with epithelium. Most patients are under30 years of age, and the minor glands are most often affected.The incidence by site is lower lip 65%, palate 4%,buccal mucosa 10%, and (in the major glands) parotid0.6%, submandibular 1.2% and sublingual 1.1%. Thepathogenesis is traumatic severance of a duct, leadingto mucus pooling. It presents in the lip as a raised, oftenblue, dome shaped swelling of the mucosa, usually2–10 mm in diameter, but it is generally larger in thesublingual gland in the floor of the mouth where it isknown as a ranula. Microscopy shows a well-definedmucin-filled cavity lacking an epithelial lining, but linedwith granulation tissue and macrophages (Fig. 5.1).

Major and Minor Salivary Glands Chapter 5 1335.2.2 Chronic Sclerosing(Atrophic) Sialadenitisof the Submandibular Gland( Küttner Tumour)In most if not all cases, this is secondary to calculi in theexcretory ducts of the major salivary glands, particularlythe submandibular gland. It can occur at any age,though the mean is 44 years. Patients present with painand/or swelling associated with eating. Histology showsacinar atrophy and a chronic inflammatory infiltrate ofvariable intensity, but it can be heavy with lymphoid germinalcentre formation. The end stage of destruction ofthe lobular architecture and scarring has been describedas salivary gland cirrhosis [172].5.3 InfectionsFig. 5.2. Necrotising sialometaplasia. Most of the ducts and aciniare replaced by mature non-keratinising squamous epithelium.The lobular architecture of the gland is preserved5.3.1 Bacteria, FungiTuberculosis may involve the gland itself or intra-parotidlymph nodes, and may present as a salivary mass.Other granulomatous infections such as cat-scratch,fungus, sarcoid, leprosy, syphilis, tularaemia, Brucellaor toxoplasmosis can also occur in the salivaryglands.5.3.2 VirusesSeveral viral diseases lead to infiltration by chronic inflammatorycells, but are rarely biopsied. This is especiallytrue of mumps, and also in Cytomegalovirus infection,which may involve the salivary glands as part ofa systemic infection in either the newborn or immunocompromisedadults, particularly those with AIDS. Thediagnosis is made by finding the characteristic enlargedcells with intranuclear inclusions [233]. Other viral infectionsinclude Epstein-Barr Virus (EBV), Coxsackievirus and influenza virus, as well as human immunodeficiencyvirus (HIV). Several lesions may be seen inthe salivary glands in patients with AIDS, in particularcystic lymphoid hyperplasia (see Sect. 5.7.4.2).5.4 Miscellaneous InflammatoryDisordersThere are a variety of non-infectious inflammatoryconditions such as sarcoidosis [230], Rosai-Dorfmandisease [75], xanthogranulomatous sialadenitis, amyloidosis[98] and Kimura’s disease [155]. They will not bediscussed here.5.5 Miscellaneous Non-InflammatoryDisorders5.5.1 Necrotising Sialometaplasia(Salivary Gland Infarction)Necrotising sialometaplasia (salivary gland infarction),is a benign, self-healing lesion, affecting especially theminor glands of the palate. Some cases follow surgery(about 1–8 weeks postoperatively) or even relatively minortrauma, such as from an ill-fitting denture, but oftenno predisposing factor is known, although the underlyingprocess is generally considered to be ischaemic [172].Microscopy shows lobular coagulative necrosis of acini(particularly in the early stages), squamous metaplasiaof ducts, a chronic inflammatory cell infiltrate and pseudoepitheliomatoushyperplasia of the overlying surface[24]. There is a superficial resemblance to either mucoepidermoidor squamous cell carcinoma, but the overalllobular architecture of the involved gland is preserved.A similar reaction can be seen in the major glands aftersurgery or radiotherapy (Fig. 5.2) [17].5.5.2 SialadenosisSialadenosis [172] is a non-inflammatory process ofthe salivary glands due to metabolic and secretorydisorders of the gland parenchyma accompanied byrecurrent painless bilateral swelling of the parotidglands. The peak ages are the fifth and sixth decades[172]. It has been related to endocrine disorders (diabetesmellitis, ovarian and thyroid insufficiencies) aswell as autonomic nervous system dysfunction; the

134 S. Di Palma · R.H.W. Simpson · A. Skalova · I. Leivounderlying process appears to be a disorder of salivarygland innervation. It is also seen in malnutrition,chronic alcoholism, bulimia, liver cirrhosis and hasbeen linked to some drugs, such as antihypertensiveagents [62].It is rarely biopsied, but histologically there is enlargementof the serous acinar cells (two or three timesthe normal size) and slight compression of the duct systemby the swollen acini.55.5.3 Adenomatoid Hyperplasiaof Mucous Salivary GlandsThis nodular hyperplastic lesion is usually asymptomatic,often being noted on routine dental examination.Most cases occur on the palate, but sometimes other minorglands can be involved [25]. It can affect all ages,although most patients are between 30 and 60 yearsold. There is a slight male predominance. Examinationreveals nodular mucosal swellings up to 30 mm in diameter.The aetiology is unknown, but possible relevantfactors include local trauma due to dentures or tobaccosmoking. The main histological feature of adenomatoidhyperplasia is the presence of hypertrophic andhyperplastic mucous lobules of minor salivary glands.Inflammation, fibrosis and cytological abnormality arenot usually seen.5.5.4 Irradiation ChangesSalivary glands are very sensitive to radiation, and xerostomiais a common complication. Acute radiationinjury of salivary glands manifests with swelling, vacuolationand necrosis of acinar cells. Initial acute inflammatoryresponse is later followed by chronic sclerosingsialadenitis characterised by loss of acini, focal squamousmetaplasia, and fibrosis. When all the salivaryglands are involved, the loss of saliva is progressive andirreversible.5.5.5 Tissue ChangesFollowing Fine Needle AspirationFig. 5.3. Focal oncocytosis of the parotid gland. Some ducts andacinar cells show cytoplasmic oncocytic featuresFine needle aspiration (FNA) is an important techniquein the investigation of salivary disease, particularly tumours,but the procedure itself can have adverse effects,causing difficulties in histological assessment and evensimulating malignancy. The effects are classified as tissueinjury with repair, infarction and reactive pseudomalignantchanges [28]. Some or all of these can occurin any tumour [126] including pleomorphic adenoma,but are most frequent in Warthin’s tumour, where infarctionmay be total and squamous metaplasia florid[55]. Possible causes include trauma by the needle [55]and an increased sensitivity of oncocytic cells to hypoxia[28].5.6 Oncocytic LesionsOncocytic change is where cells develop intensely eosinophilicgranular cytoplasm due, to increased numbers ofmitochondria [180].5.6.1 Focaland Diffuse OncocytosisFoci of oncocytic metaplasia, usually of ducts, but occasionallyalso acini, occur with increasing frequencywith advancing age (Fig. 5.3). In contrast, diffuse oncocytosisof the parotid is extremely rare. Microscopicexamination shows oncocytic metaplasia of ducts andacini involving virtually the whole gland. As with mostother oncocytic lesions, diffuse oncocytosis comprisestwo types of cells, light and dark. The former are largeand round or polygonal and have finely granular, pinkcytoplasm and a single vesicular nucleus. The darkcells are usually more sparse and have deeply eosinophilic,compressed cytoplasm and densely hyperchromaticnuclei.5.6.2 Ductal OncocytosisOncocytic metaplasia of ducts often with cystic dilation(also known as oncocytic papillary cystadenoma) occursmainly in the minor glands, particularly the larynx, and

Major and Minor Salivary Glands Chapter 5 135only occasionally in the parotid (see Sect. 5.8.10). Thelesions are often multifocal and usually small, but canreach 30 mm in diameter.5.6.3 Multifocal NodularOncocytic HyperplasiaThis rare condition consists of nodules of varying size,composed of oncocytic cells, often with relatively clearcytoplasm. The nodules appear to engulf normal acinigiving a false impression of invasion, but there is nostromal or other response by the acini. Multifocal nodularoncocytic hyperplasia (MNOH) can be mistaken fora clear cell neoplasm with satellite deposits when onenodule is much larger than the others. MNOH can alsobe bilateral, and it has been reported to co-exist with apleomorphic adenoma, which itself showed oncocyticchange [20, 158].lobular architecture, and some lobules are affectedmore severely than others. The cysts vary in size up toa few millimetres, and they are irregular in shape andoften interconnect. The lining epithelium is flat, cuboidalto low columnar, sometimes with an apocrinelikeappearance. The lumen contains secretion withspherical microliths. Remnants of salivary acini areseen between the cysts, and thick fibrous interlobularsepta are often prominent.5.7.2 MucocelesA mucocele is defined as the pooling of mucus in a cysticcavity [62]. Two types are recognised – extravasationand retention; extravasation mucocele is described inSect. 5.2.1. Retention cysts can occur at any age, and themucus pool is within an epithelium-lined cavity, likelyto be a dilated excretory duct.5.7 CystsNon-neoplastic cysts and pseudocysts accounted forabout 6% of all lesions of the salivary glands in the Hamburgregistry of salivary neoplasms and tumour-like lesions[172]. They can be classified as:1. Dysgenetic, e.g. polycystic dysgenetic disease;2. Acquired cysts lined with epithelium, e.g. lymphoepithelialcystic lesions, duct cysts;3. Pseudocysts without an epithelial lining, e.g. extravasationmucocele, including ranula;4. Cystic change in neoplasms, e.g. Warthin, variantsof mucoepidermoid and acinic cell carcinomas, lymphoepithelialsialadenitis (LESA), lymphoma, andrarely, pleomorphic adenoma;5. Miscellaneous other cysts.The commonest are mucoceles, including ranula (80%),parotid duct cysts (11%), lymphoepithelial cystic lesions(7%) and dysgenetic cysts and congenital sialectasia (together2%).5.7.1 Salivary PolycysticDysgenetic DiseaseThis very rare condition resembles cystic anomalies ofother organs, such as the kidney, liver and pancreas,although no association has been described [62, 172,177]. Some cases are familial [207], and almost allcases occurred in females. Most patients present inchildhood, but some have not been recognised untiladulthood. It only affects the parotid glands, usuallybilaterally. Microscopically, the glands maintain their5.7.3 Simple Salivary Duct CystsSalivary duct cysts are acquired, and are due to dilatationof a salivary duct following obstruction, sometimesby a tumour [62]. They can occur at any age, althoughusually in patients over 30 years old. Most (85%) arisein the parotid and are unilateral and painless. They arewell-circumscribed, unilocular and up to 100 mm in diameter(usually 10 to 30 mm). They contain fluid that iswatery to viscous brown, occasionally with mucus. Thewall comprises dense fibrous tissue, 1–3 mm thick, andthere is often mild to moderate chronic inflammation,although not the dense lymphoid infiltrate of a lymphoepithelialcyst. The epithelium is stratified squamous, ora single layer of cuboidal or columnar cells, with occasionalgoblet cells and oncocytes.5.7.4 Lymphoepithelial Cystic LesionsSeven types of salivary lesions can be characterised bysingle or multiple epithelial-lined cysts surrounded bylymphoid tissue including germinal centres: benignlymphoepithelial cyst and cystic lymphoid hyperplasiaof AIDS, in addition to Warthin’s tumour, LESAand mucosa-associated lymphoid tissue (MALT lymphoma)each with cystically dilated ducts, low-gradecyst-forming mucoepidermoid carcinoma with a heavylymphocytic response, and cystic metastases in intraparotidlymph nodes, each of which is discussed inSect. 5.14.

136 S. Di Palma · R.H.W. Simpson · A. Skalova · I. Leivo5Fig. 5.4. Simple, benign lymphoepithelial cyst. The cavity is linedwith columnar and cuboidal cells with scattered goblet cells. Thesurrounding tissue contains small lymphocytes and macrophages.Beyond this is a capsule and subcapsular space resembling that ofa lymph nodeFig. 5.5. Sclerosing polycystic adenosis. Cystic ducts of varyingsize with stromal fibrosis, resembling fibrocystic disease and sclerosisadenosis of the breast. There is also proliferation of ducts andacini in a lobular pattern5.7.4.1 Benign Lymphoepithelial CystBenign lymphoepithelial cysts are thought to arise eitherin intraparotid lymph nodes [60] or from remnants of thebranchial apparatus [10]. There is no clinical associationwith Sjögren’s syndrome, and they were described longbefore the AIDS epidemic. There is a slight male preponderance(1.6:1 in civilians in the Armed Forces Instituteof Pathology [AFIP] series), and the mean age of onset is46 years (range 18 to 79) [113]. They are usually solitary,but can occasionally be bilateral. The average diameter is25 mm, but they may reach 70 mm. Microscopy shows thelining epithelium to be squamous, respiratory, cuboidal,columnar or a combination, and small numbers of gobletcells may also be present (Fig. 5.4). This lining is surroundedby abundant lymphoid tissue composed of smalllymphocytes, plasma cells and germinal centres; lymphoepitheliallesions are not a feature. Benign lymphoepithelialcysts are not known to recur after surgical excision.5.7.4.2 Cystic LymphoidHyperplasia of AIDSA nodular or diffuse enlargement of particularly the parotidglands is often seen in HIV-positive patients – usuallybilaterally. Microscopic examination shows a denselymphoid infiltrate including follicular hyperplasia,sometimes displaying lysis of germinal centres and diminishedmantle zones. There is an elaborate dendriticreticulum cell network within which there is evidenceof active HIV replication, although the exact histogenesisof this lesion is not understood. Plasma cells (polytypic)are often numerous. The glandular parenchyma isatrophic, and multiple cystic spaces are seen, filled withmucoid or gelatinous fluid. The cysts are dilated ducts,and the lining sometimes shows squamous metaplasia.The cysts are infiltrated by lymphoid cells, includingvariable numbers of marginal zone B-cells, and in timelymphoepithelial lesions are apparent.There is considerable morphological overlap withLESA [60, 91], but only a minority of patients exhibitthe clinical features of Sjögren’s syndrome [105]. An importantpractical point is that this lesion can be the firstclinical manifestation of HIV disease, and thus histologicalidentification of it means a diagnosis of AIDS forthe patient.The lymphoid infiltrate is polyclonal and generallydoes not progress to lymphoma, although patients withHIV disease are at risk of developing aggressive B-celllymphomas, most commonly of the Burkitt-type anddiffuse large cell lymphoma [107]. An exception is thatin children with AIDS, the infiltrate more closely resemblesMALT lymphoma, and monoclonality may be demonstrated.5.7.5 Sclerosing PolycysticSialadenopathy(Sclerosing Polycystic Adenosis)This is a benign pseudoneoplastic condition of majorsalivary glands [11, 84, 200], said to be analogous to fibrocysticdisease of the breast [58]. It affects mainly femaleswith a mean age of 28 years (range 12 to 63). Mostcases have been described as slow-growing masses in theparotid gland, with a single example of submandibulargland involvement. The excised gland is largely replaced

Major and Minor Salivary Glands Chapter 5 137by multiple discrete, firm, rubbery nodules. Microscopicexamination shows a well-circumscribed, unencapsulatedmass composed of a lobular arrangement of proliferatingducts and acini with cystic ducts containingviscous secretion and, on occasions, aggregates of foamymacrophages. There is often intraluminal epithelialproliferation occasionally with a cribriform pattern andthese may contain small droplets of basement membranematerial. The lining comprises a spectrum of apocrine,mucous, squamous cells and ballooned sebaceous-likecells, although true goblet cells are not seen. Some cellscontain prominent large, intensely eosinophilic cytoplasmicgranules of varying sizes, representing aberrantzymogen granules (Fig. 5.5). On occasion there is nuclearpleomorphism, even suggesting dysplasia [200], butthere is no significant mitotic activity and no malignantcases have been described. Flattened myoepithelial cellsare present around ductal and acinar structures, andthere is periductal sclerosis and intense hyaline sclerosisof the surrounding soft tissue. Sometimes, a patchylymphocytic infiltrate is noted. About one-third of casesrecur, but none has metastasised.5.7.6 Other CystsOther salivary cysts include dermoids [141], and a varietyof epithelial and non-epithelial cysts including parasitesand gas cysts in glass blowers [163]. Keratocystomais a rare, recently described, benign parotid tumourcharacterised by multicystic keratin-filled spaces linedwith stratified squamous epithelium with no atypicalfeatures [150].5.8 Benign TumoursThere are various classifications. The revised WHOclassification (Table 5.1) [171] has the merit of being easilyapplicable in practice [181].5.8.1 Pleomorphic AdenomaFig. 5.6. Pleomorphic adenoma spectrum. Reproduced with permissionfrom Zarbo et al. [236]ICD-O:8940/0Most authors accept that there is a spectrum of benignsalivary adenomas, including pleomorphic adenoma.Benign myoepithelioma, which is composed almostentirely of myoepithelial cells represents one end of thespectrum, whereas basal cell adenoma and canalicularadenoma are at the other end [183, 236, 237]. The particularmorphology of any particular tumour reflects thedifferent proportions of the constituent cells (Fig. 5.6).Pleomorphic adenoma (PA) is the most common tumourof the salivary glands. Although most often foundin young to middle-aged women, they can occur in eithersex and at any age. Up to 80% occur in the superficiallobe of the parotid gland, and it typically presentsas a painless swelling. When the deep lobe is involved,it often manifests as an intraoral parapharyngeal mass.Approximately 5% of PAs occur in the submandibulargland, 0.1% in the sublingual gland and about 10% inminor salivary glands [30, 228]. Similar tumours arisein extrasalivary locations including bronchi, ear, lacrimalgland, breast and skin.Macroscopically, PAs are usually well-circumscribedmasses of 20–40 mm. The cut surface is usually white,and grey glistening areas are commonly seen.Histologically, PA was defined by the revised WHOClassification of 1991 as “a tumour [of the salivaryglands] of variable capsulation characterised microscopicallyby architectural rather than cellular pleomorphism”[171], i.e. the pleomorphism refers to the varietyof histological patterns, not the cytology.The pattern varies from case to case, and also fromarea to area within any individual tumour. All are composedof a mixture of ductal epithelial cells, basal andmyoepithelial cells and variable amounts of stroma,both hyaline and chondromyxoid. Attempts have beenmade to subclassify PA based on the proportions of celltypes and stroma [176], but because of the variation inany tumour, this is difficult and probably has no prognosticvalue.Ducts are lined with flat, cuboidal or columnar epithelialcells, with little or no atypia. The ducts are usuallysmall tubules, but can be cystically dilated andalso arranged in a cribriform pattern, resembling adenoidcystic carcinoma, but mitotic figures are rare andthe proliferation index low (see Sect. 5.9.3). Squamousmetaplasia with or without keratinisation is seen in upto 25% of PAs [65]. If associated with mucinous metaplasia,it may resemble mucoepidermoid carcinoma(Figs. 5.7, 5.8).Myoepithelial cells are arranged in sheets, smallerislands and trabeculae, and also surround epithe-

138 S. Di Palma · R.H.W. Simpson · A. Skalova · I. LeivoTable 5.1. Revised WHO histological classification of salivary gland tumours [171]5AdenomaDuctal papillomaCystadenomaCarcinomasNon-epithelial tumoursMalignant lymphomasSecondary tumoursUnclassified tumoursEntities not included in the classification,but described or better characterised since1991 [8a]Pleomorphic adenomaMyoepithelioma (myoepithelial adenoma)Basal cell adenomaWarthin’s tumour (adenolymphoma)Oncocytoma (oncocytic adenoma)Canalicular adenomaSebaceous adenomaInverted ductal papillomaIntraductal papillomaSialadenoma papilliferumPapillary cystadenomaMucinous cystadenomaAcinic cell carcinomaMucoepidermoid carcinomaAdenoid cystic carcinomaPolymorphous low-grade adenocarcinoma (terminal duct adenocarcinoma)Epithelial-myoepithelial carcinomaBasal cell adenocarcinomaSebaceous carcinomaPapillary cystadenocarcinomaMucinous adenocarcinomaOncocytic carcinomaSalivary duct carcinomaAdenocarcinoma (not otherwise specified)Malignant myoepithelioma (myoepithelial carcinoma)Carcinoma in pleomorphic adenomaSquamous cell carcinomaSmall cell carcinomaUndifferentiated carcinomaOther carcinomasSialoblastomaHyalinising clear cell carcinomaCribriform adenocarcinoma of the tongueEndodermal sinus tumour of the salivary glandslium-lined spaces. As in benign myoepithelioma (seeSect. 5.8.2), neoplastic myoepithelial cells may take severalforms – epithelioid, spindle, plasmacytoid, clear andoncocytic, as well as transitional forms with features oftwo or more of these types (Fig. 5.9).The stroma varies in amount and is either dense eosinophilichyaline material or chondromyxoid tissue.The former is composed of basement membrane materialand stains with PAS diastase and collagen type IV;the chondromyxoid material only rarely resembles truecartilage and is Alcian blue-positive (Fig. 5.10). Calcificationand bone formation can occur in long standingtumours. Occasionally, collagenous spherules and crystalloidsare seen, particularly in tumours rich in myoepithelialcells of the plasmacytoid type (Fig. 5.11) [197].Nuclear atypia is not common, but can be seen in tumourswhere epithelial or myoepithelial cells display oncocyticfeatures [65]. Occasional myoepithelial cell nucleiare enlarged and bizarre, somewhat analogous to“ancient” change in schwannomas. Mitotic figures aregenerally sparse, but can occur as part of the repair processafter FNA. Such tumours with these atypical featuresshould be sampled thoroughly to exclude true intracapsularcarcinoma.Similarly, areas of necrosis or haemorrhage may followsurgical manipulation, FNA or other trauma, and

Major and Minor Salivary Glands Chapter 5 139Fig. 5.7. Pleomorphic adenoma: myoepithelial cells with an epithelioidcytomorphology. These cells may also be spindle-shaped,plasmacytoid (hyaline) or have clear cytoplasm. Note also a smallduct and a focus of squamous metaplasia. Keratinising squamousmetaplasia is seen in up to a quarter of pleomorphic adenomasFig. 5.10. Pleomorphic adenoma: chondromyxoid stroma containingisolated small and small aggregates of myoepithelialcellsFig. 5.8. Pleomorphic adenoma with squamous and focal mucinousmetaplasia resembling mucoepidermoid carcinomaFig. 5.11. Collagenous spherules can be seen in some benign myoepitheliomasand myoepithelium-rich pleomorphic adenomasFig. 5.9. Pleomorphic adenoma: myoepithelial cells showing anepithelioid and plasmocytoid appearanceFig. 5.12. Vascular “invasion” is a rare finding in benign pleomorphicadenoma, due to displacement of neoplastic cells intovascular spaces. It is not indicative of malignancy

140 S. Di Palma · R.H.W. Simpson · A. Skalova · I. Leivo5Fig. 5.13. Recurrent pleomorphic adenoma. Multiple and oftenwell-separated tumour nodules of different sizes are seen in theperiparotid soft tissueFig. 5.14. Benign myoepithelioma composed of plasmocytoid(hyaline) and epithelioid cells with areas of myxoid stroma. Plasmocytoidcells have eccentric nuclei and dense eosinophilic cytoplasmthese neoplasms should also be sampled thoroughly. Tumourcells in lymphatics (“vascular invasion”) are occasionallyseen in benign PAs, but this does not necessarilyindicate malignancy (Fig. 5.12) [3]. None of the reportedcases were followed by metastases.Pleomorphic adenomas are often completely or partlysurrounded by a fibrous capsule of variable thickness,but it can be absent, especially in tumours of the minorglands. Neoplastic elements may extend into and eventhrough the capsule in the form of microscopic pseudopodiaor apparent satellite nodules.They may be the cause of future recurrence after apparentsurgical removal [97], and their presence shouldbe noted in the surgical pathology report. Special stainsand immunohistochemistry are not necessary for thediagnosis in most cases, but can be used to identify thedifferent cell types and also early malignant change (seeSect. 5.9.11).Recurrent PA occurs after incomplete surgical excisionand is usually composed of multiple nodules completelyseparate from each other. In the first recurrencethe nodules are usually seen within salivary gland tissue,but in further recurrences tumours are found in thesoft tissue of the surgical bed (Fig. 5.13). Histologically,the nodules show similar features to ordinary PA, andin particular they lack any cytological atypia. In spiteof this, confluent nodules of recurrent PA can still killthe patient. As discussed later (see Sect. 5.9.11) multiplyrecurrent PAs may rarely metastasise to distant sites,and in addition are more prone to developing malignantchanges.5.8.1.1 Salivary Gland Anlage Tumour(“ Congenital PleomorphicAdenoma”)ICD-O:8940/0This is a rare, probably hamartomatous lesion in the nasopharynxof neonates [45]. Although potentially fataldue to its location, prognosis after surgery is good. It wasnot included in the 1991 WHO classification [171]. Themicroscopic features are a biphasic pattern of squamousnests and duct-like structures at the periphery, merginginto solid, predominantly mesenchymal nodules, possiblyof myoepithelial origin. Occasionally, there is necrosisand cyst formation [136].5.8.2 Benign MyoepitheliomaICD-O:8982/0Myoepithelial cells are found in several salivary glandneoplasms (Table 5.2). Benign myoepithelioma wasfirst described in 1943 [179], and was included inthe 1991 revised WHO classification [171]. It can bedefined as a tumour composed totally, or almost totally,of myoepithelial cells. Whether or not it is trulya separate biological entity is debatable, but mostcommentators believe that it represents one end of aspectrum that also includes pleomorphic and at leastsome basal cell adenomas. Nevertheless, myoepitheliomadisplays particular microscopic features thatpose specific practical problems in the identificationand differential diagnosis, and on this basis it can beaccepted as a separate diagnostic category [188, 189].Most cases present as a well-circumscribed mass, usu-

Major and Minor Salivary Glands Chapter 5 141Table 5.2. Salivary tumours with myoepithelial cell participation. Adapted from the WHO classification [171]BenignMalignantPleomorphic adenomaMyoepitheliomaBasal cell adenoma (some)Adenoid cystic carcinomaPolymorphous low-grade adenocarcinomaEpithelial-myoepithelial carcinomaMalignant myoepithelioma (myoepithelial carcinoma)Carcinoma ex pleomorphic adenoma (some)ally 10–50 mm in diameter, in either major or minorsalivary glands. Microscopically, there are several typicalappearances, reflecting the different forms thatneoplastic myoepithelial cells can take. Solid, myxoidand reticular growth patterns may be seen, and thecomponent cells may be spindle-shaped, plasmacytoid(hyaline), clear, epithelioid or oncocytic. Manytumours show more than one growth pattern or celltype, but myoepitheliomas of the minor glands aremore often composed of plasmacytoid cells, and thoseof the parotid spindle cells [189]. Although most authorsaccept the plasmacytoid cells as myoepithelial,it has recently been suggested that these cells originatefrom luminal and not from myoepithelial cells [157],and thus the tumours should possibly be reclassifiedas plasmacytoid adenomas [157]. The clear cell variantcan occur in both major and minor glands [182], butis relatively rare [43]. Unlike their malignant counterpart[52] (see Sect. 5.9.8), benign myoepitheliomas donot usually show invasiveness, necrosis, cytologicalpleomorphism, or more than an isolated mitotic figure.The stroma is usually scanty, fibrous or myxoid,and it may occasionally contain chondroid material ormature fat cells [203]. Extracellular collagenous crystalloidsare seen in 10–20% of plasmacytoid cell-typemyoepitheliomas, (as well as sometimes in myoepithelial-richPAs); these structures are about 50–100 min diameter and consist of radially-arranged needleshapedfibres composed of collagen types I and III,which stain red with the van Gieson method [197].Scanty small ducts may be present (usually less than10% of the tumour tissue) in otherwise typical myoepitheliomas(Fig. 5.14) [43]. Immunohistochemically,almost all tumours express S-100 protein, as wellas some cytokeratins, especially subtype 14. Alphasmooth muscle actin positivity is seen to some degreein most spindle cell myoepitheliomas, but only occasionallyin the plasmacytoid cell type [189]. Stainingfor calponin, smooth muscle myosin heavy chain(SMMHC) and CD10 is inconsistent in myoepithelialcells. The nuclear transcription factor p63 is positivein most benign myoepitheliomas [166]. Electron microscopicstudies have also confirmed both epithelialFig. 5.15. Basal cell adenoma. The tumour is arranged in nests, islandsand trabeculae or basal cells without cytological abnormality.Ductal differentiation is also notedand smooth muscle differentiation [170], although focaldensities in myofilaments are not usually found[43]. The behaviour of myoepithelioma is similar tothat of pleomorphic adenoma, and complete excisionshould be curative. Neither growth pattern nor celltype appears to carry prognostic significance. Malignantchange in a benign lesion has been described [2],but too little information is available about the percentageof cases involved. However, it is reasonable topostulate that it is probably not very different fromthat of pleomorphic adenoma.5.8.3 Basal Cell AdenomaICD-O:8147/0Most tumours previously described as monomorphicadenoma are now termed basal cell adenoma (BCA).The revised WHO [171] classification recognises fourhistopathological subtypes – solid, tubular, trabecularand membranous – but it is likely that, in reality, thereare only two separate biological entities [16] – membranousand non-membranous (Figs 5.15, 5.16).

142 S. Di Palma · R.H.W. Simpson · A. Skalova · I. Leivo5Fig. 5.16. Membranous basal cell adenoma: jigsaw like pattern:multiple epithelial islands surrounded by large amounts of basalmembrane-like material. The latter is also present within the cytoplasmof some of the small dark hyperchromatic basal cells. Thereis little cellular pleomorphismNon-membranous BCAs have an equal sex incidenceand arise mostly in the major glands. They probablyrepresent part of the spectrum of myoepitheliomaand pleomorphic adenoma [70, 237]. The tumoursare ovoid, well-circumscribed masses in which islands,nests and trabeculae of basaloid cells are eachsurrounded by a distinct thin PAS-positive basementmembrane. The component cells may take two forms –small with scanty cytoplasm and a round, dark nucleus,and larger with amphophilic or eosinophilic cytoplasmand an ovoid paler staining nucleus. These twotypes are intermixed, but the smaller cells tend to bearranged around the periphery of the nests and trabeculae,giving the appearance of palisading. Ductal differentiationmay or may not be apparent, but can behighlighted by EMA. There is little pleomorphism andmitotic figures are rare. The stroma varies in amountand cellularity, but S-100 protein-positive spindle cellsmay be numerous. S-100 positive cells are also presentwithin the islands of epithelial cells, which reactstrongly with cytokeratins [220].Membranous BCA (dermal analogue tumour) occurspredominantly in men, and can be multicentric.Most arise in the major glands, including within intraparotidlymph nodes [128]. Microscopically, theyare not encapsulated and appear multinodular, oftenwith a jigsaw-like pattern. The most characteristicfeature is the deposition of large amounts of hyalinebasement membrane material, which is brightly eosinophilicand PAS-positive. It surrounds the epithelialcell islands and blood vessels, and is present withinthe islands as small droplets. There is little pleomorphismor mitotic activity. In about 40% of cases, thesalivary adenoma is associated with synchronous andoften multiple skin appendage tumours of sweat glandor hair follicle origin, usually cylindromas or eccrinespiradenomas.The most important differential diagnosis of all typesof BCA is adenoid cystic carcinoma. Useful pointers toadenoma include lack of invasiveness and cytologicalpleomorphism, low mitotic and proliferative activity,and whorled eddies of epithelial cells. S-100 protein positivityof spindled stromal cells may help, as this doesnot occur in adenoid cystic carcinoma [70]. BCA closelyresembles basal cell adenocarcinoma, which may lackcytological pleomorphism and mitotic figures, the diagnosisthen depending principally on the presence of genuineinvasion (see Sect. 5.9.7).The recurrence rate for non-membranous BCA isextremely low (0 out of 102 patients in one series) [16],and local excision with clear margins is sufficient treatment.There is a low rate of malignant transformation(about 4%) into basal cell adenocarcinoma [127]. In contrast,up to 24% of membranous BCAs recur after surgery[16], probably reflecting multicentricity and, in addition,malignancy (also as basal cell adenocarcinoma)develops in 28% [127]. Surgery for this subtype needs tobe more extensive [16, 119, 130].5.8.4 Warthin’s TumourICD-O:8561/0Warthin’s tumour (WT; adenolymphoma) is the secondcommonest neoplasm of the parotid gland, and is theeasiest salivary tumour to diagnose by microscopy [66].It arises almost exclusively in the parotid gland (usuallythe tail) and occasionally in periparotid lymph nodes.The mean age at diagnosis is 62 years (range 29–88),and WT is uncommon in blacks. Previously, there was amarked male predominance (as much as 26:1), but nowthere is an almost equal sex distribution. It is eight timesmore frequent in heavy smokers. WT is multicentric in12% of patients, and bilateral in 6%.There are two theories of its histogenesis [62] – a trueepithelial neoplasm that attracts a heavy lymphoid reaction,or alternatively a non-neoplastic lesion arisingfrom ectopic salivary inclusions in intraparotid lymphnodes. The latter theory is supported by a molecular geneticstudy using HUMARA analysis, which has shownthat WT is not a clonal process [100].Pathological examination shows a well-circumscribedoval mass, composed of slits or cystic spaceswith papillary infoldings lined with two layers ofoncocytic epithelium; the inner cells are columnarwith nuclear palisading, deep to which are flattenedor cuboidal basal cells (Fig. 5.17). Occasional mucousand squamous cells may be seen. The stroma comprisesusually plentiful lymphoid tissue with germinalcentre formation. Special stains and immunohistochemistryhave little to offer in practice; myoepi-

Major and Minor Salivary Glands Chapter 5 143Fig. 5.17. Warthin’s tumour. Cystic and slit-like spaces with papillaryinfolding lined with oncocytic cells. Lymphoid tissue occupiesthe cores of most papillaeFig. 5.20. Canalicular adenoma of the upper lip. It is composedof bi-layered strands of basal-like cells embedded in a loose oedematousstromathelial markers are negative. Histological variants includea stroma-poor form, and metaplastic WT – inthe latter, much of the original oncocytic epitheliumhas been replaced by squamous cells, and there is extensivenecrosis, fibrosis, inflammation, and granulomaformation (Fig. 5.18) [66]. This not uncommonlesion follows trauma, particularly FNA [55], and canbe mistaken for squamous or mucoepidermoid carcinomas(see Sect. 5.5.5). WT generally has a good outcome,with recurrence rates of about 2%. Malignancyoccurs in less than 1% of cases, involving either epithelialor lymphoid elements leading to carcinomas orlymphomas [62].Fig. 5.18. Metaplastic (infarcted) Warthin’s tumour. There is extensivenecrosis. A surrounding thin rim of viable tissue showssquamous metaplasia5.8.5 OncocytomaICD-O:8290/0Oncocytic change in salivary tumours is common (seeSect. 5.6) [65]. Oncocytoma is a true benign neoplasmcomposed of oncocytes. It is rare and is often associatedwith MNOH (see Sect. 5.6) [158]. It comprises awell-demarcated mass of oncocytic cells (both light anddark) with a solid, trabecular, or tubular configuration(Fig. 5.19). There is a surrounding, usually incompletefibrous capsule, and only a little internal fibrous stroma.There is a rare clear cell variant [61].5.8.6 Canalicular AdenomaFig. 5.19. Oncocytoma. Light and dark oncocytic cells are arrangedin a solid, trabecular and tubular configurationICD-O:8149/0Canalicular adenoma also has a basaloid appearance.Its location is almost exclusively intraoral, particularlyaffecting the upper lip [119] and less often thepalate. As a result, most tumours present when small

144 S. Di Palma · R.H.W. Simpson · A. Skalova · I. Leivo5– rarely more than 20 mm in diameter. It has a characteristicmorphology of branching and interconnectingbi-layered strands of darkly staining epithelialcells set in a loose vascular stroma (Fig. 5.20). Thereis no pleomorphism or significant mitotic activity.The cells express cytokeratins and S-100 protein. Notinfrequently, they are multifocal [39], and can thusmimic the true invasiveness of cribriform adenoidcystic carcinoma. The lack of destructiveness and thepresence of blood vessels in the cribriform spaces aregood guides to canalicular adenoma, which is completelybenign. Occasional recurrences are a result ofmultifocality [90].5.8.7 Sebaceous AdenomaICD-O:8410/0This rare, encapsulated epithelial tumour is composedof solid, variably shaped islands and cysts, both showingfocal sebaceous differentiation with squamous areas;these are surrounded by a fibrous, hyalinised stroma.They do not recur after complete surgical excision [12,62].5.8.8 Sebaceous LymphadenomaICD-O:8410/0This lesion comprises irregular proliferating nests andislands of epithelium including solid and gland-like sebaceouselements, surrounded by a lymphoid stroma.It is possible that, like Warthin’s tumour, sebaceouslymphadenoma develops from salivary inclusions withinlymph nodes, and shows sebaceous rather than oncocyticmetaplasia [62, 171].5.8.9 Ductal PapillomaICD-O:8503/0There are three subtypes, all rare – inverted ductal papilloma(similar to the sinonasal tumour), intraductalpapilloma and sialadenoma papilliferum (similar toskin syringocystadenoma papilliferum) [62]. Intraductalpapilloma has a fibrovascular core lined with myoepithelialand ductal cells and it is usually seen in a dilatedduct.5.8.10 CystadenomaFig. 5.21. Oncocytic (papillary) cystadenoma of the larynx. Cysticallydilated ducts are lined with oncocytic cellsICD-O:8440/0The revised WHO classification recognises two histopathologicalsubtypes –papillary cystadenoma (similarto lymphoid-poor Warthin’s tumour) and mucinouscystadenoma. Both are rare, benign tumourscharacterised by unicystic or multicystic growth patterns.The latter can be mistaken for mucinous malignancy,such as grade I mucoepidermoid carcinoma[62, 173]. Most cystadenomas are multilocular withindividual cystic spaces separated by limited amountsof intervening stroma [229]. The lumina often containeosinophilic material with scattered epithelial, foamyor inflammatory cells. Rarely, psammoma bodies andcrystalloids have been described within the luminalsecretion [199]. The lining epithelium of the cysticspaces is mostly columnar and cuboidal. Oncocytic,mucous and apocrine cells are sometimes present focallyor may predominate. An oncocytic variant ofpapillary cystadenoma is composed of oncocytes presentin unilayered or bilayered papillary structures(Fig. 5.21). Squamous epithelium may be present, butrarely predominates. The tumours are unlikely to recur,but rare cases of mucinous cystadenoma with malignanttransformation have been described (Figs 5.22,5.23) [135].5.9 Malignant EpithelialTumours5.9.1 Acinic Cell CarcinomaICD-O:8550/3Acinic cell carcinoma (AcCC) is defined as a malignantepithelial neoplasm in which some of the neoplastic cellsdemonstrate serous acinar cell differentiation.It accounts for about 2–4% of salivary gland tumours,and 12–17% of malignancies [62]. It is slightlycommoner in women and the mean age at presentationis 44 years, although AcCCs can affect children

Major and Minor Salivary Glands Chapter 5 145Fig. 5.22. Mucinous cystadenoma. Cysts are lined with mucussecretingcells without atypiaFig. 5.24. Acinic cell carcinoma solid variant. The cells showgranular cytoplasm and acinar differentiation similar to normalsalivary gland aciniFig. 5.23. Mucinous cystadenoma with malignant transformation[136]. Cellular pleomorphism and signet ring cell appearanceFig. 5.25. Acinic cell carcinoma, papillary subtype: papillae arelined with intercalated duct-like cells, some containing microvesicles,others showing a hobnail/clear cell appearanceand centenarians. The parotid is involved in 92% ofcases (3% bilateral), with only occasional examples inthe submandibular or minor glands [62], or periparotidlymph nodes [161]. The typical clinical history is ofa slowly enlarging mass (for as long as 40 years) sometimeswith pain and facial nerve weakness. Most tumoursare partly circumscribed, with a diameter of 10–30 mm, although some may reach 220 mm [4]. Microscopyshows one or more growth patterns – solid, microcystic,follicular and papillary-cystic. The follicularpattern resembles thyroid tissue, and any tumour inthe parotid with a papillary-cystic architecture shouldbe considered to be an AcCC, until proven otherwise.The cells in AcCC may take one of several forms – acinar(serous or blue dot), intercalated ductal (cuboidal,often lining small ducts), microvesicular, hob-nail orclear – the last is surprisingly rare, being seen in only6% of cases [62]. Several growth patterns and cell typesmay be seen in any individual tumour (Figs 5.24–5.26).Dedifferentiation towards a high-grade malignancyoccurs occasionally [51], and all surgical specimens ofAcCC must be sampled adequately. A lymphoid infiltrateis found in about 30% of cases, but is only of clinicalsignificance (having a good prognosis) when thetumour is a well-circumscribed nodule with a microfolliculararchitecture (Fig. 5.27) [133].The most useful special stain in AcCC is PASD,which highlights cytoplasmic zymogen granules(Fig. 5.28). Immunohistochemistry is of limited value– positivity is seen with cytokeratin, amylase, CEAand in 10% S-100 protein [221]. Other myoepithelialmarkers are negative. It has been suggested that bonemorphogenetic protein-6 (BMP-6) may be useful, butthis marker is not yet widely available [92]. Electron

146 S. Di Palma · R.H.W. Simpson · A. Skalova · I. Leivo5Fig. 5.26. Follicular variant of acinic cell carcinoma: the tumouris composed of follicle-like spaces of varying sizes lined with cuboidalintercalated duct-type cellsFig. 5.28. Acinic cell carcinoma. PAS-D emphasises coarse zymogengranules in the cytoplasm of the tumour cellsthat Ki-67 (MIB1) is an independent prognostic indicator[94, 198]. Skálová et al. found that tumours witha proliferation index

Major and Minor Salivary Glands Chapter 5 147Fig. 5.29. Mucoepidermoid carcinoma: clear, intermediate andmucus-secreting cellsFig. 5.31. High-grade mucoepidermoid carcinoma: “epidermoid”cells arranged in a solid pattern also show nuclear pleomorphism.Mucus-secreting cells may be scarcepredict outcome to some degree, and MECs should begiven one of three microscopic grades, based on the extentof the cystic component, neural invasion, necrosis,cytological pleomorphism and mitotic activity. Thisassessment has considerable prognostic significance,with death rates due to disease of 3.3, 9.7 and 46.3%for grades 1, 2 and 3 respectively [62]. Recently, a newgrading system has been proposed, but it is still underevaluation [22]. Assessment of the MIB1 proliferationindex has also been shown to be of value [196].5.9.3 Adenoid Cystic CarcinomaFig. 5.30. Low-grade mucoepidermoid carcinoma: typical cysticand solid patternance (Figs. 5.29–5.31). In fact, keratinisation is veryrare in MEC, and indeed is much commoner as partof squamous metaplasia in pleomorphic adenoma ormalignant myoepithelioma, and in metastatic squamouscarcinoma from the skin or upper aerodigestivetract. Epidermoid cells may be sparse in MECs, andhigh molecular weight cytokeratin stains (e.g. LP34)and p63 can help identify them. Intermediate cells aresmall with dark-staining nuclei and they often formthe stratified lining of cysts beneath the mucous cells.Clear cell change may be seen in either the squamousor intermediate cells and MEC may take the form of aclear cell carcinoma [182]. Similarly, oncocytes can beplentiful [109]. All MECs are malignant with a metastaticpotential, regardless of their microscopic appearance.Nevertheless, histological features can be used toICD-O:8200/3Adenoid cystic carcinoma (AdCC) is a malignant tumourwith no particular age or sex predilection. It canoccur in any gland, but most often in the submandibularor minor salivary glands, particularly the palate. However,in spite of often apparently slow growth, outcomeover the long term is poor. AdCC is an extensively infiltrativetumour with characteristic perineural invasion,and this is partly responsible for the clinical presentationof late, but repeated local recurrences. Unlike othersalivary gland malignancies, when AdCC metastasises,it tends to involve distant organs (lung, bone) ratherthan local lymph nodes [117].Histologically, AdCC is a generally solid tumour inwhich the cribriform pattern is easily recognised on microscopy,but tubular and solid structures can also bepresent. The commonest growth patterns are:Cribriform: this is the most characteristic microscopicfeature, dominated by multiple cribriform structures,composed of epithelial and basal/myoepithelial cells.The nuclei are usually dark, hyperchromatic and angulated.Mitotic figures are easy to find and may be abun-

148 S. Di Palma · R.H.W. Simpson · A. Skalova · I. Leivo5Fig. 5.32. Adenoid cystic carcinoma, cribriform variant: multiplecribriform spaces composed of basaloid cells, with hyalinised materialsurrounded by small hyperchromatic cellsFig. 5.34. Adenoid cystic carcinoma, solid variant. This is composedof multiple solid nodules, some displaying central comedolikenecrosis. The tumour can be seen to infiltrate boneFig. 5.33. Adenoid cystic carcinoma, cribriform variant. Diffusehyalinisation with compression of tumour cells. Nuclear pleomorphismmay be difficult to appreciate, leading to a false diagnosis ofpleomorphic adenomaFig. 5.35. Adenoid cystic carcinoma, solid variant. Tumour islandscontain small ducts lined with a layer of epithelial cells. Inthe absence of characteristic cribriform structures, the latter featureis diagnosticdant; the MIB1 proliferation index exceeds 10% [201].The contents of the spaces can be loose and basophilicor dense and eosinophilic. Hyalinisation is commonin adenoid cystic carcinoma and may be extreme. Inthose cases with excessive deposition of hyalinised material,the spaces are distended with loss of the cribriformpattern. Tumour cells may be sparse and bland,and thus the lesions may mimic a pleomorphic adenoma(Figs. 5.32, 5.33).Tubular: this is composed of small tubules lined withone or two cell types, luminal and abluminal withoutsignificant cytological atypia. Because of this bland cytologicalappearance it may be mistaken for basal celladenoma, except for the presence of infiltration.Solid (basaloid): this is dominated by large solid sheetsof tumour cells, sometimes with comedo-like centralnecrosis. Within the solid masses of tumour cells, thereare small duct-like spaces surrounded by a definite layerof epithelial cells (Figs. 5.34, 5.35). This latter findingdistinguishes solid variant AdCC from (relatively lowgrade)basal cell adenocarcinoma and the aggressive basaloidsquamous cell carcinoma, which in addition oftenshows intraepithelial dysplastic changes.A rare finding in all types of AdCC is squamousmetaplasia, either as single cells or with keratin pearlformation [62].A system of three grades based on the presence oftubular, cribriform and solid pattern [171] has shown

Major and Minor Salivary Glands Chapter 5 149that outcome is better in tubular ACC, while the worstprognosis is seen in solid AdCC. Nevertheless, clinicalstage appears to be a better predictor than grade[210].Another unfavourable feature of AdCC is the frequentinvolvement of resection margins in the surgicalspecimen, particularly as the result of extensive perineuralinfiltration. As complete excision of AdCC is difficult,patients often require postoperative radiotherapy.A most important histological differential diagnosisis between AdCC and polymorphous low-grade adenocarcinoma(see Sect. 5.9.4).5.9.4 PolymorphousLow-Grade AdenocarcinomaFig. 5.36. Polymorphous low-grade adenocarcinoma. Perineuralinfiltration. Tumour cells show bland cytonuclear abnormalityFig. 5.37. Polymorphous low-grade adenocarcinoma. Indian filingappearance resembling lobular carcinoma of the breastICD-O:8525/3Polymorphous low-grade adenocarcinoma (PLGA) isalso known as terminal duct or lobular carcinoma. It ismore frequent in women, and the average age at presentationis 59 years (range 21–94) [62]. Most cases arise inintra-oral minor salivary glands, particularly the palate,with only rare examples in the parotid, sometimes developinginto a pleomorphic adenoma [223]. The characteristichistological picture of PLGA is an infiltratingtumour with cytological uniformity and morphologicaldiversity [171]. The architecture comprises a variety ofpatterns, including ducts, streams, and micropapillary,cribriform and solid structures (Fig. 5.36). Diffuse infiltrationof tumour cells with Indian filing and concentricgrowth around nerves is reminiscent of lobular carcinomaof the breast (Fig. 5.37).The cells each have single regular round, ovoid or fusiformbland nuclei, sometimes with intra-nuclear vacuoles[187] and absent or small nucleoli. Variably presentare oncocytic, clear or mucous cells. Mitotic figuresare scanty, and never atypical. The stroma varies fromfibromyxoid to densely hyaline, but the chondroid matrixof a pleomorphic adenoma is not seen. Immunohistochemistryshows positivity with epithelial markers(cytokeratins, EMA), S-100, bcl-2 and sometimes CEA,SMA and vimentin [26]; MIB1 proliferation is low –mean 2.4% (range 0.2–6.4) in one study [201]. PLGAbehaves as a low-grade malignancy; a literature reviewfound a recurrence rate of 21%, regional nodal metastasisin 6.5%, distant metastasis in 1.8%, and death due tocancer in 0.9% [116]. However, after 10 years late recurrencesand metastases are perhaps more common thanthat [63], although in another study with a long followup,recurrence was in large part due to incompletenessof excision – none of the 22 excised tumours recurredor caused death [159]. In a larger series of 164 PLGA,more than 95% of the patients had no evidence of diseaseafter a long-term follow-up [26]. The recommendedtreatment of PLGA is wide, but conservative surgicalexcision, postoperative radiation and chemotherapyhave little place.The most important histopathological differential diagnosisis from the much more aggressive adenoid cysticcarcinoma. Although both are diffusely infiltratingcarcinomas that display morphological diversity, at a cytologicallevel the nuclei in AdCC are seen to be hyperchromatic,angulated, pleomorphic and densely packedwith more frequent mitotic figures, in contrast to thenuclei in PLGA, which are uniform with finely speckledchromatin. In addition, staining with S-100 protein isusually more diffuse and stronger in PLGA than AdCC[201, 225]. Other markers such as c-kit (CD117) are oflittle use in practice, as staining can be seen in AdCCand most PLGAs [59]. Much more reliable marker is theMIB1 proliferation index, which is almost always significantlylower in PLGA [201, 225]. Other differential diagnosesinclude pleomorphic adenoma, which in minorsalivary glands can be poorly circumscribed. The presenceof chondroid matrix and any circumscription fa-

150 S. Di Palma · R.H.W. Simpson · A. Skalova · I. Leivo5Fig. 5.38. Cribriform adenocarcinoma of the tongue (CAT). Avaguely nodular growth pattern is composed of solid nests withtubular structuresFig. 5.39. Epithelial myoepithelial carcinoma (EMCa): characteristicbiphasic appearance with an inner layer of ductal cells andouter layer of clear myoepithelial cells. Basal membrane-like materialsurrounds the outer cellsvours PA, but it is sometimes not possible to distinguishthese tumours, particularly on a small biopsy. Papillarystructures form part of the spectrum of growth patternsseen in PLGA [206], but when extensive, there isevidence that these tumours are slightly but significantlymore aggressive [63, 64], although they do not seemto affect long-term survival. Genuine high-grade malignancycan occur rarely, as either a poorly differentiatedPLGA or as a salivary duct carcinoma [191].5.9.4.1 Cribriform Adenocarcinomaof the TongueICD-O:8525/3A newly described tumour [134] found so far only in thetongue, shares some histological features with PLGA,to which it is probably related. Cribriform adenocarcinomaof the tongue (CAT) usually arises in adults witha mean age of 50 years and equal sex incidence in theroot of the tongue. Generally, at the time of diagnosisthere are metastases in the neck lymph nodes, eitherunilaterally or bilaterally, but distant spread has notbeen described.Microscopic examination shows lobules divided byfibrous septa, composed of areas with solid and microcysticgrowth patterns. In the solid areas, tumour nestsoften display a well-developed hyperchromatic outerlayer with a perpendicular arrangement of cells. Thislayer is frequently detached, forming papillae or glomeruloidstructures surrounded by apparent clefts. The microcysticgrowth pattern is composed of lobules of neoplasticcells with a cribriform and/or tubular architecture,the two patterns often intermingling. Typically, thetubules are approximately of the same size and consist ofone cell layer. Cytologically, there is one cell type; characteristically,the nuclei, which often overlap one another,are pale and vesicular with a “ground glass” quality,thus resembling those of papillary thyroid carcinoma(Fig. 5.38).Each nucleus can contain up to three nucleoli of varyingconspicuousness. Immunohistochemically, a strongor patchy reaction is seen with cytokeratins and S-100protein. Actin, calponin and smooth muscle myosinheavy chain react with only a few areas. They are completelynegative for thyroglobulin.Patients treated with surgical excision and subsequentirradiation have a good chance of prolonged survivalwithout recurrence or further metastatic spread[134].5.9.5 Epithelial-MyoepithelialCarcinomaICD-O:8562/3The mean age at diagnosis of epithelial-myoepithelialcarcinoma (EMCa) is 60 years (range 8–103), with asmall majority in females [62]. It occurs predominantlyin the parotid gland, less often in the submandibulargland, occasionally in minor salivary glands and rarelyin the bronchus [234]. The microscopic appearanceis characterised by small ductular lumina lined withtwo layers of cells (Fig. 5.39). The inner comprises cytokeratin-positiveepithelial cells, and it is surroundedby an outer mantle of often clear myoepithelial cells,which express SMA, smooth muscle myosin heavychain and calponin. S-100 protein also stains the outercells strongly, but is less specific and sometimes reactswith the inner layer [114] – CK 14 appears to be un-

Major and Minor Salivary Glands Chapter 5 151helpful. The outer cells are in turn surrounded by a rimof PAS-positive basement membrane material of variablethickness. This pattern is reproduced throughoutmost of the tumour, though each element may varyin prominence both between and within each lesion.Grossly, the tumours often appear to be well circumscribed,but microscopy usually reveals some invasionof surrounding structures. Cytological pleomorphismis infrequent, but mitotic figures may be numerous.The stroma is usually scanty, but on occasions it consistsof plentiful hyaline basement membrane materialwith relatively inconspicuous bilayered ducts; the tumourcan then be mistaken for a pleomorphic adenoma[186]. Other differential diagnoses encompass a widerange of salivary neoplasms, mainly those composed ofclear cells, both primary and metastatic. Many salivarytumours can be diagnosed purely on H&E morphology,but clear cell lesions are an exception, and most requireimmunohistochemistry and sometimes electronmicroscopy. EMCa can occasionally dedifferentiateas a high-grade adenocarcinoma [2] or a sarcomatoidspindle cell neoplasm of myoepithelial type [186]. Thatthey originate from intercalated ducts is supported byan unusual case of a typical EMCa in a parotid gland,which also contained multiple nodules of intercalatedduct hyperplasia (Figs. 5.40–5.42) [48].This appearance may explain why EMCa is not infrequentin hybrid tumours [31, 37]. The behaviour ofEMCa is generally considered to be low grade, and ina literature review of 67 cases, recurrences were notedin 31%, cervical lymph node metastasis in 18%, distantmetastasis in 7% and death due to tumour in 7% [13]. Incontrast, the series of Fonseca and Soares [71] found that50% of neoplasms recurred and 40% of patients died ofcancer. The only morphological feature found to correlatewith a poor prognosis was nuclear atypia in morethan 20% of tumour cells. In another study DNA analysishas shown that aneuploidy is associated with an increasedchance of recurrence [34].5.9.6 Hyalinising Clear Cell CarcinomaICD-O:8310/3Monomorphic clear cell carcinomas are either epithelialor myoepithelial (clear cell malignant myoepithelioma).The former, now known as hyalinising clear cellcarcinoma was first described by Škorpil in Czech andGerman [205] and was rediscovered recently [138, 193],but was not included in the revised WHO classification[171]. It usually arises in the minor glands and is of lowgrademalignancy. Microscopically, it is characterised bygroups and trabeculae of polygonal glycogen-rich cellsseparated by dense collagen bands. At times, particularlyin the deeper parts of the tumours, the cells maylose their clarity when their cytoplasm appears weaklyFigs. 5.40–5.42. Intercalated duct hyperplasia of the parotidgland. Top: Hyperplastic foci are composed of an inner layer ofepithelial cells surrounded by myoepithelial cells with ample andclear cytoplasm. The former stain for CAM5.2 (lower) and the latterfor smooth muscle actin (middle)eosinophilic. Immunohistochemistry reveals positivitywith epithelial markers (e.g. cytokeratin), but myoepithelialmarkers (e.g. S-100 protein and SMA) are negative[138].5.9.7 Basal Cell AdenocarcinomaThis tumour has the architecture and cytology of basalcell adenoma, but displays infiltration. Most cases arise

152 S. Di Palma · R.H.W. Simpson · A. Skalova · I. Leivo5Fig. 5.43. Basal cell adenocarcinoma. In spite of the lack of significantcellular atypia, the infiltrative pattern is diagnostic of malignancy.Courtesy of Prof. J.W. Eveson, Bristol, UKamount of basement membrane material varies, butcan be marked, especially in the membranous variant.Occasional cases show cytological pleomorphism, butgenerally this is absent, and mitotic figures are usuallysparse. The most reliable indicator of malignancy is infiltrationof the surrounding gland, and less frequentlyof blood vessels and nerves (Fig. 5.43) [16]. In addition,the Ki-67 proliferation index is usually higher in basalcell adenocarcinoma than its benign counterpart (>5%vs.

Major and Minor Salivary Glands Chapter 5 153Fig. 5.45. Myoepithelial carcinoma, solid growth pattern withcentral necrosis in one of the nodules. This finding may mimicsalivary duct carcinoma with comedo-like necrosisFig. 5.47. Myoepithelial carcinoma: focal squamous metaplasiawith keratin pearl formationFig. 5.46. Myoepithelial carcinoma. The spindle cell componentshows nuclear pleomorphism resembling a soft tissue sarcoma. Ahelpful diagnostic pointer is that other types of myoepithelial cellare usually identified elsewhereinates, but there is usually a minor component of othercell types. No true glands or lumina are seen in pure,malignant myoepitheliomas, but as with their benigncounterparts, occasional small ducts in a neoplasm withotherwise typical features should not preclude the diagnosis[183]. The nuclei can vary from relatively uniform,small with finely distributed chromatin, lacking obviousnucleoli, to markedly enlarged and pleomorphic, showingchromatin clumping and large nucleoli. Mitotic figuresmay be plentiful (range 3 to 51 per 10 high powerfields) and include atypical forms [168]. Multinucleate[33] and bizarre tumour giant cells may occasionally bepresent. The tumour-related matrix is generally prominentand is hyalinised or myxoid.Special stains in tumours without any ductal differentiationshow no mucicarmine-positive mucus,but plentiful glycogen is found in clear cells and themyxoid matrix is positive with Alcian Blue. Metaplasticchanges are frequent and include areas showingsquamous differentiation, often with keratinisation(Fig. 5.47). Perineural invasion is seen in 44% and vascularinvasion in 16%. In one series, 40% of tumourswere categorised as high grade and 60% as low grade[168]. All tumours show some positivity for S-100 protein,vimentin and broad-spectrum cytokeratin (e.g.AE1-AE3 or MNF116). Other cytokeratin antisera(CAM 5.2 and LP34) show some reactivity in most tumours,and about half display some expression of cytokeratin[13]. Of the more specific myoepithelial markers,approximately 75% of tumours including thosecomposed of plasmacytoid cells, express calponin andabout 50% are positive with αSMA; p63 was positivein 60% [166]. Amongst other markers, glial fibrillaryacidic protein (GFAP) is positive in 31% and epithelialmembrane antigen (EMA) in 20%, in addition tohighlighting any true small ducts, but carcino-embryonicantigen (CEA) is usually negative. CD117 (c-kit)was positive in the few cases studied [112]. The meanMIB1 (Ki-67) index in one series was 35% (range 15–65), with any count above 10% said to be diagnostic ofmalignancy in a myoepithelial neoplasm [151].Electron microscopy shows that some tumour cellscontain small desmosomes, but actin filaments are few[168]. It has been shown that malignant myoepitheliomassecrete matrix-degrading proteinases, as well asproteinase inhibitors [215], and this appears to be associatedwith demonstrated inhibition of angiogenesis.These features indicate an anti-invasive effect, and althoughas yet poorly understood, this is likely to have

154 S. Di Palma · R.H.W. Simpson · A. Skalova · I. LeivoTable 5.3. Classification of clear cell tumours and tumour-like conditions of the salivary glands [174]5BenignMalignant, primary(carcinomas not usually characterised byclear cells, but with rare clear cell variants)Malignant, primary(carcinomas usually characterised by clearcells)Malignant, metastaticPleomorphic adenomaMyoepitheliomaSebaceous adenomaOncocytomaMultifocal nodular oncocytic hyperplasia (MNOH)Mucoepidermoid carcinomaAcinic cell carcinomaEpithelial-myoepithelial carcinomaHyalinising clear cell carcinomaClear cell malignant myoepithelioma (myoepithelial carcinoma)Sebaceous carcinomaCarcinomas: especially kidney, thyroid. Also melanomaan effect on the biological aggressiveness of any particulartumour.The variable appearance of malignant myoepithelioma,leads to a wide differential diagnosis, includingother salivary carcinomas. Nodules with central necrosismimic the comedocarcinoma structures in salivaryduct carcinoma, but there is usually more stromal materialin the myoepithelial neoplasm and in addition, S-100 and/or myoepithelial markers are usually positive.The clear cell variant resembles many other salivaryneoplasms composed of clear cells, benign and malignant,primary and metastatic (Table 5.3) [132, 174] (seeSect. 5.9.5).The prognosis of malignant myoepithelioma is variable,but approximately one-third of patients die of disease,another third have residual tumour and the remainingthird are disease-free [62, 168]. When metastasesoccur, they can be found in neck lymph nodesand at distant sites, including lungs, kidney, brain andbones. Malignant myoepitheliomas arising in ordinarypleomorphic adenomas behave in the same way as thosethat arise de novo [168], but it has been suggested thatneoplasms developing in multiply recurrent pleomorphicadenomas may pursue a prolonged course [52]. Afurther suggestion is that malignant myoepitheliomascomposed mainly of plasmacytoid cells may be more aggressive[53, 218]. However, Savera and Sloman in theirseries of 25 cases found only a weak statistical correlationfor outcome with cytological atypia (high grade),but other parameters (tumour size, site, cell type, mitoticrate, presence of a benign tumour, necrosis, perineuraland vascular invasion) showed no relationship [168].In practice with any particular case, the various histologicalfeatures should be listed, and an attempt made todescribe the tumour as low- or high-grade, but adding arider that histological grade is as yet a far from provenguide to clinical behaviour. Treatment is surgical, andno role for radio- and chemotherapy has yet been established.5.9.9 Salivary Duct CarcinomaICD-O:8500/3Salivary duct carcinoma (SDC) is probably not as uncommonas previously thought [87, 93]. Most patientsare over 50 years old and there is at least a 3:1 male predominance.It arises mainly in the parotid, less often inthe submandibular gland and only occasionally in theminor glands of the palate [47], buccal mucosa [162],maxilla [122] and larynx [69]. It can develop de novoor in a pre-existing pleomorphic adenoma [86, 87] orpolymorphous low-grade adenocarcinoma [191]. Themicroscopic appearance of SDC bears a striking resemblanceto ductal carcinoma of the breast, both in situand invasive, where all of the features of the mammaryequivalent can be reproduced (Fig. 5.48). Perineural andlymphovascular invasion are seen in many cases. Nuclearpleomorphism is usual, and is also apparent on FNAcytology [192]. Mitotic figures are often numerous, alsoreflected in a high Ki-67 proliferation index [93].Although most cases of SDC can be diagnosed withHE alone, special stains can help in a few instances. Immunohistochemistryshows expression of epithelial markerssuch as cytokeratins (including subtype 7, but not 20),EMA and GCDFP-15. S-100 protein is usually negative, asare myoepithelial markers, although they may highlightsubtle in situ lesions [5]. Despite the morphological similarityto breast carcinoma, staining for oestrogen and progesteronereceptors is almost always negative, in contrastto that for androgen receptors (AR), where >90% of SDCsreact, even in women. AR positivity appears to be specificto SDC (including when it arises in a pleomorphic adenoma),and is not seen in for example, mucoepidermoid

Major and Minor Salivary Glands Chapter 5 155Fig. 5.48. Salivary duct carcinoma: invasive irregular ducts andcribriform structures strongly resemble ductal carcinoma of thebreastFig. 5.49. Salivary duct carcinoma, mucin-rich variant. This iscomposed of a mixture of usual-type salivary duct carcinoma andlakes of mucinous adenocarcinomacarcinoma [142]. Some studies have shown SDCs to expressprostate specific antigen (PSA) or acid phosphatase[110, 120], but another failed to confirm this [185] andsimilarly, only 1 out of 40 cases in a Mayo Clinic serieswas PSA-positive [115]. More recently cases of SDC showingpositive staining for HER-2/neu (c-erbB-2) protein onimmunohistochemistry have been published [202], andthe gene amplification has been demonstrated with FISHanalysis [204].Several rare morphological variants of SDC havebeen described, including cribriform [23], micropapillary[147], sarcomatoid [96], mucin-rich [190] and oncocytic(Figs. 5.49, 5.50) [184]. So-called low grade salivaryduct carcinoma [46] is probably a separate entity(see below).The differential diagnoses of SDC are high-grademucoepidermoid carcinoma, oncocytic carcinoma andsome metastases. The diagnosis of mucoepidermoidcarcinoma requires the presence of squamous-like cells,mucus-producing cells and cells of intermediate type,and there is no expression of androgen receptors. Manysalivary oncocytic carcinomas probably demonstrateother types of malignancy (including SDC) with plentifuloncocytic cells, but a true oncocytic carcinoma lacksany features of SDC and is AR-negative. At present, neitherof these two differential diagnoses is clinically criticalsince the prognosis is similar. However, it is importantto identify metastatic carcinoma, particularly fromthe prostate or breast. In most cases, metastases will beobvious from clinical investigation and imaging studies,but the usual immunoprofile of these tumours is different:prostatic carcinomas tend to be AR+, ER−, PSA+,CK 7+; breast carcinoma tend to be usually AR−, oftenER +, PSA−, CK 7+; SDC is AR+, ER−, usually PSA−, andCK 7+.Fig. 5.50. Salivary duct carcinoma with oncocytic differentiation.The cells have ample granular cytoplasm with vesicular nucleiand prominent nucleoli. A clear distinction between oncocyticsalivary duct carcinoma and true oncocytic carcinoma may notbe possible, as they may not be separate entitiesThe prognosis for SDC is poor, and most series haveshown that more than 70% of patients die of disease,usually within 3 years. Nevertheless, Grenko et al. [86]alluded to a minority (about 25–30%) who do well, buttheir study was unable to identify any particular featuresof this group. Amongst possible prognostic indicators,tumour size is probably important, with lesions

156 S. Di Palma · R.H.W. Simpson · A. Skalova · I. Leivo5with radical neck dissection followed by radiotherapy tothe tumour bed and chemotherapy [36, 145]. The recentidentification of androgen receptors expression in SDCraises the question as to whether anti-androgen therapy(e.g. flutamide or goserelin) might have merit [99,142, 153]. The significance of staining for HER-2/neu (cerbB-2)protein is at present uncertain [202, 204], eitherprognostically or for planning therapy with herceptin.The entity “low grade salivary duct carcinoma (lowgrade cribriform cystadenocarcinoma)” has a predominantlyintraductal growth pattern with low-grade cytologicalfeatures [46], and its relationship to usual-typeSDC is as yet uncertain. The tumour is S-100-positiveand the only case studied for AR was negative [19]. Theprognosis is good, and although only a few cases havebeen described, none of the patients has died of disease.5.9.10 Oncocytic CarcinomaICD-O:8290/3Several carcinoma types have variants composed ofoncocytic cells, but only a few dozen cases of pure oncocyticcarcinoma have been reported. The averageage is 63 years (range 29–91), and most have occurredin the parotid [62]; some have arisen in Warthin’s tumours[222]. The diagnosis of a pure oncocytic carcinomarequires the identification of malignancy,oncocytic differentiation and lack of features of anyother tumour type. It is likely that a pure oncocyticcarcinoma is an aggressive tumour, as over half of thepatients reported either died of disease or suffered recurrences[169].5.9.11 Malignancy in PleomorphicAdenoma MalignantMixed TumourThe histological diagnosis of pleomorphic adenoma(PA; benign mixed tumour) is not always straightforward,as benign lesions may display atypical histologicfeatures such as capsular infiltration, hypercellularity,cellular atypia, necrosis and vascular invasion [3, 7],which cause suspected malignancy. In addition, somePAs contain genuine cytologically malignant cells, butbehave in a benign fashion [21, 56]. A further paradoxis the rare occurrence of histologically benign-lookingPAs that metastasise [232]. Thus, the concept of malignancyin PA is much more complex than appears at firstsight. This is reflected by the variable incidence for thereported frequency of malignancy in PA. In several largeseries [83, 125, 149, 209, 223] the average was 3.6% ofall salivary gland tumours and 11.7% of malignancies;overall, malignancy develops in 6.2% of all PAs (rangein different series 1.9 to 23.3%). The incidence of malignantchange increases with the length of history ofthe PA, from 1.5% at 5 years to 10% after 15 years. Theconcept of malignant mixed tumour (MMT) as a malignanttumour that contains remnants of benign mixedtumour was developed by LiVolsi and Perzin in 1977[125]. Spiro et al. [209] agreed with this, but suggesteda possible de novo origin in cases lacking a clinical historyor histological evidence of a pre-existing salivarygland tumour.The revised WHO classification of salivary gland tumours[171] discussed the topic of MMT with the titleCarcinoma in Pleomorphic Adenoma and the sub-titleMalignant Mixed Tumour. Three entities are recognised:carcinoma in pleomorphic adenoma, carcinosarcoma(true malignant mixed tumour) and metastasising pleomorphicadenoma [171]. There is no uniform agreementon this classification as metastasising PA does not containhistological features of malignancy and therefore it isanomalous to include it as a form of malignancy in PA. Inaddition, not all carcinosarcomas arise from a PA. Finally,the possibility of myoepithelial malignancy arising in aPA is not included [49].5.9.11.1 CarcinomaEx Pleomorphic AdenomaICD-O:8941/3Two subtypes should be recognised: invasive and noninvasivecarcinoma.5.9.11.1.1 InvasiveCarcinoma Ex PAThis is the commoner form, in which the malignancyinvolves only the epithelial component. It occurs mainlyin men over 60 years old. Most cases (81.7%) involve theparotid gland, with the submandibular in 18% and thesublingual in 0.3%; the minor salivary glands, particularlyin the palate, can also be affected [229]. The typicalpresentation is a long history of a salivary gland nodulethat suddenly increases in size.The demonstration of both a carcinoma and a PA isnecessary for the diagnosis.A history of a long-standing parotid tumour is notsufficient evidence for a pre-existing PA, whilst a previouslyexcised PA at the site of a carcinoma is acceptable[62].Grossly, carcinoma ex PA is often larger than a benignPA. Histological recognition of a pre-existing PAmay be difficult, as it could be obscured by the carcinoma,or may only show degenerate changes such as

Major and Minor Salivary Glands Chapter 5 157Fig. 5.51. Non-invasive carcinoma in a pleomorphic adenoma.Ducts contain cells with atypical nuclei. Focal necrosis and calcificationis also presentFig. 5.52. True malignant mixed tumour/carcinosarcoma. Theepithelial component is a poorly differentiated carcinoma withsome features suggesting salivary duct carcinoma. The sarcomatouscomponent is a high-grade spindle cell sarcoma, in this case,without specific differentiationscarring, dystrophic calcification, necrosis and haemorrhagewith occasional transitional changes made upof cells showing features intermediate between frankmalignancy and PA [49, 124]. Although the proportionof the malignant component varies from minutefoci to almost the whole lesion, recognition of franklyinvasive carcinoma ex PA is usually simple. Capsular,perineural and vascular invasion are easily identified,as well as extension into neighbouring tissues [49,62, 124].Recent studies show adenocarcinoma not otherwisespecified and salivary duct carcinoma to be themost frequent histological types [49, 87], and there isimmunohistochemical and ultrastructural evidencethat many carcinomas previously described as “undifferentiated”are in fact myoepithelial – indeed manymyoepithelial carcinomas can be shown to have arisenin a pre-existing PA [52, 53, 151, 168]. It is not uncommonto find other concurrent differentiation,e.g. squamous, mucoepidermoid, polymorphous lowgradeadenocarcinoma [125, 149, 209]. In determiningthe prognosis, the extent of invasion is more importantthan the histological type: Tortoledo et al. [223]found that none of the patients whose tumour penetrated8 mm died of disease.A more recent study found that none of the tumoursthat invaded

158 S. Di Palma · R.H.W. Simpson · A. Skalova · I. Leivo5the history will usually be that of rapid growth in a longstandingsalivary nodule.Microscopy shows a biphasic tumour composed ofepithelial and mesenchymal elements. The former isgenerally a poorly differentiated (adeno)carcinoma,but salivary duct carcinoma is increasingly reported(Fig. 5.52) [49, 50]. The other component is usuallya chondrosarcoma, but osteogenic sarcoma, fibrosarcoma,malignant fibrous histiocytoma, pleomorphicrhabdomyosarcoma and osteoclast-type giant cellneoplasms [214, 224] have also been described.Epithelial markers are usually detected in the epithelialcomponent, which may or may not also be expressedin the sarcomatous component. Positive stainingfor epithelial markers has been used as proof of thefact that CS are carcinomas showing divergent differentiationand as an indication of their monoclonal origin.However, keratin staining can be negative castingdoubt onto the monoclonal-carcinomatous nature ofthe whole tumour. Molecular studies have been helpfulin clarifying this issue. In analogous neoplasmsin other organs such as breast, uterus and in salivaryglands, molecular studies have demonstrated that carcinomatousand sarcomatous components have similargenetic profiles. Moreover, in a subset of CS withosteoclastic-type giant cells, Tse et al. [224] found mutationof the same allele on chromosome 17p13, whichis a known mutation of salivary duct carcinoma. Thisindicates that carcinosarcoma are in fact carcinomasof high-grade malignancy and should be treated assuch. HER-2 overexpression on immunohistochemistryis also seen in the salivary duct component of CS.The meaning of this information has still not beenclarified [57].5.9.11.3 MetastasisingPleomorphic AdenomaICD-O:8940/0This tumour is histologically indistinguishable frombenign PA, yet it metastasises widely to sites includinglymph nodes, bone, lung and kidney, and can kill thepatient [232]. Whereas the WHO revised classificationlists metastasising pleomorphic adenoma (MPA)as one entity in the MMT category of [171], it differsbecause it remains histologically “benign” in the primarysite, local recurrences, and metastatic deposits[56, 232].It is a rare tumour with fewer than 100 reported casesso far. Despite this, MPA has a clear-cut clinicopathologicalprofile: the reported cases shared several similarities,such as long time intervals (up to 50 years) betweenthe primary tumour and metastases, and simultaneous,usually multiple, local recurrences and distantmetastases [232]. Although the morphology of both isalmost identical, the recurrences seem to play an importantrole in the genesis of systemic spread. This suggeststhat surgical manipulation may favour vascularimplantation or invasion eventually leading to metastases,but in many cases of MPA it was not possible histologicallyto demonstrate actual vascular permeation[56, 232].5.9.12 Sebaceous CarcinomaICD-O:8410/3Although sebaceous glands are common in the oral mucosa(Fordyce granules), sebaceous neoplasms of the salivaryglands are rare. Most sebaceous carcinomas havearisen in the parotid [62], possibly from pluripotent ductcells [219]. The sex incidence is equal, and the meanage is 69 years (range 17–93). Macroscopically, they arepartly encapsulated and vary in size from 6 to 85 mmacross the greatest diameter. Microscopy shows invasiveislands, duct-like structures and sheets of tumourcells, which may be sebaceous, squamous or basaloid;intracellular mucin may be found [12]. Sebaceous cellsare present in varying numbers, and typically comprisefoamy cytoplasm and a single vesicular nucleus witha prominent nucleolus. Areas of necrosis are frequent[85]. The tumour cells react with cytokeratin and EMA,but not with S-100 protein or actin [219]. The behaviouris intermediate to high-grade, and recurrences, metastasesand death due to disease have all been reported.Three cases of sebaceous lymphadenocarcinoma havebeen described, representing malignant transformationof sebaceous lymphadenoma. One of the patients diedbecause of the tumour [62].5.9.13 Lymphoepithelial CarcinomaICD-O:8082/3The WHO revised classification includes this tumourunder undifferentiated carcinomas [171], but it is a genuineclinicopathological entity and can be consideredseparately.Lymphoepithelial carcinoma is extremely rare exceptin Eskimos (Inuit) and in Southern China. Themedian age is 40 years (range 10–86), and it is slightlycommoner in females [62]; familial clusters have beenidentified amongst patients from Greenland [1]. Theparotid is involved in 80% of cases, with the rest occurringin the submandibular glands. Forty per cent of patientshave lymph node metastases at the time of presentation.A few examples have been described in associationwith lymphoepithelial sialadenitis [121], but amuch more important association is with Epstein-Barr

Major and Minor Salivary Glands Chapter 5 159Table 5.4. Metastases to the parotid gland, adapted from Gnepp [82]Location of primaryNumber of tumoursSkin of head and neck 422 (53.8%)Upper aero-digestive tract (mouth, nose, sinuses, pharynx) 63Eye (conjunctiva, lacrimal gland) 6Thyroid 5Head, not otherwise specified 4Central nervous system 4Submandibular salivary gland 1Lung 28Kidney 23Breast 19Colorectal 7Prostate 4Skin, distant 3Stomach 2Uterus 1Pancreas 1Total, distant sites 88 (11.2%)Skin, not otherwise specified 108Unknown primary site 84virus, and viral genomes can be detected in the malignantcells [89].There is a marked histological similarity to undifferentiatednasopharyngeal carcinoma, which has alsobeen linked to Epstein-Barr virus. Microscopic examinationshows syncytial groups of large epithelialcells with vesicular nuclei and prominent nucleoli,intimately mixed with lymphocytes and plasma cells,sometimes with germinal centre formation. Mitoticfigures are often numerous. At times, the epitheliumis difficult to identify, but it can be highlighted by cytokeratinmarkers. The most important differential diagnosisis a metastasis from a nasopharyngeal primary,which can present as a parotid mass [231], or possiblyvery poorly differentiated squamous carcinoma ofusual type originating in the skin or upper aerodigestivetract. The outcome is surprisingly good for suchan aggressive-looking carcinoma, and the 5-year survivalrate is 60%.5.9.14 Small Cell CarcinomaICD-O:8041/3Small cell carcinoma (SCC) is unlikely to be a singleentity, as electron microscopy reveals that some neoplasmsshow neuroendocrine differentiation, whilstothers have squamous and ductal features not apparenthistologically [15, 118], and occasionally both patternsare evident in the same tumours. Some neoplasmscalled small cell carcinoma may in fact be primaryprimitive neuroectodermal tumours [44]. They are seenmore often in men, and the mean age is 56 years (range5–86) [62]. The microscopic appearance may be similarto small cell carcinoma of the lung or Merkel cell carcinomaof the skin. Both comprise solid sheets, nests andcords of closely packed cells; the difference is in the cellsize – small and dark cells in the former, slightly largerand with pale chromatin in the latter.Immunohistochemistry shows positive staining forchromogranin, synaptophysin, neuron-specific enolaseand CAM5.2, often with paranuclear dots in bothtypes. However, immunohistochemistry for cytokeratin20 seems to identify two subtypes of small cell carcinoma:CK 20− lung cell type and CK 20+ Merkel celltype carcinoma. A recent study by Nagao et al. [148]showed that CK 20+ small cell carcinomas of the salivaryglands have a better prognosis than CK 20− cases.This suggests that staining for CK 20 should beperformed in SCC as the results may have prognosticvalue [148]. The differential diagnosis includes metastasisfrom small cell carcinomas of the lung and thismust be excluded before a primary small cell carcinomacan be said to be of salivary origin. Lymphomasand primary primitive neuroectodermal tumours ofthe salivary glands [44, 105] may be somewhat similarmorphologically, and can be excluded immunohistochemically.

160 S. Di Palma · R.H.W. Simpson · A. Skalova · I. Leivo5High-grade transformation is a rare but well-establishedevent in several primary low-grade salivary carcinomas,and usually heralds a more aggressive clinicalcourse. Examples have been described in acinic cell[51, 95, 154, 213], adenoid cystic [32, 140], epithelialmyoepithelial[2, 73, 186], mucoepidermoid [146] andpolymorphous low-grade adenocarcinoma [160, 191],as well as malignant myoepithelioma [156]. In eachcase, the diagnoses of high-grade change were basedon histopathological criteria, especially increased mitoticand proliferation rates. Most of the transformedcomponents were poorly differentiated adenocarcinomas,but some of those in adenoid cystic and epithelial-myoepithelialcarcinomas showed myoepithelialfeatures. The processes underlying dedifferentiation ofsalivary neoplasms remain to be established, but previousradiotherapy may have been important in some ofthe AdCCs [32] and PLGAs [160]. In general, no definitefactors in the progression of low-grade to highgradecarcinomas have been identified at a molecularlevel [208]; for example, there is conflicting evidenceregarding p53 mutations, which might have been involvedin a single case of transformed AdCC [32], butwas not a factor in dedifferentiated acinic cell carcinomas[51, 95].5.9.16 MetastaticMalignanciesFigs. 5.53, 5.54. Endodermal sinus tumour of the parotid gland.Positive staining for placental alkaline phosphatase (PLAP) is essentialto confirm the diagnosis. Courtesy of Dr. Isabela Wernicke[211]5.9.15 Higher Grade Changein CarcinomasMetastases to the major glands and the intraparotidlymph nodes constitute approximately 10% of all salivarycarcinomas [82]; the exact figure varies fromstudy to study depending on local factors such as differentincidences of particular cancers. For example,Bergensen et al. [18] in Australia reported that metastasesconstituted 72% of all malignancies, resultingfrom the high incidence of skin cancer. In an AFIP seriesand literature review in 1991 of 785 parotid metastases[82], 64% were found to have originated from thehead and neck region (including the skin), 11% fromdistant sites and 25% from an unknown primary. Ofthe distant sites, lung, kidney and breast accounted formore than four-fifths (Table 5.4); only four cases werefrom the prostate, but it is perhaps under-recognised[195]. Metastases to the submandibular glands are lesscommon than to the parotids, but are more likely to befrom distant sites [226].Microscopically, metastases in the salivary glandscan resemble almost any primary tumour, so that forexample, mammary duct carcinoma is morphologicallyidentical (but immunohistochemically different) tosalivary duct carcinoma (see Sect. 5.9.9). Similarly, renalcell carcinoma is part of the differential diagnosisof any clear cell tumour of the salivary glands, and examplesof prostate carcinoma have been mistaken foracinic cell carcinoma [195]. Immunohistochemistry isof some value, and can identify prostate and thyroidprimaries and melanoma with a reasonable degree ofaccuracy. Unlike most primary malignant salivary tumours,renal cell carcinomas are usually negative withcytokeratin 7; in contrast, CD10 stains most kidneycarcinomas, but is only positive in salivary tumourswith myoepithelial differentiation. However, the possibilityof metastasis is still best confirmed or excludedby imaging techniques of the kidneys.

Major and Minor Salivary Glands Chapter 5 1615.10 HybridCarcinomaHybrid tumours are composed of two different types oftumour, each of which conforms to an exactly definedcategory of tumour. They are rare, comprising

162 S. Di Palma · R.H.W. Simpson · A. Skalova · I. Leivo5.13.2 PredominantlyEpithelial Malignancies5Major salivary gland carcinomas with acinar/ductal epithelialdifferentiation include mucoepidermoid carcinoma(MEC), acinic cell carcinoma (AcCC) and salivaryduct carcinoma (SDC). Gene expression profiles havebeen determined in all three using Clontech’s cDNAarrays including 1,176 cancer-related genes [123]. Onlyfive such genes are overexpressed by all these carcinomatypes including fibronectin (FN1), tissue metalloproteinaseinhibitor-1 (TIMP1), biglycan (BGN), tenascin C(HXB), and insulin-like growth-factor binding protein-5 (IGFBP5). Sixteen genes, i.e. KIAA0137/TLK1, VRK2,ADSL, CREBBP, PSM/FOLH, PIK3R1, PRKACB, BAG1,SMAD4/MADH4, TRAM, LAMA4, AKAP1, MAPK13,ATP5J, ATIC, and EPS15, are underexpressed in all ofthem.Average-linkage hierarchical clustering indicatesgenes that are significantly differently expressed amongthese carcinoma types. They were identified using significanceanalysis of microarrays (SAM). In hierarchicalclustering, low-grade and high-grade MECs clusterclosely together, and separate from closely clusteredSDC [123]. A hierarchical clustering of SDC and ACCshows that each entity clusters together, and separatesfrom the other entity. In SAM, 27 genes are significantlydifferently expressed between MEC and SDC [123].Five genes, i.e. MMP11, DAP12, KIAA0324, FASN andCASP10 are overexpressed by SDC, while eight genes,including IL-6 and KRT14 are overexpressed by MEC.Another 14 genes that are mainly involved in DNAmodification, such as NME4, NTHL1, RBBP4, HMG17and NDP52, are underexpressed by MEC. QuantitativeRT-PCR confirms results including overexpression ofFN1 and TIMP1, underexpression of PSM/FOLH1 andMADH4/SMAD4, as well as the difference of expressionprofiles of IL-6, CASP10 and KRT14 between SDC andMEC. Immunohistochemistry indicates distinct expressionof cytokeratin 14 in MEC, with no expression inAcCC and SDC [123].Furthermore, major differences between predominantlymyoepithelial and predominantly epithelial carcinomasalso exist. In MEC and AdCC, the expressionof important effector molecules such as erbB-2, erbB-3, epidermal growth factor receptor and transforminggrowth factoris largely dissimilar [80].The small number of similarly deregulated genesin these major types of salivary gland carcinoma suggestsheterogenic mechanisms of tumorigenesis. Thisis consistent with the great histopathological diversityamong carcinomas of the salivary glands [171]. Diversityis also implicated by differences in gene expressionamong tumour types in hierarchical clustering. Thesmall number of genes jointly overexpressed by majorFig. 5.55. Lymphoepithelial sialoadenitis (LESA): lymphoepitheliallesions are cohesive aggregates of epithelial cells with hyalinisedbasal membrane-like material infiltrated by lymphocytessalivary gland carcinomas with epithelial differentiationrelate to cell adhesion, motility and cell shape (FN1,BGN, HXB), cancer growth, metastasis, tumour angiogenesisand apoptosis (TIMP-1, IGFBP-5). The jointlyunderexpressed genes include cell-cycle proteins, proteinsof signal transduction and translation, and extracellularmatrix and membrane proteins. Interestingly,the jointly underexpressed CREBBP and MADH4/SMAD4 are intimately involved in the TGF-β transcriptionpathway of growth inhibition, and MADH4/SMAD4 has been shown to be deleted or mutated inhalf of pancreatic carcinomas [178]. Thus, overexpressionof TIMP1, PLAT and SFN [38, 178], and underexpressionof MADH4/SMAD4 are shared by carcinomasof the salivary glands and the pancreas, but not withother exocrine carcinomas. In the salivary glands, coordinatedloss of SMAD4 and CREBBP functions couldimpair growth control and promote oncogenic transformation.5.14 Benign and MalignantLymphoid Infiltrates5.14.1 Non-AutoimmuneLymphoid InfiltratesThese can be considered in four groups – obstructive,infective, various non-infective inflammatory processes,and associated with epithelial tumours, especiallycarcinomas (see Sect. 5.9).

Major and Minor Salivary Glands Chapter 5 163Table 5.5. Overview of autoimmune and neoplastic salivary lymphoid proliferations, adapted from Quintana et al. [165]BenignBorderlineLow-grade lymphomaLESA (lymphoepithelial sialadenitis), non-clonal(Histological or clonal evidence of neoplasia, but unlikely to disseminate): LESA,clonal; LESA with halos of marginal zone B-cellsPotential for spread to nodes and less often, systemically: low-grade marginal zoneB-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)– confluent proliferation of marginal zone B-cellsLow-grade marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue(MALT lymphoma) with plasmacytic differentiation5.14.2 Benign AutoimmuneLymphoid InfiltratesThe most frequent form of autoimmune sialadenitis goesunder several synonyms, such as Mikulicz sialadenitis/disease, myoepithelial sialadenitis (MESA) and benignlymphoepithelial lesion, none of which is satisfactory[194]. In 1999, Harris introduced the much more accurateterm, lymphoepithelial sialadenitis (LESA) [91], andthis has begun to gain general acceptance, and will beused here. Sjögren’s syndrome is not a pathological term,but a clinical combination of dry eyes and mouth dueto autoimmune infiltrates of the lacrimal and salivaryglands. It is often associated with other autoimmune orconnective tissue diseases, particularly rheumatoid arthritis,but also for example scleroderma, systemic lupuserythematosus, Hashimoto’s thyroiditis and chronicactive hepatitis. Most patients with Sjögren’s syndromedevelop LESA, but not so the reverse, as up to 50% ofpatients with LESA do not develop the clinical featuresof Sjögren’s syndrome [81].Lymphoepithelial sialadenitis is considered to be anautoimmune disease [40, 77] of unknown aetiology. Severalviruses have been implicated [76, 88], but they actprobably only as cofactors.About 80% of patients with LESA are female, with amean age at presentation of 55 years (range 1 to 86). Theparotids are involved in over 80% of cases (20% bilaterally),the submandibular glands in 11%, usually in combinationwith the parotids [40], and other sites in thehead and neck in 6% [40, 81]. Tumour-like lesions of theminor glands are rare, but in contrast, subclinical focalperiductal and periacinar lymphoplasmacytic infiltratesare frequently seen in the labial salivary glands inSjögren’s syndrome, and a semi-quantitative assessmentof the amount of inflammation in a lip biopsy may beuseful as part of the investigation of patients with a drymouth [41].In the earliest stages of LESA salivary ducts are dilatedand surrounded by a lymphoid infiltrate withgerminal centres. B-cells appear to concentrate aroundthe ducts and focally infiltrate the epithelium, unlikein many non-autoimmune chronic inflammatory infiltrates,where lymphocytic invasion of the ducts isless marked. In LESA many B-cells are of monocytoidor marginal zone type [91]. They are slightly largerthan small lymphocytes of the mantle zone, and arecharacterised by nuclei with irregular outlines somewhatresembling centrocytes [105]. Plasma cells and T-lymphocytes are also present. In time, the ducts condense,with partial or complete loss of their lumina, toform lymphoepithelial lesions (LELs) [105, 172, 194];these were previously inaccurately called epimyoepithelialislands and similarly, the old usage of LEL torefer to the whole lesion should be discontinued [91].LELs consist of cohesive aggregates of epithelium withhyalinised basal lamina material containing variablenumbers of B-cells (Fig. 5.55). Myoepithelial cells arepresent as well, but are often relatively inconspicuous[42]. As the disease progresses the acini become atrophiedand are then totally replaced by lymphoid tissueleading to clinical enlargement of the salivary glands.Monoclonality by PCR can be demonstrated in over40% of patients with LESA [165], but this alone is probablyinsufficient for a diagnosis of lymphoma, andstronger evidence is required from the demonstrationof monoclonality by immunohistochemistry or flowcytometry [107].5.14.3 MalignantLymphomaICD-O:9590/3Overall, extranodal and nodal lymphomas represented16.3% of all malignant tumours of the major salivaryglands at the AFIP from 1985 to 1995 [62]. Almost allextranodal lymphomas are marginal zone B-cell lymphoma(MALT lymphomas), which is the preferred terminologyof the current WHO classification of lymphomas[108].

164 S. Di Palma · R.H.W. Simpson · A. Skalova · I. Leivo5Mucosa-associated lymphoid tissue lymphomas usuallypresent clinically as parotid enlargement, sometimesbilateral [217]. There is often a history of Sjögren’ssyndrome, but not always. Cases have been reported inpost-transplant patients [101]. General lymphadenopathyand bone marrow involvement are unusual in MALTlymphoma, and such a presentation favours a diagnosisof nodal lymphoma.The histopathology of MALT lymphoma is intimatelylinked with that of LESA from which it develops– the risk of lymphoma in LESA has been estimatedat approximately 4–7% [91]. Histological criteriaalone cannot identify exactly when a clonal B-cell populationemerges in LESA, and in practice the processcan be considered not so much a sharp change fromone (benign) entity to another (malignant) one, butrather as a spectrum of lymphoma gradually evolvingfrom a purely inflammatory process (Table 5.5) [165].It can be considered that MALT lymphoma begins asan antigen-driven lymphoid proliferation that progressesfirst to monoclonality and then, with the acquisitionof secondary genetic changes, to MALT lymphoma[105].The microscopic picture evolves with time [105]; theearliest morphologically recognisable feature of malignancyis the proliferation of marginal zone B-cells toform a distinct halo-like zone around the LELs of LESA.As the lymphoma evolves in a background of LESA marginalzones B cells expand, displace and then replace thefollicles. Alternatively, they may colonise the germinalcentres assuming a follicular-like architecture (pseudofollicles)[106]. In addition, there may be foci of sclerosis,and infiltration by epithelioid histiocytes, which canform small granulomas.Mucosa-associated lymphoid tissue lymphoma restrictedto the salivary glands is a relatively indolentdisease that is often curable with local treatment. Prognosisremains favourable even in the presence of otherextranodal sites, including bone marrow [108].Other primary non-MALT extranodal salivary lymphomasare rare, and are mainly T-cell neoplasms[29].Nodal non-Hodgkin’s lymphomas can involve theintra-salivary and adjacent lymph nodes, and theyshould be classified using the appropriate scheme [104,108].5.15 Other TumoursA variety of soft tissue and other non-salivary neoplasmsmay rarely present as tumours of the salivaryglands. These include solitary fibrous tumour, granularcell tumour, follicular dendritic cell sarcoma, inflammatorypseudotumour (inflammatory myofibroblastictumour), primary malignant melanoma, primitive neuroectodermaltumour (PNET) and teratoma.5.16 Unclassified TumoursThe revised WHO classification defines this group asbenign or malignant tumours that cannot be placed inany of the categories [171]. This designation may be unavoidableif only a small quantity of tissue is availablefor study.References1. Albeck H, Bentzen J, Ockelmann HH, Nielsen NH, Bretlau P,Hansen HS (1993) Familial clusters of nasopharyngeal carcinomaand salivary gland carcinomas in Greenland natives.Cancer 72:196–2002. Alós LL, Cardesa A, Bombí JA, Mallofré C, Cuchi A, TraserraJ (1996) Myoepithelial tumors of salivary glands: a clinicopathologic,immunohistochemical and flow-cytometricstudy. Semin Diagn Pathol 13:138–1473. Altini M, Coleman H, Kienkle F (1997) Intra-vascular tumourin pleomorphic adenoma – a report of four cases. Histopathology31:55–594. Angeles-Angeles A, Caballero-Mendoza E, Tapia-Rangel B,Cortés-González R, Larriva-Sahd J (1998) Adenocarcinomagigante de células acinares de tipo quístico papilar en parótida.Rev Invest Clin 50:245–2485. Araújo VC de, Loducca SVL, Sobral APV, Kowalski AL,Soares F, Araújo NS de (2002) Salivary duct carcinoma: cytokeratin14 as a marker of in situ intraductal growth. Histopathology41:244–2496. Auclair P (1994) Tumor-associated lymphoid proliferationin the parotid gland: a potential diagnostic pitfall. Oral SurgOral Med Oral Pathol 77:19–267. Auclair PL, Ellis GL (1996) Atypical features in salivarygland mixed tumors: their relationship to malignant transformation.Mod Pathol 9:652–6578. Barbareschi M, Pecciarini L, Cangi MG, Macrì E, Rizzo A,Viale G, Doglioni C (2001) p63, a p53 homologue, is a selectivenuclear marker of myoepithelial cells of the humanbreast. Am J Surg Pathol 25:1054–10608a. Barnes L, Eveson JW, Reichart P, Sidransky D, (eds) (2005)WHO Classification of Tumours. Pathology and Genetics.Head and Neck Tumours. Chapter 5. Salivary glands. IARCPress Lyon9. Barnes L, Rao U, Krause J, Contis L, Schwartz A, ScalamognaP (1994) Salivary duct carcinoma. I. A clinicopathologicevaluation and DNA image analysis of 13 cases with reviewof the literature. Oral Surg Oral Med Oral Pathol 78:64–7310. Batsakis JG (1979) Tumors of the head and neck: clinical andpathological considerations, 2nd edn. Williams & Wilkins,Baltimore, p 11611. Batsakis JG (1996) Sclerosing polycystic adenosis: a newlyrecognized salivary gland lesion, a form of chronic sialadenitis.Adv Anat Pathol 3:298–30412. Batsakis JG, El-Naggar AK (1990) Sebaceous lesions of salivaryglands and oral cavity. Ann Otol Rhinol Laryngol99:416–41813. Batsakis JG, El-Naggar AK, Luna MA (1992) Epithelial-myoepithelialcarcinoma of salivary glands. Ann Otol RhinolLaryngol 101:540–54214. Batsakis JG, Frankenthaler R (1992) Embryoma (sialoblastoma)of salivary glands. Ann Otol Rhinol Laryngol 101:958–960

Major and Minor Salivary Glands Chapter 5 16515. Batsakis JG, Luna MA (1991) Undifferentiated carcinomas ofsalivary glands. Ann Otol Rhinol Laryngol 100:82–8416. Batsakis JG, Luna MA (1991) Basaloid salivary carcinomas.Ann Otol Rhinol Laryngol 100:785–78717. Batsakis JG, Manning JT (1987) Necrotizing sialometaplasiaof major salivary glands. J Laryngol Otol 101:962–96618. Bergensen PJ, Kennedy PJ, Kneale KL (1987) Metastatic tumoursof the parotid region. Aust NZ J Surg 57:23–2619. Brandwein-Gensler M, Hille J, Wang BY, Urken M, GordonR, Wang LJ, Simpson JR, Simpson RH, Gnepp DR (2004)Low-grade salivary duct carcinoma: description of 16 cases.Am J Surg Pathol 28:1040–104420. Brandwein MS, Huvos AG (1991) Oncocytic tumors of majorsalivary glands. A study of 68 cases with follow-up of 44 patients.Am J Surg Pathol 15:514–52821. Brandwein M, Huvos AG, Dardick I, Thomas MG, Theise ND(1996) Noninvasive and minimally invasive carcinoma exmixed tumor. A clinicopathologic and ploidy study of 12 patientswith major salivary tumors of low malignant potential.Oral Surg Oral Med Oral Pathol 81:665–66422. Brandwein MS, Ivanov K, Wallace DI, Hille JJ, Wang B, FahmyA, Bodian C, Urken ML, Gnepp DR, Huvos A, LumermanH, Mills SE (2001) Mucoepidermoid carcinoma: a clinicopathologicstudy of 80 patients with special reference tohistological grading. Am J Surg Pathol 25:835–84523. Brandwein MS, Jagirdar J, Patil J, Biller H, Kaneko M (1990)Salivary duct carcinoma (cribriform salivary carcinoma ofexcretory ducts): a clinicopathologic and immunohistochemicalstudy of 12 cases. Cancer 65:2307–231424. Brannon RB, Fowler CB, Hartman KS (1991) Necrotizing sialometaplasia:a clinicopathologic study of sixty-nine casesand review of the literature. Oral Surg Oral Med Oral Path72:317–32525. Buchner A, Merrell PW, Carpenter WM, Leider AS (1991)Adenomatoid hyperplasia of minor salivary glands. OralSurg Oral Med Oral Pathol 71:583–58726. Castle JT, Thompson LDR, Frommelt RA, Wenig BM, KesslerHP (1996) Polymorphous low-grade adenocarcinoma: a clinicopathologicstudy of 164 cases. Cancer 86:207–21927. Chan JKC, Hui PK, Ng CS, Yuen NWF, Kung ITM, Gwi E(1989) Epithelioid haemangioma (angiolymphoid hyperplasiawith eosinophilia) and Kimura’s disease in Chinese. Histopathology15:557–57428. Chan JKC, Tang SK, Tsang WYW, Lee KC, Batsakis JG (1996)Histologic changes induced by fine-needle aspiration. AdvAnat Pathol 3:71–9029. Chan JKC, Tsang WYW, Hui P-K, Ng C-S, Sin V-C, KhanSM, Siu LLP (1997) T-and T/Natural killer-cell lymphomasof the salivary gland: a clinicopathologic, immunohistochemicaland molecular study of six cases. Hum Pathol28:238–24530. Chau MN, Radden BG (1989) A clinico-pathological study of53 intra-oral pleomorphic adenomas. Int J Oral MaxillofacSurg 18:158–16231. Chetty R (2000) Intercalated duct hyperplasia: possible relationshipto epithelial-myoepithelial carcinoma and hybridtumours of salivary gland. Histopathology 37:260–26332. Cheuk W, Chan JK, Ngan RK (1999) Dedifferentiation inadenoid cystic carcinoma of salivary gland: an uncommoncomplication associated with an accelerated clinical course.Am J Surg Pathol 23:465–47233. Chieng DC, Paulino AF (2002) Cytology of myoepithelialcarcinoma of the salivary gland: a study of four cases. Cancer(Cancer Cytopathol) 96:32–3634. Cho KJ, El-Naggar AK, Ordóñez NG, Luna MA, Austin J,Batsakis JG (1995) Epithelial-myoepithelial carcinoma of salivaryglands: a clinicopathologic, DNA flow cytometric, andimmunohistochemical study of Ki-67 and HER-2/neu oncogene.Am J Clin Pathol 103:432–43735. Claros P, Dominte G, Claros Jr A, Castillo M, Cardesa A,Claros A (2002) Parotid gland mucoepidermoid carcinomain a 4 year old child. Int J Pedriatr Otorhinolaryngol 63:67–7236. Colmenero Ruiz C, Patrón Romero M, Martín Pérez M (1993)Salivary duct carcinoma: a report of nine cases. J Oral MaxillofacSurg 51:641–64637. Croitoru CM, Suarez PA, Luna MA (1999) Hybrid carcinomaof salivary glands: report of 4 cases and review of the literature.Arch Pathol Lab Med 123:698–70238. Crnogorac-Jurcevic T, Efthimiou E, Nielsen T, Loader J, TerrisB, Stamp G, Baron A, Scarpa A, Lemoine NR (2002) Expressionprofiling of microdissected pancreatic adenocarcinomas.Oncogene 21:4587–459439. Daley TD (1984) The canalicular adenoma: considerationson differential diagnosis and treatment. J Oral MaxillofacSurg 42:728–73040. Daniels TE (1991) Benign lymphoepithelial lesion andSjögren’s syndrome. In: Ellis GL, Auclair PL, Gnepp DR (eds)Surgical pathology of the salivary glands. Saunders, Philadelphia,pp 83–10641. Daniels TE, Fox PS (1992) Salivary and oral components ofSjögren’s syndrome. Rheum Dis Clin N Am 18:571–58942. Dardick I, van Nostrand P, Rippstein P, Skimming L, HoppeD, Dairkee SH (1988) Characterization of epimyoepithelialislands in benign lymphoepithelial lesions of major salivarygland: an immunohistochemical and ultrastructural study.Head Neck Surg 10:168–17843. Dardick I, Thomas MJ, Nostrand AWP van (1989) Myoepithelioma– new concepts of histology and classification: alight and electron microscopic study. Ultrastruct Pathol13:187–22444. Deb RA, Desai SB, Amonkar PP, Aiyer PM, Borges AM(1998) Primary primitive neuroectodermal tumour of theparotid gland. Histopathology 33:375–37845. Dehner LP, Valbuena L, Perez-Atayde A, Reddick RL, AskinFB, Rosai J (1984) Salivary gland anlage tumor (“congenitalpleomorphic adenoma”): a clinicopathologic, immunohistochemicaland ultrastructural study of nine cases. Am J SurgPathol 18:25–3646. Delgado R, Klimstra D, Albores-Saavedra J (1996) Low gradesalivary duct carcinoma: a distinctive variant with a lowgrade histology and a predominant intraductal growth pattern.Cancer 78:958–96747. Delgado R, Vuitch F, Albores-Saavedra J (1993) Salivary ductcarcinoma. Cancer 72:1503–151248. Di Palma S (1994) Epithelial-myoepithelial carcinoma withco-existing multifocal intercalated duct hyperplasia of theparotid gland. Histopathology 25:494–49649. Di Palma S (2003) Malignancy in pleomorphic adenoma(malignant mixed tumour) of salivary glands. Gale N, LuzarB (eds) Proceedings in head and neck pathology. Institute ofPathology Faculty of Medicine, University of Lubljana, Lubljana4–6 September 2003, pp 92–9850. Di Palma S (2004) Case 23, slide seminar of head and neckpathology. II. Intercontinental Congress of Pathology, Iguassu,Brazil51. Di Palma S, Corletto V, Lavarino C, Birindelli S, Pilotti S(1999) Unilateral aneuploid dedifferentiated acinic cell carcinomaassociated with bilateral low grade diploid acinic cellcarcinoma of the parotid gland. Virchows Arch 434:361–36552. Di Palma S, Guzzo M (1993) Malignant myoepithelioma ofsalivary glands: clinicopathological features of ten cases.Virchows Arch A Pathol Anat 423:389–39653. Di Palma S, Guzzo M (1998) Myoepithelial carcinoma withpredominance of plasmacytoid cells arising in a pleomorphicadenoma of the parotid gland. Histopathology 33:48554. Di Palma S, Pilotti S, Rilke F (1991) Malignant myoepitheliomaof the parotid arising in a pleomorphic adenoma. Histopathology19:273–27555. Di Palma S, Simpson RHW, Skálová A, Michal M (1999)Metaplastic (infarcted) Warthin’s tumour of the parotidgland: a possible consequence of fine needle aspiration biopsy.Histopathology 35:432–43856. Di Palma S, Skálová A (1999) Malignancy in pleomorphic adenoma.Rev Esp Patol 32:431–432

166 S. Di Palma · R.H.W. Simpson · A. Skalova · I. Leivo557. Di Palma S, Skalova A, Vanecek T, Simpson RHW, StarekI, Leivo I (2005) Non invasive intracapsular) carcinoma expleomorphic adenoma: recognition of focal carcinoma byHER-2/neu and MIB-1 immunohistochemistry. Histopathology46:144–15258. Donath K, Seifert G (1997) Sclerosing polycystic siadadenopathy.Pathologe 18:368–37359. Edwards PC, Bhuiya T, Kelsch RD (2003) C-kit expressionin the salivary gland neoplasms adenoid cystic carcinoma,polymorphous low-grade adenocarcinoma, and monomorphicadenoma. Oral Surg Oral Med Oral Pathol Oral RadiolEndod 95:686–69360. Elliott JN, Oertel YC (1990) Lymphoepithelial cysts of thesalivary glands: histologic and cytologic features. Am J ClinPathol 93:39–4361. Ellis GL (1988) “Clear cell” oncocytoma of salivary gland.Hum Pathol 19:862–86762. Ellis GL, Auclair PL (1996) Malignant epithelial tumors. In:Atlas of tumor pathology, 3rd series, fascicle 17: tumors ofthe salivary glands. AFIP, Washington DC63. Evans HL, Luna MA (2000) Polymorphous low-grade adenocarcinoma:a study of 40 cases with long-term follow up andevaluation of the importance of papillary areas. Am J SurgPathol 24:1319–132864. Eveson JW (1992) Troublesome tumours 2: borderline tumoursof salivary glands. J Clin Pathol 45:369–37765. Eveson JW (1999) Oncocytic and squamous differentiationin salivary glands and tumors. Rev Esp Patol 32:433–43466. Eveson JW, Cawson RA (1989) Infarcted (‘infected’) adenolymphomas.A clinicopathological study of 20 cases. ClinOtolaryngol 14:205–21067. Feind CR (1972) The head and neck. In: Haagensen CD,Feind CR, Herter FP (eds) The lymphatics in cancer. Saunders,Philadelphia, pp 63–6468. Felix A, Rosa-Santos J, Mendoca ME, Torrinha F, Soares J(2002) Intracapsular carcinoma ex pleomorphic adenoma.Report of a case with unusual metastatic behaviour. Oral Oncol38:107–11069. Ferlito A, Gale N, Hvala H (1981) Laryngeal salivary ductcarcinoma: a light and electron microscopic study. J LaryngolOtol 95:731–73870. Ferreiro JA (1994) Immunohistochemistry of basal cell adenomaof the major salivary glands. Histopathology 24:539–54271. Fonseca I, Soares J (1993) Epithelial-myoepithelial carcinomaof the salivary glands. A study of 22 cases. Virchows ArchA Pathol Anat 422:389–39672. Fonseca I, Soares J (1996) Basal cell adenocarcinoma of minorsalivary and seromucinous glands of the head and neckregion. Semin Diagn Pathol 13:128–13773. Fonseca I, Felix A, Soares J (2000) Dedifferentiation in salivarygland carcinomas. Am. J. Surg Pathol 24:469–47174. Foschini M, Scarpellini F, Gown AM, Eusebi V (2000) Differentialexpression of myoepithelial markers in salivary,sweat and mammary glands. Int J Surg Pathol 8:29–3775. Foucar E, Rosai J, Dorfman R (1990) Sinus histiocytosis withmassive lymphadenopathy (Rosai-Dorfman disease): reviewof the entity. Semin Diagn Pathol 7:19–7376. Fox RI, Pearson G, Vaughan JH (1986) Detection of Epstein-Barr virus-associated antigens and DNA in salivary glandbiopsies from patients with Sjögren’s syndrome. J Immunol137:3162–316877. Fox RI, Kang HI (1992) Pathogenesis of Sjögren’s syndrome.Rheum Dis Clin N Am 18:517–53878. Francioso F, Carinci F, Tosi L, Scapoli L, Pezetti F, PasserellaE, Evangelisti R, Pastore A, Pelucchi S, Piattelli A, Rubini C,Fioroni M, Carinci P, Volinia S (2002) Identification of differentiallyexpressed genes in human salivary gland tumors byDNA microarrays. Mol Cancer Ther 1:533–53879. Frierson HF, El-Naggar AK, Welsh JB, Sapinoso LM, Su, AI,Cheng J, Saku T, Moskaluk CA, Hampton GM (2002) Largescale molecular analysis identifies genes with altered expressionin salivary adenoid cystic carcinoma. Am J Surg Pathol161:1315–132380. Gibbons MD, Manne U, Carroll WR, Peters GE, Weiss HL,Grizzle WE (2001) Molecular differences in mucoepidermoidcarcinoma and adenoid cystic carcinoma of the majorsalivary glands. Laryngoscope 111:1373–137881. Gleeson MJ, Cawson RA, Bennett MH (1986) Benign lymphoepitheliallesion: a less than benign disease. Clin Otolaryngol11:47–5182. Gnepp DR (1991) Metastatic disease to the major salivaryglands. In: Ellis GL, Auclair PL, Gnepp DR (eds) Surgicalpathology of the salivary glands. Saunders, Philadelphia, pp560–56983. Gnepp DR (1993) Malignant mixed tumors of salivary glands:a review. Pathol Annu 28:279–32884. Gnepp DR (2003) Sclerosing polycystic adenosis of the salivarygland: a lesion that may be associated with dysplasia andcarcinoma in situ. Adv Anat Pathol 10:218–22285. Gnepp DR, Brannon R (1984) Sebaceous neoplasms of salivarygland origin: report of 21 cases. Cancer 53:2155–217086. Grenko R T, Gemryd P, Tytor M, Lundqvist PG, Boeryd B(1995) Salivary duct carcinoma. Histopathology 26:261–26687. Guzzo M, Di Palma S, Grandi C, Molinari R (1997) Salivaryduct carcinoma: clinical characteristics and treatment strategies.Head Neck 19:126–13388. Haddad J, Deny P, Munz-Gotheil C, Ambrosini JC, TrinchetJC, Pateron D, Mal F, Callard P, Beaugrand M (1992) Lymphocyticsialadenitis of Sjögren’s syndrome associated withchronic hepatitis C virus liver disease. Lancet 339:321–32389. Hamilton-Dutoit SJ, Therkildsen MH, Nielsen NH, Jensen H,Hansen JPH, Pallesen G (1991) Undifferentiated carcinomaof the salivary gland in Greenlandic Eskimos: demonstrationof Epstein-Barr virus DNA by in situ nucleic acid hybridization.Hum Pathol 22:811–81590. Harmse JL, Saleh HA, Odutoye T, Alsanjari NA, MountainRE (1997) Recurrent canalicular adenoma of the minor salivaryglands in the upper lip. J Larygol Otol 111:985–98791. Harris NL (1999) Lymphoid proliferations of the salivaryglands. Am J Clin Pathol 111 [Suppl 1]:S94–S10392. Heikinheimo AK, Laine MA, Ritvos OV-P, Voutilainen RJ,Hogan BLM, Leivo I (1999) Bone morphogenetic protein-6 isa marker of serous acinar cell differentiation in normal andneoplastic human salivary gland. Cancer Res 59:5815–582193. Hellquist HB, Karlsson MG, Nilsson C (1994) Salivary ductcarcinoma – a highly aggressive salivary gland tumour withoverexpression of c-erbB-2. J Pathol 172:35–4494. Hellquist HB, Sundelin K, Di Bacco A, Tytor M, ManzottiM, Viale G (1997) Tumour growth fraction and apoptosis insalivary gland acinic cell carcinomas. Prognostic implicationsof Ki-67 and bcl-2 expression and of in situ end labelling(TUNEL). J Pathol 181:323–32995. Henley JD, Geary WA, Jackson CL, Wu CD, Gnepp DR (1997)Dedifferentiated acinic cell carcinoma of the parotid gland: adistinct rarely described entity. Hum Pathol 28:869–87396. Henley JD, Seo IS, Dayan D, Gnepp DR (2000). Sarcomatoidsalivary duct carcinoma of the parotid gland. Hum Pathol31:208–21397. Henriksson G, Westrin KM, Carlsöö B, Silfverswärd C (1998)Recurrent primary pleomorphic adenomas of salivary glandorigin: intrasurgical rupture, histopathologic features, andpseudopodia. Cancer 82:617–62098. Herold J, Nicholson AG (1992) Fine needle aspiration cytologyin the diagnosis of amyloid in the submandibular gland.Br J Oral Maxillofac Surg 30:393–39499. Hoang MP, Callender DL, Sola-Gallego JJ, Huang Z, SneigeN, Luna MA, Batsakis JG, El-Naggar AK (2001) Molecularand biomarker analyses of salivary duct carcinomas: comparisonwith mammary duct carcinoma. Int J Oncol 19:865–871

Major and Minor Salivary Glands Chapter 5 167100. Honda K, Kashima K, Yokohama S, Nakayama I (2000)Clonal analysis of the epithelial component of Warthin’s tumor.Hum Pathol 31:1377–1380101. Hsi ED, Singleton TP, Swinnen L, Dunphy CH, Alkan S(2000) Mucosa-associated lymphoid tissue-type lymphomasoccurring in post-transplantation patients. Am J Surg Pathol24:100–106102. Hsueh C, Gonzalez-Crussi F (1992) Sialoblastoma: a case reportand review of the literature on congenital epithelial tumorsof salivary gland origin. Pediatr Pathol 12:205–214103. Hui KK, Batsakis JG, Luna MA, MacKay B, Byers RM (1986)Salivary duct adenocarcinoma: a high grade malignancy. JLaryngol Otol 100:105–114104. Isaacson PG (1996) Malignant lymphomas with a folliculargrowth pattern. Histopathology 28:487–495105. Isaacson PG, Norton AJ (1994) Malignant lymphoma of thesalivary glands. In: Isaacson PG, Norton AG (eds) Extranodallymphomas. Churchill-Livingstone, Edinburgh, pp 67–83106. Isaacson PG, Wotherspoon AC, Diss TC, Pan LX (1991) Follicularcolonization in B-cell lymphoma of MALT. Am J SurgPathol 15:819–828107. Jaffe ES (2002) Lymphoid lesions of the head and neck: amodel of lymphocyte homing and lymphomagenesis. ModPathol 15:255–263108. Jaffe ES, Harris NL, Stein H, Vardiman JW (2001) WorldHealth Organization classification of tumours: tumours ofhaematopoietic and lymphoid tissues. Springer, Berlin HeidelbergNew York109. Jahan-Parwar B, Huberman RM, Donovan D (1999) Oncocyticmucoepidermoid carcinoma of the salivary glands. AmJ Surg Pathol 23:523–529110. James GK, Pudek M, Berean KW, Diamandis EP, ArchibaldBL (1996) Salivary duct carcinoma secreting prostate-specificantigen. Am J Clin Pathol 106:242–247111. Jayakrishnan A, Elmalah I, Hussain K, Odell EW (2003) Basalcell adenocarcinoma in minor salivary glands. Histopathology42:610–614112. Jeng YM, Lin CY, Hsu HC (2000) Expression of the c-kit proteinis associated with certain subtypes of salivary gland carcinoma.Cancer Lett 154:107–111113. Jensen JL (1991) Idiopathic diseases. In: EllisGL, Auclair PL,Gnepp DR.(eds) Surgical pathology of the salivary glands.Saunders, Philadelphia, pp 60–82114. Jones H, Moshtael F, Simpson RHW (1992) Immunoreactivityof smooth muscle actin in salivary gland tumours: a comparisonwith S 100 protein. J Clin Pathol 45:938–940115. Kay PA, Roche PC, Olsen KD, Lewis JE (2001) Salivary ductcarcinoma: immunohistochemical analysis of androgen receptor,prostate markers and HER-2/neu oncoprotein in 40cases. [Abstract]. Mod Pathol 14:150A116. Kemp BL, Batsakis JG, El-Naggar AK, Kotliar SN, Luna MA(1995) Terminal duct adenocarcinomas of the parotid gland.J Laryngol Otol 109:466–468117. Kokemueller H, Eckardt A, Brachvogel P, Hausamen JE(2004) Adenoid cystic carcinoma of the head and neck – a 20years experience. Int J Oral Maxillofac Surg 33:25–31118. Kraemer BB, MacKay B, Batsakis JG (1983) Small cell carcinomasof the parotid gland: a clinicopathologic study ofthree cases. Cancer 52:2115–2121119. Kratochvil FJ (1991) Canalicular adenoma and basal cell adenoma.In: Ellis GL, Auclair PL, Gnepp DR (eds) Surgical pathologyof the salivary glands. Saunders, Philadelphia, pp202–224120. Krieken JHJM van (1993) Prostate marker immunoreactivityin salivary gland neoplasms: a rare pitfall in immunohistochemistry.Am J Surg Pathol 17:410–414121. Krishnamurthy S, Lanier AP, Dohan P, Lanier JF, Henle W(1988) Salivary gland cancer in Alaskan natives, 1966–1980.Hum Pathol 18:986–996; erratum 19:328122. Kumar RV, Kini L, Bhargava AK, Mukherjee G, HazarikhaD, Shenoy AM, Anantha N (1993) Salivary duct carcinoma. JSurg Oncol 54:193–198123. Leivo I, Jee, KJ, Heikinheimo K, Laine M, Ollila J, Nagy B,Knuutila S (2005) Characterization of gene expression in majortypes of salivary gland carcinoma with epithelial differentiation.Cancer Genet Cytogenet 156:104–113124. Lewis JE, Olsen KD, Sebo TJ (2001) Carcinoma ex pleomorphicadenoma: pathologic analysis of 73 cases. Hum Pathol32:596–604125. LiVolsi VA, Perzin KH (1977) Malignant mixed tumor arisingin salivary gland: carcinomas arising in benign mixed tumor.A clinico-pathologic study. Cancer 39:2209–2230126. Li S, Baloch ZW, Tomaszewski JE, Livolsi VA (2000) Worrisomehistologic alteration following fine-needle aspiration ofbenign parotid lesions. Arch Pathol Lab Med 124:87–91127. Luna MA, Batsakis JG, Tortoledo ME, del Junco GW (1989)Carcinomas ex monomorphic adenoma of salivary glands. JLaryngol Otol 103:756–759128. Luna MA, Tortoledo ME, Allen M (1987) Salivary dermal analoguetumors arising in lymph nodes. Cancer 59:1165–1169129. Martinez-Madrigal F, Micheau C (1989) Histology of the majorsalivary glands. Am J Surg Pathol 13:879–899130. Maurizi M, Salvinelli F, Capelli A (1990) Monomorphic adenomasof the major salivary glands: clinicopathologicalstudy of 44 cases. J Laryngol Otol 104:790–796131. McCluggage G, Sloan J, Cameron S, Hamilton P, Toner P(1995) Basal cell adenocarcinoma of the submandibulargland. Oral Surg Oral Med Oral Pathol Oral Radiol Endod79:342–350132. Michal M, Skálová A, Simpson RHW, Rychterová V, Leivo I(1996) Clear cell malignant myoepithelioma of the salivaryglands. Histopathology 28:309–315133. Michal M, Skálová A, Simpson RHW, Leivo I, Ryška A,Stárek I (1997) Well differentiated acinic cell carcinoma ofsalivary glands associated with lymphoid rich stroma: clinicopathologicand immunohistochemical study using a proliferativemarker MIB1. Hum Pathol 28:595–600134. Michal M, Skálová A, Simpson RHW, Raslan WF, Čuřík R,Leivo I, Mukenšnábl P (1999) Cribriform adenocarcinoma ofthe tongue: a hitherto unrecognized type of adenocarcinomacharacteristically occurring in the tongue. Histopathology35:495–501135. Michal M, Skálová A, Hrabal P (2002) Micropapillary carcinomaof the parotid gland arising in mucinous cystoadenoma.Virchows Arch 437:465–468136. Michal M, Sokol L, Mukenšnábl P (1996) Salivary gland anlagetumor. A case with widespread necrosis and large cystformation (congenital pleomorphic adenoma). Pathology28:128–130137. Mikulicz J von (1982) Über eine eigenartige symmetrischeErkrankung der Tränen- und Mundspeicheldrüsen. BeitrChir Festschr Theodor Billroth, pp 610–630138. Milchgrub S, Gnepp DR, Vuitch F, Delgado R, Albores-SaavedraJ (1994) Hyalinizing clear cell carcinoma of the salivarygland. Am J Surg Pathol 18:74–82139. Mima T, Shirasuna K, Kishino M, Matsuya T (1996) Basalcell adenocarcinoma of the sublingual gland: report of a case.J Oral Maxillofac Surg 54:1121–1123140. Moles MA, Avila IR, Archilla AR (1999) Dedifferentiationoccurring in adenoid cystic carcinoma of the tongue. OralSurg Oral Med Oral Pathol Oral Radiol Endod 88:177–180141. Moody AB, Avery CME, Harrison JD (1998) Dermoid cyst ofthe parotid gland. Int J Oral Maxillofac Surg 27:461–462142. Moriki T, Ueta S, Takahashi T, Mitani M, Ichien M (2001)Salivary duct carcinoma: cytologic characteristics and applicationof androgen receptor immunostaining for diagnosis.Cancer (Cancer Cytopathol) 93:344–350143. Moritani S, Kushima R, Sugihara H, Bamba M, KobayashiTK, Hattori T (2002) Availability of CD10 immunohistochemistryas a marker of breast myoepithelial cells on paraffinsections. Mod Pathol 15:397–405144. Muller S, Barnes LE (1996) Basal cell adenocarcinoma of thesalivary glands: report of seven cases and review of the literature.Cancer 78:2471–2477

168 S. Di Palma · R.H.W. Simpson · A. Skalova · I. Leivo5145. Murrah VA, Batsakis JG (1994) Salivary duct carcinoma.Ann Otol Rhinol Laryngol 103:244–247146. Nagao T, Gaffey TA, Kay PA, Unni KK, Nascimento AG, SeboTJ, Serizawa H, Minato H, Lewis JE (2003) Dedifferentiationin low-grade mucoepidermoid carcinoma of the parotidgland. Hum Pathol 34:1068–1072147. Nagao T, Gaffey TA, Visscher DW, Kay PA, Minato H, SerizawaH (2004) Invasive micropapillary salivary duct carcinoma:a distinct histologic variant with biologic significance.Am J Surg Pathol 28:319–326148. Nagao T, Gaffey TA, Olsen KD, Serizawa H, Lewis JE (2004)Small cell carcinoma of the major salivary glands. Clinicopathologicstudy with emphasis on cytokeratin immunoreactivityand clinical outcome. Am J Surg Pathol 28:762–770149. Nagao K, Matsuzaki O, Saiga H, Sugano I, Shigematsu H,Kaneko T, Katoh T, Kitamura T (1981) Histopathologic studieson carcinoma in pleomorphic adenoma of the parotidgland. Cancer 48:113–121150. Nagao T, Serizawa H, Iwaya K, Shimizu T, Sugano I, Ishida Y,Yamazaki K, Shimizu M, Itoh T, Konno A, Ebihara Y (2002)Keratocystoma of the parotid gland: a report of two cases ofan unusual pathologic entity. Mod Pathol 15:1005–1010151. Nagao T, Sugano I, Ishida Y, Tajima Y, Matsuzaki O, KonnoA, Kondo Y, Nagao K (1998) Salivary gland malignant myoepithelioma:a clinicopathologic and immunohistochemicalstudy of ten cases. Cancer 83:1292–1299152. Nagao T, Sugano I, Ishida Y, Hasegawa M, Matsuzaki O,Konno A, Kondo Y, Nagao K (1998) Basal cell adenocarcinomaof the salivary glands; comparison with basal cell adenomathrough assessment of cell proliferation, apoptosis, andexpression of p53 and bcl-2. Cancer 82:439–447153. Nasser SM, Faquin WC, Dayal Y (2003) Expression of androgen,estrogen, and progesterone receptor in salivary glandtumours. Frequent expression of androgen receptor in a subsetof malignant salivary gland tumours. Am J Clin Pathol119:801–806154. Nunes JF, Fonseca I, Soares J (1996) Helioid inclusions in dedifferentiatedacinic cell carcinoma of the parotid gland. UltrastructPathol 20:443–449155. Nyrop M (1994) Kimura’s disease: case report and brief reviewof the literature. J Laryngol Otol 108:1005–1007156. Ogawa I, Nishida T, Miyauchi M, Sato S, Takata T (2003)Dedifferentiated malignant myoepithelioma of the parotidgland. Pathol Int 53:704–709157. Ogawa Y, Kishino M, Atsumi Y, Kimoto M, Fukuda Y, IshidaT (2003) Plasmocytoid cells in salivary-gland pleomorphicadenomas: evidence of luminal differentiation. VirchowsArch 443:625–634158. Palmer TJ, Gleeson MJ, Eveson JW, Cawson RA (1990) Oncocyticadenomas and oncocytic hyperplasia of salivaryglands. A clinicopathological study of 26 cases. Histopathology16:487–493159. Parrett TJ, Prasad AR, Raslan WF, Kakar S, Lewis JE (2002)Long term and life-long follow-up in polymorphous lowgrade adenocarcinoma (Abstract). Mod Pathol 15:223A160. Pelkey TJ, Mills SE (1999) Histologic transformation of polymorphouslow-grade adenocarcinoma of salivary gland. AmJ Clin Pathol 111:785–791161. Perzin KH, LiVolsi VA (1980) Acinic cell carcinoma arisingin ectopic salivary gland tissue. Cancer 45:967–972162. Pesce C, Colacino R, Buffa P (1986) Duct carcinoma of the minorsalivary glands: a case report. J Laryngol Otol 100:611–613163. Pieterse AS, Seymore AE (1981) Parotid cysts: an analysis of16 cases and suggested classification. Pathology 13:225–234164. Prasad AR, Savera AT, Gown AM, Zarbo RJ (1999) The myoepithelialimmunophenotype in 135 benign and malignantsalivary gland tumors other than pleomorphic adenoma.Arch Pathol Lab Med 123:801–806165. Quintana PG, Kapadia SB, Bahler DW, Johnson JT, SwerdlowSH (1997) Salivary gland lymphoid infiltrates associatedwith lymphoepithelial lesions: a clinicopathologic, immunophenotypic,and genotypic study. Hum Pathol 28:850–861166. Reis-Filho JS, Simpson RHW, Fulford LG, Steppeler Y, MartinsA, Schmitt FC (2004) p63 distribution in normal salivarygland and salivary gland neoplasms (abstract). ModPathol 17:231A167. Russo G, Zegar C, Giordano A (2003) Advantages and limitationsof microarray technology in human cancer. Oncogene22:6497–6507168. Savera AT, Sloman A, Huvos AG, Klimstra DS (2000) Myoepithelialcarcinoma of the salivary glands: a clinicopathologicstudy of 25 patients. Am J Surg Pathol 24:761–774169. Scher RL, Feldman PS, Lambert PR (1991) Oncocytic malignancyof the parotid gland. Otolaryngol Head Neck Surg105:868–876170. Sciubba JJ, Brannon RB (1982) Myoepithelioma of salivaryglands: report of 23 cases. Cancer 49:562–572171. Seifert G (1991) World Health Organization internationalhistological classification of tumours: histological typing ofsalivary gland tumours, 2nd edn. Springer, Berlin HeidelbergNew York172. Seifert G (1992) Tumour-like lesions of the salivary glands:the new WHO classification. Pathol Res Pract 188:836–846173. Seifert G (1996) Mucoepidermoid carcinoma in a salivaryduct cyst of the parotid gland: contribution to the developmentof tumours in salivary gland cysts. Pathol Res Pract192:1211–1217174. Seifert G (1996) Classification and differential diagnosis ofclear and basal cell tumors of the salivary glands. Semin DiagnPathol 13:95–103175. Seifert G (1997) Primäre Speicheldrüsentumoren in Lymphknotender Parotis: Bericht über 3 Fälle und Übersicht überdie Literatur. Pathologe 18:141–146176. Seifert G, Miehlke A, Haubrich J, Chilla R (1986) Diseases ofthe salivary glands. Thieme, Stuttgart177. Seifert G, Thomsen S, Donath K (1981) Bilateral dysgeneticpolycystic parotid glands: morphological analysis and differentialdiagnosis of a rare disease of the salivary glands. VirchowsArch A Pathol Anat Histol 390:273–288178. Servillo G, Della Fazia MA, Sassone-Corsi P (2002) CouplingcAMP signaling to transcription in the liver: pivotal role ofCREB and CREM. Exp Cell Res 275:143–154179. Sheldon WH (1943) So-called mixed tumors of the salivaryglands. Arch Pathol 35:1–20180. Shintaku M, Honda T (1997) Identification of oncocytic lesionsof salivary glands by anti-mitochondrial immunohistochemistry.Histopathology 31:408–411181. Simpson RHW (1994) Classification of tumours of salivaryglands. Histopathology 24:187–191182. Simpson RHW (1999) Clear cell tumors. Rev Esp Patol32:432–433183. Simpson RHW (2002) Myoepithelial tumours of the salivaryglands. Curr Diagn Pathol 8:328–337184. Simpson RHW (2004) Case 22, slide seminar head and neckpathology. II. Intercontinental Congress of Pathology, Iguassu,Brazil, 2004185. Simpson RHW, Clarke TJ, Sarsfield PTL, Babajews AV (1991)Salivary duct adenocarcinoma. Histopathology 18:229–235186. Simpson RHW, Clarke TJ, Sarsfield PTL, Gluckman PGC(1991) Epithelial-myoepithelial carcinoma of salivary glands.J Clin Pathol 44:419–423187. Simpson RHW, Clarke TJ, Sarsfield PTL, Gluckman PGC,Babajews AV (1991) Polymorphous low grade adenocarcinomaof the salivary glands: a clinicopathological comparisonwith adenoid cystic carcinoma. Histopathology 19:121–129188. Simpson RHW, Di Palma S (2003) Myoepithelial tumour ofsalivary glands. In: Gale N, Luzan B (eds) Proceedings inHead and Neck Pathology. Institute of Pathology Faculty ofMedicine, University of Lubljana, Lubljana 4–6 September2003, pp 92–98189. Simpson RHW, Jones H, Beasley P (1995) Myoepithelioma ofthe salivary glands: a true entity? Histopathology 27:1–9190. Simpson RHW, Prasad A, Lewis JE, Skálová A, David L(2003) Mucin-rich variant of salivary duct carcinoma: a

Major and Minor Salivary Glands Chapter 5 169clinicopathological study of four cases. Am J Surg Pathol27:1070–1079191. Simpson RHW, Reis-Filho JS, Pereira EM, Ribeiro AC, AbdulkadirA (2002) Polymorphous low grade adenocarcinomaof the salivary glands with transformation to high grade carcinoma.Histopathology 41:250–259192. Simpson RHW, Robertson NJ, Arora DS, Saunders MW(1996) Salivary duct carcinoma: a cytological and histopathologicalstudy. Cytopathology 7:141–144193. Simpson RHW, Sarsfield PTL, Clarke T, Babajews AV (1990)Clear cell carcinoma of minor salivary glands. Histopathology17:433–438194. Simpson RHW, Sarsfield PTL (1997) Benign and malignantlymphoid lesions of the salivary glands. Curr Diagn Pathol4:91–99195. Simpson RHW, Skálová A (1997). Metastatic carcinoma ofthe prostate presenting as a parotid tumour. Histopathology30:70–74196. Skálová A, Lehtonen H, von Boguslawsky K, Leivo I (1994)Prognostic significance of cell proliferation in mucoepidermoidcarcinoma of the salivary gland: clinicopathologicalstudy using MIB1 antibody in paraffin sections. Hum Pathol25:929–935197. Skálová A, Leivo I, Michal M, Saksela E (1992) Analysis ofcollagen isotopes in crystalloid structures of salivary glandtumors. Hum Pathol 23:748–754198. Skálová A, Leivo I, von Boguslawsky K, Saksela E (1994) Cellproliferation correlates with prognosis in acinic cell carcinomasof salivary gland origin. Immunohistochemical study of30 cases using the MIB1 antibody in formalin-fixed paraffinsections. J Pathol 173:13–21199. Skálová A, Leivo I, Wolf H, Fakan F (2000) Oncocytic cystoadenomaof the parotid gland with tyrosine-rich crystals.Pathol Res Pract 196:849–851200. Skálová A, Michal M, Simpson RHW, Stárek I, Přádná J,Pfaltz M (2002) Sclerosing polycystic adenosis of parotidgland with dysplasia and ductal carcinoma in situ: report ofthree cases with immunohistochemical and ultrastructuralexamination. Virchows Arch 440:29–35201. Skálová A, Simpson RHW, Lehtonen H, Leivo I (1997) Assessmentof proliferative activity using the MIB1 antibodyhelps to distinguish polymorphous low grade adenocarcinomafrom adenoid cystic carcinoma of salivary glands. PatholRes Pract 193:695–703202. Skálová A, Stárek I, Kučerová V, Szépe P, Plank L (2001) Salivaryduct carcinoma – a highly aggressive salivary gland tumorwith HER-2/neu oncoprotein overexpression. PatholRes Pract 197:621–626203. Skálová A, Stárek I, Simpson RHW, Kučerová V, DvorackovaJ, Čuřik R, Duskova M (2001) Spindle cell myoepithelial tumoursof the parotid gland with extensive lipomatous metaplasia.Virchows Arch 439:762–767204. Skálová A, Starek I, Vanecek T, Kucerova V, Plank L, SzepeP, Di Palma S, Leivo I (2003) Expression of HER-2/neu geneand protein in salivary duct carcinomas of parotid gland asrevealed by immunofluorescence in situ hybridization andimmunohistochemistry. Histopathology 42:1–9205. Škorpil F (1940) Über das Speicheldrüsenadenom. VirchowsArch A Anat Pathol 306:714–736206. Slootweg PJ (1993) Low-grade adenocarcinoma of the oralcavity: polymorphous or papillary? J Oral Pathol Med22:327–330207. Smyth AG, Ward-Booth RP, High AS (1993) Polycystic diseaseof the parotid glands: two familial cases. Br J Oral MaxillofacSurg 31:38–40208. Soares J (1999) Progression to low-grade and high-grade salivarygland tumors. Rev Esp Patol 32:434–435209. Spiro RH, Huvos AG, Strong EW (1977) Malignant mixed tumorof salivary origin: a clinicopathologic study of 146 cases.Cancer 39:388–396210. Spiro RH, Huvos AG (1992) Stage means more than grade inadenoid cystic carcinoma. Am J Surg Pathol 164:623–628211. Sredni ST, da Cunha IW, de Carvalho Filho NP, Magrin J,Pinto CA, Lopes LF (2004) Endodermal sinus tumour of theparotid gland in a child. Pediatr Dev Pathol 7:77–80212. Stallmach I, Zenklusen P, Komminoth P, Schmid S, Perren A,Roos M, Jianming Z, Heitz PU, Pfaltz M (2002) Loss of heterozygosityat chromosome 6q23-25 correlates with clinicaland histologic parameters in salivary gland adenoid cysticcarcinoma. Virchows Arch 440:77–84213. Stanley RJ, Weiland LH, Pearson BW (1988) Dedifferentiatedacinic cell (acinous) carcinoma of the parotid gland. OtolaryngolHead Neck Surg 98:155–161214. Stephen J, Batsakis JG, Luna MA, von der Heyden U, Byers RM(1986) True malignant mixed tumors (carcinosarcoma) of salivaryglands. Oral Surg Oral Med Oral Pathol 61:597–602215. Sternlicht MD, Barsky SH (1997) The myoepithelial defense:a host defense against cancer. Med Hypotheses 48:37–46216. Su AI, Welsh JB, Sapinoso LM, Kern SG, Dimitrov P, LappH, Schultz PG, Powell SM, Moskaluk CA, Frierson HF Jr,Hampton GM (2001) Molecular classification of human carcinomasby use of gene expression signatures. Cancer Res61:7388–7393217. Suchy BH, Wolf SR (2000) Bilateral mucosa-associated lymphoidtissue lymphoma of the parotid gland. Arch OtolaryngolHead Neck Surg 126:224–226218. Suzuki H, Inoue K, Fujioka Y, Ishikura H, Furuta Y, Fukuda S(1998) Myoepithelial carcinoma with predominance of plasmacytoidcells arising in a pleomorphic adenoma of the parotidgland. Histopathology 32:86–87219. Takata T, Ogawa I, Nikai H (1989) Sebaceous carcinoma ofthe parotid gland: an immunohistochemical and ultrastructuralstudy. Virchows Arch A Pathol Anat 414:459–464220. Takahashi H, Fujita S, Okabe H, Tsuda N, Tezuka F (1991)Immunohistochemical characterization of basal cell adenomasof the salivary gland. Pathol Res Pract 187:145–156221. Takahashi H, Fujita S, Okabe H (1992) Distribution of tissuemarkers in acinic cell carcinomas of salivary gland. PatholRes Pract 188:692–700222. Therkildsen MH, Christensen N, Andersen LJ, Larsen S,Katholm M (1992) Malignant Warthin’s tumour: a casestudy. Histopathology 21:167–171223. Tortoledo ME, Luna MA, Batsakis JG (1984) Carcinomas expleomorphic adenoma and malignant mixed tumors: histomorphologicindexes. Arch Otolaryngol 110:172–186224. Tse LL, Finkelstein SD, Siegler RW, Barnes L (2004) Osteoclast-typegiant cell neoplasm of salivary gland. A microdissection-basedcomparative genotyping assay and literaturereview. Am J Surg Pathol 28:953–961225. Vargas H, Sudilovsky D, Kaplan MJ, Regezi JA, Weidner N(1997) Mixed tumor, polymorphous low-grade adenocarcinomaand adenoid cystic carcinoma of the salivary gland:pathogenic implications and differential diagnosis by Ki-67(MIB1), BCL2, and S-100 immunohistochemistry. Appl Immunohistochem5:8–16226. Vessecchia G, Di Palma S, Giardini R (1995) Submandibulargland metastasis of breast carcinoma: a case report and reviewof the literature. Virchows Arch 427:349–351227. Viva E, Zorzi F, Annibale G, Stefini S, Baronchelli C, BonettiMF (1992) Endodermal sinus (yolk sac) tumour of the parotidgland, a case report. Int J Pediatr Otorhinolaryngol24:269–274228. Waldron CA (1991) Mixed tumor (pleomorphic adenoma)and myoepithelioma. In: Ellis GL, Auclair PL, Gnepp DR(eds) Surgical pathology of the salivary glands. Saunders,Philadelphia, pp 165–186229. Waldron CA, el Mofty SK, Gnepp DR (1988) Tumors of theintraoral minor salivary glands: a demographic and histologicstudy of 426 cases. Oral Surg Oral Med Oral Pathol66:323–333230. Walt JD van der, Leake J (1987) Granulomatous sialadenitisof the major salivary glands. A clinicopathological study of57 cases. Histopathology 11:131–144231. Wanamaker JR, Kraus DH, Biscotti CV, Eliachar I (1994) Undifferentiatednasopharyngeal carcinoma presenting as a parotidmass. Head Neck 16:589–593

170 S. Di Palma · R.H.W. Simpson · A. Skalova · I. Leivo232. Wenig BM, Hitchcock CL, Ellis GL, Gnepp DR (1992) Metastasizingmixed tumor of salivary glands: a clinicopathologic andflow cytometric analysis. Am J Surg Pathol 16:845–858233. Werning JT (1991) Infectious and systemic diseases. In: EllisGL, Auclair PL, Gnepp DR (eds) Surgical pathology of thesalivary glands. Saunders, Philadelphia, pp 39–59234. Wilson RW, Moran CA (1997) Epithelial-myoepithelial carcinomaof the lung: immunohistochemical and ultrastructuralobservations and review of the literature. Hum Pathol28:631–635235. Worner GC, Reis PP, Makitie AA, Sukhai MA, Arora S, JurisicaI, Wells RA, Gullane P, Irish J, Kamel-Reid S (2004)Current applications of microarrays in head and neck cancerresearch. Laryngoscope 114:241–248236. Zarbo RJ, Prasad AR, Regezi JA, Gown AM, Savera AT (2000)Salivary gland basal cell and canalicular adenomas: immunohistochemicaldemonstration of myoepithelial cell participationand morphogenetic considerations. Arch Pathol124:401–405237. Zarbo RJ, Regezi JA, Batsakis JG (1986) S-100 protein in salivarygland tumors: an immunohistochemical study of 129cases. Head Neck Surg 8:268–2755

Chapter 6Nasopharynxand Waldeyer’s RingS. Regauer6Contents6.1 Embryological Developmentof the Nasopharynx and Waldeyer’s Ring . . . . . . 1726.2 Nasopharynx . . . . . . . . . . . . . . . . . . . . . . . 1736.2.1 Anatomy and Histology . . . . . . . . . . . . . . . . 1736.2.2 Congenital Developmental Anomalies . . . . . . . . 1736.2.2.1 Nasopharyngeal Branchial Cleft Cysts . . . . . . . . 1736.2.2.2 Tornwaldt’s Cyst . . . . . . . . . . . . . . . . . . . . . 1736.2.2.3 Rathke’s Cleft Cyst/Ectopic Pituitary Tissue . . . . 1746.2.2.4 Craniopharyngioma . . . . . . . . . . . . . . . . . . 1746.2.2.5 Heterotopic Brain Tissue/Encephalocele . . . . . . 1746.2.3 Congenital Tumours . . . . . . . . . . . . . . . . . . 1746.2.3.1 Salivary Gland Anlage Tumour . . . . . . . . . . . . 1756.2.3.2 Hairy Polyp . . . . . . . . . . . . . . . . . . . . . . . 1756.2.3.3 Congenital Nasopharyngeal Teratoma . . . . . . . . 1756.2.4 Benign Tumours and Tumour-Like Lesions . . . . . 1756.2.4.1 Nasopharyngeal Angiofibroma . . . . . . . . . . . . 1756.2.4.2 Respiratory EpithelialAdenomatoid Hamartoma . . . . . . . . . . . . . . . 1786.2.4.3 Nasopharyngeal Inverted Papilloma . . . . . . . . . 1786.2.4.4 Solitary Fibrous Tumour . . . . . . . . . . . . . . . . 1796.2.4.5 Paraganglioma . . . . . . . . . . . . . . . . . . . . . . 1796.2.4.6 Meningioma . . . . . . . . . . . . . . . . . . . . . . . 1796.2.4.7 Glandular Retention Cysts . . . . . . . . . . . . . . . 1796.2.5 Nasopharyngeal Carcinoma . . . . . . . . . . . . . . 1806.2.5.1 Non-Keratinising NasopharyngealCarcinoma . . . . . . . . . . . . . . . . . . . . . . . . 1806.2.5.2 Keratinising Nasopharyngeal Carcinoma . . . . . . 1826.2.6 Nasopharyngeal Adenocarcinoma . . . . . . . . . . 1826.2.6.1 Salivary Gland-Type Adenocarcinomaof the Nasopharynx . . . . . . . . . . . . . . . . . . . 1826.2.6.2 Papillary Adenocarcinomaof the Nasopharynx . . . . . . . . . . . . . . . . . . . 1826.2.7 Malignant Non-Epithelial Tumoursof the Nasopharynx . . . . . . . . . . . . . . . . . . . 1836.2.7.1 Chordoma . . . . . . . . . . . . . . . . . . . . . . . . 1836.2.7.2 Sarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . 1836.3 Waldeyer’s Ring . . . . . . . . . . . . . . . . . . . . . 1836.3.1 Anatomy and Histology of Waldeyer’s Ring . . . . . 1836.3.2 Congenital Anomalies of Waldeyer’s Ring . . . . . . 1846.3.3 Tonsillitis . . . . . . . . . . . . . . . . . . . . . . . . . 1846.3.3.1 Bacterial Tonsillitis . . . . . . . . . . . . . . . . . . . 1846.3.3.2 Viral Tonsillitis . . . . . . . . . . . . . . . . . . . . . 1856.3.4 Benign Tumours of Waldeyer’s Ring . . . . . . . . . 1876.3.4.1 Squamous Papilloma . . . . . . . . . . . . . . . . . . 1876.3.4.2 Lymphangiomatous Tonsillar Polyp . . . . . . . . . 1876.3.5 Carcinomas of Waldeyer’s Ring . . . . . . . . . . . . 1876.3.6 Malignant Lymphomas of Waldeyer’s Ring . . . . . 1896.3.6.1 Mantle Cell Lymphoma . . . . . . . . . . . . . . . . 1896.3.6.2 Extranodal Marginal Zone B-Cell Lymphomaof Mucosa-Associated Lymphoid Tissue . . . . . . . 1906.3.6.3 Extranodal NK/T-Cell Lymphoma,Nasal Type . . . . . . . . . . . . . . . . . . . . . . . . 1906.3.6.4 Hodgkin’s Lymphoma . . . . . . . . . . . . . . . . . 1906.3.6.5 Extramedullary Plasmacytoma . . . . . . . . . . . . 1906.3.7 Systemic Disease Affecting Waldeyer’s Ring . . . . 190References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191

172 S. Regauer66.1 Embryological Developmentof the Nasopharynxand Waldeyer’s RingThe pharynx is divided into an upper portion, the nasopharynx,and a lower portion consisting of the oropharynxand hypopharynx. The nasopharynx is locatedabove the soft palate and communicates with the nasalpassages. The oropharynx extends from the soft palateand the velum palatinum to the epiglottis. The hypopharynxextends from the tip of the epiglottis to thelower margin of the cricoid cartilage. The term Waldeyer’sring refers to the ring of lymphoid tissues extendingthroughout the naso- and oropharynx and includes thepalatine, pharyngeal, lingual and tubal tonsils.The earliest embryological stage relevant for the developmentof the nasopharynx is around the 3rd week ofgestation. The embryo has already developed all threegerm layers and consists of the notochord with a notochordallumen [134]. At the cranial end, the notochordis still fused with the ecto- and endodermal germ layers,which form the bilaminar oropharyngeal (or buccopharyngeal)membrane. The first process in the formationof the pharynx is the development of a primitive mouth(or stomodeum) and a primitive pharynx during the 4thweek via rupture of the oropharyngeal membrane. Atthat time, the primitive nasal cavities and the nasopharynxare still separated from the oral cavity by the primarypalate and the oronasal membrane. The oronasalmembrane ruptures around week 6, bringing the nasaland oral cavity into continuity and forming the primitivechoanae. During the posterior extension of the primarypalate and development of the secondary palate,the choanae become located posteriorly and connect thenewly formed nasal cavities and nasopharynx. The developmentof the pituitary gland (or hypophysis) beginsaround the middle of the 4th week with an upward proliferationof the ectodermal roof of the stomodeum, theRathke’s pouch (or hypophyseal duct), and a downgrowthfrom the diencephalon called the neurohypophyseal bud.The Rathke’s pouch passes through the chondrificationcentres of the developing sphenoid bones. By the 5thweek, both portions of the pituitary gland have come incontact and the Rathke’s pouch becomes constricted atits attachment to the oronasal epithelium. The stalk degeneratesand the Rathke’s pouch involutes to a series ofmicrocysts, which persist throughout adult life in the pituitarygland. Occasionally, they can be recognised macroscopicallyby a zone of colloid cysts. Symptomatic enlargementleads to the formation of a Rathke’s cleft cyst(see Sect. 6.2.2.3). Around the same time, during the involutionof the notochord, a pharyngeal bursa is formedtemporarily at the site of early communication betweenthe notochord and the roof of the pharynx. This ectodermallyderived pharyngeal bursa normally obliteratesduring the 6th gestational week. A persistent pharyngealbursa in adults is located at the posterior median wallof the nasopharynx above the superior pharyngeal constrictormuscles at the lower end of the pharyngeal tonsiland is known as Tornwaldt’s cyst (see Sect. 6.2.2.2).Remnants of the notochord give rise to cranial chordomas(see Sect. 6.2.7.1).The oropharynx, mouth and larynx develop fromthe pharyngeal (or branchial) apparatus during the4th and 5th weeks of gestation. The growth of the forebrainand the development of the pharyngeal/branchialapparatus produce a prominent elevation of thehead with a quite distinct first and second pharyngealarch around day 24. At the end of the 4th embryonicweek, four well-defined and two rudimentary bilateralpairs of pharyngeal arches are separated by the pharyngealgrooves. Each arch consists of a core of embryonicmesenchyme with an artery, a cartilage rod, a nerveand a muscular component, and is covered externallyby ectoderm and internally by endoderm. The ectodermallyderived pharyngeal arches and grooves supportthe lateral walls of the primitive pharynx. The innerlining consists of endoderm with balloon-like diverticulicalled pharyngeal pouches, which are also presentin four well-defined pairs. The second pharyngealpouch is the major contributor to the formation ofthe pharynx and is largely obliterated when the palatinetonsils develop around weeks 12–14 post-conception.A part of the cavity of the second pouch remainsas the intratonsillar cleft (or tonsillar fossa) in the palatinetonsils (see Sect. 6.3.1). The neural crest-derivedmesenchyme will form most of the skeletal (cartilageand bone) and connective tissue structure of the headand neck, but the original mesenchyme of the secondarch forms the blood vessels and skeletal musculatureof the pharynx. The nerve supply of the pharynx developsfrom the 3rd pharyngeal arch (IX glossopharyngealnerve). The adult vascular pattern of the head andneck depends on a complex transformation of the pharyngealapparatus with involution and obliteration ofthe early vessels. Incomplete involution, particularlyof the first pharyngeal artery, has been postulated tobe responsible for the development of nasopharyngealangiofibromas (see Sect. 6.2.4.1). The auditory (Eustachian)tube is derived from the first pharyngeal archand pouch. Incomplete regression may be responsiblefor the occurrence of hairy polyps (see Sect. 6.2.3.2).The tongue also begins to develop at the end of the 4thweek. The oral part of the tongue is derived from thefirst pharyngeal arch; the posterior pharyngeal tonguedevelops by fusion of the ventromedial parts of the secondand the third pharyngeal arch. The tissues derivedfrom the second pharyngeal arch are gradually overgrownby the third pharyngeal arch.The lymphoid tissues of Waldeyer’s ring develop betweenthe 14th and 18th weeks of gestation. The developmentof the pharyngeal tonsil begins from an anlage

Nasopharynx and Waldeyer’s Ring Chapter 6 173consisting of longitudinal folds on the dorsal wall of thenasopharynx around the 12–14th gestational week. Thedevelopment of the palatine tonsils begins with a proliferationof the endodermal epithelium of the second pharyngealpouch down into the surrounding mesenchyme,forming the epithelium-lined crypts. In the connectivetissue, mesenchymal cells of the second pharyngealpouch form so-called condensation centres. The firstprimary follicles can be localised around week 14. Theparafollicular areas develop into T-cell areas and precursorsof interdigitating cells can be identified. Aroundweek 16, the epithelium shows the first signs of cornification,and the lymphocytic infiltration of the epitheliumoccurs [59, 60].6.2 Nasopharynx6.2.1 Anatomy and HistologyThe nasopharynx is bordered anteriorly by the nasalchoanae and nasal cavities. The roof and posterior wallof the nasopharynx form an arch just below the base ofthe skull with the sphenoid sinus and the floor of thesella turcica. The postero-superior roof contains the(naso)pharyngeal tonsil. At its lower end in the posteriormidline lies a blind recess known as the pharyngealbursa. The lateral walls of the nasopharynx contain thepharyngeal ostia of the auditory tubes, which are surroundedby small aggregates of lymphoid tissue, thetubal tonsil. The cartilage of the auditory tube protrudesabove the ostium and is called the torus tubarius, behindwhich the Rosenmüller fossa is located. The floor ofthe nasopharynx is formed by the soft palate and uvula.The anterior and cranial portions of the nasopharynxare lined by respiratory mucosa with ciliated columnarepithelium with goblet cells and foci of metaplasticsquamous epithelium. Squamous mucosa predominatesin the lower nasopharynx adjacent to the oropharynx.Small seromucinous glands and aggregates of lymphoidtissue are present in the submucosa throughout the nasopharynxas a normal finding without qualifying as“chronic inflammation”.6.2.2 CongenitalDevelopmental AnomaliesCongenital developmental anomalies of the nasopharynxare rare and include choanal atresias and pharyngealstenosis. Bilateral occlusion has been reported inup to 40% of patients with choanal atresias. Bilateralatresias are typically osseous, unilateral atresias aremembranous. Pharyngeal stenosis is a paediatric disorderassociated with sleep apnoea and other craniofacialanomalies [108, 137]. Far more common are congenitalcysts and tumours arising from remnants of embryonictissue.6.2.2.1 NasopharyngealBranchial Cleft CystsNasopharyngeal branchial cleft cysts and fistulas arelocated in the lateral nasopharyngeal wall and can extendto the base of the skull through the parapharyngealspace. They occur unilaterally or bilaterally and have apostulated second pharyngeal arch origin. Most nasopharyngealbranchial cleft cysts are clinically silent duringchildhood and discovery may be delayed into earlyadulthood, when chronic inflammation induces proliferationof the lymphoid tissues. This produces a massresulting in respiratory difficulties and nasal obstruction.The cysts are lined with respiratory epithelium.Chronic irritation and inflammation induces squamousmetaplasia. Surgical specimens of nasopharyngeal cystsremoved for symptomatic disease may therefore showexclusively squamous epithelium and lymphoid hyperplasiain a fibrosed cyst wall [143, 177, 185].6.2.2.2 Tornwaldt’s CystA Tornwaldt’s cyst (or pharyngeal bursitis; named afterGustav Ludwig Tornwaldt, 1843–1910) is a dilatation of apersistent pharyngeal bursa in the posterior median wallof the nasopharynx above the superior pharyngeal constrictormuscles and at the lower end of the pharyngealtonsil caudally and posteriorly to where Rathke’s cleftcysts arise [128]. The cysts arise at the site of embryoniccommunication between the notochord and the roof ofthe pharynx and can be detected in up to 7% of adultsat routine autopsies [86]. Tornwaldt’s cysts are typicallyless than 1 cm in size and asymptomatic [92]. Obstructionof the bursal orifice results in a cystic dilatation.The cysts may become infected and inflamed with subsequentabscess formation. Symptomatic disease, termedTornwaldt’s disease, may present with nasal obstructionand nasopharyngeal drainage, dull occipital headaches,pain in the ears and neck muscles and occasionally neckmuscle stiffness [130]. Tornwaldt’s cysts are lined withtall, columnar, ciliated respiratory epithelium, but inflammationand infection induces squamous metaplasiaand fibrosis of the walls. Tornwaldt’s cyst may containvarying amounts of lymphoid tissue (Fig. 6.1). Most surgicalspecimens of symptomatic Tornwaldt’s cysts areeither devoid of an epithelial lining or lined with squamousepithelium.

174 S. Regauer6Fig. 6.1. Tornwaldt’s cyst. Tornwaldt’s cysts are thin-walled cystsof varying sizes located in the nasopharyngeal submucosa. Thenasopharyngeal surface is covered either by squamous epitheliumor respiratory epithelium. The cysts are lined by respiratorytype epithelium with varying extent of squamous metaplasia. Thecyst wall contains varying amounts of inflammatory cells and maybe fibrosed6.2.2.3 Rathke’s Cleft Cyst/Ectopic Pituitary TissueRathke’s cleft cysts (or Rathke’s cyst; named after MartinHeinrich Rathke, 1793–1860) arise from the Rathke’spouch (or hypophyseal duct), an ectodermal remnant ofthe stomodeum that gives rise to the anterior lobe of thepituitary gland. The Rathke’s pouch is normally obliteratedto become microscopic clefts, but remnants of theRathke’s pouch are incidental findings in up to 33% of unselectedautopsies. Rathke’s cleft cysts can have diametersranging from 0.3 to 4 cm [90, 192]. The thin-walled cystsare lined with respiratory epithelium with interspersedgoblet cells and are filled with a clear, colloid, mucinous,viscous, turbid or haemorrhagic fluid. In cases of inflammation,metaplastic non-keratinising squamous epitheliumand a mural lymphocytic infiltrate dominate [72, 90].Rupture induces a granulomatous and xanthomatous inflammationwith fibrosis, cholesterol needles and foreignbody cell reaction, and even amyloid deposition. Rathke’scleft cysts are virtually never removed intact and surgicalspecimens typically consist of inflamed fibrous tissue.The epithelium is often elusive. Rare examples of Rathke’scleft cysts contain mural nodules of anterior pituitary tissueor concomitant pituitary adenoma. Most nasopharyngealpituitary adenomas represent nasopharyngealextension of intracranial pituitary adenomas. Primarynasopharyngeal pituitary adenomas are extremely rareand mostly non-functioning [110, 123]. Symptoms dependon the type of secreted hormone and the location ofthe adenoma. Histologically, ectopic pituitary gland tissuecan display the entire spectrum with chromophobe,acidophilic and basophilic cells [29].6.2.2.4 CraniopharyngiomaICD-O:9350/1All reported extracranial craniopharyngiomas (orRathke’s pouch tumour, craniopharyngeal duct tumour)were located in the nasopharynx, sella turcica and sphenoidsinus, and presented during the first two decades oflife with headaches, nasal obstruction and epistaxis (forreviews see [18, 67]). Intracranial craniopharyngiomasoccur classically in an adamantinomatous and papillarysubtype. The majority of the extracranial nasopharyngealcraniopharyngiomas are of the adamantinomatoussubtype with cords of basaloid squamous cells and fociof squamous differentiation and horn pearls embeddedin fibrous stroma. Other typical secondary changes arecysts filled with brown fluid, areas of necrosis, calcificationsand cholesterol crystals. Treatment is surgical andsupplemented with radiotherapy in the case of incompletelyresected tumours and recurrences.6.2.2.5 Heterotopic Brain Tissue/EncephaloceleEncephaloceles are herniations of brain through a congenitalopening of the skull. Glial heterotopias with andwithout encephaloceles cause neonatal airway obstructionand rhinorrhoea. Heterotopic brain in a nasopharyngeallocation is rare [168]. From a pathologist’s perspective,encephaloceles and brain heterotopias can bedistinguished only after correlation with the patient’sclinical and radiological findings. Histologically, matureneuroglial tissues are embedded in fibrovascularstroma. Encephaloceles/glial heterotopias involving thenasopharynx differ from the more common nasal gliomasin that they contain ependyma, choroid plexus, retinalcomponents and occasionally neoplastic tissue, suchas an oligodendroglioma [14].6.2.3 Congenital TumoursAmong the tumourous developmental abnormalities arehamartomas, choristomas and teratomas. A hamartomais a benign tumour-like nodule composed of maturecells and tissues that normally occur in the affected part,but often with one element predominating. Choristomasrepresent a mass of histologically normal mature tissueslocated at a site where these tissues do not normally occur.These tumours are also called aberrant rests or heterotopictissue. Teratomas are true neoplastic proliferationsmade up of mature or immature tissues in randomorganisation derived from all three germ layers.

Nasopharynx and Waldeyer’s Ring Chapter 6 1756.2.3.1 Salivary Gland Anlage TumourSalivary gland anlage tumours are rare tumours of neonatesthat arise from minor salivary glands of the nasopharynxand are also known as congenital pleomorphicadenoma [13, 38, 73]. The firm, polypoid, pedunculatedmidline masses can reach up to 3 cm in size and causerespiratory distress and feeding problems. Salivarygland anlage tumours are multinodular and usuallysolid tumours. Histologically, they are characterised byan epithelial proliferation imitating embryonic salivaryglands (Fig. 6.2). The epithelial proliferation can be extensivewith solid squamous areas with focal keratinisation,keratinised nests, cyst and pearls. Calcificationwithin the cysts occurs. Salivary gland anlage tumoursmay contain branching ductal and glandular structures,occasionally with complex intraluminal papillations.The surrounding stroma may be loose and myxoid withnumerous inflammatory cells, but may also show somefibrosis. Other salivary gland anlage tumours consistpredominantly of densely packed sheet and nodulesof small fusiform spindle cells with occasional regularmitoses. Rare keratinised duct and cystic structures areseen in these areas. Haemorrhage and focal necrosis canbe seen [125]. Immunohistochemically, all cells stainpositive for salivary gland amylase. The spindle cells areimmunoreactive with antibodies to vimentin, cytokeratins,EMA and smooth muscle actin, but are negative forS-100 and GFAP. The epithelial structures stain for cytokeratinand EMA. The exact classification of the salivarygland anlage tumour as a hamartoma or true (benign)neoplasm has not yet been resolved. Dehner andcolleagues favour a hamartomatous origin, although thepresent name indicates a tumourous growth [38].6.2.3.2 Hairy PolypHairy polyps (or dermoids) are found in the naso- andoropharynx of neonates or young infants. About 60% ofthe roughly 140 reported cases arose as single, pedunculatedor sessile, 0.5 to 6 cm polyps in the lateral vaultof the nasopharynx near the Eustachian tube orificeand very rarely within the Eustachian tube and middleear [17, 78, 109]. The remaining cases occurred in thetonsillar region (for tonsillar and bilateral location seeSect. 6.3.2). Hairy polyps cause respiratory distress orfeeding problems. Simultaneous congenital abnormalitiessuch as cleft palate are more common than ipsilateralbranchial sinus, congenital atresia of the carotidartery, osteopetrosis and malformations of the auricle[36, 68]. Treatment is simple surgical resection. A hairypolyp is covered by keratinised or glycogenated squamousepithelium containing hair with sebaceous glandsand sweat glands. The mesenchymal core consists ofmature fibroadipose tissue and blood vessels with occasionalsmooth muscle and striated muscle fibres. Thestalk may contain foci or plates of hyaline cartilage [27].Hairy polyps fulfil the definition of a choristoma, althoughthe literature refers to hairy polyps mistakenlyoften as “teratoma”.6.2.3.3 CongenitalNasopharyngeal TeratomaICD-O:9080/1Congenital teratomas are most common in the saccrococcygealregion; less than one-third of all teratomasarise in the head and neck region. The nasopharynx isan exceptionally rare location [84, 167, 187]. Teratomasare ill-formed, lobular solid and cystic tumour massestypically diagnosed in the neonatal period with airwayobstruction. Mature teratomas are completely benignand consist of mature tissues of ecto-, meso- and endodermalderivation in a more or less organised fashion.Optimal treatment is complete excision. Immatureteratomas contain tissues of varying degrees of differentiationand maturation. Immature teratomas in infantshave an excellent prognosis, quite in contrast to adultpatients with immature teratomas.6.2.4 Benign Tumoursand Tumour-Like Lesions6.2.4.1 Nasopharyngeal AngiofibromaICD-O:9160/0Nasopharyngeal angiofibromas (or juvenile nasopharyngealangiofibromas) are rare benign tumours with anincidence of 0.5% of all head and neck tumours. Theyoccur exclusively in adolescent males and become clinicallyevident between 10 and 25 years of age with nosebleeds, respiratory distress, headaches or sometimesvisual disturbances. Nasopharyngeal angiofibromasarise from the posterior lateral wall of the nasal cavitynear the pterygo-palatine fossa at the superior marginof the foramen sphenopalatinum and extend into adjacentstructures such as maxillary, sphenoid or ethmoidsinuses and the nasal cavity. The most advanced casesshow intracranial extension [153, 203]. The blood supplyof nasopharyngeal angiofibromas comes from the externalcarotid artery with the internal maxillary artery asfeeding branch. In a minority of cases, the feeding vesselsare the sphenopalatine artery and the ascendingpharyngeal artery [75, 153]. Diagnosis of a nasopharyngealangiofibroma is based on clinical examinationand computer tomography, which shows two consistentfeatures: 1) localisation in the posterior nasal cavityand pterygopalatine fossa, and 2) bone erosions of the

176 S. Regauer6abcdefg

Nasopharynx and Waldeyer’s Ring Chapter 6 177abcdefFig. 6.3. Nasopharyngeal angiofibroma. a–b Nasopharyngeal angiofibromasare large, white, firm, bulging tumours covered by respiratorymucosa. c–d Abnormal large muscular and smaller sinusoidalvessels are embedded in a fibrous and partly sclerotic stroma.The muscular vessels exhibit irregular muscle walls with varyingthickness and arbitrary arrangement of the individual smoothmuscle cells. e–f The stroma is either fibrous or myxoid with stellateor spindled cellsFig. 6.2. Salivary gland anlage tumour. a–c Salivary gland anlagetumours have an intact surface epithelium, which may be partlykeratinized. The branching epithelial proliferations show ductsfilled with proteinaceous casts. The stroma is myxoid and containsnumerous plasma cells and lymphocytes. d–e There are solidsquamous areas with keratin-filled cysts and calcifications. f–gOther areas are dominated by proliferations of spindle cells in solid,fascicular and nested arrangement with occasional ductal andcystic elements. Haemorrhage is common

178 S. Regauer6sphenopalatine foramen with extension to the uppermedial pterygoid plate [118]. Nasopharyngeal angiofibromasare unencapsulated, lobulated, firm, grey totan tumours. Abnormal blood vessels of different sizesand irregular architecture in arbitrary arrangement areembedded in a myofibroblastic stroma. The proportionsof both components can vary considerably (Fig. 6.3).The vascular component can be divided into small sinusoidalvessels and large muscular vessels with irregularand incomplete smooth muscle layers with abrupttransitions from a muscular coat to an endothelial celllining only. Irrespective of their architecture, all vesselsare lined with a continuous layer of single regular endothelialcells. The stromal component varies in amountand cellularity. The majority of stromal fibroblasts areplump and stellate, others assume an elongated spindledconfiguration. Mitoses are inconspicuous. The majorityof stromal cells react with vimentin only, while a subpopulationis characterised by co-expression of vimentinand smooth muscle actin.Despite the body of literature, there is still uncertaintyabout the aetiology of nasopharyngeal angiofibromas.They have been called haemangioma and vascular hamartomaarising from ectopic vascular tissue of the inferiorturbinate. Other theories have included overgrowthof paraganglionic tissue, hyperplasia in response to allergicstimulus, fibromatosis, teratoma arising from theoccipital plate, but also an androgen-dependent neoplasticprocess due to an imbalance of the pituitary–androgenitalsystem [9]. A concomitant presentation of nasopharyngealangiofibromas and the familial adenomatouspolyposis syndrome has been reported in 4 out of825 patients at the Johns Hopkins’ Registry for familialcolonic polyposis [47, 62]. A mutation in the APC gene,however, was not demonstrated in 9 patients with nasopharyngealangiofibroma, and a comparative genomichybridisation study describes a normal chromosome5 in 3 patients with nasopharyngeal angiofibroma [70,170]. The same study reports gains on chromosome 8at the site of the genes for TGF-ß inducible early growthresponse and LYN (v-yes-1 Yamaguchi sarcoma viral-relatedoncogene homologue), and on chromosome 6, onwhich the gene for the vascular endothelial growth factoris located [170]. The additional complex gains on theX chromosome and losses on the Y chromosome may explainthe exclusive occurrence in male patients. The interpretationof nasopharyngeal angiofibromas as a vascularmalformation has proved to be the most consistenttheory over the past few decades. A recent publicationproposes that nasopharyngeal angiofibromas arise froman embryological vascular remnant of the first pharyngealarch artery, which normally regresses to a vascularplexus, giving rise to the maxillary artery [75, 153, 171].Incomplete involution leaves behind vascular remnantsin the lateral nasal wall in the area of the sphenopalatineforamen from where nasopharyngeal angiofibromasoriginate. This theory explains the abnormal vascularstructures and the complex anatomical extensionsof nasopharyngeal angiofibromas. The growth stimulationduring puberty and the restriction to males remainunexplained by this theory, however. Treatment of nasopharyngealangiofibromas is surgical after embolisation,although radiation therapy and hormonal therapyhave been used extensively in the past [15, 37]. Nasopharyngealangiofibromas have no malignant potential, exceptfor radiation-related malignant transformation.6.2.4.2 Respiratory EpithelialAdenomatoid HamartomaRespiratory epithelial adenomatoid hamartoma (or polypoidhamartomas) typically arises within the nasal cavityand paranasal sinuses (see also Chap. 2), but has alsobeen reported in the nasopharynx [199]. Patients areadults with an age range of 24–81 years. The polypoidexophytic hamartomas are rubbery, tan to brown andcan reach up to 6 cm in size. They are lined with ciliatedrespiratory epithelium with mucin-secreting gobletcells. The widely spaced glandular proliferations arisefrom invagination of the surface epithelium. A thickeosinophilic basement membrane surrounds the glandsand surface epithelium. The ample stroma may be oedematousand well-vascularised or fibrous with varyingamounts of lymphocytes and inflammatory cells(Fig. 6.4). Glandular acinar proliferations may be scantand large cysts may predominate when the fibrous stromapredominates [206]. Some nasopharyngeal hamartomasinclude a chondro-osseous component and cystslined with squamous epithelium. Due to overgrowth ofa single mesenchymal element, respiratory epithelialadenomatoid hamartomas may resemble fibromas, lipomasor chondromas [199]. Treatment of choice is surgery.The differential diagnoses of respiratory epithelialadenomatoid hamartoma include inverted papillomaand adenocarcinoma. The presence of excess glands andthe respiratory epithelium distinguish the hamartomareadily from an inverted papilloma. The lack of malignantcytological and histological features and invasiondistinguishes the respiratory epithelial adenomatoidhamartoma from an adenocarcinoma.6.2.4.3 NasopharyngealInverted PapillomaICD-O:8121/1Inverted papillomas (or Schneiderian papillomas) arisingoutside the sinonasal tract are extremely rare. Onepublication reported 15 pharyngeal inverted papillomas,11 of which arose in the nasopharynx [183]. The pink orgrey firm polyps had a convoluted surface, which cor-

Nasopharynx and Waldeyer’s Ring Chapter 6 179papillomas have an increased potential for recurrence,which is higher in the nasopharynx than in the sinonasallocation. This probably reflects the high rate of incompleteinitial removal due to the unexpected nature of thelesion and the difficult nasopharyngeal anatomy. As ina sinonasal location, inverted papillomas are at risk ofmalignant transformation. For a detailed description ofinverted papillomas, see Chap. 2.6.2.4.4 Solitary Fibrous TumouraICD-O:8815/0Solitary fibrous tumours are exceptionally rare in theupper respiratory tract. In the nasopharynx, only 4 caseshave been described to date [96, 122, 201].6.2.4.5 ParagangliomabICD-O:8680/1Paraganglioma (or chemodectoma) arise in the head andneck region most commonly in the carotid body, glomustympanicus and glomus jugulare. They are extremelyrare in the nasopharynx with about 20 cases described(for review see [101]), but need to be considered whenprofuse haemorrhage and a pulsatile mass are encounteredin the nasopharynx. These slowly enlarging, painless,firm, encapsulated tumours are characterised bynests (so-called Zellballen) of small to medium-sizedpale monomorphous cells with prominent, roundedhyperchromatic nuclei and a prominent network of endothelialcell lined vascular channels (see also Chaps. 8and 9).6.2.4.6 MeningiomacFig. 6.4. Respiratory epithelial adenomatoid hamartoma. a Thisfragmented surgical specimen of polypoid hamartoma displaysnumerous fluid and mucin filled cysts. b The surface is lined bytall columnar respiratory epithelium and there are widely spacedacinar proliferations embedded in a fibrous stroma. c The acinarproliferations are in continuity with invaginations of the surfacerespiratory epithelium and recapitulate either seromucous glands.The basement membrane is typically thickenedresponded histologically to a multilayered, transitionaltypeepithelium with foci of respiratory and squamousepithelium growing endophytically into the underlyingloose and myxoid stroma. Nasopharyngeal invertedICD-O:9530/0Among the rarest tumours of the nasopharynx are extracranialmeningiomas [162]. In a series of 30 extracranialmeningiomas, 3 were located in the nasopharynx[188]. There is only a single case report of a primary tonsillarectopic meningioma [107]. Extracranial meningiomasshow the same histological subtypes, differentiationand prognosis as intracranial meningiomas, but the syncytial(meningothelial) subtype predominates. For meningiomasat other sites in the head and neck area, seeChaps. 2, 8 and 10.6.2.4.7 Glandular Retention CystsGlandular retention cysts are rather common in the oroandnasopharynx and some may become large enoughto mimic nasopharyngeal tumours. They arise from di-

180 S. Regauer6lated and occluded excretory ducts of the seromucinoussalivary glands of the nasopharynx. The cysts are filledwith mucin and lined with a single layer of cuboidalepithelium. Varying amounts of squamous metaplasiaand oncocytic metaplasia can be observed, and whenextensive, the designation oncocytic cyst or nasopharyngealoncocytoma may be most appropriate [3, 12, 136].Retention cysts may rupture. The ensuing inflammationinduced periductal fibrosis and an inflammatoryinfiltrate. The epithelium is destroyed and replaced bymacrophages. These mucin-filled cysts are then calledmucoceles.6.2.5 Nasopharyngeal CarcinomaClassification of nasopharyngeal carcinomas has undergoneseveral changes in the past editions of the WHOclassification. The 1991 edition separates nasopharyngealcarcinoma into two subtypes, the keratinising andthe non-keratinising carcinoma [176]. The non-keratinisingcarcinomas have been further subdivided intoundifferentiated and differentiated forms. This subdivision,however, is nowadays considered optional sincetheir distinction is of no clinical or prognostic significance.Whether basaloid-squamous carcinoma meritsseparate recognition or merely represents a morphologicvariant of non-keratinising carcinoma has not yet beenclarified [7, 138, 159, 194].6.2.5.1 Non-KeratinisingNasopharyngeal CarcinomaIn the past, non-keratinising nasopharyngeal carcinomashave been divided into the more common undifferentiatednasopharyngeal carcinoma (ICD-O:8082/3),(synonymous lymphoepithelial carcinoma, lymphoepitheliomaof Regaud and Schmincke, undifferentiated carcinomawith lymphoid stroma) and the less common differentiatednasopharyngeal carcinoma (ICD-O:8073/3)(or transitional-type carcinoma, intermediate cell carcinoma).The distinction between undifferentiated anddifferentiated carcinoma is considered unimportant fortherapy and prognosis, as these two subtypes representa spectrum of the same tumour. Nasopharyngeal carcinomais by far the most common carcinoma in Chinaand Taiwan, accounting for 18% of all carcinomas there,with an incidence of 10–20/100,000 [83]. Nasopharyngealcarcinomas also occur in endemic forms in Asia,Greenland, Alaska and Africa. In these high-incidenceareas, 99% of nasopharyngeal carcinomas are of thenon-keratinising subtype. In the western world – a lowincidencearea with 0.4–1/100,000 – the non-keratinisingnasopharyngeal carcinoma accounts for 75% comparedwith 25% for keratinising carcinoma [8, 43, 141]. Nasopharyngealcarcinomas show a strong male predilection.While most patients with non-keratinising nasopharyngealcarcinoma are older than 50 years in endemic areas,there is a bimodal age distribution with a peak presentationin the 2nd and 6th decades in intermediate- andlow-incidence areas [8, 43, 63, 77, 175]. The causative andaetiological role of EBV is well established in invasiveand in situ nasopharyngeal carcinomas, irrespective ofthe ethnic origin of the patient and the histological subtype[31, 158]. However, environmental factors seem toplay a role, since the incidence of non-keratinising nasopharyngealcarcinoma decreases among second andthird generation Chinese living in non-endemic areas[83]. Nasopharyngeal carcinomas arise in the lateralwalls of the nasopharynx in the area of the Rosenmüllerfossa and presenting symptoms may be nasal obstruction,epistaxis, post-nasal drip, tinnitus and cranialnerve palsy. Hearing loss and unilateral otitis mediaare related to auditory tube involvement. In more than50% of patients, however, metastases to cervical lymphnodes are the presenting sign. Since most nasopharyngealcarcinomas are difficult to visualise on endoscopicexamination, “blind” biopsies of the nasopharynx, baseof tongue and palatine tonsils are necessary to establisha histological diagnosis of undifferentiated nasopharyngealcarcinoma. In patients presenting with lymphnode metastases and clinically occult primary carcinoma,demonstration of EBV in the metastatic carcinomamay be a helpful diagnostic tool to correctly identify theprimary nasopharyngeal carcinoma [26, 40, 119, 191].Nasopharyngeal carcinomas are highly responsive toradiation therapy. The overall 5-year survival has beenreported to be between 25 and 50% in the past, but theresults of treatment have improved due to refinementsin staging and techniques of therapy [4, 115].Histologically, non-keratinising nasopharyngeal carcinomaslack glandular differentiation. The undifferentiatedsubtype consists of bland uniform undifferentiatedcells in large cohesive nests and cords as well as smallernests and groups of epithelial cells with numerous mitoses.They may be sharply outlined and separated fromthe surrounding infiltrate or permeated by a dense inflammatoryinfiltrate consisting of numerous lymphocytes,plasma cells and eosinophilic granulocytes. Thispattern often has a distinctly non-carcinomatous andlymphoma-like appearance. The infiltrating lymphocytesare a mixture of plasma cells, B-cells and T-cells,with B-cells usually predominating. Portions of the T-cells are cytotoxic cells. A variant of undifferentiatedcarcinoma shows extensive acantholysis resulting in apseudoglandular and pseudovascular pattern. The differentiatedsubtype shows cellular stratification often ina plexiform growth, reminiscent of transitional cell carcinomaof the urinary bladder (Fig. 6.5). The stroma ofnon-keratinising nasopharyngeal carcinoma can be fibrous,but is rarely desmoplastic. Coagulative necrosis

Nasopharynx and Waldeyer’s Ring Chapter 6 181abcdefFig. 6.5. Non-keratinizing nasopharyngeal carcinoma. a–b Nasopharyngealcarcinoma grows in solid sheets of large epithelialcells which are clearly demarcated by a mixed inflammatory infiltrateconsisting of lymphocytes, plasma cells and histiocytes.c globular amyloid deposition is not uncommon. d–e Non-keratinizingnasopharyngeal carcinoma can be heavily infiltrated bythe lymphocytes. f Tumour cells are large, undifferentiated, withabundant pale cytoplasms, inconspicuous cell membranes, andlarge nuclei with prominent nucleolimay be present. Small amyloid globules can be foundwithin the tumour cells or scattered among the carcinomatousstroma. Epithelioid granulomas, occasionallywith caseous necrosis, have been described in nasopharyngealcarcinoma in up to 18% of cases. Some featuresare associated with a better prognosis of nasopharyngealcarcinoma: high density of dendritic cells, highnumber of infiltrating lymphocytes, and low numbersof granzyme-B positive cytotoxic cells [58, 80, 151, 208].The most reliable and sensitive method of detection of

182 S. Regauer6EBV in paraffin sections in routine diagnostic pathologyis EBER in situ hybridisation [88, 93, 157, 196]. Themain differential diagnosis of nasopharyngeal carcinomais a non-Hodgkin’s lymphoma, particularly the largecell lymphoma. The diagnosis of a nasopharyngeal carcinomacan be confirmed by positive staining with antibodiesto cytokeratins, especially high molecular weightkeratin.6.2.5.2 KeratinisingNasopharyngeal CarcinomaICD-O:8070/3Keratinising nasopharyngeal carcinoma (squamous cellcarcinoma, SCC) occurs typically after 40 years of ageand shows obvious squamous differentiation with varyingamounts of keratinisation. The stroma is desmoplasticand infiltrated by variable numbers of lymphocytes,plasma cells, neutrophils and eosinophils. Poorly differentiatedSCC may only contain rare horn pearls orfocal areas of easily recognisable cornification. Immunohistochemicalanalysis with antibody to involucrinis helpful in identifying areas of abortive keratinisation[98]. EBV is almost always positive in nasopharyngealSCC in endemic areas for nasopharyngeal carcinoma,but only a small number of cases in low incidence areasare positive for EBV. SCC shows a greater propensityfor localised advanced tumour growth, but a lower rateof lymph node metastases [141, 164]. Radical surgery isnot performed since radiotherapy is extremely effective.Survival and prognosis of SCC depends on tumour stageand has been reported to be better than that for non-keratinisingnasopharyngeal carcinoma.6.2.6 NasopharyngealAdenocarcinomaAdenocarcinomas of the nasopharynx are extremelyuncommon tumours and can be separated into carcinomasarising from the surface epithelium or from themucoserous salivary glands. The salivary gland-typecarcinomas are more common than those arising fromthe surface epithelium [114].6.2.6.1 Salivary Gland-TypeAdenocarcinomaof the NasopharynxAdenoid cystic carcinoma (ICD-O:8200/3), the mostcommon carcinoma of the salivary type in the oral cavityand hard palate, is rare in the nasopharynx [21, 114,181]. Adenoid cystic carcinomas of the nasopharynx aremore common in Japan than in the western world. It isan insidiously growing tumour with a predispositionfor perineural spread, local recurrence and distant metastasis.Regional lymph node metastases are rare. Histologically,adenoid cystic carcinomas are classified intubular, cribriform and solid subtypes. The tubular andcribriform subtypes are considered low-grade tumours;the solid sub-type is a high-grade tumour with a rapid,fatal course and a higher incidence of distant metastasiswith a poor prognosis [114]. When compared withconventional nasopharyngeal carcinoma, adenoid cysticcarcinoma has a higher incidence of cranial nerve involvement,but a lower incidence of cervical lymph nodemetastases.Polymorphous low-grade adenocarcinoma of minorsalivary glands (ICD-O:8525/3) (or terminal ductcarcinoma, lobular carcinoma, low-grade papillary adenocarcinoma)is a low-grade neoplasm typically occurringin the oral cavity. It has been documented inthe nasopharynx in rare cases [144, 198]. The polymorphouslow-grade carcinoma has a wide diversityof histological patterns including solid areas, papillarygrowth, ductal differentiation, cystic spaces and an infiltrativegrowth pattern with perineural invasion. Themain bulk of the carcinoma is found in the submucosaand the surface epithelium is often intact. In the nasopharynx,surgery or radiotherapy is the treatment ofchoice. Polymorphous low-grade carcinomas of salivarygland origin have a potentially aggressive biologicalcourse with metastases to cervical lymph nodes.For a detailed description of salivary gland tumourssee Chap. 5.6.2.6.2 Papillary Adenocarcinomaof the NasopharynxICD-O:8260/3Papillary adenocarcinomas of the nasopharynx are extremelyuncommon, slow-growing, low-grade carcinomaswithout known risk factors [76, 114]. In a series of9 patients, aged 11 to 64 years, the papillary adenocarcinomasof the nasopharynx were confined to the roofand postero-lateral walls of the nasopharynx [198]. Papillarynasopharyngeal adenocarcinomas are unencapsulated,exophytic, cauliflower-like tumours with an occasionalgritty consistency due to numerous psammomabodies. Complex papillations arise from the surface epithelium.The papillae and crowded back-to-back glandsare lined with uniform, bland, tall, columnar cells withintermixed mucin-containing, PAS-positive goblet cells.Some areas show overlapping vesicular nuclei with granularcytoplasm resembling thyroid carcinomas. Stromalcalcifications and psammoma bodies can be found. Vascular,lymphatic or neural invasion is uncommon. Lowgradepapillary adenocarcinomas of the nasopharynxshould be distinguished from the polymorphous low-

Nasopharynx and Waldeyer’s Ring Chapter 6 183grade carcinoma of salivary gland origin because theydo not metastasise.6.2.7 Malignant Non-EpithelialTumours of the Nasopharynx6.2.7.1 ChordomaICD-O:9370/3Chordomas are tumours arising from remnants of thenotochord in the axial skeleton near its cranial and caudalends. The cranially located chordomas compriseabout one-third of all chordomas, arise earlier than thesacral chordomas, around the 3rd to the 5th decade andin children. Most chordomas in nasopharyngeal locationare extensions of cranial chordomas, but they rarelyarise de novo in the nasopharynx and paranasal sinuses[19, 34, 54]. For a more detailed description of chordoma,see Chap. 4.6.2.7.2 SarcomaThe most common sarcoma in the head and neck areais the rhabdomyosarcoma, specifically the embryonalrhabdomyosarcoma (ICD-O:8910/3) in children lessthan 5 years of age [49]. Primary nasopharyngeal rhabdomyosarcomasare rare [20, 39, 50] as are primary nasopharyngealchondrosarcomas (ICD-O:9220/3) [54,56]. Case reports of primary nasopharyngeal sarcomasinclude an osteosarcoma in an 11-year-old girl aftermulti-agent chemotherapy and radiation treatment of aretinoblastoma, a liposarcoma and a granulocytic sarcomain a 37-year-old Chinese man [5, 42, 139]. The folliculardendritic cell sarcoma, a tumour of antigen-presentingcells of B-follicles of lymphoid tissues, is commonlyfound extranodally in the head and neck area, butrarely in the nasopharynx [10, 22, 23]. It is characterisedby positivity for CD21, CD35 and CD23, as well as indolentclinical behaviour and a low risk of recurrence andmetastasis [87].6.3 Waldeyer’s Ring6.3.1 Anatomy and Histologyof Waldeyer’s RingThe term Waldeyer’s ring refers to the ring of lymphoidtissues occurring in the nasopharynx and oropharynx.The oropharynx is separated from the nasopharynxby the oropharyngeal isthmus, which is formed by themerging muscular pillars of the palatoglossal and thepalatopharyngeal muscles. In the lateral walls, at thewidest points of the pharynx, lies the triangular tonsillarfossa, which contains the palatine tonsil. The tonsilsof Waldeyer’s ring belong to the gut-associated lymphoepithelialorgans, which show a close morphological andfunctional correlation between lymphatic tissue of mesenchymalorigin and the endodermal epithelium of thesecond pharyngeal pouch. The Waldeyer’s ring tonsilsare composed of the paired palatine tonsils in the tonsillarfossa, the unpaired (naso)pharyngeal tonsil in theroof of the nasopharynx, the bilateral tubal tonsils in thelateral walls of the nasopharynx at the entrance to theauditory tube and the lingual tonsil in the retrolingualregion. Lymphoid aggregations close to the epiglottis arealso counted as part of Waldeyer’s ring.The palatine tonsils are the largest of the tonsils andlie in the tonsillar fossa along the anterolateral borderof the oropharynx between the palatoglossal and palatopharyngealmuscle arches. The lateral surface of thepalatine tonsil has a fibrous capsule, but skeletal musclefibres and islands of mostly elastic cartilage are normalfindings there. The medial surface has 10–30 epithelium-lined,extensively branching and anastomosing tonsillarcrypts that extend deeply into the lymphoid tissue.The surface of the palatine tonsils is lined by stratifiedsquamous epithelium, the crypts are covered by nonkeratinisingstratified (“transitional-type”) epitheliumwith a discontinuous basement membrane and numerousintraepithelial lymphoid cells. This so-called lymphoepitheliumrepresents the specialised epithelium ofthe tonsils and contains M-cells (resembling the intestinalmembranous [M] cells of the Peyer’s patches), T- andB-cells, and patchily distributed macrophages and dendriticcells [140, 152]. The surface epithelium is evenlyinfiltrated by T-cells and B-cells; up to 30% of the intraepithelialT-cells are T-cells, which are involved inantigen recognition independent of MHC restrictionand prior antigen processing [66, 149]. A clustering ofCD4+ T-cells with B-cells is typical within the lymphoepitheliumof the crypts and in the submucosa [66]. Thesubmucosal lymphoid tissue contains numerous primaryand secondary lymph follicles with germinal centres,a mantle zone and a network of follicular dendritic cells.T-cells, interdigitating dendritic cells, plasma cells, macrophagesand high-endothelial venules are found in theextrafollicular regions [140]. The palatine tonsils haveno afferent lymph vessels. The rich efferent lymphaticdrainage is via the retropharyngeal lymph nodes to theupper deep cervical lymph nodes.The small unencapsulated (naso)pharyngeal tonsilwith about 12–15 shallow crypts is lined with a columnarciliated respiratory surface epithelium with numerousgoblet cells, which may also be seen in the lymphoepitheliallining of the short and plump crypts [200]. Thelymphoid tissue contains numerous lymph follicles withgerminal centres. Minor salivary glands in the periph-

184 S. Regauer6ery and within the submucosa of the pharyngeal tonsilare a normal finding. The tubal tonsils are poorly definedcondensations of lymphoid tissue located aroundthe auditory tube in the nasopharynx and around thefossa of Rosenmüller. The term lingual tonsil refers to theabundant non-encapsulated lymphoid tissue in the adultposterior tongue. The crypts do not appear until birth,are shallow and much less branched than in the palatinetonsil. The surface is covered by non-keratinising squamousepithelium. Adipose tissue and skeletal muscle fibresat the base of the lingual tonsil, and mucous salivaryglands and lymph follicles within the lingual tonsilare integral parts of the tongue. Efferent lymphaticvessels of the posterior tongue drain into the deep cervicallymph nodes, after they pass through the pharyngealwall in front of or behind the external carotid artery[41].6.3.2 Congenital Anomaliesof Waldeyer’s RingCongenital anomalies include the extremely rare absenceof palatine tonsils and accessory tonsils within theoral cavity [68, 155]. Slightly more common is the “hairypolyp”, a choristoma, which arises from remnants of theectodermal and mesodermal germ layers in the palatinetonsil and nasopharynx (see also Sect. 6.2.3.2). The unilateralpedunculated hairy polyps of up to 5 cm arisemostly on the superior pole of the palatine tonsil andpresent with acute respiratory distress [129]. A rare bilateralpresentation has been described [52]. These polypsshow a mesenchymal fibrovascular core, often withadipose tissue and skeletal muscle fibres and are coveredin regular skin with hair appendages. In tonsillar hairypolyps, submucosal plates of elastic cartilage of uniformthickness resembling the external ear auricular tags andauricular cartilage have been reported [78]. Hairy polypsof the tonsils have been postulated to arise from thesecond pharyngeal pouch [17], but due to the presenceof the cartilage plates they have also been interpreted asaccessory auricles with a postulated origin from the firstpharyngeal arch [78].6.3.3 TonsillitisThe lymphoid tissues of Waldeyer’s ring play a key rolein initiating immune responses against inhaled andingested pathogens. The tonsils are responsible for therecognition and processing of antigens presented to thepharynx. The size of the tonsils is directly proportionalto the amount of lymphoid tissue, which increases duringantigen challenge. The reactive lymphoid hyperplasiaof the palatine tonsils is often simply referred to as“tonsillitis” and in the case of the pharyngeal tonsil as“(hyperplastic) adenoids”. Tonsillar hypertrophy is associatedwith normal childhood development, mostlydue to viral challenge or can be secondary to specificbacterial or viral infections. Childhood hypertrophy ofthe pharyngeal tonsil begins at approximately 2 years ofage or during infancy and usually regresses by 8 years ofage. Palatine tonsils hypertrophy at the end of the firstdecade, somewhat later than the pharyngeal tonsil. Theyregress by puberty and are atrophied in adults. The lingualtonsil enlarges at the time of puberty and regressesvery little during adult life [41]. Tonsillar hypertrophyis usually symmetrical and diffuse, but can be papillaryand unilateral.The normal flora of the naso- and oropharynx includesanaerobic bacteria such as gram-positive Actinomycesand Proprionibacterium, and gram-negativebacteria such as Bacteroides, Fusobacterium and Vibrio[202]. Actinomyces israelii is a common nosocomialsaprophyte in the oro-/nasopharyngeal cavity. The trueincidence of tonsillar manifestations of actinomyces isunknown, but has been reported to be as high as 40%[57, 120]. Occasionally, actinomyces form small sulphurgranules that can be seen as small yellow dots on thetonsillar surface. Larger aggregates of actinomyces mayproduce a tumour-like mass [172]. The tangled massesof gram-positive branching mycelial-like bacteria liewithin the crypts or are attached to the surface epitheliumof normal tonsils. Tonsillectomies for hypertrophiedtonsils or adenoids are one of the most common surgicalprocedures, but the term “tonsillitis” is still poorlydefined. Surgical resection specimens may demonstrateonly hyperplastic lymphoid tissue and lymph follicleswith enlarged germinal centres or no pathology atall [91].6.3.3.1 Bacterial TonsillitisBacterial suppurative tonsillitis is among the most frequentpaediatric infections. Group A beta-haemolyticstreptococci are the most frequent cause. Other commonisolates in bacterial tonsillitis are Hemophilus influenza,Streptococcus pyogenes, Streptococcus milleri and Staphylococcusaureus [97, 202, 205]. Children with acute streptococcaltonsillitis are significantly older than childrenwith viral tonsillitis. The treatment of choice is penicillinadministration for 10 days. Prevention of acute rheumaticfever is the principal goal of treatment. Surgicalspecimens of acute tonsillitis are rarely encountered. Thesurface epithelium may be ulcerated, and the surface andcrypt epithelium is infiltrated by neutrophilic granulocytesproducing a cryptitis with crypt abscesses. Acutebacterial infections may advance to intraparenchymaland peritonsillar abscesses (quinsy) with a lateral extensioninto the parapharyngeal space, base of skull and thesheath of the carotid artery [33, 64]. Rare other bacteria

Nasopharynx and Waldeyer’s Ring Chapter 6 185causing acute necrotising tonsillitis include Clostridiumperfringens and Bartonella henselae with an unusual presentationof cat scratch disease [61, 121].6.3.3.2 Viral TonsillitisThe most common causes of upper respiratory tractinfections and pharyngo-tonsillitis in the general population,including infants and young children, are virusessuch as influenza virus, Coxsackie’s virus (groupA), adenovirus, and the ubiquitous herpes virus Epstein-Barrvirus [205]. EBV infects epithelial cells andB-lymphocytes of Waldeyer’s ring, which representthe reservoir for life-long viral persistence [104, 186].Primary infections with EBV occur early in infancyand childhood in developing countries and are generallyasymptomatic. In contrast, in developed countries,primary infection occurs in adolescents and youngadults. EBV infections may cause the mostly self-limitingacute disease infectious mononucleosis, affectingadolescents and young adults in the western world. InJapan, however, an endemic area for EBV, acute cases ofinfectious mononucleosis are commonly diagnosed inchildren less than 4 years of age [100]. The symptomsinclude enlarged swollen palatine tonsils, occasionallywith peritonsillar abscesses, sore throat, fever, malaise,cervical lymphadenopathy, lymphocytosis andoccasional hepato-splenomegaly [133]. The diagnosisin typical cases is made clinically and/or serologically[69]. Histologically, the changes of a primary EBV infectioncan be dramatic [30]. The surface epitheliumof the palatine tonsils is often necrotic. Follicular hyperplasiawith fused or bizarre-shaped follicles andnumerous tangible body macrophages and distendedinterfollicular areas with atypical immunoblasts, plasmacells, plasmacytoid lymphocytes and histiocytes,occasionally grouped around necrotic foci, are typical.Mitoses are numerous. Rare Reed-Sternberg-like cellswith single or multiple nuclei without nucleoli may bepresent beneath the crypt epithelium. The often atypicalimmunoblasts may simulate lymphoma, but in infectiousmononucleosis, they often merge with cells inthe reactive follicles and paracortex (Fig. 6.6). The proliferatinglymphoid cells are predominantly activatedT lymphocytes with CD8-positive T-cells dominatingover CD4-positive T-cells. The immunoblasts can be ofB-cell or T-cell type, and are occasionally CD30-positive,but CD15-negative [1]. Infected cells are reactivefor EBV nuclear antigen (EBNA) [2] and latent membraneprotein (LMP) [182, 186].The most important differential diagnosis of infectiousmononucleosis, especially in older patients, is theextranodal manifestation of Hodgkin’s lymphoma andnon-Hodgkin’s lymphoma (large cell and immunoblastictypes). Immunoglobulin rearrangements and T-cellreceptor gene rearrangements are lacking in infectiousmononucleosis. The differential diagnosis of ulceratingtonsillitis includes infections with herpes virus hominis(usually Herpes simplex virus type 1). Herpes simplexvirus can produce a vesiculo-bullous pharyngitisand may involve the palatine tonsils [106, 195]. Ruptureof the vesicles results in sharply circumscribed shallowulcers infiltrated by neutrophilic granulocytes. Infectedepithelial cells show the characteristic multinucleatedgiant cells with nuclear viral inclusion. The lymphoidinfiltrate and hyperplasia of a Herpes simplex virus infectionmay mimic a NK/T-cell lymphoma [184]. GroupA Coxsackie’s virus also produces punched-out vesiclesand is often associated with a concomitant Herpes simplexvirus infection. Rare systemic autoimmune diseases,like the anti-phospholipid antibody syndrome, maycause tonsillar ulcers [79].Chronic and recurrent tonsillitis are typically associatedwith respiratory syncytial virus, reactivation of latentEpstein-Barr virus, H. influenza and Staphylococcusaureus [44, 117, 204]. After episodes of recurrent tonsillitis,the palatine tonsils show extensive fibrosis at thesite of the former capsule and scarring with entrapped,“pulled up” skeletal muscle fibres at the base of the tonsiland atrophic lymphoid tissue with small lymphoid follicleswith atrophic germinal centres. Granulomas maybe present. The crypts are distended and filled with keratinousdebris, inflammatory cells and occasional aggregatesof actinomyces. Retention cysts can be formedwithin the deep crypts of chronically irritated palatinetonsils after occlusion of the orifice. The crypt epitheliumbecomes keratinised. Calcification of the desquamateddebris following deposition of inorganic saltsmay result in tonsillar calculi, so-called tonsilloliths. Thepresence of actinomyces is not associated causally withrecurrent tonsillitis [57, 120].Human immunodeficiency virus 1 (HIV-1) infectslymphocytes of lymph nodes and extranodal lymphoidtissue. Hypertrophy of the nasopharyngeal and palatinetonsils is among the earliest clinical manifestations ofHIV-1 infections. Enlargement of the palatine tonsils isusually bilateral and large ulcers may lead to completedestruction of the tonsils [28]. The histological changesin HIV-induced tonsillar hypertrophy vary with stageand progression of the infection. The earliest changes includeflorid reactive follicular hyperplasia with irregularlyshaped germinal centres with an attenuated or absentmantle cell zone. Another early change suggesting HIVinfection is “follicle lysis”, with permeation and disruptionof germinal centres by “infiltrating” small lymphocytescreating a “moth eaten” appearance. Follicle lysis/follicular involution involves loss of tangible body macrophagesas well as the mantle zone of lymph follicles. Interfollicularhaemorrhage is another feature of follicularinvolution. Multinucleated giant cells are a typical andspecific feature of HIV tonsillitis. The multinucleated gi-

186 S. Regauer6abcdeFig. 6.6. EBV tonsillitis. a The hypertrophic palatine tonsil containsreactive lymph follicles which are distended by a dense interfollicularinfiltrate. b The surface epithelium is also heavily infiltratedby numerous atypical lymphocytes, plasma cells, histiocytes.c–d The atypical large immunoblasts with prominent nucleolishow numerous mitoses and merge with the germinal centres.e The atypical immunoblasts may be binuclear atypical lymphoblastsant cells are arranged preferentially in clusters beneaththe squamous surface and crypt epithelium, and are onlyoccasionally seen in intrafollicular areas. They have afoamy cytoplasm and the nuclei are arranged at the peripheryof the cells. The giant cells react with antibodiesto S-100 and CD68. Other features of chronic HIV infectionare monocytoid B-cell hyperplasia, paracortical andinterfollicular expansion with immunoblasts and plasmacells, often with Russell bodies, and prominent interfollicularclusters of high endothelial venules. The histolog-

Nasopharynx and Waldeyer’s Ring Chapter 6 187ical features in patients with advanced disease are effacementof nodal architecture, loss of the normal lymphoidcell population with replacement by benign plasma cellsand increased vascularity [53, 174, 197].Acute non-bacterial tonsillitis and hypertrophy canbe the first sign of a post-transplant lymphoproliferativedisorder [163]. In a study of 42 paediatric transplantpatients, 28% had involvement of Waldeyer’s ring [147].In immunosuppressed children in particular with rapidprogressive enlargement of the tonsils lymphoma shouldbe suspected [180].6.3.4 Benign Tumoursof Waldeyer’s Ring6.3.4.1 Squamous PapillomaICD-O:8121/0Squamous papillomas represent the majority of benigntonsillar and oropharyngeal tumours [89]. They arise onthe soft palate and uvula, but also on the posterior wallof the oropharynx. They have an exophytic appearance.The fibrovascular stalk is covered in a regular, stratified,non-keratinising or keratinising squamous mucosa,with occasional parakeratosis. The vast majorityshow no viral cell changes. Some papillomas, however,show HPV-related cell changes with the typical koilocyteswith small pyknotic nuclei and a perinuclear halo,the so-called tonsillar condylomata [190]. Subtyping forHPV demonstrates typically low-risk HPV 6 and 11. Fora detailed description of squamous papilloma in the oropharynxsee Chap. 1.6.3.4.2 LymphangiomatousTonsillar PolypLymphangiomatous tonsillar polyps are benign tumoursof the palatine tonsil, accounting for about 2%of all tonsillar neoplasms. They have been reportedby a number of different names such as angiomas,angiofibromas, fibrolipoma, polypoid tumour containingfibro-adipose tissue and hamartomatous tonsillarpolyp and lymphangiectatic fibrous polyp [105]. Theyare pedunculated, mostly unilateral proliferations inthe upper pole of the palatine tonsils in adults andchildren (age range of reported cases 3–63 years, witha median age of 26 years). Clinical symptoms are dysphagia,sore throat and the sensation of “a mass in thethroat”. Lymphangiomatous tonsillar polyps measurebetween 0.5 and 4 cm. They are covered by respiratoryepithelium or glycogenated or keratinised squamousepithelium with foci of hyper- and parakeratosis.Clusters of lymphocytes are found within thesquamous epithelium (lymphocytic epitheliotropism)or in the submucosa beneath the basement membrane(Fig. 6.7). The stalk consists of dense fibroustissue, adipose tissues or myxoid and oedematousstroma, which contains numerous small to mediumsized,endothelial-lined, lymphatic/vascular channelsfilled with proteinaceous fluid and lymphocytes[82]. Valves can be appreciated. Some endothelialcells stain with antibodies to factor VIII, CD31 andCD34; others are non reactive. The pathogenesis ofthe lymphangiomatous polyps is uncertain. They maybe a hamartomatous proliferation, but they may alsobe the result of a chronic inflammatory hyperplasia.Especially in children, lymphangiomatous polyps andpapillary lymphoid polyps may be a manifestation ofa chronic tonsillitis.6.3.5 Carcinomasof Waldeyer’s RingICD-O:8070/3Carcinomas of Waldeyer’s ring are typically squamouscell carcinomas (SCC) arising in the palatine tonsil andthe base of the tongue. They are more common in menthan in women and present during the 5th and 7th decades.Smoking, alcohol, poor hygiene, but also HPVinfections, are risk factors [32, 51, 160]. Some SCC maybe fungating and exophytic tumours, others present asdeeply ulcerated infiltrative lesions. The majority ofSCC of the palatine tonsil and base of the tongue typicallygrow undetected for some time as they arise fromthe crypt epithelium. At the time of clinical detection,extensive infiltration of the surrounding tissues andregional cervical lymph node metastases are typical.The metastases to cervical lymph nodes are often thepresenting symptom of tonsillar carcinomas (Fig. 6.8).Histologically, primary carcinomas of the palatinetonsil and base of the tongue can be divided into keratinisingand non-keratinising subtypes. The solidnon-keratinising carcinomas predominate. Tonsillarcarcinomas may show a “transitional type” differentiationresembling lymphoepithelial carcinoma and EBVpositivity [111, 132]. A basaloid-squamous carcinomaof Waldeyer’s ring has also been described [7, 159]. Thelymph node metastases can be quite large and are oftencystic with multilocular complex lumina and papillaryprojections [165, 166, 189]. The majority of cysticmetastases are lined with a stratified epithelium withcytological atypia and numerous mitoses. Foci of keratinisationcan be appreciated. The cysts mostly containnecrotic tumour cells and debris. A minority of thecystic lymph node metastases is filled with clear fluid.Fluid-filled cystic metastases are more common in carcinomasof the base of the tongue than those arisingfrom the palatine tonsils. It has been postulated that

188 S. Regauer6abcdeFig. 6.7. Lymphangiomatous tonsillar polyp. a Lymphangiomatouspolyps vary in size between several millimetres to severalcentimetres. The stalk may be composed of fibro-vascular stromaor adipose tissue. b The stroma may be fibrotic and contains numerousthin-walled vascular channels filled with proteinaceousffluid and lymphocytes. c–d The surface is covered by either squamousepithelium with numerous intraepithelial lymphocytes orby respiratory epithelium with a dense lymphocytic infiltrate. e–fMarkedly dilated lymphatic vessels accompanied by lymphocyticinfiltratecarcinomas that produce cystic metastases originatefrom the excretory ductal system of the submucosalminor salivary glands within the base of the tongueand the palatine tonsil [165].A search for the primary carcinoma within thepharynx in patients with clinically occult tumoursshould include multiple blind biopsies of the base ofthe tongue and oro- and nasopharynx and/or ton-

Nasopharynx and Waldeyer’s Ring Chapter 6 189lymph node or carcinoma arising in a branchiogeniccyst is probably a hypothetical entity. Reports of a supposedbranchiogenic carcinoma included an extremelywell-differentiated SCC arising in the backgroundof longstanding chronic inflammation and scarring,one carcinoma arising from pre-auricular ectodermalremnants of the first pharyngeal/branchial cleft andanother report of a well-differentiated mucoepidermoidbranchiogenic carcinoma [16, 154, 178]. Treatmentof SCC of Waldeyer’s ring is surgical resectionwith a neck dissection.6.3.6 Malignant Lymphomasof Waldeyer’s ringabFig. 6.8. Tonsillar carcinoma. a Tonsillar squamous cell carcinomasfrequently arise from the crypt epithelium. The carcinoma infiltratesdeeply into the surrounding structures including skeletalmuscles. b Cystic lymph node metastasis showing complex papillationswhich are lined by squamous epithelium; the cyst contentis necrotic debrissillectomies. This practice has provided overwhelmingevidence that isolated carcinomas in neck lymphnodes are metastases and not so-called primary“branchiogenic carcinomas” within a cervical lymphnode. The evolution of in situ or invasive SCC fromnon-neoplastic squamous epithelium through dysplasiais viewed as the most important criterion for thehistopathological diagnosis of a primary branchiogeniccarcinoma. Primary cystic carcinoma arising in aThis section gives a brief overview of lymphomas ofWaldeyer’s ring. For a more detailed description, includinggenetic characteristics of these lymphomassee the WHO classification and the revised European-American classification of lymphoid neoplasms [74,95]. Extranodal lymphomas of Waldeyer’s ring constituteabout 5–10% of all lymphomas in the USA andEurope, about 15% in Hong Kong and about 10–20%in Japan. Of all lymphomas involving Waldeyer’s ring,80% are primary to this site and the tonsillar fossa isthe most common location, followed by the nasopharynxand the base of the tongue. Up to 20% of patientswith tonsillar lymphoma have an associated gastrointestinalinvolvement. Clinical presentation is that ofa localised neoplasm, sore throat, dysphagias, and incases of nasopharyngeal involvement cranial nerve,auditory and nasal symptoms. Between 85 and 90% ofall non-Hodgkin’s lymphomas in Waldeyer’s ring areof the B-cell phenotype, the remainder are of the T-celltype, but regional differences have been reported [146,150]. The vast majority of Waldeyer’s ring lymphomasare high-grade lymphomas, with only less than 15%being of low grade [113]. The majority of AIDS-relatedextranodal head and neck lymphomas are aggressiveB-cell lymphomas of the Burkitt type or immunoblasticdiffuse large B-cell lymphomas [207].6.3.6.1 Mantle Cell LymphomaICD-O:9673/3Mantle cell lymphoma (or centrocytic (mantle cell) lymphomain the Kiel classification; diffuse, small cleavedcell type in the Working Formulation) constitutes about5% of all non-Hodgkin’s B-cell lymphomas. Commonextranodal sites are the spleen, bone marrow, gastrointestinaltract and Waldeyer’s ring, particularly the palatinetonsil.

190 S. Regauer66.3.6.2 Extranodal Marginal ZoneB-Cell Lymphomaof Mucosa-AssociatedLymphoid TissueICD-O:9699/3Mucosa-associated lymphoid tissue (MALT lymphomasor immunocytoma in the REAL classification; small lymphocytic,lymphoplasmacytoid, diffuse small cleaved celllymphoma in the Working Formulation) are low-gradeextranodal lymphomas that comprise about 8% of all B-cell lymphomas, typically in gastrointestinal locations.Up to 14% occur in the head and neck area, but MALTlymphomas arising in Waldeyer’s ring are exceptionallyrare [112, 145]. In epithelial tissues, the MALT lymphomacells infiltrate the epithelium, forming lymphoepitheliallesions. In Waldeyer’s ring, however, cautionis advised not to over-interpret the normally occurringintraepithelial lymphocytes within the tonsillar andnasopharyngeal mucosa as lymphoma [94]. In generalMALT lymphomas run an indolent course with a tendencyto remain localised. They are sensitive to radiationtherapy. Patients have prolonged disease-free intervalsafter treatment, but recurrences may involve otherextranodal sites.6.3.6.3 Extranodal NK/T-Cell Lymphoma, Nasal TypeICD-O:9719/3The extranodal NK/T-cell lymphoma, nasal type (orangiocentric T-cell lymphoma in the REAL classification;other historical names: lethal midline granuloma,malignant midline reticulosis, angiocentric immunoproliferativelesion) shows a predilection for thenasal cavity, nasopharynx and palate, but also occursin skin, soft tissues, gastrointestinal tract and testis.The denominator “nasal type” indicates that the nasalcavity is the most common and prototypic site ofinvolvement (Chap. 2). Some cases can be accompaniedby secondary lymph node involvement. Rapidsystemic dissemination is common, but bone marrowinvolvement is very rare. NK/T-cell lymphoma is morecommon in Asia, Mexico and South America than inEurope and North America, and shows a strong associationwith Epstein-Barr virus [24, 65, 99, 135, 142,148]. The prognosis of nasal NK/T-cell lymphoma isvariable despite aggressive therapy. Some patients respondwell and others die with disseminated disease.The prognostic influence of the cytological differentiationis unclear.6.3.6.4 Hodgkin’s LymphomaICD-O:9650/3Although exceptionally rare in extranodal sites, primaryHodgkin’s lymphoma does occur in Waldeyer’s ringand nasopharynx. In a review of 659 upper respiratorytract lymphomas, 6 cases of Hodgkin’s lymphoma inWaldeyer’s ring were identified [35, 103]. The WHO dividesHodgkin’s lymphomas into the nodular lymphocytepredominant Hodgkin’s lymphoma and the classicalHodgkin’s lymphoma (subdivided into lymphocyterich,nodular sclerosis, mixed cellularity and lymphocyte-depletedHodgkin’s lymphoma) [95]. Waldeyer’sring Hodgkin’s lymphomas belong predominantly tothe classical subtypes: seven primary cases of nodularlymphocyte-rich Hodgkin lymphoma were reportedin two studies with a total of 27 patients [25, 179]. Inanother series with 16 patients with Waldeyer’s ringHodgkin’s lymphoma, 50% were classified as mixedcellularity, 25% as nodular sclerosis, one case was anodular lymphocyte predominant subtype and threewere unclassified [103]. Epstein-Barr virus has beenpostulated to play a pathogenetic role in Hodgkin’slymphoma since it has been demonstrated in the majorityof Hodgkin’s lymphomas of Waldeyer’s ring at ahigher incidence than in nodal Hodgkin’s lymphomas[81, 103]. In addition, patients often had a history ofinfectious mononucleosis. Therapy is local irradiationwith or without chemotherapy.6.3.6.5 ExtramedullaryPlasmacytomaICD-O:9734/3The upper aerodigestive tract is the most common sitefor extra-osseous plasmacytomas, with 80% arising inthe head and neck area. In a series of 299 cases, 22%arose in the nasopharynx and 7% in the tonsil [55, 102,124]. Plasmacytomas of Waldeyer’s ring proceed lessoften to multiple myeloma than those of other locations.6.3.7 Systemic Disease AffectingWaldeyer’s RingTangier’s disease (familial hypo-alpha-lipoproteinemia)is an autosomal-recessive metabolic disease with a deficiencyof high-density lipoproteins and extremely lowlevels of plasma cholesterol [85]. The deranged fat metabolismresults in storage of cholesterol esters in thereticuloendothelial system and macrophages of the pharyngealand gastrointestinal tract mucosa, but also insmooth muscle cells, pericytes and Schwann cells of pe-

Nasopharynx and Waldeyer’s Ring Chapter 6 191ripheral nerves. Clinically, most patients are asymptomatic,but children with Tangier’s disease have enlarged,hyperplastic palatine and pharyngeal tonsils with yellow-orangeor yellow-grey discoloration. Histologically,large groups and accumulations of macrophages withfoamy cytoplasm can be identified in the palatine andpharyngeal tonsils [6, 48].A m y l o i d o s i s is usually a systemic disease of multifactorialorigin that may involve the head and neckarea. Particularly the upper respiratory tract is commonlyaffected by amyloidosis with a symmetrical enlargementof the tongue. Small amounts of amyloid depositionin Waldeyer’s ring have been described in plasmacytomas,nasopharyngeal carcinomas or tonsillitis.Isolated tumour-like involvement of the nasopharynxwith and without immunoglobulin light chain restriction,of the entire Waldeyer’s ring or the palatine tonsilswithout systemic disease is exceptionally rare [11,45, 116, 156].Involvement of the naso- and oropharynx by systemicsarcoidosis is well documented [127]. Unsuspectedisolated sarcoidosis of the palatine and pharyngealtonsils in the absence of systemic disease is veryrare [46, 126]. Histologically, the sarcoidosis granulomasare composed of densely packed epithelioid histiocytesand macrophages without central necrosis.Differential diagnoses include recurrent tonsillitis,which may feature giant cells and even foreign bodygiant cell granulomas. Another differential diagnosisconsists of infections with mycobacterium tuberculosisand formation of caseating tuberculoid granulomas.The majority of patients with pulmonary tuberculosishave nasopharyngeal involvement, but isolatednasopharyngeal tuberculosis is rare [2, 161, 193].Metastases from primary tumours outside the headand neck area to the naso- and oropharynx are exceptionallyrare, because the nasopharyngeal and palatinetonsils have no afferent lymph vessels. Consequently,most metastatic tumours in tonsils represent haematogenousdeposits. Bilateral metastases to the palatinetonsils have been described for pancreatic carcinoma[131]. Other metastatic tumours to the palatine tonsilinclude carcinomas of the breast, lung, stomach, colon,prostate, skin and kidneys [173]. Renal cell carcinomasare known to metastasise to the nasopharynx[169].References1. Abbondanzo S, Sato N, Straus SE, Jaffe ES (1990) Acute infectiousmononucleosis. Am J Clin Pathol 93:698–7022. Aktan B, Selimoglu E, Ucuncu H, Sutbeyaz Y (2002) Primarynasopharyngeal tuberculosis in a patient with the complaintof snoring. J Laryngol Otol 116:301–3033. Albers FW, Cuvelier CA, Renders MT, Cauwenberge PB(1993) Oncocytoma of the nasopharynx. Rhinol 31:41–434. Al-Sarraf M, Reddy MS (2002) Nasopharyngeal carcinoma.Curr Treat Options Oncol 3:21–235. Au WY, Kwong YL, Ho WK, Shek TW (2001) Primary granulocyticsarcoma of the nasopharynx. Am J Hematol 67:273–2746. Bale P, Clifton-Bligh P, Benjamin B, Whyte H (1971) Pathologyof Tangier disease. J Clin Pathol 24:609–6167. Banks ER, Frierson HF Jr, Mills SE, George E, Zarbo RJ,Swanson PE (1992) Basaloid squamous cell carcinoma of thehead and neck. A clinicopathologic and immunohistochemicalstudy of 40 cases. Am J Surg Pathol 16:939–9468. Batsakis JG, Solomon AR, Rice DH (1981) The pathology ofhead and neck tumors: carcinoma of the nasopharynx, part11. Head Neck Surg 3:511–5249. Beham A, Beham-Schmid C, Regauer S, Auböck L, StammbergerH (2000) Nasopharyngeal angiofibroma: true neoplasmor vascular malformation? Adv Anat Pathol 7:36–4610. Beham-Schmid C, Beham A, Jakse R, Auböck L, Höfler G(1998) Extranodal follicular dendritic cell tumour of the nasopharynx.Virchows Arch 432:293–29811. Beiser M, Messer G, Samuel J, Gross B, Shanon E (1980) Amyloidosisof Waldeyer’s ring. A clinical and ultrastructuralreport. Acta Otolaryngol 89:562–56912. Benke TT, Zitsch RP, Nashelsky MB (1995) Bilateral oncocyticcysts of the nasopharynx. Otolaryngol Head Neck Surg112:321–32413. Boccon-Gibod LA, Grangeponte MC, Boucheron S, JossetPP, Roger G, Berthier-Falissard ML (1996) Salivary gland anlagetumor of the nasopharynx: a clinicopathologic and immunohistochemicalstudy of three cases. Pediatr Pathol LabMed 16:973–98314. Bossen EH, Hudson WR (1987) Oligodendroglioma arisingin heterotopic brain tissue of the soft palate and nasopharynx.Am J Surg Pathol 11:571–57415. Bremer JW, Neel HB, DeSanto LW, Jones GC (1986) Angiofibroma:treatment trends in 150 patients during 40 years Laryngoscope96:1321–132916. Browder JP, Wheeler MS, Henley JT, Geratz JD (1984) Mucoepidermoidcarcinoma in a cervical cyst: a case of branchiogeniccarcinoma? Laryngoscope 94:107–11217. Burns BV, Axon PR, Pahade A (2001) ‘Hairy polyp’ of thepharynx in association with an ipsilateral branchial sinus:evidence that the ‘hairy polyp’ is a second branchial archmalformation. J Laryngol Otol 115:145–14818. Byrne MN, Session DG (1990) Nasopharyngeal craniopharyngioma.Case report and literature review. Ann Otol RhinolLaryngol 99:633–63919. Campbell WM, McDonald TJ, Unni KK (1980) Nasal and paranasalpresentations of chordomas. Laryngoscope 90:612–61820. Canalis RF, Jenkins HA, Hemenway WG, Lincoln C (1978)Nasopharyngeal rhabdomyosarcoma. A clinical perspective.Arch Otolaryngol 104:122–12621. Carrau RL, Petruzzelli G, Cass SP (1995) Adenoid cystic carcinomaof the nasopharynx. Otolaryngol Head Neck Surg112:501–50222. Chan AC, Chan KW, Chan JK, Au WY, Ho WK, Ng WM(2001) Development of follicular dendritic cell sarcoma inhyaline-vascular Castleman’s disease of the nasopharynx:tracing its evolution by sequential biopsies. Histopathology38:510–51823. Chan JK, Tsang WY, Ng CS (1994) Follicular dendritic celltumor and vascular neoplasm complicating hyaline-vascularCastleman’s disease. Am J Surg Pathol 18:517–525

192 S. Regauer624. Chan JK, Yip TT, Tsang WY, Ng CS, Lau WH, Poon YF, WongCC, Ma VW (1994) Detection of Epstein-Barr viral RNA inmalignant lymphomas of the upper aerodigestive tract. Am JSurg Pathol 18:938–94625. Chang KL, Kamel OW, Arber DA, Horyd ID, Weiss LM(1995) Pathologic features of nodular lymphocyte predominanceHodgkin’s disease in extranodal sites. Am J SurgPathol 19:1313–132426. Chao TY, Chow KC, Chang JY, Wang CC, Tsao TY, Harn HJ,Chi KH (1996) Expression of Epstein-Barr virus-encodedRNAs as a marker for metastatic undifferentiated nasopharyngealcarcinoma. Cancer 78:24–2927. Chaudhry AP, Lore JM Jr, Fisher JE, Gambrino AG (1978)So-called hairy polyps or teratoid tumors of the nasopharynx.Arch Otolaryngol 104:517–52528. Chaudhry R, Akhtar S, Lucente FE, Kim DS (1996) Largeoral ulcers leading to destruction of the tonsils in patientswith AIDS. Otolaryngol Head Neck Surg 114:474–47829. Chessin H, Urdaneta N, Smith H, Gilder JV (1976) Chromophobeadenoma manifesting as a nasopharyngeal mass. ArchOtolaryngol 102:631–63330. Childs C, Parham DM, Berard CW (1987) Infectious mononucleosis.The spectrum of morphologic changes simulatinglymphoma in lymph nodes and tonsils. Am J Surg Pathol11:122–13231. Choi P, Suen MW, Huang DP, Lo KW, Lee JC (1970) Nasopharyngealcarcinoma: genetic changes, Epstein-Barr virusinfection, or both. A clinical and molecular study of 36 patients.Cancer 72:2873–287832. Civantos FJ, Goodwin WJJ (1996) Cancer of the oropharynx.In: Myers EN, Suen YJ (1996) Cancer of the head and neck.Saunders, Philadelphia, pp 381–38033. Civen R, Vaisanen ML, Finegold SM (1993) Peritonsillar abscess,retropharyngeal abscess, mediastinitis, and nonclostridialanaerobic myonecrosis: a case report. Clin Infect Dis16:299–30334. Coffin C, Swanson P, Wick M, Dehner L (1993) Chordoma inchildhood and adolescence. A clinicopathologic analysis of12 cases. Arch Pathol Lab Med 117:927–93335. Colby TV, Hoppe RT, Warnke RA (1981) Hodgkin’s disease:a clinicopathologic study of 659 cases. Cancer 49:1848–185836. Coppit GL III, Perkins JA, Manning SC (2000) Nasopharyngealteratomas and dermoids: a review of the literature andcase series. Int J Pediatr Otorhinolaryngol 52:219–22737. Cummings BJ, Blend R, Fitzpatrick P, Clark R, Harwood A,Keane T, Beale F, Garrett P, Payne D, Rider W (1984) Primaryradiation therapy for juvenile nasopharyngeal angiofibroma.Laryngoscope 94:1599–160538. Dehner LP, Valbuena L, Perez-Atayde A, Reddick RL, AskinFB, Rosai J (1994) Salivary gland anlage tumor (“congenitalpleomorphic adenoma”). A clinicopathologic, immunohistochemicaland ultrastructural study of nine cases. Am JSurg Pathol 18:25–2639. Deutsch M, Orlando SJ (1999) Re-irradiation for recurrentrhabdomyosarcoma of the nasopharynx in a child. Oral Oncol35:343–34540. Dictor M, Siven M, Tennvall J, Rambech E (1995) Determinationof non-endemic nasopharyngeal carcinoma by in situhybridization for Epstein-Barr virus EBER1 RNA: sensitivityand specificity in cervical node metastases. Laryngoscope105:407–41241. Dolen WK, Spofford B, Selner JC (1990) The hidden tonsils ofWaldeyer’s ring. Ann Allergy 65:244–24842. Dubey SP, Sengupta SK, Vele DD (1996) Nasopharyngeal osteosarcomaas second malignant neoplasm in a post-treatedunilateral retinoblastoma: report of a case and review of literature.Int J Pediatr Otorhinolaryngol 34:265–27143. Easton J, Levine PH, Hyams VJ (1980) Nasopharyngeal carcinomain the United States. A pathologic study of 177 USand 30 foreign cases. Arch Otolaryngol 106:88–9144. Endo LH, Ferreira D, Montenegro MCS, Pinto GA, AltemaniA, Bortoleto AE Jr, Vassallo J (2001) Detection of Epstein-Barr virus in tonsillar tissue of children and the relationshipwith recurrent tonsillitis. Int J Pediatr Otorhinolaryngol58:9–1545. Eriksen HE (1970) A case of primary localized amyloidosis inboth tonsils. J Laryngol Otol 84:525–53146. Erwin SA (1989) Unsuspected sarcoidosis of the tonsil. OtolaryngolHead Neck Surg 100:245–24747. Ferouz AS, Mohr RM, Paul P (1995) Juvenile nasopharyngealangiofibroma and familial adenomatous polyposis: an association?Otolaryngol Head Neck Surg 113:435–43948. Ferrans V, Fredrickson D (1975) The pathology of Tangierdisease. A light and electron microscopic study. Am J Pathol78:101–15849. Fletcher CDM, Unni KK, Mertens F (2002) World Health OrganizationClassification of Tumours. In: Kleihues P, SobinLH (eds) Pathology and genetics of tumors of soft tissue andbone. IARC, Lyon50. Folpe AL, McKenney JK, Bridge JA, Weiss SW (2002) Sclerosingrhabdomyosarcoma in adults: report of four cases of ahyalinizing, matrix-rich variant of rhabdomyosarcoma thatmay be confused with osteosarcoma, chondrosarcoma, orangiosarcoma. Am J Surg Pathol 26:1175–118351. Fouret P, Monceaux G, Temam S, Lacourreye L, Guily JLS(1997) Human papillomavirus in head and neck squamouscell carcinomas in nonsmokers. Arch Otolaryngol HeadNeck Surg 123:513–51652. Franco V, Florena AM, Lombardo F, Restivo S (1996) Bilateralhairy polyp of the oropharynx. J Laryngol Otol 110:288–29053. Frankel S, Wenig B, Ferlito A (1997) Human immunodeficiencyvirus-1 infection of the lymphoid tissues of Waldeyer’sring. Ann Otol Rhinol Laryngol 106:611–61854. Fu YS, Perzin KH (1974) Non-epithelial tumors of the nasalcavity, paranasal sinuses and nasopharynx: a clinicopathologicstudy. III. Cartilaginous tumors (chondroma, chondrosarcoma).Cancer 34:453–46355. Fu YS, Perzin KH (1978) Nonepithelial tumors of the nasalcavity, paranasal sinuses and nasopharynx. A clinicopathologicstudy. IX. Plasmacytoma. Cancer 42:2399–240656. Gadwal SR, Fanburg-Smith JC, Gannon FH, Thompson LD(2000) Primary chondrosarcoma of the head and neck in pediatricpatients: a clinicopathologic study of 14 cases with areview of the literature. Cancer 88:2181–218857. Gaffney R, Harrison M, Walsh M, Sweeney E, Cafferkey M(1993) The incidence and role of actinomyces in recurrentacute tonsillitis. Clin Otolaryngol 18:268–27158. Gallo O, Bianchi S, Giannini A, Gallina E, Libonati G, Fini-Storchi O (1991) Correlation between histopathological andbiological findings in nasopharyngeal carcinoma and itsprognostic significance. Laryngoscope 101:487–59359. Gaudecker B von (1988) Development and functional anatomyof the human tonsilla palatina. Acta Otolaryngol Suppl454:28–3260. Gaudecker B von, Muller-Hermelink H (1982) The developmentof the human tonsilla palatina. Cell Tissue Res 224:579–60061. Gerber JE (2001) Acute necrotizing bacterial tonsillitis withClostridium perfringens. Am J Forensic Med Pathol 22:177–17962. Giardiello FM, Hamilton SR, Krush AJ, Offerhaus JA, BookerSV, Petersen GM (1993) Nasopharyngeal angiofibroma inpatients with familial adenomatous polyposis. Gastroenterology105:1550–155263. Giffler RF, Gillespie JJ, Ayala AG, Newland JR (1977) Lymphoepitheliomain cervical lymph nodes of children andyoung adults. Am J Surg Pathol 1:293–30264. Goldenberg D, Golz A, Netzer A, Flax-Goldenberg R,Joachims HZ (2001) Synergistic necrotizing cellulitis as acomplication of peritonsillar abscess. Am J Otolaryngol22:415–41965. Gorp J van, Weiping L, Jacobse K, Liu YH, Li FY, Weger RAde, Li G (1994) Epstein-Barr virus in nasal T-cell lymphomas(polymorphic reticulosis/midline malignant reticulosis)in western China. J Pathol 173:81–87

Nasopharynx and Waldeyer’s Ring Chapter 6 19366. Graeme-Cook F, Bhan AK, Harris NL (1993) Immunohistochemicalcharacterization of intraepithelial and subepithelialmononuclear cells of the upper airways. Am J Pathol143:1416–142267. Graziani N, Donnet A, Bugha TN, Dufour H, Figarella-Branger D, Grisoli F (1994) Ectopic basisphenoidal craniopharyngioma:case report and review of the literature. Neurosurgery34:346–34968. Grewal D, Hiranandani N, Kalgutkar J (1985) Congenital absenceof the palatine tonsil associated with congenital malformationof the external ear. A congenital anomaly. J LaryngolOtol 99:285–28869. Gulley ML, Amin MB, Nicholls JM, Banks PM, Ayala AG,Srigley JR, Eagan PA, Ro JY (1995) Epstein-Barr virus is detectedin undifferentiated nasopharyngeal carcinoma but notin lymphoepithelioma-like carcinoma of the urinary bladder.Hum Pathol 26:1207–121470. Gürtl B, Beham A, Zechner R, Stammberger H, Höfler G(2000) Nasopharyngeal angiofibroma: an APC-gene-associatedtumor? Hum Pathol 31:1411–141371. Haddad Jr J, Senders CW, Leach CS, Stool SE (1990) Congenitalhairy polyp of the nasopharynx associated with cleftpalate: report of two cases. Int J Pediatr Otorhinolaryngol20:127–13572. Hama S, Arita K, Nishisaka T, Fukuhara T, Tominaga A, SugiyamaK, Yoshioka H, Eguchi K, Sumida M, Heike Y, KurisuK (2002) Changes in the epithelium of Rathke cleft cyst associatedwith inflammation. J Neurosurg 96:209–21673. Har-El G, Zirkin H, Tovi F, Sidi J (1985) Congenital pleomorphicadenoma of the nasopharynx (report of a case). J Otolaryngol99:25–3674. Harris NL, Jaffe ES, Stein H, Banks PM, Chan JKC, ClearyML, Delsol G, Wolf-Peeters CD, Falini B, Gatter KC, GroganTM, Isaacson PG, Knowles DM, Mason DY, Muller-HermelinkHK, Pileri SA, Piris MA, Ralfkiaer E, Warnke RA (1994)A revised European-American classification of lymhoid neoplasms:a proposal from the International Lymphoma StudyGroup. Blood 84:1361–139275. Harrison DFN (1987) The natural history, pathogenesis, andtreatment of juvenile angiofibroma. Arch Otolaryngol HeadNeck Surg 113:936–94276. Hasselt CA van, Ng NK (1991) Papillary adenocarcinoma ofthe nasopharynx. J Laryngol Otol 105:853–85477. Hawkins E, Krischer JP, Smith BE, Hawkins HK, FinegoldMJ (1990) Nasopharyngeal carcinoma in children – a retrospectivereview and demonstration of Epstein-Barr viral genomesin tumor cell cytoplasm. A report of the Pediatric OncologyGroup. Hum Pathol 21:805–81078. Heffner DK, Thompson LD, Schall DG, Anderson V (1996)Pharyngeal dermoids (“hairy polyps”) as accessory auricles.Ann Otol Rhinol Laryngol 105:819–82479. Henning B, Buchner N, Kirchner J, Gillessen A (2000) Antiphospholipidantibody syndrome as the cause of clinicalrapidly progressing vasculopathy. Dtsch Med Wochenschr125:589–59380. Herait P, Ganem G, Lipinski M, Carlu C, Micheau C, SchwaabG, The G, Tursz T (1987) Lymphocyte subsets in tumour ofpatients with undifferentiated nasopharyngeal carcinoma:presence of lymphocytes with the phenotype of activated T-cells. Br J Cancer 55:135–13981. Herbst H, Niedobitek G, Kneba M (1990) High incidenceof Epstein-Barr virus genomes in Hodgkin’s disease. Am JPathol 137:13–1882. Hiraide F, Inouye T, Tanaka E (1985) Lymphangiectatic fibrouspolyp of the palatine tonsil. A report of three cases. JLaryngol Otol 99:403–40983. Hirayama T (1978) Descriptive and analytical epidemiologyof nasopharyngeal cancer. Ablashi DV, De-The G, Ito ?Y (eds)Nasopharyngeal carcinoma: etiology and control. IARC,Lyon, pp 167–18984. Hjertaas RJ, Morrison MD, Murray RB (1979) Teratomas ofthe nasopharynx. J Otolaryngol 8:411–41685. Hobbs HH, Rader DJ (1999) ABC1: connecting yellow tonsils,neuropathy, and very low HDL. J Clin Invest 104:1015–101786. Hollender A (1946) The nasopharynx. A study of 140 autopsyspecimens. Laryngoscope 56:282–30487. Hollowood K, Pease C, Mackay AM, Fletcher CDM (1991)Sarcomatoid tumours of lymph nodes showing folliculardendritic cell differentiation. J Pathol 103:90–9788. Hsiao J, Jin Y, Tsai S (1998) EBER1 in situ hybridization as anadjuvant for diagnosis of recurrent nasopharyngeal carcinoma.Anticancer Res 18:4585–458989. Hyams VJ (1978) Differential diagnosis of neoplasia of thepalatine tonsil. Clin Otolaryngol 3:117–12690. Ikeda H, Yoshimoto T (2002) Clinicopathological study ofRathke’s cleft cysts. Clin Neuropathol 21:82–9191. Ikram M, Khan MAA, Ahmed M, Siddiqui T, Mian MY(2000) The histopathology of routine tonsillectomy specimens:results of a study and review of literature. Ear NoseThroat J 79:880–88292. Ikushima I, Korogi Y, Makita O, Komohara Y, Kawano H,Yamura M, Arikawa K, Takahashi M (1999) MR imaging ofTornwaldt’s cysts. AJR Am J Roentgenol 172:1663–166593. Inoue H, Sato Y, Tsuchiya B, Nagai H, Takahashi H, KameyaT (2002) Expression of Epstein-Barr virus-encoded smallnuclear RNA 1 in Japanese nasopharyngeal carcinoma. ActaOtolaryngol Suppl (547)113–11794. Jaffe ES (2002) Lymphoid lesions of the head and neck: amodel of lymphocyte homing and lymphomagenesis. ModPathol 15:255–26395. Jaffe ES, Harris NL, H. HS, Vardiman VW (2001) Pathologyand genetics of tumors of haematopoietic and lymphoid tissues.In: Kleihues P, Sobin LH (eds) WHO Classification ofTumours. IARC, Lyon96. Job A, Walter N, David TM (1991) Solitary fibrous tumor ofthe nasopharynx. J Laryngol Otol 105:213–21497. Jousimies-Somer H, Savolainen S, Makitie A, Ylikoski J(1993) Bacteriologic findings in peritonsillar abscesses inyoung adults. Clin Infect Dis 16:292–29898. Kamino H, Huang SJ, Fu YS (1988) Keratin and involucrinimmunohistochemistry of nasopharyngeal carcinoma. Cancer61:1142–114899. Kanavaros P, Lescs MC, Briere J, Divine M, Galateau F, JoabI, Bosg J, Farcet JP, Reyes F, Gaulard P (1993) Nasal T-celllymphoma: a clinicopathologic entity associated with peculiarphenotype and with Epstein-Barr virus. Blood 81:2688–2695100. Kanegane H, Kanegane C, Yachie A, Miyawaki T, Tosato G(1997) Infectious mononucleosis as a disease of early childhoodin Japan caused by primary Epstein-Barr virus infection.Acta Paediatr Jpn 39:166–171101. Kanoh N, Nishimura Y, Nakamura M, Mori M, Uematsu K(1991) Primary nasopharyngeal paraganglioma: a case report.Auris Nasus Larynx 18:307–314102. Kapadia SB, Desai U, Cheng VS (1982) Extramedullary plasmacytomaof the head and neck. A clinicopathologic study of20 cases. Medicine 61:317–329103. Kapadia SB, Roman LN, Kingma DW, Jaffe ES, Frizzera G(1995) Hodgkin’s disease of Waldeyer’s ring. Clinical andhistoimmunophenotypic findings and association with Epstein-Barrvirus in 16 cases. Am J Surg Pathol 19:1431–1439104. Karajannis MA, Hummel M, Anagnostopoulos I, Stein H(1997) Strict lymphotropism of Epstein-Barr virus duringacute infectious mononucleosis in nonimmunocompromisedindividuals. Blood 89:2856–2862105. Kardon DE, Wenig BM, Heffner DK, Thompson LD (2000)Tonsillar lymphangiomatous polyps: a clinicopathologic seriesof 26 cases. Mod Pathol 13:1128–1133106. Karnauchow PN, Kaul WH (1988) Chronic herpetic laryngitiswith oropharyngitis. Ann Otol Rhinol Laryngol 97:286–288107. Kaur A, Shetty SC, Prasad D, Nirmala V (1997) Primary ectopicmeningioma of the palatine tonsil – a case report. J LaryngolOtol 111:179–181108. Kawashiro N, Koga K, Tsuchihashi N, Araki A (1994) Choanalatresia and congenital pharyngeal stenosis. Acta Otolaryngol517:27–32

194 S. Regauer6109. Kieff DA, Curtin HD, Limb CJ, Nadol JB (1998) A hairy polyppresenting as a middle ear mass in a pediatric patient. AmJ Otolaryngol 19:228–231110. Kikuchi K, Kowada M, Sasaki J, Sageshima M (1994) Largepituitary adenoma of the sphenoid sinus and the nasopharynx:report of a case with ultrastructural evaluations. SurgNeurol 42:330–334111. Klijanienko J, Micheau C, Azli N (1989) Undifferentiatedcarcinoma of nasopharyngeal type of tonsil. Arch Otolaryngol(Head Neck Surg) 115:731–734112. Kojima M, Tamaki Y, Nakamura S (1993) Malignant lymphomaof Waldeyer’s ring. A histological and immunohistochemicalstudy. APMIS 101:537–544113. Krol ADG, Cessie SL, Snijder S, Kluin-Nelemans JC, KluinPM, Noordijk EM (2001) Waldeyer’s ring lymphomas: a clinicalstudy from the Comprehensive Cancer Center West populationbased NHL registry. Leuk Lymphoma 42:1005–1013114. Kuo T, Tsang NM (2001) Salivary gland type nasopharyngealcarcinoma: a histologic, immunohistochemical, and Epstein-Barrvirus study of 15 cases including a psammomatousmucoepidermoid carcinoma. Am J Surg Pathol 25:80–86115. Lee AW, Poon YP, Foo W, Law SC, Cheung FK, Chan DK,Tung SY, Thaw M, Ho JH. (1992) Retrospective analysis of5037 patients with nasopharyngeal cancer treated during1976-1985: overall survival and patterns of failure. Int J RadiolOncol Biol Phys 23:261–270116. Lim JS, Lebowitz RA, Jacobs JB (1999) Primary amyloidosispresenting as a nasopharyngeal mass. Am J Rhinol 13:209–212117. Lindroos R (2000) Bacteriology of the tonsil core in recurrenttonsillitis and tonsillar hypertrophy – a short review. ActaOtolaryngol Suppl 543:206–208118. Lloyd G, Howard D, Lund VJ, Savy L (2000) Imaging for juvenileangiofibroma. J Laryngol Otol 114:727–730119. MacDonald MR, Freeman JL, Hui MF, Cheung RK, WardeP, Mclvor NP, Irish J, Dosch HM (1995) Role of Epstein-Barrvirus in fine-needle aspirates of metastatic neck nodes in thediagnosis of nasopharyngeal carcinoma. Head Neck 17:487–493120. Maher A, Bassiouny A, Bucci TJ, Moawad MK, Hendawy DS(1982) Tonsillomycosis: a myco-histopathological study. JLaryngol Otol 96:229–240121. McEwan J, Basha S, Rogers S, Harkness P (2001) An unusualpresentation of cat-scratch disease. J Laryngol Otol 115:826–828122. Mentzel T, Bainbridge TC, Katenkamp D (1997) Solitary fibroustumour: clinicopathological, immunohistochemical,and ultrastructural analysis of 12 cases arising in soft tissues,nasal cavity and nasopharynx, urinary bladder and prostate.Virchows Arch 430:445–453123. Mey AGL van der, Krieken JHJM van, Dulken H van, StetersAP van, Vielvoye J, Hulshof JH (1989) Large pituitary adenomaswith extension into the nasopharynx. Report of threecases with a review of the literature. Ann Otol Rhinol Laryngol98:618–624124. Michaels L, Hyams VJ (1979) Amyloid in localised depositsand plasmacytomas of the respiratory tract. J Pathol 128:29–38125. Michal M, Sokol L, Mukensnabl P (1996) Salivary gland anlagetumor. A case with widespread necrosis and large cystformation. Pathology 28:128–130126. Miglets AW, Barton CL (1970) Sarcoid of the tonsil. ArchOtolaryngol 92:516–517127. Miglets AW, Viall JH, Kataria YP (1977) Sarcoidosis of thehead and neck. Laryngoscope 87:2038–2048128. Miller R, Sneed W (1985) Tornwaldt’s bursa. Clin Otolaryngol10:21–25129. Mitchell TE, Girling AC (1996) Hairy polyp of the tonsil. JLaryngol Otol 110:101–103130. Miyahara H, Matsunaga T (1994) Tornwaldt’s disease. ActaOtolaryngol Suppl 517:36–39131. Moar E, Tovi F, Sacks M (1983) Carcinoma of the pancreaspresenting with bilateral tonsillar metastases. Ann Otol RhinolLaryngol 92:192–195132. Möller P, Wirbel R, Hofmann W (1984) Lymphoepithelialcarcinoma (Schmincke type) as a derivate of the tonsillarcrypt epithelium. Virchows Arch (Pathol Anat) 405:85–93133. Monem S, O’Connor P, O’Leary T (1999) Peritonsillar abscessand infectious mononucleosis: an association or a differentpresentation of the same condition. Ir Med J 92:278–280134. Moore KL, Persaud TVN (1993) The developing human: clinicallyoriented embryology, 5th edn. Saunders, Philadelphia135. Mori N, Yatabe Y, Oka K, Kinoshita T, Kobayashi T, Ono T,Asai J (1996) Expression of perforin in nasal lymphoma. Additionalevidence of its natural killer cell derivation. Am JPathol 149:699–705136. Morin GV, Shank C, Burgess PA, Heffner DK (1991) Oncocyticmetaplasia of the pharynx. Otolaryngol Head NeckSurg 105:86137. Morrison D, Rose EL, Smith AP, Lesser TH (1992) Dyskeratosiscongenita and nasopharyngeal atresia. J Laryngol Otol106:996–997138. Müller E, Beleites E (2000) The basaloid squamous cell carcinomaof the nasopharynx. Rhinology 38:208–211139. Nageris B, Feinmesser M, Brama I, Feinmesser R (1991) Liposarcomaof the nasopharynx: a case report. Ear Nose ThroatJ 70:520–522140. Nave H, Gebert A, Pabst R (2001) Morphology and immunologyof the human palatine tonsil. Anat Embryol 204:367–373141. Neel 3rd HB (1985) Nasopharyngeal carcinoma. Clinicalpresentation, diagnosis, treatment, and prognosis. OtolaryngolClin North Am 18:479–490142. Ng CS, Lo ST, Chan JK, Chan WC (1997) CD56+ putativenatural killer cell lymphomas: production of cytolytic effectorsand related proteins mediating tumor cell apoptosis?Hum Pathol 28:1276–1282143. Nicolai P, Luzzago F, Maroldi R, Falchetti M, Antonelli A(1989) Nasopharyngeal cysts. Report of seven cases with reviewof the literature. Arch Otolaryngol Head Neck Surg115:860–864144. Nojeg MM, Jalaludin MA, Jayalakshmi P (1998) Papillaryadenocarcinoma of the nasopharynx – case report and reviewof the literature. Med J Malaysia 53:104–106145. Norval E (1998) A mucosa-associated lymphoid tissue(MALT) type lymphoma (marginal zone B-cell lymphoma)from the palatine tonsil. Pathology 30:209–211146. Norval E, Thompson I (2001) Non-Hodgkin’s lymphomas ofWaldeyer’s ring: a clinicopathological and immunologicalstudy of 64 cases in the western Cape. SADJ 56:545–548147. Nouwen J, Smets F, Rombaux P, Hamoir M, Sokal EM (2002)Acute tonsillitis as the first manifestation of post-transplantlymphoproliferative disorder. Ann Otol Rhinol Laryngol111:165–168148. Ohshima K, Suzumiya J, Shimazaki K, Kato A, Tanaka T,Kanda M, Kikuchi M (1997) Nasal T/NK cell lymphomascommonly express perforin and Fas ligand: important mediatorsof tissue damage. Histopathology 31:444–450149. Olofsson K, Hellstrom S, Hammarstrom M (1998) The surfaceepithelium of recurrent infected palatine tonsils is richin gammadelta T cells. Clin Exp Immunol 111:36–47150. Ott G, Kalla J, Ott MM, Müller-Hermelink HK (1997) TheEpstein-Barr virus in malignant non-Hodgkin’s lymphomaof the upper aerodigestive tract. Mol Pathol 6:134–139151. Oudejans JJ, Harijadi H, Kummer JA, Tan IB, Bloemena E,Middele JM, Bladergroen B, Dukers DF, Vos W, Meijer CJ(2002) High numbers of granzyme B/CD8-positive tumourinfiltratinglymphocytes in nasopharyngeal carcinoma biopsiespredict rapid fatal outcome in patients treated with curativeintent. J Pathol 198:468–475152. Papadas T, Batistatou A, Ravazoula P, Zolota V, Goumas P(2001) S-100 protein-positive dendritic cells and CD-34 positivedendritic interstitial cells in palatine tonsils. Arch Otorhinolaryngol258:243–245153. Paris J, Guelfucci B, Moulin G, Zanaret M, Triglia JM (2001)Diagnosis and treatment of juvenile nasopharyngeal angiofibroma.Eur Arch Otorhinolaryngol 258:120–124

Nasopharynx and Waldeyer’s Ring Chapter 6 195154. Parks SS, Karmody CS (1992) The first branchial cleft carcinoma.Arch Otolaryngol Head Neck Surg 118:969–971155. Paslin D (1980) Accessory tonsils. Arch Dermatol 116:720–721156. Patel A, Pambuccian S, Maisel R (2002) Nasopharyngeal amyloidosis.Am J Otolaryngol 23:308–311157. Pathmanathan R, Prasad U, Chandrika G, Sadler R, FlynnK, Raab-Traub N (1995) Undifferentiated, nonkeratinizing,and squamous cell carcinoma of the nasopharynx. Variantsof Epstein-Barr virus-infected neoplasia. Am J Pathol146:1355–1367158. Pathmanathan R, Prasad U, Sadler R, Flynn K, Raab-TraubN (1995) Clonal proliferations of cells infected with Epstein-Barr virus in preinvasive lesions related to nasopharyngealcarcinoma. N Engl J Med 333:693–698159. Paulino AF, Singh B, Shah JP, Huvos AG (2000) Basaloidsquamous cell carcinoma of the head and neck. Laryngoscope110:1479–1482160. Paz IB, Cook N, Odom-Maryon T, Xie Y, Wilczynski SP(1997) Human papillomavirus (HPV) in head and heck cancer.An association of HPV 16 with squamous cell carcinomaof Waldeyer’s tonsillar ring. Cancer 79:595–604161. Percodani J, Braun F, Arrue P, Yardeni E, Murris-Espin M,Serrano, Pessey JJ (1999) Nasopharyngeal tuberculosis. JLaryngol Otol 113:928–931162. Perzin KH, Pushparaj N (1984) Nonepithelial tumors of thenasal cavity, paranasal sinuses, and nasopharynx. A clinicopathologicstudy. XIII: meningiomas. Cancer 54:1860–1869163. Posey LA, Kerschner JE, Conley SF (1999) Posttransplantationlymphoproliferative disease in children: otolaryngologicmanifestations and management. South Med J 92:1079–1082164. Reddy S, Raslan W, Gooneratne S, Kathuria S, Marks J (1995)Prognostic significance of keratinization in nasopharyngealcarcinoma. Am J Otolaryngol 16:103–108165. Regauer S, Beham A, Mannweiler S (2000) CK7 expression incarcinomas of the Waldeyer’s ring area. Hum Pathol 31:1096–1101166. Regauer S, Mannweiler S, Anderhuber W, Gottschuli A,Berghold A, Schachenreiter J, Jakse R, Beham A (1999) Cysticlymph node metastases of squamous cell carcinoma ofWaldeyer’s ring origin. Br J Cancer 1437–1442167. Rowe LD (1980) Neonatal airway obstruction secondaryto nasopharyngeal teratoma. Orolaryngol Head Neck Surg88:221–226168. Ruff T, Diaz JA (1986) Heterotopic brain in the nasopharynx.Orolaryngol Head Neck Surg 94:254–256169. Sabo R, Sela M, Sabo G, Herskovitz P, Feinmesser R (2001)Metastatic hypernephroma to the head and neck: unusualcase reports and review of the literature. J Otolaryngol30:140–144170. Schick B, Brunner C, Praetorius M, Plinkert PK, UrbschatS (2002) First evidence of genetic imbalances in angiofibromas.Laryngoscope 112:397–401171. Schick B, Plinkert PK, Prescher A (2002) Aetiology of angiofibromas:reflection on their specific vascular component.Laryngorhinootologie 81:280–284172. Scott A, Stansbie JM (1997) Actinomycosis presenting asa nasopharyngeal tumour: a case report. J Laryngol Otol111:163–169173. Sellars SL (1971) Metastatic tumours of the tonsil. J LaryngolOtol 85:289–292174. Shahab I, Osborne B, Butler J (1994) Nasopharyngeal lymphoidtissue masses in patients with human immunodeficiencyvirus-1. Cancer 74:3083–3088175. Sham J, Poon YF, Wei WI, Choy D (1990) Nasopharyngealcarcinoma in young patients. Cancer 65:2606–2610176. Shanmugaratnam K, Sobin LH (1991) Histological typing oftumours of the upper respiratory tract and ear. WHO InternationalHistological Classification of Tumours. Springer,Berlin Heidelberg New York177. Shidara K, Uruma T, Yasuoka Y, Kamei T (1993) Two casesof nasopharyngeal branchial cyst. J Laryngol Otol 107:453–455178. Shreedhar R, Tooley AH (1984) Carcinoma arising in a branchialcyst. Br J Surg 75:115179. Siebert JD, Stuckey JH, Kurtin PJ, Banks PM (1995) Extranodallymphocyte predominance Hodgkin’s disease. Clinicaland pathologic features. Am J Clin Pathol 103:485–491180. Smitheringale A (2000) Lymphomas presenting in Waldeyer’sring. Otolaryngology 29:183–185181. Sofferman RA, Heisse JWH Jr (1985) Adenoid cystic carcinomaof the nasopharynx after previous adenoid irradiation.Laryngoscope 95:458–461182. Strickler J, Fedeli F, Horowitz CA, Copenhaver CM, FrizzeraG (1993) Infectious mononucleosis in lymphoid tissue. Histopathology,in-situ hybridization, and differential diagnosis.Arch Pathol Lab Med 117:269–278183. Sulica RL, Wenig BM, Debo RF, Sessions RB (1999) Schneiderianpapillomas of the pharynx. Ann Otol Rhinol Laryngol108:392–397184. Taddasse-Heath L, Feldman J, Fahle GA, Fisher SH, SorbaraL, Raffeld M, Jaffe E (2003) Florid CD4+, CD56+ T-cell infiltrateassociated with Herpes simplex infection simulatingnasal NK-/T-cell lymphoma. Mod Pathol 16:166–172185. Tamagawa Y, Kitamura K, Miyata M (1995) Branchial cystof the nasopharynx: resection via the endonasal approach. JLaryngol Otol 109:139–141186. Tao Q, Srivastava G, Chan AC, Chung LP, Loke SL, Ho FC(1995) Evidence for lytic infection by Epstein-Barr virus inmucosal lymphocytes instead of nasopharyngeal epithelialcells in normal individuals. J Med Virol 45:71–77187. Tharrington C, Bossen E (1992) Nasopharyngeal teratomas.Arch Pathol Lab Med 116:165–167188. Thompson L, Gyure K (2000) Extracranial sinonasal tractmeningiomas. a clinicopathologic study of 30 cases with areview of the literature. Am J Surg Pathol 24:640–650189. Thompson LDR, Heffner DK (1998) The clinical importanceof cystic squamous cell carcinomas in the neck. Cancer82:944–956190. Tominaga S, Fukushima K, Nishizaki K, Watanabe S, MasudaY, Ogura H (1996) Presence of human papillomavirustype 6 in tonsillar condyloma acuminatum and clinicallynormal tonsillar mucosa. Jpn J Clin Oncol 26:393–397191. Tsai ST, Jin YT, Su IJ (1996) Expression of EBER1 in primaryand metastatic nasopharyngeal carcinoma tissues using insitu hybridization. A correlation with WHO histologic subtypes.Cancer 77:231–236192. Voelker JL, Campell RL, Muller L (1991) Clinical, radiographicand pathological features of symptomatic Rathke’scleft cysts. J Neurosurg 74:535–644193. Waldron J, Hasselt CAV, Skinner DW, Arnold M (1992) Tuberculosisof the nasopharynx: clinicopathological features.Clin Otolaryngol 17:57–59194. Wan SK, Chan JK, Lau WH, Yip TT (1995) Basaloid-squamouscarcinoma of the nasopharynx. An Epstein-Barr virusassociatedneoplasm compared with morphologically identicaltumors occurring in other sites. Cancer 76:1689–1693195. Wat PJ, Strickler JG, Jeffrey L, Nordstrom MR (1994) Herpessimplex infection causing acute necrotizing tonsillitis. MayoClin Proc 69:269–271196. Weiss LM, Movahed LA, Butler AE, Swanson SA, FriersonHFJ, Cooper PH, Colby TV, Mills SE (1989) Analysis of lymphoepitheliomaand lymphoepithelioma-like carcinomas forEpstein-Barr vital genomes by in situ hybridization. Am JSurg Pathol 13:625–631197. Wenig B, Thompson L, Frankel S (1996) Lymphoid changesof the nasopharyngeal and palatine tonsils that are indicativeof human immunodeficiency virus infection. Am J SurgPathol 20:572–587198. Wenig BM, Harpaz N, DelBridge C (1989) Polymorphouslow-grade adenocarcinoma of seromucous glands of the nasopharynx.A report of a case and a discussion of the morphologicand immunohistochemical features. Am J ClinPathol 92:104–109199. Wenig BM, Heffner DK (1995) Respiratory epithelial adenomatoidhamartomas of the sinonasal tract and nasopharynx:a clinicopathologic study of 31 cases. Ann Otol Rhinol Laryngol104:639–645

196 S. Regauer200. Winther B, Innes D (1994) The human adenoid. Arch OtolaryngolHead Neck Surg 120:144–149201. Witkin GB, Rosai J (1991) Solitary fibrous tumor of the upperrespiratory tract. A report of six cases. Am J Surg Pathol15:842–848202. Woodruff C (1980) Nonneoplastic and inflammatory disordersof Waldeyer’s ring. Ear Nose Throat J 59:457–465203. Yadav SP, Singh I, Chanda R, Sachdeva OP (2002) Nasopharyngealangiofibroma. Otolaryngol 31:346–350204. Yamanaka N, Kataura A (1984) Viral infections associatedwith recurrent tonsillitis. Acta Otolaryngol Suppl 416:30–37205. Ylikoski J, Karjalainen J (1989) Acute tonsillitis in youngmen: etiological agents and their differentiation, Scand J Infect21:169–174206. Zarbo R, McClatchey K (1983) Nasopharyngeal hamartoma.Laryngoscope 93:494–497207. Ziegler JL, Beckstead JA, Volberding PA, Abrams DI, LevineAM, Lukes RJ, Gill PS, Burkes RL, Meyer PR, Metroka CE(1984) Non-Hodgkin’s lymphoma in 90 homosexual men.Relation to generalized lymphadenopathy and the acquiredimmunodeficiency syndrome. N Engl J Med 311:565–570208. Zong Y, Zhang C, Zhang F, Ruan JB, Chen MY, Feng KT, YuZF (1993) Infiltrating lymphocytes and accessory cells in nasopharyngealcarcinoma. Jpn J Cancer Res 84:900–9056

Chapter 7Larynxand HypopharynxN. Gale · A. Cardesa · N. Zidar7Contents7.1 Summary of Anatomy,Histology and Embryology . . . . . . . . . . . . . . . . 1987.2 Laryngocele, Cysts, Heterotopia . . . . . . . . . . . . . 1997.2.1 General Considerations . . . . . . . . . . . . . . . . . 1997.2.2 Laryngocele . . . . . . . . . . . . . . . . . . . . . . . . 1997.2.3 Sacccular Cyst . . . . . . . . . . . . . . . . . . . . . . . 1997.2.4 Ductal Cyst . . . . . . . . . . . . . . . . . . . . . . . . . 1997.2.5 Oncocytic Cyst . . . . . . . . . . . . . . . . . . . . . . . 2007.2.6 Zenker’s Hypopharyngeal Diverticle . . . . . . . . . . 2017.2.7 Aberrant Thyroid Tissue . . . . . . . . . . . . . . . . . 2017.2.8 Tracheopathia Osteochondroplastica . . . . . . . . . 2027.3 Inflammatory Lesions . . . . . . . . . . . . . . . . . . 2027.3.1 Acute Infections . . . . . . . . . . . . . . . . . . . . . . 2027.3.1.1 Epiglottitis . . . . . . . . . . . . . . . . . . . . . . . . . 2027.3.1.2 Laryngotracheobronchitis . . . . . . . . . . . . . . . . 2027.3.1.3 Diphtheria . . . . . . . . . . . . . . . . . . . . . . . . . 2027.3.2 Chronic Infections . . . . . . . . . . . . . . . . . . . . 2027.3.2.1 Tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . 2027.3.2.2 Fungal Infections . . . . . . . . . . . . . . . . . . . . . 2037.3.2.3 Other Rare Infections . . . . . . . . . . . . . . . . . . . 2037.3.3 Non-Infectious Inflammatory Lesions . . . . . . . . . 2037.3.3.1 Wegener’s Granulomatosis . . . . . . . . . . . . . . . . 2037.3.3.2 Sarcoidosis . . . . . . . . . . . . . . . . . . . . . . . . . 2047.3.3.3 Rheumatoid Arthritis . . . . . . . . . . . . . . . . . . . 2047.3.3.4 Relapsing Polychondritis . . . . . . . . . . . . . . . . . 2057.3.3.5 Gout . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2067.3.3.6 Teflon Granuloma . . . . . . . . . . . . . . . . . . . . . 2067.3.3.7 Idiopathic Subglottic Laryngeal Stenosis . . . . . . . 2067.3.3.8 Angioneurotic Oedema . . . . . . . . . . . . . . . . . . 2077.4 Degenerative Lesions . . . . . . . . . . . . . . . . . . . 2077.4.1 Oculopharyngeal Muscular Dystrophy . . . . . . . . 2077.5 Pseudotumours . . . . . . . . . . . . . . . . . . . . . . 2077.5.1 Exudative Lesions of Reinke’s Space . . . . . . . . . . 2077.5.1.1 Reinke’s Oedema . . . . . . . . . . . . . . . . . . . . . 2087.5.1.2 Vocal Cord Polyp and Nodule . . . . . . . . . . . . . . 2087.5.2 Contact Ulcer and Granuloma,Intubation Granuloma . . . . . . . . . . . . . . . . . . 2107.5.3 Necrotising Sialometaplasia . . . . . . . . . . . . . . . 2117.5.4 Metaplastic Elastic Cartilaginous Nodules . . . . . . 2117.5.5 Amyloidosis . . . . . . . . . . . . . . . . . . . . . . . . 2117.5.6 Sinus Histiocytosis with Massive Lymphadenopathyand Other Rare Pseudotumours . . . . . . . . . . . . . 2127.5.7 Inflammatory Myofibroblastic Tumour . . . . . . . . 2137.6 Benign Neoplasms . . . . . . . . . . . . . . . . . . . . . 2147.6.1 Squamous Cell Papilloma . . . . . . . . . . . . . . . . 2147.6.2 Salivary Gland-Type Tumours . . . . . . . . . . . . . . 2147.6.2.1 Pleomorphic Adenoma . . . . . . . . . . . . . . . . . . 2147.6.2.2 Oncocytoma . . . . . . . . . . . . . . . . . . . . . . . . 2147.6.3 Haemangioma (Neonatal and Adult Types) . . . . . . 2147.6.4 Paraganglioma . . . . . . . . . . . . . . . . . . . . . . . 2157.6.5 Granular Cell Tumour . . . . . . . . . . . . . . . . . . 2167.6.6 Chondroma . . . . . . . . . . . . . . . . . . . . . . . . . 2177.7 Malignant Neoplasms . . . . . . . . . . . . . . . . . . . 2177.7.1 Potentially Malignant (Precancerous) Lesions . . . . 2177.7.2 Invasive Squamous Cell Carcinoma . . . . . . . . . . 2187.7.2.1 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . 2187.7.2.2 Aetiology . . . . . . . . . . . . . . . . . . . . . . . . . . 2187.7.2.3 Anatomic Sites . . . . . . . . . . . . . . . . . . . . . . . 2187.7.2.4 Histological Variants . . . . . . . . . . . . . . . . . . . 2197.7.2.5 TNM Grading . . . . . . . . . . . . . . . . . . . . . . . 2207.7.3 Neuroendocrine Carcinoma . . . . . . . . . . . . . . . 2207.7.3.1 Well-Differentiated NeuroendocrineCarcinoma (Carcinoid) . . . . . . . . . . . . . . . . . . 2207.7.3.2 Moderately Differentiated NeuroendocrineCarcinoma (Atypical Carcinoid) . . . . . . . . . . . . 2207.7.3.3 Poorly Differentiated NeuroendocrineCarcinoma (Small Cell Carcinoma) . . . . . . . . . . 2217.7.4 Adenocarcinoma . . . . . . . . . . . . . . . . . . . . . 2227.7.4.1 Adenoid Cystic Carcinoma . . . . . . . . . . . . . . . 2227.7.4.2 Mucoepidermoid Carcinoma . . . . . . . . . . . . . . 2227.7.5 Sarcomas . . . . . . . . . . . . . . . . . . . . . . . . . . 2237.7.5.1 Chondrosarcoma . . . . . . . . . . . . . . . . . . . . . 2237.7.5.2 Other Sarcomas . . . . . . . . . . . . . . . . . . . . . . 2247.7.6 Other Malignant Neoplasms . . . . . . . . . . . . . . . 2247.7.6.1 Malignant Lymphoma . . . . . . . . . . . . . . . . . . 2247.7.6.2 Extraosseus (Extramedullary) Plasmacytoma . . . . . 2247.7.6.3 Primary Mucosal Melanoma . . . . . . . . . . . . . . . 2257.7.6.4 Metastases to the Larynx . . . . . . . . . . . . . . . . . 225References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226

198 N. Gale · A. Cardesa · N. Zidar77.1 Summary of Anatomy,Histology and EmbryologyThe larynx and hypopharynx are constituent parts ofthe upper aerodigestive tract, intimately linked togetherwith their connective tissue elements and differentepithelia. The anatomy and histology of both organsare very complex and details are available in variousstandard textbooks and specialised papers [103, 158,238, 321, 322]. Only essential data will be given here.The larynx is a hollow tube that communicatescranially with the hypopharynx. Its upper limits arethe free edge of the epiglottis and the two aryepiglotticfolds. The lower laryngeal part continues caudallywith the trachea, and its inferior limit is the loweredge of the cricoid cartilage. The anterior border consistsof the lingual surface of the epiglottis, thyrohyoidmembrane, thyroid cartilage and the anterior arch ofthe cricoid cartilage. Posteriorly, the cricoid cartilageand area of the arytenoids limit the larynx.The larynx is divided into supraglottic, glottic andsubglottic regions, which have particular significancefor the biological behaviour and staging of tumours.The supraglottic region extends from the tip of the epiglottisdown to the superior edge of the true vocal cordand includes the epiglottis, aryepiglottic folds, arytenoids,the false vocal cords and ventricles. The glottisincludes the vocal cords with anterior and posteriorcommissures. The subglottis extends below thetrue vocal cords to the lower border of the cricoid cartilage.Our own experience suggests that marked variationsin the distribution of different types of laryngeal epitheliarelated to age seem to be the rule [177]. The lingualand, variably, laryngeal side of the epiglottis andthe true vocal cords are covered by the non-keratinisingstratified squamous cell epithelium, the rest of thelarynx is lined with the respiratory epithelium. The seromucinousglands are abundant in all compartmentsof the larynx except in the vocal cords, where they areessentially missing on their free edges and are sparse inthe rest of the cords.It is important to draw attention to some particularitiesin the laryngeal structure that considerably influencethe spread of malignant tumours. The elasticcartilage of the epiglottis with numerous fenestrationsfor vessels, nerves and glands provides a “locus minorisresistentiae” for the progress of malignant growthfrom the laryngeal to the lingual side or vice versa. Inthe anterior commissure, where the true vocal cordsmeet in the anterior midline, a band of fibrous tissue(protrusions of the two vocal ligaments) with lymphaticand blood vessels is attached to the thyroid cartilage.There is no perichondrium at this point, whichcertainly facilitates the ingrowth of malignant tu-mours in the thyroid cartilage. The network of capillariesis poorly developed in Reinke’s space of the vocalcords and lymphatics are lacking. These specificitiescontribute to the development of various exudativelesions of the vocal cords and delayed metastasesof glottic cancers.Embryologically, the supraglottic part of the larynxarises from the third and the fourth branchial arches,while the glottic and subglottic portions are derivedfrom the sixth arch. The first appearance of the respiratorytract occurs at approximately 21 days duringembryogenesis as an evagination or a vertical grooveof the cephalic portion of the foregut. This evaginationis the precursor of the epiglottis, the earliest portion ofthe larynx. Its outlines appear at the 6-mm foetal stageby 30 days. The respiratory groove begins to close andwith the formation of the arytenoids, the closure becomescomplete [103]. The covering epithelium of thegroove appears in the 3–5-mm embryo as three lines ofpolyhedral embryonic cells of endodermal origin. In a30-mm foetus, by 60–70 days, the thickness of the embryonicstratified squamous epithelium increases, andthe vocal cords begin to differentiate. The ciliated epitheliumoccurs in a 40-mm foetus on the epiglottis andlaryngeal vestibule. A sharp distinction between thetwo epithelia appears after the foetus reaches a lengthof 95 mm. The larynx of a newborn is covered in theciliated epithelium, except on the true vocal cords. Inaddition to this location, the stratified squamous epitheliumis also present on the interarytenoid area andon the tip of the epiglottis [158].The hypopharynx is the caudal part of the pharynxwith the wide part superiorly, extending from the tipof the epiglottis to the inferior level of the cricoid cartilage,where it becomes narrow and continuously proceedsto the oesophagus. The hypopharynx is dividedinto three compartments: left and right pyriform sinuses,postcricoidal region, and posterior pharyngealwalls. The pyriform sinuses are medially limited bythe aryepiglottic folds and laterally by the thyroid cartilage.The postcricoid area is the posterior side of thecricoid cartilage. The posterior wall is situated in frontof the cervical spine. The entire hypopharynx is coveredin the stratified squamous cell epithelium.Embryologically, the pharyngeal gut or pharynx extendsfrom the buccopharyngeal membrane to the tracheobronchialdiverticulum. The hypopharynx is almostentirely of endodermal origin. In the 8th throughto the 10th gestation week the pharynx, as well as thehypopharynx, is rather small and after the 10th weekof gestation, remarkable growth occurs in this region[204, 252].

Larynx and Hypopharynx Chapter 7 1997.2 Laryngocele,Cysts, Heterotopia7.2.1 General ConsiderationsA laryngocele is a rare congenital or acquired laryngeallesion that appears within and around the laryngeal saccule.Laryngeal cysts account for approximately 5% ofbenign laryngeal lesions [177, 265]. DeSanto presenteda classification of laryngeal cysts in which the lesionswere divided into ductal, saccular and thyroid cartilageforaminal cysts [80]. This classification, which ismore clinically adjusted, is based on the intramucosaldepth of the cyst and its location. Newman and coworkersfound it difficult to apply and proposed a newone, dividing the lesions into tonsillar, epithelial (saccularand ductal) and oncocytic cysts. According to theoriginal article, more than half of all laryngeal cystswere epithelial, one quarter tonsillar and less than 15%oncocytic [265].7.2.2 LaryngoceleLaryngocele is defined as an excessive elongation anddilatation of the air-filled laryngeal saccule (ventricularappendix), which communicates directly with the laryngeallumen. According to its site, there are three types oflesions: internal, external, and mixed. An internal laryngoceleextends in a superior-posterior direction, towardsthe area of the false vocal cord and aryepiglottic fold. Anexternal one expands cranially and laterally to the neckthrough the weak zone of the thyrohyoid membrane.It presents as a lateral neck mass that varies in size dependingon variations of the intralaryngeal pressure. Amixed or combined form has both internal and externalcomponents with a swelling of the neck and endolaryngealbulging [14, 15, 53]. The combined laryngocele isthe most common (44%), followed by internal (30%) andexternal (26%) forms [50].A laryngocele is quite a rare lesion, occurring ascongenital [60] or acquired, most frequently observedin infants and adults between 50 and 60 years. A malepredominance is evident with a ratio of 7:1 [227, 287].Most laryngoceles are unilateral. Aetiologically, thelesion occurs in persons with a congenital large sacculeand weakness of the periventricular soft tissue.In adults, various conditions involving a repeatedincrease in intralaryngeal pressure, such as inflictingglass-blowers, wind instrument musicians, singers,professional speakers, and patients with a chroniccough, are reported [227]. Stenosis of the saccule neck,which functions as a valve system, may also lead tothe occurrence of a laryngocele. The leading symptomsof an internal or compound lesion are hoarseness,cough, dyspnoea, dysphagia, and the sensationof a foreign body.The lesion may, however, be also asymptomatic in approximately12% of the cases [62]. The diagnosis is establishedby the history, and by physical and radiologicalexamination, especially computed tomography (CT).Histologically, a cystic extension of the saccule is evidentand its wall tends to lose its folded surface. The laryngoceleis covered by the respiratory epithelium; occasionallyan oncocytic or cuboidal metaplasia is present.Focally, chronic mononuclear inflammatory cellsare seen in the subepithelial stroma. Laryngocele-relatedcomplications include infection (laryngopyocele),aspiration and subsequent pneumonia [287]. There isalso a relationship between laryngocele and laryngealsquamous cell carcinoma in 4.9 to 28.8% of cases [140].The endoscopic surgical treatment of laryngocele is themethod of choice [354].7.2.3 Saccular CystA saccular cyst (SC) is a mucus-filled dilatation of thelaryngeal saccule that has no communication with thelaryngeal lumen [80, 161]. Most SCs are congenital inorigin; some may also appear as acquired lesions causedby various inflammatory processes, traumatic events,or tumours [1, 161, 257]. SCs, which may occur at anyage, are divided into anterior and lateral. The formerspread medially and posteriorly, and protrude into thelaryngeal lumen between the true and false vocal cord.The latter are generally larger and extend towards thefalse vocal cord and aryepiglottic fold. They may rarelyspread through the thyrohyoid membrane [10, 80, 161,357]. SCs may be asymptomatic, but the most commonsymptoms are progressive cough, dysphagia, hoarseness,dyspnoea and foreign body sensation. Diagnosisis often made by laryngoscopy combined with CT scan[69].Histologically, SCs are lined with ciliated respiratoryepithelium . An increased number of goblet cells may bepresent. Rarely, the cysts are partially or entirely linedby metaplastic squamous or oncocytic epithelium. Subepithelialstroma, i.e. the cyst wall, usually contains focallymphocytic infiltrates [177].Treatment is surgical, the decision on an endoscopicor an external approach depends on the type and size ofthe cyst, as well as the individual patient’s condition.7.2.4 Ductal CystDuctal cysts (DCs) are the most common laryngeal cystsand comprise up to 62.5% of all laryngeal cystic lesions.The characteristic retention of mucus in the dilated collectingducts of the intramucosal seromucinous glands

200 N. Gale · A. Cardesa · N. Zidar7aFig. 7.1. Ductal cyst. a Large cyst arises from the right ventricle.b Ductal cyst is covered in ductal epithelium and filled with mucinbcan be found anywhere in the larynx [10, 177]. DCs originatefrom an obstruction of the glandular ducts, causedmainly by chronic inflammation. They are mainly locatedon the vocal cords, ventricle of Morgagni , ventricularfolds , aryepiglottic folds , and on the pharyngeal side ofthe epiglottis, where they tend to be larger, even up to7.5 cm in diameter (Fig. 7.1a) [14, 177].The origin of a so-called epidermoid cyst of the vocalcord is probably related to microtraumatic inclusion ofsmall fragments of squamous epithelium into the subepithelialtissue or to the remnants of the vocal cord sulcus[251]. These cysts are usually smaller than other laryngealretention cysts , measuring 1–4 mm and not exceeding10 mm in diameter [80].Laryngoscopically, ductal cysts are seen as a sharplydelineated spherical protrusion, the overlying mucosa issmooth and stretched. Larger cysts, mainly in newbornsor in small children, can obstruct breathing.The histological picture of DCs is influenced by origin.Laryngeal retention cysts are covered in doublelayeredcylindrical, cuboidal or flattened ductal epithelium(Fig. 7.1b) . Squamous or oncocytic metaplasia ofthe ductal epithelium, partial or complete, is frequentlypresent. Classical “epidermoid” or keratinising cystsof the vocal cords are usually lined with atrophic keratinisingepithelium with intraluminal stratified basophilickeratin scales . The therapy of choice for DC is surgicalremoval.7.2.5 Oncocytic CystAlthough the oncocytic lesions dominate in the parotidgland, they may appear in the minor salivary glands ofthe upper aerodigestive tract, including the larynx. Awhole spectrum of oncocytic laryngeal lesions has beenobserved, ranging from focal to diffuse oncocytic metaplasia,papillary cystic hyperplastic lesions to benignand malignant tumours (the latter occur mainly in thesinonasal and palatal region) [44]. On the other hand, ithas been suggested that all these lesions, variously calledoncocytic cyst (OC), oncocytic papillary cystadenoma,oncocytoma, oncocytic adenomatous hyperplasia, morelikely belong to non-neoplastic rather than to true neoplasticlesions [193, 265, 291]. This opinion has beensupported by the various extent of oncocytic metaplasiain the laryngeal minor salivary glands, as well as by theoccasional appearance of multiple cystic lesions [84, 111,230, 387].Oncocytes are enlarged cells with characteristicgranular eosinophilic cytoplasm, caused by an increasednumber of tightly packed abnormal mitochondria,and small, dense, darkly stained nuclei. The exactcause of oncocytic metaplasia remains unknown,but it is related to the process of aging and especiallyto disturbance of the organisation of the mitochondrialenzymes [238]. Laryngeal OCs may show focal,inconspicuous or extensive proliferation of oncocytes,mainly with unilocular or multilocular cystic formationswith papillary projections, resembling the Warthin’stumour [119].Laryngeal OCs probably represent a separate clinicopathologicentity, showing typical age group, locationand histopathologic features. They occur on the falsevocal cords and ventricles in middle-aged to elderly personswith hoarseness or a cough as the leading symptoms[216, 265, 283, 304]. Clinically, OCs appear as solitarypolypoid lesions in the subepithelial stroma, while

Larynx and Hypopharynx Chapter 7 201An outpouching of the dorsal hypopharyngeal wallabove the upper oesophageal sphincter is known asZenker’s diverticulum (ZD). The condition is more oftenseen in northern Europe, especially the UK, thanelsewhere in the world [42]. The site of origin is betweenthe thyropharyngeal and the more horizontalpart of the cricopharyngeal muscle. The aetiologicalfactors of ZD occurrence have not been explained, butan incomplete sphincter opening with an increase inhypopharyngeal pressure during swallowing has tobe considered [266]. The lesion, which usually occursin elderly persons, is now widely accepted to be of acquiredrather than congenital origin. The symptomsare virtually pathognomonic: dysphagia, regurgitationof undigested food, weight loss, foetor ex ore, coughingand repeated aspiration [42]. Diagnosis of the diseasemay be confirmed by a barium swallow. Histologically,ZD is composed of a squamous epithelium, thinned fibroustissue of the subepithelial stroma with possibleinflammatory changes. The conservative open surgicalprocedures provide effective results [266]. Exceedinglyrarely, squamous cell carcinoma may develop inZD [42].7.2.7 Aberrant Thyroid TissueFig. 7.2. Oncocytic cyst of the ventricular cord. Cyst is lined withoncocytic epitheliuma diffuse involvement as oncocytic cystadenomatosis isexceptional [230].Histologically, the epithelium of an OC shows papillaryproliferations or a different degree of folding ofthe cystic wall. The epithelium is typically double layered;the inner layer consists of columnar eosinophiliccells encircling the cystic lumina, while the outer layeris composed of small basal cells (Fig. 7.2) . Complete endoscopicalsurgical excision is the recommended treatment,if necessary by laryngofissure [216].7.2.6 Zenker’sHypopharyngeal DiverticleThyroid tissue rarely appears in sites outside of itsembryonic development. The subglottic area of thelarynx and upper trachea are places where aberrantthyroid tissue (ATT) may be found [36], especiallybetween the lower border of the cricoid cartilage andthe upper ring of the trachea. According to differentreports, intraluminal thyroid tissue occurs anywherebetween the glottis and the bifurcation of the trachea,as a broad-based, smooth, rounded mass protrudingfrom the left subglottic posterolateral wall [305, 345].It has been pointed out that two-thirds of patients aremiddle-aged women from regions of endemic goitre[22, 36]. Intralaryngotracheal thyroid is a rare lesion.Only about 125 cases were described up to 1998 [327].Waggoner divided intralaryngotracheal thyroid tissueinto “false” and “true” aberrant thyroids. The formeris likely to arise in the pre- or neonatal period,when the thyroid gland could grow into incompletelyformed laryngotracheal cartilages that remain in continuitywith the thyroid gland. The latter, the “trueaberrant thyroid”, develops during the foetal periodas an isolated, misplaced thyroid tissue, when the thyroidgland is encroached upon and divided by the laterdeveloped laryngeal and tracheal cartilages [327, 361,372]. The most common symptom of intralaryngealATT is slowly progressive dyspnoea, but it may be alsoasymptomatic [278].Histologically, the thyroid follicles are usually small,regular, with a well-formed colloid lying close to the seromucinousglands in the laryngeal mucosa [238]. Theoverlying mucosa is commonly intact, and there may besome evidence of chronic irritation. The finding of thyroidtissue in the laryngotracheal wall raises the questionas to whether or not it represents ectopic tissue appearingthrough a developmental defect or a well-differentiatedcarcinoma. The final decision must be based onan overall clinical evaluation and not only on histologicalfindings [36, 327]. Management of ATT is often notclear-cut, but is proposed to be primarily surgical [327,345, 372].

202 N. Gale · A. Cardesa · N. Zidar77.2.8 TracheopathiaOsteochondroplasticaTracheopathia osteochondroplastica (TO) is a rare,slowly progressing lesion, characterised by the presenceof cartilaginous and bony submucosal nodules projectinginto the lumen of the trachea, larynx and majorbronchi [148, 279, 295, 355]. Most cases are recognisedat autopsy, but may be also suspected due to problems ofendotracheal intubation [186].The aetiology and pathogenesis remain uncertain.Chronic infections, chemical and mechanical irritations,metabolic disorders, ecchondrosis, exostosis andmetaplasia of the elastic tissue are thought to be causalfactors [279, 295, 355, 356]. TO appears predominantlyin late adult life, but may be seen in childhood and earlyadult life [148, 295]. TO with minimal expressions mayoften be overlooked. Typical florid cases narrow the airwaysand cause a dry cough, dyspnoea, hoarseness andrecurrent infections [356]. Laryngobronchoscopic examinationis decisive for the diagnosis. Elevated, hard,whitish nodules bulge into the lumen with the appearanceof a stalactite cave. The posterior wall of the tracheais usually spared [186, 279]. An intralaryngeal locationof TO is very rare; as a rule it appears in the subglotticregion [355], exceptionally around the arytenoids [279].Histologically, submucosal nodules of cartilage andlamellar bone with marrow spaces are characteristicfindings, usually in relation to the underlying cartilage.Calcifications, ossifications and fatty marrow formationsmay be seen within the nodules [295]. Bone morphogeneticprotein-2 and transforming growth factorbeta, the potent inducers of new bone formation, havebeen recently detected in TO immunohistochemicallyand may have some decisive roles in the pathogenesis[356]. Surgical treatment has been recommended onlyin symptomatic patients [35, 186, 250].7.3 Inflammatory Lesions7.3.1 Acute Infections7.3.1.1 EpiglottitisAcute epiglottitis (AE), or more precisely termed supraglottitis[121, 331], is a potential risk of fatal airway obstructionin previously healthy persons. In the past, AEwas mainly a childhood disease caused by Haemophilusinfluenzae type B. Due to the introduction of an immunisationprogramme in the late 1980s, the diseasehas been steadily decreasing in children, but still has ahigh incidence in the adult population, more frequentlyin a form related to infections with pyogenic cocci [75,87, 231]. The most consistently found presenting symptomis severe pain on swallowing. In children, breathingdifficulties are often the predominant symptom.Other symptoms and signs are hoarseness, drooling, fever,tachycardia and toxic appearance [75, 87]. Reddishand evidently oedematous supraglottic area, includingtongue and pharyngeal structures, is observed. Oedematousswelling rarely spreads to the glottic region.Microscopic examination shows diffuse exudative inflammationwith fibrin, neutrophils and erythrocytesinvolving supraglottic structures. An early complaint ofdyspnoea may safely discriminate between patients requiringinvasive airway management with intubation andconservative treatment with close observation [150].7.3.1.2 LaryngotracheobronchitisLaryngotracheobronchitis (LTB), also known as subglotticlaryngitis, non-diphtheric croup, virus croup,spasmodic croup and fibrinous LTB, often occurs inchildren aged 1–3 years. Generally, LTB is of limitedduration, caused by influenza, parainfluenza or otherviruses. Prolonged infection by other pathogens maybe also involved [170]. The onset of the disease is moregradual compared with acute epiglottitis. When fullydeveloped, a croupy cough with inspiratory and expiratorystridor is present. Histologically, characteristicfibrinous laryngitis is observed with destruction of therespiratory epithelium. The mortality rate of the diseasehas remained low for many years [238, 353].7.3.1.3 DiphtheriaFortunately, laryngeal diphtheria is a matter of historynow in the developed world. Very exceptionally, an individualcase has been reported [137]. Histologically,dirty white, fibrinosuppurative membranes coveringthe laryngeal mucosa, accompanied by a foul smell, arecharacteristic of the disease [203].7.3.2 Chronic Infections7.3.2.1 TuberculosisLaryngeal tuberculosis (LT) was considered one of themost common diseases in the pre-antibiotic period, affectingthe larynx in 35 to 83% of patients with pulmonarytuberculosis [268, 390]. By the 1980s, the diseasehad become very rare in the developed world, owing tothe advent of antibiotic therapy, immunisation and improvedsocial and economic conditions. However, since1980, tuberculosis has again been showing a rising in-

Larynx and Hypopharynx Chapter 7 203cidence worldwide, including developed countries,owing to the spread of the HIV infection, poor livingstandards with malnutrition, the emergence of drugresistantmycobacteria and immigration from countrieswhere tuberculosis is still endemic [61, 78, 125,184, 268, 311, 315]. Consequently, the World HealthOrganisation has declared tuberculosis to be a globalemergency [258].LT currently affects mostly males; the average ageof patients is about 50, with a history of heavy drinkingand smoking. The most common presenting symptomis dysphonia, followed by dysphagia, odynophagia,stridor, a cough, and haemoptysis, generally associatedwith more or less obvious signs of pulmonary involvement[315, 390]. The true vocal cords are most commonlyaffected, although the supraglottic region is also involved[311]. The majority of cases present as hypertrophic,exophytic, hyperaemic lesions, sometimes nodularor ulcerated.Histologically, the subepithelial stroma contains caseatinggranulomas with a central caseous necrosis, surroundedby epithelioid macrophages, Langerhans-typegiant cells and lymphocytes (Fig. 7.3) . The covering epitheliummay be normal, ulcerated or show pseudoepitheliomatoushyperplasia. Identification of Mycobacteriumtuberculosis by special stainings or molecular geneticmethods confirms the diagnosis of LB.Differential diagnosis includes a large spectrum ofgranulomatous diseases, such as sarcoidosis, cat-scratchdisease, fungal infections, Wegener’s granulomatosisand tumourous lesions. Differentiation between sarcoidosisand tuberculosis is difficult. Generally, granulomasin sarcoidosis lack caseation and stainings formycobacteria are negative. Cat-scratch disease can beruled out by the presence of rounded or stellate granulomascontaining central granular debris and neutrophils.Fungal granulomas can be confirmed by identificationof the microorganism. Granulomas in Wegener’sgranulomatosis are not closely packed, fibrinoid necrosisof collagen is prominent and vasculitis is occasionallypresent.The treatment of LT primarily consists of antituberculoustreatment, while surgical procedure is reservedfor cases of air compromise [390].7.3.2.2 Fungal InfectionsFig. 7.3. Laryngeal tuberculosis. Granulomas are composed ofepithelioid cells, Langerhans giant cells without necrosis, surroundedby mononuclear inflammatory cellsFungal infections of the larynx are very rare, but may beexpected to arise, though not exclusively, in immunocompromisedpatients. Mycotic infections tend to occuras a result of the dissemination of the fungi, especiallyfrom the bronchopulmonary foci. An important exceptionis laryngeal candidiasis, which usually occurs as aresult of direct spread from the oral cavity [280]. Differenttypes of mycotic infections have been reported,such as laryngeal histoplasmosis [302, 319], cryptococcosis[171, 236], coccidioidomycosis [41], blastomycosis[89, 307], candidiasis [280], paracoccidioidomycosis[317] and aspergillosis [272, 310]. The histological featuresare similar for each of these infections and rangefrom granulomatous lesions related to histoplasma andcryptoccocus, to abscess formation in blastomycosisand aspergillosis [291]. Pronounced epithelial hyperplasiawith prominent ortho-parakeratosis or pseudoepitheliomatoushyperplasia in laryngeal blastomycosis,candidiasis and aspergillosis may mimic the squamouscell and verrucous cell carcinoma [272, 280, 307]. Theidentification of the causal agents by special silver, PASor mucicarmine stains of the biopsy specimens and/orcultures of microorganisms are crucial for successfultreatment.7.3.2.3 Other Rare InfectionsIn non-European countries, the larynx is occasionallyinvolved in rare infections, such as rhinoscleroma [7,100, 275], leprosy [145, 342], leishmaniasis and trichinosis[238].7.3.3 Non-InfectiousInflammatory Lesions7.3.3.1 Wegener’s GranulomatosisWegener’s granulomatosis (WG) is a systemic diseasecharacterised by necrotising vasculitis, formation ofgranulomas in the upper and lower respiratory tracts,

204 N. Gale · A. Cardesa · N. Zidar7and glomerulonephritis. Limited forms of WG also occur,often with involvement of the respiratory tract,but without kidney involvement. The vast majority ofpatients have antineutrophil cytoplasmic antibodies(ANCA) in the serum with a characteristic cytoplasmicpattern (C-ANCA) [172].The upper respiratory tract is the commonest presentingsite of WG, mainly affecting the paranasal sinuses,followed by the nose, nasopharynx and larynx[82]. Local clinical symptoms and signs, such as rhinorrhoea,pain, mucosal ulcerations and hoarseness,are non-specific. They may be accompanied by systemicsymptoms and signs, such as fever, weakness andweight loss [339].Histological features include inflammation, necrotisinggranulomas, and vasculitis. Necrosis in WG hasa patchy distribution, with serpiginous borders, and isusually basophilic, with a finely granular appearance.Granulomas tend to be loose, not closely packed as insarcoidosis or tuberculosis [82]. Vasculitis typically involvessmall to medium-sized arteries and veins, withany of the following features: fibrinoid necrosis, fragmentationof the elastic lamina, acute and chronic inflammatorycells and granulomas. The lesions may undergoorganisation and fibrosis.The diagnosis of WG is based on clinical features, biopsyof the related lesions, and the cytoplasmic patternof anti-neutrophil cytoplasmic antibodies (C-ANCA) inthe serum [102]. A positive biopsy of the upper respiratorytract has a high predictive value, up to 100%, indicatingfew or even no false-positive results [173]. However,vasculitis is only rarely seen on biopsy. Histologyoften reveals non-specific features – inflammation andnecrosis, with or without granuloma formation [397].Wegener’s granulomatosis should be differentiatedfrom other forms of vasculitis, other granulomatous diseases,cocaine abuse, and from neoplasms, particularlyNK/T lymphoma of the nasal type [339]. The presenceof C-ANCA proves extremely helpful in differentiationfrom almost all the diseases mentioned [173].Wegener’s granulomatosis was almost universally fatalin the past, usually within a few months of the onsetof clinically apparent renal disease. However, with modernimmunosuppressive therapy, the prognosis of WG isexcellent. A marked improvement is seen in 90% of patientsand complete remission is achieved in 75% of patients[160]. Early detection of WG is essential to preventfully developed disease. For WG at other sites in thehead and neck, see also Chaps. 2 and 3.7.3.3.2 SarcoidosisSarcoidosis is a chronic granulomatous disease of unknownaetiology that can affect any organ system. Inaddition to the classic involvement of lungs, hilar andmediastinal lymph nodes, the eyes, skin, liver, bonesand nervous system may also be affected. Laryngeal involvementis usually a part of generalised disease withan incidence of 1–5% [72, 197]. However, laryngeal sarcoidosiscan also appear as an isolated disease [40, 197,263]. The supraglottic region is mostly affected, especiallythe epiglottis, aryepiglottic folds and arytenoids,showing oedematous, pale, diffusely enlarged mucosawith occasional nodularity, which has been consideredthe pathognomonic feature of laryngeal disease [29, 72,263]. Subglottic and true vocal cord involvement is rare[40, 237, 263]. The disease is usually self-healing withan inconspicuous course including remissions and exacerbations.Histologically, non-caseating and non-confluentgranulomas are a characteristic feature. Granulomas arecomposed of epithelioid cells and Langerhans-type giantcells with no central necrosis. Two structures are oftenfound in giant cells, although they are not pathognomonicfor sarcoidosis: asteroid bodies are stellate crystallineinclusions, and laminated concretions, composedof calcium and proteins, known as Schaumann bodies.The sarcoid granulomas can be transformed into hyalinefibrous scars.In histologically proven non-caseating granulomas,other laryngeal granulomatous diseases, such as infectiousgranulomatous diseases, granulomatous processesof unknown pathogenesis (Wegener’s granulomatosis)and inhalant granulomatous processes (berylliosis,asbestosis), must be excluded [189]. No microorganismsare found in sarcoidal granulomas with some exceptions,such as cell wall-deficient forms of mycobacteria[294]. In contrast to tuberculosis and histoplasmosis,sarcoidal granulomas are non-caseating. Sarcoidosislacks vasculitis, characteristic of Wegener’s granulomatosis.Inhalant granulomatous diseases, which result insignificant pulmonary fibrosis, rarely affect the laryngealmucosa [189].Early diagnosis and adequate treatment of laryngealsarcoidosis is important to prevent upper airway obstructionand tracheotomy. Although the course of diseasemay be of long duration, spontaneous remissionsusually occur. When treatment is necessary, the administrationof intralesional or systemic steroids is performed[72].7.3.3.3 Rheumatoid ArthritisRheumatoid arthritis (RA) is a chronic systemic, presumablyautoimmune disorder, characterised by proliferativesynovitis that often progresses to destructionof the articular cartilage and ankylosis of the joints.Other tissues and organs may also be affected, suchas the skin, blood vessels, heart, lung, nervous system,etc.

Larynx and Hypopharynx Chapter 7 205Laryngeal involvement in RA includes arthritis of thecricoarytenoid and cricothyroid joints, and/or the formationof rheumatoid nodules in the soft tissue of thelarynx [47, 95, 130].Histologically, the acute phase of arthritis is characterisedby swelling and thickening of the synovia, whichis heavily infiltrated by mononuclear cells, resulting invillous hypertrophy. In the chronic phase, there is destructionof the articular cartilage and proliferation offibrous tissue with obliteration of the joint spaces, rarelyleading to bony ankylosis [47].Rheumatoid nodules may develop in the soft tissueadjacent to the joints, or in the vocal cords. Microscopically,they consist of a central fibrinoid necrosis, surroundedby palisading macrophages, lymphocytes andplasma cells (Fig. 7.4) [95, 343].In the acute phase symptoms and signs are usuallymild, and consist of pain and voice disturbance. In thechronic phase, dyspnoea and respiratory obstructionmay develop [2, 39, 95].Arthritis and rheumatoid nodules are not pathognomonicof RA, but are also seen in patients with other autoimmunediseases, particularly systemic lupus erythematosus[241, 366].Rheumatoid arthritis is treated by anti-inflammatorydrugs and local administration of steroids by meansof injection or aerosol; in rare cases, surgical therapy isneeded to relieve airway obstruction [2, 27, 39, 95].7.3.3.4 Relapsing PolychondritisRelapsing polychondritis (RP) is a rare autoimmunedisease characterised by progressive inflammationof cartilaginous structures, both elastic and hyaline,throughout the body [68, 233, 364]. The disease typicallyinvolves the ear, nose, eye, larynx and lower respiratorytract, costal cartilages, joints, cardiovascularsystem, renal tissue and central nervous system. Themost serious consequence of RP in the larynx and tracheais destruction of the cartilaginous framework,with collapse of the airway and breathing difficulties.RP commonly affects patients between 40 and 60 years[208], and a female-to-male ratio of 3:1 was recentlynoted [364]. Aetiologically, there is strong indication ofan autoimmune origin of RP [364], which has recentlybeen supported by the finding of antibodies to type IIcollagen in two-thirds of patients [349], and linkage tothe human leukocyte antigen DR4 gene and other autoimmunediseases. The onset of RP is generally sudden,with recurrent attacks of acute inflammation ofthe auricle. The diagnosis of RP is believed to be convincingif patients have at least three of the followinginvolvements: bilateral auricular lesions, seronegativearthritis, nasal and ocular affections, respiratory tractFig. 7.4. Rheumatoid nodule of the vocal cord. Fibrinoid necrosissurrounded by palisading macrophages, lymphocytes and plasmacellschondritis, audiovestibular damages and histologicalconfirmation of the disease [233].Hoarseness, coughing, dyspnoea, choking and tendernessover the laryngotracheal cartilages are symptomsof laryngeal and lower respiratory tract involvement[152]. Although airway obstruction could be localisedto the glottic and subglottic area, a diffuse involvementof the respiratory tract is more common [247]and occurs in up to 50% of patients with RP [93].Histologically, the affected cartilage shows distinctfeatures: the cartilaginous matrix loses its basophilicstaining, peri-and intracartilaginous inflammation isevident, inflammatory cells infiltrate the perichondriumand cartilage. The chondrocytes become vacuolatedand necrotic, and fragmentation of cartilage is evident.With the progression of the disease, necrotic cartilageis replaced by granulation tissue and later by fibrosis.In the course of the disease, persistent inflammationcan destroy the cartilaginous rings and cause luminalcollapse.Differential diagnosis includes all conditions that essentiallyshow cartilage destruction: various infectious(tuberculosis and other bacterial, fungal, and viral infections),non-infectious diseases (sarcoidosis, Wegener’sgranulomatosis and other types of systemic vasculitides)and tumours (lymphoma, cartilaginous tumours).Treatment for RP is based on systemic steroid and occasionallyimmunosuppressive therapy [261]. Involvementof the larynx and the lower respiratory tract is themost serious complication. The mortality rate reported

206 N. Gale · A. Cardesa · N. Zidar7in 1972 was 50% [164], and had fallen to 10% 14 yearslater [239]. Early diagnosis can influence a better outcome,and survival rate appears more favourable thanwas previously thought [364].7.3.3.5 GoutGout is a disorder of the purine metabolism typicallyidentified by hyperuricaemia. The disease is characterisedby temporary attacks of acute arthritis caused byprecipitation of monosodium urate crystals within andabout the joints. The course of the disease may eventuallylead to deposition of urates in the joints and othersoft tissues, creating tophi. The first attack of the diseaseis mainly monoarticular with a predilection to the firstmetatarsophalangeal joint. The head and neck regionis rarely involved, although the classic site is the externalear. In addition, tophi may appear in the intervertebraldiscs, oropharynx, temporomandibular joint,and tongue. There has been limited evidence of chronicgouty involvement of the larynx, with less than 20 caseshaving been reported so far [365]. Acute gouty cricoarythenoidarthritis is the most common and may giverise to pain within the larynx, dysphonia, odynophagia,dysphagia or stridor. After repeated attacks, the articularcartilage is gradually destroyed leading to ankylosisof the joint. The fixed vocal cord may mimic growth ofa malignant tumour [365]. Tophi of the laryngeal softtissue are exceedingly rare [146], the involved mucosaof the vocal cords shows a granular surface [228]. Thehistological features of tophi are conspicuous, with largeaggregates of needle-shaped urate crystals (birefringentcrystalline deposits) surrounded by macrophages, foreign-typegiant cells, lymphocytes and fibroblasts [146].In more remote differential diagnostic possibilities, otherlesions with deposition of various substances in thelaryngeal mucosa, such as amyloid or Teflon, need to beconsidered.7.3.3.6 Teflon GranulomaInjection of Teflon paste (polytetrafluoroethylene)into the lateral thyreoarytenoid muscle has been usedin patients with unilateral paralysis of the vocal cord,with the aim of augmenting and medialising the paralysedhemilarynx. The increased bulk of the vocal cordcould, therefore, contribute to a more complete glotticclosure, prevent aspiration, and improve a poor-qualityvoice caused by impaired breathing. The most commoncause of vocal cord paralysis is surgical trauma of thelaryngeal recurrent nerve and/or malignant tumours[31, 370, 385]. In general, Teflon injection has been welltolerated, and after a short-lived inflammatory reaction,it becomes stable and walled-off by surrounding fibrosis[31, 210]. Technical errors during injections, such as overinjection or misplaced injection of Teflon may, however,cause dysphonia and airway obstruction, as well as thepresence of a neck mass, resembling a neoplasm, in thecase of an escape of Teflon via the cricothyroid membrane[264, 370].Teflon granulomas (TGs) are submucosal polypoidlesions of the vocal cord. Histologically, they are composedof a foreign body giant cell reaction with extensionto the underlying muscle and cartilage. Teflon ispresent in foreign body giant cells, and also extracellularly,as glassy crystalline deposits that are characteristicallybirefringent under polarised light. A dense fibrotictissue is evident over time, while the surrounding inflammatoryinfiltrate is not present [385]. TG is treatedby conservative surgery, although the results are unpredictable[31]. There have been no reports of cancer developmentin TG [385]. With the introduction of laryngealframework surgery and medialisation laryngoplasty,fewer centres nowadays additionally advocate Tefloninjection [370].7.3.3.7 Idiopathic SubglotticLaryngeal StenosisIdiopathic subglottic stenosis (ISS) is a rare, slowlyprogressive inflammatory disease of unknown aetiologyinvolving mainly the region of cricoid cartilage andthe first tracheal ring. The pathogenesis of the diseaseremains hypothetical. ISS has recently been associatedwith various possible causes, such as gastro-oesophagealreflux, autoimmune diseases and previous infectionsof the respiratory tract [30, 174, 369]. Maronianand co-workers suggested that the term ISS shouldeven be replaced by reflux-induced subglottic stenosis,if there is no other clear cause of the disease [229]. ISShas a strong female predilection [73, 132, 369]. The ageof females when the symptoms start to appear rangesfrom 15 to 75 years (average 43.5 years) [73].The diagnosis of disease is a matter of exclusion, andall other possible causes of a subglottic stenosis mustfirst be ruled out. Aetiologically, subglottic stenoses aremost commonly linked to endolaryngeal trauma, especiallyafter prolonged intubation. Other diseases, includinginfections, laryngotracheal localisation of systemicdiseases such as Wegener’s granulomatosis andother collagen vascular diseases, amyloidosis and sarcoidosis,are rarely associated with laryngeal stenosis.Various benign and malignant tumours may also resembleISS [132, 281]. ISS usually presents as dyspnoea,a cough and dysphonia [30, 73, 369].Histological examination characteristically showsa spreading of dense fibrous tissue, extending up tothe surface of the epithelium. Fibrosis is usually poorlycellular, with prominent augmentation of thick col-

Larynx and Hypopharynx Chapter 7 207lagenous fibres. Some inconspicuous chronic inflammatoryinfiltrate may be present around blood vessels,without evidence of vasculitis. The covering epithelium,squamous or respiratory, may be reactively hyperplastic.ISS is a chronic lifetime disease that requiresmultiple surgical dilatations for palliation [73]. Evaluationfor laryngopharyngeal reflux disease should beperformed with pharyngeal pH testing in all patients,in an attempt to clarify the aetiology of ISS [229]. Moresevere cases are managed with laryngotracheal resectionand reconstruction [369].7.3.3.8 Angioneurotic OedemaAngioneurotic oedema (ANO) is a rapidly appearing,recurrent, non-pitting oedema of the subcutaneousand/or submucosal tissues causing a life-threateningcondition, affecting the larynx, hypo-and oropharynxand oral cavity [144]. ANO can occur as a result of hereditaryand acquired deficiencies in the immune andnon-immune responses [81]. Several forms of ANO arerecognised:1. IgE-dependent, caused by pollens, foods, drugs, fungi,cold, sun and exercise;2. Complement-mediated, hereditary and acquired withdeficiency of the C1 esterase inhibitor of the complementcascade;3. Non-immunologic, direct mast cell-releasing agentscaused by different drugs and aspirin, and other nonsteroidalanti-inflammatory drugs that alter the arachidonicacid metabolism;4. Idiopathic [13].Angioneurotic oedema, either acquired or hereditary,is characterised by sudden onset with full developmentwithin a few hours and fades over the courseof 48–72 h. Gastrointestinal mucosa may also be affected,mainly in the hereditary disease, causingsevere abdominal pain, nausea, vomiting and diarrhoea.Various degrees of laryngeal oedema may bepresent, affecting mainly the anterior surface of theepiglottis, aryepiglottic folds, base of the tongue andhypopharynx [238]. Generally, ANO resolves withoutharm, but laryngeal and tracheal oedema may causeasphyxiation and remains a considerable cause ofdeath [90, 362]. The frequency of attacks in hereditaryforms varies considerably from less than 1 to 25per year. Lesions can be solitary or multiple, and primarilyinvolve the extremities, larynx, face and bowelwall [90]. Emergency treatment is required if the processleads to respiratory distress because of laryngealinvolvement.7.4 Degenerative Lesions7.4.1 OculopharyngealMuscular DystrophyOculopharyngeal muscular dystrophy (OPMD) is a lateonset,dominantly inherited, slowly progressing disease,carried by a limited expansion of the triplet of GCGnucleotides in the PABP2 gene on chromosome 14q11[43]. Although OPMD has a world-wide distribution,its prevalence is highest in patients of French-Canadianorigin [129, 155]. The onset of disease occurs in middlelife, most often presenting with ptosis and a slight degreeof ophthalmoplegia, followed later by dysphagia andoften proximal limb weakness. The disease progressesslowly, but the dysphagia may be severe and has beenreported to be a cause of death by starvation in severalcases [316]. Muscle biopsy reveals various changes inmuscle fibres, such as atrophy and regeneration with anincreased number of myocyte nuclei and their centripetalorientation. Some findings, such as intracytoplasmicrimmed vacuoles, found by light microscopy, andintranuclear filament inclusions, seen by electron microscopy,are its pathological hallmarks [316]. Hill andco-workers provided confirmation that the detection ofexpanded GCG-repeated lengths in the PABP2 gene is areliable diagnostic test for OPMD in the English population[155]. However, their results were not in accordancewith other molecular studies [43]. Simple proceduressuch as blepharoplasty and cricopharyngeal myotomyconsiderably improve the quality of life of these patients[129].7.5 Pseudotumours7.5.1 Exudative Lesionsof Reinke’s SpaceThe special anatomic framework of Reinke’s space isconsidered essential for the development of a group ofso-called exudative benign lesions of the vocal cords,including Reinke’s oedema (RO), vocal cord polyps(VCPs) and nodules (VCNs) [177, 179, 181, 238, 308].Each of three entities has its own clinical and morphologicalspecificities [85], but most of them overlap. Thecommon basic pathogenetic mechanism is blood vesselinjuries with accumulation of oedematous fluid in Reinke’sspace [85, 308].

208 N. Gale · A. Cardesa · N. Zidar7abFig. 7.5. Reinke’s oedema. a Diffuse oedematous swelling in theentire length of both vocal cords. b Diffusely oedematous, bluecolouredsubepithelial stroma is lined with hyperplastic squamousepithelium with thickened basement membrane. Epitheliumshows hyperplasia of basal and parabasal cells7.5.1.1 Reinke’s OedemaReinke’s oedema is a chronic, diffuse, mainly bilateral,oedematous swelling of the membranous part of thevocal cords [177]. Several synonyms for RO have beenused, such as polypoid vocal fold, polypoid degeneration,chronic polypoid chorditis and chronic oedematous hypertrophy[320]. The specific morphologic features ofReinke’s space , such as sparse lymphatic drainage andits sharply demarcated borders, except the lateral one,contribute to the development of RO [158, 177, 179, 308,309]. Various mechanical and chemical aetiologic factorsare related to the development of RO , including overuseor abuse of the voice, and cigarette smoking . The role ofconstitutional and hormonal disturbances such as hypothyroidism,remains uncertain [32, 177, 308, 395]. Thelesion appears most commonly in women of 20–40 yearsof age with hoarseness as the leading symptom.Laryngoscopically, the surface of the swollen vocalcords along their entire length is smooth, translucentand jelly-like, with a clearly visible capillary network.Incision yields a characteristic yellowish or gelatinousfluid (Fig. 7.5a) [177, 226].Histologically, an excessive accumulation of oedemais a leading microscopic feature. Increased thickness ofthe walls of the teleangiectatic blood vessels, and thickeningof the epithelial basement membrane completethe classical triad of morphologic changes. The sulphatedglycosaminoglycans are probably responsible for thecharacteristic blue-coloured abundant amorphous materialin the subepithelial stroma in haematoxylin andeosin (H&E)-stained slides (Fig. 7.5b) [238]. Fragilityand alterations in the walls of blood vessels, such asthin endothelium with many fenestrae and vesicles, andthickened basement membrane, revealed by electronmicroscopy, are considered important in the developmentof RO [320]. Connective tissue proliferation, especiallywith aging of the lesion, makes the lesion irreversibleunless surgical removal is provided. Changes in thecovering squamous epithelium of all three exudative lesionsare expected to be only reactive (squamous cell hyperplasia,basal and parabasal cell hyperplasia) and mayturn with aging and enlargement of the lesions into atrophicepithelium. Exceptionally, 12 (1.7%) patients withpotentially malignant lesions (atypical hyperplasia, andLIN I and II) were found in a review of two comprehensivestudies. No malignant alteration was reported withinthese two studies [177, 226].In the early stage, only voice rehabilitation and avoidanceof irritating factors should be attempted. However,microlaryngoscopic excision is required in the great majorityof cases. Following surgery, voice therapy is oftenindicated [32, 177, 386].7.5.1.2 Vocal Cord Polypand NoduleVocal cord polyp (VCP) and vocal cord nodule (VCN)are fairly common benign reactive lesions, causally relatedto phonotrauma and vocal abuse [85, 175, 177, 181,194, 308]. The distinction between a VCP and VCN is

Larynx and Hypopharynx Chapter 7 209abFig. 7.6. Vocal cord polyp. a Huge vocal cord polyp arising fromthe middle third of the right vocal cord. b Myxomatous fibrous tissuewith fibrin deposition and dilated blood vesselsprobably only a matter of terminology, since both exhibitsimilar aetiology , pathogenesis , and to a certaindegree, similar histologic characteristics.A VCP is a pedunculated or sessile, mono- or multilobulatedlesion, measuring up to 10 mm in diameter,and located between the anterior and middle thirds ofthe vocal cord [177]. Bilateral polyps are found in only15% of cases [21]. They affect primarily adults between20 and 50 years of age, although they may also occur inother age groups. Men are affected at least twice as frequentlyas women [177, 181, 194].Vocal chord nodules are smaller, often bilateral, sessile,fusiform swellings of the vocal cords, positionedsymmetrically, and rarely exceed 2 mm in diameter.They usually occur in children, more frequently in boyswith the peak between the ages of 5 and 10 years [363].In adults, the highest incidence of these lesions is inyoung to middle-aged women. VCNs are considered tobe the most common benign lesions of the vocal cords[177, 386].In addition to phonotrauma and vocal abuse, cigarettesmoking , unfavourable occupational exposure , infectionsand endocrine dysfunction , are also consideredto be possible aetiologic factors of VCPs [175, 177, 181,194, 308]. VCNs are mainly caused by chronic misuseand overuse of the voice, as well as by emotional disturbancesin children, and hormonal disorders and smokingin adults [4, 177, 308].Damage of the subepithelial blood vessels is the initialevent in the evolution of a VCP or VCN. However,the morphology of the two exudative lesions depends onthe severity of the initial damage and repeated injuries[123, 138, 177, 181, 194, 308].The gross appearance of a VCP varies from a glassytranslucent gelatinous formation, to congested and purplered in teleangiectatic variants, and finally, to whitish,firm and opalescent in the predominant fibrous forms atthe end stage of the lesions (Fig. 7.6a). VCNs start as asoft reddish swelling . Gradually, when the fibrous tissueproliferates, the VCNs become firmer, whitish in colour,and conical in shape.Hoarseness is the predominant clinical symptom inboth lesions. A great variety of voice changes , rangingfrom mild hoarseness to complete aphonia, is found, dependingon the location and size of the lesions [21, 94,177, 181, 352].Histologically, different stages of VCP developmentare noted. Initially, the subepithelial stroma is diffuselyoedematous with dilated vessels. After severe or repeatedinjuries, massive leakage of oedema, mainly fibrinas amorphous hyaline pink material, and erythrocytes,are the predominant features in the vicinity of theangiectatic vessels, which may also be thrombotic (hyalineforms of the VCP) . Evidently dilated vessels, haemorrhageswith consequent haemosiderosis and conspicuousingrowths of new blood vessels create the angiectaticor vascular stage of the VCP (Fig. 7.6b) . Finally, thelesions may be transformed into a fibrous variant containingan increased amount of fibrous tissue and bloodvessels. Not infrequently, mixed type VCPs are seen,composed of two or more different histologic patterns[21, 123, 177, 194, 308].

210 N. Gale · A. Cardesa · N. Zidar7Fig. 7.7. Intubation granuloma. a Exophytic intubation granulomalocated on the posterior third of the right vocal cord. b Polabypoid granulation tissue is ulcerated with re-epithelialisation atthe edgeRarely, scattered atypical stromal cells, not associatedwith increased mitotic activity, may be found within thecore of the VCP. This finding must not incorrectly leadto a diagnosis of malignancy [383].In the initial stage, VCNs show diffusely oedematoustissue with distended capillaries and venules and tinyperivascular haemorrhages surrounded by a minimal ormoderate inflammatory reaction. In time, the loose connectivestroma is replaced by a mild to moderate cellularfibrous tissue changing in varying stages of evolution.As previously mentioned, the covering squamous epitheliumin both lesions shows predominantly benignreactive changes. In 4 (0.8%) patients, potentially malignantchanges (atypical hyperplasia) were noted in thecovering epithelium, but there were no data on malignantalteration [177, 226].The treatment of choice for VCPs is microlaryngoscopicsurgical removal. Childhood VCNs may disappearin puberty. Small incipient VCNs in adults may alsovanish spontaneously or after voice rehabilitation . Surgicalintervention is indicated when there is no improvementafter conservative treatment.7.5.2 Contact Ulcerand Granuloma,Intubation GranulomaContact ulcer (CU), granuloma (CG) and intubationgranuloma (IG) are benign, inflammatory, exophytic orulcerative lesions, usually located in the posterior thirdof the glottic area. Aetiologically, the lesions arise inresponse to various mechanical and chemical injuries,such as voice abuse or protracted forceful coughing, acidregurgitation and intubation injuries. They display similarsymptomatology and clinical appearance, and moreor less identical histopathological features and prognosis[16, 28, 77, 177, 180, 374, 383, 384].Excessive shouting or coughing cause repeated microtraumasof the thin mucosa of the vocal cord processes.They strike each other in phonatory adductionof the arytenoids, which leads to the development of ulcerativeor exophytic lesions of one or both vocal cords[384]. Additionally, acid regurgitation due to hiatal herniaor gastritis may cause the same type of lesions in theposterior glottic area.Intubation granuloma is an undesired sequel of intubationtube pressure during anaesthesia or intensivecare treatment.Intubation granulomas are more common in females,while hyperacidic granulomas and CU/CGs are predominantin males [104, 177, 180, 383].Clinically, ulceration or exophytic lesions can befound, mono- or multilobular, frequently bilateral, measuringup to 15 mm in diameter, that range from palegrey to dark red, sometimes with an ulcerated surface(Fig. 7.7a) . Hoarseness , the sensation of a foreign body ,coughing , a sticking sensation , pain in the throat, andthe feeling of acidity, are the prevailing symptoms in allthree types of lesions .Histologically, an ulceration of the posterior mucosa,covered by necrotic tissue and fibrin, is initially seen.

Larynx and Hypopharynx Chapter 7 211The depth of the ulcers may vary from superficial todeep lesions extending down to the perichondrium ofthe arytenoid cartilage. The localised necrosis of the epithelialand subepithelial tissue triggers an acute inflammatoryreaction, with proliferation of granulation tissueinitially infiltrated by neutrophils and later by macrophages,lymphocytes and plasma cells (Fig. 7.7b) . Themarginal epithelium starts to proliferate, some regenerativeatypia of epithelial cells, such as plump nuclei, andincreased mitoses may be present [217, 383].An exuberant proliferation of granulation tissueforms an exophytic polypoid lesion . New vessels arecharacteristically arranged radially from the base tothe fibrin-covered surface of the lesion. Approximately1 week after the initial injury, connective cells and collagenousfibres become more abundant and finally thepredominant elements in the granuloma, which in theend stage is entirely covered in squamous epithelium .The covering epithelium is usually considerably thickeneddue to hyperplasia of the prickle cell layer or, rarely,of the basal and parabasal layer [177, 180].The basis of therapy in CU/CGs and hyperacidicgranulomas is the elimination of causative factors, voicerest , voice re-education , dietary measures , prohibitionof smoking and alcohol abuse , and medical therapy suchas antacids , corticosteroids and vitamins [224]. IGs frequentlydo not require treatment due to their self-limitingnature. In refractory cases, surgical treatment is indicated,either microsurgery or CO 2 laser [28].7.5.3 NecrotisingSialometaplasiaNecrotising sialometaplasia (NS) is a rare, benign, selfhealinginflammatory lesion involving the minor salivaryglands, primarily of the hard palate. The lesion isdiscussed in detail in Chap. 5. Here, some specificitiesof the extremely rare appearance of NS in the larynx arepresented [373, 380, 383]. According to previous reports[373, 380], as well as our own experience, NS occurs inthe larynx secondary to trauma or concomitantly withother non-neoplastic or neoplastic lesions. The pathogenesisis probably associated with ischaemia. Laryngeal NSappears in the supraglottic and subglottic regions whereseromucinous glands are present as a deep ulcerative orsubmucosal nodular lesion. The most prominent histologiccharacteristics that help to distinguish the lesion fromvarious forms of laryngeal carcinomas are: preservationof the lobular architecture of the necrotic glandular islands,the appearance of epithelial-myoepithelial islandswith smooth margins, no cellular atypia or occurrence ofpathologic mitoses in the rest of the cellular part, and theretention of the lumina in preserved ductal formations.The appearance of surface pseudoepitheliomatous hyperplasiamay cause additional problems in differentialdiagnosis with laryngeal cancers, especially when frozensection analysis is performed. The duration of the healingprocess is related to the size of the lesion [380].7.5.4 Metaplastic ElasticCartilaginous NodulesMetaplastic elastic cartilaginous nodules (MECN) aresmall (less than 1 cm) fibroelastic lesions occurringmost frequently in the posterior and mid-portions of theglottis and ventricular bands. Cartilaginous nodules arecomposed of a peripheral rim of fibroblasts with transitioninto fibroelastic cartilage towards the centre [112].Aetiologically, an association with laryngeal trauma hasbeen suggested [277]. The development of MECN showsa smooth transition from the initial accumulation of acidmucopolysaccharides between the collagen bundles andtheir separation, to transition of fibroblasts to enlarged,rounded cells resembling chondrocytes. Aggregates ofelastic fibres are present in the centre of the lesions [156].Nodules are usually covered by intact mucosa.Metaplastic elastic cartilaginous nodules are rarelyclinically relevant [277]. We should be aware of theirpossible existence and distinction from chondroma andlow-grade chondrosarcoma. Chondroma has a characteristiclobular pattern and low cellularity, which is notthe case with MECN. Low-grade chondrosarcomas differmainly from MECN in their locations, and cellularand structural atypia [277].7.5.5 AmyloidosisAmyloidosis is a heterogeneous group of disorders associatedwith extracellular deposition of an abnormalfibrillar protein with pathognomonic tinctorial properties.It may be hereditary or acquired, localised or systemicin distribution. The current classification of amyloidosisis based on the biochemical composition of itspeptide subunits [131].Laryngeal amyloidosis (LA) is rare and is mostly a localiseddisease. In the majority of LA cases, the amyloid iscomposed of immunoglobulin light chains (AL amyloid).LA may occasionally be part of systemic disease or can be associatedwith a tumour, such as neuroendocrine carcinomaof the larynx or medullary carcinoma of the thyroid [359].Laryngeal amyloidosis primarily affects patients between40 and 60 years of age, more frequently males[298]. A few cases have been reported in children [273].All parts of the larynx can be affected [359], but in somestudies the supraglottis was the most common site of involvement[159]. It can affect the larynx multifocally,and can also extend to the tracheobronchial tree. Themain symptom is hoarseness, in some patients accompaniedby dysphagia, dyspnoea, or haemoptysis [159].

212 N. Gale · A. Cardesa · N. Zidar7Fig. 7.8. Amyloidosis of the larynx. a Scattered reddish masses ofamyloid are seen in the subepithelial stroma by Congo red stainabing. b The same field, green birefringence of the amyloid with polarisedlightGrossly, the affected area of the larynx is swollen,sometimes polypoid, covered by an intact mucosa. On acut surface, it is firm, pale, waxy, tan-yellow to red-grey[359]. Microscopically, H&E staining shows the depositionof an amorphous, eosinophilic, hyaline, extracellularsubstance in the subepithelial stroma, blood vesselwalls, and along the basement membranes of seromucinousglands, with intact covering epithelium. The depositsmay be discrete, or may appear as large roundedmasses of variable size. They stain with Congo red anddisplay green birefringence with polarised light; thisproperty remains the diagnostic gold standard (Fig. 7.8) .Immunohistochemical analysis must also be performedto determine the amyloid type [131].Most patients can be successfully treated by a conservingsurgical excision to preserve laryngeal function for aslong as possible. In some patients, multiple proceduresmay be necessary, and recurrences may occur. A fatal outcomehas been described in patients with progressive tracheobronchialinvolvement, but association with systemicamyloidosis is rare [59]. Clinical examination is advisedto exclude the possibility of a systemic disease.7.5.6 Sinus Histiocytosiswith Massive Lymphadenopathyand Other Rare PseudotumoursSinus histiocytosis with massive lymphadenopathy(SHML), or Rosai-Dorfman disease, is an idiopathic,relatively rare benign lesion, based on a nodal and/orextranodal histiocytic proliferative disorder that usuallyresolves spontaneously. The most frequent clinicalmanifestation of the disease is cervical, bilateraland painless lymphadenopathy. However, extranodalsites may also be involved and the head and neckregion is one of the most commonly affected areas[381]. Extranodal disease may be the initial or sometimesthe sole manifestation of the disease. Foucarand co-workers reported that 43% of patients had atleast one site of extranodal location of SHML [118].Within the head and neck, the nasal cavity, paranasalsinuses and orbit are commonly involved. Some casesof laryngeal lesions have been reported too [5, 11, 52,66, 118, 207]. Typically, the SHML begins insidiouslyand progresses to a protracted course of the activestage, and ends with spontaneous remission. SHMLoccasionally appears with subsequent recurrence andserious consequences, occasionally even death, if vitalorgans are affected. Exclusive extranodal diseaseis more frequent in elderly persons [51]. LaryngealSHML usually manifests as a circumferential narrowingor polypoid mucosal lesion of a tan-white toyellow appearance. Vocal cord involvement results inimpaired mobility [51].Histologically, the laryngeal mucosa is almost diffuselyinfiltrated by lymphocytes, plasma cells, neutrophilsand clusters of histiocytes. Histiocytes are of varioussizes, with a focally vacuolated pale to pink cytoplasm,but ill-defined borders. Their nuclei are roundor oval, sometimes vesicular, with well-defined centralnucleoli. Lympho- and granulophagocytosis is evidentin the cytoplasm of these histiocytes; the phenomenonis termed emperipolesis. Immunohistochemical-

Larynx and Hypopharynx Chapter 7 213ly, the histiocytes are strongly positive for S-100 proteinand Leu-M1. No nuclear and cytoplasmic atypiais observed.Differential diagnosis includes infectious diseases(rhinoscleroma), Wegener’s granulomatosis, NK/T lymphomaof the nasal type, eosinophilic granuloma, Hodgkin’slymphoma and fibroinflammatory disorders. Rhinoscleromais characterised by a proliferation of largemacrophages (Mikulicz cells) in which Klebsiella rhinoscleromatiscan be identified. In this disease the phenomenonof emperipolesis is not found. Histologically,in Wegener’s granulomatosis the S-100 positive histiocytesare lacking, while NK/T lymphoma of the nasaltype shows an infiltration of malignant lymphoidcells. Eosinophilic granuloma is histologically similarto Rosai-Dorfman disease, but differentiation is possiblewith the morphologic specificities of the Langerhanscells, characteristic of eosinophilic granuloma: their nucleishow lobulation, indentation or longitudinal grooving.Finally, fibroinflammatory lesions, such as aggressivefibromatosis, can be easily differentiated due to therelatively acellular appearance compared with the characteristiccellular infiltration in Rosai-Dorfman disease[381].Some rare laryngeal lesions may clinically and pathologicallymimic neoplastic growth and could be rangedin a category of pseudotumours: hamartoma [282, 314],warty dyskeratoma of the vocal cord [178], and Kimuradisease of the epiglottis [58].7.5.7 InflammatoryMyofibroblastic TumourICD-O:8825/1Inflammatory myofibroblastic tumour (IMT) is clinicopathologicallya well-defined fibroinflammatory proliferativelesion with unpredictable biological behaviour.Lung, gastrointestinal and genitourinary tract systemsare the commonest sites for IMT, although the lesionhas been reported throughout the body [382]. It rarelyaffects the head and neck region, and only a few welldocumented IMTs have been found in the larynx andpharynx [65, 96, 167, 188, 382].The aetiology of the lesion is unknown, but differentinfections with an exaggerated response to someunknown microorganism or post-traumatic eventshave been attributed as causal factors [9, 76, 167, 382].Most reported laryngeal IMTs are polypoid or pedunculatedlesions that occur in the true vocal cords or inthe subglottic area. Hoarseness, foreign body sensation,dyspnoea and stridor are presenting symptoms.Patients with laryngeal IMTs are mainly adult males[382].Histologically, IMT is composed of myofibroblasticspindle cells, admixed with a prominent infiltrateFig. 7.9. Inflammatory myofibroblastic tumour. Lesion is composedof uniform spindle cells, intermingled with inflammatorycellsof lymphocytes, plasma cells and neutrophils. The nucleiof the spindle cells are elongated, slightly polymorphous,containing one or more small nucleoli, the cytoplasmis palely eosinophilic (Fig. 7.9) . Occasional regularmitoses are seen. Inflammatory cells are unevenlydistributed within the lesion.Three basic histological patterns have been described:1. Myxoid/vascular pattern, resembling inflammatorygranulation tissue;2. Compact spindle cell pattern with fascicular and/orstoriform areas with various cellular density;3. Hypocellular pattern, densely collagenised and reminiscentof a fibrous scar [64].Immunohistochemistry confirms the myofibroblasticphenotype of the spindle cells, which are typically reactiveto vimentin, smooth muscle actin, and muscle-specificactin [64, 382]. Additionally, ALK1 and/or p80 werereported in a cytoplasmic pattern in 40% of cases of IMT[56]. Both markers are useful indicators of a 2p23 abnormality,suggesting the neoplastic nature of positive casesof IMT. However, it must be interpreted in the context ofhistologic and other clinicopathologic data if used as anadjunct to differential diagnosis [56].Radical excision of the lesions has been reported to becurative in more than 90% of extrapulmonary IMTs, includinghead and neck lesions [63]. Six out of seven patientswith laryngeal IMTs in Wenig’s series were free ofdisease over periods of 12 to 36 months after completeexcision. In one patient, laryngectomy was required afterrecurrence of the disease [382]. A metastatic potentialhas been exceptionally noted in patients with abdominaland mediastinal IMTs. However, a fatal outcomeof a patient with IMT of the paranasal sinuses has

214 N. Gale · A. Cardesa · N. Zidar7been recently reported [124]. Aggressive behaviour supportsrecent observations that at least a subset of IMTsrepresents true neoplasms rather than reactive myofibroblasticproliferation [124, 165].Differential diagnosis mainly includes spindleshapedlesions, such as spindle cell carcinoma, differenttypes of sarcomas and lesions composed of myofibroblastsand fibroblasts. The presence of cytokeratinreactivity cannot reliably distinguish between spindlecell carcinoma and IMT. In contrast, a lack of nuclearatypia and considerable mitotic activity favour a diagnosisof IMT and help to differentiate the lesion fromdifferent variants of laryngeal malignant tumours.Compared with myofibroblastic lesions, IMTs are generallylarger than nodular fasciitis, tend to occur inyounger age groups and are composed of longer fasciclesof spindle cells in an inflammatory backgroundrich in plasma cells [333]. In contrast, nodular fasciitisusually lacks the striking inflammatory infiltratecharacteristically present in IMT. The recently describedlaryngeal myofibroblastoma shares many similaritieswith IMT, except for a lack of inflammatoryinfiltrate and could be considered its pure spindle cellproliferation form [218].7.6 Benign Neoplasms7.6.1 Squamous Cell PapillomaICD-O:8052/0Squamous cell papillomas (SCPs) are the most commonbenign epithelial tumours of the larynx, causally relatedto human papillomavirus (HPV) infection. SCPs arediscussed in detail in Chap. 1.Fig. 7.10. Subglottic haemangioma. A dense proliferation of capillariesinfiltrates the subepithelial stroma around ductal structurescystic carcinoma and mucoepidermoid carcinoma, needto be excluded.7.6.2.2 OncocytomaICD-O:8290/0As has been previously discussed in the Sect. 7.2.5, thewhole spectrum of laryngeal oncocytic lesions may beconsidered to be ductal hyperplasia and metaplasia witha cystic character rather than true neoplasms. Solid oncocytomaof the larynx, similar to those in the majorsalivary glands, probably does not exist in this location.7.6.2 Salivary Gland-Type Tumours7.6.2.1 Pleomorphic AdenomaICD-O:8940/0Pleomorphic adenoma (PA) has rarely been reported inthe larynx [88, 219, 323]. To date, only about 20 caseshave been described. Men predominate slightly overwomen, and the patients’ ages range from 15 to 82 years[88]. The supraglottis is by far the most common site oforigin. PA, which may grow up to several centimetresin diameter, occurs as a submucosal mass without ulceration.Histologically, PA shows all the characteristicsof a tumour arising in the major salivary glands (seeChap. 5). The diagnosis of laryngeal PA should be consideredvery carefully due to its rarity in this locationand other tumours, such as chondrosarcoma, adenoid7.6.3 Haemangioma(Neonatal and Adult Types)ICD-O:9120/0Laryngeal haemangiomas (LH) are uncommon lesionsof vascular origin, defined as benign proliferation ofthe blood vessels. They are divided into two distinctclinicopathologic entities: the neonatal and adultforms.Neonatal LH is a rare congenital malformation characteristicallyinvolving the subglottic area. Although thelesion is present at birth, symptoms become clinicallyevident during the first 6 months. A progressive crouplikedisease with inspiratory stridor turns into biphasicstridor as the obstruction progresses. Characteristically,the symptoms are intermittent, accentuated during crying,when the vessels are filled up under increased pressure[195, 196, 290, 312, 328].

Larynx and Hypopharynx Chapter 7 215Subglottic LH appears more frequently in girls, witha ratio of 2:1 [334]. A co-existence of haemangiomas ofthe skin and mucosa of the oral cavity and pharynx, aswell as in other organs [195, 337], may also be an importantindicator of disease.The gross appearance of the lesion ranges from a flatto polypoid, soft, compressible submucosal mass, pinkreddishto blue in colour. The lesion is usually one-sided,and is located in the posterolateral subglottic area. However,some haemangiomas are horseshoe-shaped and arepresent as a bilateral subglottic reddish swelling [195].The diagnosis is based on characteristic clinical featuresand endoscopic appearance. Biopsy should be avoidedbecause of an increased risk of excessive bleeding.Laryngeal haemangiomas of adults, which are usuallylocalised in the glottic and supraglottic region, areseen as inconspicuous, submucosal, reddish blue lesions.Common symptoms are hoarseness, dyspnoea and/orforeign body sensation [336].Histologically, subglottic LHs are divided into capillaryand cavernous forms. The majority of lesions areof the capillary type [334], consisting of the proliferatingcapillaries that infiltrate the surrounding submucosalstructures (Fig. 7.10) .Vascular channels may be of various sizes, lined withplump endothelial cells in which some regular mitosesmay be present. Vascular tissue is intertwined with fibroustissue and infiltrated with a variable amount ofinflammatory cells. Focally, depositions of haemosiderinmay be found in the fibrous stroma. It is importantto note that haemangiomas in infants are considerablymore cellular than adult ones [48]. The cavernous formof LH is less frequent, composed of proliferation of largeangiectatic vascular spaces, lined with thin, spindleshapedendothelial cells, and filled with erythrocytes.This type of lesion is more common in adults. Immunohistochemicalanalysis helps to confirm endothelial cellproliferations in both forms, with positivity for CD31,CD34 and factor XIIIa antigens.In differential diagnosis, various lesions of vascularorigin, such as the vascular type of the vocal cord polyp(VCP), pyogenic granuloma, intravascular papillaryendothelial hyperplasia and even angiosarcoma, mustbe considered. The vascular variant of VCP is usuallycharacterised by highly angiectatic vascular spaces surroundedby massive leakage of fibrin as amorphous hyalinepink material, a feature not characteristic of capillaryhaemangioma. Pyogenic granuloma is diffuselyinfiltrated with neutrophils, which is not the case inhaemangiomas, if the covering epithelium is intact. Papillaryendothelial hyperplasia represents an organisationof thrombosis with papillary proliferation of the endothelialcells, which is not a striking histological featureof haemangioma. The distinction between the cellularvariant of haemangioma and angiosarcoma may sometimesbe problematic. However, anastomoses of the vascularchannels, lined with considerably pleomorphic endothelialcells with evident pathologic mitoses, certainlyfavour a diagnosis of angiosarcoma [48].Subglottic LH of infants is generally a self-limited butpotentially fatal lesion, causing progressive airway obstruction.Various treatment modalities have been proposed,including expectant policy, systemic steroids andinterferon alfa-2a applications, CO 2 laser excision andtracheostomy, but no very promising treatments are yetavailable [139, 196, 328].7.6.4 ParagangliomaICD-O:8680/1Paragangliomas are rare benign tumours, originatingfrom the anatomically dispersed neuroendocrinesystem (paraganglia), characterised by similar neurosecretorycells derived from the neural crest andassociated with autonomic ganglia. The extra-adrenalportions of the paraganglia are divided into fourgroups according to their distribution and innervations:branchiomeric, intravagal, aortosympatheticand visceral autonomic. The paraganglia of the larynxare part of the branchiomeric paraganglionic system,together with the jugulotympanic, carotid body,subclavian, coronary, aorticopulmonary, pulmonaryand orbital paraganglia [18].Laryngeal paragangliomas (LP) are extremely rare,almost always benign tumours originating in the superiorand inferior paired paraganglia. The former are localisedin the false vocal cords, the latter in the vicinityof the cricoid cartilage [18, 255]. Patients are usually ofmiddle age with a median age of 47 years. Surprisingly,compared with other neuroendocrine tumours, the LPsare three times more common in women. The predominantsite is the supraglottic (82%), followed by the subglotticin 15% and the glottic area in 3% of cases. Signsand symptoms are mainly related to the localisation andsize of the tumour [45, 289]. LPs are rarely functional,multicentric or associated with other head and neckparagangliomas.Macroscopically, the tumour usually presents as arounded submucosal mass with an intact covering mucosa,ranging in size from 0.5 to 6 cm [18]. The tumoursare firm; on the cut surface they may be homogenous ornodular, from pink to tan and dark red in colour. Prominentvascularity of the tumour may cause abundantbleeding during biopsy.Histologically, LPs are composed of two cell types:chief and sustentacular or supporting cells. The chiefcells of epithelioid appearance are packed into roundnests showing an organoid pattern, surrounded byhighly vascular fibrous tissue (i.e. Zellballen; Fig. 7.11a) .However, the characteristic cell nests may be squeezedand not apparent in a small biopsy specimen. The chief

216 N. Gale · A. Cardesa · N. Zidar7Fig. 7.11. Paraganglioma. a Characteristic arrangement into“Zellballen” composed of central chief and peripheral sustentacabular cells. b Chief cells stain immunohistochemically for synaptophysincells typically have an eosinophilic, finely granular cytoplasmand central vesicular nuclei. Cellular pleomorphismmay be present and is occasionally prominent,but prognostically unimportant. Rare mitoses can befound, usually less than 2–3 per 10 high power fields.The supporting cells are usually inconspicuous, spindleshaped,and most frequently found at the edge of the cellballs [18, 375].Immunohistochemical findings are characteristicand decisive for the diagnosis. The chief cells are positivefor neuroendocrine markers, such as chromogranin,synaptophysin and neuron-specific enolase (Fig. 7.11b) .The paragangliomas usually stain negatively for epithelialmarkers, such as cytokeratin, epithelial membraneantigen, carcinoembryonic antigen, and calcitonin.Sustentacular cells are positively stained with S-100protein and glial fibrillary acid protein [18, 375].Laryngeal paragangliomas must be primarily differentiatedfrom typical and atypical carcinoids. The mostreliable aid is positivity for both epithelial (cytokeratin,epithelial membrane antigen and carcinoembryonic antigen)and neuroendocrine markers in both types of carcinoids[107, 110]. Other, more remote differential diagnosticpossibilities include malignant melanoma, renalcell carcinoma and medullary thyroid carcinoma. Melanomacan be confirmed by melan A and HMB-45 positivity.Renal cell carcinoma, in contrast to paraganglioma,does not express neuroendocrine markers. Medullarycarcinoma expresses positive staining for calcitonin,amyloid and CEA [18, 106, 375].Since paragangliomas are only exceptionally malignant,conservative surgical treatment is suggested [18,20, 110]. There are no histological criteria that could reliablypredict the biological behaviour of the lesion [18].In a recent genetic study, it was postulated that sporadichead and neck paragangliomas have deletions at thesame or closely related loci (11q13 and 11q22-23) as theirfamily counterparts [33].7.6.5 Granular Cell TumourICD-O:9580/0Granular cell tumour (GCT) is an uncommon benign,slowly growing lesion and about half of the cases occurin the head and neck region [201, 205, 371]. Varioushistogenetic origins have been attributed to GCT,but recent prevailing opinion supports a relationshipto Schwann cells. The tongue and subcutaneous tissueof the head and neck are the most common sites of thetumour, while laryngeal involvement is less frequent[162, 176, 187, 205, 286, 330, 371], and comprises about10% of all cases [205]. These tumours most commonlyappear in the posterior area of the true vocal cords andhalf of them extend into the subglottis as a smooth,polypoid and sessile lesion [205, 286, 371]. GCT typicallyappears between the fourth and fifth decades andthe average age for laryngeal forms is 36 years [286].The tumour rarely occurs in children [162]. Hoarseness,stridor and dysphagia are the most common complaints.Histologically, the tumour is poorly circumscribedand consists of clusters and sheets of rounded and polygonalcells with indistinct cellular borders and small,bland-looking and central nuclei. A mild degree of nuclearpleomorphism may be present, but mitotic activityis low. Cytoplasm of tumourous cells is abundant,characteristically coarsely granular and eosinophilic.

Larynx and Hypopharynx Chapter 7 217Cytoplasmic granula are PAS-positive and resistant todigestion. Marked desmoplasia is often present in olderlesions, thereby masking the presence of granularcells. In about 50–60% of cases, the covering epitheliumshows pseudoepitheliomatous hyperplasia of the overlyingsquamous epithelium [190]. This curious histologicalfeature mimicking infiltrative growth of islands ofsquamous epithelium may lead to the lesion being mistakenfor a squamous cell carcinoma. However, the coexistenceof GCT and true squamous cell laryngeal carcinomahas also been reported [206].Immunohistochemical positivity for S-100 protein,vimentin, CD-68 and neuron-specific enolase, and negativityfor keratin is in accordance with the proposedtheory [49, 198, 232]. It is also confirmed by electronmicroscopic examination; the cytoplasmic granula werefound to be lysosomal structures that contain infoldingsof cell membranes similar to those in Schwann cells[245].Differential diagnosis should include benign lesionssuch as rhabdomyoma, paraganglioma or histiocyticproliferations. In contrast to GCT, rhabdomyoma doesnot show infiltrative growth, its cells are larger withwell-defined cellular borders and evidence of cross-striation.Paraganglioma typically shows an organoid pattern(i.e., Zellballen) and positivity for neuroendocrinemarkers. Proliferation of histiocytes is usually related toinflammatory reaction. Sheets of histiocytes are characteristicallyintermingled with inflammatory cells notcommonly found in GCT. Covering pseudoepitheliomatoushyperplasia of the GCT may lead to incorrect diagnosisof squamous cell carcinoma. An identificationof the underlying granular cells may resolve this sometimesdifficult diagnostic problem.Complete surgical excision, with an attempt to preservethe normal structures, is the treatment of choice[371].but the tumours may also be asymptomatic. Computerisedtomography is a method of choice for radiologicalevaluation [324].Histologically, chondromas show a characteristicwell-defined lobular pattern with benign looking andevenly distributed chondrocytes that lack nuclear pleomorphismand mitotic activity. The cellularity is judgedto be low, when a given high power (×40) field is unlikelyto contain more than 40 nuclei of chondrocytes[83, 209].Pathologic diagnosis of laryngeal chondroma, especiallyfrom a small biopsy specimen, should be reportedwith due reservation. A misleading chondroma-likearea may present in a well-differentiated caseof a chondrosarcoma [26]. It has become apparent thatmany of the so-called chondromas from the past thatrecurred locally were actually misdiagnosed as lowgradechondrosarcomas [83]. It is obvious that the distinctionbetween chondroma and low-grade chondrosarcomaremains a very difficult task. Increased cellularity,nuclear pleomorphism and hyperchromasia, andthe appearance of clusters of malignant-looking chondrocytesin a single lacuna, are the most conspicuoushistological features of chondrosarcoma. A thoroughexamination of the entire specimen is suggested, tryingto avoid an incorrect diagnosis of a given tumour.Chondromas should also be distinguished from laryngealchondrometaplasia, which appears as small nodulesof the fibroelastic cartilage in the submucosal tissueof the glottic region [112].Local conservative excision is preferred for treatmentof laryngeal chondromas. Each recurrence of thelesion should be considered a low-grade chondrosarcoma[358].7.7 Malignant Neoplasms7.6.6 ChondromaICD-O:9220/0Chondromas of the larynx are exceedingly uncommon,well-circumscribed, small (less than 2 cm) cartilaginoustumours that most commonly originate from the posteriorlamina of the cricoid (70–78%) and thyroid cartilage(15–20%) [26, 57, 83, 209, 324, 358], and exceptionallyfrom the epiglottis [166, 209]. They are morecommon in men than in women, the peak incidence rateis in the fifth decade [57]. The development of chondromasin the older population is probably related to thealteration of the ossification process, which starts in thecricoid and thyroid cartilages in the third decade, andincreases with advanced years [358]. Hoarseness, dyspnoea,dysphagia are the usual complaints of patients,7.7.1 Potentially Malignant(Precancerous) LesionsPotentially malignant (precancerous) lesions are histologicallydefined as alterations of the squamous epitheliumfrom which invasive SCC develops more often thanfrom other epithelial lesions [127, 177, 215]. Differentgrades of epithelial lesions that appear during the multistepprocess of carcinogenesis can easily be identifiedhistologically. They are cumulatively called squamousintraepithelial lesions of the larynx (SILs) and representa wide spectrum of histomorphologic changes, rangingfrom benign, reactive lesions, to potentially malignant(risky epithelium) and intraepithelial carcinoma. SILsare discussed in detail in Chap. 1.

218 N. Gale · A. Cardesa · N. Zidar77.7.2 Invasive SquamousCell CarcinomaICD-O:8070/3Squamous cell carcinoma (SCC) is by far the most commonmalignant tumour of the larynx and hypopharynx,accounting for about 95–96% of all malignant tumoursat this location. The majority are conventional-typeSCC.7.7.2.1 EpidemiologySquamous cell carcinoma of the larynx and hypopharynxis the second most common respiratory cancer, afterlung cancer [54]. It accounts for 1.6–2% of all malignanttumours in men, and 0.2–0.4% in women [37,293]. Its incidence is increasing in much of the world,being slightly higher in urban than in rural areas. It isalso higher among blacks than whites [54, 299].Laryngeal and hypopharyngeal SCC occur most frequentlyin the sixth and seventh decades of life. It rarelyoccurs in children and adolescents [17, 274]. It is morecommon in men [54, 299], with a male:female ratio ofabout 5:1 worldwide [253]. The male:female ratio is decreasingin some countries, reflecting a greater incidenceamong women. The increasing incidence of laryngealcancer in women has been attributed to the increasedincidence of smoking over the last two decades[79].7.7.2.2 AetiologyCigarette smoking and alcohol consumption are thechief risk factors in laryngeal and hypopharyngealcancer, and smoking has been shown to have the greatesteffect. Epidemiological studies have shown that therelative risk of laryngeal cancer associated with cigarettesmoking is approximately 10 for all subsites of thelarynx and hypopharynx. The role of alcohol independentof that of tobacco is less striking, although plausible[38] and is demonstrated in some studies [329].Smoking and drinking combined have a multiplicativerather than additive effect [222, 223, 254, 367, 393].Avoidance of smoking and alcohol consumption couldprevent about 90% of the current incidence of laryngealcancer [101].Some other factors, such as gastro-oesophageal reflux,diet and nutritional factors [38, 98, 120, 200, 276,396] have also been related to an increased risk of laryngealcancer development, particularly in patients wholack the major risk factors [12, 122].Much attention has recently been paid to the possiblerole of infection with human papillomavirus (HPV)in the pathogenesis of laryngeal and hypopharyngealcancer, but the results are conflicting. HPV, mainly type16, has been found in 3–85% of laryngeal cancers [213].Moreover, HPV DNA has been detected in 12–25% ofindividuals with a clinically and histologically normallarynx [271, 313]. It appears, therefore, that HPV infectionplays little role, if any, in laryngeal carcinogenesis[126, 177, 211, 213].7.7.2.3 Anatomic SitesThe larynx is anatomically divided into three compartments:supraglottic, glottic and subglottic. Superiorlyand posteriorly, it is continuous with the hypopharynx.Because of this anatomic proximity, the tumours of thelarynx often extend to the hypopharynx, as well as viceversa, so that in large tumours, it is impossible to determinewhether it originates from the larynx or hypopharynx.There are geographic differences in the topographicdistribution of the laryngeal SCC [19, 301]. In France,Spain, Italy, Finland and the Netherlands, supraglotticSCC predominates, while in the USA, Canada, UK andSweden glottic SCC is more common. In Japan, SCC isapproximately equally distributed between the two sites.The rarest localisation of laryngeal cancer is the subglottis(1–5%) [19, 318].Determining the primary site of origin of laryngeal/hypopharyngeal cancer is important as it has a significantimpact on the clinical presentation, spread, behaviour,and prognosis [117, 300]. This, however is not alwayspossible, especially in large tumours.The most common location of supraglottic SCC is theepiglottis (45–55% of supraglottic cancer; Fig. 7.12a) ,followed by the false vocal cords (12–33%) and the aryepiglotticfolds (8–21%). The remaining cases arise fromthe ventricles and the arytenoids [19]. Supraglottic SCCtends to spread to oropharynx and pyriform sinus, but itrarely invades the glottis and thyroid cartilage.The most common symptoms in supraglottic cancerare: dysphagia, change in the quality of the voice, a sensationof a foreign body in the throat, haemoptysis, andodynophagia.Lymph node metastases are present in 30–40% of patients.The overall 5-year survival rate in supraglotticSCC is 65–75% [19, 301].Glottic SCC arises mostly from the anterior half of thevocal cord or from the anterior commissure (Fig. 7.12b) ;a posterior origin is rare. Because of poor lymphatic supply,glottic SCC tends to remain localised for a long period.As SCC progresses, it invades the vocal muscle resultingin the fixed vocal cord, which is an ominous clinicalsign [192]. In the late stages of the disease, it may extendto the opposite true vocal cord, to the supraglottisand subglottis; it may also extend through the thyroidcartilage and invade the soft tissue of the neck.

Larynx and Hypopharynx Chapter 7 219The most common early symptom in glottic cancer ishoarseness. Other symptoms include dysphagia, changein the quality of the voice, a sensation of a foreign bodyin the throat, haemoptysis and odynophagia.The incidence of lymph node metastases in the earlystages is low (0–11% for T1 and T2) and increases to 14–40% in the advanced stages. The overall 5-year survivalrate is 80–85% [19, 301].If SCC crosses the ventricles and involves the supraglottisand subglottis, it is termed transglottic SCC (Fig. 7.12c) .Transglottic carcinoma is rare, accounting for 5% of alllaryngeal SCC, and is associated with a high incidence oflymph node metastases and a poor prognosis [235].Subglottic carcinoma is rare. The most common presentingsymptoms are dyspnoea and stridor [113], oftenrequiring an emergency tracheotomy [350]. The subglotticSCC may spread to the thyroid gland, cervicaloesophagus, hypopharynx and trachea.About 20–25% of patients have cervical lymph nodemetastases at presentation, but about 50% of patientshave clinically undetectable metastases in the paratracheallymph nodes. It has therefore been suggested thatparatracheal and superior mediastinal nodes should beremoved in patients with subglottic cancer [149]. A frequentcomplication in the course of the disease is a stomalrecurrence, which is defined as a recurrent SCC inthe mucocutaneous junction of the tracheostomy afterlaryngectomy [169, 392, 394]. The overall 5-year survivalrate in subglottic SCC is 40–47% [19, 318].Hypopharyngeal SCC occurs most frequently in the pyriformsinus (60–85% of hypopharyngeal SCC), and rarelyin other localisations, such as the posterior pharyngeal wall(10–20%) and postcricoid area (5–15%) [151, 368].Hypopharyngeal cancer frequently extends to thelarynx.The most frequent symptoms in hypopharyngealSCC are odynophagia, dysphagia and a neck mass. Othersymptoms include voice changes, otalgia, and constitutionalsymptoms [368].The prognosis of hypopharyngeal cancer is poor. Becauseof the rich lymphatic supply, unrestricted areafor tumour growth, and late symptoms, patients mostlypresent in the advanced stages. About 70% of patientshave lymph node metastases at presentation. Haematogenousdissemination is rather frequent (in 20–40% ofpatients) [346]. The overall 5-year survival rate in hypopharyngealSCC is 62.5% [346].ab7.7.2.4 Histological VariantsSeveral variants of SCC occur in the larynx and hypopharynx,including verrucous carcinoma, spindlecell carcinoma, basaloid SCC, papillary SCC, lymphoepithelialcarcinoma, adenoid (acantholytic) SCC andadenosquamous carcinoma, which are dealt with sepa-cFig. 7.12. Macroscopic appearance of the squamous cell carcinomaof the larynx. a Supraglottic carcinoma: an exophytic tumourat the base of the epiglottis. b Carcinoma of the vocal cord, endoscopicview. c Transglottic carcinoma crossing the ventricles, involvingglottis and supraglottis

220 N. Gale · A. Cardesa · N. Zidar7ICD-O:8249/3It is the most frequent type of NEC in the larynx, constituting54% of all laryngeal neuroendocrine neoplasms,with approximately 300 cases described in the literature[106, 242].Similar to other types of NEC, MD-NEC is morecommon in males, with a wide age range from 20 to83 years. The majority of patients are heavy smokers. Itarises mostly in the supraglottic region. Hoarseness anddysphagia are the most common symptoms; 20–30% ofpatients also experience pain [19, 243]. MD-NEC is rarelyassociated with carcinoid syndrome [388]. Some paratelyin Chap. 1. Their recognition is important becausemost of them are true clinicopathologic entities, with animportant prognostic implication: basaloid SCC, adenosquamouscarcinoma and lymphoepithelial carcinomaare more aggressive than conventional SCC, while verrucousSCC and arguably, papillary SCC, have a betterprognosis than conventional SCC.7.7.2.5 TNM GradingFor the staging of laryngeal cancer, the TNM system(T – tumour, N – node, M – metastasis), establishedby the International Union Against Cancer (UICC) iswidely used [340]. Stage remains the most significantpredictor of survival. The size of the tumour and thepresence of regional and distant metastases are independentpredictors of survival.An important parameter ignored in the TNM systemis extracapsular spread. Several studies have shown thatthe presence of extracapsular spread in the lymph nodesis strongly associated with both regional recurrence anddistant metastases, resulting in decreased survival [71,116, 157, 344]. Some studies, on the contrary, have notconfirmed the independent prognostic significance ofextracapsular spread [225, 292].7.7.3 Neuroendocrine CarcinomaNeuroendocrine carcinomas (NEC) of the larynx areuncommon, accounting for less than 1% of laryngealtumours. NEC are divided into well-differentiated NEC(WD-NEC; carcinoid), moderately differentiated NEC(MD-NEC; atypical carcinoid), and poorly differentiatedNEC (PD-NEC; small cell carcinoma). MD-NEC isthe most common type of NEC in the larynx, followedby PD-NEC and WD-NEC [19, 92, 106].The putative cells of origin are the Kultschitzky-likeargyrophilic cells, which have been described in the humanlaryngeal mucosa, and are similar or identical tothe Kultschitzky cells in the bronchial mucosa [285,288]. Other possible cells of origin are the pluripotentstem cells of the surface or glandular epithelium.7.7.3.1 Well-DifferentiatedNeuroendocrine Carcinoma(Carcinoid)ICD-O:8240/3Well-differentiated neuroendocrine carcinoma (WD-NEC) is the least common type of laryngeal NEC. Ina critical review of the world literature, El-Naggar andBatsakis found only 12 well-documented cases of laryngealWD-NEC [91]. Since then, a few more cases havebeen described in the English-language literature [67,191, 242, 326, 341, 391].Well-differentiated NEC occurs predominantlyin males, the average age is 58 years, and the majority(83%) are located in the supraglottis [92]. They presentclinically with dyspnoea, hoarseness and/or sore throat.Grossly, laryngeal WD-NEC is typically a submucosalnodule or a polypoid lesion measuring up to2 cm in diameter. Microscopically, like WD-NEC elsewherein the body, they are composed of small uniformcells growing in islands, ribbons and cords, occasionallyforming gland-like structures. Mucin may occasionallybe present. The nuclei are round, with finelydispersed chromatin and inconspicuous nucleoli; thecytoplasm is scant, clear or eosinophilic. Mitoses aresparse or absent, and there is no necrosis or cellularpleomorphism.Immunohistochemically, laryngeal WD-NEC expressesmarkers of neuroendocrine differentiation (suchas chromogranin, synaptophysin, neuron-specific enolase,Leu-7), and markers of epithelial differentiation(such as cytokeratins and epithelial membrane antigen)[106]. Electron microscopy reveals dense-core neurosecretorygranules [91, 106].Differential diagnosis includes moderately differentiatedNEC, paraganglioma, and adenocarcinoma, and isdiscussed in the next section.The treatment of choice is complete but conservativesurgical excision. Neck dissection is not indicated. Radiotherapyand chemotherapy have not proven effective[106, 248].The prognosis is favourable, although metastases tothe lymph node, liver, bones and skin have been reportedin one-third of patients. Only one patient has died ofthe disease [91]. These data suggest the more aggressivebehaviour of laryngeal WD-NEC compared with bronchialWD-NEC, but the number of patients is too smallto draw any conclusions [19].7.7.3.2 Moderately DifferentiatedNeuroendocrine Carcinoma(Atypical Carcinoid)

Larynx and Hypopharynx Chapter 7 221Fig. 7.13. Moderately differentiated neuroendocrine carcinomaof the larynx. a Islands of closely packed small cells with hyperabchromatic nuclei beneath the surface squamous cell epithelium. bImmunohistochemical expression of CD56 in tumour cellstients with MD-NEC have an elevated level of the serumcalcitonin [23, 338].Grossly, it presents as a submucosal nodule or as apolypoid lesion measuring up to 4 cm in diameter (average1.6 cm), with or without surface ulceration.Microscopically, the tumour grows in rounded nests,trabeculae, cords, ribbons and glandular structures; thetumour cells are round, with round nuclei and a moderateamount of cytoplasm, which is slightly eosinophilicor occasionally oncocytic. Mucin production may bepresent [234].In contrast to WD-NEC, cellular pleomorphism, increasedmitotic activity and necroses are frequentlypresent in MD-NEC. Vascular and perineural invasionmay be present.Immunohistochemically, MD-NEC usually expressessynaptophysin, cytokeratin, and chromogranin; theymay also express CD56, calcitonin and carcinoembryonicantigens, but rarely serotonin (Figs. 7.13) [97, 234,242, 388].Differential diagnosis includes paraganglioma, adenocarcinoma,other neuroendocrine carcinomas andmedullary carcinoma of the thyroid gland.The differentiation between paraganglioma and MD-NEC is important because the former usually behaves asa benign tumour, while the latter behaves as an aggressivetumour. The correct diagnosis is usually possible with theuse of immunohistochemistry: MD-NEC expresses cytokeratinand carcinoembryonic antigen (CEA), whileparaganglioma does not. Both tumours express markersof neuroendocrine differentiation [18, 242]. Adenocarcinomacan be distinguished from carcinoid by the absenceof neuroendocrine markers. The presence of cellular pleomorphism,increased mitotic activity and necroses helpsto distinguish MD-NEC from WD-NEC.Differentiation from thyroid medullary carcinomamay be difficult, especially when dealing with cervicalmetastases, as tumour cells in both medullary carcinomaand MD-NEC express calcitonin by immunohistochemistry.The most important distinguishing featureis the different locations of the primary tumours. Additionaluseful information may be obtained by measuringthe serum level of CEA, which is elevated in metastaticmedullary carcinoma of the thyroid, and normalin MD-NEC [19]. The elevated serum level of calcitoninshould not be considered as a reliable feature of medullarycarcinoma, as it has been reported in patients withMD-NEC [92, 338].Moderately differentiated NEC is an aggressive, potentiallylethal tumour. Lymph node metastases havebeen reported in 43% of patients, cutaneous metastasesin 22% and distant metastases in 44% of patients, mostlyto the lungs, liver and bones [97, 234, 388].Surgery is the treatment of choice. Neck dissectionis also advised because of the high incidence of cervicallymph node metastases. Radiation and chemotherapyhave not been effective [248]. The 5- and 10-year survivalrates are 48 and 30% respectively [388].7.7.3.3 Poorly DifferentiatedNeuroendocrine Carcinoma(Small Cell Carcinoma)ICD-O:8041/3Poorly differentiated neuroendocrine carcinoma is theleast differentiated and the most aggressive type of NEC.It is rare, accounting for less than 0.5% of all laryngealcarcinomas. Approximately 160 cases have been describedin the literature [106, 244].

222 N. Gale · A. Cardesa · N. Zidar7Poorly differentiated NEC arises most often in thesupraglottis, but it also occurs in other parts of the larynx.It affects men more frequently than women, mostlybetween 50 and 70 years of age; most patients are heavysmokers. The most common presenting symptoms arehoarseness and dysphagia, frequently associated withpainless enlarged cervical lymph nodes due to metastases.It may be associated with a paraneoplastic syndrome[108, 244].Grossly, PD-NECs are submucosal nodular or polypoidmasses, frequently ulcerated and cannot be distinguishedfrom other laryngeal carcinomas.Microscopically, laryngeal PD-NECs are identicalto their pulmonary counterparts [243]. They are composedof closely packed small cells with hyperchromaticround, oval or spindle nuclei and very scant cytoplasm.Necroses, mitoses, as well as vascular and perineural invasionare frequently present. PD-NEC can also be composedof slightly larger cells with more cytoplasm. Themucosa is often ulcerated, but there is no carcinoma insitu or significant atypia.Immunohistochemically, the tumour cells variablyexpress cytokeratins and neuroendocrine markers, suchas synaptophysin, neuron-specific enolase, chromogranin,S-100 protein and CD56.By electron microscopy, sparse neurosecretory granulesare occasionally found, but they may be absent.In the differential diagnosis, the possibility of a metastasisfrom the lung must be excluded. PD-NEC mustalso not be confused with the basaloid squamous carcinoma,malignant lymphoma, and malignant melanoma.Basaloid squamous carcinoma is composed oflarger cells, contains areas of squamous differentiation,tends to stain for high molecular-weight cytokeratins,and is frequently associated with atypia of theoverlying squamous epithelium. Malignant lymphomascharacteristically express leukocyte common antigenand B- or T-cell markers, which are absent in PD-NEC. Malignant melanoma occasionally consists ofsmall undifferentiated cells, thus resembling PD-NEC,but, in contrast to PD-NEC, it typically expresses S-100protein, melan A and/or HMB45.The clinical course is aggressive, characterised byearly metastases to the regional lymph nodes and distantsites, especially to the lungs, bones and liver. In contrastto lung PD-NEC, laryngeal PD-NEC does not frequentlymetastasise to the brain.Radiation with chemotherapy is the treatment ofchoice. Surgical therapy is not indicated because mostpatients have disseminated disease at presentation. Theprognosis is poor, and the 2- and 5-year survival ratesare 16 and 5% respectively [114, 135].7.7.4 AdenocarcinomaIn spite of rather prominent salivary gland tissue in thesupraglottic and subglottic larynx, laryngeal adenocarcinomais rare, accounting for 1% of all laryngealneoplasms [3, 25, 347]. The majority of laryngeal adenocarcinomasare of the salivary gland type. The mostcommon types are adenoid cystic carcinoma and mucoepidermoidcarcinoma. Rare examples of other types ofadenocarcinoma have been also described in the larynx,such as acinic cell carcinoma [306], clear cell carcinoma[262], malignant myoepithelioma [168], epithelial-myoepithelialcarcinoma [240], salivary duct carcinoma[109], etc.The aetiology is unknown, although exposure to asbestosor lead, alcohol abuse, viral infections, ionisingradiation and genetic risk factors have been implicatedas possible aetiologic factors [221].7.7.4.1 Adenoid Cystic CarcinomaICD-O:8200/3In contrast to other laryngeal carcinomas, adenoidcystic carcinoma (ACC) occurs at a younger age, withno gender predominance, and is more common in thesubglottis [348]. Symptoms are similar to those of othertumours in the same localisation. In addition, pain isfrequently present, probably because of the tendency ofACC towards perineural invasion.Macroscopically, the tumour usually grows as a submucosalmass, covered by normal mucosa.The microscopic features of laryngeal ACC are thesame as in other locations.Laryngeal ACC is characterised by a slowly progressivecourse, with a high incidence of local recurrence,long survival and a low cure rate. ACC has a tendencytowards haematogenic spread, mostly to the lungsand less frequently to the bones, liver and other organs[86, 348]. It does not usually metastasise to the regionallymph nodes.The treatment of choice is complete surgical excision.The 5-year survival rate is 30% [221, 347].7.7.4.2 Mucoepidermoid CarcinomaICD-O:8430/3Mucoepidermoid carcinoma (MEC) occurs at all ages,even in childhood, but it usually presents in the 6th and7th decades, predominantly in males. The majority occursin the supraglottis, but it has also been described inthe glottis and subglottis, as well as in the hypopharynx[221, 335]. The clinical picture correlates with the localisationand size of the tumour.

Larynx and Hypopharynx Chapter 7 223aFig. 7.14. Chondrosarcoma of the cricoid cartilage of the larynx.a Typical macroscopic appearance of the tumour located in thecricoid cartilage: cut section reveals a glistening, lobulated, glassybtumour. b Microscopically, there is slightly increased cellularity,binucleation in the lacunar spaces, mild nuclear pleomorphismand hyperchromasiaMacroscopically, they mostly present as submucosalmasses [335].Microscopically, they are similar to MEC in othersites, and are classified as low-, intermediate-, and highgradeMEC (see Chap. 5).The behaviour is unpredictable, and is related to thegrade and stage of the disease. The best treatment iscomplete surgical excision. Radiotherapy has been reportedto be successful in a limited number of patients[335]. Neck dissection may be necessary, as 50% of patientswith MEC have metastases in the regional lymphnodes. The 5-year survival is 90–100% for low-gradeMEC, and 50% for high-grade MEC [115].7.7.5 SarcomasSarcomas of the larynx are uncommon, accounting for1–2% of all laryngeal neoplasms. Among them, chondrosarcomais the most frequent type, comprising 75%of all laryngeal sarcomas [209].7.7.5.1 ChondrosarcomaICD-O:9220/3Chondrosarcoma (CS) is the most common non-epithelialneoplasm in the larynx. It appears that laryngeal CSbehaves less aggressively than its counterpart in the restof the body. The majority of laryngeal CS are low gradeCS [209, 360].Laryngeal CS affects men more frequently than women,mostly in the 7th decade [209]. It usually presentswith hoarseness; other symptoms include dyspnoea,dysphonia, a cough, a neck mass, airway obstructionand pain [209, 360]. The symptoms are frequently presentfor a long time before the diagnosis is established.Chondrosarcoma arises predominantly in the cricoidcartilage, especially at the inner posterior plate; it canalso arise in the thyroid and arytenoid cartilages. It veryrarely arises in the epiglottis [209, 360].The aetiology is unknown, although disordered ossificationof the laryngeal cartilages and ischaemic changesin a chondroma have been suggested as possible predisposingrisk factors [360]. Other possible risk factorsinclude previous radiation exposure [134] and Teflon injection[147].Grossly, CS is characteristically a lobulated, submucosalmass covered by normal mucosa; on its cut surfaceit is glassy, firm white or grey (Fig. 7.14a) . Radiographicfindings are characteristic showing coarse or stippledcalcifications [360, 377]. Microscopically, laryngealCS is indistinguishable from CS of bone origin elsewherein the body, and is graded according to the histologiccriteria proposed by Evans and co-workers [99]for CS of the bones. Low-grade CS (grade I) has slightlyincreased cellularity, binucleation in the lacunar spaces,slight nuclear pleomorphism, and hyperchromasia(Fig. 7.14b) . High-grade CS (grade III) has remarkablecellularity, multinucleation in the lacunar spaces, nuclearpleomorphism, nuclear hyperchromasia, necrosisand mitotic activity, whereas the intermediate grade CS(grade II) has medium cellularity and less nuclear pleomorphism[128].The vast majority of laryngeal CS are of low- or intermediategrade. High-grade CS are considered to be rare;in a large series of 111 laryngeal CS, only 6 (6%) were ofa high grade [360]. Dedifferentiated (mesenchymal) CS

224 N. Gale · A. Cardesa · N. Zidar7characterised by the presence of both well-differentiatedCS and a high-grade non-cartilaginous sarcoma is evenrarer [46, 128, 259, 360].Immunohistochemically, CS expresses S-100 proteinand vimentin [46].Differential diagnosis includes chondroma and chondrometaplasia.Differentiation between low-grade CSand chondroma can be extremely difficult, and is onlypossible with adequate tumour sampling. Chondromasare considered to be exceedingly rare in the larynx; theyare smaller than CS and less cellular, with less pleomorphism,lacking mitoses and necrosis.The treatment of choice is conservative surgery [46,182, 209]. Total laryngectomy should be avoided as longas possible, even in recurrent CS. Radiation therapy isgenerally regarded as ineffective though a few cases witha favourable response to radiation have been reported[141].The prognosis is favourable. CS is characterised bya slowly progressive growth, with frequent recurrences(18–40%) that are related to incomplete surgical excisionand/or higher tumour grade [360]. Metastases fromlaryngeal CS are unusual and are reported in approximately10% of patients, most commonly to the lungsand lymph nodes [259, 360]. The 5- and 10-year survivalrates are 90 and 80.9% respectively.7.7.5.2 Other SarcomasRare examples of other sarcomas have been described inthe larynx and hypopharynx, such as liposarcoma [136],osteosarcoma [220, 256, 332], angiosarcoma [214], synovialsarcoma [34], malignant fibrous histiocytoma [143],Kaposi’s sarcoma [246, 325], leiomyosarcoma [202, 297],etc.The aetiology of laryngeal sarcomas is unknown, althoughexposure to radiation [284] has been implicatedas a possible aetiologic factor for osteosarcoma [332]and malignant fibrous histiocytoma [143], and infectionwith HIV for Kaposi’s sarcoma [246, 325].7.7.6 Other Malignant NeoplasmsThe larynx may be rarely involved in disseminatedsystemic lymphoma or leukaemia [163]. It can also bethe primary site of a haematopoietic or lymphoid neoplasm.Extramedullary plasmacytoma seems to be themost common primary lymphoid neoplasm of the larynx.Various types of non-Hodgkin’s lymphoma of B-cell type and T-cell type have also been reported in thelarynx, as well as rare cases of granulocytic sarcoma andmast cell sarcoma [163].7.7.6.1 Malignant LymphomaPrimary non-Hodgkin’s lymphoma (NHL) of the larynxis rare, accounting for less than 1% of all laryngeal neoplasms[8] and approximately 1% of all primary extranodallymphomas [389]. By definition, the bulk of thedisease should occur in the larynx [389]. About 65 caseshave been reported in the English-language literature [8,55, 70, 249].The majority of laryngeal NHL are of B-cell type, especiallydiffuse large B-cell lymphoma, and extranodalmarginal lymphoma of the MALT type. Rare cases of T-cell NHL have been reported, such as NK/T cell lymphomaof the nasal type, and peripheral T-cell lymphoma[389]. All regions of the larynx may be involved, withthe exception of the extranodal marginal lymphoma ofthe MALT type, which has been described in the supraglottisonly [70, 199], presumably because mucosa-associatedlymphoid tissue has been found mostly in the supraglotticregion [199].They present mostly at stage I or II and are limitedto the larynx, with or without regional lymph node involvement.The most common symptoms are hoarseness,foreign body sensation, and airway obstruction.The prognosis is favourable. Laryngeal NHL shouldbe treated according to the histologic type of NHL. Itusually responds well to radiation therapy. Systemicchemotherapy is indicated for recurrent or disseminateddisease [8].7.7.6.2 Extraosseous(Extramedullary) PlasmacytomaICD-O:9734/3Extraosseous plasmacytoma is a clonal proliferation ofplasma cells forming a tumour at an extraosseous andextramedullary site. By definition, there is no evidenceof plasma cell myeloma on bone marrow examinationor by radiography [142]. The malignant plasma cellsexpress monotypic cytoplasmic immunoglobulins, andplasma cell-associated antigens, with an absence of immatureB-cell antigens [142, 389].The majority of extraosseous plasmacytomas occurin the upper respiratory tract; among them, the larynxis involved in only 6–18%. An incidence of 1–5 plasmacytomasin 1,000 laryngeal tumours has been reported[269].Laryngeal plasmacytoma is more frequent in males,with a mean age of 60 years. The epiglottis is the mostcommon site of involvement, followed by the vocalcords, false cords, ventricles and the subglottis [183, 269,270, 303, 378]. It generally presents as a solitary, submucosallesion, or as a polypoid lesion. It may occasionallyinvolve multiple sites in the larynx [269, 303].

Larynx and Hypopharynx Chapter 7 225Histologically, the tumour consists of sheets of plasmacells that vary in differentiation from well- to poorlydifferentiated. They may contain Russell bodies orgrape-like inclusions of retained immunoglobulin (Mottcells), which are also found in reactive plasma cells anddo not help in establishing the diagnosis of plasmacytoma[142].Well-differentiated plasmacytoma cannot be distinguishedmorphologically from reactive (polyclonal) proliferationof plasma cells. Therefore, the monoclonalityof plasma cells must be proven, which is best achieved bydemonstrating the cytoplasmic immunoglobulin heavyand/or light chain restriction. Besides immunohistochemistry,non-isotopic paraffin section in situ hybridisationis useful in the assessment of clonality for kappaor lambda light chain mRNA [389].Poorly differentiated plasmacytoma must be differentiatedfrom other lymphoid neoplasms and from othermalignant tumours, such as malignant melanoma andcarcinoma. This is achieved by appropriate immunohistochemicalanalysis; plasmacytoma, in contrast to lymphoma,does not express CD45 and immature B- andT-cell markers [351]. It also does not express antigenscharacteristic of malignant melanoma (i.e. S-100 protein,HMB-45 and melan-A), carcinoma (cytokeratins)and neuroendocrine neoplasms (i.e. synaptophysin,chromogranin).Plasmacytoma is radiosensitive and complete eradicationby radiation and/or surgery is potentially curative[183, 269, 270, 303, 378]. The prognosis is favourable,although the development of a plasma cell myelomamay occur in 15% of patients with extraosseous plasmacytoma[142].7.7.6.3 Primary Mucosal MelanomaICD-O:8720/3Primary malignant melanoma (MM) of the larynx is extremelyrare; less than 60 cases have been described inthe literature. They represent 3.6 to 7.4% of all mucosalmelanomas of the head and neck [6, 185, 212, 379].Primary laryngeal MM is more common in men,mostly in the 6th and 7th decades. It occurs primarilyin the supraglottic region and less often in the glottic region,but it has not yet been described in the subglottis.The symptoms vary according to the site of involvementand generally occur over a short period of time [379].Macroscopically, it may present as a polypoid, exophytic,nodular, sessile, or pedunculated lesion, with orwithout surface ulceration, varying in colour from blackor brown, to tan-grey or white.Microscopically, primary laryngeal MM is indistinguishablefrom MM of the skin and other mucous membranes.It may be composed of epithelioid cells, spindlecells, or both. Nuclear and cellular pleomorphism, nuclearpseudoinclusions, mitoses and necroses are usuallyprominent.The diagnosis is based on histological examination,together with special stainings for melanin, such as Fontana-Masson,and immunohistochemistry.The differential diagnosis must always include thepossibility of a metastatic MM because in the larynx,metastatic MM is considerably more common than primaryMM [153]. Histologic features that favour the diagnosisof primary MM are junctional activity and/oran in situ component. However, as normal melanocytesare also normally present in the subepithelial compartment,junctional changes are not required for the diagnosisof primary MM [379].Apart from metastatic MM, the differential diagnosisincludes carcinoma (especially spindle cell carcinoma),sarcoma and lymphoma. Positive staining for wellknownMM markers, such as S-100 protein, HMB-45,melan-A and vimentin, and negative staining for CD45,B- and T-cell markers, as well as markers of epithelialdifferentiation (cytokeratins, epithelial membrane antigen)is diagnostic for MM.The treatment of choice is complete surgical excision.The prognosis of primary laryngeal MM is poor, similarto primary mucosal malignant melanoma in general,with an average survival of less than 3.5 years [260,379].7.7.6.4 Metastases to the LarynxMetastases to the larynx from distant primary tumoursare uncommon, accounting for less than 0.5%of all laryngeal neoplasms. Metastases to the hypopharynxand trachea are even less common. The mostcommon source is malignant melanoma (Fig. 7.15),followed by renal cell carcinoma. Other tumours withproven laryngeal metastases include cancer of thebreast, lung, prostate, colon, stomach and ovary [24,74, 105, 154, 267, 296]. The rare occurrence of metastasesto the larynx seems to be related to the terminallocation of this organ in the lymphatic and vascularcirculation.Laryngeal metastases are most commonly located inthe supraglottic and subglottic regions, presumably dueto their rich vascular supply [24, 133]. They can be dividedinto those located in the soft tissue (metastasesfrom melanoma and renal cell carcinoma) and those locatedprimarily in the marrow spaces of the ossified laryngealcartilage (metastases from breast, prostate, andlung cancer).The signs and symptoms of metastatic laryngeal tumoursdo not differ from those of other laryngeal tumoursand vary according to the site of involvement.Haemoptysis may be present, especially in highly vascularisedmetastatic renal cell carcinoma.

226 N. Gale · A. Cardesa · N. Zidar7Fig. 7.15. Metastastic malignant melanoma of the larynx. An ulceratedtumour composed of large, atypical epithelioid cells withfocal melanin pigment. Primary tumour was located on the leftheelThe prognosis for patients with laryngeal metastasesis generally poor as laryngeal involvement is usually asign of dissemination in the terminal stage of the disease.In such patients, only palliative treatment is advised; laserendoscopic resection has been reported to be an excellenttool for relieving airway obstruction [267]. However,cases of isolated laryngeal metastases have been described,in which local excision and/or radiation therapywas associated with prolonged survival [74, 105].References1. Abramson AL, Zielinski B (1984) Congenital laryngeal saccularcyst of the newborn. Laryngoscope 94:1580–15822. Absalom AR, Watts R, Kong A (1998) Airway obstructioncaused by rheumatoid cricoarytenoid arthritis. Lancet351:1099–11003. Alavi S, Namazie A, Calcaterra TC, Blackwell KE (1999)Glandular carcinoma of the larynx: the UCLA experience.Ann Otol Rhinol Laryngol 108:485–4894. Allen MS, Pettit JM, Sherblom JC (1991) Management ofvocal nodules: a regional survey of otolaryngologists andspeech-language pathologists. J Speech Hear Res 34:229–2355. Aluffi P, Prestinari A, Ramponi A, Castri M, Pia F (2000) Rosai-Dorfmandisease of the larynx. J Laryngol Otol 114:565–5676. Amin HM, Petruzzelli GJ, Husain AN, Nickoloffi BJ (2001)Primary malignant melanoma of the larynx. Arch PatholLab Med 125:271–2737. Amoils CP, Shindo ML (1996) Laryngotracheal manifestationsof rhinoscleroma. Ann Otol Rhinol Laryngol 105:336–3408. Ansell S, Habermann TM, Hoyer JD, Strickler JG, Chen MG,McDonald TJ (1997) Primary laryngeal lymphoma. Laryngoscope107:1502–15069. Arber DA, Weiss LM, Chang KL (1998) Detection of Epstein-Barrvirus in inflammatory pseudotumor. Semin DiagnPathol 15:155–16010. Arens C, Glanz H, Kleinsasser O (1997) Clinical and morphologicalaspects of laryngeal cysts. Eur Arch Otorhinolaryngol254:430–43611. Asrar L, Facharzt EH, Haque I (1998) Rosai-Dorfman disease:presenting as isolated extranodal involvement of larynx.J Otolaryngol 27:85–8612. Assimakopoulos D, Patrikakos G (2002) The role of gastroesophagealreflux in the pathogenesis of laryngeal carcinoma.Am J Otolaryngol 23:351–35713. Austen KF (2001) Allergies, anaphylaxis and systemic mastocytosis.In: Braunwald E, Fauci AS, Kasper DL, Hauser SL,Longo DL, Jameson JL (eds) Harrison’s principles of internalmedicine, 15th edn, McGraw Hill, New York, pp 1913–192214. Bachman AL (1978) Benign, non-neoplastic conditions of thelarynx and pharynx. Radiol Clin North Am 16:273–29015. Baker HL, Baker SR, McClatchey KD (1982) Manifestationsand management of laryngoceles. Head Neck Surg 4:450–45616. Balestrieri F, Watson CB (1982) Intubation granuloma. OtolaryngolClin North Am 15:567–57917. Barnes C, Sexton M, Sizeland A, Tiedemann K, BerkowitzRG, Waters K (2001) Laryngo-pharyngeal carcinoma inchildhood. Int J Pediatr Otorhinolaryngol 61:83–8618. Barnes L (1991) Paraganglioma of the larynx. A critical reviewof the literature. ORL J Otorhinolaryngol Relat Spec53:220–23419. Barnes L (2001) Diseases of the larynx, hypopharynx, andesophagus. In: Barnes L (ed) Surgical pathology of the headand neck. Dekker, New York, pp127–23720. Barnes L, Ferlito A, Wenig BM (1997) Laryngeal paragangliomas.A review and report of a single case. J Laryngol Otol111:197–19821. Barnes L, Peel RL (1990) Head and neck pathology: a text/atlasof differential diagnosis. Igaku-Shoin, New York, pp 70–7722. Batsakis JG (1987) Laryngeal involvement by thyroid disease.Ann Otol Rhinol Laryngol 96:718–71923. Batsakis JG, El-Naggar AK, Luna MA (1992) Neuroendocrinetumors of the larynx. Ann Otol Rhinol Laryngol101:710–71424. Batsakis JG, Luna MA, Byers RM (1985) Metastases to thelarynx. Head Neck Surg 7:458–46025. Batsakis JG, Luna MA, El-Naggar AK (1992) Nonsquamouscarcinomas of the larynx. Ann Otol Rhinol Laryngol102:1024–102626. Batsakis JG, Raymond AK (1988) Cartilage tumors of the larynx.South Med J 81:481–48427. Bengtsson M, Bengtsson A (1998) Cricoarytenoid arthritis– a cause of upper airway obstruction in the rheumatoid arthritispatient. Intensive Care Med 24:64328. Benjamin B, Croxson G (1985) Vocal cord granulomas. AnnOtol Rhinol Laryngol 94:538–54129. Benjamin B, Dalton C, Croxson G (1995) Laryngoscopic diagnosisof laryngeal sarcoid. Ann Otol Rhinol Laryngol104:529–55330. Benjamin B, Jacobson I, Eckstein R (1997) Idiopathic subglotticstenosis: diagnosis and endoscopic laser treatment.Ann Otol Rhinol Laryngol 106:770–77431. Benjamin B, Robb P, Clifford A, Eckstein R (1991) Giant Teflongranuloma of the larynx. Head Neck 13:453–45632. Bennett S, Bishop S, Lumpkin SM (1987) Phonatory characteristicsassociated with bilateral diffuse polypoid degeneration.Laryngoscope 97:446–45033. Bikhazi PH, Messina L, Mhatre AN, Goldstein JA, LalwaniAK (2000) Molecular pathogenesis in sporadic head andneck paraganglioma. Laryngoscope 110:1346–134834. Bilgic B, Mete Ö, Öztürk AS, Demiryont M, Keles N, BasaranM (2003) Synovial sarcoma: a rare tumor of the larynx.Pathol Oncol Res 9:242–245

Larynx and Hypopharynx Chapter 7 22735. Birzgalis AR, Farrington WT, O’Keefe L, Shaw J (1993) Localizedtracheopathia osteoplastica of the subglottis. J LaryngolOtol 107:352–35336. Bone RC, Biller HF, Irwin TM (1972) Intralaryngotrachealthyroid. Ann Otol Rhinol Laryngol 81:424–42837. Boring CC, Squires TS, Tong T, Montgomery S (1994) Cancerstatistics, 1994. CA Cancer J Clin 44:7–2638. Bosetti C, Talamini R, Levi F, Negri E, Franceschi S, AiroldiL, La Vecchia C (2002) Fried foods: a risk factor for laryngealcancer? Br J Cancer 87:1230–123339. Bossingham DH, Simpson FG (1996) Acute laryngeal obstructionin rheumatoid arthritis. BMJ 312:295–29640. Bower JS, Belen JE, Weg JG, Dantzker DR (1980) Manifestationsand treatment of laryngeal sarcoidosis. Am Rev RespirDis 122:325–33241. Boyle JO, Coulthard SW, Mandel RM (1991) Laryngeal involvementin disseminated coccidioidomycosis. Arch OtolaryngolHead Neck Surg 117:433–43842. Bradley PJ, Kochaar A, Quraishi MS (1999) Pharyngealpouch carcinoma: real or imaginary risks? Ann Otol RhinolLaryngol 108:1027–103243. Brais B, Bouchard JP, Xie YG, Rochefort DL, Chretien N,Tome FM, Lafreniere RG, Rommens JM, Uyama E, NohiraO, Blumen S, Korczyn AD, Heutink P, Mathieu J, DuranceauA, Codere F, Fardeau M, Rouleau GA, Korcyn AD (1998)Short GCG expansions in the PABP2 gene cause oculopharyngealmuscular dystrophy. Nat Genet 18:164–16744. Brandwein M, Huvos A (1995) Laryngeal oncocytic cystadenomas.Eight cases and a literature review. Arch OtolaryngolHead Neck Surg 121:1302–130545. Brandwein M, Levi G, Som P, Urken ML (1992) Paragangliomaof the inferior laryngeal paraganglia. A case report. ArchOtolaryngol Head Neck Surg 118:994–99646. Brandwein M, Moore S, Som P, Biller H (1992) Laryngealchondrosarcomas: a clinicopathologic study of 11 cases includingtwo chondrosarcomas with additional malignantmesenchymal component. Laryngoscope 8:858–86747. Bridger MW, Jahn AF, van Nostrand AW (1980) Laryngealrheumatoid arthritis. Laryngoscope 90:296–30348. Brodsky L, Yoshpe N, Ruben RJ (1983) Clinical-pathologicalcorrelates of congenital subglottic hemangiomas. Ann OtolRhinol Laryngol 105:4–1849. Buley ID, Gatter KC, Kelly PM, Heryet A, Millard PR (1988)Granular cell tumours revisited. An immunohistologicaland ultrastructural study. Histopathology 12:263–27450. Canalis RF, Maxwell DS, Hemenway WG (1977) Laryngocele– an updated review. J Otolaryngol 6:191–19951. Carbone A, Passannante A, Gloghini A, Devaney KO, RinaldoA, Ferlito A (1999) Review of sinus histiocytosis withmassive lymphadenopathy (Rosai-Dorfman disease) of headand neck. Ann Otol Rhinol Laryngol 108:1095–110452. Carpenter RJ III, Banks PM, McDonald TJ, Sanderson DR(1978) Sinus histiocytosis with massive lymphadenopathy(Rosai-Dorfman disease): report of a case with respiratorytract involvement. Laryngoscope 88:1963–196953. Cassano L, Lombardo P, Marchese-Ragona R, Pastore A(2000) Laryngopyocele: three new clinical cases and reviewof the literature. Eur Arch Otorhinolaryngol 257:507–51154. Cattaruzza MS, Maisonneuve P, Boyle P (1996) Epidemiologyof laryngeal cancer. Oral Oncol Eur J Cancer 32B:293–30555. Cavalot AL, Preti G, Vione N, Nazionale G, Palonta F, FaddaGL (2001) Isolated primary non-Hodgkin’s malignant lymphomaof the larynx. J Laryngol Otol 115:324–32656. Cessna MH, Zhou H, Sanger WG, Perkins SL, Tripp S, PickeringD, Daines C, Coffin CM (2002) Expression of ALK1and p80 in inflammatory myofibroblastic tumor and its mesenchymalmimics: a study of 135 cases. Mod Pathol 15:931–93857. Chiu LD, Rasgon BM (1996) Laryngeal chondroma: a benignprocess with long-term clinical implications. Ear NoseThroat J 75:540–542; 544–54958. Cho MS, Kim ES, Kim HJ, Yang WI (1997) Kimura’s diseaseof the epiglottis. Histopathology 30:592–59459. Chow LT, Chow WH, Shum BS (1993) Fatal massive upper respiratorytract haemorrhage: an unusual complication of localizedamyloidosis of the larynx. J Laryngol Otol 107:51–5360. Chu L, Gussack GS, Orr JB, Hood D (1994) Neonatal laryngoceles.A cause for airway obstruction. Arch OtolaryngolHead Neck Surg120:454–45861. Cleary KR, Batsakis JG (1995) Mycobacterial disease of thehead and neck: current perspective. Ann Otol Rhinol Laryngol104:830–83362. Close LG, Merkel M, Burns DK, Deaton CW Jr, Schaefer SD(1987) Asymptomatic laryngocele: incidence and associationwith laryngeal cancer. Ann Otol Rhinol Laryngol 96:393–39963. Coffin CM, Humphrey PA, Dehner LP (1998) Extrapulmonaryinflammatory myofibroblastic tumor: a clinical andpathological survey. Semin Diagn Pathol 15:85–10164. Coffin CM, Watterson J, Priest JR, Dehner LP (1995) Extrapulmonaryinflammatory myofibroblastic tumor (inflammatorypseudotumor). A clinicopathologic and immunohistochemicalstudy of 84 cases. Am J Surg Pathol 19:859–87265. Corsi A, Ciofalo A, Leonardi M, Zambetti G, Bosman C(1997) Recurrent inflammatory myofibroblastic tumor of theglottis mimicking malignancy. Am J Otolaryngol 18:121–12666. Courteney-Harris RG, Goddard MJ (1992) Sinus histiocytosiswith massive lymphadenopathy (Rosai-Dorfman disease):a rare case of subglottic narrowing. J Laryngol Otol 106:61–6267. Cuzzourt JC, Pezold JC, Dunn CW (2002) Typical carcinoidtumor of the larynx occurring with otalgia. Ear Nose Throat81:40–4368. Damiani JM, Levine HL (1979) Relapsing polychondritis: reportof ten cases. Laryngoscope 89:929–94669. Danish HM, Meleca RJ, Dworkin JP, Abbarah TR (1998) Laryngealobstructing saccular cysts: a review of this diseaseand treatment approach emphasizing complete endoscopiccarbon dioxide laser excision. Arch Otolaryngol Head NeckSurg 124:593–59670. De Bree R, Mahieu HF, Ossenkoppele GJ, van der Valk P(1998) Malignant lymphoma of mucosa-associated lymphoidtissue in the larynx. Eur Arch Otorhinolaryngol 255:368–37071. De Carvalho MB (1998) Quantitative analysis of the extentof extracapsular invasion and its prognostic significance: aprospective study of 170 cases of carcinoma of the larynx andhypopharynx. Head Neck 20:16–2172. Dean CM, Sataloff RT, Hawkshaw MJ, Pribikin E (2002) Laryngealsarcoidosis. J Voice 16:283–28873. Dedo HH, Catten MD (2001) Idiopathic progressive subglotticstenosis: findings and treatment in 52 patients. Ann OtolRhinol Laryngol 110:305–31174. Dee SL, Eshghi M, Otto CS (2000) Laryngeal metastasis7 years after radical nephrectomy. Arch Pathol Lab Med124:1833–183475. Deeb ZE (1997) Acute supraglottitis in adults: early indicatorsof airway obstruction. Am J Otolaryngol 18:112–11576. Dehner LP (2000) The enigmatic inflammatory pseudotumours:the current state of our understanding, or misunderstanding.J Pathol 192:277–27977. Delahunty JE (1972) Acid laryngitis. J Laryngol Otol 86:335–34278. Delap TG, Lavy JA, Alusi G, Quiney RE (1997) Tuberculosispresenting as a laryngeal tumour. J Infect 34:139–14179. DeRienzo DP, Greenberg SD, Fraire AE (1991) Carcinoma ofthe larynx. Changing incidence in women. Arch OtolaryngolHead Neck Surg 117:681–68480. DeSanto LW, Devine KD, Weiland LH (1970) Cysts of thelarynx – classification. Laryngoscope 80:145–17681. Deutsch ES, Zalzal GH (1991) Quincke’s edema, revisited.Arch Otolaryngol Head Neck Surg 117:100–10282. Devaney KO, Ferlito A, Hunter BC, Devaney SL, Rinaldo A(1998) Wegener’s granulomatosis of the head and neck. AnnOtol Rhinol Laryngol 107:439–445

228 N. Gale · A. Cardesa · N. Zidar783. Devaney KO, Ferlito A, Silver CE (1995) Cartilaginous tumorsof the larynx. Ann Otol Rhinol Laryngol 104:251–25584. Dhingra JK, Aqel NM, McEwen J, Bleach NR (1995) Multipleoncocytic cysts of the larynx. J Laryngol Otol 109:1226–122885. Dikkers FG, Nikkels PG (1995) Benign lesions of the vocalfolds: histopathology and phonotrauma. Ann Otol RhinolLaryngol 104:698–70386. Donovan DT, Conley J (1983) Adenoid cystic carcinoma ofthe subglottic region. Ann Otol Rhinol Laryngol 92:491–49587. Dort JC, Frohlich AM, Tate RB (1994) Acute epiglottitis inadults: diagnosis and treatment in 43 patients. J Otolaryngol23:281–28588. Dubey SP, Banerjee S, Ghosh LM, Roy S (1997) Benign pleomorphicadenoma of the larynx: report of a case and reviewand analysis of 20 additional cases in the literature. Ear NoseThroat J 76:548-550; 552; 554–55789. Dumich PS, Neel HB III (1983) Blastomycosis of the larynx.Laryngoscope 93:1266–127090. Ebo DG, Stevens WJ (2000) Hereditary angioneurotic edema:review of the literature. Acta Clin Belg 55:22–2991. El-Naggar AK, Batsakis JG (1991) Carcinoid tumor of thelarynx. A critical review of the literature. ORL OtorhinolaryngolRelat Spec 53:188–19392. El-Naggar AK, Batsakis JG, Luna MA (1992) Neuroendocrinetumors of larynx. Ann Otol Rhinol Laryngol 101:710–71493. Eng J, Sabanathan S (1991) Airway complications in relapsingpolychondritis. Ann Thorac Surg 51:686–69294. Epstein SS, Winston P, Friedmann I, Ormerod FC (1957) Thevocal cord polyp. J Laryngol Otol 71:673–68895. Erb N, Pace AV, Delamere JP, Kitas GD (2001) Dysphagia andstridor caused by laryngeal rheumatoid arthritis. Rheumatology40:952–95396. Ereno C, Lopez JI, Grande J, Santaolalla F, Bilbao FJ (2001)Inflammatory myofibroblastic tumour of the larynx. J LaryngolOtol 115:856–85897. Ereno C, Lopez JI, Sanchez JM (1997) Atypical carcinoid oflarynx: presentation with scalp metastases. J Laryngol Otol111:89–9198. Esteve J, Riboli E, Pequignot G, Terracini B, Merletti F, CrosignaniP, Ascunce N, Zubiri L, Blanchet F, Raymond L,Repetto F, Tuyns AJ (1996) Diet and cancers of the larynxand hypopharynx: the IARC multi-center study in southwesternEurope. Cancer Causes Control 7:240–25299. Evans HL, Ayala AG, Romsdahl MM (1977) Prognostic factorsin chondrosarcoma of bone: a clinicopathologic analysiswith emphasis on histologic grading. Cancer 40:818–831100. Fajardo-Dolci G, Chavolla R, Lamadrid-Bautista E, Rizo-AlvarezJ (1999) Laryngeal scleroma. J Otolaryngol 28:229–231101. Farchi G (1992) Estimation of the impact of cigarette smokingreduction on mortality. Ann Ist Super Sanita 28:147–53102. Fauci AS (1998) The vasculitis syndromes. In: Fauci AS,Braunwald E, Isselbacher KJ, Wilson JD, Martin JB, KasperDL, Hauser SL, Longo DL (eds) Harrison’s principles of internalmedicine, 14th edn. McGraw-Hill, New York, pp 1910–1922103. Fechner RE, Mills SE (1997) Larynx and pharynx. In: SterrnbergSS (ed) Histology for pathologists. Lippincott-Raven,Philadelphia, pp 391–403104. Feder RJ, Michell MJ (1984) Hyperfunctional, hyperacidic,and intubation granulomas. Arch Otolaryngol 110:582–584105. Ferlito A (1993) Secondary neoplasms. In: Ferlito A (ed) Neoplasmsof the larynx. Churchill Livingstone, Edinburgh, pp349–360106. Ferlito A, Barnes L, Rinaldo A, Gnepp DR, Milroy CM (1998)A review of neuroendocrine neoplasms of the larynx: updateon diagnosis and treatment. J Laryngol Otol 112:827–834107. Ferlito A, Barnes L, Wenig BM (1994) Identification, classification,treatment, and prognosis of laryngeal paraganglioma.Review of the literature and eight new cases. Ann OtolRhinol Laryngol 103:525–536108. Ferlito A, Friedmann I (1993) Neuroendocrine neoplasms.In: Ferlito A (ed) Neoplasms of the larynx. Churchill Livingstone,Edinburgh, pp 169–205109. Ferlito A, Gale N, Hvala A (1981) Laryngeal salivary ductcarcinoma: a light and electron microscopic study. J LaryngolOtol 95:731–738110. Ferlito A, Milroy CM, Wenig BM, Barnes L, Silver CE (1995)Laryngeal paraganglioma versus atypical carcinoid tumor.Ann Otol Rhinol Laryngol 104:78–83111. Ferlito A, Recher G (1981) Oncocytic lesions of the larynx.Arch Otorhinolaryngol 232:107–115112. Ferlito A, Recher G (1985) Chondrometaplasia of the larynx.ORL J Otorhinolaryngol Relat Spec 47:174–177113. Ferlito A, Rinaldo A (2000) The pathology and managementof subglottic cancer. Eur Arch Otorhinolaryngol 257:168–173114. Ferlito A, Rinaldo A (2003) Small cell neuroendocrine carcinomaof the larynx: a preventable and frustrating diseasewith a highly aggressive lethal behavior. ORL J OtorhinolaryngolRelat Spec 65:131–133115. Ferlito A, Rinaldo A, Devaney KO, Devaney SL, Milroy CM(1998) Impact of phenotype on treatment and prognosis oflaryngeal malignancies. J Laryngol Otol 112:710–714116. Ferlito A, Rinaldo A, Devaney KO, MacLennan K, Myers JN,Petruzzelli GJ, Shaha AR, Genden EM, Johnson JT, de CarvalhoM, Myers EN (2002) Prognostic significance of microscopicand macroscopic extracapsular spread from metastatictumor in the cervical lymph nodes. Oral Oncol 38:747–751117. Ferlito A, Shaha AR, Silver CE, Rinaldo A, Mondin V (2001)Incidence and sites of distant metastases from head and neckcancer. ORL J Otorhinolaryngol Relat Spec 63:202–207118. Foucar E, Rosai J, Dorfman R (1990) Sinus histiocytosis withmassive lymphadenopathy (Rosai-Dorfman disease): reviewof the entity. Semin Diagn Pathol 7:19–73119. Foulsham CK II, Snyder GG III, Carpenter RJ III (1981) Papillarycystadenoma lymphomatosum of the larynx. OtolaryngolHead Neck Surg 89:960–964120. Franceschi S (2003) Fibre intake and laryngeal cancer risk.Ann Oncol 14:162–167121. Frantz TD, Rasgon BM, Quesenberry CP Jr (1994) Acute epiglottitisin adults. Analysis of 129 cases. JAMA 272:1358–1360122. Freije JE, Beatty TW, Campbell BH, Woodson BT, Schultz CJ,Toohill RJ (1996) Carcinoma of the larynx in patients withgastroesophageal reflux. Am J Otolaryngol 17:386–390123. Frenzel H, Schmitt-Graff A, Seitz RJ (1985) An immunohistochemicaland electron-microscopic study of vascular endothelialcells in vocal fold polyps. Arch Otorhinolaryngol241:271–278124. Gale N, Zidar N, Podboj J, Volavšek M, Luzar B (2003) Inflammatorymyofibroblastic tumour of paranasal sinuseswith fatal outcome: reactive lesion or tumour? J Clin Pathol56:715–717125. Galli J, Nardi C, Contucci AM, Cadoni G, Lauriola L, FantoniM (2002) Atypical isolated epiglottic tuberculosis: acase report and a review of the literature. Am J Otolaryngol23:237–240126. Gallo O, Bianchi S, Giannini A, Boccuzzi S, Calzolari A, Fini-Storchi O (1994) Lack of detection of human papillomavirus(HPV) in transformed laryngeal keratoses by in situ hybridization(ISH) technique. Acta Otolaryngol 114:213–217127. Gallo A, de Vicentiis M, Della Rocca C, Moi R, Simonelli M,Minni A, Shaha AR (2001) Evolution of precancerous lesions:a clinicopathologic study with long-term follow-up on 259patients. Head Neck 23:42–47128. Garcia RE, Gannon FH, Thompson LDR (2002) Dedifferentiatedchondrosarcoma of the larynx: a report of two cases andreview of the literature. Laryngoscope 112:1015–1018129. Gervais M, Dorion D (2003) Quality of life following surgicaltreatment of oculopharyngeal syndrome. J Otolaryngol32:1–5130. Geterud A (1991) Rheumatoid arthritis in the larynx. ScandJ Rheumatol 20:215131. Gillmore JD, Hawkins PN, Pepys MB (1997) Amyloidosis: areview of recent diagnostic and therapeutic developments. BrJ Haematol 99:245–256

Larynx and Hypopharynx Chapter 7 229132. Giudice M, Piazza C, Foccoli P, Toninelli C, Cavaliere S, PerettiG (2003) Idiopathic subglottic stenosis: management byendoscopic and open-neck surgery in a series of 30 patients.Eur Arch Otorhinolaryngol 260:235–238133. Glanz H, Kleinsasser O (1978) Metastasen im Kehlkopf.HNO 26:163–167134. Glaubiger DL, Casler JD, Garrett WL, Yuo HS, Lilis-HearnePK (1991) Chondrosarcoma of the larynx after radiationtreatment for vocal cord cancer. Cancer 68:1828–1831135. Gnepp DR (1991) Small cell neuroendocrine carcinoma ofthe larynx: a critical review of the literature. ORL J OtorhinolaryngolRelat Spec 53:210–219136. Gonzales-Lois C, Ibarrola C, Ballestin C, Martanez-Tello FJ(2002) Dedifferentiated liposarcoma of the pyriform sinus:report of a case and review of the literature. Int J Surg Pathol10:75–79137. Goutas N, Simopoulou S, Papazoglou K, Agapitos E (1994) Afatal case of diphtheria. Pediatr Pathol 14:391–395138. Gray SD, Hammond E, Hanson DF (1995) Benign pathologicresponses of the larynx. Ann Otol Rhinol Laryngol 104:13–18139. Gregg CM, Wiatrak BJ, Koopmann CF Jr (1995) Managementoptions for infantile subglottic hemangioma. Am JOtolaryngol 16:409–414140. Gregor RT, Loftus B, Cohen P, Balm AJ, Hilgers FJ (1994)Saccular mucocele in association with laryngeal cancer. AnnOtol Rhinol Laryngol 103:732–736141. Gripp S, Pape H, Scmitt G (1998) Chondrosarcoma of the larynx– the role of radiotherapy revisited – case report and reviewof the literature. Cancer 82:108–115142. Grogan TM, Van Camp B, Kyle RA, Muller-Hermelink HK,Harris NL (2001) Plasma cell neoplasms. In: Jaffe ES, HarrisNL, Stein H, Vardiman JW (eds) Tumours of haematopoieticand lymphoid tissues. IARC Press. Lyon, pp 142–156143. Guney E, Yigitbasi OG, Balkanli S, Canoz OM (2002) Postirradiationmalignant fibrous histiocytoma of the larynx: acase report. Am J Otolaryngol 23:293–296144. Gunkel AR, Thurner KH, Kanonier G, Sprinzl GM, ThumfartWF (1996) Angioneurotic edema as a reaction to angiotensin-convertingenzyme inhibitors. Am J Otolaryngol17:87–91145. Gupta OP, Jain RK, Tripathi PP, Gupta S (1984) Leprosy ofthe larynx: a clinicopathological study. Int J Lepr Other MycobactDis 52:171–175146. Guttenplan MD, Hendrix RA, Townsend MJ, Balsara G(1991) Laryngeal manifestations of gout. Ann Otol RhinolLaryngol 100:899–902147. Hakky M, Kolbusz R, Reyes CV (1989) Chondrosarcoma ofthe larynx. Ear Nose Throat 68:60–62148. Härmä RA, Suurkari S (1977) Tracheopathia chondro-osteoplastica.A clinical study of thirty cases. Acta Otolaryngol84:118–123149. Harrison DFN (1971) The pathology and management ofsubglottic cancer. Ann Otol Rhinol Laryngol 80:6–12150. Hébert PC, Ducic Y, Boisvert D, Lamothe A (1998) Adult epiglottitisin a Canadian setting. Laryngoscope 108:64–69151. Helliwell TR (2003) Evidence based pathology: squamouscarcinoma of the hypopharynx. J Clin Pathol 56:81–85152. Heman-Ackah YD, Remley KB, Goding GS Jr (1999) A newrole for magnetic resonance imaging in the diagnosis of laryngealrelapsing polychondritis. Head Neck 21:484–489153. Henderson LT, Robbins KT, Weitzner S (1986) Upper aerodigestivetract metastases in disseminated malignant melanoma.Arch Otolaryngol Head Neck Surg 112:659–663154. Hilger AW, Prichard AJ, Jones T (1998) Adenocarcinoma ofthe larynx – a distant metastasis from a rectal primary. J LaryngolOtol 112:199–201155. Hill ME, Creed GA, McMullan TF, Tyers AG, Hilton-JonesD, Robinson DO, Hammans SR (2001) Oculopharyngealmuscular dystrophy: phenotypic and genotypic studies in aUK population. Brain 124:522–526156. Hill MJ, Taylor CL, Scott GB (1980) Chondromatous metaplasiain the human larynx. Histopathology 4:205–214157. Hirabayashi H, Koshii K, Uno K, Ohgaki H, Nakasone Y, FujisawaT, Syouno N, Hinohara T, Hirabayashi K (1991) Extracapsularspread of squamous cell carcinoma in neck lymphnodes: prognostic factor of laryngeal cancer. Laryngoscope101:501–506158. Hirano M, Sato K (1993) Histological color atlas of the humanlarynx. Singular, San Diego, pp 1–112159. Hočevar-Boltežar I, Zidar N, Žargi M, Župevc A, Lestan B,Andoljšek D (2000) Amyloidosis of the larynx. Wien KlinWochenschr 112:732–734160. Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, LebovicsRS, Travis WD, Rottem M, Fauci AS (1992) Wegener granulomatosis:an analysis of 158 patients. Ann Intern Med116:488–498161. Holinger LD, Barnes DR, Smid LJ, Holinger PH (1978) Laryngoceleand saccular cysts. Ann Otol Rhinol Laryngol87:675–685162. Holland RS, Abaza N, Balsara G, Lesser R (1998) Granularcell tumor of the larynx in a six-year-old child: case reportand review of the literature. Ear Nose Throat J 77:652–654;656; 658163. Horny HP, Kaiserling E (1995) Involvement of the larynx byhemopoietic neoplasms. An investigation of autopsy casesand review of the literature. Pathol Res Pract 191:130–138164. Hughes RA, Berry CL, Seifert M, Lessof MH (1972) Relapsingpolychondritis. Three cases with a clinico-pathologicalstudy and literature review. Q J Med 41:363–380165. Hussong JW, Brown M, Perkins SL, Dehner LP, Coffi n CM(1999) Comparison of DNA ploidy, histologic, and immunohistochemicalfindings with clinical outcome in inflammatorymyofibroblastic tumors. Mod Pathol 12:279–286166. Hyams VJ, Rabuzzi DD (1970) Cartilaginous tumors of thelarynx. Laryngoscope 80:755–767167. Hytiroglou P, Brandwein MS, Strauchen JA, Mirante JP,Urken ML, Biller HF (1992) Inflammatory pseudotumor ofthe parapharyngeal space: case report and review of the literature.Head Neck 14:230–234168. Ibrahim R, Bird DJ, Sieler MW (1991) Malignant myoepitheliomaof the larynx with massive metastatic spread to the liver– an ultrastructural and immunocytochemical study. UltrastructPathol 15:69–76169. Imauchi Y, Ito K, Takasago E, Nibu KI, Sugasawa M, IchimuraK (2002) Stomal recurrence after total laryngectomy forsquamous cell carcinoma of the larynx. Otolaryngol HeadNeck Surg 126:63–66170. Inglis AF Jr (1993) Herpes simplex virus infection. A rarecause of prolonged croup. Arch Otolaryngol Head Neck Surg119:551–552171. Isaacson JE, Frable MA (1996) Cryptococcosis of the larynx.Otolaryngol Head Neck Surg 114:106–109172. Jennette JC (1994) Pathogenic potential of anti-neutrophilcytoplasmic autoantibodies. Lab Invest 70:135–137173. Jennings CR, Jones NS, Dugar J, Powell RJ, Lowe J (1998) Wegener’sgranulomatosis – a review of diagnosis and treatmentin 53 subjects. Rhinology 36:188–191174. Jindal JR, Milbrath MM, Shaker R, Hogan WJ, Toohill RJ(1994) Gastroesophageal reflux disease as a likely cause of“idiopathic” subglottic stenosis. Ann Otol Rhinol 103:186–191175. Johns MM (2003) Update on the etiology, diagnosis, andtreatment of vocal fold nodules, polyps, and cysts. Curr OpinOtolaryngol Head Neck Surg 11:456–461176. Kamal SA, Othman EO (1998) Granular cell tumour of thelarynx. J Laryngol Otol 112:83–85177. Kambič V, Gale N (1995) Epithelial hyperplastic lesions ofthe larynx. Elsevier, Amsterdam, pp 1–265178. Kambič V, Gale N, Radšel Z (1982) Warty dyskeratoma of thevocal cord. First reported case. Arch Otolaryngol 108:385–387179. Kambič V, Gale N, Radšel Z (1989) Anatomical markers ofReinke’s space and the etiopathogenesis of Reinke edema.Laryngorhinootologie 68:231–235180. Kambič V, Radšel Z (1984) Acid posterior laryngitis. Aetiology,histology, diagnosis and treatment. J Laryngol Otol98:1237–1240

230 N. Gale · A. Cardesa · N. Zidar7181. Kambič V, Radšel Z, Žargi M, Ačko M (1981) Vocal cord polyps:incidence, histology and pathogenesis. J Laryngol Otol95:609–618182. Kambič V, Žargi M, Gale N (1989) Laryngeal chondrosarcoma:is conservative surgery adequate treatment? J LaryngolOtol 103:970–972183. Kamijo T, Inagi K, Nakajima M, Motoori T, Tadokoro K,Nishiyam S (2002) A case of extramedullary plasmacytomaof the larynx. Acta Otolaryngol Suppl 547:104–107184. Kandiloros DC, Nikolopoulos TP, Ferekidis EA, TsangaroulakisA, Yiotakis JE, Davilis D, Adamopoulos GK (1997) Laryngealtuberculosis at the end of the 20th century. J LaryngolOtol 111:619–621185. Karagiannidis K, Noussios G, Sakellariou T (1998) Primarylaryngeal melanoma. J Otolaryngol 27:104–106186. Karlikaya C, Yuksel M, Kilicli S, Candan L (2000) Tracheobronchopathiaosteochondroplastica. Respirology 5:377–380187. Kawaida M, Fukuda H, Kohno N (2000) Granular cell tumorsarising nearly simultaneously in the larynx and subcutaneouscervical region. Ear Nose Throat J 79:162–166188. Kendall CH, Johnston MN (1998) Pseudo-malignant laryngealnodule (inflammatory myofibroblastic tumour). Histopathology32:286–287189. Kenny TJ, Werkhaven J, Netterville JL (2000) Sarcoidosisof the pediatric larynx. Arch Otolaryngol Head Neck Surg126:536–539190. Kershisnik M, Batsakis JG, Mackay B (1994) Granular celltumors. Ann Otol Rhinol Laryngol 103:416–419191. Kienast U, Neumann HJ, Stintz S (1997) Isolated carcinoid ofthe larynx – a rare neuroendocrine tumor of the upper airways.Otorhinolaryngol Nova 7:286–287192. Kirchner JA, Som JL (1971) Clinical significance of fixed vocalcord. Laryngoscope 81:1029–1044193. Kleidermacher P, Mastros NP, Miller FR, Jones EW, WoodBG (1995) Pathologic quiz case 2. Oncocytic cyst of the larynx.Arch Otolaryngol Head Neck Surg 121:1430–1431; 1433194. Kleinsasser O (1982) Pathogenesis of vocal cord polyps. AnnOtol Rhinol Laryngol 91:378–381195. Kleinsasser O (1988) Tumors of the larynx and hypopharynx.Thieme, Stuttgart196. Kontzoglou G, Triaridis S, Noussios G, Valeri R, Nanas C(2002) Subglottic hemangioma treated with interferon alpha2A. Acta Otorhinolaryngol Belg 56:83–85197. Krespi YP, Mitrani M, Husain S, Meltzer CJ (1987) Treatmentof laryngeal sarcoidosis with intralesional steroid injection.Ann Otol Rhinol Laryngol 96:713–715198. Kurtin PJ, Bonin DM (1994) Immunohistochemical demonstrationof the lysosome-associated glycoprotein CD68 (KP-1) in granular cell tumors and schwannomas. Hum Pathol25:1172–1178199. Kutta H, Steven P, Tillmann BN, Tsokos M, Paulsen FP(2003) Region-specific immunological response of the differentlaryngeal compartments: significance of larynx-associatedlymphoid tissue. Cell Tissue Res 311:365–371200. La Veccia C, Negri E, D’Avanzo B, Franceschi S, Decarli A,Boyle P (1990) Dietary indicators of laryngeal cancer risk.Cancer Res 50:4497–4500201. Lack EE, Worsham GF, Callihan MD, Crawford BE, KlappenbachS, Rowden G, Chun B (1980) Granular cell tumor: aclinicopathologic study of 110 patients. J Surg Oncol 13:301–316202. Lan MY, Guo YC, Chu PY, Ho DM, Chang SY (2001) Pathologyquiz case 2: leiomyosarcoma of the larynx. Arch OtolaryngolHead Neck Surg 127:1503–1505203. Lang WS (1965) Diphtheria at the present time. Laryngoscope75:1092–1102204. Larsen WJ (1997) Human embryology, 2nd edn. ChurchillLivingstone, New York, pp 347–374205. Lassaletta L, Alonso S, Ballestin C, Martinez-Tello FJ, Alvarez-VicentJJ (1999) Immunoreactivity in granular cell tumoursof the larynx. Auris Nasus Larynx 26:305–310206. Lassaletta L, Alonso S, Granell J, Ballestin C, Serrano A, Alvarez-VincentJJ (1998) Synchronous glottic granular cell tumorand subglottic spindle cell carcinoma. Arch OtolaryngolHead Neck Surg 124:1031–1034207. Leighton SE, Gallimore AP (1994) Extranodal sinus histiocytosiswith massive lymphadenopathy affecting the subglottisand trachea. Histopathology 24:393–394208. Lerner DM, Deeb Z (1993) Acute upper airway obstructionresulting from systemic diseases. South Med J 86:623–627209. Lewis JE, Olsen KD, Inwards CY (1997) Cartilaginous tumorsof the larynx: clinicopathologic review of 47 cases. AnnOtol Rhinol Laryngol 106:94–100210. Lewy RB, Millet D (1978) Immediate local tissue reactions toTeflon vocal cord implants. Laryngoscope 88:1339–1342211. Lie ES, Karlsen F, Holm R (1996) Presence of human papillomavirusin squamous cell laryngeal carcinomas. A study ofthirty-nine cases using polymerase chain reaction and in situhybridization. Acta Otolaryngol 116:900–905212. Lin SY, Hsu CY, Jan YJ (2001) Primary laryngeal melanoma.Otolaryngol Head Neck 125:569–570213. Lindeberg H, Krogdahl A (1999) Laryngeal cancer and humanpapillomavirus: HPV is absent in the majority of laryngealcarcinomas. Cancer Lett 146:9–13214. Loos BM, Wieneke JA, Thompson LDR (2001) Laryngeal angiosarcoma:clinicopathologic study of five cases with a reviewof the literature. Laryngoscope 111:1197–1202215. Luna MA, Pineda-Daboin K (2001) Upper aerodigestivetract. In: Henson D, Albores-Saavedra J Pathology of incipientneoplasia, 3rd edn. Oxford University Press, New York,pp 57–85216. Lundgren J, Olofsson J, Hellquist H (1982) Oncocytic lesionsof the larynx. Acta Otolaryngol 94:335–344217. Luzar B, Gale N, Klopčič U, Fischinger J (2000) Laryngealgranuloma: characteristics of the covering epithelium. J LaryngolOtol 114:264–267218. MacGregor AR, Batsakis JG, El-Naggar AK (2003) Myofibroblastomaof the larynx: a study of two cases. Head Neck25:606–611219. MacMillan RH III, Fechner RE (1986) Pleomorphic adenomaof the larynx. Arch Pathol Lab Med 110:245–247220. Madrigal FM, Godoy LM, Daboin KP, Casiraghi O, GarciaAM, Lu MA (2002) Laryngeal osteosarcoma: a clinicopathologicanalysis of four cases and comparison with a carcinosarcoma.Ann Diagn Pathol 6:1–9221. Mahlstedt K, Uβmüller J, Donath K (2002) Malignant sialogenictumours of the larynx. J Laryngol Otol 116:119–122222. Maier H, Dietz A, Gewelke U, Heller WD, Weidauer H (1992)Tobacco and alcohol and the risk of head and neck cancer.Clin Invest 70:320–327223. Maier H, Tisch M (1997) Epidemiology of laryngeal cancer:results of the Heidelberg case-control study. Acta OtolaryngolSuppl 527:160–164224. Maier W, Lohle E, Welte V (1994) Pathogenetic and therapeuticaspects of contact granuloma. Laryngorhinootologie73:488–491225. Mamelle G, Pampurik J, Luboinski B, Lancar R, Lusinchi A,Bosq J (1994) Lymph node prognostic factors in head andneck squamous cell carcinomas. Am J Surg 168:494–498226. Marcotullio D, Magliulo G, Pietrunti S, Suriano M (2002)Exudative laryngeal diseases of Reinke’s space: a clinicohistopathologicalframing. J Otolaryngol 31:376–380227. Marcotullio D, Paduano F, Magliulo G (1996) Laryngopyocele:an atypical case. Am J Otolaryngol 17:345–348228. Marion RB, Alperin JE, Maloney WH (1972) Gouty tophus ofthe true vocal cord. Arch Otolaryngol 96:161–162229. Maronian NC, Azadeh H, Waugh P, Hillel A (2001) Associationof laryngopharyngeal reflux disease and subglottic stenosis.Ann Otol Rhinol Laryngol 110:606–612230. Martin-Hirsch DP, Lannigan FJ, Irani B, Batman P (1992)Oncocytic papillary cystadenomatosis of the larynx. J LaryngolOtol 106:656–658231. Mayo-Smith MF, Spinale JW, Donskey CJ, Yukawa M, LiRH, Schiffman FJ (1995) Acute epiglottitis. An 18-year experiencein Rhode Island. Chest 108:1640–1647232. Mazur MT, Shultz JJ, Myers JL (1990) Granular cell tumor.Immunohistochemical analysis of 21 benign tumors and onemalignant tumor. Arch Pathol Lab Med 114:692–696

Larynx and Hypopharynx Chapter 7 231233. McAdam LP, O’Hanlan MA, Bluestone R, Pearson CM(1976) Relapsing polychondritis: prospective study of 23 patientsand a review of the literature. Medicine 55:193–215234. McCluggage WC, Cameron CH, Arthure K, Toner PG (1997)Atypical carcinoid tumor of the larynx: an immunohistochemical,ultrastructural, and flow cytometric analysis. UltrastructPathol 21:431–438235. McGavran MH, Bauer WC, Ogura JH (1961) The incidence ofcervical lymph node metastases from epidermoid carcinomaof the larynx and their relationship to certain characteristicsof the primary tumor. A study based on the clinical and pathologicalfindings for 96 patients treated by primary en bloclaryngectomy and radical neck dissection. Cancer 14:55–66236. McGregor DK, Citron D, Shahab I (2003) Cryptococcal infectionof the larynx simulating laryngeal carcinoma. SouthMed J 96:74–77237. McLaughlin RB, Spiegel JR, Selber J, Gotsdiner DB, SataloffRT (1999) Laryngeal sarcoidosis presenting as an isolatedsubmucosal vocal fold mass. J Voice 13:240–245238. Michaels L, Hellquist HB (2001) Ear, nose and throat histopathology,2nd edn. Springer, London239. Michet CJ Jr, McKenna CH, Luthra HS, O’Fallon WM (1986)Relapsing polychondritis. Survival and predictive role of earlydisease manifestations. Ann Intern Med 104:74–78240. Mikaelian DO, Contrucci RB, Batsakis JG (1986) Epithelial-myoepithelialcarcinoma of the subglottic region: a casepresentation and review of the literature. Otolaryngol HeadNeck Surg 95:104–106241. Miller FR, Wanamaker JR, Hicks DM, Tucker HM (1994)Cricoarytenoid arthritis and ankylosing spondylitis. ArchOtolaryngol Head Neck Surg 120:214–216242. Mills SE (2002) Neuroendocrine neoplasms of the head andneck with emphasis on neuroendocrine carcinomas. ModPathol 15:264–278243. Milroy CM, Rode J, Moss E (1991) Laryngeal paragangliomasand neuroendocrine carcinomas. Histopathology 18:201–209244. Mineta H, Miura K, Takebayashi S, Araki K, Ueda Y, HaradaH, Misawa K (2001) Immunohistochemical analysis of smallcell carcinoma of the head and neck: a report of four patientsand a review of sixteen patients in the literature with ectopichormone production. Ann Otol Rhinol Laryngol 110:76–82245. Mittal KR, True LD (1988) Origin of granules in granularcell tumor. Intracellular myelin formation with autodigestion.Arch Pathol Lab Med 112:302–303246. Mochloulis G, Irving RM, Grant HR, Miller RF (1996) LaryngealKaposi’s sarcoma in patients with AIDS. J LaryngolOtol 110:1034–1037247. Mohsenifar Z, Tashkin DP, Carson SA, Bellamy PE (1982)Pulmonary function in patients with relapsing polychondritis.Chest 81:711–717248. Moisa II, Silver CE (1991) Treatment of neuroendocrineneoplasms of the larynx. ORL J Otorhinolarngol Rel Spec53:259–264249. Mok JSW, Pak MW, Chan KF, Chow J, van Hasselt CA (2001)Unusual T- and T/NK- cell non-Hodgkin’s lymphoma of thelarynx: a diagnostic challenge for clinicians and pathologists.Head Neck. 23:625–628250. Molloy AR, McMahon JN (1988) Rapid progression of trachealstenosis associated with tracheopathia osteo-chondroplastica.Intensive Care Med 15:60–62251. Monday LA, Cornut G, Bouchayer M, Roch JB (1983) Epidermoidcysts of the vocal cords. Ann Otol Rhinol Laryngol92:124–127252. Moore KL, Persaud TVN (1998) The developing human, 6thedn. Saunders, Philadelphia, pp 215–256253. Muir C, Weiland L (1995) Upper aerodigestive tract cancers.Cancer 75:147–153254. Muscat JE, Wynder EL (1992) Tobacco, alcohol, asbestos,and occupational risk factors for laryngeal cancer. Cancer69:2244–2251255. Myssiorek D, Halaas Y, Silver C (2001) Laryngeal and sinonasalparagangliomas. Otolaryngol Clin North Am 34:971–982256. Myssiorek D, Patel M, Wasserman P, Rofeim O (1998) Osteosarcomaof the larynx. Ann Otol Rhinol Laryngol 107:70–74257. Myssiorek D, Persky M (1989) Laser endoscopic treatmentof laryngoceles and laryngeal cysts. Otolaryngol Head NeckSurg 100:538–541258. Nakajima H (1993) Tuberculosis: a global emergency. WorldHealth Forum 14:438259. Nakayama M, Brandenburg JH, Hafez GR (1993) Dedifferentiatedchondrosarcoma of the larynx with regional and distantmetastases. Ann Otol Rhinol Laryngol 102:785–791260. Nandapalan V, Roland NJ, Helliwell TR, Williams EM, HamiltonJ, Jones AS (1998) Mucosal melanoma of the head andneck. Clin Otolaryngol 23:107–116261. Narozny W, Stankiewicz C, Przewozny T, Bakowska A,Czuszynska Z (2001) A case of multisymptomatic relapsingpolychondritis in a 22-year-old woman. Acta OtorhinolaryngolBelg 55:227–233262. Nayak DR, Balakrishnan R, Rao RV, Hazarika P (2001) Clearcell carcinoma of the larynx. Int J Pediatr Otorhinolaryngol57:149–153263. Neel HB III, McDonald TJ (1982) Laryngeal sarcoidosis: reportof 13 patients. Ann Otol Rhinol Laryngol 91:359–362264. Netterville JL, Coleman JR Jr, Chang S, Rainey CL, ReinischL, Ossoff RH (1998) Lateral laryngotomy for the removal ofTeflon granuloma. Ann Otol Rhinol Laryngol 107:735–744265. Newman BH, Taxy JB, Laker HI (1984) Laryngeal cystsin adults: a clinicopathologic study of 20 cases. Am J ClinPathol 81:715–720266. Nguyen HC, Urquhart AC (1997) Zenker’s diverticulum. Laryngoscope107:1436–1440267. Nicolai P, Puxeddu R, Cappiello J, Peretti G, Battochio S,Facchetti F, Antonelli AR (1996) Metastatic neoplasms to thelarynx: report of three cases. Laryngoscope 106:851–855268. Nishiike S, Irifune M, Doi K, Sawada T, Kubo T (2002) Laryngealtuberculosis: a report of 15 cases. Ann Otol RhinolLaryngol 111:916–918269. Nosfinger YC, Mirza N, Rowan PT, Lanza D, Weinstein G(1997) Head and neck manifestations of plasma cell neoplasms.Laryngoscope 107:741–746270. Nowak-Sadzikowska J, Weiss M (1998) Extramedullary plasmacytomaof the larynx. Analysis of 5 cases. Eur J Cancer34:1468271. Nunez DA, Astley SM, Lewis FA, Wells M (1994) Humanpapilloma viruses: a study of their prevalence in the normallarynx. J Laryngol Otol 108:319–320272. Ogawa Y, Nishiyama N, Hagiwara A, Ami T, Fujita H, YoshidaT, Suzuki M (2002) A case of laryngeal aspergillosis followingradiation therapy. Auris Nasus Larynx 29:73–76273. O’Halloran LR, Lusk RP (1994) Amyloidosis of the larynx ina child. Ann Otol Rhinol Laryngol 103:590–594274. Ohlms LA, McGill T, Healy GB (1994) Malignant laryngealtumors in children: a 15-year experience with four patients.Ann Otol Rhinol Laryngol 103:686–692275. Omeroglu A, Weisenberg E, Baim HM, Rhone DP (2001)Pathologic quiz case. Supraglottic granulomas in a youngCentral American Man. Arch Pathol Lab Med 125:157–158276. Oreggia F, De Stefani E, Boffetta P, Brennan P, Deneo-PellegriniH, Ronco AL (2001) Meat, fat and risk of laryngealcancer: a case-control study in Uruguay. Oral Oncol 37:141–145277. Orlandi A, Fratoni S, Hermann I, Spagnoli LG (2003) Symptomaticlaryngeal nodular chondrometaplasia: a clinicopathologicalstudy. J Clin Pathol 56:976–977278. Osammor JY, Bulman CH, Blewitt RW (1990) Intralaryngotrachealthyroid. J Laryngol Otol 104:733–736279. Paaske PB, Tang E (1985) Tracheopathia osteoplastica in thelarynx. J Laryngol Otol 99:305–310280. Pabuççuoğlu U, Tuncer C, Sengiz S (2002) Histopathology ofcandidal hyperplastic lesions of the larynx. Pathol Res Pract198:675–678281. Park SS, Streitz JM Jr, Rebeiz EE, Shapshay SM (1995) Idiopathicsubglottic stenosis. Arch Otolaryngol Head Neck Surg121:894–897

232 N. Gale · A. Cardesa · N. Zidar7282. Patterson HC, Dickerson GR, Pilch BZ, Bentkover SH (1981)Hamartoma of the hypopharynx. Arch Otolaryngol 107:767–772283. Peeters A, Schmelzer B, Beernaert A, Fannes H (2001) Oncocyticlaryngeal cysts: a case report and literature review. ActaOtorhinolaryngol Belg 55:71–75284. Pelliteri PK, Ferlito A, Bradley PJ, Shaha AR, Rinaldo A(2003) Management of sarcomas of the head and neck inadults. Oral Oncol 39:2–12285. Pelucchi C, Talamini R, Levi F, Bosetti C, La Vecchia C, NegriE, Parpinel M, Pesce C, Tobia-Gallelli F, Toncini C (1984)APUD cells of the larynx. Acta Otolaryngol 98:158–162286. Pelucchi S, Amoroso C, Grandi E, Carinci F, Pastore A(2002) Granular cell tumour of the larynx: literature reviewand case report. J Otolaryngol 31:234–235287. Pennings RJ, van den Hoogen FJ, Marres HA (2001) Giantlaryngoceles: a cause of upper airway obstruction. Eur ArchOtorhinolaryngol 258:137–140288. Pesce C, Tobia-Gallelli F, Toncini C (1984) APUD cells of thelarynx. Acta Otolaryngol 98:158–162289. Peterson KL, Fu YS, Calcaterra T (1997) Subglottic paraganglioma.Head Neck 19:54–56290. Phipps CD, Gibson WS, Wood WE (1997) Infantile subglottichemangioma: a review and presentation of two cases ofsurgical excision. Int J Pediatr Otorhinolaryngol 41:71–79291. Pilch BZ (2001) Larynx and hypopharynx. In: Pilch BZ (ed)Head and neck surgical pathology. Lippincott Williams &Wilkins, Philadelphia, pp 230–283292. Pinsolle J, Pinsolle V, Majoufre C, Duroux S, Demeaux H, SiberchicotF (1997) Prognostic value of histologic findings inneck dissections for squamous cell carcinoma. Arch OtolaryngolHead Neck Surg 123:145–148293. Pompe-Kirn V (2002) Epidemiological features of laryngealcancer in Slovenia. Zdrav Vestn 71:59–63294. Popper HH, Winter E, Hofler G (1994) DNA of Mycobacteriumtuberculosis in formalin-fixed, paraffin-embedded tissuein tuberculosis and sarcoidosis detected by polymerase chainreaction. Am J Clin Pathol 101:738–741295. Pounder DJ, Pieterse AS (1982) Tracheopathia osteoplastica:a study of the minimal lesion. J Pathol 138:235–239296. Prescher A, Schick B, Stütz A, Brors D (2002) Laryngeal prostaticcancer metastases: an underestimated route of metastases?Laryngoscope 112:1467–1473297. Preti G, Palonta F, Vione N, Rosso P, Cavalot AL (2003) Leiomyosarcomaof the larynx. Tumori 89:321–323298. Pribitkin E, Friedman O, O’Hara B, Cunnane MF, Levi D,Rosen M, Keane WM, Sataloff RT (2003) Amyloidosis of theupper aerodigestive tract. Laryngoscope 113:2095–2101299. Rafferty MA, Fenton JE, Jones AS (2001) The history, aetiologyand epidemiology of laryngeal carcinoma. Clin Otolaryngol26:442–446300. Raitiola H, Pukander J (2000) Symptoms of laryngeal carcinomaand their prognostic significance. Acta Oncol 39:213–216301. Raitiola H, Pukander J, Laippala P (1999) Glottic and supraglotticlaryngeal carcinoma: differences in epidemiology,clinical characteristics and prognosis. Acta Otolaryngol119:847–851302. Rajah V, Essa A (1993) Histoplasmosis of the oral cavity, oropharynxand larynx. J Laryngol Otol 107:58–61303. Rakover Y, Bennett M, David R, Rosen G (2000) Isolated extramedullaryplasmacytoma of the vocal fold. J LaryngolOtol 114:540–542304. Ramesar K, Albizzati C (1988) Laryngeal cysts: clinical relevanceof a modified working classification. J Laryngol Otol102:923–925305. Randolph J, Grunt JA, Vawter GF (1963) The medical and surgicalaspects of intratracheal goiter. N Engl J Med 268:457–461306. Rassaei N, Frye DA, Harter KW, Troost TR, Ozdemirli M(2003) Acinic cell carcinoma of the glottis: case report. Am JOtolaryngol 24:258–260307. Reder PA, Neel HB III (1993) Blastomycosis in otolaryngology:review of a large series. Laryngoscope 103:53–58308. Remacle M, Degols JC, Delos M (1996) Exudative lesions ofReinke’s space. An anatomopathological correlation. ActaOtorhinolaryngol Belg 50:253–264309. Remenar E, Elo J, Frint T (1984) The morphological basis fordevelopment of Reinke’s oedema. Acta Otolaryngol 97:169–176310. Richardson BE, Morrison VA, Gapany M (1996) Invasive aspergillosisof the larynx: case report and review of the literature.Otolaryngol Head Neck Surg 114:471–473311. Richter B, Fradis M, Kohler G, Ridder GJ (2001) Epiglottictuberculosis: differential diagnosis and treatment. Case reportand review of the literature. Ann Otol Rhinol Laryngol110:197–201312. Riding K (1992) Subglottic hemangioma: a practical approach.J Otolaryngol 21:419–421313. Rihkanen H, Peltomaa J, Syrjänen S (1994) Prevalence of humanpapillomavirus DNA in vocal cords without laryngealpapillomas. Acta Otolaryngol 114:348–351314. Rinaldo A, Mannara GM, Fisher C, Ferlito A (1998) Hamartomaof the larynx: a critical review of the literature. AnnOtol Rhinol Laryngol 107:264–267315. Rizzo PB, Da Mosto MC, Clari M, Scotton PG, Vaglia A,Marchiori C (2003) Laryngeal tuberculosis: an often forgottendiagnosis. Int J Infect Dis 7:129–131316. Salvesen R, Brautaset NJ (1996) Oculopharyngeal musculardystrophy in Norway. Survey of a large Norwegian family.Acta Neurol Scand 93:281–285317. Sant’Anna GD, Mauri M, Arrarte JL, Camargo H Jr (1999)Laryngeal manifestations of paracoccidioidomycosis (SouthAmerican blastomycosis). Arch Otolaryngol Head Neck Surg125:1375–1378318. Santoro R, Turelli M, Polli G (2000) Primary carcinoma ofthe subglottic larynx. Eur Arch Otorhinolaryngol 257:548–551319. Sataloff RT, Wilborn A, Prestipino A, Hawkshaw M, HeuerRJ, Cohn J (1993) Histoplasmosis of the larynx. Am J Otolaryngol14:199–205320. Sato K, Hirano M, Nakashima T (1999) Electron microscopicand immunohistochemical investigation of Reinke’s edema.Ann Otol Rhinol Laryngol 108:1068–1072321. Sato K, Kurita S, Hirano M (1993) Location of the preepiglotticspace and its relationship to the paraglottic space. AnnOtol Rhinol Laryngol 102:930–934322. Sato K, Umeno T, Hirano M, Nakashima T (2002) Cricoidarea of the larynx: its physiological and pathological significance.Acta Otolaryngol 122:882–886323. Sawatsubashi M, Tuda K, Tokunaga O, Shin T (1997) Pleomorphicadenoma of the larynx: a case and review of the literaturein Japan. Otolaryngol Head Neck Surg 117:415–417324. Saydam L, Koybasi S, Kutluay L (2003) Laryngeal chondromapresenting as an external neck mass. Eur Arch Otorhinolaryngol260:239–241325. Schiff NF, Annino DJ, Woo P, Shapshay SM (1997) Kaposi’ssarcoma of the larynx. Ann Otol Rhinol Laryngol 106:563–567326. Schmidt U, Metz KA, Schrader M, Leder LD (1994) Well-differentiated(oncocytoid) neuroendocrine carcinoma of thelarynx with multiple skin metastases – a brief report. J LaryngolOtol 108:272–274327. See AC, Patel SG, Montgomery PQ, Rhys Evans PH, Fisher C(1998) Intralaryngotracheal thyroid-ectopic thyroid or invasivecarcinoma? J Laryngol Otol 112:673–676328. Seikaly H, Cuyler JP (1994) Infantile subglottic hemangioma.J Otolaryngol 23:135–137329. Seitz HK, Simanowski UA, Kommerell B (1988) Alcohol andcancer. Z Gastroenterol Suppl 3:106–119330. Shapiro AM, Rimell FL, Kenna MA (1995) Pathologic quizcase 1. Granular cell tumor (GCT) of larynx. Arch OtolaryngolHead Neck Surg 121:1058; 1060–1061331. Shapiro J, Eavey RD, Baker AS (1988) Adult supraglottitis. Aprospective analysis. JAMA 259:563–567332. Sheen TS, Wu CT, Heieh T, Hsu MM (1997) Postirradiationlaryngeal osteosarcoma: case report and literature review.Head Neck 19:57–62

Larynx and Hypopharynx Chapter 7 233333. Shek AW, Wu PC, Samman N (1996) Inflammatory pseudotumourof the mouth and maxilla. J Clin Pathol 49:164–167334. Shikhani AH, Jones MM, Marsh BR, Holliday MJ (1986) Infantilesubglottic hemangiomas. An update. Ann Otol RhinolLaryngol 95:336–347335. Shonai T, Hareyama M, Sakata K, Oouchi A, Nagakura H,Koito K, Morita K, Satoh M, Asakura K, Kataura A, HinodaY (1998) Mucoepidermoid carcinoma of the larynx: a casewhich responded completely to radiotherapy and a review ofthe literature. Jpn J Clin Oncol 28:339–342336. Shpitzer T, Noyek AM, Witterick I, Kassel T, Ichise M,Gullane P, Neligan P, Freeman J (1997) Noncutaneous cavernoushemangiomas of the head and neck. Am J Otolaryngol18:367–374337. Sie KC, McGill T, Healy GB (1994) Subglottic hemangioma:ten years’ experience with the carbon dioxide laser. Ann OtolRhinol Laryngol 103:167–172338. Smets G, Warson F, Dehou MF, Storme G, Sacre R, Van BelleS, Somers G, Gepts W, Kloppel G (1990) Metastasizing neuroendocrinecarcinoma of the larynx with calcitonin and somatostatinsecretion and CEA production, resembling medullarythyroid carcinoma. Virchows Arch 416:539–543339. Sneller MC (1995) Wegener’s granulomatosis. JAMA273:1288–1291340. Sobin LH, Wittekind CH (2002) TNM classification of malignanttumors, 6th edn, Wiley, New York341. Soga J, Osaka M, Yakuwa Y (2002) Laryngeal endocrinomas(carcinoids and relevant neoplasms): analysis of 278 reportedcases. J Exp Cancer Res 21:5–13342. Soni NK (1992) Leprosy of the larynx. J Laryngol Otol106:518–520343. Sorensen WT, Moller-Andersen K, Behrendt N (1998) Rheumatoidnodules of the larynx. J Laryngol Otol 112:573–574344. Souglu Y, Erdamar B, Katircioglu OS, Karatay MC, Sunay T(2002) Extracapsular spread in ipsilateral neck and contralateralneck metastases in laryngeal cancer. Ann Otol RhinolLaryngol 111:447–454345. Soylu L, Kiroglu F, Ersoz C, Ozcan C, Aydogan B (1993) Intralaryngotrachealthyroid. Am J Otolaryngol 14:145–147346. Spector JG, Sessions DG, Emami B, Simpson J, Haughey B,Harvey J, Fredrickson JM (1995) Squamous cell carcinoma ofthe pyriform sinuses: a nonrandomized study comparison oftherapeutic modalities and long-term results. Laryngoscope105:397–406347. Spiro RH (1986) Salivary neoplasms: overview of a 35-yearexperience with 2807 patients. Head Neck Surg 8:177–184348. Spiro RH (1997) Distant metastasis in adenoid cystic carcinomaof the salivary origin. Am J Surg 174:495–498349. Spraggs PD, Tostevin PM, Howard DJ (1997) Management oflaryngotracheobronchial sequelae and complications of relapsingpolychondritis. Laryngoscope 107:936–941350. Stell PM, Tobin KE (1975) The behaviour of cancer affectingthe subglottic space. Can J Otolaryngol 4:612–617351. Strickler JG, Audeh MW, Copenhaver CM, Warnke RA(1988) Immunophenotypic differences between plasmacytoma,multiple myeloma and immunoblastic lymphoma. Cancer61:1782–1786352. Strong MS, Vaughan CW (1971) Vocal cord nodules and polyps– the role of surgical treatment. Laryngoscope 81:911–923353. Szpunar J, Glowacki J, Laskowski A, Miszke A (1971) Fibrinouslaryngotracheobronchitis in children. Arch Otolaryngol93:173–178354. Szwarc BJ, Kashima HK (1997) Endoscopic management of acombined laryngocele. Ann Otol Rhinol Laryngol 106:556–559355. Šmid L, Lavrenčak B, Žargi M (1992) Laryngo-tracheo-bronchopathiachondro-osteoplastica. J Laryngol Otol 106:845–848356. Tajima K, Yamakawa M, Katagiri T, Sasaki H (1997) Immunohistochemicaldetection of bone morphogenetic protein-2and transforming growth factor beta-1 in tracheopathia osteochondroplastica.Virchows Arch 431:359–363357. Thabet MH, Kotob H (2001) Lateral saccular cysts of the larynx.Aetiology, diagnosis and management. J Laryngol Otol115:293–297358. Thome R, Thome DC, de la Cortina RA (2001) Long-termfollow-up of cartilaginous tumors of the larynx. OtolaryngolHead Neck Surg 124:634–640359. Thompson LD, Derringer GA, Wenig BM (2000) Amyloidosisof the larynx: a clinicopathologic study of 11 cases. ModPathol 13:528–535360. Thompson LDR, Gannon FH (2002) Chondrosarcoma of thelarynx. A clinicopathologic study of 111 cases with review ofthe literature. Am J Surg Pathol 26:836–851361. Thoren L (1947) Intratracheal goitre. Acta Chir Scand95:495–512362. Tisch M, Lampl L, Groh A, Maier H (2002) Angioneuroticedemas of the upper aerodigestive tract after ACE-inhibitortreatment. Eur Arch Otorhinolaryngol 259:419–421363. Toohill RJ (1975) The psychosomatic aspects of children withvocal nodules. Arch Otolaryngol 101:591–595364. Trentham DE, Le CH (1998) Relapsing polychondritis. AnnIntern Med 129:114–122365. Tsikoudas A, Coatesworth AP, Martin-Hirsch DP (2002) Laryngealgout. J Laryngol Otol 116:140–142366. Tsunoda K, Soda Y (1996) Hoarseness as the initial manifestationof systemic lupus erythematosus. J Laryngol Otol110:478–479367. Tuyns AJ, Estève J, Raymond L, Berrino F, Benhamou E,Blanchet F, Boffetta P, Crosignani P, del Moral A, LehmannW, Merletti F, Péquignot G, Riboli E, Sancho-Garnier H, TerraciniB, Zubiri A, Zubiri L (1988) Cancer of the larynx/hypopharynx,tobacco and alcohol: IARC international casecontrolstudy in Turin and Varese (Italy), Zaragoza and Navarra(Spain), Geneva (Switzerland) and Calvados (France).Int J Cancer 41:483–491368. Uzcudun EA, Fernandez PB, Sanchez JJ, Grande AG, RetolazaIR, Baron MG, Bouzas JG (2001) Clinical features of pharyngealcancer: a retrospective study of 258 consecutive patients.J Laryngol Otol 115:112–118369. Valdez TA, Shapshay SM (2002) Idiopathic subglottic stenosisrevisited. Ann Otol Rhinol Laryngol 111:690–695370. Varvares MA, Montgomery WW, Hillman RE (1995) Teflongranuloma of the larynx: etiology, pathophysiology, andmanagement. Ann Otol Rhinol Laryngol 104:511–515371. Victoria LV, Hoffman HT, Robinson RA (1998) Granular celltumour of the larynx. J Laryngol Otol 112:373–376372. Waggoner LG (1958) Intralaryngeal intratracheal thyroid.Ann Otol Rhinol Laryngol 67:61–71373. Walker GK, Fechner RE, Johns ME, Teja K (1982) Necrotizingsialometaplasia of the larynx secondary to atheromatousembolization. Am J Clin Pathol 77:221–223374. Wani MK, Woodson GE (1999) Laryngeal contact granuloma.Laryngoscope 109:1589–1593375. Wasserman PG, Savargaonkar P (2001) Paragangliomas:classification, pathology, and differential diagnosis. OtolaryngolClin North Am 34:845–862376. Waterhouse JAH (1993) Epidemiology. In: Ferlito A (ed)Neoplasms of the larynx. Churchill Livingstone, Edinburgh,pp 49–64377. Weber AL, Shortsleeve M, Goodman M, Montgomery W,Grillo HC (1978) Cartilaginous tumors of the larynx and trachea.Radiol Clin North Am 16:261–267378. Welsh J, Westra WH, Eisele D, Hogan R, Lee DJ (1998) Solitaryplasmacytoma of the epiglottis: a case report and reviewof the literature. J Laryngol Otol 112:174–176379. Wenig BM (1995) Laryngeal mucosal malignant melanoma.A clinicopathologic, immunohistochemical, and ultrastructuralstudy of four patients and review of the literature. Cancer75:1568–1577380. Wenig BM (1995) Necrotizing sialometaplasia of the larynx.A report of two cases and a review of the literature. Am J ClinPathol 103:609–613381. Wenig BM, Abbondanzo SL, Childers EL, Kapadia SB, HeffnerDR (1993) Extranodal sinus histiocytosis with massivelymphadenopathy (Rosai-Dorfman disease) of the head andneck. Hum Pathol 24:483–492

234 N. Gale · A. Cardesa · N. Zidar7382. Wenig BM, Devaney K, Bisceglia M (1995) Inflammatorymyofibroblastic tumor of the larynx. A clinicopathologicstudy of eight cases simulating a malignant spindle cell neoplasm.Cancer 76:2217–2229383. Wenig BM, Devaney K, Wenig BL (1995) Pseudoneoplasticlesions of the oropharynx and larynx simulating cancer.Pathol Annu 30:143–187384. Wenig BM, Heffner DK (1990) Contact ulcers of the larynx.A reacquaintance with the pathology of an often underdiagnosedentity. Arch Pathol Lab Med 114:825–828385. Wenig BM, Heffner DK, Oertel YC, Johnson FB (1990) Teflonomasof the larynx and neck. Hum Pathol 21:617–623386. Werkhaven J, Ossoff RH (1991) Surgery for benign lesions ofthe glottis. Otolaryngol Clin North Am 24:1179–1199387. Westerberg BD, Durham JS, Berean KW (1995) Multiple oncocyticlaryngeal cysts presenting as acute airway obstruction.J Otolaryngol 24:319–321388. Woodruff JM, Senie RT (1991) Atypical carcinoid tumor ofthe larynx. A critical review of the literature. ORL 53:194–209389. World Health Organization Classification of Tumours (2005)Pathology and genetics of tumours of the head and neck.IARC, Lyon390. Yencha MW, Linfesty R, Blackmon A (2000) Laryngeal tuberculosis.Am J Otolaryngol 21:122–126391. Yuan YG, Han DM, Yang BQ, Yu ZK (1999) Laryngeal carcinoidtumours: Report of three cases. J Otolaryngol 28:54–56392. Yuen APW, Wei WI, Ho WK, Hui Y (1996) Risk factors oftracheostomal recurrence after laryngectomy for laryngealcarcinoma. Am J Surg 172:263–266393. Zatonski W, Becher H, Lissowska J, Wahrendorf J (1991) Tobacco,alcohol, and diet in the etiology of laryngeal cancer: apopulation-based case-control study. Cancer Causes Control2:3–10394. Zbaren P, Greiner R, Kengelbacher M (1996) Stomal recurrenceafter laryngectomy: an analysis of risk factors. OtolaryngolHead Neck Surg 114:569–575395. Zeitels SM, Hillman RE, Bunting GW, Vaughn T (1997) Reinke’sedema: phonatory mechanisms and managementstrategies. Ann Otol Rhinol Laryngol 106:533–543396. Zheng W, Blot WJ, Shu X, Gao YT, Ji BT, Ziegler RG, FraumeniJr (1992) Diet and other risk factors for laryngeal cancer inShanghai, China. Am J Epidemiol 136:178–191397. Zidar N, Volavšek M, Trček C, Kern I, Gale N (2000) Wegener’sgranulomatosis in the upper respiratory tract. Wien KlinWochenschr 112:676–679

Chapter 8Earand Temporal BoneL. Michaels8Contents8.1 Summary of Embryology,Anatomy and Histology . . . . . . . . . . . . . . . . . 2368.1.1 Embryology . . . . . . . . . . . . . . . . . . . . . . . . 2368.1.2 Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . 2368.1.3 Histology . . . . . . . . . . . . . . . . . . . . . . . . . . 2378.2 External Ear and Auditory Canal . . . . . . . . . . . . 2378.2.1 Inflammatory and Metabolic Lesions . . . . . . . . . 2378.2.1.1 Diffuse External Otitis . . . . . . . . . . . . . . . . . . 2378.2.1.2 Perichondritis . . . . . . . . . . . . . . . . . . . . . . . 2378.2.1.3 Malignant Otitis Externa . . . . . . . . . . . . . . . . . 2378.2.1.4 Relapsing Polychondritis . . . . . . . . . . . . . . . . . 2388.2.1.5 Gout . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2388.2.1.6 Ochronosis . . . . . . . . . . . . . . . . . . . . . . . . . 2388.2.2 Pseudocystic and Cystic Lesions . . . . . . . . . . . . 2388.2.2.1 Idiopathic Pseudocystic Chondromalacia . . . . . . . 2388.2.2.2 First Branchial Cleft Cyst . . . . . . . . . . . . . . . . . 2388.2.3 Tumour-Like Lesions . . . . . . . . . . . . . . . . . . . 2398.2.3.1 Chondrodermatitis Nodularis Helicis . . . . . . . . . 2398.2.3.2 Keratosis Obturans and Cholesteatomaof External Canal . . . . . . . . . . . . . . . . . . . . . 2398.2.3.3 Keratin Granuloma . . . . . . . . . . . . . . . . . . . . 2398.2.3.4 Angiolymphoid Hyperplasiawith Eosinophilia and Kimura’s Disease . . . . . . . . 2398.2.3.5 Accessory Tragus . . . . . . . . . . . . . . . . . . . . . 2408.2.3.6 Keloid . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2408.2.4 Benign Neoplasms . . . . . . . . . . . . . . . . . . . . . 2408.2.4.1 Adenoma of Ceruminal Glands . . . . . . . . . . . . . 2408.2.4.2 Pleomorphic Adenomaof Ceruminal Glands . . . . . . . . . . . . . . . . . . . 2418.2.4.3 Syringocystadenoma Papilliferumof Ceruminal Glands . . . . . . . . . . . . . . . . . . . 2418.2.4.4 Bony Lesions . . . . . . . . . . . . . . . . . . . . . . . . 2418.2.5 Malignant Neoplasms . . . . . . . . . . . . . . . . . . . 2428.2.5.1 Adenocarcinoma of Ceruminal Glands . . . . . . . . 2428.2.5.2 Adenoid Cystic Carcinomaof Ceruminal Glands . . . . . . . . . . . . . . . . . . . 2428.2.5.3 Basal Cell Carcinoma . . . . . . . . . . . . . . . . . . . 2428.2.5.4 Squamous Cell Carcinoma . . . . . . . . . . . . . . . . 2438.2.5.5 Melanotic Neoplasms . . . . . . . . . . . . . . . . . . . 2438.3 Middle Ear and Mastoid . . . . . . . . . . . . . . . . . 2448.3.1 Inflammatory Lesions . . . . . . . . . . . . . . . . . . 2448.3.1.1 Acute and Chronic Otitis Media . . . . . . . . . . . . 2448.3.1.2 Cholesteatoma . . . . . . . . . . . . . . . . . . . . . . . 2448.3.1.3 Unusual Inflammatory Lesions . . . . . . . . . . . . . 2478.3.2 Neoplasms and LesionsResembling Neoplasms . . . . . . . . . . . . . . . . . . 2478.3.2.1 Choristoma(Salivary Gland, Glial and Sebaceous Types) . . . . . 2478.3.2.2 Adenoma . . . . . . . . . . . . . . . . . . . . . . . . . . 2478.3.2.3 Papillary Tumours . . . . . . . . . . . . . . . . . . . . . 2488.3.2.4 Jugulotympanic Paraganglioma . . . . . . . . . . . . . 2498.3.2.5 Squamous Carcinoma . . . . . . . . . . . . . . . . . . 2508.3.2.6 Meningioma . . . . . . . . . . . . . . . . . . . . . . . . 2518.3.2.7 Rhabdomyosarcoma . . . . . . . . . . . . . . . . . . . 2518.3.2.8 Metastatic Carcinoma . . . . . . . . . . . . . . . . . . 2528.4 Inner Ear . . . . . . . . . . . . . . . . . . . . . . . . . . 2528.4.1 Bony Labyrinth . . . . . . . . . . . . . . . . . . . . . . 2528.4.1.1 Otosclerosis . . . . . . . . . . . . . . . . . . . . . . . . 2528.4.1.2 Paget’s Disease . . . . . . . . . . . . . . . . . . . . . . . 2538.4.1.3 Osteogenesis Imperfecta . . . . . . . . . . . . . . . . . 2548.4.1.4 Osteopetrosis . . . . . . . . . . . . . . . . . . . . . . . . 2548.4.2 Membranous Labyrinth and Cranial Nerves . . . . . 2548.4.2.1 Viral, Bacterial and Mycotic Infections . . . . . . . . 2548.4.2.2 Lesions of the Vestibular System . . . . . . . . . . . . 2568.4.2.3 Tumours and Tumour-Like Lesions . . . . . . . . . . 2578.4.2.4 Presbyacusis . . . . . . . . . . . . . . . . . . . . . . . . 2608.4.2.5 Malformations . . . . . . . . . . . . . . . . . . . . . . . 260References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260

236 L. Michaels88.1 Summary of Embryology,Anatomy and Histology8.1.1 EmbryologyThe ear is not a single organ, but two, being the peripheralreceptor site both for stimuli derived from soundwaves and for changes in posture. The structures subservingboth of those functions are developed from aninvagination of the ectoderm early in embryonic life– the otocyst – to produce the epithelia of the membranouslabyrinth of the inner ear. Superimposed upon,and developing slightly later, the first and second branchialarch systems provide structures that augment thehearing function. The endodermal component of thefirst branchial system, the branchial pouch, gives riseto the Eustachian tube and middle ear epithelia and thecorresponding ectodermal outgrowth, the first branchialcleft, to the external ear epidermis. The connectivetissue part of the local branchial cranial (auditory vestibular)nerve outflow from the central nervous system,both its vestibular and cochlear branches, grows to linkup with the sensory epithelia lining the otocyst-derivedcochlear and vestibular endolymph-containing cavities;there is recent evidence that terminal ganglion cells, e.g.spiral ganglion cells, may also be otocyst-derived. Cartilaginous,bony and muscular configurations of the earare developed from the mesenchyme surrounding theseearly epithelia. The seventh cranial (facial) nerve developsin close relation to the structures of the ear for muchof its course.8.1.2 AnatomyThe anatomy of the ear may be considered by referenceto its functions in hearing and balance (Fig. 8.1).The pinna and external canal conduct sound wavesin the air to the tympanic membrane, which transmitsthem by very delicate vibrations. The middle ear enhancesthis sound energy transmission by conveying vibrationsfrom the larger area of the tympanic membranethrough the ossicular chain (malleus, incus and stapes)to the much smaller area of the footplate of the stapes,which lies in the oval window of the vestibule in contactwith the perilymph. In this way vibrations representingsound are conducted to the fluids of the inner ear. Theair space of the middle ear cavity is magnified by themastoid air cells, which are complex expansions into themastoid bone. There is a connection of the middle earspace with the nasopharynx and so with the external airthrough the Eustachian tube, by which air pressure canbe adjusted.From the vestibular perilymph, vibrations derivedfrom sound waves pass directly via the scala vestibuliinto the spirally coiled perilymphatic spaces of the cochlea,where it forms an upper compartment ascendingfrom the vestibule and oval window. A lower compartment,the scala tympani, descends spirally to the roundwindow membrane, a connective tissue disc separatingthe perilymph compartment from the middle ear. Betweenthe scalae vestibuli and tympani there is an endolymph-containingcoiled middle compartment, thecochlear duct (scala media), which houses the senso-Fig. 8.1. Anatomical diagram of theear. Reproduced from Michaels andHellquist [68]Tympanicmembrane

Ear and Temporal Bone Chapter 8 237ry organ of sound reception, the organ of Corti. Wavesof vibration are conveyed from the perilymph to thewalls of the scala media, from which, through the endolymph,they affect the sensory cells of the organ ofCorti.The cochlear duct communicates with the vestibularendolymph-containing sacs through two fine canalsso that the endolymphatic system of the cochleaand vestibule is continuous, like the perilymphaticone. Gravitational acceleration of the head is detectedin a sensory organ arranged within endolymph-containingsacs in the vestibule (the utricle and saccule),and angular acceleration is detected within tubes emanatingin three dimensions from the utricle (lateral,posterior and superior semicircular canals). The sensorycells are located as a thickened portion of epithelium,the macula, in the saccule and utricle and araised prominence of epithelium, the crista, in expansionsof each semicircular canal, the ampullae. Thevestibular aqueduct contains the endolymphatic ductand sac, which constitute a blind offshoot of the endolymphaticsystem, probably functioning to absorbendolymph. The cochlear aqueduct is a communicationbetween the cerebrospinal fluid in the subarachnoidspace to the perilymph of the scala tympani nearthe round window. Cochlea, vestibule and semicircularcanals are surrounded by very dense bone, the oticcapsule.The cochlear and vestibular sensory structuresare supplied by a double nerve, the audiovestibularnerve or eighth cranial nerve, which enters the temporalbone through the internal auditory meatus. Thefacial nerve or seventh cranial nerve, enters the temporalbone through the same canal, and after a rightangledbend in the genu, where the geniculate ganglionis located, reaches the posterior wall of the middleear, from which it passes down through the mastoid toemerge in the region of the parotid salivary gland, afterwhich it provides motor nerve supply for the musclesof the face.8.1.3 HistologyThe ear and temporal bone are composed of many differenttissues, the normal histology of which is best consideredwhen describing the pathologic appearances ofthese parts.8.2 External Earand Auditory Canal8.2.1 Inflammatoryand Metabolic Lesions8.2.1.1 Diffuse External OtitisThis is a common condition, most frequently associatedwith Pseudomonas aeruginosa infection, but localtrauma is also an important causative factor. Histologicalfeatures include acute inflammation of the dermis,together with acanthosis and hyperkeratosis of the epidermis.8.2.1.2 PerichondritisPerichondritis most commonly affects the pinna, whereit may follow surgical trauma. As in the diffuse acute inflammationof the ear canal, Pseudomonas aeruginosa isthe most common infecting organism. Pus accumulatesbetween the perichondrium and cartilage of the pinna.This may interfere with the blood supply of the cartilageand so lead to its necrosis.8.2.1.3 Malignant Otitis ExternaMalignant otitis externa was first described as a severeinfection of the external auditory canal [16]. It usually(but not always [101]) affects elderly diabetics, resultingin unremitting pain, purulent discharge and invasion ofcartilage, nerve, bone and adjacent soft tissue. The causativeagent is usually Pseudomonas aeruginosa, but otherorganisms including fungi have been incriminated. Thecondition frequently goes on to ninth, tenth, eleventhand twelfth cranial nerve palsies and meningitis anddeath may result.Histopathological changes in the temporal bones oftwo patients who had been diagnosed clinically as havingmalignant otitis externa and were thought to havedied of this condition [123] were those of severe otitismedia and osteomyelitis of the jugular foramen secondaryto it. It seems likely that the manifestations of malignantotitis media are due to the spread of inflammationfrom the tympanic cavity and mastoid air spaces tothe petrous apex through bone marrow spaces by a processof osteomyelitis [85]. In recent years several patientswith AIDS have been reported to have malignant otitisexterna, and in one of them the presence of acute osteomyelitisof the skull base in addition supported the conceptof osteomyelitis as the pathologic basis for malignantotitis externa put forward above [121].

238 L. Michaels8.2.1.4 Relapsing Polychondritis8Relapsing polychondritis is a rare disease of unknownaetiology characterised by recurring bouts of inflammationaffecting cartilaginous structures and the eye.Although the cartilage of the external ear is most frequentlyinvolved and that of the nose next in frequency,it is the inflammation with destruction of the cartilagesof the respiratory tract, particularly those of the larynx,which threatens life, and in most cases where death hasresulted from the condition it is from respiratory obstructiondue to such cartilage damage.The cartilage of the pinna, is recurrently acutely inflamedand this leads eventually to a cobblestone appearanceresembling boxer’s ear. Inflammation of thenasal septum leads to a sinking of this structure, producinga “saddle nose” appearance. Involvement of laryngealand tracheal cartilages may lead to respiratorydifficulty. Rib cartilages may be swollen and tender.Episcleritis or scleritis, iritis, conjunctivitis or keratitismay also be found in relapsing polychondritis. Heart lesionsare characteristically aortic, showing signs of regurgitation.The histology of this affliction is dealt within Chap. 7.8.2.1.5 GoutGout is manifested both as an acute arthritis that is relatedto deposits of urates in the joint capsule, most frequentlyin the big toe joint, and as tophi in non-articulartissues. The external ear is one of the most frequentplaces for the latter and deposits may occur in the helixand antihelix. They may ulcerate, discharging a creamywhite material within which needle-like crystals of sodiumurate may be detected on microscopy. For histology,see Chap. 7.8.2.1.6 OchronosisOchronosis (alkaptonuria) is an inherited disease of themetabolism in which a step in tyrosine metabolism isdisturbed, resulting in accumulation of homogentisicacid in a variety of places, but especially in the cartilages.The substance is colourless in the urine whenfirst passed, but darkens to a black or brown polymeron standing. The disease is inherited as an autosomalrecessive.In the external ear there may be one or both of twomanifestations: (a) dark colour of the wax; when seenin a child this may be the first manifestation of ochronosis;(b) dark colour of the aural cartilage due to thebinding of the homogentisic acid to the cartilage groundsubstance.Fig. 8.2. Idiopathic pseudocystic chondromalacia of the cartilageof the auricle. Note the cystic cavity in the cartilage lined with degeneratedcartilage that has lost its elastic tissue. Normal elastictissue is present further away from the pseudocyst at the left handcorner. Reproduced from Michaels and Hellquist [68]8.2.2 Pseudocysticand Cystic Lesions8.2.2.1 Idiopathic PseudocysticChondromalaciaIdiopathic pseudocystic chondromalacia occurs mainlyin young and middle-aged adults. The gross appearanceis one of a localised swelling of the auricular cartilage. Acut surface shows a well-defined cavity in the cartilage,which is distended with yellowish watery fluid [42]. Microscopically,the cavity shows a lining of degeneratedcartilage on one surface (Fig. 8.2); on the other surfacethe cartilage is normal. It seems possible that the fluid isan exudate from undamaged perichondrial vessels thatcannot be absorbed by the damaged perichondrial vessels.The association of this lesion with severe atopic eczemain four children [27] suggested that minor traumafrom repeated rubbing of the auricle may play a part.Small pseudocysts of the elastic cartilage of the pinnamay also be seen in the vicinity of inflammatory or neoplasticlesions of that region.8.2.2.2 First Branchial Cleft CystA developmental origin from the first branchial cleft hasbeen assumed in some fistulas, sinuses, and cysts arisingin the periauricular and the parotid region and also insome fistulas arising in the neck that are located abovea horizontal plane passing through the hyoid bone. Thecommonest of these lesions is the preauricular sinus.This usually shows a stratified squamous epithelial lining,but occasionally it may be of respiratory epithelium,

Ear and Temporal Bone Chapter 8 239deep to which the connective tissue is chronically inflamed.There is often elastic cartilage in the deep wallof the sinus. Branchial cleft cysts are more extensivelydiscussed in Chap. 9.8.2.3 Tumour-Like Lesions8.2.3.1 ChondrodermatitisNodularis HelicisIn chondrodermatitis nodularis chronica helicis, sometimesknown as Winkler’s disease, a small nodule formson the auricle, usually in the superior portion of the helix.Pain is always a prominent feature.Histological examination of biopsies of such lesionsin which the elastic cartilage underlying the skin of theauricle is particularly well-represented, shows ulcerationof the skin of the auricle and complete necrosis of the tipof the underlying elastic cartilage of the auricle. In somecases a piece of extruded necrotic cartilage may be seenon the floor of the ulcer. The perichondrium of the elasticcartilage in this region shows obstructive thickeningof small arteries.The helix is one of the furthest points from the sourceof the arterial blood supply of the pinna. It seems likelythat obstruction of small arteries of the perichondriumis the primary lesion leading to cartilage necrosis,and that the acute inflammation and epidermal ulcerationare secondary to the nearby cartilage necrosis. Anassociation between chondrodermatitis nodularis helicisand systemic sclerosis has been described [12]. In thiscondition obstructive changes are frequently found insmall arteries.8.2.3.2 Keratosis Obturansand Cholesteatomaof External CanalIn keratosis obturans the keratin produced by exfoliationfrom the skin of the tympanic membrane and externalcanal is retained on the epithelial surface and forms asolid plug. This enlarges and may cause circumferentialerosion of the bony canal. Keratosis obturans is probablythe result of a defect of the normal migratory propertiesof the squamous epithelium of tympanic membraneand adjacent ear canal that causes the accumulation ofkeratinous debris [20]. A minor degree of this process –keratosis of the tympanic membrane – in which depositsof keratin grow on the eardrum and cause tinnitus hasalso been found to be associated with absent or defectiveauditory epithelial migration [103].A condition that has been distinguished from keratosisobturans is cholesteatoma of the external canal. Inthis lesion epidermoid tissue appears to penetrate intothe wall of the deep external canal causing localised osteonecrosisand bone erosion [87].8.2.3.3 Keratin GranulomaA granulomatous process may result in the external earcanal when keratin squames become implanted into thedeeper tissues following traumatic laceration [39]. Thegranuloma contains foreign body-type giant cells, histiocytes,lymphocytes, plasma cells and flakes of keratin.The latter are strongly eosinophilic and birefringentin polarised light. Aural polyps frequently contain suchgranulomas, but the keratin is then more likely to be derivedfrom a middle ear cholesteatoma (see below).8.2.3.4 Angiolymphoid Hyperplasiawith Eosinophiliaand Kimura’s DiseaseSynonyms for angiolymphoid hyperplasia with eosinophiliaare epithelioid haemangioma, benign angiomatousnodules of face and scalp, atypical pyogenic granuloma,and several other terms. Although this entity wasfirst described by Kimura, “Kimura’s disease” is nowbelieved to be a different condition (see below).Angiolymphoid hyperplasia with eosinophilia mayoccur anywhere in the skin, especially on the scalp andface, but there is a particular predilection for the externalauricle and external auditory meatus. It is a lesion ofyoung and middle-aged of both sexes and all races.Grossly, there are sessile or plaque-like red or reddish-bluelesions from 2 to 10 mm in diameter, whichmay coalesce to form large plaques that obstruct the earcanal. On transection the lesion is seen to be presentin the dermis and subcutaneous tissue. Microscopically,there is a mixture of two proliferated elements in thedermis: blood vessels and lymphoid tissue. The bloodvessels are mainly capillaries lined by plump, often protruding(hobnailed) sometimes multilayered, endothelialcells (Fig. 8.3). Occasionally an artery or vein showingintimal fibrous thickening is part of the vascular component.Solid clusters of cells, which are often vacuolated,show features intermediate between endothelial cellsand histiocytes are also observed [6]. The lymphoid tissuemay possess germinal centres. Eosinophils (oftenextremely numerous), mast cells and macrophages mayalso be prominent.Kimura’s disease is commoner in orientals, mainlyaffecting young males. It is a chronic inflammatory conditionof unknown aetiology. It presents as large, deepand often disfiguring, subcutaneous masses in the preauricular,parotid and submandibular regions. Often,there is enlargement of regional lymph nodes. Occasion-

240 L. Michaelsof the oculoauriculovertebral syndrome (Goldenhar’ssyndrome) [49]. The lesion, which may be bilateral, isusually situated anterior to the normal tragus. Like thelatter, the accessory tragus is composed of elastic cartilagewith a covering of skin. In rare cases a similar structurehas been found in the neck [8] or in the suprasternalregion [54].8Fig. 8.3. Epithelioid haemangioma showing “hobnailed” endotheliumof the capillary on the left and lymphocytic infiltrationally, only lymph nodes are involved. There is a peripheralblood eosinophilia and raised levels of IgE.Microscopically, the subcutaneous masses are foundto be composed of lymphoid follicles surrounded by oedematousconnective tissue rich in eosinophils and containingnumerous thin-walled blood vessels resemblinghigh endothelial venules [6]. Infiltration of the germinalcentres with eosinophils and follicle lysis is a frequentfinding, as is the presence of multinucleated cells. Thereis deposition of IgE on the processes of the folliculardendritic cells and there are also numerous mast cells,the latter well shown by immunostaining with IgE mAb.Plasma cells may also be prominent.Diagnostic confusion between angiolymphoid hyperplasiawith eosinophilia and Kimura’s disease is likelyto occur if the characteristic vascular appearances inangiolymphoid hyperplasia with eosinophilia have notbeen recognised and if there is very prominent lymphoidhyperplasia with follicle formation and markedtissue eosinophilia in the latter. In Kimura’s disease theendothelial cells in the proliferating vessels never showan epithelioid/histiocytoid appearance, nor is there anassociated large vessel with intimal thickening. In angiolymphoidhyperplasia with eosinophilia there is neverlymph node enlargement or tissue deposition of IgE.Both epithelioid haemangioma and Kimura’s diseaseare benign entities. Recurrence is rare in the former ifit is completely excised. It is more frequent in the latter,but eventually it becomes stationary. A nephrotic syndromemay rarely occur in Kimura’s disease.8.2.3.5 Accessory TragusAccessory tragus is a fairly common congenital malformationof the external ear. In the majority of cases itis an isolated developmental defect not associated withother abnormalities. It is, however, a consistent feature8.2.3.6 KeloidKeloid, a common benign skin lesion, follows injury tothe skin of the ear, often after piercing the earlobes forwearing an ear-ring. It is particularly frequent in blackpeople. Grossly, there is a lobulated swelling covered innormal skin. Microscopically, the dermis is enlarged bydeposits of eosinophilic, poorly cellular collagen.8.2.4 Benign NeoplasmsExternal ear neoplasms derived from ceruminal glandsare very uncommon. Only the adenoma can usually becategorised with certainty as being derived specificallyfrom ceruminous glands, since its component acini displayan apocrine secretory structure. Syringocystadenomapapilliferum and adenoid cystic carcinoma arisingin this region can sometimes appear to be developingfrom ceruminous glands.8.2.4.1 Adenoma of Ceruminal GlandsICD-O:8420/0Adenomas are unusual neoplasms that present with ablockage of the lateral part of the external auditory meatus,often associated with deafness and discharge. Animportant part of the clinical investigation of all glandularneoplasms of the ear canal is exclusion of an originin the parotid gland.Gross appearances are those of a superficial greymass up to 4 cm in diameter, which is covered in skin.Microscopically this neoplasm lacks a definite capsule.It is composed of regular glands often with intraluminalprojections (Fig. 8.4). The glandular epithelium isbilayered, the outer layer being myoepithelial, but thismay not be obvious in all parts of the neoplasm. Theglands are often arranged in groups surrounded by fibroustissue. In some ceruminomas, acid-fast fluorescentpigment may be found in the tumour cells that issimilar to that found in normal ceruminal glands [15,125].Adenoma of ceruminal glands is a benign neoplasm.Recurrence should not be expected if it is carefully excised.

Ear and Temporal Bone Chapter 8 241Fig. 8.4. Ceruminoma of the external canal. Note peg-like protrusionsinto the lumina, indicating apocrine secretion. Reproducedfrom Michaels and Hellquist [68]Fig. 8.5. Osteoma of the deep external canal. Reproduced fromMichaels and Hellquist [68]8.2.4.2 Pleomorphic Adenomaof Ceruminal GlandsICD-O:8940/0A benign neoplasm of the skin with a structure similarto that of pleomorphic adenoma of salivary glands isalso occasionally seen in the external auditory meatus.Cartilage, myoepithelial and adenomatous structuresare features of this neoplasm.8.2.4.3 SyringocystadenomaPapilliferumof Ceruminal GlandsICD-O:8406/0Syringocystadenoma papilliferum is seen in children oryoung adults usually on the scalp or face. Occasionallyit occurs in the ear canal. The histological appearanceof the neoplasm is that of an invagination from the surfaceepithelium forming a cyst-like structure. Projectinginto the lumen are papillae lined with bilayered glandularepithelium, which may show decapitation secretiontypical of apocrine (ceruminal) glands.8.2.4.4 Bony LesionsBecause of the difficulty of classifying a solitary benignneoplasm composed of woven bone and fibrous tissueinto one or other of the classical groups – monostoticfibrous dysplasia or ossifying fibroma – the designationbenign fibro-osseous lesion (fibrous dysplasia) maybe used in most circumstances without loss of accuracy.Lesions of this type are found in the temporal bone oftenpresenting deep to the external ear [65, 80]. On othersides, this lumping is less appropriate, as discussed inChap. 4.The main clinical features are progressive loss ofhearing, conductive in most, sensorineural, which canbe profound, in some and enlargement of the temporalbone with progressive bony occlusion of the external auditorymeatus. Facial nerve palsy is present in some patientsdue to involvement of the facial nerve by the pathologicalprocess.The gross appearance of benign fibro-osseous lesionsis one of yellowish-white resilient tissue, whichoccasionally includes small cysts filled with an ambercolouredfluid. The transition to normal bone is sharp.Microscopically, irregular trabeculae of woven bone areembedded in a connective tissue stroma. The constrictionof the ear canal may cause an epidermoid cyst lateralto the tympanic membrane, referred to in some publicationsas “cholesteatoma” [65].Although fibrous dysplasia has been on rare occasionsassociated with malignant disease such as osteogenicsarcoma, fibrosarcoma, chondrosarcoma and giantcell tumour, the temporal bone is not one of the siteswhere this change has been described.Osteoma and exostosis are two types of benign bonyenlargement of the deeper bony portion of the externalauditory canal. Osteoma is a spherical mass arising fromthe region of the tympanosquamous or tympanomastoidsuture line by a distinct bony pedicle. Symptoms areusually those of ear canal obstruction. Microscopically,the osteoma is composed of lamellar bone and may showouter cortical and inner cancellous trabeculated areas,the latter with marrow spaces. There may be a thin layerof woven bone on the surfaces of the lamellar bone. Theosteoma is covered in the normal squamous epitheliumof the ear canal (Fig. 8.5).Exostosis is a broad-based lesion, which is often bilateraland symmetrical. It is usually situated deeperin the ear canal than osteomas. In the bony portionof the normal external auditory meatus there are noadnexal structures, and the subcutaneous tissue and

242 L. Michaels8.2.5 Malignant Neoplasms8Fig. 8.6. Exostosis of the deep external canal. Note thin epidermallayer on the exostosis and canal skin and their proximity tothe bone. Reproduced from Michaels and Hellquist [68]periosteum merge to form a thin layer. The distancebetween the epidermal surface and underlying bone isconsequently small. This explains the propensity towardsexostoses of the tympanic bone to develop inthis region in those who swim frequently in cold water.It seems likely that the water, after dribbling intothe deep external auditory canal, exerts a cooling effecton the bone surface and stimulates it to producenew bone. Unlike osteoma (Fig. 8.5) the bone formationsof exostosis are said not to possess any marrowspaces (Fig. 8.6).Osteoma and exostosis are often associated with infectionof the external canal on their tympanic membraneside and surgical removal may be required to enhancedrainage as well as to relieve the conductive hearingloss.Five cases of a benign circumscribed bony lesion ofthe external auditory canal distinct from exostosis andosteoma have recently been described [91]. They allshowed a hard, round, unilateral, skin-covered mass occludingthe superficial external auditory canal with norelationship to the cartilaginous tissue or to the bonystructure surrounding that canal. Histologically, thelesion displayed an osteoma-like bone formation withsparse osteoblastic areas; mature lamellar bone was observedsome cases, and also bone marrow containingadipose tissue and hematopoietic remnants. The boneshowed irregular trabeculae, bordered by osteoid osteoblasts.8.2.5.1 Adenocarcinomaof Ceruminal GlandsICD-O:8420/3Adenocarcinoma of ceruminal glands is a rare neoplasmpresenting in the superficial part of the external ear canal.There is always local infiltration. The neoplasmpossesses a glandular structure with evidence of apocrinedifferentiation, but the glands show loss of a myoepitheliallayer and the cells are markedly atypical withincreased mitotic activity. Recurrence is to be expectedfollowing surgical removal. Death due to involvement oflocal vital structures has been reported. Rare examplesof low-grade adenocarcinoma of ceruminal glands havebeen documented.8.2.5.2 Adenoid Cystic Carcinomaof Ceruminal GlandsICD-O:8200/3This malignant neoplasm has the gross and microscopicfeatures of the corresponding major or minor salivarygland neoplasm, including its tendency to invade alongnerve sheaths. Relentless though often delayed recurrenceand eventual bloodstream metastasis, particularlyto the lungs, are likewise features of this cancer.8.2.5.3 Basal Cell CarcinomaICD-O:8090/3The great majority of malignant epithelial neoplasmsof the pinna are basal cell carcinomas, a small numberonly being squamous cell carcinomas. The few basal cellcarcinomas that occur in the ear canal arise near the externalopening. Their preference for the exposed part ofthe external ear is in keeping with the accepted view thatsunlight is in most cases the causal factor in skin insufficientlyprotected by melanin pigment.The gross appearance of basal cell carcinoma is usuallyone of a pearly wax-like nodule that eventually ulcerates.Twenty-five per cent of basal cell carcinomas ofthe pinna are of the morphea type (see below). The importanceof this variety is that although the edge of thetumour tends to infiltrate subcutaneously, this cannotbe recognised clinically or on gross pathological examination.The classical and most frequent form of basalcell carcinoma is composed of solid masses of cells,which are seen to be arising from the basal layers of theepidermis or the outer layers of the hair follicles. Thecells are uniform with basophilic nuclei and little cy-

Ear and Temporal Bone Chapter 8 243Fig. 8.7. Morphea type of basal cell carcinoma showing thindowngrowths with stroma of inflammatory connective tissue. Reproducedfrom Michaels and Hellquist [68]toplasm. At the periphery of the neoplastic lobules thecells tend to be palisaded. Mitoses are frequent as are alveolaror cystic spaces. Squamous cell differentiation isalso common.The splitting up of cell groups by much hyaline fibroustissue, so that the carcinoma appears compressedinto thin strands, is referred to as the morphea type ofbasal cell carcinoma (Fig. 8.7). The suggestion that tumourswith this histology have a worse outlook is probablyrelated to their tendency towards insidious infiltration(see above). There is otherwise no convincingevidence of the relationship of a particular histologicalappearance to prognosis in basal cell carcinoma.However, when immunohistochemical assessment forKi-67 antigen (MIB1 in paraffin sections), a proliferation-associatedantigen, is performed on basal cell carcinomas,those tumours that recur have been shown topossess a higher proportion of cells positive for that antigenthan those that do not [40]. The degree of tumourangiogenesis is another histologic factor that showspromise in judging the prognosis of basal cell carcinoma[107].This is not an aggressive neoplasm and in at least 90%of cases a 3-year cure can be easily achieved by surgicalexcision. In a few cases repeated recurrences with deepextension to the middle ear, mastoid and even cranialcavity may, however, take place. Metastasis is rare.Pinna lesions in a prominent position are identifiedearly. A serious problem with the canal lesions is the delayin diagnosis because of the minimal symptoms thatmay be present. Pain, hearing loss and drainage of bloodor pus are the main features in that group. A plaque-likeor even polypoid mass may be felt or even seen.Squamous carcinomas arising on the pinna grosslyresemble those seen elsewhere on the skin. The appearancesof the canal lesions are those of a mass, sometimeswarty, occluding the lumen and invading deeply intothe surrounding tissues. There may be dissolution of thetympanic membrane with invasion of the middle ear.Squamous cell carcinoma of the external ear usuallyshows significant degrees of keratinisation. In thecases with a canal origin evidence of origin from canalepidermis is usually present. In cases arising deepwithin the ear canal there is usually a concomitant originfrom middle ear epithelium and dissolution of thetympanic membrane (see below). The neoplasm may beso well differentiated that it can be confused with benignpapilloma. The association of a well-differentiatedsquamous carcinoma with marked desmoplasia mayalso delay the correct diagnosis. The verrucous form ofsquamous cell carcinoma has been seen in the externalear [105]. Metastatic spread of squamous carcinomaof the pinna and external auditory meatus to lymphnodes is unusual. Squamous carcinoma of the externalcanal is an aggressive disease with a high propensitytowards local recurrence. The outcome of the diseasefollowing surgical excision is related to the clinicalstage at presentation; the higher the stage the worsethe outcome [83].8.2.5.5 Melanotic NeoplasmsMelanotic neoplasms are unusual in the external ear.Nevi arise mainly in the ear canal, but are rare on theauricle. Malignant melanomas, on the other hand usuallyarise on the auricle; origin in the external canal isextremely unusual [72]. Malignant melanoma of the externalear is a highly malignant disease. In a review of 16patients with this condition as many as 9 cases showedinvasion to Clark level IV or more [22]. It is likely thatcervical and parotid gland lymph nodes will be involvedwhen malignant melanoma of the external ear is firstdiagnosed [99].8.2.5.4 Squamous Cell CarcinomaICD-O:8070/3The majority of squamous cell carcinomas of the externalear arise in the pinna; a lesser number arise in theexternal canal.

244 L. Michaels88.3 Middle Earand Mastoid8.3.1 Inflammatory Lesions8.3.1.1 Acuteand Chronic Otitis MediaOtitis media is one of the most common of all diseases,particularly in young children. The disease is usuallycaused by bacterial infection, Haemophilus influenzaeand Gram-positive cocci usually being incriminated inthe acute form and Gram-negative bacilli in the chronicform. The clinical forms of the acute and chronic conditionscorrespond to the pathological changes, but intermediateor mixed states are frequent. Perforation ofthe tympanic membrane may occur at any phase of otitismedia, but an effusion, accompanied by all of the othermanifestations of chronic otitis media, is often presentbehind an intact tympanic membrane, a conditionknown as serous otitis media.The appearances of the middle ear mucosa in acute otitismedia may be seen in the bone chips removed at mastoidectomy.There is congestion and oedema of the mucosaof the mastoid air cells. Haemorrhage may be severeand the mucosa and air cells are filled with neutrophils.Pus destroys bone, the actual dissolution being carriedout by osteoclasts. At the same time new bone formationtakes place, commencing as osteoid, later becoming wovenand finally lamellar. Fibrosis may also be active evenin the acute stage. Acute inflammatory changes are alsoprominent in other parts of the middle ear. The tympanicmembrane shows marked congestion, the dilated vesselsdistending the connective tissue layer. Pus cells fill themiddle ear cavity. The acute inflammation may spreaddeep into the temporal bone as osteomyelitis.The chronic form of otitis media is associated withnecrosis, caused by the bacterial infection. There is, as inthe acute form, marked congestion. The latter results inhaemorrhage in many cases. Because of the poor lymphdrainage in the middle ear old haematoma becomesconverted into cholesterol granuloma, with cholesterolclefts surrounded by foreign body-type giant cells, andhaemosiderin.Associated with these changes and representing animportant part of the pathological picture, is proliferativeactivity of middle ear tissue. The columnar epitheliumof the middle ear has, in the presence of inflammationor other pathological changes in the middle ear,the remarkable property of invaginating itself to produceglands, which often develop luminal secretion.The glandular transformation of the middle ear mucosa,known as glandular metaplasia, may be seen in anypart of the cleft, including the mastoid ear cells. The secretionof the glands contributes to the exudate in otitismedia with effusion. Fibrous tissue proliferation mayalso occur in combination with glandular transformation– a process which, in the advanced state, has beencalled “fibrocystic sclerosis” [95].A specific form of reparative reaction following inflammationis the development of granulation tissue. Inthis process, the endothelium of blood vessels and fibroblastsare the newly formed cells. Mononuclear inflammatorycells usually accompany the latter. The granulationtissue is usually particularly prominent in the middleear under the mucosa covering the promontory fromwhich it frequently protrudes into the external canalthrough a perforation of the tympanic membrane, formingan aural polyp that is covered in pseudostratified columnar,ciliated respiratory or stratified squamous epithelium.Fibroblasts and collagen are abundant in theterminal phase of the reparative stage.A normal degree of fibroblast cellularity in the fibrousreaction is seen in adhesive otitis media. A peculiar form ofscar tissue production occurs in the middle ear, in whichthe collagen is poorly cellular and hyalinised. This condition,known as tympanosclerosis, is also characterised bydeposition of calcium salts in the hyaline fibrous tissue.The bony walls of the middle ear also frequently react tothe inflammatory process with a new formation of bone.This is woven in the early stages and lamellar later.8.3.1.2 CholesteatomaCholesteatoma is the presence of stratified squamousepithelium in considerable quantities in the middle ear.The common acquired form of cholesteatoma is associatedwith severe otitis media.Stratified squamous epithelium in the normal foetalmiddle ear: small colonies of cells being epidermoidin nature as confirmed by immunohistochemistryare found near the tympanic membrane on the lateralanterior superior surface of the middle ear in everytemporal bone after 15 weeks’ gestation. These epidermalcolonies, which are known as “epidermoid formations”,increase significantly in size with increasing age andpari passu undergo increasing epidermoid differentiation[58]. During the first postpartum year these epidermoidformations disappear. It is possible that the entryand growth of epidermoid formations in the foetal middleear may lead to a local cellular immunity as a defencemechanism against the entry of keratinocytes into themiddle ear. This could cause the eventual dissolutionof all epidermoid formations. If immunity is delayed ordefective epidermis could continue to grow and lead tocongenital cholesteatoma.Stratified squamous epithelium in the middle ear of ayoung child (congenital cholesteatoma): congenital cholesteatomais seen, in most cases as a spherical whitish

Ear and Temporal Bone Chapter 8 245object in the anterosuperior part of the tympanic cavitybehind an intact tympanic membrane (Fig. 8.8). In somecases the lesion may fill most of the tympanic cavity. Atoperation the cholesteatoma is reported usually to be acyst in the anterosuperior part of the middle ear. Boneerosion is not present when the cholesteatoma is small.In larger lesions some degree of this change is present[61] and eventually it may enlarge to involve the mastoid,cause a perforation of the tympanic membrane andeven grow into the middle cranial fossa [34] so that itbecomes indistinguishable from acquired cholesteatoma(see below). Indeed, it is possible that many cases ofacquired cholesteatoma originated from congenital cholesteatoma.In approximately 10% of cases the cholesteatoma isnot cystic, but open and shows layers of squames and amatrix (living basal and malpighian layers of epidermis)that is plastered to the wall of the tympanic cavity [19].The microscopic appearances of the matrix of congenitalcholesteatoma are those of skin epidermis, comprisinga single row of basal cells, several rows of malpighiancells and a thin granular layer. The surface of dead, keratinoussquames merges with the keratinous contents ofthe cyst, or lamellae in the case of the open type. Whenthe histological appearance of these cases is comparedwith that of acquired cholesteatoma, little difference canbe seen.Stratified squamous epithelium in the middle ear ofan older child or adult, acquired cholesteatoma: typicallyin acquired cholesteatoma a lesion far more commonthan that of congenital cholesteatoma, the patientpresents with a foul-smelling aural discharge and conductivehearing loss. On examination of the tympanicmembrane there is, in most cases, a perforation of thesuperior or posterosuperior margin. The cholesteatomaappears as a pearly grey structure in the middle ear cavity.The wall of the cyst may often be seen as a thin membrane.The cholesteatoma is usually situated in the upperposterior part of the middle ear cleft and dischargesusually through a perforation of the pars flaccidaof the tympanic membrane, sometimes through aperforation located at the edge of the tympanic membranenear the annulus. The cholesteatoma may extendthrough the aditus into the mastoid antrum and mastoidair cells. Frequently, the outline of the cholesteatomatoussac is adapted to that of normal structuressuch as ossicles. Chronic inflammatory changes are alwayspresent. In most cases at least one ossicle is seriouslydamaged, thus interrupting the continuity of theossicular chain. The scutum, the upper part of the bonyring of the tympanic opening, is eroded in most cholesteatomas.Under the microscope acquired cholesteatoma isusually “open” rather than “closed” or cystic. The pearlyFig. 8.8. Congenital cholesteatoma seen as a small cyst in the anterosuperiorpart of the middle ear. Reproduced from Michaelsand Hellquist [68]Fig. 8.9. Acquired cholesteatoma showing keratinising stratifiedsquamous epithelium with a granular layer. Reproduced from Michaelsand Hellquist [68]material of the cholesteatoma consists of dead, fully differentiatedanucleate keratin squames. This is the corneallayer of the squamous cell epithelium. As in any normalstratified epithelium there are one to three basal layersof cells above which is a prickle (malpighian or spinous)layer composed of five or six rows of cells withintercellular bridges (Fig. 8.9).The deeper layers of the epithelium of the cholesteatomamatrix frequently show evidence of activity in theform of downgrowths into the underlying connectivetissue (Fig. 8.10). Such excessive activity has been confirmedby:1. The strong expression of cytokeratin 16, a marker forhyperproliferative keratinocytes, by cholesteatoma,but its absence in middle ear and external ear epithelium,except in the annulus region of the externaltympanic membrane epithelium [13];

246 L. Michaels8Fig. 8.10. Acquired cholesteatoma showing downgrowths fromthe deeper layer of cholesteatoma epithelium2. The strong expression of MIB1, an antigen related toKi-67, which also indicates hyperproliferative activity[113];3. Counts of silver-stained argyrophil nucleolar organiserregions, a technique that likewise displaysproliferative activity, showed significantly largernumbers of these structures in the nuclei of acquiredcholesteatoma compared with those of theepidermis of the deep external auditory meatal skin[115];4. Acquired cholesteatomatous epithelium shows anabnormally high concentration of IL-1, TGF-alpha,EGF-R and 4F2, all being growth factors [114] indicatinggreater growth and differentiating activitythan is present in normal epidermis.Congenital cholesteatoma probably arises due to thecontinued growth of the epidermoid formation. Thisstructure is derived from external ear epidermis (seeabove). It seems likely that acquired cholesteatoma isalso derived from entry of external ear canal epidermisinto the middle ear. This is clearly shown in those casesof acquired cholesteatoma that follow blast injury withperforation of the tympanic membrane at the time ofthe injury [56]. Acquired cholesteatoma is also knownto follow the retraction pocket of the tympanic membrane.This is not due to obstruction of the mouth of aretraction pocket, but rather, it seems, to the ingrowthof a band of stratified squamous epithelium from thefundus of the retraction pocket deeply into the middleear (Fig. 8.11) [122]. A similar entry of stratifiedsquamous epithelium from the external ear epidermisthrough the tympanic membrane may sometimes beobserved in human temporal bone sections in cases ofsevere otitis media (Fig. 8.12). The placement of irritantsor bacteria into the middle ear cavity of animalsFig. 8.11. The fundus of a retraction pocket is seen in the top righthand part of the illustration. Emanating from it and passing downto the bottom centre is a band of stratified squamous epithelium,within which is a bluish staining zone of stratum granulosum andkeratin – a “mini-cholesteatoma”. An ossicle lies to the right of theepidermal band. It is an eroded incus, damage to which has probablybeen caused by previous otitis mediaFig. 8.12. A thin strand of stratified squamous epithelium is seenpassing from the epidermis of the tympanic membrane towardsthe middle ear epithelium, almost touching it. To the left of thisepidermal band the middle collagenous layer of the eardrum isdistorted by a deposit of tympanosclerosis, composed of partiallycalcified hyaline collagenhas been known to provoke an otitis media that is associatedwith epidermal invasion through the tympanicmembrane with the subsequent development of cholesteatoma.In chinchillas, destruction of the epitheliumof both middle ear and lateral tympanic membranesurfaces takes place in the early stages of such an artificialacute otitis media, induced by insertion of propyleneglycol into the middle ear. This is followed by reepithelialisationwith hyperplastic epidermal cells andthen penetration of the thickened fibrous layer of thetympanic membrane by the epidermal cells to reachthe middle ear cavity and the formation of keratinousmasses in the middle ear typical of cholesteatoma [60,127].

Ear and Temporal Bone Chapter 8 2478.3.1.3 Unusual Inflammatory LesionsTuberculous otitis media is an unusual form of chronicotitis media, which is generally associated with activepulmonary tuberculosis. In the initial stages multipleperforations of the tympanic membrane develop.Granulations in the middle ear may appear pale andare often profuse. Complications, especially involvementof the facial nerve, are more frequent than in thecommoner form of chronic otitis media. The diagnosisis usually made by histopathological examination ofbiopsy material from middle ear contents. This is oftendelayed because surgeons are reluctant to take biopsiesfrom cases of chronic otitis media that seem fairly typical.Culture of middle ear inflammatory tissue may producetubercle bacilli. Histological examination showstuberculoid granulation tissue composed of epithelioidcells, Langerhans giant cells and areas of caseation situatedin the middle ear mucosa. There is much bone destruction.Acid-fast bacilli are found with difficulty inthe granulomatous material.8.3.2 Neoplasmsand Lesions ResemblingNeoplasms8.3.2.1 Choristoma(Salivary Gland, Glialand Sebaceous Types)A hamartoma is a focal overgrowth, in improper proportions,of tissues normally present in that part of thebody. A choristoma is similar to hamartoma, exceptthat the tissues of which it is composed are not normallypresent in the part of the body where it is found.Choristomas are occasionally seen in the middle ear.They are composed of one or other of three types oftissue: salivary gland, glial or sebaceous glandular tissue.Salivary gland choristomas consist as a rule of mixedmucous and serous elements like the normal submandibularor sublingual gland, but unlike the parotidgland. The lesion typically consists of a lobulated massof histologically normal salivary gland tissue in the middleear attached posteriorly in the region of the oval window.Frequently, the mass is intimately associated withthe facial nerve. There are usually absent or malformedossicles [44].Glial choristomas are composed largely of astrocyticcells with large amounts of glial fibrils, the identityof which may be confirmed by immunohistochemicalstaining for glial acidic fibrillary protein. When suchmasses are identified in biopsy material from the middleFig. 8.13. Adenoma of the middle ear. Reproduced from Michaelsand Hellquist [68]ear a bony deficit with consequent herniation of braintissue into the middle ear should be ruled out [53]. Threecases of heterotopic brain tissue in the middle ear associatedwith cholesteatoma have been reported [62]. It ispossible that in all three, brain herniation occurred as aresult of inflammatory damage to the tegmen tympani.Spontaneous herniations of brain (encephaloceles) mayoccur into the middle ear through a congenital deficiencyof the tegmen or other sites [47].A case of sebaceous choristoma of the middle ear hasbeen described [82].8.3.2.2 AdenomaICD-O:8140/0Adenoma is the commonest neoplasm of the middle ear.The epithelium of the middle ear has a propensity towardsgland formation in otitis media (see above) andadenoma would seem to represent a benign neoplastictransformation of the epithelium along the same lines.The neoplasm has been described as being white, yellow,grey or reddish brown at operation and unlike paragangliomais usually not vascular. It is usually situatedin the middle ear cavity, sometimes extending into themastoid. It seems to peel away from the walls of the surroundingmiddle ear with ease, although ossicles maysometimes be entrapped in the tumour mass and mayeven show destruction.Adenoma is formed by closely apposed small glandswith a “back to back” appearance (Fig. 8.13). In someplaces a solid or trabecular arrangement is present.Sheet-like, disorganised areas are seen in which theglandular pattern appears to be lost. This may be artefactualand related to the effects of trauma used intaking the biopsy specimen on the delicate structure ofthe cells, but the appearance may erroneously lead oneto suspect malignancy. The cells are regular, cuboidalor columnar and may enclose luminal secretion. A dis-

248 L. Michaels8tinct and predominant “plasmacytoid” appearance ofthe epithelial cells of the neoplasm may be displayed[92].No myoepithelial layer is seen. PAS and Alcian bluestains may be positive for mucoprotein secretion in thegland lumina and in the cytoplasm of the tumour cells.Benign glandular tumours of the middle ear were notdescribed until 1976 [26, 45]. It was soon reported that aglandular tumour of the middle ear, otherwise apparentlyidentical to an adenoma, was Grimelius positive andon electron microscopy, showed numerous membraneboundgranules [75]. The use of immunohistochemistryfrom 1987, further confirmed the presence of neuroendocrinefeatures in some of these neoplasms [108]. In an investigationof five cases of adenoma of the middle ear bylight microscopic methods, immunohistochemistry andtransmission electron microscopy, the glandular areas ofthe tumour in each patient showed bidirectional mucinousand neuroendocrine differentiation. This was demonstratedby the presence of two cell types. Apically situateddark cells contained mucous granules; these cellswere negative for neuroendocrine markers. Basally situatedcells contained neuroendocrine granules; these cellswere positive for neuroendocrine markers – vasoactiveintestinal polypeptides or neuron-specific enolase [120].It seems likely that there is but a single benign glandularneoplasm of the middle ear, the adenoma. Neuroendocrineas well as mucinous differentiation is frequent,perhaps universal, in these neoplasms. Contraryto what has been suggested by some authors there is noevidence that the presence of neuroendocrine differentiationreflects a more aggressive potential in adenomas,which are benign tumours.8.3.2.3 Papillary TumoursFig. 8.14. Aggressive papillary tumour of the middle earICD-O:8260/0, 8260/3Aggressive papillary tumour is characterised by a papillary,non-stratified epithelial histological pattern thatshows aggressive, often invasive behaviour. Forty-sixcases in which the temporal bone was affected by thisneoplasm were collected from the literature in 1994 [31].Some of these had been reported as low-grade adenocarcinomaof probable endolymphatic sac origin (seebelow and also Sect. 8.4.2.3) [41]. I have reviewed eachof the case reports cited in these two studies togetherwith cases reported in the literature more recently, andthis has produced a total of 25 cases in which the middleear was definitely involved in the neoplasm. Some of theliterature sources reported more than one case [1, 9, 10,21, 31–33, 35, 38, 41, 50, 86, 88, 109, 111, 118].The 25 literature cases with this middle ear neoplasmcomprised 18 females and 7 males. The age-range at timeof diagnosis was between 16 and 55 years with a medianage of 33 and a mean age of 34 years. In many of the cases,however, the patient had already suffered symptomssubsequently ascribable to the tumour for some yearswhen the diagnosis was made, so that the age of onsetmay be considerably younger than is suggested.The tumour is found in any area of the middle ear,including the mastoid process and air cells and may fillthe tympanic cavity. In all of the described cases, exceptthree [21, 109, 118], there was extensive invasion outsidethe middle ear, involving the apical portion of the petrousbone in most and in a few the tumour reached thecerebellopontine angle and the cerebellum.It has been suggested that cases of aggressive papillarymiddle ear tumour with widespread involvement ofthe temporal bone may arise from a primary papillaryadenocarcinoma of the endolymphatic sac (endolymphaticsac tumour, low-grade adenocarcinoma of probableendolymphatic sac origin) [41]. The frequent associationof papillary tumours in the middle ear with apicalpetrous bone neoplasia of the same type, the similarityof the histological appearances of the neoplasmin the two regions and the association of some cases ofpapillary tumours in both regions with von Hippel-Lindaudisease would seem to favour this concept. Such anorigin has not yet been confirmed by autopsy study. Indeed,in the single description of the pathological changesof aggressive papillary tumour of the middle ear in anautopsy-acquired temporal bone, widespread depositsof tumour at inner ear sites are depicted, but no mentionis made of involvement of the endolymphatic sacor duct [100]. Thus, a middle ear origin for some casesof this neoplasm at least has not been definitely excluded.Whatever the site or sites of origin of this tumour, itshould be recognised that papillary epithelial tumour ofthe middle ear is an aggressive neoplasm, in contrast tothe non-papillary adenoma of the middle ear, which isquite benign [73].In view of the association of some cases of von Hippel-Lindaudisease with aggressive papillary middle eartumours it is suggested that the clinical assessment of

Ear and Temporal Bone Chapter 8 249each case with the latter neoplasm should include an investigationof the gene mutations of von Hippel-Lindaudisease.In most cases of this neoplasm, clinical and audiologicalfeatures point to a middle ear lesion. Suspicionof a neoplasm of the middle ear is enhanced by the otoscopicfeatures.The middle ear cleft, including the mastoid air cells,is usually filled with the papillary tumour. Bone invasionis often seen. A papillary glandular pattern is presentwith complex interdigitating papillae lying looselyor infiltrating fibrous connective tissue. The papillae arelined with a single layer of low cuboidal to columnar epithelialcells with uniform nuclei, eosinophilic cytoplasmand indistinct cell borders (Fig. 8.14). Thyroid folliclelikeareas may be present similar to those seen in endolymphaticsac carcinoma (see below).Markers for cytokeratin, epithelial membrane antigenand S-100 are positive. The absence of thyroglobulinmust be determined to exclude metastatic papillarycarcinoma of the thyroid. Markers for CK 7, CK 20 andcarcinoembryonic antigen may also be useful to excludemetastatic deposits from lung and colon.Schneiderian papillomas (ICD-O:8121/0) are tumoursof the nose and paranasal sinuses that are statedto be derived from the Schneiderian epithelium, a termused to denote the normal respiratory-type ciliated epitheliumof the nose and paranasal sinuses. Three typesof such papillomas are described: inverted (endophytic),exophytic (fungiform, everted) and oncocytic (cylindriccell). Intermediate types are said to be found amongthe three forms [73]. It has, however, been denied thatsuch intermediate forms exist and it is suggested that thethree types are each separate and distinct entities of thenose and paranasal sinuses [71]. Of the three histologicalforms only inverted papilloma is characteristcally asinonasal neoplasm. The other two types of Schneiderian-typepapilloma may be seen at other sites. Low-gradesquamous carcinoma in the nose may sometimes bemistaken for inverted papilloma [67].Fourteen cases of middle ear tumours purportedlyresembling Schneiderian-type papilloma have beenfound in the literature. Each of these cases is listed inTable 8.1; wherever possible the histological appearancesare summarised in the table. In some insufficient orno histological description was given. In two cases onlywere the features of inverted papilloma depicted: inCase 1 the term “inverted” and in Case 2 the term “endophytic”were used to describe the neoplasm. “Inverted”or “endophytic” features comprised only a portionof the tumours in the two cases. In Case 2 [52] the termtransitional cell papilloma was used. This is a term thathas been frequently applied to describe everted squamouscell papilloma. In this case inverted papillomawas found in the nasal cavity and it was suggested thatthe papillomas may have spread from there to the middleear by way of the Eustachian tube. In Cases 1, 4 and10 inverted papilloma was found in the middle ear concomitantlywith in situ or invasive squamous carcinomaand it seems possible that the inverted papilloma areasmight have been, in reality, areas of low-grade squamouscarcinoma.I would suggest that a good case has not been madefor the occurrence of inverted papilloma in the middleear. Some of the lesions may have been papillomas ofthe middle ear as described above. In Case 2 an invertedpapilloma could conceivably have colonised the middleear from the nasal cavity. Further detailed descriptionsof the entity are required to justify the diagnosis of sucha diagnostic category in this situation.8.3.2.4 JugulotympanicParagangliomaICD-O:8690/1Most jugulotympanic paragangliomas arise from theparaganglion situated in the wall of the jugular bulb.These tumours have been referred to as jugular paragangliomasor glomus jugulare tumours. A minorityarise from the paraganglion situated near the middleear surface of the promontory. These tumours have beenreferred to as tympanic paragangliomas or glomus tympanicumtumours. The distinction between jugular andtympanic paragangliomas can easily be made in the patientby modern imaging methods by which the jugularneoplasm is identified as arising from the jugular bulbregion and shows evidence of invasion of the petrousbone, while the tympanic neoplasm is confined to themiddle ear.The gross and histological appearances of the twotypes of neoplasm in the middle ear are, however, identical.Solitary jugulotympanic paragangliomas arisepredominantly in females. The neoplasm has beenseen at ages between 13 and 85 years with a mean age ofabout 50 years. Most patients present with conductivehearing loss. Pain in the ear, facial palsy, haemorrhageand tinnitus are also described as symptoms of this lesion.On examination a red vascular mass is seen eitherbehind the intact tympanic membrane or sproutingthrough the latter into the external canal. Surgicalapproach to the mass at biopsy often results in severebleeding.Jugulotympanic paragangliomas may also be multicentricor coexist with tumours of other types. Theymay be bilateral in the same patient and coexist withcarotid body paragangliomas that may be bilateral[84]. They may also coexist with adrenal gland pheochromocytomas,which can produce hypertension. Afamilial tendency to grow paragangliomas has beennoted particularly in cases with multiple tumours ofthis type. In families containing patients with head

250 L. MichaelsTable 8.1. Schneiderian-type or inverted papillomas of the middle ear described in the literatureCasenumberLiteraturesourceHistological description givenPossible alternative diagnosis81 [110] “Inverted papilloma” and high-grade carcinoma Squamous cell carcinoma ofthe middle ear2 [52] “Transitional cell papilloma”Inverted papilloma in noseInverted papilloma derivedfrom a nasal tumour3 [93] Entirely papillary Papilloma of the middle ear4 [98] Malignant change in inverted papilloma Squamous cell carcinomaof the middle ear5 [124]Case 16 [124]Case 27 [124]Case 38 [124]Case 49 [124]Case 5“Epidermoid papilloma” with “inverted” and “cylindriccell papilloma”“Epidermoid papilloma” with exophytic and endophyticgrowth“Epidermoid papilloma” with features of “cylindric cellpapilloma”“Epidermoid papilloma” with features of “cylindric cellpapilloma”“Epidermoid papilloma” with features of “cylindric cellpapilloma”Papilloma of the middle earPapilloma of middle earPapilloma of the middle earPapilloma of the middle earPapilloma of the middle ear10 [51] Squamous epithelium with areas of carcinoma in situ Squamous carcinoma ofthe middle ear11 [17] Papillary with areas of squamous epithelium adjacent to Papilloma of the middle earrespiratory epithelium12 [90]None ?Case 113 [90]?Case 214 [11]Two casesInsufficient description ?and neck, including jugulotympanic, paragangliomasthere is, unlike the solitary jugulotympanic paraganglioma,a preponderance for the male sex and inheritanceis autosomal dominant, with increased penetrancewith age [5]. There is evidence from moleculargenetic studies that the gene underlying familial paragangliomasis located on chromosome 11q proximal tothe tyrosinase gene locus [59].The neoplasm is a reddish sprouting mass at its externalcanal surface. In the jugular variety the petroustemporal bone is largely replaced by red, firm materialand the middle ear space is occupied by soft neoplasm asfar as the tympanic membrane. The otic capsule is rarelyinvaded by paraganglioma. Investigation of a paragangliomain an autopsy temporal bone by the microslicingmethod showed the origin of the tumour to be inthe jugular bulb region and its spread through the petrousbone and middle ear to the tympanic membrane(Fig. 8.15). The histology of paraganglioma is describedin Chap. 9 (Fig. 8.16) [55].The incidence of clinically functioning paragangliomawith symptoms and signs of norepinephrine excess,particularly hypertension, is only 1–3% [97].Jugulotympanic paraganglioma is a neoplasm of slowgrowth. The jugular variety infiltrates the petrous bone,but distant metastasis is rare. Radiation therapy, and insome cases surgery, offers a high rate of cure for theseneoplasms and the number of patients who do badly aftersuch therapy is very small.8.3.2.5 Squamous Cell CarcinomaICD-O:8070/3Squamous cell carcinoma is uncommon in the middleear. It sometimes accompanies squamous cell carcinomaof the external canal or may arise solely from themiddle ear epithelium. The patient always has an auraldischarge and conductive hearing loss. Pain in the ear,bleeding and facial palsy are common.

Ear and Temporal Bone Chapter 8 251Fig. 8.15. Microsliced specimen of jugular paraganglioma removedat autopsy. Two slices of the temporal bone in the regionof the neoplasm are seen. The one on the left shows invasion ofthe temporal bone by the reddish paraganglioma from its apicalregion as far as the tympanic membrane. The slice on the right istaken at a higher level and shows sparing of the cochlea and bonylabyrinth by the tumourIn microscopic sections the tumour may be seen arisingfrom surface stratified squamous epithelium, itselfmetaplastic from the normal cubical epithelium.In certain areas an origin directly from basal layers ofcubical or columnar epithelium may be seen. There isno evidence that the epidermoid formation, a cell restthat occurs normally in the middle ear during development(see above), may be a source of squamous cell carcinoma.The neoplasm is squamous cell carcinoma withvariable degrees of differentiation. Atypical change andeven carcinoma in situ may be seen in some parts of themiddle ear epithelium adjacent to the growth. The modeof spread of the neoplasm from the middle ear epitheliumhas been ascertained in temporal bone autopsy sections[70] and this pattern has been confirmed by imagingin living patients. The carcinoma tends to growinto and erode the thin bony plate that separates the medialwall of the middle ear, at its junction with the Eustachiantube, from the carotid canal. This bony wall isnormally up to 1 mm in thickness and may be recognisedradiologically. Having reached the carotid canalthe growth will extend rapidly along the sympatheticnerves and the tumour is then impossible to eradicatesurgically. Another important method of spread isthrough the bony walls of the posterior mastoid air cellsto the dura of the posterior surface of the temporal bone.From there it spreads medially, enters the internal auditorymeatus and may then invade the cochlea and vestibule.Spread into the lamellar bone in both of these situationsis along vascular channels between bone trabeculae.A similar type of bone invasion may also occur fromother parts of the middle ear surface such as in the regionof the facial nerve. The special bone of the otic capsuleis, on the other hand, peculiarly resistant to directspread of growth from tumours within the middle ear,and even the round window membrane is not invaded.When invasion does occur it takes place after entry ofthe tumour into the internal auditory meatus and penetrationof the bone by way of the filaments of the vestibularand cochlear divisions of the eighth nerve. In thelater stages tumour grows extensively in the middle cranialfossa; it may also invade the condyle of the mandible.Death is usually due to direct intracranial extension.Lymph node metastasis is unusual and spread bythe bloodstream even more so [70].8.3.2.6 MeningiomaFig. 8.16. Jugular paraganglioma. The cells form small clusters,each surrounded by a row of flattened cells, probably sustentacularcells, and separated by blood vesselsICD-O:9530/0Meningioma is a benign tumour that usually growsintracerebrally, but is sometimes seen involving bonystructures around the brain including the middle ear.It arises from the pia-arachnoid cells of the meninges.These structures may be formed at a number of sites inthe temporal bone, including the internal auditory meatus,the jugular foramen, the geniculate ganglion regionand the roof of the Eustachian tube. Thus, meningiomasthat arise from them may be found in a wide area withinthe temporal bone itself [78].Meningioma of the middle ear affects females morethan males, shows an age range of between 10 and80 years (with a mean age of 49.6 years), with female patientspresenting at an older age (mean 52.0 years) thanmale patients (mean, 44.8 years) [116].The commonest temporal bone site for primary meningiomais in the middle ear cleft. In a recent study of36 cases, most of which involved the middle ear, but afew involved adjacent structures such as the external canalor temporal bone, only 2 showed a CNS connectionon radiography [116].Patients present clinically with hearing change, otitismedia, pain, and/or dizziness/vertigo.

252 L. Michaels8Gross appearances are those of a granular or even grittymass. Microscopically, the neoplasm takes the sameforms as any of the well-described intracranial types ofmeningioma. The commonest variety seen in the middleear is the meningothelial type, in which the tumourcells form masses of epithelioid, regular cells often disposedinto whorls, which may be large or small. Fibroblasticand psammomatous varieties are also sometimesseen in the middle ear.Histological diagnosis of meningioma may be difficultbecause the above features are indistinct. Underthese circumstances immunocytochemistry may be ofsome diagnostic value. Meningiomas are negative formost markers, including cytokeratins. The majority ofmeningiomas, however, are positive for vimentin andepithelial membrane antigen.Nager’s review of temporal bone meningiomas indicatedthat only 2 out of 30 patients survived a 5-year period[78]. More recent experience of middle ear meningiomassignals a better outlook after careful local excision.In a recent study of 35 patients with follow up inwhich the tumour was sited mainly in the middle ear[116] surgical excision was used in all patients. Ten patientsdeveloped a recurrence from 5 months to 2 yearslater and 5 patients died with recurrent disease (mean,3.5 years); the remaining 30 patients were alive (n=25,mean: 19.0 years) or had died (n=5, mean: 9.5 years) ofunrelated causes without evidence of disease. Meningiomasof the middle ear behave as slow-growing neoplasmswith a good overall prognosis (raw 5-year survival,83%). Extent of surgical excision is probably the mostimportant factor in determining outlook because recurrencesdevelop in 28% of cases.8.3.2.7 RhabdomyosarcomaICD-O:8900/3Rhabdomyosarcoma is seen occasionally in the middleear of young children [126]. On rare occasions it isfound in the middle ear of adults [81]. The tympanicmembrane is usually eroded by the growth, which extendsinto the external canal. Grossly, the tumour islobulated and dark red with a haemorrhagic cut surface.Almost all temporal bone rhabdomyosarcomasare of the embryonal type, displaying mainly spindleor round primitive skeletal muscle cells, some of whichhave clear cytoplasm staining positively for glycogenand others have eosinophilic areas in the cytoplasm.Cross striations are unusual in this neoplasm. Immunohistochemicalmarkers for desmin, muscle-specificactin and antibodies against MyoD1 and myogeninconfirm this diagnosis.Rhabdomyosarcoma of the temporal bone is highlymalignant and spreads extensively into the cranial cavity,externally or to the pharyngeal region. Lymph nodeand bloodstream metastases frequently develop in thesepatients.8.3.2.8 Metastatic CarcinomaMetastasis of malignant neoplasms to the temporal boneincluding the middle ear is not uncommon. The breast isthe commonest primary source of metastatic tumours,followed by lung, kidney, stomach, larynx and cutaneousmalignant melanoma [43, 48]. Two distinct modesof spread may be involved in bringing the neoplasmsfrom their primary sites to the middle ear: (a) alongvascular channels in the petrous bone (these convey tumourdeposits to the temporal bone from distant sites),and (b) along nerves emanating from the internal auditorymeatus into the labyrinthine structures and bone.In this way, tumours reaching the meninges may spreadinto the temporal bone. In addition, direct spread maybring tumours into the ear from primary sites in areasadjacent to the temporal bone.8.4 Inner Ear8.4.1 Bony Labyrinth8.4.1.1 OtosclerosisOtosclerosis is a disease of the bony labyrinth, which,by involvement and fixation of the stapes footplate,leads to severe conductive hearing loss. Otosclerosishas some features of a hereditary disease, but its geneticsstill remain incompletely elucidated. Ultrastructuraland immunohistochemical evidence for measles virusand isolation and identification of DNA and RNA sequencesof that virus have been found in otosclerotictissue [18].Otosclerosis usually affects both ears symmetrically.The disease process is probably confined to the temporalbone. The pink swelling of otosclerosis may sometimeseven be detected clinically through a particularlytransparent tympanic membrane as a well-demarcatedand pink focus near the promontory. A characteristictranslucency of bone adjacent to the cochlea and anteriorto the footplate is identified on a CT scan.The lesion always commences in the otic capsuletissue anterior to the footplate of the stapes. In thisposition it does not produce symptoms. These occurwhen the otosclerosis invades the adjacent stapes footplateand produces fixation of that structure and thusconductive hearing loss. It later spreads widely in theotic capsule and may involve the round window ligament.Blood vessels are prominent and evenly dis-

Ear and Temporal Bone Chapter 8 253Fig. 8.18. Focus of otosclerosis involving both the anterior (upper)and posterior (lower) part of footplate of the stapes. The anteriorfocus has invaded onto the footplate and the anterior crus.This would have produced fixation of the stapes and its attendantconductive hearing loss. Notice that the otosclerotic foci are moredarkly staining and vascular than the adjacent normal bone. Reproducedfrom Michaels and Hellquist [68]Fig. 8.17. Radiograph of microslice of autopsy temporal bonewith focus of otosclerosis. The focus is an area of mottled translucencyin the region of the fissula ante fenestram (arrowheads). Reproducedfrom Michaels and Hellquist [68]tributed. X-rays of temporal bone specimens show thewell-defined lesion as a patch of mottled translucency(Fig. 8.17).The histological characteristic of otosclerosis is thepresence of trabeculae of new bone, mostly of the woventype with marked vascularity. This contrasts withthe well-developed lamellar bone under the outer periosteum,the endochondral middle layer and the endosteallayer of the otic capsule, a sharply demarcated edgebetween normal and otosclerotic bone being a prominentfeature. In most places osteocytes are very abundantwithin the woven bone. The footplate of the stapesis often invaded by otosclerotic bone, and the lowerend of the anterior crus of the stapes is sometimes invaded(Fig. 8.18). Otosclerotic bone sometimes reachesthe endosteum of the cochlear capsule. In some casesit may lead to a fibrous reaction deep to the spiral ligament.These changes are probably the basis of the sensorineuralhearing loss that is also occasionally found incases of otosclerosis.Stapedectomy with insertion of a prosthesis to replacethe fixed stapes and so reinstate the mobility of theossicular chain is frequently performed as a treatmentfor otosclerosis. If the specimen of stapes is composedof the head and crura only microscopical examinationwill not show the changes of otosclerosis. On the otherhand, if the whole stapes is removed, as is usually thecase, otosclerotic bone will possibly be observed in sectionsof the anterior part of the footplate.8.4.1.2 Paget’s DiseasePaget’s disease (osteitis deformans) is a common conditionaffecting particularly the skull, pelvis, vertebralcolumn and femur in people over 40 years of age. Thecause is not yet certain, but the presence in many casesof paramyxovirus-like structures seen within osteoclastshas prompted the suggestion that Paget’s diseasemay be of viral aetiology and the measles virus andcanine distemper viruses have been under scrutiny ascandidates. The pathological change is one of activebone formation proceeding alongside active bone destruction.The affected bones are enlarged, porous anddeformed. Microscopically, bone formation is seen intrabeculae of bone with a lining of numerous osteoblasts.A mosaic appearance is formed by the frequentsuccessive deposition of bone, cessation of depositionresulting in thin, blue “cement lines”, followed againby resumption of deposition and its cessation, and soproduction of further cement lines. Bone destructionis shown by the presence of numerous, large osteoclasticgiant cells with Howship’s lacunae. Areas of chronicinflammatory exudate intermixed with the bone arecommon.In the temporal bone the petrous apex, the mastoidand the bony part of the Eustachian tube are most frequentlyaffected [23, 79]. The periosteal part of the bonylabyrinth is the first to undergo pagetoid changes andthe pagetoid changes spread through the bone towardsthe membranous labyrinth, usually with a sharp line of

254 L. Michaelsdemarcation between the pagetoid area and the normalbony labyrinth.8.4.1.3 Osteogenesis Imperfecta8Osteogenesis imperfecta is a general bone disease with atriad of clinical features: multiple fractures, blue scleraeand conductive hearing loss. There is a congenital recessiveform in newborns that is often rapidly fatal anda tardive one in adults that is inherited as a mendeliandominant and is more benign. Mutations of type I collagengenes have been established as the underlying causeleading to a general disturbance in the development ofcollagen, hence the thin sclerae appearing blue as well aspoorly formed bone tissue.In the long bones the resorption of cartilage in thedevelopment of bone is normal, but the bony trabeculaethemselves are poorly formed and the same may beseen in the temporal bone [46]. The ossicles in the tardiveform are very thin and subject to fractures. The stapesfootplate is also frequently fixed. The disturbance inlamellar bone formation can lead to extreme thinness,dehiscence, and non-union of the stapedial superstructurewith the footplate, or thickening with fixation ofthe footplate. The nature of the bony tissue causing thisfixation is problematical. It has been suggested that osteogenesisimperfecta can be associated with otosclerosisso that the fixation is indeed otosclerotic [28]. Otosclerosis,like osteogenesis imperfecta, may indeed bepart of a general connective tissue disturbance [4].Indeed, some cases of clinical otosclerosis may berelated to mutations within the COL1A1 gene that aresimilar to those found in mild forms of osteogenesis imperfecta[63].8.4.1.4 OsteopetrosisFig. 8.19. Cytomegalovirus infection of vestibular nerve in theregion of Scarpa’s ganglion. The nerve is inflamed with the infiltrationof neutrophils, leucocytes and plasma cells. Four enlargedcells, three to the left of centre, the fourth on the far right) withpurplish inclusions, each surrounded by a pale halo, features characteristicof cytomegalovirus infection, can be identified. Autopsyfindings in a patient with AIDS. Reproduced from Michaels andHellquist [68]Osteopetrosis (often known as marble bone disease)is a rare disease of bone, in which there is a failure toabsorb calcified cartilage and primitive bone due todeficient activity of osteoclasts. A relatively benignform, inherited as a dominant, presents in adults, and amalignant one, inherited as a recessive, in infants andyoung children. The patients with the benign form oftensurvive to old age and present prominent otologicalsymptoms. The intermediate, endochondral portionof the otic capsule is swollen and appears as an exaggeratedlythickened form of the normal state. Globuliossei composed of groups of calcified cartilage cells arenormally present in this region, and in osteopetrosisthey are greatly increased in number and are arrangedinto a markedly thickened zone. The periosteal bone isnormal. The ossicles are of foetal shape and filled withunabsorbed, calcified cartilage. The canals for the seventhand eighth cranial nerves are greatly narrowed bythe expanded cartilaginous and bony tissue and thesechanges are probably responsible for the characteristicsymptoms of facial palsy and hearing loss respectively[36, 74, 77].8.4.2 Membranous Labyrinthand Cranial Nerves8.4.2.1 Viral, Bacterialand Mycotic InfectionsCytomegaloviruses are DNA-containing members ofthe herpesvirus group. General infection is frequent,an intrauterine source often being incriminated. Thedeveloping human ear has been thought to be particularlysusceptible to CMV infection [106] and thevirus has been incriminated on clinical and virologicalgrounds as the most common cause of congenitalhearing loss [24, 25, 37, 76, 112]. In infant inner earsthe endolabyrinth is mainly involved. CMV infectionis commonly seen in patients with AIDS. Thirty-ninepercent of patients with AIDS were found to have ahearing loss of sensorineural type [104]. In a study ofthe temporal bones at autopsy of 25 patients CMV infectionwas identified in the inner ears of 5 patients bythe presence of the characteristic inclusions. The inclusionswere found in the vestibular nerve in the internalcanal (Fig. 8.19), in the stria and in the saccule, utricleand lateral semicircular duct [69].It is likely, therefore, that the hearing loss in patientswith AIDS is due to cochlear CMV infection.

Ear and Temporal Bone Chapter 8 255Maternal rubella is an important factor in the genesisof congenital sensorineural hearing loss. The virus is anRNA one. In two cases the temporal bones showed inflammatorycollections at the upper end near the junctionwith Reissner’s membrane and adherent to it [29].The organ of Corti was mainly normal.In herpes zoster auris (Ramsay Hunt syndrome), thevirus (the DNA herpes varicella virus) enters the inner earalong the seventh and eighth cranial nerves, presumablyfrom nerve ganglia where it lies dormant until the immunologicalstatus of the patient deteriorates. In histopathologicalstudies previously described there were extensiveinflammatory changes mainly in those two cranialnerves serving in the transmission of the virus. Varicellazoster has also been detected in the cytoplasm and nucleiof inflammatory cells of the middle ear in two cases ofthe Ramsay-Hunt syndrome by an immunofluorescencemethod [30]. Herpes varicella-zoster viral (VZV) DNAhas been identified, using the polymerase chain reaction,in archival celloidin-embedded temporal bone sectionsfrom two patients who clinically had Ramsay-Hunt syndrome(herpes zoster oticus) [119].A condition possibly due to viral infection in the innerear is that of Bell’s palsy, which is manifested clinicallyas a peripheral facial paralysis. The suggestion hasbeen made, with some virological support, that this conditionis the result of infection with herpes simplex virus,type 1. There have been a very small number of reportsof temporal bone studies from patients with Bell’spalsy. In two cases of Bell’s palsy I studied, serial sectionsof the temporal bones both showed the followinghistological findings. In the genu region there appearedto be constriction of the facial nerve by inflammatorytissue, which formed a sheath around it and encroachedon its interior. The adjacent bone showed foci of resorptionwith abundant osteoclasts (Fig. 8.20). The geniculateganglion was infiltrated by lymphocytes. In someplaces the affected facial nerve appeared severely oedematousand nerve cells were shrunken and showed aneosinophilic cytoplasm. The descending part of the facialnerve presented swelling and vacuolation of myelinsheaths with some loss of axis cylinders. These findingsare compatible with geniculate ganglionitis. In one ofthese cases, herpes simplex viral type 1 was demonstratedin archival paraffin-embedded sections of the affectedgeniculate ganglion by carrying out PCR followed byelectrophoresis on agarose gel [14].Pe t ro s i t i s : bacterial infections of the inner ear may involveboth the petrous bone itself and the labyrinthinestructures within it. Bacterial infection of the petrousbone is frequently derived by extension from middle earinfection. There are four possible routes by which infectionmay extend from the middle ear into the petrousbone [68]:1. Via air cells. Mastoid air cells frequently extend inthe temporal bone as far as the apical region. It isFig. 8.20. Interface between geniculate ganglion and adjacentbone in a case of Bell’s palsy, showing numerous osteoclasts withHowship’s lacunae. Reproduced from Michaels and Hellquist [68]possible, therefore, that infection to the petrous apexmay extend from the middle ear by the medium ofinfection of air cells;2. As direct spread of the inflammatory process by bonenecrosis (osteitis);3. By extension through the bone marrow of the petrousbone (osteomyelitis);4. Along vessels and nerves.In addition to inflammatory infiltration the pathologicalprocess of petrositis comprises three main changesin the bone tissue, all of which may be seen simultaneously:(a) bone necrosis, (b) bone erosion, (c) new boneformation. Petrositis is of great importance because involvementof the labyrinth, nerves, artery, veins, meningesand cerebral tissue embedded in and surroundingthe petrous bone may each cause serious symptoms, andperhaps death.Extension to the labyrinth may lead to labyrinthitiswith destruction of the organs of hearing and balance.Important nerves may be damaged. The facial nerveis at risk early on. Involvement of the trigeminal ganglionand the sixth cranial nerve lead to “Gradenigo’ssyndrome”. Extension to the jugular foramen region bythe inflammatory process may cause palsy of the ninth,tenth and eleventh cranial nerves (“jugular foramensyndrome”).The wall of the internal carotid artery may becomeinflamed and this may lead to thrombosis of the vesselwith possible cerebral complications. Similarly, thelateral sinus may become thrombosed and this and/orextension of the thrombus to the superior sagittal sinusmay be associated with the somewhat arcane syndromeof otitic hydrocephalus. Spread of the infectionto the immediately adjacent cranial structures will leadto meningitis and cerebral abscess.Labyrinthitis: the source of labyrinthitis is, in manyinstances, otitis media, as with petrositis. Infection may

256 L. Michaels8enter the labyrinth by penetrating the oval or the roundwindow. An infected air cell may rupture into the labyrinthinesystem at some point of its complex periphery.Occasionally, damage to bone by the inflammation mayproduce a fistula between the middle ear and the labyrinth,usually in the lateral semicircular canal becausethis is the nearest vulnerable point to the middle ear.The latter complication takes place in most cases when acholesteatoma is present, which has the effect of stimulatingthe inflammatory process.Infection may also be conveyed from meningitisthrough the cochlear aqueduct and the internal auditorymeatus into the labyrinth. Sensorineural hearingloss is an important sequela of acute bacterial meningitis[66].In suppurative labyrinthitis the perilymph spaces displaya usually massive exudate of neutrophils. If the processextends to the endolymphatic spaces there is concomitantdestruction of membranous structures and irreparabledamage to sensory epithelia.Healing is at first by fibrosis, but later osseous repairis frequent, leading to a condition of “labyrinthitis ossificans”.In this condition the spaces of the bony labyrinthare filled in by a newer bone, which appears instriking contrast with the normal bone surrounding thebony labyrinth.Cryptococcosis is a fungus infection that usually infectsthe meninges. There may be extension by the organismCryptococcus neoformans, from the meningesalong the internal auditory meatus and then into the cochleavia the modiolus. Such a progression was clearlypresent in two cases of AIDS with cryptococcal meningitisthat had spread to the labyrinth [69].8.4.2.2 Lesionsof the Vestibular SystemThe pathology of the vestibular labyrinth has not beenas well studied as that of the cochlea and other parts ofthe labyrinth. This is the result of the paucity of operativeprocedures with biopsy carried out in this area andalso of the rapidity of autolysis, which takes place afterdeath so that histological study of this area is difficult.The non-neoplastic lesions listed below are described indetail by Michaels and Hellquist [68].Ototoxicity: many drugs damage the sensory epitheliaof the inner ear. The most obvious clinical effect is whenthe cochlear sensory cells are involved so that hearingloss results. Part of the damage produced by aminoglycosideantibiotics such as gentamycin, however, may beto the sensory epithelium of the cristae and maculae,producing symptoms of imbalance.Virus infection: in rubella and cytomegalovirus infectionchanges have been observed in the utricle andsaccule (see above).Fig. 8.21. Hydrops of scala media of the cochlea. Reisner’s membraneis distended to such a degree that it touches the top of thescala vestibuli. Reproduced from Michaels and Hellquist [68]Bacterial infection: bacterial infection may involvethe vestibular system as part of labyrinthitis. In mostbacterial infections, spread occurs from the middle earvia the oval window. A direct fistula resulting from thebone erosion of otitis media may take place leading intothe lateral semicircular canal, particularly in the presenceof cholesteatoma.Bone diseases: Paget’s disease frequently involves thebony vestibule and semicircular canals to a severe degreeand as a result clinical symptoms referable to thissystem are likely to occur. Otosclerosis, although frequentlypresent in relation to the bony wall of the vestibule,rarely involves the membranous structures of thevestibular system so that vestibular symptoms are rarein this condition.Hydrops of the saccule, which sometimes extends tothe utricle, is the major pathological feature of Ménière’sdisease and is responsible for the characteristic symptomof that disease – vertigo. The scala media of the cochleais usually distended in Ménière’s disease (Fig. 8.21), andthis is the pathological basis of the hearing loss and tinnitusthat are the other disturbing symptoms in attacksof the disease. Saccular hydrops may also be a manifestationof syphilitic and bacterial inflammation involvingthe labyrinth.Positional vertigo is a very common condition inwhich vertigo is induced in the patient by alterationin the position of the head. In 1969, Schuknecht describedthe temporal bone findings in two cases ofpositional vertigo [94]. Attached to the posterior surfaceof the cupula of the left posterior semicircularcanal in each of the cases was a basophilically stainedhomogeneous deposit. On the basis of these cases,Schuknecht has built up an explanation of the symptomatologyof positional vertigo postulating that thecalcific material derived from otoconia in a degeneratedutricular macula will descend by gravity along

Ear and Temporal Bone Chapter 8 257Fig. 8.22. Vestibular schwannoma in a microsliced temporalbone. The neoplasm is arising from the vestibular division of theeighth nerve and compressing the cochlear division. Note thegranular deposit lining the cochlea. Reproduced from Michaelsand Hellquist [68]Fig. 8.23. Small vestibular schwannoma. It arises from the vestibulardivision of the eighth nerve in the region of the glial neurilemmaljunction and causes only a small indentation of the bonywall of the internal canal. There is exudate in the vestibule, but notin the cochlea. Reproduced from Michaels and Hellquist [68]the endolymph and form on the crista of the posteriorsemicircular canal, the lowest region of the labyrinthinesensory epithelium. This ingenious theory hasattracted much interest and the term “cupulolithiasis”is nowadays frequently used as a synonym for positionalvertigo.8.4.2.3 Tumoursand Tumour-Like LesionsThe most important neoplasm of the vestibular systemis schwannoma (acoustic neuroma, ICD-O:9560/0) of thevestibular division of the eighth cranial nerve. This doesnot usually invade the vestibule, but may do so in casesof neurofibromatosis [2] (see below). The saccule andutricle show an exudate of proteinaceous fluid in thepresence of a schwannoma of the internal auditory meatus.Another much rarer neoplasm is the low-grade adenocarcinomaof the endolymphatic sac (endolymphaticsac tumour; see below). Metastatic deposits are unusual;invasion of the vestibular system from the internal auditorymeatus by way of the vestibular nerve may occur inmetastatic neoplasm or in carcinoma of the middle ear(see above).Vestibular schwannoma is stated to arise most commonlyat the glial-neurilemmal junction of the eighthnerve, which is usually within the internal auditory meatus.In one study of five temporal bones with small vestibularschwannomas, the tumour arose more peripherally,however [128]. When seen at surgery or autopsyvestibular schwannoma in most cases is found to occupya much greater part of the nerve. Usually it is the vestibulardivision of the nerve that is affected; in a few the cochleardivision is the source of the neoplasm (Fig. 8.22).Growth takes place from origin, both centrally onto thecerebellopontine angle, and distally along the canal.Vestibular schwannoma is usually unilateral, but may bebilateral (see below).The neoplasm may grow slowly for years withoutcausing symptoms and may be first diagnosed only atpost-mortem where it has been found in about 1 in 220consecutive adults [57]. Although it arises on the vestibularbranch of the eighth cranial nerve, hearing loss andtinnitus are early symptoms produced by involvement ofthe cochlear division of the nerve; in the later stages vertigoand abnormal caloric and electronystagmographicresponses develop from damage to the vestibular divisionitself. Surgical removal may be carried out by drillingfrom the external canal through the temporal bone,by craniotomy and the middle fossa approach to the internalauditory meatus, or by stereotactically guidedgamma knife surgery.The neoplasm, seen grossly, is of variable size and ofround or oval shape. Small tumours either do not widenthe canal at all or produce only a small indentationin the bone (Fig. 8.23). The larger tumours often have amushroom shape with two components, the stalk – anelongated part in the canal – and an expanded part inthe region of the cerebellopontine angle. The bone of theinternal auditory canal is widened funnel-wise as theneoplasm grows. The tumour surface is smooth and lobulated.The cut surface is yellowish, often with areas ofhaemorrhage and cysts. The vestibular division of theeighth nerve may be identified on the surface of the tumour.Acoustic neuroma has the features of a neoplasm ofSchwann cells showing Antoni A and Antoni B areas.Antoni A areas display spindle cells closely packed togetherwith palisading of nuclei. Verocay bodies, whichmay be present in the Antoni A areas, are whorled formationsof palisaded tumour cells. The degree of cellularityof the neoplasm can be high or low. The spindlecells frequently are moderately pleomorphic, but mitotic

258 L. Michaels8Fig. 8.24. Lipoma of the internal auditory canal. Note nervebranch passing through adipose tissue near the bottom. Reproducedfrom Michaels and Hellquist [68]figures are unusual. The presence of pleomorphism doesnot denote a malignant tendency. Antoni B areas, probablya degenerated form of the Antoni A pattern, show aloose reticular pattern, sometimes with histiocytic proliferation.Thrombosis and necrosis may be present insome parts of the neoplasm. A mild degree of invasionof modiolus or vestibule along cochlear or vestibularnerve branches may be present even in solitary vestibularschwannomas. Granular or homogeneous fluid exudateis usually present in the perilymphatic spaces ofthe cochlea and vestibule. This may arise as a result ofpressure by the neoplasm on veins draining the cochleaand vestibule in the internal auditory meatus. Hydropsof the endolymphatic system may occur (see above) andin larger tumours there is atrophy of spiral ganglion cellsand nerve fibres in the basilar membrane.The tumour is benign and usually grows slowly. Serioussymptoms and even death may occur, however, dueto damage to cerebral structures if the neoplasm growsto a large size.Neurofibromatosis 2 (Bilateral Vestibular Schwannoma,ICD-O:9540/1): bilateral vestibular schwannomaacoustic neuroma (neurofibromatosis 2, NF2) is, unlikeneurofibromatosis 1 (von Recklinghausen’s disease), notassociated with large numbers of cutaneous neurofibromasand cafe-au-lait spots, but the temporal bone localityof the neural tumour and its bilaterality are inherited asan autosomal dominant trait. This condition has been relatedto a gene localised near the centre of the long arm ofchromosome 22. At autopsy of cases of neurofibromatosis2, neural neoplasms are present in both eighth nervesand other central nerves. There are often many smallschwannomas and collections of cells of neurofibromatousand meningiomatous appearance growing on cranialnerves and on the meninges in the vicinity of the vestibularschwannomas and sometimes even intermixedwith them. The NF2 tumours are histologically similarto those of the single tumours except that the former havemore Verocay bodies and more foci of high cellularity.The NF2 tumours are more invasive, however, tending toinfiltrate the cochlea and vestibule more deeply.As with all schwannomas, the strongest and mostconsistent immunohistochemical reaction is the positivitydisplayed when staining with a polyclonal antibodyagainst S-100 protein is carried out. The vimentinmarker is also usually positive. These findings arecommon to both unilateral vestibular schwannoma andthe schwannomas of NF2. Glial fibrillary acidic proteinand neuron-specific enolase markers are also sometimespositive; the tumours are consistently negative forCD34, a marker widely used for the diagnosis of solitaryfibrous tumours, unless the vestibular schwannoma iswidely degenerated [117].An antibody against Ki67 (MIB1 in paraffin sections)has been utilised in a number of investigations to determinewhether the degree of positivity with this proliferationmarker can be related to the clinical activity of thetumour. It has been demonstrated that tumours 18 mmor smaller in diameter have lower proliferation indicesand growth rates, compared with tumours larger than18 mm [6]. The degree of labelling with the proliferationmarker is higher in cases of NF2 than in those of solitaryvestibular schwannoma [2].Men i ng ioma s (ICD-O:9530/0) are usually intracranialmasses. They arise from arachnoid villi, which aresmall protrusions of the arachnoid membranes into thevenous sinuses. Arachnoid villi may be found in parts ofthe temporal bone, including the inner ear, and on occasionmeningiomas may arise from these structures as primaryneoplasms of the inner ear region. The most likelyposition for a primary inner ear meningioma is in thewall of the internal auditory meatus, where arachnoid villiare normally frequent. The histological appearances ofa meningioma are those of a tumour with a whorled arrangementof cells: meningotheliomatous if the tumourcells appear epithelioid, psammomatous if calcification ofthe whorled masses is prominent and fibroblastic if thetumour cells resemble fibroblasts. Meningiomas as wellas acoustic neuromas may appear in the inner ear in theNF2 syndrome. The meningioma is a slowly growing tumourof the temporal bone that has had a reputation forcomplete benignity. In the temporal bone, however, middleear meningioma sometimes has a strong propensitytowards local recurrence and invasion (see above).Li p o m a s (ICD-O:8850/0) of the internal auditory canaland cerebellopontine angle are rare tumours thatmay be confused clinically with the much commonervestibular schwannoma. On magnetic resonance usingfat-suppressed T1-weighted images after gadoliniumenhancement, however, this tumour displays characteristicsof adipose tissue rather than those of schwannoma.There may be erosion of the walls of the internal auditorycanal as with vestibular schwannoma, and lipomamay appear similar to the latter at operation. Since

Ear and Temporal Bone Chapter 8 259Fig. 8.25. Low-grade adenocarcinoma of probable endolymphaticsac origin showing a papillary pattern. The epidermoid epitheliumon the right is probably that of the external auditory canal towhich the tumour had extended. Reproduced from Michaels andHellquist [68]Fig. 8.26. Low-grade adenocarcinoma of probable endolymphaticsac origin showing a thyroid-like glandular pattern from anotherarea of the tumour shown in Fig. 8.25. Reproduced from Michaelsand Hellquist [68]the seventh and eighth cranial nerves or their branches(Fig. 8.24) may pass through the lesion and their integritybe damaged by removal of the tumour it is recommendedthat diagnosis be made whenever the possibilityof this neoplasm is suspected at operation by examinationof frozen sections. If a diagnosis of lipomais made in this way the tumour should not be resected,since its further growth does not constitute a threat tovital structures [102].Low-grade adenocarcinoma of probable endolymphaticsac origin ( endolymphatic sac tumour): there is evidenceof the existence of an epithelial neoplasm of the endolymphaticsystem, mainly in the endolymphatic sac [35,38, 41]. Although of bland histological appearance andof slow growth the neoplasm seems to have considerableinvasive capacity and therefore the term “low-grade adenocarcinomaof probable endolymphatic sac origin” hasbeen applied. Other terms, such as endolymphatic sac tumourand Heffner’s tumour, are also in use. Some caseshave presented bilateral neoplasms of the same typeand some have also been associated with von Hippel-Lindaudisease [64]. The course of the tumour’s growth mayextend over many years. Tinnitus or vertigo, similar oridentical to the symptoms of Ménière’s disease, are presentin about one-third of patients. It is presumed that earlyobstruction of the endolymphatic sac leads to hydropsof the endolymphatic system of the labyrinth and so tothe Ménière’s symptoms. Imaging reveals a lytic temporalbone lesion, appearing to originate from the regionbetween the internal auditory canal and sigmoid sinus(which is the approximate position of the endolymphaticsac). There is usually prominent extension into the posteriorcranial cavity and invasion of the middle ear.In most cases the tumour has a papillary-glandularappearance, the papillary proliferation being linedby a single row of low cuboidal cells. The vascular natureof the papillae in some cases has given the tumoura histological resemblance to choroid plexus papilloma(Fig. 8.25). In some cases the tumour also shows areasof dilated glands containing secretion that has some resemblanceto colloid and under these circumstances thelesion may resemble papillary adenocarcinoma of thethyroid (Fig. 8.26). Such thyroid-like areas may evendominate the histological pattern. A few cases show aclear cell predominance resembling carcinoma of thekidney. On immunohistochemistry the epithelial cellsof this neoplasm contain antigens of cytokeratins. Sometumours contain glial fibrillary acidic protein. Thyroglobulinis always absent.It seems possible that many cases of the so-called“aggressive papillary middle ear tumours” may be lowgradeadenocarcinomas of the endolymphatic sac withextension of the neoplasm to the middle ear (see alsoSect. 8.3.2.3) [31]. Not all of such tumours may arise inthe endolymphatic sac [89].The histological appearances of low-grade adenocarcinomasof probable endolymphatic sac origin are indeedin keeping with the normal histological structureof the endolymphatic sac, which is lined by a papillarycolumnar epithelial layer.Cholesteatoma (epidermoid cyst) usually presentswith symptoms relating to its involvement of the seventhand eighth cranial nerves in the cerebellopontineangle. The histological appearance is similar to that ofmiddle ear cholesteatoma (see above). It is probably ofcongenital origin, but no cell rest has been discoveredfrom which it might arise.Cholesterol granuloma is a lesion of the petrous apexwith the typical features of cholesterol granuloma asseen in the middle ear and mastoid in chronic otitis media,and has been identified in recent years with increasingfrequency. At operation it appears cystic, the contentsbeing altered blood and cholesterol clefts with aforeign body giant cell reaction.

262 L. Michaels879. Nager GT (1975) Paget’s disease of the temporal bone. AnnOtol Rhinol Laryngol 84 [Suppl] 22:3–3280. Nager GT, Kennedy DW, Kopstein E (1982) Fibrous dysplasia:a review of the disease and its manifestations in the temporalbone. Ann Otol Rhinol Laryngol 91:Suppl 9281. Nakhleh RE, Swanson PE, Dehner LP (1991) Juvenile (embryonaland alveolar) rhabdomyosarcoma of the head andneck in adults. A clinical, pathologic, and immunohistochemicalstudy of 12 cases. Cancer 67:1019–102482. Nelson EG, Kratz RC (1993) Sebaceous choristoma of themiddle ear. Otolaryngol Head Neck Surg 108:372-37383. Nyrop M, Grantved A (2002) Cancer of the external auditorycanal. Arch Otolaryngol Head Neck Surg 128:834–83784. Ophir D (1991) Familial multicentric paragangliomas in achild. J Laryngol Otol 105:376–38085. Ostfeld E, Segal M, Czernobilsky B (1982) External otitis:early histopathologic changes and pathogenic mechanism.Laryngoscope 91:965–97086. Palmer JM, Coker NJ, Harper RL (1989) Papillary adenomaof the temporal bone in von Hippel-Lindau disease. OtolaryngolHead Neck Surg 100:64–6887. Persaud R, Hajioff D, Thevasagayam MS, Wareing MJ, WrightA (2004) Keratosis obturans and external ear canal cholesteatoma:how and why we should distinguish between theseconditions. Clin Otolaryngol 29:1–588. Polinsky MN, Brunberg JA, McKeever PE, Sandler HM, TelianS, Ross D (1994) Aggressive papillary middle ear tumors:a report of two cases with review of the literature. Neurosurgery35:493–497; discussion 49789. Pollak A, Bohmer A, Spycher M, Fisch U (1995) Are papillaryadenomas endolymphatic sac tumors? Ann Otol Rhinol Laryngol104:613–61990. Pou AM, Vrabec JT (2002) Inverting papilloma of the temporalbone. Laryngoscope 112:140–14291. Ramirez-Camacho R, Vicente J, Garcia Berrocal JR, Ramony Cajal S (1999) Fibro-osseous lesions of the external auditorycanal. Laryngoscope 109:488–49192. Ribe A, Fernandez PL, Ostertarg H, Claros P, Bombi JA, PalacinA, Cardesa A (1997) Middle-ear adenoma (MEA): a reportof two cases, one with predominant “plasmacytoid” features.Histopathology 30:359–36493. Roberts WH, Dinges DL, Hanly MG (1993) Inverted papillomaof the middle ear. Ann Otol Rhinol Laryngol 102:890–89294. Schuknecht H (1969) Cupolithiasis. Arch Otolaryngol90:765–77895. Schuknecht HF (1993) Pathology of the ear, 2nd edn. Lea &Febiger, Philadelphia, pp 209–21096. Schuller DE, Conley JJ, Goodman JH, Clausen KP, Miller WJ(1983) Primary adenocarcinoma of the middle ear. OtolaryngolHead Neck Surg 91:280–28397. Schwaber MK, Glasscock ME, Jackson CG, Smith PG (1984)Diagnosis and management of catecholamine secreting glomustumors. Laryngoscope 94:1008–101598. Seshul MJ, Eby TL, Crowe DR, Peters GE (1995) Nasal invertedpapilloma with involvement of middle ear and mastoid.Arch Otolaryngol Head Neck Surg 121:1045–104899. Shah JP, Kraus DH, Dubner S, Sarkar S (1991) Patterns of regionallymph node metastases from cutaneous melanomas ofthe head and neck. Am J Surg 162:320–323100. Siedentop KH, Jeantet C (1961) Primary adenocarcinoma ofthe middle ear. Report of three cases. Ann Otol Rhinol Laryngol.70:719–733101. Shpitzer T, Stern Y, Cohen O, Levy R, Segal K, Feinmesser R(1993) Malignant external otitis in nondiabetic patients. AnnOtol Rhinol Laryngol 102:870–872102. Singh SP, Cottingham SL, Slone W, Boesel CP, Welling DB,Yates AJ (1996) Lipomas of the internal auditory canal. ArchPathol Lab Med 120:681–683103. Soucek S, Michaels L (1993) Keratosis of the tympanic membraneand deep external canal: a defect of auditory epithelialmigration. Eur Arch Otorhinolaryngol 250:140–142104. Soucek S, Michaels L (1996) The ear in the acquired immunodeficiencysyndrome. II. Clinical and audiologic investigation.Am J Otol 17:35–39105. Stafford ND, Frootko NJ (1986) Verrucous carcinoma in theexternal auditory canal. Am J Otol 7:443–445106. Stagno S, Reynolds DW, Amos CS, Dahle AJ, McCollister FP,Mohindra I, Ermocilla R, Alford CA (1977) Auditory and visualdefects resulting from symptomatic and subclinical congenitalcytomegaloviral and toxoplasma infections. Pediatrics59:669–678107. Staibano S, Boscaino A, Salvatore G, Orabona P, PalombiniL, De Rosa G A (1996) The prognostic significance of tumorangiogenesis in nonaggressive and aggressive basal cell carcinomaof the human skin. Hum Pathol 27:695–700108. Stanley MW, Horwitz CA, Levinson RM, Sibley RK (1987)Carcinoid tumors of the middle ear. Am J Clin Pathol 87:592–600109. Stendel R, Suess O, Prosenc N, Funk T, Brock M (1998) Neoplasmof endolymphatic sac origin: clinical, radiological andpathological features. Acta Neurochir (Wien) 140:1083–1087110. Stone DM, Berktold RE, Ranganathan C, Wiet RJ (1987) Invertedpapilloma of the middle ear and mastoid. OtolaryngolHead Neck Surg 97:416–418111. Stone HE, Lipa M, Bell RD (1975) Primary adenocarcinomaof the middle ear. Arch Otolaryngol 101:702–705112. Strauss M (1990) Human cytomegalovirus labyrinthitis. AmJ Otolaryngol 11:292–298113. Sudhoff H, Bujia J, Fisselereckhoff A, Holly A, Schuflake C,Hildmann H (1995) Expression of a cell-cycle-associated nuclearantigen (MIB1) in cholesteatoma and auditory meatalskin. Laryngoscope 105:1227–1231114. Sudhoff H, Bujia J, Holly A, Kim C, Fischler-Eckhoff (1994)Functional characterization of middle ear mucosa residuesin cholesteatomatous samples. Am J Otol 15:217–221115. Sudhoff H, Fisseler-Eckhoff A, Stark T, Borkowski G, LuckhauptH, Cooper J, Michaels L (1997) Argyrophilic nucleolarorganizer regions in auditory meatal skin and middle earcholesteatoma. Clin Otolaryngol 22:545–548116. Thompson LD, Bouffard JP, Sandberg GD, Mena H (2003)Primary ear and temporal bone meningiomas: a clinicopathologicstudy of 36 cases with a review of the literature. ModPathol 16:236–245117. Tosaka M, Hirato J, Miyagishima T, Saito N, Nakazato Y, SasakiT (2002) Calcified vestibular schwannoma with unusualhistological characteristics – positive immunoreactivity forCD-34 antigen. Acta Neurochir (Wien) 144:395–399118. Tysome JR, Harcourt J, Patel MC, Sandison A, Michaels L(2006) Aggressive papillary tumour of the middle ear. Ear,Nose and Throat Journal, in press119. Wackym PA (1997) Molecular temporal bone pathology. II.Ramsay Hunt syndrome (herpes zoster oticus). Laryngoscope107:1165–1175120. Wassef M, Kanavaros P, Polivka M, Nemeth J, Monteil JP,Frachet B, Tran Ba Huy P (1989) Middle ear adenoma. A tumordisplaying mucinous and neuroendocrine differentiation.Am J Surg Pathol 13:838–847121. Weinroth SE, Schessel D, Tuazon CU (1992) Malignant otitisexterna in AIDS patients: case report and review of the literature.Ear Nose Throat J 73:772–774122. Wells MD, Michaels L (1983) Role of retraction pockets incholesteatoma formation. Clin Otolaryngol 8:39–45123. Wells M, Michaels L (1984) “Malignant otitis externa”: amanifestation of chronic otitis media with complications?Clin Otolaryngol 9:131 (abstract)124. Wenig BM (1996) Schneiderian-type mucosal papillomasof the middle ear and mastoid. Ann Otol Rhinol Laryngol105:226–233125. Wetli CV, Pardo V, Millard M, Gersdon K (1972) Tumors ofceruminous glands. Cancer 29:1169–1178126. Wiatrak BJ, Pensak ML (1989) Rhabdomyosarcoma of theear and temporal bone. Laryngoscope 99:1188–1192127. Wright CG, Meyerhoff WL, Burns DK (1985) Middle ear cholesteatoma:an animal model. Am J Otolaryngol 6:327–341128. Xenellis JE, Linthicum FH Jr (2003) On the myth of the glial/schwann junction (Obersteiner-Redlich zone): origin of vestibularnerve schwannomas. Otol Neurotol 24:1

Chapter 9Cysts and Unknown Primaryand Secondary Tumours of the Neck,and Neck DissectionM. A Luna · K. Pineda-Daboin9Contents9.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . 2649.2. Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . 2649.2.1 Triangles of the Neck . . . . . . . . . . . . . . . . . . . 2649.2.2 Lymph Node Regions of the Neck . . . . . . . . . . . . 2649.3 Cysts of the Neck . . . . . . . . . . . . . . . . . . . . . 2649.3.1 Developmental Cysts . . . . . . . . . . . . . . . . . . . 2659.3.1.1 Branchial Cleft Cysts, Sinuses and Fistulae . . . . . . 2659.3.2 Branchiogenic Carcinoma . . . . . . . . . . . . . . . . 2679.3.3 Thyroglossal Duct Cyst and Ectopic Thyroid . . . . . 2689.3.4 Cervical Thymic Cyst . . . . . . . . . . . . . . . . . . . 2699.3.5 Cervical Parathyroid Cyst . . . . . . . . . . . . . . . . 2709.3.6 Cervical Bronchogenic Cyst . . . . . . . . . . . . . . . 2709.3.7 Dermoid Cyst . . . . . . . . . . . . . . . . . . . . . . . 2719.3.8 Unclassified Cervical Cyst . . . . . . . . . . . . . . . . 2719.3.9 Non-Developmental Cysts . . . . . . . . . . . . . . . . 2719.3.9.1 Ranula . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2719.3.9.2 Laryngocele . . . . . . . . . . . . . . . . . . . . . . . . 2719.4 Cystic Neoplasms . . . . . . . . . . . . . . . . . . . . . 2729.4.1 Cystic Hygroma and Lymphangioma . . . . . . . . . . 2729.4.2 Haemangioma . . . . . . . . . . . . . . . . . . . . . . . 2729.4.3 Teratoma . . . . . . . . . . . . . . . . . . . . . . . . . . 2729.4.4 Cervical Salivary Gland Cystic Neoplasms . . . . . . 2739.4.5 Miscellaneous Lesions . . . . . . . . . . . . . . . . . . 2739.5 Paraganglioma . . . . . . . . . . . . . . . . . . . . . . . 2739.6 Unknown Primaryand Secondary Tumours . . . . . . . . . . . . . . . . . 2749.6.1 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . 2749.6.2 Clinical Features . . . . . . . . . . . . . . . . . . . . . . 2759.6.3 Search for the Primary Tumour . . . . . . . . . . . . . 2759.6.4 Common Location of the Primary Tumour . . . . . . 2769.6.5 Histologic Type of Metastasesand Immunohistochemical Features . . . . . . . . . . 2769.6.6 Differential Diagnosis . . . . . . . . . . . . . . . . . . . 2769.6.7 Treatment and Results . . . . . . . . . . . . . . . . . . 2789.7 Neck Dissection . . . . . . . . . . . . . . . . . . . . . . 2789.7.1 Classification of Neck Dissections . . . . . . . . . . . 2789.7.2 Gross Examinationof Neck Dissection Surgical Specimens . . . . . . . . 2799.7.3 Histologic Evaluation of Neck Dissection . . . . . . . 279References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280

264 M. A Luna · K. Pineda-Daboin9.1 IntroductionThe neck connects the organs of the head with those ofthe thorax. It contains important anatomic structures,including blood and lymphatic vessels, nerves and paraganglia,muscles and vertebrae, and numerous lymphnodes, in addition to parenchymatous glands, salivary,thyroid, and parathyroid. The neck also contains organsof the upper aerodigestive tract: larynx, hypopharynxand segments of the oesophagus and trachea.The fact that a neck mass can originate in any of thecervical structures means that a host of disorders challengesthe diagnostic ability of the surgical pathologist.The differential diagnosis of a neck mass includes developmental,inflammatory, benign and malignant neoplasticlesions. The purpose of this chapter is to reviewthe pathology and diagnosis of cervical cysts. Occultprimary tumours of the neck and neck dissection alsoare discussed.99.2 Anatomy9.2.1 Trianglesof the NeckIt is customary to divide the neck into two large triangles,the anterior cervical triangle and the posteriorcervical triangle. The anterior triangle is bounded bythe midline of the neck, the anterior border of the sternocleidomastoidmuscle, and the inferior border of themandible. The posterior triangle is bounded by the anteriormargin of the trapezius muscle, the posterior borderof the sternocleidomastoid muscle and the clavicle.The anterior cervical triangle can be further subdividedinto four lesser triangles (submental, submandibular,superior carotid and inferior carotid) and the posteriortriangle into two (occipital and supraclavicular)the boundaries of which are described in greater detailin other sources [12].9.2.2 Lymph Node Regionsof the NeckThe cervical lymph nodes can be divided into superficialand deep nodes, and each of these groups into lateraland medial. The deep lateral nodes are distributedamong several large groups:1. The submental and submandibular group;2. The internal jugular chain (superior, middle, and inferior);3. The spinal accessory nerves chain;4. The supraclavicular node chain.Fig. 9.1. Cervical nodes by levels and sublevels: IA submental,IB submandibular, II upper jugular, IIA jugulogastric, IIB supraspinalaccessory, III middle jugular, IV lower jugular, V Posteriorcervical, VA spinal accessory nerve nodes, VB transverse cervicalnodes, SC supraclavicular, VI anterior groupThe deep medial cervical group consists of the prelaryngeal,prethyroidal, pretracheal and paratracheal lymphnodes. The superficial medial lymph nodes are distributedaround the anterior jugular vein. The superficiallateral cervical nodes are located along the externaljugular vein.Figure 9. 1 shows the system for describing the locationof lymph nodes in the neck, and used the levels recommendedby the Committee for Head and Neck Surgeryand Oncology of the American Academy for Otolaryngology-Headand Neck Surgery [99].9.3 Cystsof the NeckCysts of the neck are pathological cavities lined withepithelium. The type of epithelium varies, and the cavitymay contain fluid, keratin, mucus or other products.Cervical cysts can be divided into two large groups: developmentaland non-developmental. Establishing theprecise nature of these cysts is important because thereare considerable differences in their biological and clini-

Neck Cysts, Metastasis, Dissection Chapter 9 265Table 9.1. Order of frequency of cervical cystic tumours according to age (extracted from [52, 68, 70, 115]). CA carcinomaInfants and children Adolescents AdultsThyroglossal duct cystBranchial cleft cystLymphangiomaHaemangiomaTeratoma and dermoidBronchogenic cystThymic cystLaryngoceleMetastatic thyroid caThyroglossal duct cystBranchial cleft cystBronchogenic cystThymic cystTeratoma and dermoidMetastatic thyroid caMetastatic cystic caThyroglossal duct cystCervical ranulaBranchial cleft cystLaryngoceleParathyroid cystThymic cystcal behaviour [26]. Because of the frequent similarities inthe morphological aspects of various cysts, a definitivediagnosis is dependent on clinical data. These include theexact location of the lesion and the age of the patient. Theclinical manifestations of cysts depend largely on theirsize. Most cysts in the early stages are asymptomatic andare found on routine physical or radiographic examination.Rupture and drainage leads to infection, abscess,and sinus formation, which are frequently accompaniedby pain and swelling. In certain instances, computed tomographyscan can be of benefit in establishing the diagnosisand/or extension into adjacent structures [59].Aspiration needle biopsy can also be useful in distinguishingbetween cysts and other pathoses that presenta similar roentgenographic appearance [41].In adults, an asymptomatic neck mass should be consideredmalignancy until proven otherwise. With the exceptionof thyroid nodules and salivary gland tumours,neck masses in adults have the following characteristics:80% of the masses are neoplastic, 80% of neoplasticmasses are malignant, 80% of malignancies are metastatic,and in 80%, the primary tumour is located abovethe level of clavicle [70]. In contrast, 90% of neck massesin children represent benign conditions. In a review of445 children with neck masses, 55% of the masses werecongenital cysts, 27% were inflammatory lesions, 11%were malignant and 7% were miscellaneous conditions[117]. Table 9.1 lists the causes of neck masses in orderof the frequency with which they occur, according to theage of the patient.9.3.1 Developmental Cysts9.3.1.1 Branchial Cleft Cysts,Sinuses and FistulaeBranchial apparatus anomalies are lateral cervical lesionsthat result from congenital developmental defectsarising from the primitive branchial arches, clefts andpouches.The branchial apparatus appears around the 4thweek of gestation and gives rise to multiple structures orderivatives of the ears, face, oral cavity and neck. Thesestructures are described in more detail in other sources[126]. Anatomically, the branchial apparatus consistsof a paired series of six arches, five internal pouchesand five external clefts or grooves. The external groovesare of ectodermal origin and are called branchial clefts.The internal pouches are of endodermal origin and areknown as pharyngeal pouches; they are separated bytheir branchial plates [126]. Each branchial arch is suppliedby an artery and a nerve and develops into well-definedmuscles, bone and cartilage. Thus, all three germcelllayers contribute to formation of the branchial apparatus.The arches are numbered 1–6, from cranial tocaudal, and the clefts and pouches 1–5. The correspondingcleft and pouch lie immediately caudal to their numericalarch, that is, the first cleft and pouch lie betweenthe first and second arches, the second cleft and pouchlie between the second and third arches, and so on.A number of theories exist to explain the genesis ofbranchial cleft anomalies. Regauer and associates haveproposed that the cysts arise from the endodermally derivedsecond branchial pouch [95]. An alternative explanationis that the cysts develop from cystic epithelial inclusionsin lymph nodes that are either of salivary glandorigin or from displaced epithelium from the palatinetonsil [43]. Golledge and Ellis recently reviewed the varioustheories on the histogenesis of branchial cleft cysts[43].Papers dealing with anomalies of the branchial apparatusdo not always distinguish between the terms sinusand fistula and often use them interchangeably as synonyms.A sinus is a tract that has only one opening, eithercutaneous or mucosal. A fistula is a tract that hastwo openings, one cutaneous and one mucosal. A cystmay occur independently or in association with a sinusor fistula.Most anomalies of the branchial apparatus of concernto the surgical pathologist present clinically as acyst, fistula, sinus or skin tag. Fistulae, sinuses and skintags occur in younger patients than cysts do [20]. Bran-

266 M. A Luna · K. Pineda-Daboin9Fig. 9.2. Branchial cleft cyst. Wall lined with stratified squamousepitheliumchial cleft cysts constitute approximately 75–80% of allbranchial anomalies, and fistulae and sinuses togetheraccount for 15–20% of all such malformations [1]. Insome series, external fistulae, sinuses and skin tags aremore common than cysts [57].Of all branchial anomalies, 92–99% are associatedwith the second branchial clefts apparatus, probably becauseit is deeper and longer than the others [8]. Use ofthe name “branchial cyst” without further qualificationgenerally refers to a cyst of second branchial origin. Cystsare three times more common than sinuses and fistulaein this apparatus. They typically occur along the anteriorborder of the sternocleidomastoid muscle from the hyoidbone to the suprasternal notch, but have infrequentlybeen described in the midline, just as a thyroglossal ductcyst may occur laterally, as bilateral branchial cleft cysts,or even in the lateral wall of the nasopharynx [8, 85].Branchial cleft anomalies have no gender preference.Most patients (75%) are aged 20–40 years at the time ofdiagnosis. Since fewer than 3% of cysts are found in patientsolder than 50 years, the pathologist must be carefulin making this diagnosis in this age group; a metastaticcystic squamous cell carcinoma in a cervicallymph node may masquerade as a branchial cleft cyst.On pathologic examination the cysts are unilocular,usually between 2 and 6 cm in diameter, and lined withstratified squamous epithelium (90%), respiratory epithelium(8%), or both (2%; Fig. 9.2). Lymphoid aggregateswith or without reactive germinal centres beneaththe lining epithelium are found in the majority of cysts(75–80%). Acute and chronic inflammation, foreignbody giant-cell reaction and fibrosis are the secondarymicroscopic changes in the wall of the cyst. In exceptionalcases, heterotopic salivary tissue may even befound in the wall of the cyst [111]. Carcinoma in situ hasseldom been described in the lining of the cysts [132].Regauer et al. have postulated that the cysts are initiallylined with the endodermally derived pouch type of respiratoryepithelium, which is replaced by squamous epitheliumthrough an intermediate stage of pseudostratifiedtransitional-type epithelium [95].Fistulae and sinuses are more often found at birthor in early childhood than cysts. The external opening,when present, is usually located along the anterior borderof the sternocleidomastoid muscle at the junction ofits middle and lower thirds. The tract, if there is one,follows the carotid sheath; it crosses over the hypoglossalnerve, runs between the internal and external carotidarteries and ends at the tonsillar fossa [122].Thymic cyst and cystic low-grade mucoepidermoidcarcinoma with prominent lymphoid stroma are considerationsin the differential diagnosis. The cyst’s benignlining distinguishes it from metastatic cystic squamouscarcinoma.Complete surgical excision of the cyst, sinus, or fistulais indicated. In a review of 274 patients with branchialremnants treated at the Mayo Clinic, the recurrence ratewas only 2.7% for patients with no history of surgery orinfection, 14% in those with a history of infection and21.2% in those who had undergone prior attempts at surgicalremoval [28].Anomalies from the first branchial arch accountedfor only 8% of all branchial cleft anomalies at the MayoClinic [82]. Of these, 68% were cysts, 16% sinuses and16% fistulae. These anomalies occur predominantly infemales and are found in all age groups. In general, sinusesand fistulae tend to develop in infants and children,whereas cysts are more common in older groups.Clinically, they may masquerade as parotid tumours oras otitis with ear drainage [82].Disorders of the first branchial cleft are classified intotwo types [119]. Type I are those that embryologically duplicatethe membrane (cutaneous) external auditory canal.Accordingly, only ectodermal components are observedunder the microscope. On histologic examinationthey are often confused with epidermoid cysts, for theyare lined solely by keratinised, stratified squamous epithelium,with no adnexal structures or cartilage. Characteristically,they are located medial, inferior or posteriorto the concha and pinna. Drainage from cysts or fistulaemay occur in any of these sites. The fistula tract or sinusmay parallel the external auditory canal and ends in ablind cul de sac at the level of the mesotympanum.Type II deformities are composed of both ectodermaland mesodermal elements and therefore contain,in addition to skin, cutaneous appendages and cartilage(Fig. 9.3). Patients with this defect usually present withan abscess or fistula at a point just below the angle of themandible, through the parotid gland, toward the externalauditory canal. Type II defects are therefore more intimatelyassociated with the parotid gland than are type Idefects. Sometimes an anomaly cannot be distinguishedas type I or type II. In those instances, Olsen et al. suggestedthat the abnormality be classified only as to whetherit is a cyst, sinus, or fistula [82]. Complete excision is

Neck Cysts, Metastasis, Dissection Chapter 9 267Fig. 9.3. First branchial cleft cyst, Type II. Squamous epitheliumlining the cystic cavity. Note the presence of skin appendage structuresand cartilage in the stromaFig. 9.5. Branchogenic carcinoma. Inset: malignant squamousand respiratory epithelium lining the cystic wallNeither the fifth nor the sixth branchial arch formsclefts or pouches in humans [126]. Branchial cleft cystshave been reported infrequently in the parotid, thyroidand parathyroid glands, floor of the mouth, tonsil,pharynx and mediastinum [17]. Many of these cystshave the microscopic features of lymphoepithelial cysts(Fig. 9.4).9.3.2 Branchiogenic CarcinomaFig. 9.4. Lymphoepithelial cyst. Note the absence of lymphoidhyperplasiathe only effective treatment. In some cases, this may necessitatea superficial parotidectomy. First branchial cleftabnormalities must be differentiated pathologically fromepidermal cysts (especially type I), dermoids (especiallytype II), and cystic sebaceous lymphadenoma.Anomalies from the third and fourth branchial apparatusesare rare and together account for fewer than 5% ofall branchial cysts, sinuses and fistulae [80]. A fistula inthe pyriform sinus is one of the more common manifestationsof a third branchial anomaly [32]. Recurrent infectionsof the lower neck, including suppurative thyroiditis,and a fistulous tract into the pyriform sinus are the featuresof a fourth branchial cleft or pouch anomaly [80].Third and fourth branchial sinus anomalies can bedistinguished only by detailed surgical exploration. Athird branchial sinus always extends from the pyriformsinus through the thyroid membrane cranial to the superiorlaryngeal nerve. In contrast, a fourth branchialsinus extends from the pyriform sinus caudal to the superiorlaryngeal nerve and exits the larynx near the cricothyroidjoint [127].Branchiogenic carcinoma or primary cervical neoplasticcysts are of interest from an historical viewpoint [69,96]. Few of the purported examples of this entity fulfilthe four criteria that Martin et al. considered necessaryto establish the diagnosis, which are as follows:1. The cervical tumour occurs along the line extendingfrom a point just anterior to the tragus, along theanterior border of the sternocleidomastoid muscle, tothe clavicle;2. The histologic appearance must be consistent with anorigin from tissue known to be present in the branchialvestigial;3. No primary source of the carcinoma should be discoveredduring follow-up for at least 5 years;4. Cancer arising in the wall of an epithelium-lined cystsituated in the lateral aspect of the neck can be demonstratedhistologically (Fig. 9.5) [69].The fulfilment of these criteria is practically impossible,and the existence of “ branchiogenic carcinoma” mustremain entirely hypothetical [69, 73, 96, 116]. The criteriahave been criticised on the grounds that they aremuch too restrictive and nearly preclude a diagnosis ofbranchiogenic carcinoma [15, 86].Several authors have estimated that, even acceptingtentative examples of branchiogenic carcinoma, its incidencewould be minuscule (0.3% of all malignant su-

268 M. A Luna · K. Pineda-Daboin9praclavicular tumours) [15, 58]. There is no doubt thatmost, if not all of them are actually cervical node metastaseswith a cystic pattern. The palatine tonsil, or moregenerally the anatomic region of Waldeyer’s ring, is notoriousfor producing cystic solitary metastases that resemblethe usual appearance of branchial cleft cysts [69,73, 96, 116].All of the suspected branchiogenic carcinomas havebeen squamous-cell in type, and all but one have beenin the region of the second branchial apparatus [15, 58,86]. The patients have been predominantly males rangingin age from 38 to 71 years [15, 58]. Nearly all of thesemasses have been cystic and have resided in a lymphoidmatrix, hence the presumed relationship to a branchialcyst. It should be obvious that neither cystic architecturenor association with lymphoid tissue is, in itself, an acceptablecriterion for diagnosis of branchiogenic carcinoma[73, 96, 116].An absence or presence or peripheral lymphatic sinusesand/or follicular centres in the lymphoid tissuehas been used to exclude or confirm metastasis to thelymph nodes. This criterion is not valid. Branchial cleftcysts often lie within lymph nodes, and metastases canobscure the architecture of a lymph node [96, 116].9.3.3 Thyroglossal Duct Cystand Ectopic ThyroidCysts and sinuses may be found along the course of thethyroglossal duct; these cysts develop during the migrationof the thyroid gland from the base of the tongue.The cysts are situated in the midline of the neck, usuallybelow the hyoid bone. A fistula may develop froman infected cyst.The thyroid begins to develop during the 4th weekof gestation when the embryo is about 2–2.5 mm long[126]. It is an endodermal derivative composed of twosmall lateral anlagen and the more substantial mediananlage from the foramen caecum at the base ofthe tongue. Because of elongated cephalad embryonicgrowth rather than active descent, the orthotopic pretracheallocation of the thyroid is caudal to the foramencaecum [126].Thyroglossal duct cysts (TDC) are twice as commonas branchial cleft cysts. In a review of 1,534 cases in theliterature, Allard observed that, at the time of presentation,67% of patients had a cyst and 33% a fistula [5].Approximately 90% of TDC occur in the midline ofthe neck, although some may occur paramedially, mostoften on the left. Overall, 73.8% occur below the hyoidbone, 24.1% are suprahyoid, and 2.1% are intralingual[65]. Spinelli et al. reviewed their experience with neckmasses in children and noted that 17 (26%) of 154 caseswere TDC, and branchial cleft cysts were less common[115].Most patients with a TDC have no symptoms; theyseek evaluation for a midline neck mass discovered incidentallyby themselves or a family member. The mostcommon manifestations are pain, a draining sinus orfistula, infection, or dysphagia. A cyst in the floor ofthe mouth may cause feeding problems in newborns,whereas a cyst at the base of the tongue has, in rare instances,been responsible for sudden death in infancy[106].Thyroglossal duct cysts range in size from 0.5 to4 cm in diameter. They can be either unilocular or multilocularand usually contain mucoid material if the cystis not infected or mucopurulent material or pus if it is.The type of epithelium lining the cyst varies from onecase to another, or even within the same surgical specimen.A columnar to stratified cuboidal epithelium withcilia is the most common type of epithelial lining, foundin 50–60% of cases (Fig. 9.6). Lymphoid nodules in thewall of the cyst are found in 15–20% of cases, while theyoccur in 75% of branchial cleft cysts. A TDC with squamouslining and lymphoid tissue may be difficult to differentiatefrom a branchial cleft cyst. Immunoperoxidasestaining for thyroglobulin may be of help. Ectopicthyroid tissue is identified (as collections of thyroid folliclesin the soft tissues adjacent to the cyst) in 3 –20%of TDCs, although these figures are related to some extentto the number of tissue slides taken for histologicexamination and the extent of inflammatory and reactivechanges present in the surrounding tissue.Mucous glands were identified in 60% of the TDCstudied by Sade and Rosen [102]. These authors believethe mucous glands to be part of the normal thyroglossalapparatus and not just glands found at the base ofthe tongue.Thyroglossal duct remnants are treated by completesurgical excision using the Sistrunk operation [112].This consists of a block excision of the entire thyroglossaltract to the foramen caecum, as well as removal ofthe central 1–2 cm of the hyoid bone. If this procedure isperformed, the TDC recurrence rate is less than 5% [91].If the central portion of the bone is not removed, the recurrencerate is as high as 50% [3, 74].Ectopic thyroid is defined by identification of gross ormicroscopic thyroid tissue outside of the thyroid gland.Most commonly from the base of the tongue (lingualthyroid) to the mid-lower neck superior to the orthotopicthyroid [25]. The ectopia can be complete or more oftenassociated with an orthotopic thyroid.Hypothyroidism is a frequent finding in patients withlingual thyroid [105]. Batsakis and collaborators noted aclinical prevalence of lingual thyroid of 1 in 10,000 individuals,but an autopsy prevalence of 1 in 10 [10]. Ectopicthyroid is histologically composed of uniform, oftensmall, follicles containing minimal colloid. The microfolliclesare usually intercepted by the skeletal muscleof the tongue.

Neck Cysts, Metastasis, Dissection Chapter 9 269Fig. 9.6. Thyroglossal duct cyst. Thyroid follicles are present inthe wallFig. 9.7. Cervical thymic cyst. Notice Hassall’s corpuscles in thewall (arrow)Patients with presumed ectopic thyroid should undergoa preoperative thyroid scan to rule out ectopicthyroid gland, because patients with an ectopic thyroidgland have no additional normally functional tissue,and thus are rendered permanently athyroid by excisionof the ectopic gland [88].Carcinoma from the thyroglossal duct (Hürthle celladenomas and papillary carcinomas) have been reportedin less than 1% of TDC [6, 118]. Yoo et al. reviewed115 cases of papillary carcinoma arising in TDC publishedin the literature [128]. These tumours are typicallyintracystic, and usually the thyroid gland proper isuninvolved. However, multifocal papillary carcinomashave been documented in TDC as well as in the gland [6,118]. Most researchers agree that a) total thyroidectomyis not routinely indicated as long as there are no palpableabnormalities in the gland and no significant scintiscanfindings, and b) the Sistrunk operation probably offers areasonable chance of cure [6, 63, 118, 128].9.3.4 Cervical Thymic CystFaulty development of the third and fourth pharyngealpouches results in abnormalities of the thymus andparathyroid glands.Cervical thymic cysts (CTC) are morphologicallyidentical to their mediastinal counterparts. They arefound in the anterior triangle of the neck along the normalpath of descent of the thymus, with or without parathyroidglands, and they have a fibrous band or a solidthymic cord connection to the pharynx or mediastinum.The thymus develops as paired structures from thethird branchial pouch in the 6th week of gestation.The endodermal primordium of the thymus has a ductalor luminal connection to the pouch that is knownas the thymopharyngeal duct. Ventromedial and caudalgrowth of the respective anlage results in separationof the thymus from the pharynx. The fragmented remnantsof the solid thymopharyngeal duct are thought tobe the progenitors of accessory parathyroid and thymictissue in the neck [62]. The inferior parathyroid glandsalso originate from the third pouch, and their descentwith the thymus explains their localisation relative tothe superior parathyroids, which arise from the fourthbranchial pouch. By the end of the 8th week, the lowerpoles of the thymic anlage approach each other, but donot fuse, at the level of the aortic arch. Failures to involuteor descend of any of the thymic anlage are responsiblefor a variety of abnormalities, such as thymic cysts.The reader is referred to the excellent paper by Zarbo etal. for the classification of these developmental abnormalitiesof the thymus [130].Cervical thymic cysts are uncommon; approximately120 cases in children were reported through 2001 [51,89]. Males are affected more commonly than females. Accordingto Guba et al., 70% of CTC are on the left side ofthe neck, 23% on the right and the remainder in the midline[47]. They can be found anywhere from the angle ofthe mandible to the sternum, paralleling the sternocleidomastoidmuscle and normal descent of the thymus. Sixtysevenpercent occur in the first decade of life. The remainderoccur in the second and third decades [51].The cysts range between 2 and 15 cm and may be eitherunilocular or multilocular. The epithelial liningmay be cuboidal, columnar, or stratified squamous. Insome areas, the epithelium may be replaced by fibrous orgranulation tissue containing cholesterol clefts and multinucleatedgiant cells. To qualify a cyst as a CTC, thymictissue must be found within the cyst wall (Fig. 9.7);detection of this tissue may require numerous sections.Cervical thymic cysts rarely have malignant potential.Recently, Moran et al. reported for the first timecarcinomas arising in CTC [76]. This contrasts with mediastinalthymic cysts, in which malignancies are oftenseen. CTC also have not demonstrated pseudoepitheliomatoushyperplastic changes, as in some mediastinalcysts.

270 M. A Luna · K. Pineda-DaboinFig. 9.8. Cervical parathyroid cyst lined with cuboidal epithelium.Parathyroid tissue is present in the wallFig. 9.9. Cervical bronchogenic cyst. Respiratory epithelium linesthe cyst wall9The differential diagnosis includes the other developmentalcysts of the neck, as well as rare cystic presentationsof Hodgkin’s disease, thymoma, and germinoma.These three neoplasms are more likely, however, to presentin the anterior mediastinum. The reader is referredto the excellent paper by May for clinical features usefulin differentiating these conditions [70]. Complete surgicalexcision is the treatment of choice.9.3.5 Cervical ParathyroidCystCysts of the parathyroid glands, like thymic cysts, haveseveral characteristic morphologic features, including apersistent hollow tract with the third or fourth branchialpouch. It is estimated that 5% of neck cysts or fewer areparathyroid in origin. Few parathyroid cysts have beenreported in childhood, implying that most are acquired,including cystic parathyroid adenoma.There appear to be two distinct types of parathyroidcysts: non-functioning and functioning. The formermake up the majority of these cysts and are about twoto three times more common in women than in men.The mean age of patients with a non-functioning cyst is43.3 years. Functioning cysts account for 11.5 to 30% ofthese cysts [48]. They are more common in men by a ratioof 1.6:1 and tend to occur in sites other than the inferiorparathyroid glands, from the angle of the mandibleto the mediastinum [120]. The mean age of patients withfunctioning cysts is 51.9 years.About 95% of these cysts occur below the inferiorthyroid border, and 65% are associated with the inferiorparathyroid glands. Cysts have been identified fromthe angle of the mandible to the mediastinum, however,and they can occur in the thyroid lobe or posteriorly[36].Fine-needle aspiration is the principal diagnostictool. Aspiration of clear fluid with an elevated parathyroidhormone level is a definite indication of a parathyroidcyst. The C-terminal/midmolecular zone of theparathyroid hormone should be assayed, because theN-terminal-specific assay is frequently associated withfalse-negative results [81].Histologic studies show that a parathyroid cyst’s wallis usually formed by a solitary layer of compressed cuboidalor low columnar epithelium, with either chief oroxyphilic cells present in the fibrous capsule (Fig. 9.8).Some cysts may not have any identifiable parathyroidtissue, but even in these cases a diagnosis can be establishedby testing the cystic fluid. Immunostaining forparathyroid hormone could be of help.Aspiration may be curative, but persistence or recurrenceof the cyst is a sign that surgical removal is in order.Functional cysts are associated with a high risk ofother parathyroid gland abnormalities such as hyperplasiaor adenoma [92].9.3.6 Cervical BronchogenicCystCervical bronchogenic cysts are uncommon congenitallesions found almost invariably in the skin or subcutaneoustissue in the vicinity of the suprasternal notch or manubriumsterni, rarely in the anterior neck or shoulder.Bronchial cysts are derived from small buds of diverticulathat separate from the foregut during formation ofthe tracheobronchial tree. When they occur outside thethoracic cavity, the cyst presumably arises from erraticmigration of sequestered primordial cells.They are usually discovered at or soon after birthand appear as asymptomatic nodules that slowly increasein size or as draining sinuses exuding a mucoidmaterial. They are more common in males, in some seriesby a margin of 3:1 [31]. The cysts range from 0.3to 6 cm in size. They are lined by ciliated, pseudostratifiedcolumnar epithelium (Fig. 9.9). If the cyst is infect-

Neck Cysts, Metastasis, Dissection Chapter 9 271ed squamous epithelium is found. The cyst wall containssmooth muscle, elastic fibres and seromucous glands. Inthe 30 cases studied by Fraga et al., smooth muscle wasidentified in 24 and seromucous glands in 16. In contrastto their intrathoracic counterparts, only 2 containedcartilage [39].A bronchogenic cyst can be distinguished from a teratomaby a complete absence of tissues other than thosethat can be explained on the basis of a malformation.The lack of ciliated epithelium distinguishes a lateralcervical cyst containing gastric mucosa from a cervicalbronchogenic cyst. TDC can be differentiated from abronchogenic cyst by finding thyroid follicles; furthermore,TDC do not contain smooth muscle or cartilage.Complete surgical excision of a bronchogenic cystalong with its sinus tract is curative. Malignancies havenot been described in cervical bronchogenic cysts.9.3.7 Dermoid CystICD-O:9084/0The term dermoid cyst should be reserved for a cysticneoplasm that originates from the ectoderm and mesoderm;endoderm is never found in these cysts [101]. Thehead and neck area is a common site of occurrence fordermoid cysts, accounting for 34% of cases. These cystsare located in the skin and subcutaneous tissues [113].The position of these dermoid cysts at the midlineand along the lines of embryonic fusion of the facialprocesses is consistent with their origin by inclusions ofectodermal tissue along lines of closure at junctions ofbone, soft tissue, and embryonic membranes [87].Dermoid cysts in the neck account for 22% of midlineor near-midline neck lesions [101]. They have beendescribed in the upper neck, near the thyroid cartilage,and as low as the suprasternal notch. They may occur inpeople of almost any age. More than 50% are detected bythe time a person is 6 years old, and approximately onethirdare present at birth [87, 101, 113]. The distributionbetween the sexes is approximately equal.Dermoid cysts range in size from a few millimetresto 12 cm in diameter. On microscopic examination theyare lined by stratified squamous epithelium supportedby a fibrous connective tissue wall. Ectodermal derivativesmay be seen, including dermal adnexa such as hairfollicles, sebaceous glands, and sweat glands.9.3.8 Unclassified CervicalCystSome cysts may be difficult to classify because of anapparent discrepancy between the anatomic site of presentationand the histologic features, indeterminate microscopicfindings, loss of an intact epithelial lining, ormixed histologic appearance. When a final determinationregarding the type of cyst is not possible, the term“congenital or developmental cyst, indeterminate type”should be used [121].9.3.9 Non-DevelopmentalCystsMost of the non-developmental cysts in the head andneck region occur in the jaw bones, oral cavity or parenchymaorgans, such as the thyroid gland, salivaryglands and parathyroid glands. Mucoceles, ranulas, andlaryngoceles are considered non-developmental cyststhat may occur in the neck. Ranulas are actually pseudocysts:they lack an epithelial lining. Because they mimictrue cysts histopathologically as well as clinically or radiographically,however, it is reasonable and convenientto include them in a general discussion of cystic lesions.Mucoceles are discussed in Chap. 5.9.3.9.1 RanulaA ranula is a special type of mucous retention cyst mostcommonly caused by partial obstruction of the excretoryduct of the sublingual gland. Rarely, it may originatefrom the cervical sinus or from branchial cleft remnants.The classic or simple ranula is a true cyst linedwith cuboidal, columnar or squamous epithelium andfilled with mucoid material similar to that found in mucoceles.It produces a mass in the floor of the mouth toone side of the midline. Dissection of the mucus into thefascial planes of the neck results in a pseudocyst calledplunging ranula. Simple ranulas are distinguished frommucoceles by their location and by the presence of anepithelial lining [11].The plunging ranula may mimic other cystic or glandularswellings, such as dermoid and epidermoid cysts,TDC or cystic hygroma. Quick and Lowell [90] havepointed out that no specific clinical diagnostic tests areavailable to distinguish these lesions. Consequently, adefinitive diagnosis is dependent on postoperative histopathologicevaluation of the surgical specimen.The management of these lesions requires removal ofthe sublingual gland and excision of the ranula. The recurrencerate after this procedure is 0%. Excision of onlythe ranula was followed by a 25% recurrence rate, whereasmarsupialisation results in a 36% recurrence rate [129].9.3.9.2 LaryngoceleLaryngocele is a dilatation of Morgagni’s ventricle or itsappendages, which is filled with air or fluid [16, 37, 49].For more details on this lesion, see Chap. 7.

272 M. A Luna · K. Pineda-Daboin9.4 Cystic Neoplasms9.4.1 Cystic Hygromaand Lymphangioma9Cystic hygroma and lymphangioma represent the twoends of the spectrum of the histopathologic classificationof lymphatic lesions [124]. Whether these are trueneoplasms or represent malformations or hamartomas isstill debated, but this issue is of no clinical consequence.These lymphatic lesions may be divided into three morphologictypes: capillary (lymphangioma circumscriptum,ICD-O:9171/0), cavernous (lymphangioma cavernosum,ICD-O:9172/0), and cystic (cystic hygroma,ICD-O:9173/0) [34].Lymphangiomas are relatively rare. Almost alllymphangiomas appear during the first 2 years of life,most commonly in the oral cavity, parotid gland, neckor axilla. Lymphangiomas often lie in the lateral cervicalregion beneath the platysma, less frequently in theanterior cervical region, and may extend into the mediastinum.Cervical cystic hygroma (hygroma colli cysticum) isa cystic lymphangioma of the neck. It can be associatedwith foetal hydrops and Turner’s syndrome [27]. Thislesion consists microscopically of lymphatic channelsof variable size and shape lined with typical endothelialcells. Focal infiltrates of lymphocytes in the stromaare common.The main differential diagnosis of lymphangiomasof the head and neck is cavernous haemangioma.Lymphangiomas contain proteinaceous fluid and thinvalves, and the surrounding tissue is usually infiltratedby lymphocytes, whereas cavernous haemangiomas arefilled with red blood cells and lack valve structures.Treatment of lymphangioma consists of surgery;staged procedures may be required for large lesions. Recurrencerates range from 15 to 80% [38].9.4.2 HaemangiomaHaemangiomas are a heterogeneous group of vascularlesions commonly located in the head and neck. Mosthaemangiomas in this region are superficial; however,they may arise within skeletal muscle and involve parenchymaltissue such as salivary glands and the thyroidgland. Haemangiomas are classified by morphologyinto capillary, cavernous, arteriovenous, venous andepithelioid types [78]. Of these types, cavernous is theone that most often simulates a cyst. The other typesmore often manifest themselves as solid lesions.Fig. 9.10. Mature teratoma. Cysts lined with squamous and respiratoryepithelium. Cartilage is presentFig. 9.11. Immature teratoma composed of primitive neuroectodermaltissue9.4.3 TeratomaICD-O:9080/1Teratomas are neoplasms composed of elements frommore than one of the three germ layers (ectoderm, endodermand mesoderm). Cervical teratomas representonly about 3% of all teratomas [9]. In the head and neckregion, lesions are also found in the central nervous system,orbit, temporal fossa, oropharynx, oral cavity, nasopharynx,nasal cavity, palate and tonsil [60].Teratomas arising in the cervical region are rare. Althoughthey were previously divided into those arisingfrom the thyroid gland and those arising elsewhere, thisdistinction has not proved to be clinically useful. Themost significant clinical marker divides the tumourspresenting in infancy or early childhood from those presentingafter the first decade of life. The former groupexhibits primarily benign clinical behaviour. However,such lesions are associated with a high mortality rate atthe time of birth, generally because the airway and pulmonaryfunction are compromised. The latter group is

Neck Cysts, Metastasis, Dissection Chapter 9 273composed of tumours that are usually smaller and morelikely to be malignant [9, 33, 44, 50].Various systems of classification for teratomas havebeen proposed. The majority of these were consideredby Gonzalez-Crussi, who presented a tentative new classificationsystem for all teratomas that does not rely onthe primary site of occurrence of the tumour [44].On gross examination, these tumours are usuallycystic, but they can be solid or multiloculated. They arecommonly encapsulated, lobulated masses that measureup to 15 cm in their greatest dimension [44]. On microscopicexamination, the cervical teratomas are similar tothose found in other anatomical regions. They may containskin, hair, fatty tissue, central nervous tissue, cartilage,bone and components of the respiratory or digestivetract (Fig. 9.10). Areas of more immature or embryonaltissue may be present (Fig. 9.11).It is exceedingly important to adequately sampleall potentially teratomatous tumours. Specifically, solidareas with necrosis or haemorrhage should be carefullyexamined. It is not unusual to find, in teratomasthroughout the body, small foci of malignant germ celltumours, especially endodermal sinus tumour or choriocarcinoma.The presence of either of these two tissuetypes adversely affects patient prognosis. It is also importantfor the pathologist to recognise that the moreimmature foetal tissues have malignant potential [10, 33,44, 50]. Patients with these tumours require especiallyclose clinical follow-up.Cervical teratomas in the neonate are almost alwaysbenign, whereas the few reported cases of cervical teratomaarising in adults were malignant [44]. To the bestof our knowledge, only seven cases of congenital cervicalteratoma with metastasis have been reported [50].Resection seems to offer the best control in cases of aggressivebiologic behaviour.Most authors strongly favour the operative managementof teratomas [33, 44, 50]. When malignant componentsare found in a teratoma, the patient may need chemotherapyand/or radiotherapy in addition to surgery.9.4.4 Cervical SalivaryGland Cystic NeoplasmsHeterotopic normal salivary glands and salivary glandneoplasms arising in cervical lymph nodes may simulatecervical cysts [107, 131]. These are uncommon neoplasms,and the pathologist may confuse them with metastaticsalivary gland tumours [23, 131]. Ectopic islands of salivarygland tissue within lymph nodes have been implicatedin the pathogenesis of lymphoepithelial cysts andsome neoplastic lesions by several authors [22, 108].This type of neoplasm presents as a painless mass,often cystic, located in the periparotid region, the upperneck, or the anterior cervical triangle. Occasionally,however, these tumours have been described in thelower neck [108, 131]. In the series reported by Zatchuzet al., the age of the patients ranged from 10 to 81 years,with a mean of 45 years. Females were affected morecommonly than males, with a ratio of 3:1 [131].The tumours that more often arise in ectopic salivarygland tissue in the lymph nodes and simulate cysts areWarthin’s tumour and sebaceous lymphadenoma. Otherrare types of salivary gland tumours that may resemblecervical cysts, are dermal analogue tumours, mucoepidermoidcarcinomas and acinic cell carcinomas [67, 103].The pathology of these lesions is discussed in Chap. 5.Surgical excision is the treatment of choice. In sialocarcinomas,excision of the adjacent salivary gland mayappear to be the appropriate treatment to define the siteof the primary tumour, because malignant salivary tumourslocated within lymph nodes suggest metastaticdisease.9.4.5 Miscellaneous LesionsOther tumours that may appear as cervical cysts arecystic neurogenic neoplasms and cervical thymomas.In the neck, the most common locations for neuromaswith cystic degeneration are along the course of the vagusnerve or the cervical sympathetic chain [4]. Cervicalthymomas are classified as being one of four types:1. Ectopic hamartomatous thymoma,2. Cervical thymoma,3. Spindle epithelial tumour with thymus-like differentiation(SETTLE),4. Carcinoma showing thymus-like differentiation(CASTLE).Of these, the first is benign and the second can be locallyaggressive. The third and fourth types are malignant[18].Infectious processes often simulate cervical cysts.Such infections can be bacterial, fungal, parasitic, or viral[46, 104, 114]. Amyloidosis and carotid artery aneurysmshave been reported to mimic cervical cystic tumours[24, 35].9.5 ParagangliomaICD-O:8680/1Paraganglioma, often referred to as chemodectoma, is atumour derived from paraganglia, structures of neuroectodermalcrest derivation that are found throughoutthe body. Paragangliomas are intimately associated withvascular and neural structures in the head and neckregion and are most commonly classified according totheir location: jugulotympanic, vagal, carotid body, andothers, including laryngeal, nasal and ocular [30, 61]. In

274 M. A Luna · K. Pineda-Daboin9Fig. 9.12. Zellballen pattern in a carotid body tumourthis section, only neoplasms of the carotid body and intravagalparaganglia are discussed.Carotid body paragangliomas are the most commontumours of the head and neck paraganglia, making up60–70% of the tumours of this type [30, 61, 100]. Lack etal. found 69 paragangliomas of the head and neck in morethan 600,000 operations (0.12%), and only 1 in 13,400 autopsiesat Memorial Hospital in New York city [61].The tumour, typically located in the carotid bifurcation,is typically found in individuals of either sex in thethird to the eighth decades of life. It often presents as apainless, slowly enlarging mass. It is the only neoplasmthat arises in that particular location. Carotid angiographyis a valuable diagnostic aid. The risk of developingthis tumour is higher in persons living at high altitudesthan those living at sea level [100]. Carotid body paragangliomaswith endocrine activity are rare. The tumour seldomundergoes malignant transformation; histologic criteriaare of little prognostic value. The incidence of metastasisis estimated to be less than 10% [14, 61].The vagal region is the third most frequent site of involvementafter the carotid body and jugulotympanicregion. Unlike the circumscribed carotid body, the vagalparaganglioma represents collections of microscopicnests located along the vagus nerve distal to the ganglionnodosum. Because of the variability in location of thenormal vagal paraganglia, paragangliomas arising fromthese structures also vary in location. At the time of diagnosis,patients are usually in the fourth to fifth decadeof life, and there is a female predominance [14, 30].Patients generally report a slowly growing neck mass,and, because of the intimate relationship with the vagusnerve, cranial nerve palsies may also be present [14, 30].Vagal paragangliomas displace the carotid vessels anteriorly,are grossly round or fusiform, and abut the baseof the skull. Multiple, also bilateral, and familial occurrencesof paragangliomas have been documented.Paragangliomas have a tan, soft cut surface. Paragangliomasfrom all regions of the head and neck arehistologically similar. They are well circumscribed andcomposed of chief cells arranged in nests known as Zellballen(Fig. 9.12). The tumour cells have granular cytoplasmand round nuclei with prominent nucleoli. Nuclearpleomorphism may be present, but mitosis is rare, andnecrosis is usually present only if the patient underwentpreoperative embolisation or if the nests of cells are verylarge. Compressed sustentacular cells and a rich capillarynetwork surround each nest. A reticulin stain highlightsthe Zellballen arrangement of the cells. Malignantvarieties are difficult to distinguish on histologic examination,but generally they have a higher mitotic rate andmore necrosis than benign tumours. Vascular invasionmay be present in both benign and malignant paragangliomas.The chief cells are positive for neuroendocrine markerssuch as chromogranin and synaptophysin. They areusually negative for cytokeratin, but an occasional casehas been reported to be positive [55]. The sustentacularcells are positive for S-100 protein [55].Electron microscopy studies show the tumour cellsto contain neurosecretory granules. The cells have cytoplasmicprocesses that surround neighbouring cells,and the cytoplasm contains abundant large mitochondriaand inconspicuous Golgi apparatus, smooth andrough endoplasmic reticulum.Although histologic findings are generally quite distinctive,the differential diagnosis of paragangliomas ofthe head and neck may include endocrine neoplasms arisingfrom the thyroid (medullary carcinoma) or parathyroidglands and other neuroendocrine carcinomas. Lesscommonly, alveolar soft part sarcoma, melanoma, granularcell tumour and metastatic renal cell carcinoma are includedin the differential diagnosis [14, 30, 55, 61].Surgery is the treatment of choice for paragangliomas.If the neoplasm is completely excised, recurrence isrelatively rare; recurrence rates are 10% for carotid bodytumours and 5–25% for vagal paragangliomas [14, 30,55, 61]. Radiotherapy may be useful as a palliative methodfor those tumours that cannot be controlled by surgicalmeans. Local infiltration of vagal body tumours andextension into the cranial cavity represent significantproblems in disease control. The rate of metastasis in intravagaltumours is estimated at 16%, but most of theseare to regional lymph nodes [14, 30].9.6 Unknown Primaryand Secondary Tumours9.6.1 DefinitionIn head and neck oncology, the term “ unknown primarytumour” means a primary neoplasm that has not beenfound in a patient with neck metastasis, even after a

Neck Cysts, Metastasis, Dissection Chapter 9 275Table 9.2. Location of lymph node metastasis and predominant sites of their primary tumours (extracted from [75, 99, 125]. ENT earnose throat, GI gastrointestinal, GU genitourinaryLymph node region affected by metastasisSublevel IA (submental)Sublevel IB (submandibular)Sublevel IIA (upper jugular)Sublevel IIB (upper jugular)Level III (middle jugular)Level IV (lower jugular)Sublevels VA, VB (posterior cervical)SupraclavicularPredominant sites(s) of primary tumourAnterior floor of mouth; anterior oraltongue, anterior mandibular ridge lower lipOral cavity, anterior nasal cavity,midface, submandibular glandWaldeyer’s ring, oral cavity, nasalcavity, oropharynx, supraglottis, floorof mouth, pyriform sinusAnterior tongue, nasopharynx, tonsilHypopharynx, base of tongueposterior pharyngeal wall, supraglottic larynxHypopharynx, thyroidNasopharynx, thyroid, oropharynxLungs (40%), thyroid (22%)GI tract (12%), GU tract (8%)all ENT regions (20%)thorough work-up. The neck metastasis may representregional or distant primary disease.shows the probable primary sites by region of metastasis[75, 109, 125].9.6.2 Clinical FeaturesAn enlarged cervical lymph node is frequently the firstclinical manifestation of a neoplastic process in the headand neck. Cervical lymph node metastasis is the presentingsymptom in 25% of patients with cancer of theoral cavity or pharynx, in 47% of patients with nasopharyngealcarcinoma, and in 23% of patients with thyroidcarcinoma. In some instances, however, despite a thoroughsearch, a primary tumour cannot be found [45, 64,72, 79, 93, 123].Patients with a high probability of a metastatic tumourin the cervical lymph nodes are men (male: femaleratio 4:1) older than 40 years, who smoke anddrink alcohol heavily. They usually present with apainless node larger than 2 cm along the jugular chainor the supraclavicular fossa. Various groups of lymphnodes can be affected by metastatic neoplasms, but themost frequently involved are the upper jugular (71%),the midjugular (22%), the supraclavicular (18%), andthe posterior cervical nodes (12%). Approximately 14%of patients with such disease have more than one lymphnode group affected by metastases and 10% have bilaterallymph node metastases [45, 123]. The lymphaticdrainage of the head and neck region is highly predictable,and the location of the adenopathy may providea clue to the location of the primary lesion. Table 9.29.6.3 Searchfor the Primary TumourIf the search is conducted systematically, the primarycancer can be discovered in 75–90% of patients presentingwith cervical adenopathy. Evaluation protocols havebeen outlined by several authors [66, 72]. With advancesin upper aerodigestive tract examination that use flexiblefibre optic endoscopes and rigid telescopes, the failureof radiographic tests to determine the location of anunknown primary has become even more apparent. Thismay change in the future, however, with the applicationof advanced radiologic techniques that allow functionalassessment of tissues. Single-photon emission computedtomography (SPECT) using 2-(18-F) fluoro-2-deoxy-D-glucose was able to detect 9 out of 11 histologicallyproven occult primary neoplasms of the upper aerodigestivetract [77].The success rates of the ultimate detection of occultprimaries (by various authors) vary between 10and 75% [64, 72, 79]. As might be expected, occultprimary tumours are significantly less likely to be detectedin patients treated with radiation [98]. Nearly50% of primary carcinomas originally considered occultthat are eventually found in patients after treatmentof the cervical lymph node are located in the regionof Waldeyer’s ring [73, 116]. Of originally un-

276 M. A Luna · K. Pineda-DaboinTable 9.3. Frequency of histologic type of metastases from unknown primary tumours (Extracted from [64, 66, 75])CervicalSquamous cell carcinomaUndifferentiated carcinomaMelanomaThyroid carcinomaAdenocarcinomaSalivary gland carcinomaSupraclavicularAdenocarcinomaSquamous cell carcinomaUndifferentiated carcinomaThyroid carcinomaProstate carcinomaSarcoma9known primary tumours found below the clavicle, thelargest number are in the lungs, followed by the gastrointestinaltract.In cases in which the primary tumour is not found,the most likely explanations are that either the primarylesion is so small that it is not visible or it has regressedspontaneously. The latter consideration is speculative,since spontaneous regression cannot be proved. Althoughthe origin of a carcinoma in the wall of a branchiogeniccyst is possible, this remains entirely hypothetical.Few observers are willing to agree that primarysquamous cell carcinoma (SCC) or other types of carcinomaarise in branchiogenic cysts. The most attractivehypothesis, therefore, is that the primary neoplasm istoo small to be detected.9.6.4 Common Locationof the Primary TumourThe gross appearance of a metastasis is important onlywhen it is present in a cystic node, because in cystic metastases,the primary tumour is most frequently locatedin the palatine tonsils or in Waldeyer’s ring [79, 96, 116].In other situations, the metastatic deposits may adopt amultitude of appearances, from the solid white-grey toyellow haemorrhagic deposits of renal cell carcinoma tothe deeply pigmented focus of metastatic melanoma.9.6.5 Histologic Type of Metastasesand ImmunohistochemicalFeaturesNearly any histologic type of malignancy can present asa metastasis to the cervical lymph nodes, but metastaticSCC is by far the most common tumour to do so. In casesof metastases of an unknown primary tumour to thecervical lymph nodes, 80–85% are of this histologic type(Table 9.3). Undifferentiated carcinomas, adenocarcinomas,thyroid carcinomas, melanoma, rhabdomyosarcomasand sialocarcinomas are the other neoplasms thatoften metastasise to cervical lymph nodes. Adenocarcinomas,undifferentiated carcinomas and thyroid carcinomasmore commonly metastasise to the supraclavicularand scalene nodes. Most of the adenocarcinomas inthe upper jugular region are metastases from lesions ofthe sinonasal tract or salivary glands.The origin of a keratinising SCC, regardless of differentiation,cannot be suggested by its morphology alone.The location of the node can, however, be a clue about thelocation of the primary neoplasm (Table 9.2). The cytokeratin(CK) pattern may be of some help in determiningthe origin of the metastasis. SCC of the upper aerodigestivetract are positive for CK 5/6, 10, 13,14 ,17 and 19,whereas SCC of the lung are positive for CK 5/6, 12 and14 in 100% of cases and CK 17, 8/18 and 19 in 80% of cases.Fewer than 4% of cases are positive for CK 7 and 20[21]. Furthermore, thyroid transcription factor 1 (TTF-1)is positive in 10 to 37% of pulmonary SCC [83].A cystic neoplasm composed of poorly differentiatednon-keratinising carcinoma recapitulating tonsillarcrypt epithelium (Fig. 9.13) most likely originates in thelingual or faucial tonsil [73, 96, 116]. Metastases fromthe tonsil are often unicystic, whereas those from thetongue are more often multicystic [96]. Since the carcinomasare deep in the tonsils, tonsillectomy ratherthan biopsy is needed to demonstrate the primary neoplasm[97]. A subset of these crypt carcinomas are oftenpositive for CK 7, especially those with basaloid features(Fig. 9.14) [94]. These two types of metastatic cysticcarcinoma are often mistaken for a branchial cleftcyst or branchogenic carcinomas by the unwary pathologist[73, 96, 116].9.6.6 Differential DiagnosisCystic metastatic SCC should be distinguished frombenign lesions lined with benign squamous epithelium,such as branchial cleft cysts, AIDS-related cystic lymphoidhyperplasia, benign lymphoepithelial cysts, thymiccysts and cystic cervical thymomas. In all these lesions,the bland appearance of the epithelium rules outmetastatic SCC.The most common location of metastatic adenocarcinomasin the neck is in the lower regions, and the primaryneoplasms are usually located in the thyroid, lung,

Neck Cysts, Metastasis, Dissection Chapter 9 277Fig. 9.13. Metastatic cystic tonsillar crypt carcinoma, resemblinga branchial cleft cyst. Inset: high power view of non-keratinisingcarcinoma, human papilloma virus type 16 positiveFig. 9.14. Cytokeratin 7 positive metastatic tonsillar basaloid carcinomain a cervical lymph nodeTable 9.4. Immunohistochemical approach to metastasis of unknown primary tumour. (Extracted from references [19, 21, 29 ,40, 56,66, 83, 84, 94])Cytokeratin-positiveKeratinizing squamous cell carcinoma CKs 5/6, 7 and 20Non-keratinizing squamous carcinoma CKs 5/6, 7 and 20EBV, HPV 16Adenocarcinoma CKs 7, 20TTF-1ThyroglobulinFemales: GCDFP-15, WT-1, CA 125Males: PSA .Young males: AFP, HCGUndifferentiated carcinoma CKs 7 and 20SynaptophysinChromograninEBVCytokeratin-negativeVarious tumoursS-100 proteinHMB 45Melan ADesminLymphoma markersgastrointestinal tract, or prostate. In the upper and middleneck, on the other hand, the primary lesions are locatedin the sinonasal tract and salivary glands. Only incases of thyroid carcinoma or prostate carcinoma is theorigin of an adenocarcinoma apparent from the morphologyof the nodal metastases. Metastatic adenocarcinomaswith enteric morphology can arise in the sinonasalregion; they are CK 20-positive, like their counterpartsof colonic origin [21]. Thyroglobulin, calcitonin,and TTF-1 are useful markers to probe the thyroid originof a neoplasm of unknown origin [83]. Adenocarcinomaof the prostate may present as metastasis in the leftside of the neck, especially in the supraclavicular nodes.The diagnosis can be confirmed by using the prostatespecificantigen (PSA) test (Table 9.4).The presence of oestrogen receptors and gross cysticdisease fluid protein 15 (GCDFP-15) would suggest abreast origin for adenocarcinoma, but these markers arenon-specific for the breast. Lung adenocarcinomas arepositive for TTF-1 and B 72.3 (Table. 9.4) [83].Benign glandular inclusions in cervical lymph nodesshould not be mistaken for metastatic adenocarcinomas;heterotopic glands of salivary tissue are commonin the paraparotid lymph nodes and less common in theupper cervical nodes. Acinic cell carcinomas, mucoepidermoidcarcinomas, Warthin’s tumour and pleomorphicadenomas have been described in cervical lymphnodes, and they should not be confused with metastaticadenocarcinomas [23, 67, 131].

278 M. A Luna · K. Pineda-Daboin9Metastatic spindle cell neoplasms most likely representsarcomatoid carcinomas, melanomas and sarcomas,especially rhabdomyosarcomas. Pankeratin, MART-1, HMB-45, S-100 protein, desmin, smooth muscle actinand myogenin are some immunostains that help todistinguish these neoplasms [29]. Primary spindle celllesions arising in lymph nodes, such as Kaposi’s sarcoma,presumed tumours of the reticulum cell lineage andbenign intranodal myofibroblastomas, must be distinguishedfrom metastatic spindle neoplasms [2, 56].Undifferentiated malignant neoplasms in cervicallymph nodes need to be investigated with immunohistochemicalstudies. CK-positive malignancies with themorphology of the nasopharyngeal type of carcinomas(NPC) are usually located in the posterior neck, whereasmetastasis from undifferentiated sinonasal carcinomas(SNUC) are present in the upper and mid-cervical regions.If the metastases are located in the lower neck, thelung is the most likely source. If the carcinomas in additionexhibited neuroendocrine differentiation, Merkelcell carcinoma or small cell neuroendocrine carcinoma,from either the lung or the larynx, is the best diagnosis.Merkel cell carcinomas are CK 20-positive [19] and pulmonarysmall cell carcinomas are CK 20-negative andTTF-1 positive in 83–100% of cases [83]. Benign nevuscells have been found in the capsules of submandibularlymph nodes. This rare finding should not lead to an erroneousdiagnosis of malignancy [54].Paccioni et al. evaluated 25 cases of occult metastasisto cervical lymph nodes for the presence of Epstein-Barr virus (EBV) by in situ hybridisation following fineneedleaspiration biopsies of the neck mass and correlatedthe findings with the histologic types of the surgicalspecimens (after locating the primary site of origin).These authors reported that EBV was expressed in 7 metastases,ultimately proving their origin from the nasopharynx,while the remaining 18 cases (not of Waldeyer’sring origin) were negative for EBV [84]. The authorsindicated that detection of EBV in cervical metastasesmay assist in the localisation of the occult primary toWaldeyer’s ring. SNUC do not express EBV [84].The pattern of CK expression is significantly differentin SNUC and NPC, which could be of diagnosticaid. Franchi et al. demonstrated that SNUC expressCK 8 in 100% of cases and CK 19 and CK 7 in 50%, andare negative for CK 5/6, while NPC express CK 5/6 andCK 13 in 90% of cases and are negative for CK 7 [40].Metastases from melanoma, rhabdomyosarcoma,and rarely from olfactory neuroblastoma should beconsidered with the CK-negative undifferentiated neoplasmsand proper immunohistochemical markers investigated(Fig. 9.15). In CK-negative tumours, the possibilityof malignant lymphoma should be consideredand CD 20, CD 3 and antibodies for leukocyte commonantigen should be measured [29].Fig. 9.15. Metastatic spindle cell melanoma in a cervical lymphnode9.6.7 Treatment and ResultsFactors that affect survival in patients with metastasisfrom an unknown primary tumour are clinical stageof the neck, extranodal extension of metastasis and thepresence of recurrent or residual disease after treatment.Surgery combined with irradiation has resultedin better local control of the disease than either therapyalone [53]. The 5-year survival results in series ofpatients with SCC metastatic to the neck from an unknownprimary origin range from 0 to 54% [45, 64, 72,75]. In the last series from the University of Texas M.D.Anderson Cancer Center, the 5-year actuarial survivalrate was 55% [123].9.7 Neck Dissection9.7.1 Classificationof Neck DissectionsThe American Academy of Otolaryngology-Head andNeck Surgery and the American Society of Head andNeck Surgery classified neck dissection into four categories:radical, modified radical, extended and selective[99].Neck dissection is classified primarily by the cervicallymph node groups that are removed, and secondarilyon the anatomic structures that may be preserved, suchas the spinal accessory nerve, the sternocleidomastoidmuscle, and the internal jugular vein [71, 99].The cervical lymph node groups are referred to usingthe level system as described by the Sloan-Kettering MemorialHospital Group (Fig. 9.1). Definition of the anatomicboundaries of the different lymph node groupsis beyond the scope of this chapter and can be found inother sources [99, 110].

Neck Cysts, Metastasis, Dissection Chapter 9 279Table 9.5. Updated classification of neck dissection (extracted from [99]). SCM sternocleidomastoid, IJV internal jugular vein, SANspinal accessory nerveType of dissection Lymph node levels removed Non-lymphatic structures resectedRadical neck dissection I, II, III, IV, V SCM, IJV, SANModified radical neck dissection I, II, III, IV, V Preservation of one or more of the following:SCM, IJV, SANSelective neck dissection Preservation of one or Nonemore of the following:I, II, III, IV, V. Bracketsare used to denote levelsor sublevels removed. (e.g.SND {I, II, III})Extended neck dissection Resection of one or more Resection of one or moreor additional lymph nodes non-lymphatic structureslevels routinely notroutinely not removed byremoved by the radicalthe radical neck dissectionneck dissection(e.g. carotid artery)(e.g. parapharyngeal)Radical neck dissection consists of the removal of allfive lymph node regions of one side of the neck ( levelsI–V). This includes removal of the sternocleidomastoidmuscle, the internal jugular vein, and the spinal accessorynerve. Modified radical neck dissection refers to excisionof all lymph nodes routinely removed by radicalneck dissection, with preservation of one or more of thenon-lymphatic structures (i.e. spinal accessory nerve,internal jugular vein, and/or sternocleidomastoid muscle).The term extended radical neck dissection refers to aneck dissection that is extended to include either lymphnode groups or non-lymphatic structures that are notroutinely removed in a standard radical neck dissection.Selective neck dissection is any type of cervicallymphadenectomy in which one or more of the lymphnode groups that are removed in a radical neck dissectionis preserved [13, 71, 99] (Table 9.5).9.7.2 Gross Examinationof Neck DissectionSurgical SpecimensThe following procedure pertains to standard radicalneck dissections and needs to be modified for the otherthree types. When the main anatomic landmarks suchas the submandibular gland and internal jugular veinare lacking in a neck dissection specimen, the surgeonmust identify and label the lymph node groups. This isespecially important in selective and extended neck dissections.After the neck dissection specimen has been orientedas it appears in vivo, its overall dimensions are measured.The lengths of the sternocleidomastoid muscle and theinternal jugular vein are measured separately. The jugularvein should be opened along its entire length. Tumourinvolvement, including thrombosis, should benoted, described and sampled adequately. Next, thesubmandibular gland, the sternocleidomastoid muscle,and the internal jugular vein should be divided, and thenode-containing fat separated into the five levels:1. Sublingual and submandibular,2. Superior jugular,3. Middle jugular,4. Inferior jugular,5. Posterior.The presence of tumour in soft tissues, submandibulargland and muscle should be described. All lymph nodesvisible and palpable are carefully dissected from connectivetissue with a rim of perinodal connective tissueor fat. The number of lymph nodes (by level) should benoted; if a tumour is present, the actual size of metastasesin centimetres and the presence of extracapsularextension are also noted and recorded. It is generallyrecognised that most masses larger than 3 cm in diameterare not single nodes but are confluent nodes ortumour in soft tissues [7]. Midline nodes, if found, areconsidered ipsilateral nodes. The contralateral neck dissectionis treated similarly. Nodes larger than 2–3 cm

280 M. A Luna · K. Pineda-Daboin9are bisected along their longest axis plane and bothhalves submitted. Smaller lymph nodes are submittedin toto. The tissue sections of lymph nodes submittedfor processing should include a capsule of lymph node,including a rim of perinodal connective tissue or fat. Ifa group of matted lymph nodes is present, two or threesections through the nodes are often adequate to documentthe extent of the tumour. Tissue sections submittedfor processing include all lymph nodes (by level), thesubmandibular gland, the sternocleidomastoid muscle,and the internal jugular vein. If the neck dissection isof the extended type, sections of all extra lymph nodegroups and non-lymphatic structures that were removedshould be submitted for tissue processing.9.7.3 Histologic Evaluationof Neck DissectionThe major aim of the histologic evaluation of the statusof lymph nodes in cases of carcinoma of the headand neck is to provide information required for stagingdisease, planning further treatment and predictingpatient outcome. The histologic evaluation alsodocuments and confirms the pathologist’s own grossevaluation of the dissected specimen. More importantly,increasingly important histologic parameters,such as number, sizes and levels of positive nodes, thepresence or absence of extracapsular spread, the presenceof desmoplastic reaction, the presence of gross residualtumour and the presence of tumour emboli inintervening lymphatics, among others, can be assessedby a thorough histologic evaluation. These histologicfindings by themselves and in combination with otherhistologic parameters have been increasingly identifiedas important prognostic factors in disease controland survival, recurrence of neck disease and distantmetastasis. The five factors that are currently indicatorsfor adjuvant postoperative therapy can be reliablyprovided only by histologic evaluation; they are:1. Extranodal spread of disease,2. Number of lymph nodes involved,3. Number of lymph node regions involved,4. Size of metastases,5. Presence of desmoplastic reaction in metastatic disease[42].References1. Agaton-Bonilla FC, Gay-Escola C (1996) Diagnosis andtreatment of branchial cleft cysts and fistulae. A retrospectivestudy of 183 patients. Oral Maxillofac Surg 25:449–4452. Aguacil-Garcia A (1992) Intranodal myofibroblastoma in asubmandibular lymph node. A case report. Am J Clin Pathol978:69–723. Al-Dousary S (1997) Current management of thyroglossalductremnant. J Otolaryngol 126:259–2654. Al-Ghandi S, Black MJ, Lafond G (1992) Extracranial headand neck schwannomas. J Otolaryngol 2:86–885. Allard RHB (1982) The thyroglossal duct cyst. Head Neck1:134–1366. Aluffi P, Pino M, Boldorin R et al. (2003). Papillary thyroidcarcinoma identified after Sistrunk procedure, report of twocases and review of the literature. Tumori 89:207–2107. American Joint Committee on Cancer (1997) Cancer stagingmanual. Lippincott, Philadelphia8. Ayache D, Ducroz V, Roger G et al. (1997) Midline cervicalcleft. Int Pediatr Otorhinolaryngol 40:189–1939. Batsakis JG, El-Naggar AK, Luna MA (1995) Teratomas ofthe head and neck with emphasis on malignancy. Ann OtolRhinol Laryngol 104:456–50010. Batsakis JG, El Naggar AK, Luna MA (1996) Thyroid glandectopia. Ann Otol Rhinol Laryngol 105:996–100011. Baurmash HD (2003) Mucoceles and ranulas. J Oral MaxillofacSurg 61:369–37812. Bielamowicz SA, Storper BA et al. (1994) Spaces and trianglesof head and neck. Head Neck 164:383–38813. Byers RM (1985) Modified neck dissection: a study of 967cases from 1970 to 1980. Am J Surg 150:414–42114. Carlsen CS, Godballe C, Krogdahl AS et al. (2003). Malignantvagal paraganglioma: report of a case treated with embolization.Auris Nasus Larynx 30:443–44615. Carroll W, Zappia JL, McClatchey K (1993) Branchiogeniccarcinoma. J Otolaryngol 22:26–2816. Cassano L, Lombardo P, Marchese-Ragona R et al. (2000).Laryngopyocele: three new cases and review of the literature.Eur Arch Otorhinolaryngol 257:507–51117. Cassarino DS, Milas M, Folpe AL (2003) Bilateral intrathyroidallymphoepithelial cyst. Arch Pathol Lab Med 127:251–25218. Chan JK, Rosai J (1991) Tumors of the neck showing thymicor related brachial pouch differentiation. A unifying concept.Hum Pathol 22:349–36719. Chan JKC, Suster S, Wenig B et al. (1997) Cytokeratin 20 immunoreactivitydistinguishes Merkel cell (primary cutaneousneuroendocrine) carcinomas and salivary gland smallcell carcinomas from small cell carcinomas of various sites.Am J Surg Pathol 21:226–23420. Choi SS, Zalzal GH (1995). Branchial anomalies a review of52 cases. Laryngoscope 105:909–91321. Chu PG, Weiss LM (2002) Keratin expression in human tissueand neoplasms. Histopathology 40:403–43922. Cleary K, Batsakis JG (1990) Lymphoepithelial cyst of the parotidgland region. A new face on an old lesion. Ann OtolRhinol Laryngol 99:62–6423. Croce A, Moreti H, Bianchedi M et al. (1996) Carcinoma inectopic Warthin’s tumor: a case study and review of the literature.Acta Otorhinolaryngol Ital 16:543–54924. Cunningham MJ, Rueger RG, Rothfus WE (1989) Extracranialcarotid aneurysm: an unusual neck mass in a youngadult. Ann Otol Rhinol Laryngol 98:396–39925. Damiano A, Glickman AB, Rubin JS et al. (1996) Ectopic thyroidtissue presenting as a midline neck mass. Int J PediatrOtorhinolaryngol 34:141–14826. Davenport M (1996) Lumps and swelling of the head andneck. BMJ 312:368–37127. De Serres L, Sie KCY, Richardson MA (1995) Lymphaticmalformations of the head and neck. A proposal for staging.Arch Otolaryngol Head Neck Surg 121:577–58228. Deane SA, Telander RL (1978) Surgery for thyroglossal ductand branchial cleft anomalies. Am J Surg 136:348–35329. DeYoung BR, Wick MR (2000) Immunohistochemical evaluationof metastatic carcinoma of unknown origin: an algorithmicapproach. Semin Diagn Pathol 17:184–19330. Diaz Manzano JA, Medina Benegas A, Osete Alaladejo JM etal. (2003) Paraganglioma of the vagus. A case report and reviewof the literature. An Otorrinolaringol Ibero Am 30:127–13631. Dolgin SE, Groisman GM, Shah K (1995) Subcutaneousbronchogenic cysts and sinuses. Otolaryngol Head NeckSurg 112:763–766

Neck Cysts, Metastasis, Dissection Chapter 9 28132. Edmonds JL, Girod DA, Woodroof JM et al. (1997) Thirdbranchial anomalies. Avoiding recurrences. Arch OtolaryngolHead Neck Surg 123:438–44133. Elmasalme F, Giacomantonio M , Clark KD et al. (2000)Congenital cervical teratoma in neonates, case report and review.Eur J Pediatr Surg 10:252–25734. Emery PJ, Baily CM, Evans JNG (1984) Cystic hygroma of thehead and neck. A review of 37 cases. J Laryngol Otol 98:613–61935. Endicott JN, Cohen JJ (1979) Amyloidosis presenting as amass in the neck. Laryngoscope 89:1224–122836. Entwistle JWC, Pierce CV, Johnson DE et al. (1994) Parathyroidcyst: report of the sixth and youngest pediatric case. JPediatr Surg 29:1528–152937. Ettema SL, Carothers DG, Hoffman HT (2003) Laryngoceleresection by combined external and endoscopic laser approach.Ann Otol Rhinol Laryngol 112:361–36438. Farmand M, Kuttenberger JJ (1996) A new therapeutic conceptfor the treatment of cystic hygroma. Oral Surg Oral MedOral Pathol Oral Radiol Endod 81:389–39539. Fraga S, Helwig EB, Rosen SH (1971) Bronchogenic cysts inthe skin and subcutaneous tissue. Am J Clin Pathol 56:230–23840. Franchi A, Meroni M, Massi D et al. (2002) Sinonasal undifferentiatedcarcinoma, nasopharyngeal-type undifferentiatedcarcinoma, and keratinizing and nonkeratinizing squamouscell carcinoma express differentiated cytokeratin patterns.Am J Surg Pathol 25:1597–160441. Frierson HF (1996) Cysts of the head and neck sampled byfine-needle aspiration. Am J Clin Pathol 106:559–56042. Gillies EM, Luna MA (1998) Histologic evaluation of neckdissection specimens. Otolaryngol Clin North Am 31:759–77143. Golledge L, Ellis H (1994) The etiology of lateral cervical(branchial) cysts past, present theories. Laryngol Otol108:653–65944. Gonzalez-Crussi F (1982) Extragonadal teratomas. In: Atlasof tumor pathology, 2nd edn. Fascicle 18. Armed Forces Instituteof Pathology, Washington DC45. Grau C, Johansen LV, Jakobsen J et al. (2000). Cervical lymphnode metastases from unknown primary tumours. Resultsfrom a national survey by Danish Society for Head and NeckOncology. Radiother Oncol 55:121–12946. Gruber B, Rippon J, Dayal VS (1988) Phaeomycotic cyst(chromoblastomycosis) of the neck. Arch OtorhinolaryngolHead Neck Surg 114:1031–103347. Guba Am, Adam AE, Jacques DA et al. (1978) Cervical presentationof thymic cysts. Am J Surg 130:430–43648. Hamy A, Masson S, Heymann MF et al. (2002) Parathyroidcyst. Report of 10 cases. Ann Chir 127:203–20749. Harney M, Pat IN, Walsh R et al. (2001) Laryngoceles andsquamous cell carcinoma of the larynx. J Laryngol Otol115:590–59250. Heifetz SA, Cushings B, Giller R et al. (1998) Immature teratomain children: pathologic, considerations: a report fromthe combined Pediatric Oncology Group/Children’s CancerGroup. Am J Surg Pathol 22:1115–112451. Hendrickson M, Azarow K, Ein S et al. (1998) Congenitalthymic cysts in children mostly misdiagnosed. J Pediatr Surg33:821–82552. Hsieh YY, Hsueh S, Hsueh S et al. (2003) Pathologic analysisof congenital cervical cysts in children : 20 years experienceat Chang Gung Memorial Hospital. Chang Gung Med J26:107–11353. Iganej S, Kagan R, Anderson P et al. (2002) Metastatic squamouscell carcinoma of the neck from an unknown primary:management options and patterns of relapse. Head Neck24:236–24654. Jensen JL, Corell RW (1980) Nevus cells aggregates in submandibularlymph nodes. Oral Surg Oral Med Oral Pathol50:552–55655. Johnson TL, Zarbo RJ, Looyd RV et al. (1988) Paragangliomasof head and neck immunohistochemical neuroendocrineand intermediate filaments typing. Mod Pathol 1:216–22356. Jones D, Amin M, Ordonez NG (2001) Reticulum cell sarcomaof lymph nodes with mixed dendritic and fibroblastic features.Mod Pathol 14:1059–106757. Kenealy JF, Torsinglieri AR, Tom LW (1990) Branchial cleftanomalies: a five year retrospective study. Trans Pa AcadOphthalmol Otolaryngol 42:1022–102558. Khali RA, Prichep R, Minkowitz S (1984) Primary branchiogeniccarcinoma. Head Neck 11:153–15659. Koeller KK, Alamo L, Adair CF et al. (1999) Congenital cysticmasses of the neck: radiographic-pathologic correlation.Radiographics 19:121–14660. Kountakis SE, Minotti AM, Maillard A et al. (1994) Teratomasof the head and neck. Am J Otolaryngol 15:292–29661. Lack E, Cubilla AZ, Woodruff JM (1979) Paragangliomas ofthe head and neck region: a pathologic study of tumors from73 patients. Hum Pathol 10:191–21862. Langman J (1975) Pharyngeal gut. In: Lagman J (eds) Medicalembryology, 3rd edn. Williams & Wilkins, Baltimore, pp260–28163. LaRouere MJ, Drake AF, Baker SR et al. (1987) Evaluationand management of a carcinoma arising in a thyroglossalduct cyst. Ann J Otolaryngol 8:351–35564. Lefebvre JL, Coche-Dequenant B, Ton Van J et al. (1990) Cervicallymph nodes from unknown primary tumor in 190 patients.Am J Surg 160:443–44665. Liu TP, Jeng KS, Yang TL et al. (1992) Thyroglossal duct cyst.An analysis of 92 cases. Clin Med J 49:72–7566. Luna MA, Pfaltz M (2000) Cysts of the neck, unknown primaryand neck dissection. In: Gnepp D, (ed) Diagnostic surgicalpathology of the head and neck. Saunders, Philadelphia,p 67167. Luna MA, Tortoledo ME, Allen M (1987) Salivary dermal analoguetumor arising in lymph nodes. Cancer 59:1165–116968. Maisel RH (1980) When your patient complains of a neckmass. Geriatrics 35:3–869. Martin H, Morfit HM, Ehrlich H (1950) The case for branchiogeniccancer (malignant branchioma). Ann Surg132:867–88770. May M (1978) Neck masses in children: diagnosis and treatment.Ear Nose Throat J 57:136–15871. Medina JE, Houck JR (1995) Advances in neck dissection.Arch Otolaryngol Head Neck Surg 9:183–19672. Mendenhall WM, Mancuso AA, Parson J T et al. (1998) Diagnosticevaluation of squamous cell carcinoma metastaticto cervical lymph nodes from unknown head and neck primarysite. Head Neck 20:739–74473. Micheau C, Kijanienko J, Luboinski B et al. (1990) So-calledbranchiogenic carcinoma is actually cystic metastasis in theneck from a tonsillar primary. Laryngoscope 100:878–88374. Michelini ME, Casadio G, Franchella A (2003) Thyroglossalduct cysts: a retrospective study. Minerva Pediatr 55:51–5475. Molinari R, Cantu G, Chiesa F et al. (1977) A statistical approachto detection of the primary cancer based on the site ofneck lymph node metastases. Tumori 63:267–28276. Moran C, Suster S, El-Naggar et al. (2004) Carcinoma arisingin multilocular thymic cysts of the neck: a clinicopathologicalstudy of three cases. Histopathology 44:64–6877. Mukherji SK, Drane WE, Mancuso AA et al. (1996) Occultprimary tumors of the head and neck: detection with 2-[F-18] fluoro-2-deoxy-d-glucose SPECT. Radiology 199:761–76678. Mulliken JB, Glowacki J (1982) Hemangiomas and vascularmalformations in infants and children: a classification basedon endothelial characteristics. Plastic Reconstr Surg 69:412–42079. Nguyen C. Shenouda G, Black MJ et al. (1994) Metastaticsquamous cell carcinoma to cervical lymph nodes from unknownprimary mucosal sites. Head Neck 16:58–6380. Nicollas R, Ducroz NE, Garabedian EN et al. (1998) Fourthbranchial pouch anomalies: a study of six cases and review ofthe literature. Int J Pediatr Otorhinolaryngol 44:5–1081. Nozeran S, Duquenne M, Guyetan S et al. (2000) Diagnosisof parathyroid cysts: value of parathyroid hormone. PresseMed 29:939–941

282 M. A Luna · K. Pineda-Daboin982. Olsen KD, Maragos NE, Weiland LH (1980) First branchialcleft anomalies. Laryngoscope 90:423–43683. Ordonez NG (2000) Expression of thyroid transcription inhuman tumors. Adv Anat Pathol 7:120–12684. Paccioni D, Negro F, Valente G et al. (1994) Epstein-Barr virusby in situ hybridization in fine needle aspiration biopsy.Diagn Mol Pathol 3:100–10585. Papay FA, Kalucis C, Eliachar I et al. (1994) Nasopharyngealpresentation of a second branchial cleft cyst. OtolaryngolHead Neck Surg 110:232-23486. Park SS, Kamody CS (1992) The first branchial cleft carcinoma.Arch Otolaryngol Head Neck Surg 118:969–97187. Peter JC, Sinclair-Smith C, de Villiers JC (1991) Midline dermalsinuses and cysts and their relationship to the centralnervous system. Eur J Pediatr Surg 1:73–7988. Pinczower E, Crocket DM, Atkinson JB et al. (1992) Preoperativethyroid scanning in presumed thyroglossal duct cysts.Arch Otolaryngol Head Neck Surg 118:985–98889. Prasad KK, Gupta RK, Jain M et al. (2001) Cervical thymiccyst: report of a case and review of the literature. Indian JPathol Microbiol 44:483–48590. Quick CA, Lowell SH (1977) Ranula and the sublingualgland. Arch Otolaryngol 103:397–40091. Radkowski D, Arnold J, Healy GB et al. (1991) Thyroglossalduct remnants. Preoperative evaluation and management.Arch Otolaryngol Head Neck Surg 117:1378–138192. Rangnekar H, Bailer WJ, Ghani A et al. (1996) Parathyroidcysts. Report of four cases and review of the literature. IntSurg 81:412–41493. Redaelli de Zinis LO, Nicolai P, Piccioni LO et al. (1998) Cervicalmetastatic carcinoma from an unknown primary: astudy on 65 patients. Br J Cancer 77S:2894. Regauer S, Beham A, Mannweiler MO (2000) CK7 expressionin carcinomas of the Waldeyer’s ring area. Hum Pathol31:1096–110195. Regauer S, Gogg-Kamerer, Braun H et al. (1997) Lateral neckcyst the branchial theory revisited. A critical review andclinicopathologic study of 97 cases with special emphasis oncytokeratin expression. APMIS 105:623–63096. Regauer S, Manhweller S, Anderhuber A et al. (1999) Cysticlymph node metastases of squamous cell carcinoma ofWaldeyer’s ring. Br J Cancer 79:1437–144297. Rhigi JD, Sofferman RA (1995) Screening unilateral tonsillectomyin the unknown primary Laryngoscope 105:548–55098. Richard JM, Micheau C (1997) Malignant cervical adenopathiesfrom carcinomas of unknown origin. Tumori 63:249–25899. Robbins KT, Clayman G, Levine PA et al. (2002) Neck dissectionclassification update. Revisions proposed by the AmericanHead and Neck Society and the American Academy ofOtolaryngology—Head and Neck Surgery. Arch OtolaryngolHead Neck Surg 128:751–758100. Rodriguez-Cuevas S, Lopez-Garza J, Labastida-Almendaro S(1998) Carotid body tumors in inhabitants of altitudes higherthan 2000 meters above sea level. Head Neck 20:374–37101. Rosen D, Wirtschafer A, Rao VM et al. (1998) Dermoid cystof the lateral neck, a case report and literature review. EarNose Throat J 125:129–132102. Sade J, Rosen G (1968) Thyroglossal cysts and tracts: a histologicaland histochemical study. Ann Otol Rhino Laryngo177:139–145103. Saenz J, Catalina F, Fernández MJJ et al. (2003) Mucoepidermoidcarcinoma arising in cervical lymph nodes. A report ofthree cases with FNA findings. Acta Cytol 47:470–474104. Saitz EW (1981) Cervical lymphadenitis caused by atypicalmycobacteria. Pediatr Clin North Am 28:823–839105. Sambola-Cabrer I, Fernandez-Real JM, Ricard W (1996) Ectopicthyroid tissue presenting as a submandibular mass.Head Neck 18:87–90106. Samuel M, Freeman NV, Sajwany MJ (1993) Lingual thyroglossalduct cyst presenting in infancy 28:891–893107. Scherer K, Szeimies RM, Landthaler M (2000) Ectopic parotidtissue. An unusual differential cervical cystic tumor diagnosis.Hautarzt 51:865–868108. Senger MI, Applebaum EL, Ley KD (1979) Heterotopic salivarytissue in the neck. Laryngoscope 80:1772–1778109. Shah JP (1990) Patterns of cervical lymph node metastasisfrom squamous cell carcinoma of the upper aerodigestivetract. Am J Surg 160:405–409110. Shah JP, Strang E, Spiro RH et al. (1981) Neck dissection, currentstatus and future possibilities. Clin Bull 11:25–33111. Shvero J, Hadar TA, Vidos I et al. (1986) Heterotopic salivarytissue and branchial sinuses. Laryngol Otol 100:243–246112. Sistrunk WE (1920) The surgical treatment of cysts of thethyroglossal tract. Ann Surg 71:121–122113. Smirniotopoulos JG, Chiechi MV (1995) Teratomas, dermoids,and epidermoids of the head and neck. Radiographics15:1437–1455114. Soyla L, Aydogan LB, Kiroglu M et al. (1995) Hydatidic cystin the head and neck area. Am J Otolaryngol 16:123–125115. Spinelli C, Ricci E, Berti P et al. (1990) Neck mass in childhood.Surgical experience of 154 cases. Minerva Pediatr42:169–172116. Thompson L, Heffner DK (1998) The clinical importance ofcystic squamous cell carcinoma in the neck. Cancer 82:944–956117. Torsiglier AJ Jr, Tom LW, Ross AJ et al. (1988) Pediatric neckmasses: guidelines for evaluation. Int Pediatr Otorhinolaryngol16:199–210118. Tovi F, Fliss DM, Inbar-Yanai I (1988) Hürthle cell adenomaof the thyroglossal duct. Head Neck Surg 10:346–349119. Triglia JM, Nicollas R, Ducroz V et al. (1998) First branchialcleft anomalies. A study of 39 cases and a review of the literature.Arch Otolaryngol Head Neck Surg 124:291–295120. Turner A, Lampe FB, Cramer H (1989) Parathyroid cysts. JOtolaryngol 18:11–13121. Tyson RW, Groff DB (1993) An unusual lateral neck cyst withthe combined features of a bronchogenic, thyroglossal, andbranchial cleft origin. Pediatr Pathol 13:567–572122. Vermeire VM, Dale JJ (1991) Second branchial cleft-pouchset fistulae, sinuses and cysts in children. Acta OtorhinolaryngolBelg 45:437–442123. Wang RC, Goepfert H, Barber AE et al. (1990) Unknown primarySCC metastatic to the neck. Arch Otolaryngol HeadNeck Surg 116:1388–1393124. Wassef M (1992) Cervicophalic hemangiomas and vascularmalformations. Histological appearance and classification. JMal Vasc 17:20–25125. Werner AJ, Dunne AA, Myers JN (2003) Functional anatomyof the lymphatic drainage system of the upper aerodigestivetract and its role in metastasis of squamous cell carcinoma.Head Neck 25:322–332126. Wilson DB (1979) Embryonic development of the head andneck. II. The branchial region. Head Neck Surg 2:59–66127. Yang C, Cohen J, Everts E et al. (1999) Fourth branchial archsinus: clinical presentation, diagnostic workup, and surgicaltreatment. Laryngoscope 109:442–446128. Yoo KS, Chengazi VU, O’Mara RE (1998) Thyroglossal ductcyst with papillary carcinoma in a 11-year-old girl. J PediatrSurg 33:745–746129. Yoshimura Y, Obara S, Kondoh T et al. (1995) A comparisonof three methods used for treatment of ranula. J Oral MaxoillofacSurg 53:280–282130. Zarbo RJ, McClatchey KD, Arcen RG et al. (1983) Thymopharyngealduct cyst; a form of cervical thymus. Ann OtolRhinol Laryngol 92:284–289131. Zatchuz JT, Paton CA, Hyams VJ (1982) Cervical heterotopicsalivary gland neoplasms: a diagnostic dilemma. OtolaryngolHead Neck Surg 80:178–181132. Zimmermann CE, Domarus H von, Moubayed P (2002) Carcinomain situ in a lateral cervical cyst. Head Neck 24:965–969

Chapter 10Eyeand Ocular AdnexaM.R. Canninga-Van Dijk10Contents10.1 Summary of Anatomy and Histology . . . . . . . . . 28410.1.1 Conjunctiva . . . . . . . . . . . . . . . . . . . . . . . 28410.1.2 Cornea . . . . . . . . . . . . . . . . . . . . . . . . . . 28410.1.3 Intraocular Tissues . . . . . . . . . . . . . . . . . . . 28410.1.4 Optic Nerve . . . . . . . . . . . . . . . . . . . . . . . 28410.1.5 Lacrimal Glands and Lacrimal Passages . . . . . . . 28410.1.6 Eyelids . . . . . . . . . . . . . . . . . . . . . . . . . . 28410.1.7 Orbit . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28510.2 Conjunctiva . . . . . . . . . . . . . . . . . . . . . . . 28510.2.1 Developmental Anomalies . . . . . . . . . . . . . . . 28510.2.1.1 Dermoid, Dermolipoma and Complex Choristoma 28510.2.2 Cysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28510.2.2.1 Inclusion cysts . . . . . . . . . . . . . . . . . . . . . . 28510.2.3 Degeneration . . . . . . . . . . . . . . . . . . . . . . . 28610.2.3.1 Pinguecula and Pterygium . . . . . . . . . . . . . . . 28610.2.4 Inflammatory Processes . . . . . . . . . . . . . . . . 28610.2.4.1 Acute Conjunctivitis . . . . . . . . . . . . . . . . . . 28610.2.4.2 Chronic Non-Granulomatous Conjunctivitis . . . . 28710.2.4.3 Granulomatous Conjunctivitis . . . . . . . . . . . . 28710.2.4.4 Ligneous Conjunctivitis . . . . . . . . . . . . . . . . 28710.2.4.5 Chlamydia Trachomatis (TRIC Agent) Infection . . 28710.2.5 Dermatologic and Systemic Diseases . . . . . . . . . 28810.2.5.1 Keratoconjunctivitis Sicca . . . . . . . . . . . . . . . 28810.2.5.2 Dermatologic Diseases . . . . . . . . . . . . . . . . . 28810.2.5.3 Metabolic Diseases . . . . . . . . . . . . . . . . . . . 28810.2.6 Tumours and Tumour-Like Conditions . . . . . . . 28810.2.6.1 Epithelial . . . . . . . . . . . . . . . . . . . . . . . . . 28810.2.6.2 Melanocytic . . . . . . . . . . . . . . . . . . . . . . . 29010.2.6.3 Other Neoplasms . . . . . . . . . . . . . . . . . . . . 29110.3 Cornea . . . . . . . . . . . . . . . . . . . . . . . . . . 29210.3.1 Keratitis and Corneal Ulcers . . . . . . . . . . . . . . 29210.3.1.1 Herpes Simplex Keratitis . . . . . . . . . . . . . . . . 29210.3.1.2 Corneal Ulceration Due to Systemic Disease . . . . 29210.3.2 Keratoconus . . . . . . . . . . . . . . . . . . . . . . . 29210.3.3 Hereditary Corneal Dystrophies . . . . . . . . . . . 29310.3.3.1 Epithelial Dystrophies . . . . . . . . . . . . . . . . . 29310.3.3.2 Stromal Dystrophies . . . . . . . . . . . . . . . . . . 29310.3.3.3 Endothelial Dystrophies . . . . . . . . . . . . . . . . 29310.3.4 Failed Previous Grafts . . . . . . . . . . . . . . . . . 29410.4 Intraocular Tissues . . . . . . . . . . . . . . . . . . . 29410.4.1 Developmental Anomalies . . . . . . . . . . . . . . . 29410.4.1.1 Congenital Glaucoma . . . . . . . . . . . . . . . . . . 29410.4.1.2 Retinopathy of Prematurity . . . . . . . . . . . . . . 29410.4.1.3 Persistent Primary Hyperplastic Vitreous . . . . . . 29410.4.1.4 Retinal Dysplasia . . . . . . . . . . . . . . . . . . . . 29410.4.1.5 Aniridia . . . . . . . . . . . . . . . . . . . . . . . . . . 29410.4.1.6 Congenital Rubella Syndrome . . . . . . . . . . . . . 29410.4.2 Inflammatory Processes . . . . . . . . . . . . . . . . 29510.4.2.1 Acute Inflammation . . . . . . . . . . . . . . . . . . 29510.4.2.2 Chronic Non-Granulomatous Inflammation . . . . 29510.4.2.3 Granulomatous Inflammation . . . . . . . . . . . . . 29510.4.3 Trauma . . . . . . . . . . . . . . . . . . . . . . . . . . 29610.4.4 Degeneration . . . . . . . . . . . . . . . . . . . . . . . 29610.4.4.1 Glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . 29610.4.4.2 Cataracts . . . . . . . . . . . . . . . . . . . . . . . . . 29710.4.4.3 Phtisis Bulbi . . . . . . . . . . . . . . . . . . . . . . . 29810.4.4.4 Retinal Vascular Disease . . . . . . . . . . . . . . . . 29810.4.4.5 Retinal Detachment . . . . . . . . . . . . . . . . . . . 29810.4.4.6 Retinitis Pigmentosa . . . . . . . . . . . . . . . . . . 29810.4.5 Tumours and Tumour-Like Conditions . . . . . . . 29810.4.5.1 Melanocytic . . . . . . . . . . . . . . . . . . . . . . . 29810.4.5.2 Lymphoid . . . . . . . . . . . . . . . . . . . . . . . . . 30010.4.5.3 Retinoblastoma and Pseudoretinoblastoma . . . . . 30010.4.5.4 Glial . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30110.4.5.5 Vascular . . . . . . . . . . . . . . . . . . . . . . . . . 30110.4.5.6 Other Primary Tumours . . . . . . . . . . . . . . . . 30110.4.5.7 Metastatic Tumours . . . . . . . . . . . . . . . . . . . 30210.5 Optic Nerve . . . . . . . . . . . . . . . . . . . . . . . 30210.5.1 Papilloedema . . . . . . . . . . . . . . . . . . . . . . . 30210.5.2 Optic Neuritis . . . . . . . . . . . . . . . . . . . . . . 30210.5.3 Optic Atrophy . . . . . . . . . . . . . . . . . . . . . . 30210.5.4 Tumours . . . . . . . . . . . . . . . . . . . . . . . . . 30210.5.4.1 Glioma . . . . . . . . . . . . . . . . . . . . . . . . . . 30210.5.4.2 Meningioma . . . . . . . . . . . . . . . . . . . . . . . 30210.6 Lacrimal Gland and Lacrimal Passages . . . . . . . 30210.6.1 Inflammatory Processes . . . . . . . . . . . . . . . . 30210.6.2 Tumours and Tumour-Like Conditions . . . . . . . 30310.7 Eyelids . . . . . . . . . . . . . . . . . . . . . . . . . . 30310.7.1 Cysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30310.7.1.1 Dermoid Cyst . . . . . . . . . . . . . . . . . . . . . . 30310.7.1.2 Epidermal Cyst . . . . . . . . . . . . . . . . . . . . . 30310.7.1.3 Hidrocystoma . . . . . . . . . . . . . . . . . . . . . . 30310.7.2 Inflammatory Processes . . . . . . . . . . . . . . . . 30310.7.2.1 Chalazion and Other Ruptured Cysts . . . . . . . . 30410.7.2.2 Deep Granuloma Annulare . . . . . . . . . . . . . . 30410.7.2.3 Necrobiotic Xanthogranuloma . . . . . . . . . . . . 30410.7.3 Amyloidosis . . . . . . . . . . . . . . . . . . . . . . . 30510.7.4 Tumours and Tumour-Like Conditions . . . . . . . 30510.7.4.1 Xanthelasmata . . . . . . . . . . . . . . . . . . . . . . 30510.8 Orbit . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30510.8.1 Inflammatory Processes . . . . . . . . . . . . . . . . 30510.8.1.1 Dysthyroid Ophthalmopathy . . . . . . . . . . . . . 30510.8.1.2 Cellulitis . . . . . . . . . . . . . . . . . . . . . . . . . 30510.8.1.3 Pseudotumour . . . . . . . . . . . . . . . . . . . . . . 30610.8.2 Tumours and Tumour-Like Conditions . . . . . . . 30610.8.2.1 Developmental Cysts . . . . . . . . . . . . . . . . . . 30610.8.2.2 Optic Nerve and Meningeal Tumours . . . . . . . . 30610.8.2.3 Metastatic Tumours . . . . . . . . . . . . . . . . . . . 307References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307

284 M.R. Canninga-Van Dijk1010.1 Summary of Anatomyand Histology10.1.1 ConjunctivaThe conjunctiva is a thin mucous membrane, coveringmost of the anterior surface of the eye and the innersurface of the eyelids. The conjunctiva is composedof two to five layers of stratified columnar epitheliumcontaining mucin-secreting goblet cells. At the corneoscleraljunction, the limbus, a gradual transition fromstratified columnar to stratified squamous cornealepithelium is seen. At the palpebral margins, a relativelyabrupt transition into the epidermis is present.The basal layer contains melanocytes and Langerhanscells. The conjunctival stroma is composed of fibrousconnective tissue containing fibroblasts, some inflammatorycells, blood vessels, smooth muscle, nerves andlymphatic channels. In the fornices the conjunctivalepithelium contains more goblet cells and the stromacan additionally contain cartilage. In the medial interpalpebralarea of the eye, a nodular mass is present: thecaruncle. The caruncle is covered by stratified non-keratinisedsquamous epithelium and the subepithelialstroma contains sebaceous glands, hair follicles andmuscle fibres.10.1.2 CorneaThe cornea is divisible into five distinctive layers: theepithelium, Bowman’s layer, the stroma, Descemet’smembrane and the endothelium. The non-keratinisingstratified squamous epithelium consists in the centre ofthe cornea of five layers, increasing to nine or ten layersat the periphery. Bowman’s layer is believed to representa modified layer of the stroma. It is composed of smallcollagen fibrils surrounded by a mucoprotein groundsubstance. The stroma is avascular and consists of collagenouslamellae arranged in an almost parallel mannerinterspersed with flattened fibroblasts (keratocytes).Descemet’s membrane is a faintly eosinophilic staining,PAS-positive, acellular structure, formed by corneal endothelialcells. The underlying endothelium is a singlelayer of polygonal cells.10.1.3 Intraocular TissuesThe intra-ocular tissue is formed by the uveal tract,the retina, the lens and the vitreous gel. The uveal tractconsists of highly vascularised, loosely arranged stroma,which can be found in all three parts of the tract:the iris, the ciliary body and the choroid. In the iris,in addition to the stroma, the pigment epithelium andthe smooth muscles of the musculus sphincter pupillaeand musculus dilator pupillae can be found. The ciliarybody consists of two parts: the pars plicata containsthe ciliary processes, the pars plana serves as an attachmentfor the vitreous gel. In both parts, layers of ciliarymuscle are present. The choroid contains nerves and avariable number of melanocytes, related to race. Theretina consists of a nerve fibre layer, peripheral ganglioncells, the bipolar cell layer, the photoreceptor cellsand the retinal pigment epithelium. The thickness ofthe retina varies in different regions. The biconvex lensis a transparent structure, the form of which is easilyaltered by contraction of the ciliary muscles. The shapeof the lens is maintained by the elastic lens capsule. Ina fixed specimen the lens is rigid, caused by coagulationof the soluble crystallins. The inner surface of theanterior lens capsule is covered with a single layer ofcuboidal epithelium. A loose framework of type II collagencontaining mainly water and acid mucopolysaccharidesforms the vitreous gel.10.1.4 Optic NerveThe axons from the retinal nerve fibre layer converge atthe optic disc. The axons in the nerve fibre layer of theoptic disc form a bulge as they pass through the laminacribrosa, a sieve-like plate of connective tissue formedby fibroblasts, ingrowing from the posterior part of theadjacent sclera. This bulge is larger on the nasal side.The tissue anterior to the lamina derives blood supplyfrom the posterior ciliary arteries, and the tissueposterior to the lamina has a meningeal blood supplyderived from branches of the ophthalmic and centralretinal artery.10.1.5 Lacrimal Glandsand Lacrimal PassagesThe pale brown and ovoid lacrimal gland is located inthe upper outer orbit. The large ducts pass through theconjunctival epithelium into the superior fornix. Thetear fluids drain into the canaliculi, ending in the lacrimalsac. The secretory gland is composed of lobulargrouped acini, secreting solutes and glycosaminoglycans.The drainage system consists of ductules, formedby epithelial cells surrounded by myoepithelium. Thecanaliculi are covered with stratified epithelium, whilethe lacrimal sac is covered with columnar epithelium.10.1.6 EyelidsThe eyelids are covered by an epidermis above a thindermis with small sweat glands and pilosebaceous units.

Eye and Ocular Adnexa Chapter 10 285The dermis covers the musculus orbicularis oculi, locatedon the anterior surface of the tarsal plate, which iscomposed of compact stroma. In the anterior part of theeyelids, the pilosebaceous units are much larger to formthe lashes. The parts of the tarsal plates closest to thelid margins, contain the large sebaceous (Meibomian)glands. A transition from keratinised squamous epitheliumof the outer eyelid into columnar epithelium of thetarsal conjunctiva is present in the transition zone. Smallpilosebaceous glands (Zeis) and sweat glands (Moll) arepresent at the lid margins.10.1.7 OrbitThe orbital septum and globe divide the orbit intoanterior and posterior compartments. The anteriorcompartment consists of the lids, lacrimal apparatusand anterior soft tissues. The posterior compartmentis also called the retrobulbar space. The cone of thisretrobulbar space consists of the extraocular musclesand an envelope of fascia. The optic nerve is locatedwithin the intraconal space, surrounded by fibrous andfatty tissue.Fig. 10.1. Dermolipoma: excision of a limbal mass, consisting ofcollagen and adipose tissue10.2 ConjunctivaBecause conjunctival biopsies and excisions are verythin, they tend to fold when placed into fixative. Withoutcausing compression artefacts, the surgeon shouldspread the tissue onto a piece of cardboard or filter paperand let it dry for a few seconds, before placing it into thefixative.10.2.1 Developmental AnomaliesFig. 10.2. Dermolipoma: detail of the stratified squamous epitheliumcontaining hair follicles10.2.1.1 Dermoid, Dermolipomaand Complex ChoristomaICD-O:9084/0Dermoid tumours are firm or cystic masses, typically occurringat the limbus on the temporal side and are themost frequent epibulbar tumours in children [30]. Theyare composed of epithelial and/or connective tissue elementsthat become entrapped within embryonic clefts. Onhistological examination, the surface epithelium consistsof stratified squamous epithelium, frequently containingskin appendages. The stromal component consists of collagenarranged in thick bundles; it contains blood vesselsand nerve fibres. If adipose tissue is present, the lesion iscalled dermolipoma (Figs. 10.1, 10.2). Sometimes cartilageor lacrimal gland tissue is present, these lesions areknown as complex choristoma [28, 35].Dermoids are present at birth and have little or nogrowth potential. The lesions can occur as isolated ocularlesions or in association with anomalies affectingother organs (Goldenhar’s syndrome, mandibulofacialdysostosis and neurocutaneous syndrome) [22, 41, 46,55, 100, 118].10.2.2 Cysts10.2.2.1 Inclusion CystsConjunctival inclusion cysts are acquired lesions, usuallyarising following surgical or accidental trauma [9, 42,83]. The cysts are lined with non-keratinising cuboidal

286 M.R. Canninga-Van Dijkepithelium with apocrine changes and containing gobletcells (Fig. 10.3). In the underlying stroma, chronic inflammatorycells may be present.10.2.3 Degeneration10.2.3.1 Pingueculaand Pterygium10Pingueculae are raised, localised, yellowish-grey lesionsthat occur in the bulbar conjunctiva, close to the limbuson the nasal or temporal side of the cornea. Pterygiaare similar in appearance and also develop in these areas,but involve the peripheral cornea, mostly the nasalside, as well. Pingueculae and pterygia are degenerativelesions causally related to prolonged actinic exposure.The lesions are often bilateral and occur in middleagedand elderly patients, especially in areas with highlevels of sunlight. On histologic examination both lesionsare identical. The essential feature is elastotic degenerationof the collagen, resulting in a subepithelialzone of amorphous, basophilic material (Fig. 10.4). Thismaterial stains black with the Elastica van Gieson stain(Fig. 10.5). In older lesions calcification can occur. Theoverlying epithelium may show a wide variety of changes,but most frequently it is thin, atrophic conjunctivalepithelium or acanthosis without cellular atypia. In theepithelium an actinic keratosis or even a squamous cellcarcinoma may develop [110].Since pingueculae are not progressive, they are seldomexcised. Pterygia are of more clinical importancebecause of their extension to the cornea.10.2.4 Inflammatory ProcessesThe conjunctiva is prone to inflammations with manydifferent causes, either infectious or as a part of a noninfectiousdermatologic or systemic disease. Usuallythese lesions do not cause diagnostic problems, but abiopsy can be useful in making the correct diagnosis[97]. In this chapter the inflammatory processes of theconjunctiva are divided into acute, chronic and granulomatous.The only lesions mentioned separately are ligneousconjunctivitis and lesions caused by Chlamydiainfections.Fig. 10.3. Conjunctival inclusion cyst: a cystic space is covered withnon-keratinising cuboidal epithelium, containing goblet cellsFig. 10.4. Pinguecula: amorphous, basophilic material in thestroma represents the elastotic degenerated collagen10.2.4.1 Acute ConjunctivitisIn acute conjunctivitis there is a rapid onset of a swollen,hyperaemic conjunctiva accompanied by increasedtear formation. There may be a watery (viral infections),fibrinous (bacterial infections) or mucoid (allergic reac-Fig. 10.5. Pinguecula: the elastotic collagen stains black in elasticastaining (Elastica van Gieson stain)

Eye and Ocular Adnexa Chapter 10 287tions) discharge [124]. The histological pattern dependson the cause of the inflammation. In viral infectionsthe infiltrate consists mostly of mononuclear cells. In abacterial infection many neutrophilic leukocytes can beseen [124]. When the cause is an allergic response, manyeosinophils are usually found.10.2.4.2 Chronic Non-GranulomatousConjunctivitisChronic conjunctivitis can be caused by many infectious,immunological and toxic agents. Also, anatomic aberrations(like ectropion or proptosis) can cause inflammation.In chronic conjunctivitis the epithelium becomeshyperplastic and the goblet cells increase in number.Crypt-like epithelial infoldings can occur, forming subepithelialretention cysts. These cysts contain mucus inwhich calcification can be seen over time. The presenceof perivascular infiltrate in the stroma can induce fibrousbands between the epithelium and the tarsus, which cancause surface irregularities, the so-called papillary conjunctivitis.In fact, the epithelial and stromal responses ofa papillary conjunctivitis are non-specific and can also beseen in atopic conjunctivitis and, in a more extreme formin individuals wearing contact lenses (giant papillary conjunctivitis)[108, 114]. When lymph follicles are found inthe superficial stroma, it is called follicular conjunctivitis.The presence of these follicles is associated with adenoviralinfections [25]. It can also be seen in early chlamydialinfections [37], Borrelia burgdorferi infections [60, 132]and in patients using topical medication. In these situationsa lymphoma has to be excluded by immunohistochemistry[2, 48, 131].With long-standing inflammation the epitheliumcan become atrophic, with loss of goblet cells. The epitheliumcan show keratinisation, resulting in a white appearance(leukoplakia). The long-standing inflammationmay result in scarring of the conjunctival stroma.10.2.4.3 Granulomatous ConjunctivitisGranulomatous inflammation of the conjunctiva is usuallyassociated with systemic diseases. The presence ofexogenous material or parasites may cause an isolatedgranulomatous inflammation of the conjunctiva. In thecase of a chalazion the palpebral conjunctiva may alsobe affected (see Sect. 10.7.2.1).10.2.4.3.1 InfectiousLike in other anatomic sites, a caseating necrotisinggranulomatous infection can be caused by tuberculosis,especially in children [32, 45, 76].10.2.4.3.2 SarcoidosisIn sarcoidosis the granulomas are usually small andsharply demarcated [6, 39]. Serial sections can be necessaryto confirm the diagnosis.10.2.4.4 Ligneous ConjunctivitisLigneous conjunctivitis (chronic pseudomembranousconjunctivitis) is a rare bilateral disease, mainly occurringin young girls. It presents as a subacute inflammationof the tarsal conjunctiva, often accompanied bynasopharyngitis and vaginitis. The disease seems to bedue to a defective fibrinolysin system. Microscopically,granulation tissue is present, covered with plaques offibrinous material, later forming a hyalinised mass. Afterremoval of the plaque, recurrence is common. It canbe complicated by corneal involvement and perforationwith loss of the eye may occur [15, 17, 99].10.2.4.5 Chlamydia Trachomatis(TRIC Agent) InfectionChlamydia trachomatis (TRIC agent: TR = trachoma,IC = inclusion conjunctivitis) is an obligate intracellularpathogen of columnar epithelial cells [79]. In hotclimates it can cause trachoma, primarily affecting theconjunctiva and corneal epithelium, ultimately causingcicatrisation of this tissue. Trachoma commonlyaffects children and is one of the world’s major causesof blindness. Trachoma is spread from eye to eye bytransfer of ocular discharges. In temperate climateschlamydial infection is venereal, with only mild conjunctivalinfection, called inclusion conjunctivitis. Athird manifestation of this pathogen is ophthalmianeonatorum [75].10.2.4.5.1 TrachomaThe clinical manifestations of trachoma vary withthe severity and duration of the initial infection andalso depend upon environmental factors, the patient’snutritional and immune status, the number of reinfections,and the presence or absence of secondarybacterial infection. It is usually bilateral. The courseof trachoma can be divided into four stages (the Mc-Callan classification) [68]. During the active stages ofinfection inclusions can be found in Giemsa-stainedcells scraped from the surface of infected epithelium.More easy to recognise is a positive direct immunofluorescencefor Chlamydia trachomatis on the scraping,it can be very helpful in making the correct diagnosis[62, 90]. The diagnosis can also be made by isolation of

288 M.R. Canninga-Van Dijk10the causative agent in cell cultures and the detection ofchlamydial antibody in blood or tear fluid. At Stage Ithere is epithelial infection by Chlamydia trachomatis.It is characterised clinically by the formation of conjunctivalfollicles and diffuse punctate inflammationof the cornea. The histology is indistinguishable fromthat of follicular conjunctivitis caused by other agents.Lymphocytes and plasma cells infiltrate the subepithelialtissue; polymorphonuclear leukocytes infiltrate thecorneal and conjunctival epithelium. At Stage II, theinflammatory reaction occupies the stroma, with thefurther formation of follicles. Large macrophages withphagocytised debris (Leber cells) are seen in the conjunctiva,accompanying the epithelial hyperplasia withround cell infiltration and subepithelial oedema [125].At Stage III the follicles disappear and cicatrisationoccurs. The fibrosis causes inversion of the upper lid(cicatricial entropion), misdirected lashes (trichiasis)and decreased tear formation. On histologic examination,scattered lymphocytes and plasma cells can stillbe seen along with subepithelial scar tissue. At StageIV, there is spontaneous arrest of the disease, which isno longer contagious. The residual entropion and trichiasislead to continuing corneal damage. Denudingof the epithelium leaves the cornea vulnerable to infectionand further opacification as a result of scarring.10.2.4.5.2 Inclusion ConjunctivitisThe conjunctival involvement of the sexually transmittedchlamydial infection is mild and can even be asymptomatic.In adults, it presents as a subacute follicularconjunctivitis. It is accompanied by a chronic urethritisin the male and a symptomless cervicitis in the female.In newborns, it occurs with an acute mucopurulentdischarge, 5 to 10 days after birth. It is accompaniedby infection of the maternal vagina by the same agent.Because the extranodal lymphoid tissues are not fullydeveloped, the conjunctivitis is more papillary than follicular.Like trachoma it can be diagnosed by Giemsastaining on conjunctival scrapings.10.2.5 Dermatologicand Systemic Diseases10.2.5.1 Keratoconjunctivitis SiccaIn this condition the cornea and conjunctiva are dry,causing a painful and gritty sensation. Keratoconjunctivitissicca was described first by Sjögren in 1933 [106,107]. It is therefore best known as one of the symptomsof Sjögren’s syndrome. However, it can also be seen inother auto-immune diseases like scleroderma or rheumatoidarthritis. Moreover, keratoconjunctivitis sicca isthe most frequent cause of eye involvement in graft-versus-hostdisease [20, 50, 64]. Histologically, there is atrophyof the lacrimal acinar parenchyma, accompanied byfibrosis and fatty infiltration, but with preservation ofthe lobular architecture. There is a focal or diffuse presenceof lymphocytes and plasma cells. Sometimes lymphoepitheliallesions can be seen (See Chap. 5 for moredetail.).10.2.5.2 Dermatologic DiseasesMany skin diseases can involve the conjunctiva. Mostfrequently seen are bullous diseases like pemphigus [72],bullous pemphigoid, Stevens-Johnson syndrome [43],paraneoplastic pemphigus [58, 74] and less commonly,dermatitis herpetiformis [43] and linear IgA disease [4].Other dermatologic diseases with conjunctival involvementare lupus erythematosus [40, 115, 122], familialchronic benign pemphigus (Hailey-Hailey disease) [80]and lichen planus [78, 116].10.2.5.3 Metabolic DiseasesA conjunctival biopsy can be of diagnostic value in metabolicdiseases with specific ultrastructural features,like galactosialidosis and different types of mucopolysaccharidoses[14, 121].10.2.6 Tumoursand Tumour-Like Conditions10.2.6.1 EpithelialEpithelial tumours of the conjunctiva can be dividedinto tumours of the surface epithelium (papilloma, intraepithelialneoplasia and squamous cell carcinoma)and adnexal tumours. Since the caruncle contains accessorylacrimal glands, sweat glands, hair follicles andsebaceous glands, adnexal tumours of different kindscan be found.10.2.6.1.1 PapillomaICD-O:8560/0The commonest epithelial tumours of the conjunctivaare papillomas, usually presenting as a red, papillomatousmass. These benign tumours histologicallyconsist of a fibrovascular core, lined with conjunctivalepithelium, eventually with squamous metaplasia(Figs. 10.6, 10.7). The sessile variant usually shows only

Eye and Ocular Adnexa Chapter 10 289Fig. 10.6. Conjunctival papilloma: papillomatous mass consistingof a fibrovascular core covered with squamous metaplastic epitheliumFig. 10.8. Conjunctival intraepithelial neoplasia: the epitheliumconsists of atypical cells without orderly differentiationof dysplasia, the epithelial cells show atypia (Fig. 10.8). Inactinic keratosis the epithelium is thin and the stromashows damage of elastic tissue. In the Bowenoid type mitoticfigures can be seen in the upper epithelial layers andHPV-related epithelial changes like multinucleated cellsand koilocytes can be found [47, 71, 82].10.2.6.1.3 Malignant Tumoursof the Surface EpitheliumFig. 10.7. Conjunctival papilloma: detail of the squamous metaplasticepitheliumSquamous cell carcinomas are rare and usually well differentiated.After adequate therapy total cure is oftenachieved [13, 120]. More aggressive variants of this carcinoma,like the acantholytic or adenoid type [70] and thespindle cell type are even more rare. Mucoepidermoidcarcinoma of the conjunctiva has also been reported [34,101] (See Chaps. 1 and 5 for more details.).metaplastic epithelium, without goblet cells. There is astrong association between HPV and conjunctival papillomas.HPV type 6/11 is the most common HPV typein conjunctival papilloma. The sensitivity of koilocytosisas an indicator of HPV in conjunctival papillomais low [105]. Papillomas are more extensively discussedin Chap. 1.10.2.6.1.2 ConjunctivalIntraepithelial NeoplasiaIntraepithelial neoplasia of the conjunctiva can be causedby sun-damage (actinic keratosis) or by HPV-induced premalignanttransformation (Bowenoid type). In both types10.2.6.1.4 OncocytomaICD-O:8290/0An oncocytoma (oxyphil cell adenoma, oxyphillicgranular cell adenoma) is a benign tumour that canoccur in the conjunctiva, the lacrimal gland and thelacrimal sac [7, 111]. It presents as an asymptomatic,slowly progressive swelling of the caruncle in olderpersons. The lesion consists of large epithelial cellswith eosinophilic, granular cytoplasm, due to a largenumber of mitochondria. The cells can be arrangedin cords, sheets or nests. Ductal and cystic glandularstructures can be found. The malignant variant of thistumour, the oncocytic adenocarcinoma of the lacrimalsystem is very rare.

290 M.R. Canninga-Van DijkFig. 10.9. Intraepithelial component of a sebaceous adenocarcinoma:intraepithelial pagetoid spread of tumour cells may be misinterpretedas dysplasia; positive staining for EMA can be veryhelpful (EMA immunostaining)Fig. 10.11. Sebaceous adenocarcinoma: detail of the clear cells,showing sebaceous differentiation10like EMA and CAM 5.2 can help in differentiating thisaggressive tumour from a squamous cell carcinoma(Figs. 10.09–10.11). Treatment of choice is wide excision,which can cure patients at an early stage of thelesion. However, the mortality rate from metastases is25%, and even higher in a poorly differentiated tumourwith angioinvasive growth.10.2.6.2 Melanocytic10.2.6.2.1 NaevusFig. 10.10. Sebaceous adenocarcinoma: basaloid epithelial nestswith a clear cell component10.2.6.1.5 Sebaceous AdenocarcinomaICD-O:8410/3This lesion is important because it can be a pitfall forboth the clinician and the pathologist. The tumourpresents as a solitary nodule, that can clinically be misdiagnosedas a basal cell carcinoma or even as a chalazionor blepharoconjunctivitis [1, 36, 81]. Histologically,the tumour is composed of epithelial nests withvarying sebaceous differentiation. The well-differentiatedsebaceous carcinomas are not very hard to recognise,but the poorly differentiated ones can be easilymissed. The intraepithelial pagetoid spread of tumourcells (which is frequently present) may be misinterpretedas dysplasia. Immunohistochemical stainingsICD-O:8720/0The most common melanocytic lesion of the conjunctivais the compound naevus. Other types of naevi thatcan be found in the conjunctiva are intraepithelial,subepithelial, Spitz and blue naevi. Their histology issimilar to melanocytic skin lesions. The naevus mostlyarises in the first or second decade as a nodule in thebulbar conjunctiva. A band of melanocytes in the basallayer of the epithelium represents the intraepithelialcomponent. These melanocytes can be melanin-containing,but can also present as clear cells. Melanocytescan also be found in the epithelium of the inclusioncysts, which are almost invariably present. These large,mucin-containing cysts are formed by incarceratedepithelial nests and can give an erroneous clinical impressionof growth. The stromal component is formedby nests of mature cells with maturation to smaller cellsin the deeper parts of the lesion (Fig. 10.12). Especiallyat a young age, a considerable variation in cell size canbe seen; these active lesions are easily overdiagnosed asmalignant melanomas.

Eye and Ocular Adnexa Chapter 10 291Fig. 10.12. Compound conjunctival naevus: the intraepithelialcomponent is represented by a band of clear melanocytes in thebasal layer of the epithelium. A small inclusion cyst is present, surroundedby unsuspicious naevoid cells with maturation to smallercells in the deeper part of the lesionFig. 10.14. Malignant melanoma arising from primary acquiredmelanosis with atypia: the conjunctival epithelium is ulceratedand the atypical cells spread into the underlying stromaspontaneously, can remain stationary or may progress tomalignant melanoma. Histologically, there is an increasein atypical melanocytes in the conjunctival epithelium(Fig. 10.13). The atypia can be graded mild to severe. Toexclude invasive growth, use of the immunohistochemicalmarker CD68 can be helpful in identifying melanin-containingcells in the stroma as macrophages.10.2.6.2.3 Malignant MelanomaFig. 10.13. Primary acquired melanosis with atypia: an almostcontinuous proliferation of atypical melanocytes is present in theconjunctival epithelium10.2.6.2.2 Primary Acquired MelanosisICD-O:8741/2Primary acquired melanosis (PAM) arises in middle-agedor elderly patients as a stippled, yellow-brown, flat pigmentationof the conjunctiva. Two subgroups of PAM can berecognised: PAM without atypia (benign acquired melanosis)and PAM with atypia. In benign acquired melanosis,there is hyperpigmentation of the basal layer, but there isonly a mild increase in melanocytes. The melanocytes canbe large, but show little or no cytologic atypia. Although theevolution of PAM is unpredictable, lesions without atypiahave a good prognosis. PAM with atypia can disappearICD-O:8720/3The majority of conjunctival melanomas arise withinprimary acquired melanosis with atypia. Developmentof a melanoma in a pre-existing naevus or de novo ispossible, but uncommon [44, 61]. In malignant melanomaclusters of atypical melanocytes are present in thestroma (Figs. 10.14, 10.15). The melanocytes are mostfrequently epithelioid, but can also be spindle-shapedor bizarre. The intraepithelial component shows large,atypical melanocytes, often without ascending cells.This differs from skin melanocytic lesions, where ascendingmelanocytes can be very helpful in diagnosinga malignant melanoma. These cytological characteristicsdo not seem to influence prognosis. Depth of thetumour, however, does have prognostic value: thicknessless than 1.5 mm means a low risk of metastatic disease.10.2.6.3 Other NeoplasmsLymphomas may involve the conjunctiva. Also, tumoursfrom adjacent locations may extend into this site. Theyare discussed under their appropriate headings.

292 M.R. Canninga-Van DijkFig. 10.15. Malignant melanoma: detail of the nested, atypicalmelanocytes without maturation in the stromaFig. 10.16. Mucopolysaccharidosis: this cornea showed no abnormalitieson H&E staining, but colloidal iron showed deposits ofmucopolysaccharides very clearly1010.3 CorneaInflammation and ulceration of the cornea can becaused by trauma, surgery to the eye, infectious diseasesand systemic diseases. The trauma can be mechanical,chemical or caused by heat or irradiation. The increasingincidence of cataract extraction has led to an increasein cases with corneal damage during the surgical procedure.Infectious keratitis can be viral, bacterial, fungalor parasitic. In chronic granulomatous keratitis, causeslike leprosy, syphilis and tuberculosis should be considered.Especially in immunocompromised patients infectiouscauses should be excluded by additional stainslike PAS, Grocott and Gram. In corneal ulcers withouta clear aetiology, artificial keratitis has to be considered.Factitious injury is rare and can be either the result ofmechanical trauma or the abuse of toxic eye drops [26].Histology of factitious lesions is non-specific. An exampleof a systemic disease affecting the cornea is mucopolysaccharidosis(Fig. 10.16).10.3.1 Keratitisand Corneal Ulcersor punctate spots (punctate keratopathy). If the diseaserecurs, the virus may infect stromal keratocytes, causingchronic destruction with ulceration. Histologically,an early herpetic ulcer shows multinucleated epithelialcells with intranuclear viral inclusions. DNA in situhybridisation, immunohistochemistry and PCR aremodern techniques replacing the transmission electronmicroscopy that was used to demonstrate theherpes virus particles in earlier days [49]. In end-stagedisease, epithelial changes are no longer present; thereis just fibrosis with scarring. Often, Bowman’s layer isfocally replaced by fibrosis.10.3.1.2 Corneal UlcerationDue to Systemic DiseaseSystemic vasculitides like systemic lupus erythematosus,polyarteritis nodosa and Wegener’s granulomatosiscan cause peripheral corneal ulceration due to vascularocclusion by immune complex deposition in thelimbal vessels [73, 85]. In rheumatoid arthritis cornealulceration can occur due to the release of collagenases[92].10.3.1.1 Herpes Simplex KeratitisType 1 herpes simplex virus is the most common causeof corneal disease. After primary infection of the lip,the virus remains latent in the sensory trigeminal ganglion.Transneural migration and proliferation of thevirus is triggered by stress, sunlight or cold. The virusparasitises the epithelium, leading to superficial epithelialloss in a branching pattern (dendritic ulceration)10.3.2 KeratoconusThis condition presents at puberty and has been foundin association with systemic disorders like Marfan’s syndrome,Down’s syndrome [52, 88], neurofibromatosis,Ehlers-Danlos syndrome [56, 94, 129] and atopic dermatitis[93, 109, 119]. It can also be seen in combinationwith ocular disorders like aniridia, cataract and retinitispigmentosa [11, 33, 53]. A progressive, non-inflamma-

Eye and Ocular Adnexa Chapter 10 293tory, bilateral thinning of the central corneal stromaleads to severe astigmatism. Aetiology and pathogenesisare unclear. At histological examination the epitheliumcan be either atrophic or hyperplastic. The most strikingfinding is interruption of Bowman’s membrane, withdowngrowths of epithelium or upgrowths of cornealstroma in the breaking spot. The breaks may be narrowand the pathology is often restricted to a narrow 1–2 mmzone, sometimes serial sections are required to find thelesion. At the edge of the conus, iron can be found in theepithelium (Fleischer’s ring). The axial stroma showsmucoid degeneration, the peripheral stroma is of normalappearance. In severe cases, rupture of Descemet’smembrane and the endothelium can occur, resulting inan inflow of water and the appearance of cystic spaces.Keratoconus can be treated by surgery with use of stromalcornea grafts.10.3.3 Hereditary Corneal DystrophiesCorneal dystrophies are inherited, bilateral disordersthat can be divided into epithelial, stromal and endothelialabnormalities. Routine stains for suspected cornealdystrophy must include PAS, Masson, Alcian blue,Congo red and Trichrome stains. In end-stage dystrophiesa keratopathy can develop, in which all layers ofthe cornea are involved. Many patients with cornealdystrophies have a point mutation in a gene on chromosome5q31 [54, 77, 113].10.3.3.1 Epithelial DystrophiesEpithelial corneal dystrophies are Cogan’s microcysticdystrophy, Meesman’s dystrophy and Reis-Buckler’sring dystrophy [123]. The epithelial dystrophies presentwith photophobia and/or foreign body sensation.The most common form of epithelial dystrophy isCogan’s microcystic dystrophy, affecting females ofmiddle age. A thickened and folded basement membranewith epithelial cysts containing necrotic debrisis characteristic. Bowman’s membrane is not involved.In Meesman’s dystrophy small layers of the basementmembrane can be found between the epithelial cells.Reis-Buckler ring dystrophy is a bilateral, autosomaldominant dystrophy, not only affecting the epithelium,but also the anterior corneal stroma. The epithelium isoedematous and atrophic, Bowman’s membrane is interruptedand the anterior stroma contains abnormalfibrous tissue. Histology is not specific and transmissionelectron microscopy, which will show electrondenserods in the superficial stroma, is necessary toconfirm the diagnosis [87].10.3.3.2 Stromal Dystrophies10.3.3.2.1 Granular DystrophyGranular dystrophy is an autosomal dominant disorder,presenting in early childhood with discrete, opaquegranules in the otherwise transparent anterior cornealstroma. Histologically, non-birefringent hyaline bodiesare present in the stroma. The deposits are strongly positivewith Masson stain [67].10.3.3.2.2 Lattice DystrophyLattice dystrophy is an autosomal dominant disorder, clinicallypresenting in early childhood (type I) [66] or in the2nd decade (type II) [95] with linear opacities. Histologically,eosinophilic deposits are found in the corneal stroma.They consist of amyloid and are strongly Congo red-positive[67, 112]. The disease is treated by keratoplasty.The presence of amyloid in the corneal stroma canalso be seen in chronic inflammatory conditions, thesesecondary amyloid deposits should not be confused withlattice dystrophy.10.3.3.2.3 Avellino DystrophyA combined granular-lattice dystrophy with both hyalineand amyloid deposits in the corneal stroma was firstdescribed in the Italian village of Avellino [29].10.3.3.2.4 Macular Corneal DystrophyMacular dystrophy presents in childhood as a bilateralprocess with irregular opacities between cloudy cornealstroma. It is a disease disabling vision, inherited as anautosomal recessive trait. The disease is considered to bea localised metabolic disorder with production of excessiveamounts of acid mucopolysaccharide by fibroblasts[24, 67]. The disease is not associated with systemic mucopolysaccharidoses.10.3.3.3 Endothelial Dystrophies10.3.3.3.1 Fuchs DystrophyThis disorder affects elderly patients and is quite commonin routine histopathology. It presents clinicallywith bilateral diffuse cloudy and oedematous stroma.Histologically, the corneal epithelium is oedematous,

294 M.R. Canninga-Van Dijk10Descemet’s membrane is thickened and there is reductionof the endothelial cell population. A PAS stainsometimes shows lamination of Descemet’s membrane.On the posterior surface of Descemet’s membrane, nodularexcrescences can be seen.10.3.4 Failed Previous GraftsMany corneal diseases can be treated by keratoplasty.Complications are rejection, formation of a retrocornealfibrous membrane and recurrence of the original disease.Rejection of the graft can occur immediately afterthe operation or many years later. Histologically, there isvascularisation of the corneal stroma, accompanied by alymphocytic infiltrate.Formation of retrocorneal fibrous membranes occursfollowing fibroblastic metaplasia of keratocytes at theposterior edges of the host-graft junction. This complicationis diminishing with advances in microsurgery.Over a longer period of time, recurrence of the originaldisease is common in patients with corneal dystrophies.10.4 Intraocular TissuesPathology of the intraocular tissues can be divided intodevelopmental anomalies, inflammatory processes,trauma, degeneration and tumours.10.4.1 Developmental Anomalies10.4.1.1 Congenital GlaucomaGlaucoma due to congenital malformation is rare. Associationswith systemic disorders like neurofibromatosis[8, 84, 130] and Sturge-Weber syndrome [18, 19] havebeen described. A malformation of the trabecular meshwork(goniodysgenesis) or persistence of embryonic tissuein the chamber angle causes an outflow obstruction.The corneoscleral envelope of the infant is distensible,so that a raised intraocular pressure can produce an enlargementof the globe (buphthalmos). A hypercellulartrabecular meshwork with hyaloid degeneration is thebest visible histopathological finding in those specimens[133].10.4.1.2 Retinopathy of PrematurityIn premature children requiring artificial breathingwith high oxygen pressures to survive, disordered neovascularisationat the periphery of the retina can occur[91]. A white retrolental fibrous membrane can form inthe most extreme cases, causing bilateral blindness ( retrolentalfibroplasia). At the end stage of the disease neovascularglaucoma leads to enucleation. The distortedretina is macroscopically visible, most frequently forminga straight band behind the lens. Histology showsretinal gliosis and optic atrophy [21].10.4.1.3 Persistent PrimaryHyperplastic VitreousIn the embryo, the lens is supported posteriorly by amass of vascular tissue, the primary vitreous. If this primaryvitreous fails to involute before birth, embryonicfibrovascular tissue persists in the anterior or posteriorpart of the vitreous and becomes hyperplastic. In persistentanterior primary hyperplastic vitreous, a retrolentalfibrovascular mass can penetrate the posterior lens capsuleand lens cortex, causing an autoimmune inflammatoryresponse. In persistent posterior hyperplasticprimary vitreous, the fibrovascular mass damages theoptic disc.10.4.1.4 Retinal DysplasiaFailure of organisation of the layers of the retina leadsto retinal dysplasia, in which nests of neuroblastic cellsform rosettes within the retina. Clustering of rosettesleads to thickening of the retina, which may become detached.Retinal dysplasia is a common feature of trisomy13, trisomy 18 and other chromosomal disorders. As anisolated entity, retinal dysplasia is very rare [65].10.4.1.5 AniridiaAniridia is a rare bilateral disease. It occurs as a conditionthat may be inherited as an autosomal dominantdisorder or as part of several systemic syndromes. Insome cases of aniridia, deletion of the short arm ofchromosome 11 occurs. Because this locus lies closeto the gene for nephroblastoma (Wilms’ tumour), therecognition of a child with sporadic aniridia shouldalert physicians to the increased risk of development ofWilms’ tumour [10, 23]. Histology of enucleated eyesor trabeculectomy specimens shows a rudimentaryiris, consisting of hypercellular stroma, often with anabnormal proliferation of pigment epithelium.10.4.1.6 Congenital Rubella SyndromeMaternal rubella infection during the first trimester ofpregnancy can affect the development and function ofthe entire eye. It can manifest as a congenital cataract,

Eye and Ocular Adnexa Chapter 10 295retinitis can also be visualised with DNA in situ hybridisation.10.4.2.2 Chronic Non-GranulomatousInflammationChronic non-granulomatous inflammation of the uvealtract is a poorly understood condition. It can be dividedinto anterior uveitis, with risk of secondary angle closureglaucoma, and posterior uveitis with risk of degenerationof retinal pigment epithelium. The histology isnon-specific, with only a few lymphocytes in the uvealtissues.Fig. 10.17. Cytomegaloviral retinitis: large eosinophilic inclusionsare present in the infected endothelial cells. In this biopsythe retina showed almost no signs of necrosis, which is uncommonin cytomegalovirus retinitisdisciform keratitis, retinopathy, microphthalmus oropen-angle glaucoma [3, 51]. In societies with immunisationthe condition is rare. The histologic findings inthe lens are characteristic, but it should be mentionedthat the features may not yet be apparent in foetal eyesafter early elective termination of pregnancy [38]. Thecentral nucleus of the lens, which is normally free ofcells, shows pyknotic nuclei. There is an abrupt transitionfrom the central nucleus into the normal peripheralcortex of the lens [128].10.4.2 Inflammatory Processes10.4.2.1 Acute InflammationAcute endophthalmitis or panophthalmitis can occuras a postoperative complication or following a trauma[12, 57]. Endocarditis or injection of contaminatedmaterial in drug addicts can be the cause of metastaticbacterial infection, especially in immunocompromisedpatients [89]. Not only bacterial, but also fungal andviral infections can cause acute endophthalmitis. Histologyshows an extensive infiltrate of leukocytes withdestruction of intraocular tissues. The pathogen cansometimes be found in Gram, PAS or Silver stains.Acute necrotising retinitis and low-grade uveitiscan be seen in cytomegaloviral and herpes infection(Fig. 10.17). The characteristic eosinophilic inclusionsof the cytomegalovirus can be found in the cytoplasmand nuclei of infected cells. Immunohistochemicalstaining with anti-cytomegalovirus can be helpful inidentifying the virus. The inclusions of herpes simplex10.4.2.3 Granulomatous InflammationThe specific granulomatous inflammations of the intra-oculartissues can be divided into infectious andautoimmune causes. The autoimmune diseases are sarcoidosis,sympathetic ophthalmitis and lens-induceduveitis. While many of these diseases may be appropriatelytreated with immunosuppressive medication, themanagement of infectious uveitis is antimicrobial therapy.Inappropriate immunosuppressive therapy may bedisastrous for patients with an infection. Chorioretinalbiopsy may provide useful information for determiningthe diagnosis and guiding the subsequent managementof patients with progressive chorioretinal lesions of unknownaetiology [69].10.4.2.3.1 InfectiousThe most important causes of infectious granulomatousinflammatory diseases of the intraocular tissues are tuberculosisand toxoplasmosis.Tuberculosis is rare and shows caseating granulomas,in which tubercle bacilli can be found in a Ziehl-Neelsenstaining.Toxoplasmic retinochoroiditis in neonates infectedin utero with Toxoplasma gondii can show a wide variationin the pattern of tissue destruction. The disease canbe limited to a low grade uveitis and retinal lymphocyticperivasculitis. In more severely affected eyes focal, sectorialor total retinal destruction can be seen. Toxoplasmacysts can be found in the retina and optic nerve. Inthe most severely affected eyes the retina is necrotic andcalcified [5].10.4.2.3.2 SarcoidosisIn patients with systemic sarcoidosis, ocular involvementcan occur. Most frequently affected are the retina, the

296 M.R. Canninga-Van Dijk10uveal tract and the optic nerve. Histology shows sharplydemarcated, non-caseating granulomas [59, 96].10.4.2.3.3 Sympathetic OphthalmitisSympathetic ophthalmitis is an uncommon, but fearedcomplication because of its potential to blind botheyes. It can result not only from penetrating trauma orocular surgery, but also from non-penetrating ocularprocedures. Early enucleation of the traumatised eyereduces the risk of occurrence of sympathetic ophthalmitisin the non-traumatised (“sympathetic”) eye.The condition seems to be caused by a T-cell-mediatedautoimmune response and can be treated with immunosuppressivetherapy. Infectious causes must be ruledout before starting this therapy. Histology of the enucleatedtraumatised eye shows a granulomatous uveitiswith a thickened choroid featuring non-caseatinggranulomas with a few plasma cells and eosinophils,very similar to sarcoidosis [16]. Fine melanin granulescan be seen in the cytoplasm of the histiocytes.The granulomatous inflammatory reaction can spreadaround small nerves.10.4.2.3.4 Lens-Induced UveitisLens-induced uveitis or phacoanaphylactic endophthalmitisis a chronic endophthalmitis with a zonal granulomatousinflammation surrounding a ruptured lens.Most cases occur after trauma, surgical or non-surgical.The condition may result in vision-threatening intraocularinflammation that is poorly responsive to medicalmanagement. Leaking of lens proteins through an intactlens capsule may result in a lympho-plasmacytic anterioruveitis [102, 127]. The inflammation can be confinedto the anterior aspect of the eye, but the choroid canalso be involved. Surgical removal of the lens materialis generally indicated shortly after the injury in an effortto save vision. Normally, small amounts of circulatinglens proteins maintain a normal T-cell tolerance for lensproteins. Lens-induced uveitis develops when a breakdownoccurs of this normal T-cell tolerance. Immunecomplexes play an important role in the tissue damageassociated with the ensuing inflammation.10.4.3 TraumaMechanical injury is the most frequent cause of traumaof the eye. It can be caused by many different forces, likebroken glass, airguns, knives and golf balls. Chemical,toxic and radiation damage is less often seen. Traumatisedeyes can be enucleated at three different momentsin the time following the injury.The first moment to make the decision for enucleation isimmediately or within a day or two following the injury.The globe is ruptured, massive intraocular bleeding ispresent and there is evidence that repair will not restorevisual function. To lower the risk of sympathetic ophthalmitis,the eye will be enucleated at an early phase.A wide range of foreign bodies can be found in theseeyes. The inflammation is usually mild or absent. Themost important mission for the pathologist is to confirmthe irreparable damage. The lens is often absent or prolapsedthrough the corneal wound, a retinal tear showsthe side of penetration, the vitreous is haemorrhagic,papilloedema is present and the retina can show exudativedetachment (Fig. 10.18).When attempts to repair the eye are made, mild uveitisdevelops. Within a period of 2–3 weeks the uveitisshould diminish. If not, many ophthalmologists willmake the decision to enucleate the eye to avoid the riskof sympathetic ophthalmitis. In these eyes, removedwithin a few weeks after the trauma, reparative changeslike fibrous ingrowth of the corneal wound can befound. The blood in the vitreous will show organisation.Traumatised eyes with residual vision and withoutinflammatory complications can become hypotonic andatrophic over a period of years. Secondary glaucoma candevelop and the eyes are removed because of pain or forcosmetic reasons. Frequently, the secondary changes arevery complicated and the primary pathology is not visibleanymore. At macroscopic examination, the site ofthe trauma can be identified by the presence of scars,suture tracks or just by episcleral thickening. Post-traumaticglaucoma is most often caused by secondary angleclosure. Furthermore, dislocation of the lens and lensinduceduveitis can be seen. The retina is usually partiallyor totally detached, and is thickened by reactivegliosis.10.4.4 Degeneration10.4.4.1 GlaucomaThe normal pressure (13–21 mmHg) in the corneoscleralenvelope is maintained by a balance betweenthe aqueous inflow and the resistance in the outflowsystem. The fluid is pumped into the eye by the ciliaryepithelium, passes through the pupil to the chamberangle and leaves the eye via the trabecular meshworkand the canal of Schlemm to the collector canals inthe sclera, draining into the episcleral venous system.Impaired outflow can cause high intraocular pressuresand when the intraocular pressure is high enough tocause damage to the intraocular tissues, the term glaucomais used. The primary cause of glaucoma can in

Eye and Ocular Adnexa Chapter 10 29710.4.4.1.2 Primary AngleClosure GlaucomaIn primary angle closure glaucoma, the aqueous outflowis obstructed by apposition of the iris to the innersurface of the cornea and the trabecular meshwork. Theacute form of the disease occurs unilaterally in middleagedand elderly patients and presents with a rapid andpainful rise in intraocular pressure. Both in acute andchronic angle closure glaucoma, three ageing processesseem to cause the closure of the angle: shrinkage of theeye, reduction in depth of the anterior chamber and increasedsize of the lens.Fig. 10.18. Trauma caused by a wooden stick: this eye was enucleated1 week after the trauma and showed scleral perforation, retinaldetachment and haemorrhagic vitreousmost cases not be detected in the tissue without thecomplete clinical history. Depending upon the rapidityof the rise in pressure, glaucoma causes tissue damage.In a pressure rise to 80 mmHg within 1 or 2 days(acute glaucoma) severe corneal oedema, infarction ofthe iris, necrosis of the lens and retinal oedema occur.When the pressure rises over a longer period of timemore chronic changes can be found. The cornea showsfibrovascular tissue ingrowth at the periphery. The angleis closed by a corneal endothelial downgrowth andthe trabecular tissue is fused and hyalinised. The irisstroma and ciliary body become atrophic and fibrotic.The nucleus of the lens becomes sclerotic. The vitreousmay be unaffected, but in cases of retinal vasculardisease, the vitreous contains blood and macrophageswith fibrous strands. Atrophy of the optic disc is visibleby cupping and shrinkage down to the lamina cribrosa,which becomes bowed posteriorly. The choroid andretinal pigment epithelium are able to withstand highpressure and will only show atrophy and fibrosis inend-stage disease. Pathologic examination of enucleatedglaucomatous eyes is often complicated by previoussurgical procedures. Glaucoma can be divided intofour subgroups.10.4.4.1.1 Primary OpenAngle GlaucomaPrimary open angle glaucoma occurs predominantlyin the elderly and is caused by an acquired unilateral orbilateral disease of the trabecular meshwork, visible athistopathological examination by hyalinisation of thetrabecular meshwork.10.4.4.1.3 Secondary OpenAngle GlaucomaParticulate or cellular elements present in the trabecularmeshwork can cause outflow obstruction. Examplesare iatrogenic glaucoma (caused by silicone oil, topicalsteroids or viscoelastic substances used to coat lens implants),haemolytic glaucoma, lens protein glaucoma,post-traumatic glaucoma and glaucoma in associationwith tumours (caused by necrotic cells of malignantmelanomas and retinoblastomas). The outflow systemcan also be blocked by melanin pigment granules releasedfrom iris stroma or pigment epithelium when theiris is traumatised or becomes atrophic.10.4.4.1.4 Secondary AngleClosure GlaucomaIn secondary angle closure glaucoma, iridotrabecular oriridocorneal contact is present. This is most frequentlycaused by neovascular glaucoma, in which neovascularisationwith fibrosis of the iris occurs, for example inretinopathy of prematurity. Other causes are end-stageinflammatory disease, retinal detachment, tumours ortrauma.10.4.4.2 CataractsProlonged exposure to ultraviolet light seems to be animportant cause of cataracts, a frequent disorder in elderlypatients. An extracted lens should be fixed, embeddedin paraffin wax and cut in two halves in the anteroposteriordirection. Slides can be made by sectioning thecut surface. Cutting the lens before processing can causeartefacts. In cataracts of the elderly degenerated lens fibresform discrete globules and the epithelium coveringthe inner surface of the anterior lens capsule may extendto the posterior part of the lens. Similar observations aremade in cataracts in children [104].

298 M.R. Canninga-Van Dijk1010.4.4.3 Phtisis BulbiA long period of time after a trauma or an inflammatorydisease, the total eye becomes atrophic. As long as choroidaland retinal anatomy are preserved, this is calledatrophia bulbi. As soon as disorganisation of choroideaand retina occurs, it is called phtisis bulbi. A reactive cellproliferation dominates the histology. This proliferationcan be fibroblastic (trauma of cornea, sclera, choroideaor iris), or glial (retinal damage). Also, proliferation ofretinal pigment epithelium or ciliary body epitheliumcan be seen. The optic nerve is usually completely atrophic.10.4.4.4 Retinal Vascular DiseaseLoss of vision caused by ischaemic disease of the retinais common. It can be due to several different vasculardisorders. Most frequently it is caused by central retinalvein occlusion, diabetes, or occlusion of a branch vein.More rare are vasculitis, retinopathy of prematurity,radiation retinopathy, central retinal artery occlusion,hypertension and disseminated intravascular coagulopathy.Occlusion of an artery causes white infarction,while occlusion of veins leads to haemorrhagic infarction.The ischaemic area can vary between focal (occlusionof branch vessels), segmental, or total (occlusion ofthe central retinal vein or artery). Ischaemia of the retinawith damage of retinal vasculature shows leakage ofred cells, followed by neovascularisation and formationof microaneurysms. In the final stage, secondary angleclosure glaucoma can develop with corneal ulcerationand cataract formation, resulting in a not only blind butalso painful eye. The globes are often enucleated to relievepain. At macroscopic examination an ectropion ofthe iris pigment epithelium, caused by the neovascularmembrane on the iris surface is visible (but only if thecornea is transparent). At microscopic examination, theproliferation of endothelial cells in the retina is the moststriking finding. Sometimes CD31 and GFAP stainingare necessary to differentiate the vascular proliferationfrom reactive gliosis.10.4.4.5 Retinal DetachmentSeveral degenerative conditions predispose to retinal detachment.The separation between the neural retina andthe retinal pigment epithelium can be caused by traction,exudate, or by so-called rhegmatogenous detachment.Traction detachment occurs when the vitreousshows fibrosis or gliosis, following trauma or by neovascularisation.Accumulation of fluid between the layersof the retina is called exudative detachment. It can becaused by processes with excessive permeability of retinalor choroidal vessels, like inflammatory or neoplasticdisorders. In rhegmatogenous detachment, passage offluid from the vitreous cavity to the subretinal space ispresent. It occurs through a hole in the retina, caused bydegeneration or a minor trauma. Enucleated eyes withretinal detachment usually show many signs of previoussurgical intervention. The most important informationfor the surgeons is whether the retina survived the separationand reattachment or not and if a reason for surgicalfailure can be found.10.4.4.6 Retinitis PigmentosaRetinitis pigmentosa presents in early life with nightblindness and a progressive reduction in the visual field,starting at the periphery. Retinal architecture remainsbest preserved at the macula, so the patient ends up withtunnel vision. Different chromosomal abnormalities havebeen found in patients with retinitis pigmentosa. Microscopicexamination shows retinal atrophy with proliferationof Müller cells (retinal supporting cells at the outerside of the retina) replacing the outer nuclear layer. Theretinal pigment epithelium proliferates and can surroundsmall hyalinised vessels in the retina. A marked variationin the extent of retinal degeneration can be seen in tworelatives with retinitis pigmentosa [117].10.4.5 Tumoursand Tumour-Like Conditions10.4.5.1 MelanocyticMelanocytes in the uveal tract can give rise to both benignand malignant tumours. Racial differences mayreflect themselves by variance in prominence and enlargementof melanocytes in the choroid, ciliary bodyand iris. It is very important for pathologists to be awareof these differences.10.4.5.1.1 NaevusICD-O:8720/0Iris naevi present as pigmented macular lesions, arevery slowly progressive, and often completely static overyears. When the clinical presentation is not suspicious,in most cases the lesion will not be excised. For that reason,naevi of the uveal tract are most commonly incidentalfindings. Histology shows a symmetrical lesion,located in the anterior part of the iris stroma, and usuallycomposed of small spindle cells with small, uniformnuclei. Large nucleoli and especially mitotic figures indicatea suspected malignant melanoma.

Eye and Ocular Adnexa Chapter 10 299Fig. 10.19. Uveal tract melanoma arising in the choroidFig. 10.20. Uveal tract melanoma: detail of closely packed spindle-shapedcells; in this area almost no pigment is presentIn the ciliary body naevi are very rare; the histologyis comparable with iris naevi: spindle-shaped cellswithout atypia and without mitotic figures. In the choroid,naevus cells are spindle-shaped and often heavilypigmented, nuclei are uniform, and no mitotic figuresare seen. Depigmentation of the slides may be helpful inevaluating cytological details.10.4.5.1.2 Malignant MelanomaICD-O:8720/3The major part of uveal tract melanomas arise in thechoroid (Fig. 10.19). Most frequently affected are whiteindividuals in the sixth and seventh decades of life.Most melanomas are single and confined to one eye.In most cases they arise from pre-existing naevi in thechoroid. Ciliary body and iris melanomas are rare.Malignant melanoma of the choroid presents with lossof vision in one eye, or with secondary closed angleglaucoma. The glaucoma is caused by detachment ofthe retina with lens–pupil block. Spread of the tumourinto the orbita can cause proptosis. The primary clinicaldifferential diagnosis for melanoma is choroidalmetastasis. At macroscopic examination of an enucleatedeye with a choroidal melanoma, it is important tolocate the tumour before cutting the eye. The tumourcan be located by palpation and transillumination. Ifpossible, the main histological section should containthe centre of the pupil, the optic nerve and the centreof the tumour. Small pigmented nodules can be seenon the external surface of the sclera in case of transscleralextension of the tumour. The sample taken atthis point sometimes needs section at multiple levelsto demonstrate the tumour passing through the scleralcanals. Microscopically, the melanomas consist ofFig. 10.21. Uveal tract melanoma: a more pigmented areaspindle-shaped cells, epithelioid cells, or a combinationof both (mixed cell type). The spindle-shapedcells are closely packed elongated cells, often with pronouncednucleoli and a few mitotic figures. In epithelioidlesions, the cytoplasm is more eosinophilic andmitotic figures are easily found. Melanin pigment isusually is present, but amelanotic lesions can be seen(Figs. 10.20–10.23). Positive immunohistochemistrywith S-100, melan A or HMB45 confirms the diagnosisin those cases. The final report should include theorigin of the tumour (choroid, ciliary body, iris), thethickness of the tumour (in mm), the cell type (spindlecell type, epithelioid cell type or mixed cell type) andextraocular growth. The 5-year survival of pure spindletumours is 80%, while pure epithelioid tumourshave a 5-year survival of 35%. The 20-year survival ofboth groups is only 20%.

300 M.R. Canninga-Van DijkFig. 10.22. Uveal tract melanoma: detail of an epithelioid lesionconsisting of cells with a large amount of eosinophilic cytoplasmFig. 10.24. Retinoblastoma: a detached retina with small blueround cell proliferation10Fig. 10.23. Uveal tract melanoma: trans-scleral extension of thetumour10.4.5.2 LymphoidIntraocular lymphomas are not different from those occuringelsewhere in the body. Therefore, discussion oftheir features lies beyond the scope of this chapter.10.4.5.3 Retinoblastomaand PseudoretinoblastomaICD-O:9510/3Retinoblastoma is rare, but nevertheless the most commonintraocular malignant tumour of childhood, clinicallypresenting as a white mass behind the lens, resultingin the so-called cat’s eye reflex. Vision in the eye isimpaired, leading to strabismus. The tumour affectschildren younger than 5 years and can be unilateral orbilateral (30%). Retinoblastoma in adults is extremelyrare. Lesions with the typical clinical presentation butare of other kinds are called pseudoretinoblastoma. Theycan be other tumours (astrocytic hamartomas, haemangioblastomas),congenital malformations or inflammatoryconditions (especially solitary Toxocara granuloma).The accuracy of clinical diagnosis has been improvedby radiology, ultrasonography, CT scanning andnuclear magnetic resonance, and this has brought abouta considerable reduction in the number of such cases.The retinoblastoma gene, located on chromosome13q14 is a tumour-suppressor gene. Retinoblastoma canbe inherited (bilateral tumours in the first 2 years oflife) or sporadic (unilateral tumours in children aged 2–5 years). One-third of the patients with a sporadic retinoblastomashow a germline mutation and can transmitthe disease to their offspring. Compared with the generalpopulation, carriers of germline mutations in the retinoblastomagene, who survive retinoblastoma are at increasedrisk of early-onset second cancers, particularlysarcomas and brain tumours. External beam radiotherapyhas been a standard treatment for medium andlarge, or vision-threatening, intraocular retinoblastoma,but it markedly increases the risk of cosmetic deformitiesand secondary cancer in children with germline mutations.For that reason primary systemic chemotherapycalled “chemoreduction” has been employed to avoid radiotherapyand enucleation. The cure rate of retinoblastomais more than 90% in specialised centres.Retinoblastomas are tumours originating from pluripotentgerminal retinoblasts; the tumour can grow endophytically(growing into the vitreous), exophytically(growing into the subretinal space, leading to retinal detachment)or diffusely (a rare pattern with widespread

Eye and Ocular Adnexa Chapter 10 301From the glial tumours, only astrocytomas can be foundin the retina and optic nerve. Optic pathway gliomas arefrequently asymptomatic; sometimes they demonstraterapid growth, causing considerable visual dysfunction,neurologic deficits, and endocrine disturbances. Mostoptic pathway gliomas are diagnosed in patients withneurofibromatosis. Children with optic pathway gliomasassociated with neurofibromatosis 1 predominantlyhave multifocal lesions.Benign astrocytic tumours of the retina ( astrocytichamartomas) most frequently occur in patients with tuberoussclerosis. Retinal astrocytic hamartoma and retinoblastomamay be very similar clinically and their differentiationin atypical cases can be difficult, even withthe use of ultrasonography and computed tomography.Histologically, a well-circumscribed glial cell proliferation,sparing the outer layers of the retina will be visible.10.4.5.5 Vascular10.4.5.5.1 Angiomatosis RetinaeFig. 10.25. Retinoblastoma: detail of the small blue round cellswith high mitotic and apoptotic activitynodular thickening of the retina). The diffuse growthpattern has a bad prognosis. Trans-scleral spread of retinoblastomais uncommon. The tumour usually spreadsinto the meninges or parenchyma of the optic nerve. Forthis reason, it is important to take transverse blocks ofthe cut surface of the optic nerve, before cutting the enucleatedeye. Microscopic examination will show a smallblue round cell tumour with a high mitotic rate. Thecells have ill-defined cytoplasm and inconspicuous nucleoli.Rosettes are frequently seen and apoptosis is common(Figs. 10.24, 10.25). Glial differentiation is rare. Ifthe tumour was irradiated before enucleation, amorphouscalcified structures will be present. Immunohistochemistryof retinoblastomas will show positivity forS-100, GFAP and NSE. Use of these markers can be helpfulnot only in identifying the tumour, but also in identifyingthe spread of the tumour. Choroidal invasion inparticular can be hard to recognise in an H&E staining.Axonal degeneration in the optic nerve, with reactiveproliferation of astrocytes has to be differentiated fromreal tumour spread.Von Hippel-Lindau disease is an autosomal dominantlyinherited multi-system disorder characterised by haemangioblasticlesions of the central nervous system andvisceral organs [126]. Angiomatosis retinae (retinal haemangioblastoma)is often the first observable manifestationof von Hippel-Lindau disease. Histology showsa proliferation of capillary endothelial cells and vacuolatedstromal cells.In some patients with von Hippel-Lindau disease orin the close relatives of such patients, unusual retinalvascular hamartomas other than retinal angiomas canbe detected.10.4.5.5.2 Cavernousand Capillary HaemangiomaICD-O:9120/0Haemangiomas of the choroid can be diagnosed clinicallyby fluorescein angiography. Diffuse haemangiomatosiswith facial skin involvement can be seen in theSturge-Weber syndrome. The treatment of these vascularlesions is radiation (external beam or radioactiveplaque); for this reason pathologists do not see theselesions very often. Only when the haemangiomas leadto retinal attachment and blindness will enucleation follow.The excised globe usually shows reactive changesdue to radiotherapy.10.4.5.4 Glial10.4.5.6 Other Primary TumoursTumours other than melanocytic, lymphoid, retinoblasticand vascular can be found in the intraocular structures,but they are extremely rare. In the iris leiomyoma,leiomyosarcoma, schwannoma, juvenile xanthogranuloma,rhabdomyosarcoma, inclusion cysts of the pigmentepithelium, primary adenoma of the iris pigmentepithelium and adenocarcinoma have been reported.In the ciliary body leiomyomas, leiomyosarcomas,schwannomas, adenomas and medulloepitheliomas can befound, and in the choroid osteomas, adenomas and adenocarcinomasof the retinal pigment epithelium and hamar-

302 M.R. Canninga-Van Dijk10tomas have been described [63]. Choroidal osteomas candevelop within a degenerated choroidal haemangioma oran inflammatory scar, but can also be idiopathic.10.4.5.7 Metastatic TumoursMetastatic tumours to the eye have a predilection forthe highly vascular choroid. The metastases can be discoveredin a patient known to have a malignancy, butthey can also be the first presentation of the malignantdisease. Histology most often shows an adenocarcinomaand the primary tumour is found in the breast or lung[86]. More rare are metastases from thyroid carcinoma,carcinoid tumours, endometrial carcinoma, haemangiosarcomaand adenocarcinoma of the intestinal tract.The lesions usually show severe necrosis due to palliativeradiotherapy.10.5 Optic Nerve10.5.1 PapilloedemaAny condition in which the intracranial pressure israised can cause papilloedema. The prelaminar part ofthe optic disc is swollen and the peripapillary photoreceptorsare placed laterally. If the reason for the papilloedemais not identified, the oedema can present as atumour. This so-called pseudotumour cerebri is treatedby optic nerve fenestration to relieve the pressure in thesubarachnoid space. The pathologist will receive themeninges surrounding the optic nerve, which are histologicallycompletely normal.10.5.2 Optic NeuritisOptic neuritis presents as acute, unilateral and painfulvision loss. It can result from inflammatory disorders,can occur as isolated inflammation, or may be part ofthe spectrum of multiple sclerosis. Magnetic resonanceimaging is indicated to rule out compressive optic neuropathy.Spontaneous outcome of optic neuropathiesis favourable. Secondary inflammatory optic neuritis(infection, vasculitis, sarcoidosis) is rare and usuallypresents with atypical evolution or other symptoms.Histologically, the optic nerve in multiple sclerosis willshow a perivascular lymphocytic infiltrate with focalareas of demyelination and axonal atrophy at the endstage.10.5.3 Optic AtrophyIn a normal optic disc, a large bulge of nerve fibre isformed. In enucleated glaucomatous eyes, the optic discis obviously cupped and shrinks down to the laminacribrosa, which becomes bowed posteriorly. Reactive fibrovasculartissue fills the cupped disc.10.5.4 Tumours10.5.4.1 GliomaICD-O:9380/3Most glial tumours of the optic nerve are of the juveniletype. They present with slowly progressive proptosis.The juvenile tumours have a good prognosis,unlike the more rare adult types, which are invariablylethal. Bilateral optic nerve gliomas can be found inpatients with neurofibromatosis. Histologically, thejuvenile tumours are of the pilocytic type, while theadult tumours resemble the high-grade glioblastomamultiforme.10.5.4.2 MeningiomaICD-O:9530/0Meningiomas surrounding the optic nerve can resultfrom a primary tumour arising in the meningeal sheetof the optic nerve or can result from an intracranialmeningioma spreading into the orbit. As in the intracranialcompartment, meningiomas of the orbit occurmost commonly in middle-aged females. The tumourspresent with proptosis. Optic nerve sheath meningiomasin the adult group grow slowly and have a goodprognosis. Meningiomas at other sites in the head andneck are mentioned in Chaps. 2, 6 and 8.10.6 Lacrimal Glandand Lacrimal Passages10.6.1 Inflammatory ProcessesEnlargement of the lacrimal gland is often caused bychronic inflammatory processes that can have manydifferent causes. When chronic dacryoadenitis is associatedwith enlargement of the salivary glands, it iscalled Mikulicz syndrome. Mikulicz syndrome can becaused by many different diseases like sarcoidosis, tu-

Eye and Ocular Adnexa Chapter 10 303berculosis, mumps, malignant lymphoma and syphilis.The most frequent cause of Mikulicz syndromeis Mikulicz disease; the histology is similar to that ofbenign lymphoepithelial lesions seen in the salivaryglands. Acute and chronic dacryocystitis and canaliculitisare the result of inflammation, mostly nonspecific,of the lacrimal passages. It may lead to dacryolithiasis(stones in the lacrimal sac) and to lacrimalmucocele.10.6.2 Tumoursand Tumour-Like ConditionsIf a mass is found in the superolateral quadrant of theorbit, dermoid cysts and lacrimal gland masses shouldbe considered. Fifty percent of lacrimal gland tumoursare pleomorphic adenomas and the other half are malignant[27, 98, 134]. The malignant category includes predominantlyadenoid cystic, carcinoma ex pleomorphicadenoma and mucoepidermoid carcinoma. The lacrimaltumours have few distinguishing imaging features,showing mostly a homogeneous character and moderatecontrast enhancement. Poorly defined margins withbone destruction suggest a malignancy, but even themalignant lesions can be relatively well defined. Thehistology of lacrimal gland tumours is similar to that ofsalivary gland tumours as discussed in Chap. 5. Papillomasand squamous cell carcinomas are the benign andmalignant tumours most commonly seen in the lacrimalsac. Their microscopic features are similar to those arisingfrom the mucosa of the nose (see Chap. 2) or in theconjunctiva.10.7 Eyelids10.7.1 CystsBecause of the numerous adnexal glands present in theeyelids, cysts are very common at this localisation. Thecysts can be of developmental origin (dermoid cysts) orcan be caused by inclusion or retention.10.7.1.1 Dermoid CystThe most common type of a cyst of the eyelids in childrenis the dermoid cyst, a developmental cyst caused byinclusion of ectodermal rests within the lines of closureof the branchial arches. Dermoid cysts are lined withstratified squamous epithelium with small pilosebaceousunits attached to the wall (Fig. 10.26). The lumenusually contains small hairs and keratin. The presenceFig. 10.26. Dermoid cyst: lined with squamous epithelium withsmall pilosebaceous units in the wallof pilosebaceous units differentiates this cyst from epidermalcysts.10.7.1.2 Epidermal cystsEpidermal cysts (epidermoid cysts, keratinous cysts) arefirm, often yellow-brown masses, diagnosed clinicallyas “sebaceous cysts”. However, real sebaceous cysts (steatocystomas)are very rare and most cysts will histologicallyshow a lining with stratified squamous epitheliumwithout pilosebaceous glands. The cysts are filled withstrands of keratin. Epidermal cysts can be caused bydermal inclusion of epithelial cells after a microtrauma,but also by occlusion of a pilosebaceous unit. If an epidermalcyst ruptures, keratin will be released betweenthe collagen bundles of the dermis, causing a granulomatousforeign body reaction.10.7.1.3 HidrocystomaCysts derived from the small sweat glands present inthe eyelids present as bluish, round lesions and areclinically often misdiagnosed as haemangiomas. Theterm hidrocystoma is preferred, but many other names,like cysts of Moll’s glands and sudiferous cysts, can befound in the literature. The eccrine cysts are lined withcuboidal to flattened epithelium with a myoepithelialbase (Fig. 10.27). Sometimes only one epithelial layeris visible, showing eosinophilic cytoplasm with snouts,characteristic of apocrine differentiation. It can be veryhard to differentiate between eccrine or apocrine originsand sometimes both components can be found inthe cysts.

304 M.R. Canninga-Van DijkFig. 10.27. Hidrocystoma: cystic space lined with flattened epitheliumwith a myoepithelial baseFig. 10.28. Chalazion: optical empty spaces surrounded by histiocytesforming granulomas. The infiltrate also contains lymphocytesand neutrophils1010.7.2 Inflammatory ProcessesA very common inflammatory condition of the eyelidsis a chalazion. Furthermore, many inflammatory skindiseases can involve the periorbital region. Periorbitaleczema may be an expression of a constitutional disease,an irritant or allergic dermatitis. Other inflammatorydermatoses that can involve the eyelids are seborrheicdermatitis, psoriasis, rosacea and dermatomyositis.Other causes of inflammation of the eyelids include bacterial,fungal and viral infections.10.7.2.1 Chalazionand Other Ruptured CystsChalazia are very common. The clinical presentation isusually very typical, with an acute swelling in the tarsalconjunctiva. In a few days the swelling becomes afirm nodule. Excision or excochleation is the treatmentof choice. Because of the typical clinical presentation,many ophthalmologists will not offer the material forroutine histological examination. Chalazia are causedby the obstruction of the duct of a small (Zeis) or larger(Meibomian) sebaceous gland. A small retention cyst isformed and rupture of this cyst causes the escape of fattyproducts into the surrounding tissues. The fatty materialtriggers an acute inflammatory reaction first, followedby a chronic granulomatous reaction (Fig. 10.28).In the very late stages of chalazia, fibrosis and scarringcan be seen. The presence of fatty cells or even largeroptical empty spaces within a granulomatous reaction ischaracteristic of a chalazion. The only other conditionswith similar lipogranulomatous reactions are leakage ofimplants (for example silicon) and dermatitis artefacta.If patients with dermatitis artefacta use oily fluids to inject,the histological picture is identical to that of a chalazion.All other cysts (dermoid, epidermal and hidrocystomas)can rupture. The wall of the cyst is sometimes nolonger identifiable. The presence of small pieces of thecontent of the former cyst (hair, keratin) in multinucleatedgiant cells proves the diagnosis of an inflamed andruptured cyst.10.7.2.2 Deep Granuloma AnnulareGranuloma annulare usually occurs on the dorsum ofthe hands and the lower arms. It is considered to be acutaneous reaction pattern, most frequently associatedwith diabetes mellitus. However, in children the deepvariant of granuloma annulare is a benign, relativelycommon dermatosis, not related to systemic disease. Ingranuloma annulare of childhood lesions typically occuron the extremities and resolve spontaneously overa period of several months to years. Localised facial involvement,sometimes with involvement of the eyelids, israre. The clinical relevance is that granuloma annulare,presenting in the periocular region, may mimic otherlesions. This diagnosis should be considered for any acquiredpapules of the periorbital area, especially if thereis a history of antecedent trauma. Unnecessary surgicalexcision can then be avoided. Histology shows deep fociof degeneration of collagen, surrounded by histiocytes.Often there is increased dermal mucin.

Eye and Ocular Adnexa Chapter 10 30510.7.2.3 Necrobiotic XanthogranulomaNecrobiotic xanthogranuloma is a rare chronic andoften progressive disorder with a predilection for theperiorbital skin. Other areas of the face, as well as thetrunk and limbs, can also be involved. Lesions presentas sharply demarcated violaceus, partly xanthomatousnodules and plaques. Ulceration may develop. Almostall patients with necrobiotic xanthogranuloma are diagnosedwith a paraproteinaemia. Other, more rare associationsare hyperlipidaemia and leukopenia. Scleritis,episcleritis and keratitis are common ophthalmiccomplications. The histological changes are present inthe dermis and in the subcutis. Large zones of necrobioticcollagen with hyaline and sometimes mucinouschanges are present in the deep dermis. These areasare surrounded by histiocytes, partly with a foamycytoplasm. Sometimes the xanthomatous changesare only minor. Multinucleated giant cells are easilyfound; they can be of the Touton type, but also of theforeign body type with bizarre nuclei. In ulceratinglesions, transepidermal elimination of debris can beseen.10.7.3 AmyloidosisSolitary or multiple nodules of amyloid may occur bothin the eyelids and in the conjunctiva. Most frequently itis a localised process, without signs of systemic amyloidosis.Histology shows amorphous, eosinophilic, Congored-positive masses in the stroma. The walls of bloodvessels often also contain amyloid.10.7.4 Tumoursand Tumour-Like ConditionsTumours of the eyelids are very similar to tumours occurringin the conjunctiva and the skin. The most importanttumours of the eyelids are basal cell carcinomas,squamous cell carcinomas and sebaceous adenocarcinomas.These tumours are discussed in Sect. 10.2.6. Atumour-like condition with a predilection for the eyelidsand the surrounding skin is xanthelasma.Fig. 10.29. Xanthelasmata: multiple foamy histiocytes are presentin the dermis10.8 Orbit10.8.1 Inflammatory ProcessesThe most common inflammatory diseases of the orbitinclude Graves’ disease (dysthyroid ophthalmopathy),orbital cellulitis and pseudotumours.10.8.1.1 Dysthyroid OphthalmopathyThe most common cause of bilateral proptosis is Graves’disease. Seventy percent of cases are bilateral and symmetrical.In cases of unilateral involvement, other diseasesmust be considered. Females are more frequentlyaffected than males. The disease is characterised by symmetricalswelling of the extraocular muscles. The inferiorand medial rectus muscles are most often involved.The muscle enlargement characteristically involves thebody of the muscle, sparing the tendinous attachment tothe globe. Histologically, the fibrous tissue of the orbitand the swollen muscles show oedema and chronic inflammationin early stages and fibrosis in end-stage disease.The degenerated muscle fibres become hyalinised.10.7.4.1 XanthelasmataXanthelasmata are yellow papules and plaques, most frequentlyoccurring on the eyelids and the skin surroundingthe eyes. They are relatively frequent. Xanthelasmatacan be a manifestation of hypercholesterolaemia,but most cases are idiopathic. Histology shows multiplefoamy histiocytes in the superficial dermis (Fig. 10.29).10.8.1.2 CellulitisAcute bacterial infection (cellulitis) of the orbit is uncommon.It is most frequently caused by direct spreadof an infection from the paranasal sinuses or eyelids. Itmay also be of odontogenic origin and can be one of thepresenting features of retinoblastoma or other tumours.Chronic intranasal cocaine abuse can result in exten-

306 M.R. Canninga-Van Dijkand fat in the earliest stages. This will be followed bylymphocytic infiltration and end with fibrous changes.In cases of massive infiltration by lymphocytes, immunohistochemistryis necessary to rule out malignantlymphoma (Fig. 10.30). Another disease that canmimic pseudotumours is sarcoidosis. Sarcoidosis ishistologically characterised by typical granulomas, notsurrounded by lymphocytes.10Fig. 10.30. Pseudotumour of the orbit: fibrous tissue with necroticfat cells is infiltrated by large groups of lymphocytes. Immunohistochemistryis necessary to rule out a malignant lymphomasive bony destruction of the orbital walls with associatedorbital cellulitis. In patients with poorly controlleddiabetes, but also in immunocompromised patients,orbital cellulitis can also be caused by fungal agents,for example mucormycosis. Presenting symptoms mostfrequently include oedema of the upper eyelid, headacheand facial pain. Sometimes it can be asymptomatic.Clinically, orbital cellulitis is of great importance,as it is a severe disease with potentially disastrous consequences.Despite antifungal or antibacterial therapy,disease can progress. It may lead to optic neuritis, opticatrophy, blindness, cavernous sinus thrombosis, intracranialabscess formation, meningitis, subdural empyema,and even death. An incision biopsy of the processcan be helpful in the diagnostic work-up. Histology willshow an extensive neutrophilic infiltration of the orbitalfibrous tissue and fat. The causative microorganismscan often be found with PAS, Gram and silver stainings.It is important for the pathologist to look for underlyingcauses, like tumours.10.8.1.3 PseudotumourNon-specific inflammation of orbital tissues is knownas orbital pseudotumour. It tends to be unilateral andaccounts for 25% of all cases of unilateral exophthalmos.Spontaneous regression can occur and a responseto steroids is often seen. However, orbital pseudotumourscan also be chronic and progressive. The diagnosishas to be confirmed by an incision biopsy, especiallyin cases in which the pseudotumour appearsas a discrete mass and simulates a neoplastic lesion.Histology shows oedema of the orbital fibrous tissue10.8.2 Tumoursand Tumour-Like ConditionsA variety of tumours and pseudotumours can involvethe orbit. Most orbital lesions are benign (65%). The percentageof malignant tumours increases with age, with60% of malignancies in patients over 60 years of age, becauseof the higher incidence of lymphoma and metastatictumours in the elderly. Orbital tumours of childhoodare distinct from tumours that occur in adults. Manyare congenital with early presentations. Most paediatricorbital tumours are benign (80%); developmental cystscomprise half of orbital cases, with capillary haemangiomabeing the second most common orbital tumourin children. The most common orbital malignancy inchildren is rhabdomyosarcoma. Whereas the malignanttumours may be life-threatening, both malignant andbenign tumours may be vision-threatening. Almost alllymphomas, soft tissue and bone tumours may involvethe orbit.10.8.2.1 Developmental CystsEpithelial rests found at sutural sites within the orbitcan give rise to epithelial cysts. Cysts of the surfaceepithelium are further divided into simple epithelialcysts (epidermal, conjunctival, respiratory and apocrinegland), and dermoid cysts (epidermal and conjunctival).Epidermal dermoid cyst (dermoid) is by far the mostcommon orbital cystic lesion in children, accountingfor over 40% of all orbital lesions of childhood. Otherdevelopmental cysts are teratomatous cysts, neural cysts(congenital cystic eye and colobomatous cyst) and thoseassociated with brain and meningeal tissue (encephaloceleand optic nerve meningocele) [103]. Developmentalcysts have to be differentiated from secondary cysts, likemucocele and inflammatory cysts. Mucocele can occurin children with cystic fibrosis. Inflammatory cystsare generally due to parasitic infestations and are morecommon in tropical areas of the world. Furthermore,non-cystic tumourous lesions with a cystic component(like rhabdomyosarcoma and lymphangioma) can presentas a cyst.

Eye and Ocular Adnexa Chapter 10 307The orbit is the most common location for metastasesto the eye and adjacent structures in children (neuroblastoma),whereas the choroid is the predominant sitein adults. Approximately 5% of all orbital tumour-likelesions are metastatic lesions. However, because malignanciesare far more frequent in adults, most orbitalmetastatic lesions are found in elderly patients. Themean period of time between the onset of the primarydisease and orbital manifestation is 5 years. The mainprimary symptoms are lid swelling, red eye, diplopia andproptosis. The most frequent primary tumour is a breastcarcinoma, but many other carcinomas can metastasiseto the orbit (Figs. 10.31, 10.32). Metastatic melanomas tothe eye and orbit are rare and generally occur in patientswith disseminated metastases during the terminal stagesof the disease, with a short life expectancy.Fig. 10.31. Carcinoid metastatic to the orbit: this haemorrhagicorbital mass contained small nests of monomorphous epithelialcells. Immunohistochemistry was consistent with a carcinoidFig. 10.32. Renal cell adenocarcinoma metastatic to the orbit:nests of clear epithelioid cells were found; immunohistochemistryshowed positivity for both vimentin and cytokeratin10.8.2.2 Optic Nerveand Meningeal TumoursOptic nerve and meningeal tumours can spread intothe orbit. Together they represent 8% of all orbital tumours.10.8.2.3 Metastatic TumoursReferences1. Akpek EK, Polcharoen W, Chan R, Foster CS (1999) Ocularsurface neoplasia masquerading as chronic blepharoconjunctivitis.Cornea 18:282–2882. Akpek EK, Polcharoen W, Ferry JA, Foster CS (1999) Conjunctivallymphoma masquerading as chronic conjunctivitis.Ophthalmology 106:757–7603. Armstrong NT (1992) The ocular manifestations of congenitalrubella syndrome. Insight 17:14–164. Aultbrinker EA, Starr MB, Donnenfeld ED (1988) Linear IgAdisease. The ocular manifestations. Ophthalmology 95:340–3435. Balayre S, Gomez K, Tribut A, Dore P, Gobert F (2003) Toxoplasmagondii and necrotizing retinitis: a case report. J FrOphtalmol 26:837–8416. Bastiaensen LA, Verpalen MC, Pijpers PM, Sprong AC (1985)Conjunctival sarcoidosis. Doc Ophthalmol 59:5–97. Biggs SL, Font RL (1977) Oncocytic lesions of the caruncleand other ocular adnexa. Arch Ophthalmol 95:474–4788. Bost M, Mouillon M, Romanet JP, Deiber M, Navoni F (1985)Congenital glaucoma and Von Recklinghausen’s disease. Pediatrie40:207–2129. Bourcier T, Monin C, Baudrimont M, Larricart P, Borderie V,Laroche L (2003) Conjunctival inclusion cyst following parsplana vitrectomy. Arch Ophthalmol 121:106710. Breslow NE, Norris R, Norkool PA, Kang T, Beckwith JB,Perlman EJ, Ritchey ML, Green DM, Nichols KE (2003)Characteristics and outcomes of children with the Wilms tumor-Aniridiasyndrome: a report from the National WilmsTumor Study Group. J Clin Oncol 21:4579–458511. Bruna F (1954) Association of keratoconus with retinitis pigmentosa.Boll Ocul 33:145–15712. Busbee BG (2004) Advances in knowledge and treatment: anupdate on endophthalmitis. Curr Opin Ophthalmol 15:232–23713. Cervantes G, Rodriguez AA Jr, Leal AG (2002) Squamouscell carcinoma of the conjunctiva: clinicopathological featuresin 287 cases. Can J Ophthalmol 37:14–19; discussion19–2014. Ceuterick C, Martin JJ (1984) Diagnostic role of skin or conjunctivalbiopsies in neurological disorders. An update. JNeurol Sci 65:179–19115. Chai F, Coates H (2003) Otolaryngological manifestationsof ligneous conjunctivitis. Int J Pediatr Otorhinolaryngol67:189–19416. Chan CC, BenEzra D, Hsu SM, Palestine AG, NussenblattRB (1985) Granulomas in sympathetic ophthalmia and sarcoidosis.Immunohistochemical study. Arch Ophthalmol103:198–202

308 M.R. Canninga-Van Dijk1017. Chen S, Wishart M, Hiscott P (2000) Ligneous conjunctivitis:a local manifestation of a systemic disorder? J AAPOS4:313–31518. Cibis GW (1987) Congenital glaucoma. J Am Optom Assoc58:728–73319. Cibis GW, Tripathi RC, Tripathi BJ (1984) Glaucoma inSturge-Weber syndrome. Ophthalmology 91:1061–107120. Claes K, Kestelyn P (2000) Ocular manifestations of graftversus host disease following bone marrow transplantation.Bull Soc Belge Ophtalmol 21–2621. Cogan DG (1971) Congenital anomalies of the retina. BirthDefects Orig Artic Ser 7:41–5122. Craitoiu S (1992) Goldenhar’s oculoauricular dysplasia, limbicdermoid and conjunctival dermolipoma. Oftalmologia36:357–36123. Crolla JA, van Heyningen V (2002) Frequent chromosomeaberrations revealed by molecular cytogenetic studies in patientswith aniridia. Am J Hum Genet 71:1138–114924. Cursiefen C, Hofmann-Rummelt C, Schlotzer-Schrehardt U,Fischer DC, Kuchle M (2000) Immunophenotype classificationof macular corneal dystrophy: first case report of immunophenotypeI A outside of Saudi Arabia. A clinical histopathologicalcorrelation with immunohistochemistry andelectron microscopy. Klin Monatsbl Augenheilkd 217:118–12625. Darougar S, Pearce R, Gibson JA, McSwiggan DA (1978)Adenovirus type 21 keratoconjunctivitis. Br J Ophthalmol62:836–83726. Dart J (2003) Corneal toxicity: the epithelium and stroma iniatrogenic and factitious disease. Eye 17:886–89227. De Rosa G, Zeppa P, Tranfa F, Bonavolonta G (1986) Aciniccell carcinoma arising in a lacrimal gland. First case report.Cancer 57:1988–199128. Dokonalova E, Vymazalova Z, Vymazal M, Riegrova D(1990) A complex choristoma of the conjunctiva. Acta UnivPalacki Olomuc Fac Med 126:227–23129. El-Ashry MF, El-Aziz MM, Larkin DF, Clarke B, Cree IA,Hardcastle AJ, Bhattacharya SS, Ebenezer ND (2003) A clinical,histopathological, and genetic study of Avellino cornealdystrophy in British families. Br J Ophthalmol 87:839–84230. Elsas FJ, Green WR (1975) Epibulbar tumors in childhood.Am J Ophthalmol 79:1001–100731. Faraj HG, Hoang-Xuan T (2001) Chronic cicatrizing conjunctivitis.Curr Opin Ophthalmol 12:250–25732. Fernandes M, Vemuganti GK, Pasricha G, Bansal AK, SangwanVS (2003) Unilateral tuberculous conjunctivitis withtarsal necrosis. Arch Ophthalmol 121:1475–147833. Freedman J, Gombos GM (1971) Bilateral macular coloboma,keratoconus, and retinitis pigmentosa. Ann Ophthalmol3:664–66534. Gamel JW, Eiferman RA, Guibor P (1984) Mucoepidermoidcarcinoma of the conjunctiva. Arch Ophthalmol 102:730–73135. Gayre GS, Proia AD, Dutton JJ (2002) Epibulbar osseouschoristoma: case report and review of the literature. OphthalmicSurg Lasers 33:410–41536. Gloor P, Ansari I, Sinard J (1999) Sebaceous carcinoma presentingas a unilateral papillary conjunctivitis. Am J Ophthalmol127:458–45937. Haller EM, Auer-Grumbach P, Stuenzner D, Kessler HH,Pierer K, Zenz H, Muellner K (1996) Evaluation of two noncultureantigen tests and three serotests for detection of antichlamydialantibodies in the diagnosis of ocular chlamydialinfections. Graefes Arch Clin Exp Ophthalmol 234:510–51438. Hanna C (1976) Embryopathic time-table of cataract formationin congenital rubella. J Pediatr Ophthalmol 13:266–27339. Hegab SM, al-Mutawa SA, Sheriff SM (1998) Sarcoidosis presentingas multilobular limbal corneal nodules. J PediatrOphthalmol Strabismus 35:323–32640. Heiligenhaus A, Dutt JE, Foster CS (1996) Histology and immunopathologyof systemic lupus erythematosus affectingthe conjunctiva. Eye 10:425–43241. Ho MW, Crean SJ, Sharma A, Sukhija J, Das A, Saroha V,Sukhi S, Mohan K (2003) Simultaneous occurrence of sublingualdermoid cyst and oral alimentary tract cyst in an infant:a case report and review of the literature. Int J PaediatrDent 13:441–446.42. Ho VT, Rao VM, Flanders AE (1994) Postsurgical conjunctivalepithelial cysts. AJNR Am J Neuroradiol 15:1181–118343. Hochman MA, Mayers M (1997) Stevens-Johnson syndrome,epidermolysis bullosa, staphylococcal scalded skin syndrome,and dermatitis herpetiformis. Int Ophthalmol Clin37:77–9244. Jakobiec FA, Folberg R, Iwamoto T (1989) Clinicopathologiccharacteristics of premalignant and malignant melanocyticlesions of the conjunctiva. Ophthalmology 96:147–16645. Jordaan HF, Schneider JW, Schaaf HS, Victor TS, Geiger DH,Van Helden PD, Rossouw DJ (1996) Papulonecrotic tuberculidin children. A report of eight patients. Am J Dermatopathol18:172–18546. Kallor AD, Hendricks WM, Salvitti C, Azulay RD, HeringerML, Almeida de Faria IA (1979) Oculoauriculovertebral dysplasia(Goldenhar’s syndrome). Cutis 24:41-4247. Karcioglu ZA, Issa TM (1997) Human papilloma virus inneoplastic and non-neoplastic conditions of the external eye.Br J Ophthalmol 81:595–59848. Kawamoto K, Miyanaga Y, Toriyama S (1996) A case of bilateralMALT (mucosa-associated lymphoid tissue) typeconjunctival malignant lymphoma. Nippon Ganka GakkaiZasshi 100:246–25249. Kaye SB, Baker K, Bonshek R, Maseruka H, Grinfeld E, TulloA, Easty DL, Hart CA (2000) Human herpesviruses in thecornea. Br J Ophthalmol 84:563–57150. Kerty E, Vigander K, Flage T, Brinch L (1999) Ocular findingsin allogeneic stem cell transplantation without totalbody irradiation. Ophthalmology 106:1334–133851. Khandekar R, Al Awaidy S, Ganesh A, Bawikar S (2004) Anepidemiological and clinical study of ocular manifestationsof congenital rubella syndrome in Omani children. ArchOphthalmol 122:541–54552. Kim JH, Hwang JM, Kim HJ, Yu YS (2002) Characteristic ocularfindings in Asian children with Down syndrome. Eye16:710–71453. Knoll A (1955) Simultaneous occurrence of degenerative retinitispigmentosa and keratoconus. Szemeszet 92:165–16854. Korvatska E, Munier FL, Djemai A, Wang MX, Frueh B,Chiou AG, Uffer S, Ballestrazzi E, Braunstein RE, ForsterRK, Culbertson WW, Boman H, Zografos L, Schorderet DF(1998) Mutation hot spots in 5q31-linked corneal dystrophies.Am J Hum Genet 62:320–32455. Kruk J, Kallor AD, Hendricks WM, Salvitti C, Azulay RD,Heringer ML, Almeida de Faria IA (1979) Goldenhar’s syndrome:aetiopathogenesis, morphology and treatment. KlinOczna 81:485–48656. Kuming BS, Joffe L (1977) Ehlers-Danlos syndrome associatedwith keratoconus. A case report. S Afr Med J 52:403–40557. Kunimoto DY, Tasman W, Rapuano C, Recchia F, Busbee B,Pearlman R, Belmont J, Cohen E, Vander J, Laibson P, RaberI (2004) Endophthalmitis after penetrating keratoplasty: microbiologicspectrum and susceptibility of isolates. Am JOphthalmol 137:343–34558. Lam S, Stone MS, Goeken JA, Massicotte SJ, Smith AC, FolbergR, Krachmer JH (1992) Paraneoplastic pemphigus, cicatricialconjunctivitis, and acanthosis nigricans with pachydermatoglyphyin a patient with bronchogenic squamous cellcarcinoma. Ophthalmology 99:108–11359. Langlois M, Evain B, Fournier E, Potier F (1986) Choroidalpseudotumoral granuloma in sarcoidosis (apropos of a case).Bull Soc Ophtalmol Fr 86:223–22460. Lesser RL (1995) Ocular manifestations of Lyme disease. AmJ Med 98:60S–62S61. Liesegang TJ (1994) Pigmented conjunctival and scleral lesions.Mayo Clin Proc 69:151–161

Eye and Ocular Adnexa Chapter 10 30962. Lin J, Li Y, Zhang J, Feng G, Zhang P, Zheng H, Zheng J(1999) Rapid diagnosis of chlamydial conjunctivitis in laboratory.Yan Ke Xue Bao 15:191–19463. Liu CC, Kou HK, Tsai MH, Su CC, Kao ML, Chen YJ, TsaiSH (2001) Choroidal masses: a fourteen-year analysis. ChangGung Med J 24:502–51164. Livesey SJ, Holmes JA, Whittaker JA (1989) Ocular complicationsof bone marrow transplantation. Eye 3:271–27665. Lloyd IC, Colley A, Tullo AB, Bonshek R (1993) Dominantlyinherited unilateral retinal dysplasia. Br J Ophthalmol77:378–38066. Longanesi L, Cavallini GM, Iammarino A, Vaccina F, GuerraR, De Pol A (1998) Ultrastructural localization of gelsolin inlattice corneal dystrophy type I. Ophthalmologica 212:415–42167. Luo Q, Wang L, Feng X, Cai R, Shen G, Deng Y, Xia R (1999)Observation of special stain and ultrastructure of lattice,granular and macular corneal dystrophy. Zhonghua Yan KeZa Zhi 35:268–27068. MacCallan A (1931) The epidemiology of trachoma. Br JOphthalmol 15:369–41169. Martin DF, Chan CC, de Smet MD, Palestine AG, Davis JL,Whitcup SM, Burnier MN Jr, Nussenblatt RB (1993) The roleof chorioretinal biopsy in the management of posterior uveitis.Ophthalmology 100:705–71470. Mauriello JA Jr, Abdelsalam A, McLean IW (1997) Adenoidsquamous carcinoma of the conjunctiva – a clinicopathologicalstudy of 14 cases. Br J Ophthalmol 81:1001–100571. McDonnell JM, McDonnell PJ, Sun YY (1992) Human papillomavirusDNA in tissues and ocular surface swabs of patientswith conjunctival epithelial neoplasia. Invest OphthalmolVis Sci 33:184–18972. Merchant S, Weinstein M (2003) Pemphigus vulgaris: theeyes have it. Pediatrics 112:183–18573. Messmer EM, Foster CS (1999) Vasculitic peripheral ulcerativekeratitis. Surv Ophthalmol 43:379–39674. Meyers SJ, Varley GA, Meisler DM, Camisa C, Wander AH(1992) Conjunctival involvement in paraneoplastic pemphigus.Am J Ophthalmol 114:621–62475. Mohile M, Deorari AK, Satpathy G, Sharma A, Singh M(2002) Microbiological study of neonatal conjunctivitis withspecial reference to Chlamydia trachomatis. Indian J Ophthalmol50:295–29976. Mubarik M, Nabi B, Ladakhi GM, Sethi AS (2000) Childhoodtuberculosis. I. Epidemiology, pathogenesis, clinicalprofile. JK Pract 7:12–1577. Munier FL, Korvatska E, Djemai A, Le Paslier D, Zografos L,Pescia G, Schorderet DF (1997) Kerato-epithelin mutationsin four 5q31-linked corneal dystrophies. Nat Genet 15:247–25178. Neumann R, Dutt CJ, Foster CS (1993) Immunohistopathologicfeatures and therapy of conjunctival lichen planus. AmJ Ophthalmol 115:494–50079. Oehme A, Musholt PB, Dreesbach K (1991) Chlamydiae aspathogens – an overview of diagnostic techniques, clinicalfeatures, and therapy of human infections. Klin Wochenschr69:463–47380. Oguz O, Gokler G, Ocakoglu O, Oguz V, Demirkesen C,Aydemir EH (1997) Conjunctival involvement in familialchronic benign pemphigus (Hailey-Hailey disease). Int JDermatol 36:282–28581. O’Neal ML, Brunson A, Spadafora J (2001) Ocular sebaceouscarcinoma: case report and review of the literature. ComprTher 27:144–14782. Palazzi MA, Erwenne CM, Villa LL (2000) Detection of humanpapillomavirus in epithelial lesions of the conjunctiva.Sao Paulo Med J 118:125–13083. Panda A, Arora R, Mohan M (1987) Cystic lesions of conjunctiva.Ann Ophthalmol 19:60–6284. Payne MS, Nadell JM, Lacassie Y, Tilton AH (2003) Congenitalglaucoma and neurofibromatosis in a monozygotictwin: case report and review of the literature. J Child Neurol18:504–50885. Pleyer U, Bergmann L, Krause A, Hartmann C (1996) Autoimmunediseases of the peripheral cornea. Immunopathology,clinical aspects and therapy. Klin Monatsbl Augenheilkd208:73–8186. Potter De P (1998) Ocular manifestations of cancer. CurrOpin Ophthalmol 9:100–10487. Pouliquen Y, Giraud JP, Savoldelli M (1978) Reis-Buckler’sdystrophy. Albrecht Von Graefes Arch Klin Exp Ophthalmol208:25–3188. Rabinowitz YS (1998) Keratoconus. Surv Ophthalmol42:297–31989. Ravault MP, Trepsat C, Chatenoud F (1983) Candida albicansendophthalmitis in drug addicts: apropos of 2 cases. Bull SocOphtalmol Fr 83:1307–130890. Reccia R, Del Prete A, Scala A, Masciello M, Di Giovanni A,Sebastiani A (1994) Direct immunofluorescence and scrapingconjunctival cytology in the study of 912 patients affectedby microfollicular conjunctivitis. Ophthalmologica 208:295–29791. Reedy EA (2004) The discovery of retrolental fibroplasia andthe role of oxygen: a historical review, 1942–1956. NeonatalNetw 23:31–3892. Riley GP, Harrall RL, Watson PG, Cawston TE, HazlemanBL (1995) Collagenase (MMP-1) and TIMP-1 in destructivecorneal disease associated with rheumatoid arthritis. Eye9:703–71893. Ring CC (1958) Atopic dermatitis with cataracts; a report ofthree cases, one with keratoconus. Trans Ophthalmol Soc NZ 10:41–4794. Robertson I (1975) Keratoconus and the Ehlers-Danlos syndrome:a new aspect of keratoconus. Med J Aust 1:571–57395. Rosenberg ME, Tervo TM, Gallar J, Acosta MC, Muller LJ,Moilanen JA, Tarkkanen AH, Vesaluoma MH (2001) Cornealmorphology and sensitivity in lattice dystrophy type II(familial amyloidosis, Finnish type). Invest Ophthalmol VisSci 42:634–64196. Ryckewaert M, Zanlonghi X, Castier P, Francois P (1988)Choroidal granuloma in sarcoidosis. Discussion apropos of2 cases. J Fr Ophtalmol 11:773–77897. Sanchez-Tocino H, Saornil MA, Herreras JM, Blanco G,Calonge M, Rodriguez De La Rua E (2001) Usefulness of conjunctivalbiopsy as diagnostic technique. Arch Soc Esp Oftalmol76:31–3698. Sanders TE, Ackerman LV, Zimmerman LE (1962) Epithelialtumors of the lacrimal gland. A comparison of the pathologicand clinical behavior with those of the salivary glands. AmJ Surg 104:657–66599. Schuster V, Seregard S (2003) Ligneous conjunctivitis. SurvOphthalmol 48:369–388100. Sehgal VN, Ramesh V, Ghorpade A (1984) Naevus sebaceousassociated with ocular dermolipoma. J Dermatol 11:97–98101. Seitz B, Henke V (1995) Mucoepidermoid carcinoma of theepibulbar connective tissue with diffuse intraocular epithelialinvasion. Klin Monatsbl Augenheilkd 207:264–265102. Sekundo W, Augustin AJ (2001) Differences in the compositionof inflammatory cell infiltrate in lens-induced uveitisunder therapy with allopurinol or steroids. Eur J Ophthalmol11:264–268103. Shields JA, Shields CL (2004) Orbital cysts of childhood –classification, clinical features, and management. Surv Ophthalmol49:281–299104. Shirai K, Saika S, Okada Y, Oda S, Ohnishi Y (2004) Histologyand immunohistochemistry of fibrous posterior capsuleopacification in an infant. J Cataract Refract Surg 30:523–526105. Sjo NC, Heegaard S, Prause JU, von Buchwald C, LindebergH (2001) Human papillomavirus in conjunctival papilloma.Br J Ophthalmol 85:785–787106. Sjoegren H (1933) Angeborenes Fehlen der Tranensekretionund der Keratoconjunctivitis sicca bei Kindern. KlinMonatsbl Augenheilkd 22:554–559107. Sjoegren H (1933) Zur Kenntnis der Keratoconjunctivitis sicca(Keratitis filiformes bei hypofunktion der Tranendrusen).Acta Opthalmol 2:1–151

310 M.R. Canninga-Van Dijk10108. Skotnitsky C, Sankaridurg PR, Sweeney DF, Holden BA(2002) General and local contact lens induced papillary conjunctivitis(CLPC). Clin Exp Optom 85:193–197109. Spencer WH, Fisher JJ (1959) The association of keratoconuswith atopic dermatitis. Am J Ophthalmol 47:332–344110. Spraul CW, Grossniklaus HE (1996) Tumors of the corneaand conjunctiva. Curr Opin Ophthalmol 7:28–34111. Spraul CW, Lang GK (1996) Oncocytoma of the conjunctiva.Klin Monatsbl Augenheilkd 209:176–177112. Starck T, Kenyon KR, Hanninen LA, Beyer-Machule C, FabianR, Gorn RA, McMullan FD, Baum J, McAdam KP (1991)Clinical and histopathologic studies of two families with latticecorneal dystrophy and familial systemic amyloidosis(Meretoja syndrome). Ophthalmology 98:1197–1206113. Stewart H, Black GC, Donnai D, Bonshek RE, McCarthy J,Morgan S, Dixon MJ, Ridgway AA (1999) A mutation withinexon 14 of the TGFBI (BIGH3) gene on chromosome 5q31causes an asymmetric, late-onset form of lattice corneal dystrophy.Ophthalmology 106:964–970114. Suchecki JK, Donshik P, Ehlers WH (2003) Contact lenscomplications. Ophthalmol Clin North Am 16:471–484115. Thorne JE, Jabs DA, Nikolskaia O, Anhalt G, Nousari HC(2002) Discoid lupus erythematosus and cicatrizing conjunctivitis:clinicopathologic study of two cases. Ocul ImmunolInflamm 10:287–292116. Thorne JE, Jabs DA, Nikolskaia OV, Mimouni D, AnhaltGJ, Nousari HC (2003) Lichen planus and cicatrizing conjunctivitis:characterization of five cases. Am J Ophthalmol136:239–243117. To K, Adamian M, Dryja TP, Berson EL (2002) Histopathologicstudy of variation in severity of retinitis pigmentosa dueto the dominant rhodopsin mutation Pro23His. Am J Ophthalmol134:290–293118. Tranos L (1954) Mandibulofacial dysostosis associated withdermolipoma of the conjunctiva. Am J Ophthalmol 37:354–359119. Tuft SJ, Kemeny DM, Dart JK, Buckley RJ (1991) Clinical featuresof atopic keratoconjunctivitis. Ophthalmology 98:150–158120. Tunc M, Char DH, Crawford B, Miller T (1999) Intraepithelialand invasive squamous cell carcinoma of the conjunctiva:analysis of 60 cases. Br J Ophthalmol 83:98–103121. Usui T, Sawaguchi S, Abe H, Iwata K, Oyanagi K (1993) Conjunctivalbiopsy in adult form galactosialidosis. Br J Ophthalmol77:165–167122. Uy HS, Pineda R II, Shore JW, Polcharoen W, Jakobiec FA,Foster CS (1999) Hypertrophic discoid lupus erythematosusof the conjunctiva. Am J Ophthalmol 127:604–605123. Waring GO III, Rodrigues MM, Laibson PR (1978) Cornealdystrophies. I. Dystrophies of the epithelium, Bowman’s layerand stroma. Surv Ophthalmol 23:71–122124. Weber CM, Eichenbaum JW (1997) Acute red eye. Differentiatingviral conjunctivitis from other, less common causes.Postgrad Med 101:185–196125. Wilhelmus KR, Robinson NM, Tredici LL, Jones DB (1986)Conjunctival cytology of adult chlamydial conjunctivitis.Arch Ophthalmol 104:691–693126. Wizigmann-Voos S, Plate KH (1996) Pathology, geneticsand cell biology of hemangioblastomas. Histol Histopathol11:1049–1061127. Woerdt van der A (2000) Lens-induced uveitis. Vet Ophthalmol3:227–234128. Wolff SM (1972) The ocular manifestations of congenital rubella.Trans Am Ophthalmol Soc 70:577–614129. Woodward EG, Morris MT (1990) Joint hypermobility inkeratoconus. Ophthalmic Physiol Opt 10:360–362130. Wu SX (1987) Neurofibromatosis accompanied by congenitalglaucoma (report of 2 cases). Yan Ke Xue Bao 3:43–46131. Yeung L, Tsao YP, Chen PY, Kuo TT, Lin KK, Lai LJ (2004)Combination of adult inclusion conjunctivitis and mucosaassociatedlymphoid tissue (MALT) lymphoma in a youngadult. Cornea 23:71–75132. Zaidman GW (1997) The ocular manifestations of Lyme disease.Int Ophthalmol Clin 37:13–28133. Zhang J (1991) Histo- and ultrahistopathology of the anteriorchamber angle in congenital glaucoma. Zhonghua Yan KeZa Zhi 27:151–153134. Zhu JB, Li B, Sun XL, Li LQ, Shi JT, An YZ (2004) Clinicaland pathological features of 273 cases of lacrimal epithelialtumors. Zhonghua Yan Ke Za Zhi 40:220–224

Subject IndexAabscess 184peritonsillar 184abuse of the voice 208accessory tragus 240external ear 240acinic cell carcinoma 60sinonasal 60Addison disease 88adenocarcinoma 149, 150, 151, 182,222, 242basal cell 151ceruminal glands 242cribiform of the tongue 150larynx 222nasopharynx 182polymorphous low-grade 149adenoid cystic carcinoma 59, 182, 222,242ceruminal glands 242larynx 222nasopharynx 182sinonasal 60adenoid squamous cell carcinoma 22adenoma 48, 137, 140, 141, 143, 144, 158,174, 214, 240, 241, 247, 248basal cell 141canalicular 143ceruminal glands 240ceruminal glands pleomorphic 241congenital pleomorphic 140larynx pleomorphic 214middle ear 247middle ear neuroendocrine 248middle ear plasmacytoid 248nasopharyngeal pituitary 174pleomorphic 48, 137pleomorphic metastasising 158sebaceous 144sinonasal pituitary 48adenomatoid hyperplasia 134salivary glands 134adenomatoid odontogenic tumour 112adenosquamous carcinoma 23differential diagnosis 23agenesis 132salivary glands 132aggressive papillary tumour 248middle ear 248amalgam tattoo 86ameloblastic carcinoma 119ameloblastic fibro-dentinoma 116ameloblastic fibro-odontoma 116ameloblastic fibro-odontosarcoma 120ameloblastic fibrodentinosarcoma 120ameloblastic fibroma 116granular cell 116ameloblastic fibrosarcoma 120ameloblastoma 110, 111, 112, 119acanthomatous 111basaloid 111basal cell 111desmoplastic 111granular cell type 111malignant 119metastasing 119peripheral 112unicystic 111amyloidosis 43, 191, 211, 305larynx 211sinonasal 43Waldeyer‘s ring 191aneurysmal bone cyst 124angiofibroma 50, 175nasopharyngeal 50, 175angiolymphoid hyperplasiawith eosinophilia 239external ear 239aniridia 294with Wilm‘s tumour 294aphthae 77herpetiform 77major 77minor 77aplasia 132salivary glands 132aspergillosis 44, 203invasive 44larynx 203sinonasal 44astrocytic hamartoma 301in tuberous sclerosis 301of retina 301atresia 132salivary glands 132atypical hyperplasia 10BB-cell lymphoma 61sinonasal 61basaloid squamous cell carcinoma 20basal and parabasal cell hyperplasia 9basal cell carcinoma 242external ear 242Behçet disease 78Bell‘s palsy 255blastomycosislarynx 203Bohn’s nodules 109botryoid odontogenic cyst 107branchial 265arch 265cleft 265cyst 265fistula 265pouch 265sinus 265branchial cleft cyst 238first 238branchiogenic carcinoma 267Ccalcifying cystic odontogenic tumour 118calcifying epithelial odontogenic tumour112calcifying odontogenic cyst 118candidiasis 203larynx 203candidosis 81, 82chronic hyperplastic 82carcinoma 119, 144, 146, 147, 150, 151,152, 154, 156, 157, 158, 159, 180, 189,252, 267, 290acinic cell 144adenoid cystic 147branchiogenic 189, 267epithelial-myoepithelial 150ex pleomorphic adenoma 156ex pleomorphic adenoma,non-invasive 157hyalinising clear cell 151lymphoepithelial 158middle ear metastatic 252mucoepidermoid 146myoepithelial 152nasopharyngeal keratinising 180nasopharyngeal non-keratinising 180nasopharyngeal undifferentiated 180oncocytic 156primary intraosseous 119salivary duct 154sebaceous 158sebaceous of conjunctiva 290small cell 159carcinoma in situ 11carcinosarcoma 157salivary gland 157

312 Subject Indexcataract 297cellulitis 306in orbit 306cemento-ossifying fibroma 121cementoblastoma 115cementoma 124familial gigantiform 124ceruminoma 240ear canal 240chalazia 304cheilitis granulomatosa 92cherubism 124Chickenpox 73Chievitz’s organ 72chlamydia trachomatis 287cholesteatoma 239, 244, 246, 259cerebellopontine angle 259congenital 246external canal 239middle ear 244cholesterol granuloma 43, 259maxillary sinus 43petrous apex 259chondrodermatitis nodularis helicis 239chondroid chordoma 125chondromas 217larynx 217chondrosarcoma 125, 183, 223larynx 223nasopharynx 183chordoma 125, 183chondroid 125nasopharynx 183choristoma 247glial middle ear 247salivary gland middle ear 247sebaceous middle ear 247clear cell odontogenic carcinoma 120clear cell odontogenic tumour 120cocaine abuse 46nasal 46coccidioidomycosislarynx 203complex odontoma 117compound odontoma 117condyloma acuminatum 2conjunctivitis 286, 287, 288acute 286chronic 287inclusion 287, 288in dermatologic diseases 288ligneous 287contact ulcer 210glottic 210corneal 294failed graft 294corneal dystrophies 293Avellino 293Cogan‘s 293Fuchs 293granular 293lattice 293macular 293Meesman‘s 293Reis-Buckler‘s 293corneal ulceration 292in systemic disease 292coxsackie virus 73craniopharyngioma 118, 174nasopharynx 174Crohn’s disease 91cryptococcosis 203larynx 203cylindrical cell carcinoma 52sinonasal 52cyst 42, 105, 106, 107, 108, 109, 124, 135,173, 174, 179, 199, 200, 268, 269, 270,271, 273, 285, 303, 306aneurysmal bone 124benign lymphoepithelial 136botryoid odontogenic 107bronchial 270bronchogenic 270calcifying odontogenic 118conjunctival inclusion 285dentigerous 106dermoid 271, 303epidermal 303eruption 106gingival 108glandular odontogenic 107glandular retention 179larynx ductal 199larynx epidermoid 200larynx oncocytic 200larynx saccular 199lateral periodontal 107lymphoepithelial 273nasolabial 109nasopalatine duct 109nasopharyngeal branchial 173nose dermoid 42of orbit 306paradental 106parathyroid 270primordial 107radicular 105Rathke’s cleft 174residual 105salivary duct 135salivary glands 135sialo-odontogenic 107simple bone 109solitary bone 109surgical ciliated 109thymic 269thyroglossal duct 268Tornwaldt’s 173traumatic bone 109cystadenoma 144mucinous 144oncocytic 144papillary 144cystic hygroma 272cystic lymphoid hyperplasia of AIDS 136cytomegalovirus 133, 254cochlear infection 254salivary glands 133Ddacryoadenitis 302dental follicle 114, 115, 117dental papilla 114dentigerous cyst 106dentinogenic ghost cell tumour 118dermatitis herpetiformis 76dermoid 285dermolipoma 285desmoid fibromatosis 49sinonasal 49desmoplastic ameloblastoma 111desmoplastic fibroma 115diphtheria 202larynx 202dysplasia 5, 8Eendodermal sinus tumour 161endolymphatic sac tumour 259temporal bone 259endophthalmitis 295eosinophilic angiocentric fibrosis 43sinonasal 43eosinophilic ulcer 79epidermoid cyst 200epiglottitis 202acute 202Epstein-Barr virus 133salivary glands 133Epstein’s pearls 109epulis 90, 93fibrous 90giant cell 93eruption cyst 106erythema multiforme 77erythroplakia 6exostosis 241ear canal 241Ffacial paralysis 255familial gigantiform cementoma 124fibro-osseous lesions 121fibrosarcoma 62sinonasal 62fibrous dysplasia 121fibrous histiocytoma 49sinonasal 49focal osseous dysplasia 124focal epithelial hyperplasia 2Fordyce granules 72foreign body 210frictional keratosis 86Ggenetic alterations 161salivary gland tumours 161

Subject Index 313geographic tongue 85giant-cell hyalin angiopathy 93giant cell epulis 93, 124giant cell fibroma 94giant cell granuloma 124central 124peripheral 93, 124gingival 91fibromatosis 91hypertrophy 91gingival cyst 108gingival hyperplasia 93inflammatory 93gingivitis 79, 82, 92acute necrotising 79chronic marginal 92desquamative 82glandular odontogenic cyst 107glaucoma 294, 296neurofibromatosis 294Sturge-Weber syndrome 294glial heterotopia 43glioma 301, 302in neurofibromatosis 302nasal 43of optic nerve 302of optic pathway 301gout 206, 238external ear 238larynx 206granular cell ameloblastic fibroma 116granular cell odontogenic fibroma 116granular cell tumour 96, 216larynx 216granuloma 206, 210, 211glottic 210glottic intubation 210vocal cord teflon 206granulomatous infections 133salivary glands 133granuloma annulare 304Graves‘ disease 305Hhaemangioblastoma 301of retina 301haemangioma 48, 95, 214, 215, 272, 301of choroid 301sinonasal 48larynx 214subglottic 215haemangiopericytoma 48sinonasal 48hairy tongue 85hamartoma 42, 178, 247middle ear 247nasopharynx 178respiratory epithelial adenomatoid 42,178sinonasal 42hand-foot-and-mouth disease 73herpangina 74herpes simplex 72Hertwig sheath of 104heterotopic brain 174nasopharyngeal 174hidrocystoma 303Hippel-Lindau disease 248middle ear 248histoplasmosis 203larynx 203hygroma 95, 272cystic 95, 272hyperacidic granulomas 211hyperplastic vitreous 294hypoplasia 132salivary glands 132Iidiopathic pseudocystic chondromalacia238pinna 238inflammatory myofibroblastic tumour213larynx 213intercalated duct hyperplasia 151intestinal-type adenocarcinoma 58sinonasal 58intraepithelial neoplasia 289of conjunctiva 289Kkeloid 240ear 240keratinising cysts 200keratin granuloma 239external ear 239keratitis 292herpes simplex 292keratoameloblastoma 111keratoconjunctivitis sicca 288keratoconus 292syndrome-associated 292keratocyst 107keratocystic odontogenic tumour 108keratocystoma 137keratosis 5keratosis obturans 239ear canal 239Kimura‘s disease 239external ear 239Küttner tumour 133Llabyrinthitis 255lacrimal gland 303tumours 303laryngocele 199, 271laryngotracheobronchitis 202lateral periodontal cyst 107Laugier Hunziker syndrome 89leiomyoma 49sinonasal 49leiomyosarcoma 63sinonasal 63leishmaniasis 45, 203larynx 203nasal 45leprosy 45, 203larynx 203nasal 45leukoplakia 5, 6, 85hairy 85lichenoid drug eruption 83lichen planus 82linear IgA disease 76lipoma 258inner ear 258Lipschutz bodies 72Ljubljana grading system 9low-grade adenocarcinoma 60sinonasal 60lupus erythematosus 83lymphadenoma 144sebaceous 144lymphangioma 95, 272lymphoepithelial carcinoma 24differential diagnosis 25larynx 24nasopharynx 24oropharynx 24lymphoepithelial sialadenitis 163lymphoid hyperplasia 184palatine tonsil 184pharyngeal tonsil 184lymphoma 61, 164, 189, 190, 224larynx 224MALT 164sinonasal 61Waldeyer‘s ring 189Waldeyer‘s ring Hodgkin 190Waldeyer‘s ring MALT 190Waldeyer‘s ring mantel cell 189Waldeyer‘s ring NK/T-cell 190lymph nodes 264cervical groups 264Mmacule 86oral melanotic 86Malassez rests of 104malignant epithelial odontogenic ghostcell tumour 120malignant fibrous histiocytoma 62sinonasal 62malignant melanoma 243external ear 243malignant peripheral nerve sheath tumour63sinonasal 63Marfan’s syndrome 107melanoacanthoma 87melanoma 55, 87, 225, 291, 299in situ 88larynx 225of conjunctiva 291

314 Subject Indexof uveal tract 299sinonasal 55melanosis 89, 291of conjunctiva 291smoker’s 89melanotic neuroectodermal tumour ofinfancy 126melanotic nevi 243external ear 243Melkersson Rosenthal syndrome 92Ménière‘s disease 256meningioma 50, 123, 125, 179, 251,258, 302chordoid 125middle ear 251nasopharynx 179sinonasal 50inner ear 258metastases 160, 225, 307larynx 225of orbit 307salivary glands 160metastatic renal cell carcinoma 61sinonasal 61metastatic tumour 191, 302of the eye 302nasopharynx 191Miescher’s syndrome 92migratory stomatitis 85Mikulicz syndrome 302mucocele 43, 132, 135extravasation 132sinonasal 43mucoepidermoid carcinoma 61, 222larynx 222sinonasal 61mucormycosissinonasal 44multiple endocrine neoplasia syndrome96mumps 133salivary glands 133muscular dystrophy 207oculopharyngeal 207myoepithelioma 140, 152malignant 152myospherulosis 43sinonasal 43myxoma 114Nnaevi 87blue 87intramucosal 87melanocytic 87naevus 84, 290, 298of conjunctiva 290of uveal tract 298oral epithelial 84unius lateris 84white sponge 84nasolabial cyst 109nasopalatine duct cyst 109nasopharyngeal-type undifferentiatedcarcinomas 54sinonasal 54neck triangles 264neck dissection 278examination 279level 278types 279necrobiotic xanthogranuloma 305necrotising sialometaplasia 133larynx 211neurilemmoma 96neurinoma 96neuritis 302optic 302neuroendocrine carcinoma 220, 221larynx 220larynx moderately differentiated 220larynx poorly differentiated 221larynx well differentiated 220neurofibroma 49, 96sinonasal 49neurofibromatosis 96, 124, 258acoustic 258neuromas 96mucosal 96nevoid basal cell carcinoma syndrome 107NK/T cell lymphoma 61sinonasal 61nodule 208, 211glottic metaplastic elastic cartilaginous211vocal cord 208Noonan’s syndrome 124Oochronosis 238external ear 238odonto-ameloblastoma 118odontogenic carcinosarcoma 121odontogenic epithelial hamartoma 115odontogenic fibroma 114, 115, 116granular cell 115, 116peripheral 115odontogenic ghost cell carcinoma 120odontogenic ghost cell tumour 120malignant epithelial 120odontogenic gingival epithelial hamartoma112odontogenic granular cell tumour 115odontogenic keratocyst 107odontogenic myxoma 114odontoma 117complex 117compound 117oedema 207, 208larynx angioneurotic 207vocal cord Reinke‘s 208olfactory neuroblastoma 57oncocytic hyperplasia 135oncocytic metaplasia 134, 200oncocytoma 143, 214, 289larynx 214of conjunctiva 289oncocytosis 134ophthalmitis 296sarcoidosis 295sympathetic 296optic atrophy 302orofacial granulomatosis 92osseous dysplasia 123, 124florid 124focal 124periapical 124ossifying fibroma 90, 115, 121, 122, 241juvenile psammomatoid 122juvenile trabecular 122peripheral 90, 115temporal bone 241osteoblastoma 115osteogenesis imperfecta 254stapes 254osteoma 125, 241ear canal 241Gardner’s syndrome 125osteomyelitis 104osteopetrosis 254otic 254osteoporotic bone marrow defect 109osteosarcoma 183nasopharynx 183otitis 237, 244malignant externa 237media 244otosclerosis 252bony labyrinth 252stapes footplate 252PPaget‘s disease 253, 256inner ear 256temporal bone 253panophthalmitis 295papillary adenocarcinoma 182nasopharynx 182papillary hyperplasia 90papillary squamous cell carcinoma 19differential diagnosis 20papilloedema 302papilloma 46, 47, 144, 178, 249, 288ductal 144exophytic 46middle ear schneiderian 249nasopharynx inverted 178of conjunctiva 288sinonasal 46sinonasal exophytic 46sinonasal inverted 46sinonasal oncocytic 47papillomatosis 3recurrent respiratory 3paracoccidioidomycosis 203larynx 203paradental cyst 106paraganglioma 50, 215, 249, 273middle ear jugulotympanic 249multicentric jugulotympanic 249sinonasal 50

Subject Index 315solitary jugulotympanic 249larynx 215pemphigoid 75cicatricial 75mucous membrane 75pemphigus 74paraneoplastic 75vegetans 74vulgaris 74periapical osseous dysplasia 124perichondritis 237pinna 237periostitis 104peripheral ameloblastoma 112petrositis 255bacterial 255Peutz Jeghers syndrome 89phonotrauma 209phtisis bulbi 298pigmentation 89, 90drugs associated 90heavy metals 90racial 89Pindborg tumour 112pinguecula 286plasmacytoma 62, 190, 224larynx 224sinonasal 62Waldeyer‘s ring 190polycystic dysgenetic disease 135polymorphous low-grade adenocarcinoma182nasopharynx 182polyp 41, 90, 175, 184, 187, 208allergic sinonasal 41antrochoanal 41antronasal 42atypical fibroblasts 41fibroepithelial 90immobile cilia syndrome 41Kartagener’s syndrome 41mucoviscidosis 41nasopharynx hairy 175oropharynx hairy 175palatine tonsil hairy 184tonsillar lymphangiomatous 187vocal cord 208postintubation granuloma 211presbyacusis 260primary intraosseous carcinoma 119primitive neuroectodermal tumour 58sinonasal 58primordial cyst 107proliferative verrucous hyperplasia 6pseudotumour 306of orbit 306psoriasis 86pterygium 286pulse granuloma 93pyogenic granuloma 93Rradicular cyst 105ranula 132, 271Reinke’s oedema 208Reinke’s space 208Reiter disease 78relapsing polychondritis 205, 238larynx 205pinna 238residual cyst 105retention cyst 200retinal detachment 298retinal dysplasia 294retinal ischaemia 298retinitis pigmentosa 298retinoblastoma 300retinochoroiditis 295toxoplasma gondii 295retrolental fibroplasia 294rhabdomyosarcoma 63, 183, 252middle ear 252nasopharynx 183sinonasal 63rheumatoid arthritis 204larynx 204rhinitis 40allergic 40atrophic 41bacterial 40hypertrophic 41viral 40rhinoscleroma 45, 203larynx 203nasal 45rhinosinusitis 40bacterial 40rhinosporidiosis 44sinonasal 44rhomboid glossitis 78Riga-Fede disease 79Rubella syndrome 294congenital 294Rushton bodies 105, 108Ssaccular cysts 199salivary duct carcinomas 60sinonasal 60salivary gland anlage tumour 140, 175nasopharynx 175salivary gland neoplasms 273cervical cystic 273sarcoidosis 45, 191, 204larynx 204sinonasal 45Waldeyer‘s ring 191sarcoma 183, 224larynx 224larynx granulocytic 224larynx mast cell 224nasopharynx granulocytic 183schwannoma 49, 96, 257acoustic 257sinonasal 49sclerosing polycystic sialadenopathy 136Serres rests of 104sialadenosis 133sialo-odontogenic cyst 107sialoblastoma 161simple bone cyst 109sinusitis 44allergic mucinous 44sinus histiocytosis with massive lymphadenopathy212larynx 212Sjögren‘s syndrome 288small cell neuroendocrine carcinoma 54sinonasal 54smoker’s keratosis 84solitary bone cyst 109solitary fibrous tumour 48, 179nasopharynx 48, 179sinonasal 48spindle cell carcinoma 16differential diagnosis 17, 21squamous cell carcinoma 13, 15, 25, 51,96, 187, 218, 243, 250acantholytic 22adenoid 22alcohol 14basaloid 20conventional 13cystic metastasis 187differential diagnosis 15external ear 243glottic 218grading 15hypopharyngeal 219invasive front 15larynx aetiology 218larynx epidemiology 218metastases 25microinvasion 13micrometastasis 27middle ear 250molecular pathology 28nasal vestibule 51pseudoglandular 22second primary tumours 25sinonasal 51smoking 14spindle 16stromal reaction 15subglottic 219supraglottic 218transglottic 219treatment and prognosis 15Waldeyer‘s ring 187squamous cell hyperplasia 9squamous cell papilloma 2, 187, 214larynx 214malignant transformation 4oral cavity 2oropharyngeal 187oropharynx 2tonsillar 187nasal vestibule 46squamous intraepithelial lesions 4, 217genetic progression 12larynx 5, 12, 217oral cavity 5oropharynx 5

316 Subject Indexsquamous odontogenic tumour 113steroid injections 46nasal 46stomatitis nicotina 84subglottic stenosis 206idiopathic 206surgical ciliated cyst 109syringocystadenoma papilliferum 241ceruminal glands 241TTangier’s disease 190Waldeyer‘s ring 190teratocarcinosarcoma 63sinonasal 63teratoma 175, 272cervical 272nasopharynx congenital 175thymoma 273cervical 273thyroid 94, 201, 268ectopic 268ectopic lingual 94larynx aberrant 201tonsillitis 184, 185bacterial suppurative 184viral 185tori 125tracheopathia osteochondroplastica 202trachoma 287stages 287traumatic bone cyst 109trichinosis 203larynx 203tuberculosis 45, 81, 133, 191, 202, 247larynx 202middle ear 247nasal 45salivary glands 133Waldeyer‘s ring 191tuberous sclerosis 115tubulopapillary carcinoma 61sinonasal 61Turner‘s syndrome 95, 272tympanosclerosis 244Tzanck cells 74Uundifferentiated carcinoma 53sinonasal 53unicystic ameloblastoma 111unknown primary tumour 274uveitis 296lens-induced 296Vvaricella zoster 73verruca vulgaris 2verrucous carcinoma 17differential diagnosis 18verrucous hyperplasia 7vertigo 256positional 256vocal cord polyp 209voice changes 209voice re-education 211voice rehabilitation 208, 210voice rest 211von Hippel-Lindau disease 301von Recklinghausen disease 96WWarthin’s tumour 142Wegener‘s disease 45, 80, 203larynx 203sinonasal 45Xxanthelasmata 305xanthoma 95verruciform 95ZZenker‘s diverticulum 201hypopharynx 201

Pathology of the Head and Neck

Create successful ePaper yourself

Delete template?

Save as template?