Contemporary Oral Medicine [PDF]

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Camile S. Farah Ramesh Balasubramaniam Michael J. McCullough Editors



Contemporary Oral Medicine A Comprehensive Approach to Clinical Practice



https://t.me/MBS_MedicalBooksStore



Contemporary Oral Medicine



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Camile S. Farah Ramesh Balasubramaniam Michael J. McCullough Editors



Contemporary Oral Medicine A Comprehensive Approach to Clinical Practice



With 1623 Figures and 299 Tables



https://t.me/MBS_MedicalBooksStore



Editors Camile S. Farah UWA Dental School and Oral Health Centre of Western Australia Faculty of Health and Medical Sciences University of Western Australia Perth, WA, Australia



Ramesh Balasubramaniam UWA Dental School and Oral Health Centre of Western Australia Faculty of Health and Medical Sciences University of Western Australia Perth, WA, Australia



Michael J. McCullough Oral Anatomy, Medicine, and Surgery Section Melbourne Dental School Faculty of Medicine, Dentistry and Health Sciences The University of Melbourne Carlton, VIC, Australia



ISBN 978-3-319-72301-3 ISBN 978-3-319-72303-7 (eBook) ISBN 978-3-319-72302-0 (print and electronic bundle) https://doi.org/10.1007/978-3-319-72303-7 Library of Congress Control Number: 2018960941 # Springer Nature Switzerland AG 2019 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG. The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland



This book is dedicated to our families Tess, Maya, Hannah, and Kayla Davinia, Dhruva, and Mandira Lindy, Meredith, Amelia, and Edward in appreciation of our mentors, students, and patients. Camile S. Farah Ramesh Balasubramaniam Michael J. McCullough



Foreword



The dominant pattern of education of oral health professionals and provision of health care of oral and maxillofacial diseases throughout the world is provided by a separate dental profession frequently leading to the unfortunate separation of oral care from whole patient care. In order to correct this deficiency, the specialty of oral medicine was pioneered by dentists including Lester Burket, Sol Silverman, Thomas Lehner, and David Mason, among others, who understood the growing importance of teaching medicine to dental students and developing a dental specialty devoted to the diagnosis and medical management of oral and maxillofacial disease as well as dental treatment for patients with complex medical disorders. Their vision and foresight resulted in the development of an international specialty devoted to the expanding medical needs of patients with oral and maxillofacial diseases. Recent major medical progress has resulted in the development of new drugs and procedures to more successfully treat cancer, infectious diseases, and cardiovascular and neuromuscular diseases. These dramatic advances have resulted in an aging population taking multiple drugs and who often have undergone multiple surgical procedures to maintain their health. This has resulted in increasing the complexity of diagnosis and management of oral and maxillofacial diseases. In addition, the undergraduate medical education often includes minimal training of management of oral diseases and complications, broadening the scope of the disorders managed by oral medicine specialists. There remains no doubt that all general and specialty dentists trained to care for patients in the twenty-first century will require a solid foundation in medicine and that proper care of complex medical problems of the maxillofacial region will require an increasing number of highly trained specialists in oral medicine to work closely with other medical, surgical, and dental colleagues. Drs. Farah, Balasubramaniam, and McCullough have made an important contribution to oral medicine by organizing and writing a new, modern, comprehensive textbook developed for the oral medicine specialist but which also serves as an important reference for other dental and medical practitioners. The editors should be congratulated for their efforts and their choice of coauthors who are internationally recognized academics, researchers, and clinicians in their fields who have authored comprehensive, up-to-date, clearly written chapters.



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Foreword



The text starts with scholarly discussions of principles of diagnosis and focused discussions of clinical immunology, neurophysiology, and neurosensory disorders and then proceeds to detailed well-organized discussions of oral mucosal, head and neck, pain, and neurosensory disorders. The sections on orofacial pain are very welcome, as physicians including headache specialists and those with a special interest in pain often have limited knowledge in this area. We are pleased to note that the orofacial pain sections are comprehensive and provide a welcome biopsychological approach to management which will be valuable not just to specialists in oral medicine but to a range of other health-care professionals. It is encouraging to note the emphasis placed on a science-based approach to temporomandibular disorders as recent large studies provide evidence that they may be precursors of other chronic pain conditions requiring management by multidisciplinary teams. The three of us are delighted to have been asked to write this foreword. We are based in three corners of the globe but all from English-speaking nations with a common educational heritage. We realize the challenges of writing a text devoted to providing the best oral and maxillofacial care to varied cultures, economies, and societies with differing disease burdens. We congratulate the editors and authors of this text for their accessible and egalitarian approach and their major contribution to the progress of international oral medicine. Philadelphia, USA Gold Coast, Australia London, UK



Martin S. Greenberg Newell Johnson Joanna Zakrzewska



Preface



Oral medicine is that specialist branch of dentistry concerned with the diagnosis, prevention, and predominantly nonsurgical management of medically related disorders and conditions affecting the oral and maxillofacial region, in particular oral mucosal disease and orofacial pain, as well as the oral health care of medically complex patients. As such, it occupies a unique interface between dentistry and medicine, bringing them together for the advancement of both oral and systemic health. Progressive patient care in oral medicine requires a thorough understanding of many disciplines of medicine and dentistry. Likewise, other cognate disciplines benefit from their understanding of the art and science of oral medicine for overall patient management. Contemporary Oral Medicine is the most comprehensive textbook in oral medicine and includes 45 chapters arranged into 3 volumes. Volume 1 covers foundation and diagnostic head and neck sciences in oral medicine; Vol. 2 covers oral and maxillofacial diseases and disorders; and Vol. 3 covers orofacial pain and dental sleep medicine. It is a fresh holistic approach to clinical practice. This unique all-inclusive international textbook brings together 149 worldrenowned authors from 25 different countries, covering a wide variety of disciplines including oral medicine, oral and maxillofacial pathology, dentomaxillofacial radiology, head and neck radiology, oral and maxillofacial surgery, head and neck surgery, dermatology, anatomy, pathology, immunology, microbiology, physiology, general medicine, neurology, pain medicine, and sleep medicine. The book is fully referenced and includes 1623 figures composed of thousands of black and white and color images, in addition to 299 tables covering a spectrum of diagnostic algorithms, treatment regimes, and photographs of all disease processes related to oral medicine. In this book, we have focused our attention on the commonly accepted designation of oral medicine and dedicated extensive parts of the book to its content. We acknowledge that oral medicine clinicians may encounter more common conditions of the oral cavity such as dental caries and periodontal diseases, but these are only covered in brief as they sit better in the realm of pediatric dentistry, restorative dentistry, endodontics, and periodontics. Our focus was on diseases and conditions that are diagnosed and managed on a regular basis by oral medicine specialists internationally. Each chapter is authored by a group of international experts in their designated field, offering the book a consensus approach to diagnosis and treatment of oral medicine



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conditions without favoring one school of thought over another or one geographical area over another. We have pitched this book at the level of a new graduate in oral medicine, attempting to stay true to competencies of newly graduated specialists as described in advanced training programs across the globe particularly Australia, New Zealand, the United Kingdom, and the United States. We acknowledge that the remit of practice of oral medicine in various countries around the world differs based on local health system requirements, legislation, regulation, politics, disease distribution, interest, and workforce demands. In compiling this book however, we have taken a comprehensive all-encompassing approach, rather than limit the remit of practice, and hence the designation of a subtitle, A Comprehensive Approach to Clinical Practice. Another purposeful approach was the comprehensiveness of each of the chapters with deliberate overlap of topics and conditions covered and the general headings used in each chapter. Many of the diseases and disorders outlined in the book can be covered under a myriad of headings and chapter titles. We felt it was very important for the reader to encounter the material and interact with the content from multiple points of view, taking into account the many ways possible to classify and manage ailments of the head and neck region. Importantly, we felt that each chapter should be self-contained, independent but cross-referenced with other chapters, and also structured in a way that provided consistency and purpose for the reader. Where we felt the topic should be covered in detail we did, while in other instances we only briefly mention the same condition in a different context for completeness. The intention was that if a reader only read a chapter of particular interest, its contents would suffice, but if the reader wished to explore the content in more detail, then reading more of the book would provide an all-inclusive treatise. We trust you will enjoy reading and using this text as much as we have enjoyed writing and compiling it. January 2019



Camile S. Farah Ramesh Balasubramaniam Michael J. McCullough



Acknowledgments



This book is a culmination of 4 years’ work. Our dream was to realize a comprehensive textbook in oral medicine of international standing, and this would not have been possible without the expert contributions and significant input from luminary contributing authors, colleagues, mentors, and friends from around the world. We thank the contributing authors for their dedication and patience, while we worked through multiple versions of revised and edited chapters to produce a product of the highest standard. We are grateful to those who were willing to participate in such a massive undertaking, to give generously of their time and resources, and to join us in an international coming together of knowledge, expertise, and collegiality in our chosen discipline. The process has been both rewarding and instructive. The comprehensiveness and clinical usefulness of this book are enhanced by the many illustrations, clinical images, radiographs, and photomicrographs generously supplied by many colleagues from all around the world. We are indebted to our many colleagues who have shared their cases so generously in an effort to improve the text, and they have been credited in the figure legends for their contributions. In particular, we would like to thank Dr. Hala Al Janaby for her original hand-drawn illustrations throughout the text and for the stunning front cover, Dr. Andy Whyte for the many detailed radiographic images he has provided, and Dr. Robert Anthonappa for the many cases related to pediatric dentistry. Special thanks also to Drs. Rudolf Boeddinghaus, Marie Matias, Kurt Gebauer, Mariana Villarroel Dorrego, Ajay Parihar, Tim Hodgson, Chady Sader, Chris Van Vliet, Chris Dhepnorrarat, Amanda Phoon Nguyen, Lalima Tiwari, and Qutaibah Alfadalah. We are also thankful to all our patients who have allowed us to care for them but also allowed us to document their cases for presentation in this book. Their contributions are a reminder of why we do what we do. We would like to thank our assistant staff Jane Burnell, Elai Justo, and Maya Janik for their dedicated editing, referencing, and overall assistance and Penny Comans for the provision of articles. We acknowledge the staff at Springer Nature for their hard work, organization, and dedication to this project including Karin Bartsch, Rebecca Urban, Tanja Maihoefer, Wilma McHugh, Susanne Friedrichsen, Alison Wolf, Shruti Datt, and Sharmila Thirumaniselvan. Finally, we are eternally indebted to our families for their love, support, and patience. Over the 4-year life-span of this book, we have spent significant xi



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Acknowledgments



portions of time away from them writing and editing this comprehensive text. They have endured our neglect, while we simultaneously received their encouragement. Their understanding of our passion for our specialty and their tolerance for our desire to complete this project are equally appreciated. Camile S. Farah Ramesh Balasubramaniam Michael J. McCullough



Contents



Volume 1 Normal Variation in the Anatomy, Biology, and Histology of the Maxillofacial Region . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Rita Hardiman, Omar Kujan, and Nabil Kochaji Interface Between Oral and Systemic Disease . . . . . . . . . . . . . . . . . Michele D. Mignogna and Stefania Leuci



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Clinical Evaluation of Oral Diseases . . . . . . . . . . . . . . . . . . . . . . . . 137 Chizobam N. Idahosa and A. Ross Kerr Diagnostic Imaging Principles and Applications in Head and Neck Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 Andy Whyte, Rudolf Boeddinghaus, and Marie Anne Teresa J. Matias Laboratory Medicine and Diagnostic Pathology . . . . . . . . . . . . . . . 255 Tim Hodgson, Barbara Carey, Emma Hayes, Richeal Ni Riordain, Priya Thakrar, Sarah Viggor, and Paula Farthing Clinical Immunology in Diagnoses of Maxillofacial Disease . . . . . . 315 Nathaniel Treister, Arturo Saavedra, and Alessandro Villa Soft and Hard Tissue Operative Investigations in the Diagnosis and Treatment of Oral Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341 Marieke T. Brands, Ivan Alajbeg, Peter A. Brennan, and Camile S. Farah Pharmacotherapeutic Approaches in Oral Medicine . . . . . . . . . . . 401 Sandra Goncalves, Ray A. Dionne, Geraldine Moses, and Marco Carrozzo Odontogenic Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 471 Takashi Takata, Mutsumi Miyauchi, Ikuko Ogawa, and Alan Mighell Non-odontogenic Bone Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . 555 Hedley Coleman, Jos Hille, Willie van Heerden, Sonja Boy, and Annabelle Mahar xiii



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Head and Neck Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 627 Moni A. Kuriakose, Swagnik Chakrabarti, Sok Ching Cheong, Luiz P. Kowalski, Tiago Novaes Pinheiro, and Camile S. Farah Cutaneous Pathology of the Head and Neck . . . . . . . . . . . . . . . . . . 763 Tami Yap, Johannes S. Kern, Benjamin Wood, and Laura Scardamaglia



Volume 2 Odontogenic Bacterial Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . 819 Stuart G. Dashper, Alf Nastri, and Paul V. Abbott Non-odontogenic Bacterial Infections . . . . . . . . . . . . . . . . . . . . . . . 871 Agnieszka M. Frydrych and Camile S. Farah Oral and Maxillofacial Fungal Infections . . . . . . . . . . . . . . . . . . . . 935 Maddalena Manfredi, Luciano Polonelli, Laura Giovati, Ali Alnuaimi, and Michael J. McCullough Oral and Maxillofacial Viral Infections . . . . . . . . . . . . . . . . . . . . . . 983 Stephen Porter, Jair C. Leão, and Luiz Alcino Gueiros Oral Ulcerative Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1009 Giovanni Lodi, Elena Varoni, Jairo Robledo-Sierra, Alessandro Villa, and Mats Jontell Oral Lichen Planus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1043 Michael J. McCullough, Mohammad S. Alrashdan, and Nicola Cirillo Oral Vesicular and Bullous Lesions . . . . . . . . . . . . . . . . . . . . . . . . . 1083 Stephen J. Challacombe and Jane F. Setterfield Gingival Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1143 Anne Hegarty and Alison Rich Pigmented Lesions of the Oral Mucosa . . . . . . . . . . . . . . . . . . . . . . 1175 Eric T. Stoopler and Faizan Alawi White and Red Lesions of the Oral Mucosa . . . . . . . . . . . . . . . . . . 1207 Maryam Jessri, Hani Mawardi, Camile S. Farah, and Sook-Bin Woo Oral Mucosal Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1249 Camile S. Farah, Omar Kujan, Stephen Prime, and Rosnah Binti Zain Salivary Gland Disorders and Diseases . . . . . . . . . . . . . . . . . . . . . . 1437 Siri Beier Jensen, Arjan Vissink, and Norman Firth Oral Manifestations of Systemic Diseases and Their Treatments . . . 1523 Sue-Ching Yeoh, Hong Hua, Juan Fernando Yepes, and Douglas E. Peterson



Contents



Contents



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Pediatric Oral Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1641 Anastasia Georgiou, Angus Cameron, and Ramesh Balasubramaniam Halitosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1719 Jaisri R. Thoppay, Andreas Filippi, Katharine Ciarrocca, John Greenman, and Scott S. De Rossi



Volume 3 Neurophysiology of Orofacial Pain . . . . . . . . . . . . . . . . . . . . . . . . . 1749 Koichi Iwata, Mamoru Takeda, Seog Bae Oh, and Masamichi Shinoda Clinical Evaluation of Orofacial Pain . . . . . . . . . . . . . . . . . . . . . . . 1773 Jeffrey P. Okeson and Isabel Moreno Hay Biopsychosocial Aspects of Orofacial Pain Richard Ohrbach and Justin Durham



. . . . . . . . . . . . . . . . . . . 1797



Classification of Orofacial Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1819 Gary D. Klasser, Jean-Paul Goulet, Antoon De Laat, and Daniele Manfredini Masticatory Muscle Pain and Disorders . . . . . . . . . . . . . . . . . . . . . 1843 Tommaso Castroflorio, Andrea Bargellini, Andrea Deregibus, and Peter Svensson Internal Derangements of the Temporomandibular Joint James J. R. Huddleston Slater and Reny de Leeuw



. . . . . . . 1881



Arthritic Conditions Affecting the Temporomandibular Joint . . . . 1919 L. G. Mercuri and S. Abramowicz Headache . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1955 Steven J. Scrivani, Steven B. Graff-Radford, Shehryar N. Khawaja, and Egilius L. H. Spierings Neurovascular Orofacial Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1983 Yair Sharav, Yaron Haviv, Galit Almoznino, and Rafael Benoliel Neuropathic Orofacial Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2005 Olga A. Korczeniewska, Eli Eliav, and Rafael Benoliel Oral Dysesthesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2081 Giulio Fortuna, Joel Napenas, Nan Su, Miriam Gruskha, and Gary D. Klasser Neurosensory Disturbances Including Smell and Taste . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2107 Saravanan Ram, Tomoko Wada, and Soma Sahai-Srivastava Orofacial Pain in the Medically Complex Patient . . . . . . . . . . . . . . 2135 Martina K. Shephard and Gary Heir



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Orofacial Pain in Patients with Cancer and Mucosal Diseases . . . . 2187 Noam Yarom, Herve Sroussi, and Sharon Elad Orofacial Pain and Sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2213 Barry J. Sessle, Kazunori Adachi, Dongyuan Yao, Yoshitaka Suzuki, and Gilles J. Lavigne Sleep Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2241 David Hillman, Olivier Vanderveken, Atul Malhotra, and Peter Eastwood Sleep Bruxism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2267 Ramesh Balasubramaniam, Daniel Paesani, Kiyoshi Koyano, Yoshihiro Tsukiyama, Maria Clotilde Carra, and Gilles J. Lavigne Oral Appliance Therapy for Sleep-Disordered Breathing . . . . . . . 2303 Joachim Ngiam, Kate Sutherland, Ramesh Balasubramaniam, Marie Marklund, Fernanda Almeida, and Peter Cistulli Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2333



Contents



About the Editors



Camile S. Farah BDSc, MDSc (OralMed, OralPath), PhD, GCEd (HE), GCExLead, FRACDS (OralMed), FOMAA, FIAOO, FICD, FPFA Professor of Oral Oncology Dean and Head, UWA Dental School, University of Western Australia Director, Oral Health Centre of Western Australia Convenor, Oral Medicine Postgraduate Training Program, UWA Dental School, University of Western Australia Oral Medicine Consultant, Oral Health Centre of Western Australia Oral Medicine Specialist, Perth Oral Medicine & Dental Sleep Centre Consultant, Qscan Radiology Clinics Camile is Professor of Oral Oncology, Dean and Head of the UWA Dental School, and Director of the Oral Health Centre of Western Australia at the University of Western Australia, Perth, Australia. Camile is a Registered Specialist in both Oral Medicine and Oral Pathology with subspecialty training in Oral Oncology. He is a Consultant in Oral Medicine at the Oral Health Centre of WA and maintains a part-time private practice in Oral Medicine at Perth Oral Medicine & Dental Sleep Centre focused on oral mucosal diseases, salivary gland pathology, bone pathology, xvii



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and orofacial pain. He is Convenor of the postgraduate training program in Oral Medicine at the UWA Dental School, a Member of the Head & Neck Cancer Multidisciplinary Team at Sir Charles Gairdner Hospital, Director of the Australian Centre for Oral Oncology Research & Education, and Consultant at Qscan Radiology Clinics. Camile is a Fellow of the Royal Australasian College of Dental Surgeons (Oral Medicine) by examination, the Oral Medicine Academy of Australasia, the International Academy of Oral Oncology, the International College of Dentists, and the Pierre Fauchard Academy. He is the Inaugural and Past President of the Oral Medicine Academy of Australasia, Past President of the Australian and New Zealand Division of the International Association for Dental Research, President of the Asia Pacific Region of the International Association for Dental Research, Chairman of the Australian Dental Research Foundation, and Past Chairman of its Research Advisory Committee. Camile has authored more than 160 peer-reviewed publications including 18 book chapters. He has personally attracted $7.5 million in competitive research funding, has been involved in other successful collaborative grants totaling nearly $10 million, and has mentored over 50 postgraduate students and postdoctoral staff. Camile is Associate Editor of Journal of Oral Pathology & Medicine and Oral Cancer and Reviewing Editor for Oral Diseases. Camile is clinician-scientist with expertise in oral oncological translational research. His clinical and laboratory research focuses on optical imaging modalities, molecular genomics, clinical trials in early detection and oncological surgery, and personalized patient care particularly related to oral cancer and oral potentially malignant disorders. His laboratory has explored diagnostic biomarker signatures for oral premalignant lesions, predictive biomarker profiles for oral cancer progression, and a multigene discriminatory biomarker panel for oral squamous cell carcinoma and epithelial dysplasia. He is a supporter of patient and clinician education and professional development and overall advocacy for patients with oral cancer.



Ramesh Balasubramaniam BSc, BDSc, MS, Cert Orofacial Pain, Cert Oral Medicine, MRACDS (OralMed), ABOP, FOMAA, FADI, FPFA, FICD



About the Editors



About the Editors



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Clinical Associate Professor, UWA Dental School, University of Western Australia Oral Medicine Consultant, Oral Health Centre of Western Australia Oral Medicine Consultant, Perth Children’s Hospital Oral Medicine Specialist, Perth Oral Medicine & Dental Sleep Centre Ramesh graduated with a BDSc from the University of Western Australia in 2000 and subsequently practiced General Dentistry. In 2006, he completed a certificate and Master of Science degree in Orofacial Pain at the University of Kentucky. While at the University of Kentucky, Ramesh also underwent training in the field of Dental Sleep Medicine. He is a Diplomate of the American Board of Orofacial Pain. In addition, Ramesh completed a specialist training in Oral Medicine as well as a Fellowship in Interdisciplinary Geriatrics at the University of Pennsylvania in 2008. Ramesh has numerous peer-reviewed publications, has contributed to several chapters in various texts, and coedited the May 2008 Oral and Maxillofacial Surgery Clinics of North America on Orofacial Pain and Dysfunction. In addition, he serves as a reviewer for a number of peer-reviewed journals. Ramesh has an appointment as a Clinical Associate Professor at the UWA Dental School, University of Western Australia, and is actively involved in teaching and research. He also holds public appointments at the Oral Health Centre of Western Australia and the Perth Children’s Hospital. He is PresidentElect of the Oral Medicine Academy of Australasia having served as its Secretary. His Oral Medicine Specialist practice focuses on orofacial pain, oral diseases and disorders, and dental sleep medicine.



Michael J. McCullough BDSc, MDSc (OralMed, OralPath), PhD, FRACDS (OralMed), FOMAA, FPFA, FICD Professor of Oral Medicine Deputy Head, Melbourne Dental School, University of Melbourne Convenor, Oral Medicine Postgraduate Training Program, Melbourne Dental School, University of Melbourne Oral Medicine Consultant, Melbourne Dental School, University of Melbourne Michael is Professor of Oral Medicine at the Melbourne Dental School, the University of Melbourne. He is the Convenor of both the postgraduate and



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graduate courses in Oral Medicine, has published 128 articles in peer-reviewed scientific journals, and was on the Expert Panel for both editions of the Therapeutic Guidelines book titled Oral and Dental. Michael is an Oral Medicine Clinical Consultant to the Royal Dental Hospital of Melbourne, the Royal Melbourne Hospital, and the University of Melbourne’s Dental Clinic. Michael gained a bachelor’s degree in Dental Science in 1982, a master’s degree in Oral Medicine and Oral Pathology, and a PhD in 1995, all from the University of Melbourne. He spent several years as a Postdoctoral Research Fellow at Stanford University in California during 1996 and 1997, followed by 3 years as a Lecturer in Oral Medicine at the Eastman Dental Institute, University College London. Michael has 27 years of experience in clinical and academic Oral Medicine, was an Inaugural Fellow of the Royal Australasian College of Dental Surgeons in Oral Medicine by examination, and is a Fellow of the International College of Dentists, the Pierre Fauchard Academy, and the Oral Medicine Academy of Australasia. Michael has supervised to completion 18 research higher degree students, and currently he is Principal Supervisor to 4 PhD students and co-supervisor to 3 PhD and 6 MPhil students. Michael has published 128 clinical and scientific articles including 3 book chapters. His work is mostly published in ERA A*/A ranked journals in the highest-ranking journals in his specialty. Michael is the current President of the Oral Medicine Academy of Australasia and the Inaugural Chair of the Australian and New Zealand Council of Dental Specialists. He was the Chairperson of the Dental Therapeutics Committee of the Australian Dental Association from 2006 to 2012 and an active member until 2016. He was on the Expert Panel of the Therapeutic Guidelines book, Oral and Dental, whose first edition was in 2007 and the revised second edition published in 2012. Michael has been a member of the Australian Dental Research Foundation’s Research Advisory Committee since 2013 and served as its Chair from 2016 to 2018.



About the Editors



Contributors



Paul V. Abbott UWA Dental School and Oral Health Centre of Western Australia, The University of Western Australia, Perth, Australia S. Abramowicz Oral and Maxillofacial Surgery and Pediatrics, Emory University and Children’s Healthcare of Atlanta, Atlanta, GA, USA Kazunori Adachi Division of Pharmacology, Meikai University School of Dentistry, Saitama, Japan Ivan Alajbeg University of Zagreb School of Dental Medicine, Zagreb, Croatia Faizan Alawi Department of Pathology, University of Pennsylvania School of Dental Medicine, Philadelphia, PA, USA Fernanda Almeida Department of Oral Health Sciences, Faculty of Dentistry, The University of British Columbia, Vancouver, BC, Canada Galit Almoznino Department of Oral Medicine, Sedation and Maxillofacial Imaging, School of Dental Medicine, Hebrew University-Hadassah, Jerusalem, Israel Department of Oral Medicine, Oral and Maxillofacial Center, Medical Corps, Israel Defense Forces, Tel-Hashomer, Israel Ali Alnuaimi Oral Anatomy, Medicine, and Surgery Section, Melbourne, Dental School, Faculty of Medicine, Dentistry and Health, Sciences, The University of Melbourne, Carlton, VIC, Australia Mohammad S. Alrashdan Faculty of Dentistry, Department of Oral Medicine and Oral Surgery, Jordan University of Science and Technology, Irbid, Jordan Ramesh Balasubramaniam UWA Dental School and Oral Health Centre of Western Australia, Faculty of Health and Medical Sciences, University of Western Australia, Perth, WA, Australia



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Andrea Bargellini Gnathology Unit, Department of Surgical Sciences, Lingotto Dental School, University of Torino, Torino, Italy Specialization School of Orthodontics, Department of Surgical Sciences, Dental School, University of Torino, Torino, Italy Rafael Benoliel Department of Diagnostic Sciences, Rutgers School of Dental Medicine, Rutgers State University of New Jersey, Newark, NJ, USA Rudolf Boeddinghaus Perth Radiological Clinic, Subiaco, WA, Australia University of Western Australia, Nedlands, WA, Australia Sonja Boy Department of Oral Pathology, Sefako Makgatho Health Sciences University, Pretoria, South Africa Marieke T. Brands Department of Oral and Maxillofacial Surgery, Queen Alexandra Hospital, Portsmouth, UK Peter A. Brennan Department of Oral and Maxillofacial Surgery, Queen Alexandra Hospital, Portsmouth, UK Angus Cameron The University of Sydney, Sydney, NSW, Australia University of Newcastle, Ourimbah, NSW, Australia Charles Sturt University, Sydney, NSW, Australia Barbara Carey Eastman Dental Hospital, London, UK Maria Clotilde Carra Department of Periodontology, Service of Odontology, Rothschild Hospital, AP-HP, Université Paris 7 – Denis Diderot, U.F.R. of Odontology, Paris, France Marco Carrozzo Center for Oral Health Research, Department of Oral Medicine, School of Dental Sciences, Newcastle University, Newcastle upon Tyne, UK Tommaso Castroflorio Gnathology Unit, Department of Surgical Sciences, Lingotto Dental School, University of Torino, Torino, Italy Specialization School of Orthodontics, Department of Surgical Sciences, Dental School, University of Torino, Torino, Italy Swagnik Chakrabarti Head and Neck Oncology Services, Tata Memorial Hospital, Mumbai, India Stephen J. Challacombe Department of Oral Medicine, King’s College London, London, UK Guys and St Thomas’ Hospital NHS Foundation Trust, London, UK Sok Ching Cheong Cancer Research Malaysia, CARIF Oral Cancer Research Team, Subang Jaya, Malaysia Katharine Ciarrocca Dental College of Georgia, Augusta University, Augusta, GA, USA



Contributors



Contributors



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Nicola Cirillo Melbourne Dental School and Oral Health CRC, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Carlton, VIC, Australia Peter Cistulli Centre for Sleep Health and Research, Department of Respiratory and Sleep Medicine, Royal North Shore Hospital, Northern Sydney Local Health District, St Leonards, NSW, Australia Charles Perkins Centre and Northern Clinical School, University of Sydney, Sydney, NSW, Australia Hedley Coleman Department of Tissue Pathology and Diagnostic Oncology, Pathology West, Westmead Hospital, ICPMR, Sydney, NSW, Australia Stuart G. Dashper Melbourne Dental School, Oral Health Cooperative Research Centre, The University of Melbourne, Melbourne, Australia Antoon De Laat Department of Oral Health Sciences, K.U. Leuven, Leuven, Belgium Department of Dentistry, University Hospitals Leuven, Leuven, Belgium Reny de Leeuw Division of Orofacial Pain, College of Dentistry, University of Kentucky, Lexington, KY, USA Scott S. De Rossi UNC School of Dentistry, Chapel Hill, NC, USA Andrea Deregibus Gnathology Unit, Department of Surgical Sciences, Lingotto Dental School, University of Torino, Torino, Italy Specialization School of Orthodontics, Department of Surgical Sciences, Dental School, University of Torino, Torino, Italy Ray A. Dionne Department of Pharmacology and Toxicology, Brody School of Medicine, and Department of Foundational Sciences, School of Dental Medicine, East Carolina University, Greenville, NC, USA Justin Durham School of Dental Sciences, Newcastle University, NewcastleUpon-Tyne, UK Peter Eastwood Centre for Sleep Science, School of Human Sciences, University of Western Australia, Perth, Australia West Australian Sleep Disorders Research Institute, Sir Charles Gairdner Hospital, Perth, Australia Sharon Elad Department of Oral Medicine, Eastman Institute for Oral Medicine, University of Rochester Medical Center, Rochester, NY, USA Eli Eliav Eastman Institute for Oral Health, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, NY, USA Camile S. Farah UWA Dental School and Oral Health Centre of Western Australia, Faculty of Health and Medical Sciences, University of Western Australia, Perth, WA, Australia Paula Farthing School of Clinical Dentistry, University of Sheffield, Sheffield, UK



xxiv



Andreas Filippi Department for Oral Surgery, Oral Radiology and Oral Medicine and Center of Salivary Diagnostics and Hyposalivation, University Center for Dental Medicine Basel, University of Basel, Basel, Switzerland Norman Firth UWA Dental School, University of Western Australia, Nedlands, WA, Australia Giulio Fortuna Department of Diagnostic Sciences, Louisiana State University School of Dentistry, New Orleans, LA, USA Agnieszka M. Frydrych UWA Dental School, University of Western Australia, Perth, WA, Australia Anastasia Georgiou Macquarie Oral and Maxillofacial Specialists, Sydney, NSW, Australia Sydney Skin, Sydney, NSW, Australia Laura Giovati Dipartimento di Medicina e Chirurgia, University of Parma, Parma, Italy Sandra Goncalves Oral Medicine Department, Charles Clifford Dental Hospital, Sheffield, UK Jean-Paul Goulet Faculté de Médecine dentaire, Université Laval, Québec, QC, Canada Steven B. Graff-Radford Director, Division of Headache and Orofacial Pain, Pain Center, Cedar Sinai Medical Center, Los Angeles, CA, USA John Greenman Faculty of Health and Life Sciences, Bristol, UK Miriam Gruskha Department of Dentistry, William Osler Hospital (Etobicoke), Toronto, ON, Canada Luiz Alcino Gueiros Oral Medicine Unit, Departamento de Clínica e Odontologia Preventiva, Universidade Federal de Pernambuco, Recife, PE, Brazil Rita Hardiman Melbourne Dental School, The University of Melbourne, Melbourne, VIC, Australia Yaron Haviv Department of Oral Medicine, Sedation and Maxillofacial Imaging, School of Dental Medicine, Hebrew University-Hadassah, Jerusalem, Israel Emma Hayes Eastman Dental Hospital, London, UK Anne Hegarty Oral Medicine, Sheffield Teaching Hospitals, Sheffield, UK Gary Heir Center for Temporomandibular Disorders and Orofacial Pain, Rutgers School of Dental Medicine, Newark, NJ, USA Jos Hille Department Oral and Maxillofacial Pathology, University of the Western Cape/National Health Laboratory Service, Cape Town, South Africa Oral/Head and Neck Pathology, University of the Western Cape, Cape Town, South Africa



Contributors



Contributors



xxv



David Hillman Department of Pulmonary Physiology and Sleep Medicine, West Australian Sleep Disorders Research Institute, Sir Charles Gairdner Hospital, Perth, Australia Centre for Sleep Science, School of Human Sciences, University of Western Australia, Perth, Australia Tim Hodgson Eastman Dental Hospital, London, UK Hong Hua Department of Oral Medicine, Peking University, School of Stomatology, Beijing, China James J. R. Huddleston Slater Groningen, The Netherlands Chizobam N. Idahosa Department of Oral and Maxillofacial Pathology, Medicine and Surgery, Temple University Kornberg School of Dentistry, Philadelphia, PA, USA Koichi Iwata Department of Physiology, School of Dentistry, Nihon University, Tokyo, Japan Siri Beier Jensen Department of Dentistry and Oral Health, Aarhus University, Aarhus C, Denmark Maryam Jessri Division of Oral Medicine and Dentistry, Brigham and Women’s Hospital, Boston, MA, USA Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, USA UWA Dental School and Oral Health Centre of Western Australia, University of Western Australia, Perth, WA, Australia Mats Jontell Department of Oral Medicine and Pathology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden Johannes S. Kern Department of Dermatology, Royal Melbourne Hospital, Parkville, VIC, Australia A. Ross Kerr Department of Oral and Maxillofacial Pathology, Radiology and Medicine, New York University College of Dentistry, New York, NY, USA Shehryar N. Khawaja Resident, Orofacial Pain Program, Department of Oral and Maxillofacial Surgery, Massachusetts General Hospital, Boston, MA, USA Gary D. Klasser Department of Diagnostic Sciences, School of Dentistry, Louisiana State University Health Sciences Center, New Orleans, LA, USA Nabil Kochaji Faculty of Dentistry, Damascus University, Damascus, Syrian Arab Republic Olga A. Korczeniewska Department of Diagnostic Sciences Rutgers School of Dental Medicine, Rutgers The State University of New Jersey, Newark, NJ, USA



xxvi



Luiz P. Kowalski Head and Neck Surgery and Otorhinolaryngology Department, A.C. Camargo Cancer Center, São Paulo, Brazil Kiyoshi Koyano Faculty of Dental Science, Kyushu University, Fukuoka, Japan Omar Kujan UWA Dental School, University of Western Australia, Perth, WA, Australia Moni A. Kuriakose Department of Head and Neck Surgery/Plastic and Reconstructive Surgery, Roswell Park Cancer Institute, Buffalo, NY, USA Gilles J. Lavigne Faculty of Dental Medicine, Univeristé de Montréal, Montreal, QC, Canada Centre for Advanced Research in Sleep Medicine and Trauma Unit, Surgery Department, Hôpital du Sacré-Cœur de Montréal, Montreal, QC, Canada Jair C. Leão Oral Medicine Unit, Departamento de Clínica e Odontologia Preventiva, Universidade Federal de Pernambuco, Recife, PE, Brazil Stefania Leuci Oral Medicine Complex Unit, Department of Neuroscience, Reproductive and Odontostomatological Sciences, Federico II University of Naples, Naples, Italy Giovanni Lodi Dipartimento di Scienze Biomediche, Chirurgiche e Odontoiatriche, Università degli Studi di Milano, Milan, Italy Annabelle Mahar Department of Tissue Pathology and Diagnostic, Royal Prince Alfred Hospital, Camperdown, NSW, Australia Atul Malhotra Critical Care and Sleep Medicine, UC San Diego School of Medicine, La Jolla, CA, USA Maddalena Manfredi Dipartimento di Medicina e Chirurgia, Centro Universitario di Odontoiatria, University of Parma, Parma, Italy Daniele Manfredini School of Dentistry, University of Padova, Padova, Italy Marie Marklund Department of Orthodontics, Umeå University, Umeå, Sweden Marie Anne Teresa J. Matias Perth Radiological Clinic, Subiaco, WA, Australia Qscan Radiology Clinics, Herston, QLD, Australia Hani Mawardi Faculty of Dentistry, King Abdulaziz university, Jeddah, Saudi Arabia Division of Oral Medicine and Dentistry, Brigham and Women’s Hospital, Boston, MA, USA Michael J. McCullough Oral Anatomy, Medicine, and Surgery Section, Melbourne Dental School, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Carlton, VIC, Australia



Contributors



Contributors



xxvii



L. G. Mercuri Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL, USA TMJ Concepts, Ventura, CA, USA Alan Mighell Department of Oral Medicine, School of Dentistry, University of Leeds, Leeds, UK Michele D. Mignogna Oral Medicine Complex Unit, Department of Neuroscience, Reproductive and Odontostomatological Sciences, Federico II University of Naples, Naples, Italy Mutsumi Miyauchi Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan Isabel Moreno Hay Orofacial Pain Program, College of Dentistry, University of Kentucky, Lexington, KY, USA Geraldine Moses Academic Practice Unit, Pharmacy Services, Mater Public Hospital, South Brisbane, QLD, Australia Joel Napenas Department of Oral Medicine, Carolinas Medical Center, Charlotte, NC, USA Alf Nastri Department of Maxillofacial Surgery, Royal Melbourne Hospital, The University of Melbourne, Melbourne, Australia Joachim Ngiam Centre for Sleep Health and Research, Department of Respiratory and Sleep Medicine, Royal North Shore Hospital, Northern Sydney Local Health District, St Leonards, NSW, Australia Richeal Ni Riordain Eastman Dental Hospital, London, UK Tiago Novaes Pinheiro Anatomic Pathology Service, Amazonas State University, Manaus, Brazil Ikuko Ogawa Center of Oral Clinical Examination, Hiroshima University Hospital, Hiroshima, Japan Seog Bae Oh Department of Neurobiology and Physiology, School of Dentistry, Seoul National University, Seoul, Republic of Korea Richard Ohrbach Department of Oral Diagnostic Sciences, University at Buffalo, Buffalo, NY, USA Jeffrey P. Okeson Orofacial Pain Program, College of Dentistry, University of Kentucky, Lexington, KY, USA Daniel Paesani School of Odontology, University of Salvador/AOA, Buenos Aires, Argentina Douglas E. Peterson Department of Oral Health and Diagnostic Sciences, School of Dental Medicine, Neag Comprehensive Cancer Center, UConn Health, Farmington, CT, USA



xxviii



Luciano Polonelli Dipartimento di Medicina e Chirurgia, University of Parma, Parma, Italy Stephen Porter UCL Eastman Dental Institute, University College London, London, UK Stephen Prime School of Oral and Dental Sciences, University of Bristol, Bristol, UK Saravanan Ram Division of Diagnostic Sciences, Ostrow School of Dentistry of USC, Los Angeles, CA, USA Alison Rich The Department of Oral Diagnostic and Surgical Sciences, University of Otago, Dunedin, Otago, New Zealand Jairo Robledo-Sierra Department of Oral Medicine and Pathology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden Arturo Saavedra Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Soma Sahai-Srivastava Headache and Neuralgia Center, Keck School of Medicine of USC, Los Angeles, CA, USA Laura Scardamaglia Department of Dermatology, Royal Melbourne Hospital, Parkville, VIC, Australia Steven J. Scrivani Chief, Division of Oral and Maxillofacial Pain, Department of Oral and Maxillofacial Surgery, Massachusetts General Hospital, Boston, MA, USA Barry J. Sessle Faculty of Dentistry and Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada Jane F. Setterfield Department of Oral Medicine, King’s College London, London, UK Department of Dermatology, King’s College London, London, UK Guys and St Thomas’ Hospital NHS Foundation Trust, London, UK Yair Sharav Department of Oral Medicine, Sedation and Maxillofacial Imaging, School of Dental Medicine, Hebrew University-Hadassah, Jerusalem, Israel Martina K. Shephard Oral Medicine Unit, Eastman Dental Hospital, University College London Hospitals NHS Trust, London, UK Masamichi Shinoda Department of Physiology, School of Dentistry, Nihon University, Tokyo, Japan Egilius L. H. Spierings Craniofacial Pain Center, Tufts University School of Dental Medicine, Headache and Facial Pain Program, Department of Neurology, Tufts Medical Center and Tufts School of Medicine, Boston, MA, USA Herve Sroussi Division of Oral Medicine and Dentistry, Brigham and Women’s Hospital, Boston, MA, USA



Contributors



Contributors



xxix



Eric T. Stoopler Department of Oral Medicine, University of Pennsylvania School of Dental Medicine, Philadelphia, PA, USA Nan Su Norman Bethune College of Medicine, Jilin, China Kate Sutherland Centre for Sleep Health and Research, Department of Respiratory and Sleep Medicine, Royal North Shore Hospital, Northern Sydney Local Health District, St Leonards, NSW, Australia Charles Perkins Centre and Northern Clinical School, University of Sydney, Sydney, NSW, Australia Yoshitaka Suzuki Facultés de médecine dentaire et de médecine, Université de Montréal, Montreal, QC, Canada Department of Stomatognathic Function and Occlusal Reconstruction, Tokushima University Graduate School, Tokushima, Japan Peter Svensson Section of Orofacial Pain and Jaw Function, Department of Dentistry and Oral Health, Aarhus University, Aarhus, Denmark Department of Dental Medicine, Karolinska Institutet, Scandinavian Center for Orofacial Neurosciences (SCON), Huddinge, Sweden Takashi Takata Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan Mamoru Takeda Laboratory of Food and Physiological Sciences, Department of Food and Life Sciences, School of Life and Environmental Sciences, Azabu University, Sagamihara, Kanagawa, Japan Priya Thakrar Eastman Dental Hospital, London, UK Jaisri R. Thoppay Oral Medicine, Orofacial Pain and Geriatric Programs, Orofacial Pain and Geriatric Oral Health Programs, Department of Oral and Maxillofacial Surgery, VCU School of Dentistry and VCU Medical Center, Virginia Commonwealth University, Richmond, VA, USA Nathaniel Treister Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, USA Yoshihiro Tsukiyama Section of Dental Education, Faculty of Dental Science, Kyushu University, Fukuoka, Japan Willie van Heerden Department of Oral Pathology and Oral Biology, University of Pretoria, Pretoria, South Africa Olivier Vanderveken Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium Department of ENT, Head and Neck Surgery, Antwerp University Hospital, Edegem, Belgium Elena Varoni Dipartimento di Scienze Biomediche, Chirurgiche e Odontoiatriche, Università degli Studi di Milano, Milan, Italy Sarah Viggor Eastman Dental Hospital, London, UK



xxx



Alessandro Villa Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, USA Division of Oral Medicine and Dentistry, Brigham and Women’s Hospital, Boston, MA, USA Arjan Vissink Department of Oral and Maxillofacial Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Tomoko Wada Orofacial Pain and Oral Medicine Center, Division of Diagnostic Sciences, Ostrow School of Dentistry of USC, Los Angeles, CA, USA Andy Whyte University of Melbourne, Carlton, VIC, Australia University of Western Australia, Nedlands, WA, Australia Perth Radiological Clinic, Subiaco, WA, Australia Ear Science Institute, Subiaco, WA, Australia Sook-Bin Woo Division of Oral Medicine and Dentistry, Brigham and Women’s Hospital, Boston, MA, USA Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, USA Benjamin Wood QEII Medical Centre, Nedlands, WA, Australia Dongyuan Yao Jiangxi Mental Hospital and School of Pharmaceutical Science, Nanchang University, Nanchang, Jiangxi, China Tami Yap Melbourne Dental School, University of Melbourne, Carlton, VIC, Australia Department of Dermatology, Royal Melbourne Hospital, Parkville, VIC, Australia Noam Yarom Oral Medicine Unit, Sheba Medical Center, Tel Hashomer, Israel Department of Oral Pathology and Oral Medicine, School of Dental Medicine, Tel-Aviv University, Tel-Aviv, Israel Sue-Ching Yeoh Sydney Oral Medicine, Baulkham Hills, NSW, Australia Chris O’Brien Lifehouse, Camperdown, NSW, Australia Juan Fernando Yepes Department of Pediatric Dentistry, James Whitcomb Riley Hospital for Children, Indiana University School of Dentistry, Indianapolis, IN, USA Rosnah Binti Zain Department of Oral Pathology, MAHSA University, Kuala Lumpur, Malaysia Oral Cancer Research and Coordinating Centre, University of Malaya, Kuala Lumpur, Malaysia



Contributors



Normal Variation in the Anatomy, Biology, and Histology of the Maxillofacial Region Rita Hardiman, Omar Kujan, and Nabil Kochaji



Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anatomy, Histology, Biology, and their Normal Variations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Link between Oral Structures and Other Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Role of Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Genetic Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .



3 3 3 4 5



Development and Growth of the Craniofacial Region . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Early Embryogenesis, Germ Layers, and Neural Crest Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Development of the Jaws, Face, and Skull . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Odontogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Variations in the Dentition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 Gross Anatomy, Histology, and Biology of the Maxillofacial Region . . . . . . . . . . . . . . . Osteology of the Skull . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anatomical Variations of the Skull . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Histology of Hard Tissues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Scalp and Facial Soft Tissues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Soft Tissue Structures in the Superficial Face . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Variation and Aging in Facial Soft Tissues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Histology of the Epidermis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .



13 13 14 17 17 18 21 22



R. Hardiman (*) Melbourne Dental School, The University of Melbourne, Melbourne, VIC, Australia e-mail: [email protected] O. Kujan UWA Dental School, University of Western Australia, Perth, WA, Australia e-mail: [email protected] N. Kochaji Faculty of Dentistry, Damascus University, Damascus, Syrian Arab Republic e-mail: [email protected] # Springer Nature Switzerland AG 2019 C. S. Farah et al. (eds.), Contemporary Oral Medicine, https://doi.org/10.1007/978-3-319-72303-7_2



1



2



R. Hardiman et al. Infratemporal Region and Pterygopalatine Fossa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 Trigeminal Nerve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CNV1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CNV2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CNV3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .



24 24 28 29



Gross Anatomy of the Temporomandibular Joint . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 Muscles of Mastication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 Histology of the Temporomandibular Joint . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 Nose and Paranasal Sinuses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 Gross Anatomy of the Nose, Nasal Cavity, and Paranasal Sinuses . . . . . . . . . . . . . . . . . . . . . 34 Histology of Respiratory Epithelium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 Oral Cavity and Tongue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 Dental Hard Tissues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 Gross Anatomy of the Tongue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 Salivary Glands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Major Salivary Glands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Histology of Salivary Glands and Duct Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Minor Salivary Glands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .



44 44 44 46



Histology of Oral Tissues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dental Pulp . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Periodontal Ligament . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tongue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lips . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tonsillar Tissue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .



47 49 50 50 52 52



Tissue Spaces of the Maxillofacial Region . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fascial Layers and Spaces of the Head and Neck . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Submandibular Space . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lateral Pharyngeal Space . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Retropharyngeal Spaces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .



53 53 54 54 54



Lymphatic Drainage of the Head and Oral Structures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Retropharyngeal Nodes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Submental Nodes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Submandibular Nodes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Upper Deep Cervical Nodes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lower Deep Cervical Nodes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .



54 55 55 56 56 56



Pharynx and Larynx . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Waldeyer’s Ring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gross Anatomy of the Pharynx and Larynx Including Anatomical Variations . . . . . . . . . Histology of Pharyngeal Mucosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Histology of the Thyroid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .



56 56 57 58 58



Orbits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 Gross Anatomy of the Orbits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 Vascular Supply of the Maxillofacial Region . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Facial Artery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Lingual Artery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Maxillary Artery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Superficial Temporal Artery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .



58 60 60 60 62



Conclusions and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62



Normal Variation in the Anatomy, Biology, and Histology of the Maxillofacial Region



Abstract



This chapter discusses the normal anatomy of the maxillofacial region and variations thereof when present and clinically relevant. Single or rare cases of an anatomical variation are excluded, as are very minor variations, such as deviations in the course of a nerve in the range of millimeters. Gross anatomy and histology of the most relevant structures in the maxillofacial region are described by anatomical region. Keywords



Anatomy · Histology · Osteology · Variation · Oral · Mucosa · Aging



Introduction Anatomy, Histology, Biology, and their Normal Variations The maxillofacial region is an intricate anatomical region providing our main perceptual and communication interface with the outside world, as well as the first line of defense against inhaled or ingested infectious or toxic agents. The special senses of sight, smell, and taste have sensory receptors in the maxillofacial region. This chapter begins with the scaffolding to which all other structures in the maxillofacial region are attached, the skull. Subsequently, the soft tissues of the maxillofacial region and superficial face are covered including their structure and function. Regions of the deep face are then presented. Throughout, special attention is paid to the oral cavity, its regions, and tissues, including anatomical and regional variations and changes occurring throughout the human lifespan. Innervation is discussed within each region, as well as vascular supply, drainage, and lymphatics. Comments on the embryological development are made if these are pertinent to the structure in the fully formed human, especially if the origin is related to anatomical variations. Oftentimes it is easier to study the anatomy of the maxillofacial region by compartmentalizing this by region or system; however, it must be borne in mind that



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anatomical components exist in close proximity and are intimately located. In recent times, there has been an increased reporting of occurrence of anatomical variations, particularly in the variability found in foramina, due to the use of highresolution 3D imaging techniques such as computerized tomography (CT) and cone beam CT (CBCT) scans (Eliades et al. 2016; Wolf et al. 2016) or high-resolution magnetic resonance imaging (MRI) (Jacobs et al. 2007). Conventional radiographs may not be sensitive enough to show small canals such as the incisive canal of the mandible or accessory foramina (Jacobs et al. 2007). CBCT has been shown to detect a higher rate of anatomical variations in the maxillary sinus compared with panoramic radiographs (Kazunobu et al. 2014). These high-resolution noninvasive techniques also enable investigators to visualize structures in great detail without risk of damaging or destroying the structures in question (Stratmann et al. 1996).



The Link between Oral Structures and Other Systems The oral cavity and associated structures are unique. The mouth, lips, and other oral tissues are anatomically structured to complement other body systems. The oral structures also share similar biological, molecular, and histological compositions and functions with other systems, mainly the upper digestive system, respiratory system, and skin. Therefore, several systemic diseases can manifest orally, and as a result, there is a need to view oral diseases in the context of other systems. Recognition of the fact that an oral medicine specialist is an oral physician, it is critical to have a profound understanding of oral diseases and their potential relevance to other systemic diseases, and vice versa. For example, “a normal healthy dentition functioning in a healthy oral cavity is critical to the patient’s nutritional wellbeing. Anything that interferes with mastication at the beginning of the digestive process only makes the functions of the patient’s other system more difficult” (Walker 1990). Diseases such as gastroesophageal reflux disease, bulimia, or anorexia



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may be associated with irreversible dental erosion due to the exposure of tooth enamel to acidic gastric contents. The oral manifestations of systemic diseases will be discussed in other chapters of this textbook in far more detail. The unique interrelationship between oral structures and other systems often results in diseases of non-oral origin to manifest orally. Moreover, often at early stages of systemic diseases, oral signs and symptoms are early diagnostic features. The oral-related systemic changes should be distinguished from normal variations of oral structures and will be addressed in the context of the spectrum of the clinical presentations of these systemic diseases (Walker 1990). Table 1 lists examples of systemic diseases that may have manifestations in the oral and perioral region.



The Role of Aging Aging is a complex process and reflects the changes that occur over the lifespan (Rattan 2015). In some population groups worldwide, life expectancy has increased remarkably during the latter half of the last century. The United Nations has projected that the number of persons aged 60 or above is expected to more than double and triple in 2050 and 2100, respectively, compared to that in 2017. The number of persons aged 60 or above will rise from 962 million globally in 2017 to 2.1 billion in 2050 and 3.1 billion in 2100 (United Nations 2017). Recognizing the manifestations of age changes in the oral and dental tissues can help oral medicine specialists to distinguish healthy aging changes from pathological conditions, even though the incidence and prevalence of several oral disorders and conditions, such as oral lichen planus, oral ulceration, oral potentially malignant disorders, and oral cancer, frequently increase with aging (Yap and McCullough 2015). Increasing evidence supports that osteoporosis contributes to the loss of teeth (Merchant 2017; Kaye et al. 2017). Osteoporosis is associated with decreased bone mineral density that may contribute to the loss of alveolar bone and potentially basal bone (Merchant 2017; Kaye et al. 2017). It can be difficult to distinguish aging changes from those of osteoarthritis (Guiglia et al. 2013;



R. Hardiman et al. Table 1 Examples of systemic diseases that may present in the oral and perioral region (Mays et al. 2012; Chi et al. 2010) Diseases of the heart and blood vessels



Diseases of the respiratory tract



Diseases of the genitourinary system



Diseases of the liver and biliary tract



Diseases of the gastrointestinal tract



Diseases of the hematopoietic system (blood and bone marrow) Diseases of the immune system



Diseases of the lymph nodes and spleen



Congenital anomalies of the heart: Tetralogy of Fallot Rheumatoid endocarditis/ bacterial endocarditis Myocardial infarction Coronary insufficiency Thrombophlebitis Lymphangitis Tumor metastatic deposits Tuberculosis Lung infection Uremia Tumor metastatic deposits Glomerulonephritis Nephrotic syndrome Jaundice Liver cirrhosis Hepatitis Tumor metastatic deposits Neoplasms and cysts of liver Gastritis Peptic ulcer Chronic ulcerative colitis Inflammatory bowel disease Plummer-Vinson syndrome Peutz-Jeghers syndrome Osler-Rendu disease Tumor metastatic deposits Anemias Leukemias Thrombocytopenia Hemorrhagic disorders Behcet’s disease Chronic graft-versus-host disease Sjögren’s syndrome Lupus erythematosus Lymphadenopathies Lymphomas Gaucher’s disease Niemann-pick disease Malaria (continued)



Normal Variation in the Anatomy, Biology, and Histology of the Maxillofacial Region Table 1 (continued) Diseases of the endocrine system



Diseases of the skin



Diseases of the musculoskeletal system and joints



Diabetes mellitus Thyroid gland diseases and tumors Gigantism Pituitary dwarfism Acromegaly Addison’s disease Cushing’s syndrome Tumor metastatic deposits Lichen planus Scleroderma Angioneurotic edema Psoriasis Vesiculobullous diseases (pemphigus, erythema multiforme) Reiter’s syndrome Bowen’s disease Nevi and melanoma Osteogenesis imperfecta Scurvy Rickets Osteomalacia Osteomyelitis Osteoporosis Paget’s disease Giant cell lesions and tumors Osteoarthritis Myositis Muscular dystrophy Myasthenia gravis Tumors



Gulsahi 2015; McKenna and Burke 2010). The use of bisphosphonates to treat osteoporosis has been found to increase the incidence of osteonecrosis of the jaw (ONJ) in some cases. This relationship has been established in different populations throughout the world. With aging, an individual may lose some or all of their teeth. Teeth become worn, and muscles of mastication may be subject to atrophy. These changes lead to impairments in oral function, particularly speech and mastication.



Genetic Factors Defective genes/genetic factors are responsible for the evolution of developmental mouth/dental



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anomalies, dysfunctions, and diseases of oral tissues and dentition. Many genetic dental/oral abnormalities represent more complex disorders and are linked to inherited traits and defects or result from spontaneous genetic mutations. Cleft lip and palate, anodontia and hypodontia, amelogenesis imperfecta and dentinogenesis imperfecta, supernumerary teeth, malocclusion, and gingival fibromatosis are examples of these genetic disorders (Madani et al. 2014). These are discussed in more detail in relevant chapters such as ▶ “Odontogenic Pathology.”



Development and Growth of the Craniofacial Region Early Embryogenesis, Germ Layers, and Neural Crest Cells Early embryogenesis involves cell proliferation, migration, and organization to establish the bulk of the embryo as well as define axes: craniocaudal, mediolateral, and anteroposterior (dorsoventral). A detailed discussion of every step in the process of embryogenesis is not within the scope of this chapter, so only aspects of development pertinent to the establishment of the craniofacial and dental complexes are included. The early embryo consists of a mass of uniform cells, before these organize into a bilayered disc, essentially endoderm and ectoderm. At this stage, the axes of the embryo are established. A depression forms along the cranio-caudal axis on the dorsal (ectoderm) surface of the embryonic disc, the primitive streak. At the point of establishment of this depression is the primitive node. Here some ectodermal cells lose their orientation and begin to migrate into the primitive streak (Fig. 1). These cells undergo a transformation from epithelial morphology and function to mesenchymal morphology and function (Morriss-Kay et al. 1993). These cells form the intervening mass between endoderm and ectoderm: the mesoderm. A trilaminar embryo is now established, and all mature tissues of the human body will be formed from one of the three germ layers (see Table 2 for adult craniofacial derivatives of the three germ layers).



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R. Hardiman et al.



Fig. 1 A diagram of the embryonic disc as migration of ectodermal cells to become the mesoderm is underway. (Original drawing by Dr Hala Al Janaby, Perth WA, Australia)



Table 2 Adult derivatives of primary germ layers with a focus on the head and oral cavity Primary germ layer Ectoderm



Mesoderm



Endoderm



Tissue derivative Nervous tissue, epidermis and derivatives (hair, sebaceous and sweat glands), eye (cornea and lens), oral and nasal cavity epithelium (including epithelium of paranasal sinuses), cranial nerve ganglia for cranial nerves V, VII, VIII (vestibulocochlear), IX (glossopharyngeal), and X (vagus), enamel organs Skeletal and smooth muscle, cartilage and bone, blood, marrow, lymph, endothelial cells, synovial membranes Digestive tract epithelium (except oral cavity), respiratory epithelium (of tract), auditory tube and tonsillar epithelium, thyroid, parathyroid and thymus



A rod of condensed tissue forms along the cranio-caudal axis of the embryo, beneath the dorsal surface. This is the notochord, and it induces the formation of the neural groove, later to become the neural tube, and neural crest. Cells from the neural crest sit within the ridge of cells between the neuroepithelium and the epidermis. Once they undergo epithelio-mesenchymal transition (Theveneau and Mayor 2012), similar to that seen during gastrulation (Morriss-Kay et al.



Table 3 Neural crest cell derivatives in the mature human being Anatomical region/system Craniofacial region



Nervous system Musculoskeletal system Integumentary system Endocrine system



Neural crest cell derivatives Cartilage and bone (e.g., mesenchymal derivatives of the frontal, parietal, squamous temporal, nasal and vomer, palatine bones, maxilla and mandible), dentin, connective tissue of salivary and lacrimal glands Neurons and glial cells of the peripheral nervous system Smooth muscle cells and tendons Melanocytes Endocrine cells



1993), they migrate throughout the embryo contributing to the formation of a number of tissues in the human body. Neural crest cell derivatives are outlined in Table 3 and are particularly important in the development of the craniofacial region.



Development of the Jaws, Face, and Skull The first step in the development of the jaws, face, and skull following the establishment of



Normal Variation in the Anatomy, Biology, and Histology of the Maxillofacial Region



anatomical axes is the formation of the branchial (or pharyngeal) arches. These are six bilateral transverse bars of tissue bulging from the embryo. Externally they are lined with ectoderm, internally with endoderm, apart from the region of the future oral cavity, where the internal lining is also formed by ectoderm (Table 2). Between each arch externally is a pharyngeal cleft. Internally, the equivalent furrow is called a pouch. The bulk of each branchial arch consists of cartilage, mesenchymal cells, nerves, and vessels. Specific nerves, cartilage, and muscle groups are associated with particular arches. Figure 2 shows a diagram of the branchial arches in the embryo, and Table 4 highlights the tissue associations with each arch. Note that the fifth branchial arch is taken over by adjacent arches and so disappears from descriptions of arch derivatives. Several genes, transcription factors, and growth factors regulate the craniofacial development (Francis-West et al. 1998). Several types of



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the homeobox (HOX) gene family have been shown to be necessary for normal development of the cranium, face, and jaws (Francis-West et al. 1998). For example, Msx-I is directly linked to the development of secondary palate and teeth (Thesleff 1995). Animal studies have confirmed that altered msx genes are associated with severe facial abnormalities. Further, retinoic acid (a metabolite of vitamin A) has a major role in developing the lower part of the face and first arch structures. Animal studies show that retinoic acid interacts with HOX genes and that altered retinoic acid signaling pathways can lead to remarkable facial abnormalities. Disturbances in development are beyond the scope of this chapter; however, these are highlighted in the chapter on ▶ “Odontogenic Pathology,” ▶ “Pigmented Lesions of the Oral Mucosa,” ▶ “Cutaneous Pathology of the Head and Neck,” and ▶ “Pediatric Oral Medicine.” These are caused by changes in the fusion of



Fig. 2 A diagram showing the structure of the branchial (pharyngeal) arches in the embryo, with their associated nerves. (Original drawing by Dr Hala Al Janaby, Perth WA, Australia)



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Table 4 Branchial (pharyngeal) arch tissue associations Arch 1 2



3 4



6



Nerve Trigeminal-mandibular division (CNV3) Facial (CN VII)



Muscle Muscles of mastication, anterior belly of digastric muscle, tensor veli palatini and tensor tympani Facial muscles, auricular muscles, occipitofrontalis, posterior belly of digastric muscle, and stylohyoid



Cricothyroid



Cartilage/bone Meckel’s cartilage, malleus and incus Lesser horn and superior part of body of hyoid, stapes Greater horn and inferior part of body of hyoid Thyroid cartilage



Glossopharyngeal (CN IX) Superior laryngeal branch of the vagus (CN X) Recurrent laryngeal branch of the vagus (CN X)



Stylopharyngeus



Intrinsic laryngeal muscles



Arytenoid cartilage



different developmental processes (either premature, delayed, or lack of fusion) or changes in relative development of different components of the face, jaws, or skull. Certain developmental disturbances with consistent physical features can indicate the presence of a developmental syndrome such as Crouzon’s syndrome or fetal alcohol syndrome. The causes may be genetic or environmental and may point to any number of syndromes that have effects throughout the body. These syndromes and developmental disturbances are not within the scope of this chapter as they move beyond normal anatomical variation, but have significant clinical relevance. Nevertheless, to understand the mechanism by which these developmental disturbances occur, it is essential to understand human craniofacial development.



Development of the Face In a 4-week-old embryo, the primitive oral cavity (stomodeum), which is an ectoderm lined depression at the site of the future oral cavity, appears as a result of the approximation of five facial processes: the frontonasal prominence superiorly, the two maxillary swellings on either side laterally, and the mandibular prominences inferiorly (Berkovitz et al. 2016). The maxillary and mandibular processes are derived from the first pharyngeal arches. At this stage, the oropharyngeal membrane separates the primitive oral cavity (ectoderm-lined) from the developing pharynx (endoderm-lined). This membrane later breaks



down and allows a continuity of stomodeum and pharynx. A week later, the nasal and optic placodes appear due to a localized thickening of ectoderm. These will later develop to form the nasal pits and eyes. A groove that reaches the medial aspect of the developing eye separates the lateral nasal process from the maxillary process. This groove closes over to form the nasolacrimal duct. In some cases, the nasolacrimal groove fails to close, leaving a nasolacrimal fissure. In the 6th week of embryonic life, the two mandibular processes merge at the midline to construct the lower jaw. In very rare occasions, the persistence of a midline groove in this region can produce a mandibular cleft. The mandibular and maxillary processes fuse at the angles of the mouth, thus defining its outline. Disturbances in the development at this stage may cause microstomia, macrostomia, or very rarely astomia (Berkovitz et al. 2016). The maxillary processes continue from the corners of the mouth toward the medial nasal processes of the upper lip, thus contributing to the formation of the upper lip. Disturbance in the fusion of the maxillary process with the medial nasal process can disrupt upper lip formation, leading to a cleft lip (often associated with cleft palate). Clefts are usually unilateral, rather than bilateral or central.



Development of the Palate The palate develops between the sixth and eighth week of embryonic life. During the sixth week, an



Normal Variation in the Anatomy, Biology, and Histology of the Maxillofacial Region



intermaxillary segment appears anteromedially due to the growth of the medial nasal process. Later, the intermaxillary segment merges with the medial side of the maxillary processes to form the primary palate or premaxilla that bears the maxillary central and lateral incisors. As the primary palate develops horizontally, it begins to separate the primitive oral and nasal cavities. Concurrently, two lateral palatal shelves grow from the maxillary processes posterior to the primary palate. These shelves change growth orientation to a horizontal plane above the forming tongue at the 8th week. The processes merge during the 9th–12th weeks of embryonic life to form the secondary palate (Fig. 3). The lateral palatal



NC



P



*



OC



B T MC



9



processes fuse at the midline marking the mid palatine suture. Fusion begins at the junction between the premaxilla and two maxillary shelves. In the fully formed human, this point of initial fusion remains as the incisive foramen. Any disturbance to palatal fusion presents as a type of cleft palate (Berkovitz et al. 2016).



Development of the Tongue The first, second, and third branchial arches contribute to the development of the tongue. These contributions form the floor of primitive mouth. Protrusions from these arches appear in weeks 4 and 5 of embryonic life. The tuberculum impar (a central swelling in the floor of the mouth) appears along with two lateral swellings. All of these swellings merge to constitute the anterior two thirds of the tongue. The hypobranchial eminence (a midline swelling from the third arch) grows rapidly to form the posterior third of the tongue. Given that the tongue develops from different branchial arches explains the complexity in the tongue’s innervation (Berkovitz et al. 2016). The fusion of the anterior and posterior parts of the tongue is marked by the presence of a V-shaped groove on the dorsum of the tongue: the terminal sulcus. Posterior to this sulcus is the foramen cecum, the point of thyroid gland migration initiation, from which it moves through the thyroglossal duct to its final position in the neck. Ectopic thyroid gland tissue may be found at points along the migratory path (Berkovitz et al. 2016).



Mb



Fig. 3 Hematoxylin and eosin stained histology slide shows a coronal section through a developing face. On the right of the image, from superior to inferior, are the nasal cavity (NC), the developing palate (P) – note the growth of the bony palatal shelf towards the midline of the face (*), the oral cavity (OC), and tongue (T). On the left of the image are a maxillary and mandibular tooth bud (B), growing into the underlying mesenchyme towards the developing upper and lower jaws. The developing mandible (Mb) is seen, with its bony shelves surrounding the tooth bud, and its position lateral to Meckel’s cartilage (MC)



Development of the Jaws Both the mandible and maxilla develop intramembranously as there is no cartilaginous precursor to ossification. However, the mandible undergoes subsequent growth at sites of secondary cartilage, the most long-lasting of which is deep to the surface of the condyle. The mandible develops around Meckel’s cartilage (Fig. 3), a first branchial arch structure appearing at the 6th week of embryonic life. The main function of this cartilage is to provide a framework around which the bone of the mandible forms. The ossification site is at the point of division of the inferior alveolar nerve into its



10



mental and incisive branches. The bone of the body of the mandible develops lateral to Meckel’s cartilage and around the developing tooth buds (Fig. 3). Right and left halves of the mandible meet at the midline and remain separated by fibrous tissue that forms a mandibular symphysis. Meckel’s cartilage eventually undergoes resorption, but the posterior extremes ossify into two inner ear ossicles: the malleus and incus. The ramus of the mandible appears due to the posterior growth of mandibular body and the appearance of secondary cartilages during the 10–14th weeks of embryonic life. These cartilages play a significant role in mandibular growth; the condylar cartilage is the largest and most important, the other two are the coronoid process and in the region of mandibular symphysis. In the second year of life after birth, the mandibular symphysis undergoes complete ossification that allows the two sides of the mandible to become a single fused bone (Berkovitz et al. 2016). The temporomandibular joint develops intramembranously from the mesenchyme between the temporal bone superiorly and the developing condylar cartilage inferiorly during the 12th week of embryonic life. Like the mandible, the maxilla develops intramembranously; a center of ossification appears near the future site of the maxillary deciduous canine during the 8th week of embryonic life. Bone formation extends from the ossification center to form the palatine, zygomatic, frontal, and alveolar processes. The incisor-bearing area is called premaxilla and is an extension of the frontonasal process (Berkovitz et al. 2016). Bone remodeling plays an important role in the subsequent growth of both the mandible and maxilla and helps to shape the terminal morphology of the jaw bones.



Odontogenesis Odontogenesis begins with the formation of a “general dental lamina” (Nanci 2013) in the location of the future dental arches. The general dental lamina forms the 20 primary teeth. Succedaneous permanent teeth develop from a successional lamina deep to the general lamina. Where there is no



R. Hardiman et al.



primary tooth preceding the permanent, teeth develop from the general lamina. Thus, the dental lamina begins in the sixth week of embryonic life and ceases activity when the third molar develops, at around 15 years of age. Developing teeth undergo a number of recognizable stages: bud, cap, and bell (named for the shape of the developing tooth) to form the crown before they begin root development. A complex interaction between the dental lamina (ectodermal in origin) and the underlying mesenchyme (with a contribution from neural crest cells) must occur for odontogenesis to take place. Primary and permanent dentitions undergo the same odontogenic process, however differ in the number, morphology, and emergence timing (Arda et al. 2014; Berkovitz et al. 2016). For the purposes of this text, a brief description and defining features, both morphological and functional, are given for each stage of odontogenesis, before variations are discussed.



Bud Stage Epithelial buds form from the dental lamina and invade the undifferentiated mesenchymal tissue that lies deep to the dental lamina at the sites of future teeth, 20 buds for the primary dentition and between 28 and 32 for the permanent dentition (Fig. 4). Cap Stage As the epithelial bud enlarges, its morphology changes to a concave cap shape. The epithelial cells are now ready to form the enamel organ, and the mesenchyme directly adjacent to the concave part of the cap becomes the dental papilla. The surrounding mesenchyme becomes the dental follicle (Fig. 5). Bell Stage In the final soft tissue stage of odontogenesis, the bell stage (Fig. 6), the cells that will produce the mineralized tissue of teeth, as well as their supporting cells, undergo morpho- and histodifferentiation. At the end of the bell stage, ameloblasts and odontoblasts are recognizable. The enamel organ now consists of a number of distinct cell groupings: the inner enamel epithelium (IEE)



Normal Variation in the Anatomy, Biology, and Histology of the Maxillofacial Region



OC



DL



SL



Mc



TB B



Fig. 4 Hematoxylin and eosin stained section shows a tooth in the tooth “bud” stage (TB) including the dental lamina (DL) with surrounding mesenchymal cells (Mc). Inferior to the tooth bud is the developing bone of the jaw (B) and deep to it is the successional lamina (SL) which will become a permanent tooth. The immature oral cavity (OC) can be seen at the top of the image



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directly adjacent to the dental papilla, the outer enamel epithelium (OEE) forming the outer boundary of the enamel organ, the stellate reticulum (SR) forming the bulk of the enamel organ, and a layer of cells between the SR and IEE, the stratum intermedium (SI). The shape of the future crown is taken on by the IEE, and its cells differentiate into ameloblasts (Robinson et al. 2017), starting at the cusp tips or incisal edges of developing teeth. The OEE serves as the covering and protecting layer for the enamel organ, and the SR and SI support the function of ameloblasts. Bell stage is the last soft tissue stage of tooth formation. Ameloblasts influence the adjacent layer of cells in the dental papilla to differentiate into odontoblasts that will start producing predentin, a mesh of collagen layer that mineralizes within 24 hours, into dentin. As ameloblasts are the initiators of odontoblast differentiation, amelogenesis imperfecta affects both enamel and dentin (Robinson et al. 2017) The formation of dentin in turn influences the ameloblasts to produce enamelin, a mesh of collagen fibers but with 25% embedded hydroxyapatite (Nanci 2013). Predentin production continues throughout life, but the speed of apposition differs. Before tooth eruption into the oral cavity, odontoblasts



DL SL



OEE



SR SI



IEE DP



DF



Fig. 5 Hematoxylin and eosin stained histology section shows a developing tooth in the “cap” stage. The inner and outer enamel epithelia (IEE and OEE) are present and separated by the stellate reticulum (SR) and stratum intermedium (SI). The dental lamina (DL) is still present,



and the successional lamina (SL) can be seen to the right of the image. The dental papilla, comprised of mesenchymal cells, is surrounded by the IEE, and the dental follicle (DF) surrounds the developing tooth structure



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OM



Ab



OEE



D Ob



B



SR



SI



BV



Fig. 6 Hematoxylin and eosin stained histology section shows a developing tooth at the “bell” stage. Dentin (D) can be seen (in its greatest quantity at this stage at the future cusp tip) being laid down by odontoblasts (Ob). Ameloblasts (Ab) are also present. The stellate reticulum is still present (SR) as are parts of the stratum intermedium (SI). The pulp is more developed at this stage too, and



blood vessels (BV) are infiltrating it. The outer enamel epithelium (OEE) can be seen and will soon fuse with the stratum intermedium (SI) to become the reduced enamel epithelium. Bone (B) can be seen forming around the developing tooth, and the oral mucosa (OM) is visible at the top right corner of the image



deposit 4μm of well-structured predentin daily (primary dentin). After eruption and functional occlusion, odontoblasts deposit 1.5μm of wellstructured predentin daily. Tertiary or reparative dentin is produced by odontoblasts in response to stimulation of odontoblasts from abrasion, attrition, or other causes. This is a dentin whose production is limited to areas of odontoblast stimulation. The speed at which it is produced dictates its structure, from well-structured slow production to disorganized fast production (Chiego 2014; Provenza 1988).



disturbances are thought to be genetic, developmental, environmental, and evolutive. If the anomalies are present in the primary dentition, particularly if they are bilateral, it is more likely that the anomaly will be present in the permanent dentition (Gomes et al. 2014; Mukhopadhyay and Mitra 2014). Many variations have little effect on the function of the dentition in humans. As tooth formation has a defined and relatively stable timeline throughout human populations, any effect on dental variation occurs within the timeframe of odontogenesis. Failure of odontogenesis (tooth agenesis) leads to a decrease in the number of teeth in the dental arch (hypodontia), usually the last tooth in a sequence (e.g., lateral incisor, second premolar, and third molar). Hypodontia can affect either arch. It can be uni- or bilateral, and if the primary teeth are affected, it is likely the condition will be carried over to the permanent dentition. Hypodontia can bring about a lack of alveolar bone and malocclusion (Choi et al. 2017). The reported incidence of hypodontia ranges from 2.7% to 12.2% in the permanent dentition (Al-Abdallah et al. 2015). The third molars, however, are so commonly missing in modern times, that if they are missing, it is not considered hypodontia in the scientific literature (Al-Abdallah et al. 2015).



Root Formation At the limits of the crown, IEE and OEE fuse to form Hertwig’s epithelial root sheath. This sheath directs the formation of the tooth’s root or roots (Nanci 2013). Odontoblasts differentiate and form root dentin, and cells external to these differentiate into cementoblasts and form cementum (Gonçalves et al. 2015) (Fig. 7).



Variations in the Dentition Variations in the dentitions encompass tooth number, morphology (Mukhopadhyay and Mitra 2014), and/or structure. The causes of these



Normal Variation in the Anatomy, Biology, and Histology of the Maxillofacial Region



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REE ES



B



D



E Sr



D



Ab



R



P R Ob



B



ED PDL



B



P



Fig. 7 Hematoxylin and eosin stained demineralized section showing a developing tooth at the root formation stage. Surrounding bone tissue (B) can now be seen close to the tooth’s root (R). The enamel space (ES) is caused by the demineralization process, and the reduced enamel epithelium (REE) has now created a protective layer around the crown of the tooth. The epithelial root diaphragm (ED) is visible in the enlarged section to the right.



Developing periodontal ligament fibers (PDL) can be seen in the enlarged section, connecting the root (R) to the adjacent bone (B). The enlarged section on the left shows mature dentin (D) in addition to odontoblasts (Ob). Ameloblasts (Ab) are present secreting enamel (E). The stellate reticulum is still present (Sr). The pulp (P) is more developed. Bone (B) can be seen forming around the developing tooth root



The converse of hypodontia is hyperdontia, an increase in the number of teeth by one or more supernumerary teeth. Causes of hyperdontia have been proposed as a dichotomy of the tooth bud, an overactive dental lamina, and genetic and craniofacial anomalies (Aslan and Akarslan 2013). Other disturbances of odontogenesis can include variations in the morphology of teeth. These can be considered variations because they are not often diagnosed or noticed until a thorough examination of the oral cavity is undertaken. Variations in tooth morphology have a strong population affinity such as shovel-shaped incisors in Asian populations and Carabelli’s cusp in people with Mediterranean ancestry. Morphological variations may also be closely associated with hypodontia. Maxillary hypodontia, for example, has been found to have a significant association with maxillary lateral incisor hypodontia (Al-Abdallah et al. 2015). Variations in the structure of the teeth (enamel, cementum, and dentin) occur during the time of



tissue formation. Some of these are clinically significant, such as amelogenesis and dentinogenesis imperfecta, and will not be discussed here but are covered in the chapter on “Odontogenic Pathology.” Environmental effects such as staining of teeth or disruptions in amelogenesis/dentinogenesis will appear as discolorations and morphological defects in the crown of the tooth such as hypoplasia of enamel (Fig. 8).



Gross Anatomy, Histology, and Biology of the Maxillofacial Region Osteology of the Skull The skeleton of the head can be categorized in a number of different ways, depending on the focus of the discussion. The skull can be separated into the calvaria (skullcap) and cranial base or



14 Fig. 8 Close-up photograph of the left lower lateral incisor and canine. The incisor and canine both show broad horizontal regions of linear enamel hypoplasia (H). In the lateral incisor, the normal external expression of amelogenesis can be seen as perikymata (P)



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P



H



alternatively divided according to contents as the neurocranium and viscerocranium. While the adult skull may retain sutures separating individual bones, some or all of these may become obliterated over time. The synchondroses that are present in the midline of the cranial base to allow for its growth in childhood and adolescence are all fused by the age of approximately 14 years. Premature obliteration of sutures or fusion of synchondroses leads to dysfunctional growth of the skull to compensate for the inability of the fused or obliterated growth surfaces to expand. The mature cranium is a single unit. It has articulations with the mandible and C1 vertebra (atlas). The cranium has many foramina to allow the passage of nerves and vessels between the cranial cavity and orofacial structures and the rest of the body. The foramina transmitting nerves and vessels are discussed in the relevant craniofacial regions below. The driving force of the early growth of the neurocranium or cranial vault is the growth of the brain and eyes. The remainder of the skull grows at the somatic growth rate. Craniofacial growth is subject to changes in relative size and proportions of individual elements. This leads to considerable variation in size and proportion of the adult craniofacial complex (Wood 2015). The mandible is constructed from both cortical bones as a liner and spongy bone in the center, while the maxilla has a greater percentage of spongy bone making it



lighter and can be of great pathological importance as the intraosseous lesions in the maxilla normally spread faster than that of the mandible (Garant 2003). The flat bones of the calvaria are bilayered; there is an inner layer of compact bone, the inner table, and an external layer, the outer table. The intervening tissue is also bone, though less compact than either the inner or outer tables. The bones of the face are compact bone. The “pneumatic bones” are hollowed out by sinuses or air cells. The presence of these warms and moistens inhaled air, resonates the human voice, and may have a role in decreasing the weight of the skull. Paranasal air sinuses are discussed in the relevant sections below.



Anatomical Variations of the Skull The skeletal regions of the skull that have direct attachment of skeletal muscle are subject to variations corresponding to each muscle’s crosssectional size, with larger muscles leading to larger biomechanical forces and, consequently, thicker cortical bone at the site of muscle attachment (Iván and Daniela 2012). For example, if there is a preference for chewing on one side of the mouth, the attachment of masseter to the angle of the mandible on that side will be considerably larger than the contralateral angle and may even be everted slightly. This is because of the increased



Normal Variation in the Anatomy, Biology, and Histology of the Maxillofacial Region



force being applied by the larger masseter on the preferred chewing side. In other cases, the lack of balance between different structures can lead to changes in skeletal morphology. In children with pharyngeal tonsil hypertrophy (adenoids), the blocking of the nasopharynx necessitates mouth breathing. This leads individuals to retain an open mouth, and the tongue moves inferiorly. This in turn leaves the forces of buccinators on the upper arch unopposed. The resulting lateral compression leads to a short transverse axis in the upper arch and a high-set palate (Nishimura and Suzuki 2003). Differences in skull morphology occur between populations as a process of adaptation to environmental and subsistence patterns and drift as a factor of population size or isolation (Hanihara and Ishida 2001). Where foramina exist in the skull for the passage of nerves and vessels, considerable variation in their form and position can be found. Foramina may be single or may consist of multiple smaller accessory foramina. Their position relative to other anatomical landmarks may also vary. The position of the palatine foramen in the hard palate, for example, may be found opposite the third molar, distal to it, or between the third and second molars (Fig. 9) (Chrcanovic and Custódio 2010). Recent three-dimensional studies have improved the visualization capabilities of clinically important regions of the skull. One study



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found fibers of the lingual nerve and mylohyoid nerve and branches of the lingual artery and sublingual/submental artery branches entering the superior and inferior genial spinal foramina, an important consideration when planning mandibular implants (Jacobs et al. 2007). The skull expresses sexual dimorphism in humans. The differences are established at puberty and are due to sex hormone expression. In general, males have an overexpression of bony elevations in the skull compared with females; in men, the size of ridges, tubercles, and processes is greater than in women. These effects are increased by the action of muscle forces on the bone. In general, the male skull is larger and more robust than the female skull, with bony features more prominent in the male. The forehead is steeper in males. The body and ramus of the mandible are greater in size in males compared with females. These differences are to be taken in general and are certainly not universal determinants of gender in humans. The body of the mandible may be subject to developing a mandibular torus, torus mandibularis (Fig. 10a), on the medial surface of the body. This is not a pathological process and mostly does not interfere with function. These can also occur on the palate, torus palatinus (Fig. 10a and c). However, over time these can become very large and may interfere with the construction of



Fig. 9 Palatine views of two skulls, showing the variable position of the greater palatine foramen (GPf.) relative to the upper right third molar



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Fig. 10 Tori can occur in the mandible, torus mandibularis (a) or the palate, torus palatinus (b and c), be relatively small, not change over time and be of very little consequence. However, they can increase with time and potentially be of concern, particularly to the fit of full dentures and may require preprosthetic removal (Image a)



dentures should the patient require these (Fig. 10a, b, and c). The bony canal for the inferior alveolar nerve and vessels in the mandible are subject to variations in their course and structure. Double and bifid canals may be present, the location of the mandibular foramen varies, and the location of the canal in relation to the roots of mandibular teeth can also vary (Fig. 11). Approximately 20% of individuals have asymmetrically sized mental foramina (Berge and Bergman 2001). Age changes are an important consideration for the study of landmarks. The bony tissue of the skull is subject to remodeling as a result of muscle and masticatory forces and as a result of changes in the structure and number of teeth. The mandibular foramen, an important landmark for the



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courtesy of Professor Michael McCullough, Melbourne Dental School, University of Melbourne, Carton VIC and images (b and c) courtesy of Professor Camile Farah, Perth Oral Medicine & Dental Sleep Centre, Perth WA, Australia)



Fig. 11 Inferior alveolar canal dissected on a dry mandible showing also the mental foramen



Normal Variation in the Anatomy, Biology, and Histology of the Maxillofacial Region



administration of local anesthetic to the mandibular arch, changes its position relative to the occlusal plane, alveolar crest plane, anterior border of the ramus of the mandible, angle of the mandible, and the head of the mandible with increasing age (Rodella et al. 2012). The mandibular foramen moves superiorly relative to the occlusal plane with increasing age (Hung-Huey 2004). There is considerable variation in the timing of suture closure over the human lifespan. Sutures close on the endocranial surface first, followed by the external surface.



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facilitates tissue turnover (Fig. 13), which is of great importance both physiologically for growth and maintenance of calcium homeostasis, and also allows for orthodontic treatment (Hand and Frank 2014).



Scalp and Facial Soft Tissues



The skull consists of bone formed by either intramembranous ossification (flat bones of the cranial vault and mandible) or endochondral ossification (bones of the cranial base). Mature bone is osteonal in nature and consists of an inorganic/ organic matrix. Osteons (Haversian systems) have concentric lamellae of matrix containing osteocyte lacunae (Fig. 12). Similar to cementum (Fig. 13), the bone consists of 66% mineral, but the presence of both osteoblasts and osteoclasts



The scalp is a multilayer of soft tissues that envelops the skull. It specifically covers the frontal, parietal, temporal, and occipital regions (Fehrenbach and Herring 2012). It borders the supraorbital margin anteriorly, the external occipital protuberance and superior nuchal line posteriorly, and the superior temporal line laterally. The five layers of the scalp are the skin, connective tissue, aponeurosis, loose areolar connective tissue, and pericranium (conveniently forming the acronym “SCALP”) (Norton and Netter 2012). The skin is the thickest layer of the scalp; it contains hair follicles and other adnexal structures particularly oil-secreting sebaceous glands. The subcutaneous layer of the scalp is formed by dense fibrous tissue and firmly attaches the overlying skin to the underlying epicranial



Fig. 12 Toluidine blue stained decalcified histological slide shows two flat bones of the calvaria joined by a suture (S) composed of fibrous tissue and fibroblasts. The inner and outer tables of the skull are composed of osteonal bone tissue (OB) and the inner and outer tables are separated by



the diploё, which in this skull contains hematopoietic bone marrow (BM). Pericranium (periosteal tissue) lines the external surface of the skull (P), just deep to the muscle which overlies the skull in some places (M). An osteon is highlighted by a dotted line



Histology of Hard Tissues



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Fig. 13 Hematoxylin and eosin stained decalcified section of the lower jaw showing newly erupted teeth embedded in alveolar bone (A) by the periodontal ligament (P). Teeth are present on the left and right of the image, with dentin forming the visible bulk of the tooth (D), and a thin layer of cementum (C) facing the periodontal ligament. Rf resorption front, Oc osteoclast, Ob osteoblast



Fig. 14 Histological sagittal section through a developing rabbit head, showing the layers of the scalp (x 8.5). All layers of the scalp are visible: skin (S), connective tissue (C), aponeurosis (A), loose areolar tissue (L), pericranium (P), and bone (B). The immature membranous bone of the skull is also visible, separating the scalp from the cranial cavity. Hair follicles (HF) and shafts (Sh) can be seen embedded in the connective tissue



aponeurosis (the fascia of the muscle occipitofrontalis) (Snell 2012; Agur and Grant 2013). The scalp is highly vascular and vessels anastomose freely. Combined with the tension produced anteroposteriorly by occipitofrontalis muscle, this causes scalp wounds to gape and bleed profusely. The principal arteries of the scalp, the superficial temporal, posterior auricular, and occipital arteries, are branches of the external carotid artery, while the supraorbital and supratrochlear arteries are branches of the ophthalmic artery, a branch of the internal carotid artery (Norton and Netter 2012). Lymph from the part of the scalp anterior to the auricles drains to the parotid, submandibular, and deep cervical lymph nodes. Lymph from the posterior part of the scalp drains



to the posterior auricular (mastoid) and occipital lymph nodes (Norton and Netter 2012; Snell 2012). The skin of the scalp and face is innervated partly by cutaneous sensory branches of the cervical spinal nerves but mostly by the fifth cranial nerve: the trigeminal nerve (Norton and Netter 2012; Snell 2012) (Fig. 14). Note that C1 has no cutaneous distribution.



Soft Tissue Structures in the Superficial Face Despite that much of the facial contour is dictated by underlying facial bone morphology, control of



Normal Variation in the Anatomy, Biology, and Histology of the Maxillofacial Region



facial sphincters and facial expressions is affected principally by the compartments of the facial soft tissue. There are six groups of muscles that are responsible: oral, nasal, orbital, auricular, scalp, and neck (Table 5). Superficial facial muscles (Fig. 15) are difficult to identify with routine imaging methods as these muscles are closely intertwined (Hutto and Vattoth 2015) and lack bulk. Their common innervation derives from their embryological origin in the mesoderm associated with the second branchial arch. The best assessment for facial muscle, and therefore ipsilateral facial nerve function, is a visual assessment of their function, asking the patient to raise their eyebrows, frown, puff out their cheeks, smile, wrinkle their nose, and purse their lips. These facial muscles are all innervated by the facial nerve (cranial nerve VII). Embryologically,



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these muscles are associated with the second branchial arch, hence their common innervation. The facial nerve exits the skull through the stylomastoid foramen. It enters the face via the substance of the parotid gland, which it does not innervate (Gray et al. 1995). Two trunks are given off, the temporofacial and the cervicofacial. These two trunks then give the five branches of the facial nerve with some branching variations. Table 6 outlines the innervation of individual facial muscles as well as variations of the facial nerve branches. Several consistent ligaments that act to tether the facial skin to underlying structures have been identified; the zygomatic ligaments stabilize the skin of the cheek by attaching them to the inferior border of the zygoma, mandibular ligament fibers tether the anterior mandible to overlying skin, and



Table 5 Facial muscles (Modified from Netter’s Head and Neck Anatomy for Dentistry; Norton and Netter 2012) Group Oral



Muscle Orbicularis oris Depressor anguli oris Levator anguli oris Zygomaticus major Zygomaticus minor Levator labii superioris Levator labii superioris alaeque nasi Risorius Depressor labii inferioris Mentalis Buccinator



Nasal



Nasalis compressor naris Nasalis dilator naris Depressor septi Procerus



Orbital



Orbicularis oculi orbital Orbicularis oculi lacrimal Orbicularis oculi palpebral Corrugator supercilii Anterior Superior Posterior Frontalis Occipitalis Platysma



Auricular



Scalp Neck



Actions Produces oral seal, protrusion of lips and pursing of lips Depresses the corners of the mouth Elevates the angle of the mouth Moves the angle of the mouth superiorly and laterally Helps elevate the upper lip Elevates the upper lip Elevates the upper lip and dilates the nostrils Moves the angle of the mouth laterally Depresses the lower lip Protrudes the lower lip Aids in mastication and helps to forcibly expel air or create a sucking action Compresses the nostril Dilates the nostril Draws nasal septum anteriorly to constrict nostril Brings skin together producing transverse wrinkles on the bridge of the nose Forcible closure of the eye Aids the flow of tears Closure of eyelids gently (blinking) Draws the eyebrows medially and inferiorly Draws auricle anteriorly Draws auricle superiorly Draws auricle posteriorly Elevates eyebrows and wrinkles forehead Wrinkles the back of the head Wrinkles the skin of the neck



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Fig. 15 Diagram showing locations of facial muscles. (Original drawing by Dr Hala Al Janaby, Perth WA, Australia)



the platysma-auricular ligament is a flat ligament attaching the posterior border of the platysma to the skin anterior to the auricle (Furnas 1989). The arteries of the face anastomose freely (Norton and Netter 2012; Snell 2012). The principal vascular supply of the facial soft tissue



structures arises from the facial branches of the external carotid artery. The anterior part of the forehead is supplied by branches from the internal carotid artery. The ophthalmic artery branches supply the dorsal surfaces of the external nose (Norton and Netter 2012).



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Table 6 Branches of the facial nerve and observed variations Division Temporofacial



Branches Temporal



Zygomatic



Buccal



Cervicofacial



Marginal mandibular Cervical



Posterior auricular Chorda tympani (intratemporal)



Innervation Corrugator Procerus supercilii Orbicularis Anterior and oculi orbital superior Orbicularis auricular oculi Frontalis lacrimal Orbicularis Levator oculi anguli oris palpebral Zygomaticus major Buccinator Zygomaticus Nasalis minor compressor Levator labii naris superioris Nasalis Levator labii dilator naris superioris Depressor alaeque nasi septi Depressor labii inferioris Mentalis Depressor anguli oris Platysma Occipitalis Posterior auricular muscle Taste sensation to anterior two thirds of the tongue, parasympathetic fibers to submandibular and sublingual glands (Singh et al. 2015). Postganglionic parasympathetic fibers hitchhike with branches of the third division of the trigeminal nerve to the submandibular and sublingual glands. Taste fibers hitchhike with the lingual nerve (Baker et al. 2015)



The facial veins begin as small venules and become larger as they join proximally (Fehrenbach and Herring 2012). These veins follow a similar distribution pattern to that of facial arteries (Norton and Netter 2012). The facial vein is the main drainage of the face and joins the internal jugular vein on its way to the heart (Fehrenbach and Herring 2012; Snell 2012). However, other areas of the face drain via the retromandibular vein to the external jugular vein (Fehrenbach and Herring 2012). The face is innervated by motor and sensory nerves. The facial nerve (Fig. 16) covers all motor nerves in the face and supplies the muscles of



Variations Six variations of facial nerve patterning have been identified (Gataa and Faris 2016): Type I: No anastomosis between the two main branches Type II: Anastomosis only between branches of the temporofacial division (second-most common variation) Type III: One anastomotic incidence between the two divisions – Buccal and zygomatic branches (most common variation) Type IV: Combination of type II and III, with temporal, zygomatic, and buccal branch anastomoses Type V: Double anastomosis between the two divisions (least-common variation) Type VI: Complex anastomosis between the two divisions



None to mention None to mention



facial expression (Fehrenbach and Herring 2012; Norton and Netter 2012). The three divisions of the trigeminal nerve are responsible for supplying the sensory innervation for facial structures, and the cervical plexus does similarly (Norton and Netter 2012).



Variation and Aging in Facial Soft Tissues Physical maturity is reached approximately in the early 20s, and subsequently human facial soft tissues begin to undergo changes not as a



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Fig. 16 Diagram showing the course of the branches of the facial nerve (CNVII) over the face. (Original drawing by Dr Hala Al Janaby, Perth WA, Australia)



consequence of growth but due to the onset of “aging.” The aging process involves gradual decrease in skin elasticity, reduction in subcutaneous fatty tissue volumes, increase in muscle tone, and the effects of gravity. These factors lead to an increase in skin folds “wrinkles,” usually perpendicular to facial muscle fiber direction, and a decrease in overall facial volume (Mydlová et al. 2015). Facial soft tissue thickness varies between different regions of the face, generally



being thinnest over the tip and bridge of the nose and infraorbital rim and thickest over the lips, chin, cheek, and lower jaw (Stephan et al. 2013).



Histology of the Epidermis The epidermal covering of the head and neck varies in thickness from the scalp to the skin overlying the eyelids. Most of the epidermis



Normal Variation in the Anatomy, Biology, and Histology of the Maxillofacial Region



contains hair follicles, sweat, and sebaceous glands. The epidermis overlies dermis, containing numerous blood vessels that anastomose freely, especially over the face. The epidermis of the head and face is a stratified squamous keratinized epithelium. The epithelial layers are avascular and receive their nutrition from the dermis and subcutaneous tissue that lie deep to the basement membrane of the epidermis (Fig. 17).



Fig. 17 Hematoxylin and eosin stained cross-section of stratified squamous keratinized epithelium. The papillary layer of the dermis is seen beneath the epithelial layer (P). A basement membrane (not visible in light microscopy) supports the epithelial cells. The deepest layer is the stratum basale (SB), a layer of undifferentiated epithelial cells. The next superficial layer is the stratum germinativum (SGe). In this region of the epithelium, the cells have not yet changed their shape to a squamous morphology. The stratum spinosum (SS) is the next superficial layer. Here, the keratinocytes begin to flatten. They appear as having small spiny processes projecting from the membrane. The next layer, present in keratinized epithelia, is the stratum granulosum (SGr), where the keratinocytes appear to have granular cytoplasm. More superficial to this (stratum lucidum – SL and keratinized layer – K), the keratinocytes begin to lose their nuclei and become flatter in the very thick keratin layer, eventually to be sloughed off from the surface



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Infratemporal Region and Pterygopalatine Fossa The infratemporal region is located inferior to the horizontal shelf of the temporal bone, in a space referred to as the infratemporal fossa. It forms a clinically important region because it contains major muscles, nerves, vessels, glands, and joints of the head. The infratemporal fossa communicates with the middle cranial fossa via the foramen ovale and foramen spinosum that transmit the mandibular division of the trigeminal nerve and the middle meningeal artery, respectively. It communicates with the pterygopalatine fossa via the pterygomaxillary fissure and inferiorly with the parapharyngeal space, a potential fascial space lateral to the pharynx (discussed elsewhere in this chapter). The main boundaries of the infratemporal fossa are the zygomatic bone and infratemporal surface of the greater wing of sphenoid bone superiorly, with a small contribution from the squamous part of the temporal bone, the ramus of the mandible laterally, the styloid process posteriorly as well as the carotid sheath and its contents, the infratemporal surface of the maxilla anteriorly, the lateral pterygoid plate and pyramidal process of the palatine bone medially, and the level of a transverse plane through the lower border of the mandible inferiorly. The bony borders of the infratemporal fossa are incomplete (Fig. 18), and so there is much open communication between structures within and immediately adjacent to the fossa. The most clinically relevant of these is the pterygopalatine fossa, which communicates with the infratemporal fossa via the pterygomaxillary fissure. The contents of the infratemporal fossa are the lateral and medial pterygoid muscles, the tendinous insertion of the temporalis muscle, the mandibular division of the trigeminal nerve, the posterior superior alveolar branch of the maxillary division of the trigeminal nerve, the otic ganglion, the lesser petrosal nerve, the chorda tympani, and the maxillary artery and accompanying veins. The temporomandibular joint is also placed just within the infratemporal fossa (Mohl 1988).



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structures. Within the fossa, the artery gives off five branches: the infraorbital, sphenopalatine, posterior superior alveolar, descending palatine branches, and the artery of the pterygoid canal. These are discussed in greater detail elsewhere. The maxillary division of the trigeminal nerve enters the pterygopalatine fossa via the foramen rotundum.



Trigeminal Nerve



Fig. 18 Inferior view of the cranium outlining the boundaries of the infratemporal fossa



Clinically, the infratemporal fossa is accessed in its anterior aspect to carry out a posterior superior alveolar nerve block. The pterygopalatine fossa is a small inversepyramid-shaped fossa. Its roof is formed by the greater wing of the sphenoid bone, its anterior wall is formed by the infratemporal surface of the maxilla, and its posterior wall by the root of the pterygoid processes of the sphenoid. Laterally, it communicates with the infratemporal fossa via the pterygomaxillary fissure. Narrow pterygomaxillary fissures can be found in approximately 8% of individuals, hampering access to the fossa for anesthesia (Stojčev Stajčić et al. 2010). An enlarged sphenoidal spine may obstruct access to the pterygomaxillary fissure in 15% of individuals (Stojčev Stajčić et al. 2010). Inferiorly the fossa communicates with the oral cavity via the greater palatine canal. The volume of the pterygopalatine fossa (on dry skulls) has been measured at between 0.1cm3 and 1.0cm3, without significant bilateral asymmetry (Stojčev Stajčić et al. 2010). The pterygopalatine fossa contains the pterygopalatine part of the maxillary artery, one of the terminal branches of the external carotid artery and one of the main arteries supplying facial



The trigeminal nerve (CNV) has a wide distribution in the craniofacial region. It supplies sensory innervation to the face and scalp up to the vertex, including most parts of the oral cavity. Being a first pharyngeal arch structure, it is responsible for motor innervation of the muscles of mastication. The trigeminal nerve has three divisions, the ophthalmic (CNV1), maxillary (CNV2), and mandibular (CNV3) whose territories roughly divide the face into thirds: CNV1 from the vertex of the scalp to the eyelid and a central strip of the nose, CNV2 from the lower eyelid to the upper lip, and CNV3 from the lower lip to the chin and angle of the jaw (Fig. 19). Minor variations occur in branching.



CNV1 The ophthalmic division of the trigeminal nerve (Fig. 19a) is wholly sensory and is essentially the nerve of the embryonic frontonasal process. The nerve leaves the ganglion and passes by the cavernous sinus, picking up sympathetic fibers for the dilator pupillae muscles. After giving off a meningeal branch, the ophthalmic division splits into three branches that leave the cranial cavity and enter the orbit via the superior orbital fissure (Fig. 19a). The three branches are the frontal, lacrimal, and nasociliary nerves. The frontal nerve, which runs along the roof of the orbit, divides into the supraorbital and supratrochlear branches. The supraorbital nerve supplies the frontal sinus, upper eyelid, most of the forehead, and scalp to the vertex. The supratrochlear nerve supplies a small medial vertical strip of the forehead.



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Fig. 19 The trigeminal nerve and its branches. The first branch, ophthalmic branch (V1) is highlighted in pink, the second, maxillary branch (V2) highlighted in green, and



the third, mandibular branch (V3) highlighted in blue. (Original drawing by Dr Hala Al Janaby, Perth WA, Australia)



The lacrimal nerve courses along the lateral wall of the orbit. Secretomotor fibers from the zygomatic nerve “hitchhike” with the lacrimal nerve to the lacrimal gland. It supplies a small part of the upper eyelid and associated conjunctiva. The nasociliary nerve passes along the medial wall of the orbit, carrying the “hitchhiking” sympathetic nerves to the dilator pupillae, and gives



sensory innervation to the globe of the eye. It passes through the anterior ethmoidal foramen, becomes the anterior ethmoidal nerve, and supplies the ethmoidal air cells. It then passes anteriorly into the roof of the nose, where it innervates the anterosuperior lateral nasal wall and septum. The nerve then supplies the external nose as the external nasal nerve. For variations, refer to Table 7.



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Table 7 Innervation of the face relevant to the maxillofacial region with variations Nerve Olfactory (CN I)



Branches None



Trigeminal ophthalmic division (CNV1)



Lacrimal nerve



Frontal nerve (supratrochlear and supraorbital branches)



Trigeminal maxillary division (CNV2)



Nasociliary nerve Middle meningeal nerve Zygomatic nerve (temporal and facial branches)



Posterior superior Alveolar nerve



Infraorbital nerve (middle and anterior superior alveolar nerves)



Nasopalatine nerve



Posterior superior nasal nerve (lateral and medial posterior superior nasal nerves)



Distribution Special sensation of smell via olfactory bulbs in the roof of the nasal cavity Lacrimal gland and adjacent conjunctiva. Receives a branch from the zygomaticotemporal branch of the maxillary nerve, which is thought to be secretomotor to the lacrimal gland



Variations Occasional absence of olfactory nerve, bulbs, tracts, and lobes has been reported Sometimes receives a branch from the trochlear nerve (CN IV). The lacrimal nerve is sometimes absent, in which case the zygomaticotemporal branch of the maxillary nerve performs its function. The reverse is also sometimes true



The supratrochlear branch supplies a fiber to the nasociliary nerve. It supplies the conjunctiva and skin of the upper eyelid and the skin of the inferior part of the forehead close to the midline. The supraorbital nerve passes through the supraorbital fissure, divides into medial and lateral branches, and gives sensory supply to the scalp to the vertex Meninges of the middle cranial fossa Sensory to skin overlying the temple (temporal branch) and upper lateral cheek (facial branch)



Sensory to upper molar teeth, buccal mucosa, and gingivae associated with these teeth; the maxillary sinus Sensory to inferior lid of the eye including conjunctiva and maxillary sinus (infraorbital), maxillary teeth (premolars – Middle superior alveolar, incisors, and canines – Anterior superior alveolar), associated gingiva and mucosa of the cheek (Leo et al. 1995) Sensory to anterior hard palate and inferior nasal septum Sensory to posterior ethmoid air cells and mucosa of the posterior superior and middle conchae (lateral posterior superior nasal



None to mention The two branches may emerge separately or via one foramen in the zygomatic bone. The distribution may be taken over by the infraorbital nerve (facial branch) or lacrimal nerve (temporal branch) *see entries for long buccal nerve and palatine nerve below



There may be accessory infraorbital foramina (Rodella et al. 2012). The middle superior alveolar nerve may be absent (Rodella et al. 2012). The nerve may exist as a single trunk or plexus (the single trunk being more common) (Rodella et al. 2012) May give some branches to maxillary incisors (Rodella et al. 2012) None to mention



(continued)



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Table 7 (continued) Nerve



Branches



Palatine nerve (greater and lesser palatine nerves)



Trigeminal mandibular division (CNV3) Anterior division



Pharyngeal nerve Recurrent meningeal Nerve to medial pterygoid Nerve to masseter Deep temporal nerves Nerve to lateral pterygoid Long buccal nerve



Trigeminal mandibular division (CNV3) Posterior division



Auriculotemporal nerve



Lingual nerve



Distribution nerve) and mucosa of the posterior roof and septum (medial posterior superior nasal nerve) Sensory to hard palate mucosa, gingivae and glands (greater), soft palate, palatine tonsils, and uvula (lesser) Sensory to mucosa of nasopharynx Sensory to meninges of middle cranial fossa Motor to medial pterygoid and motor to tensor tympani and tensor veli palatini Motor to masseter, sensory to temporomandibular joint Motor to temporalis Motor to lateral pterygoid Sensory to cheek skin and mucosa and molar buccal gingivae



The Auriculotemporal nerve supplies sensation to the temporomandibular joint capsule, the skin over the ear and temple, as well as carrying postganglionic parasympathetic fibers from the otic ganglion Provides general sensory innervation to the anterior two thirds of the tongue, floor of mouth, and lingual gingiva. Carries parasympathetic fibers to the submandibular and sublingual salivary glands



Variations



Branches from the palatine nerve may innervate maxillary molars and premolars (Rodella et al. 2012) None to mention



None to mention



None to mention None to mention None to mention The buccal nerve’s territory can be covered by the posterior superior alveolar nerve. The buccal nerve may arise as a branch of the inferior alveolar nerve (Bergman et al. 2006). The long buccal nerve may be responsible for innervation of the molars by entering through retromolar foramina (Rodella et al. 2012) There may be some anastomosis of innervation between the auriculotemporal nerve and inferior alveolar nerve (Rodella et al. 2012)



The lingual nerve may pierce the lateral pterygoid in its course and may occasionally carry motor branches to the pterygoids and palatoglossus (Bergman et al. 2006). The course of the lingual nerve varies in relation to the alveolar crest, with the vertical distance between the two ranging from approximately 2 to 8 mm (Rodella et al. 2012). The lingual nerve may provide some fibers to the inferior alveolar nerve (Rodella et al. 2012). The lingual nerve may also innervate the lingual gingiva around the third molar region (Rodella et al. 2012) (continued)



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Table 7 (continued) Nerve



Branches Inferior alveolar nerve (incisive and mental branches, nerve to mylohyoid)



Distribution The inferior alveolar nerve is sensory to the mandibular molars and their associated gingiva. A branch to mylohyoid innervates mylohyoid muscle and anterior belly of the digastric muscle; mental nerve innervates the skin of the lower lip and chin and the inferior labial mucosa. The incisive branch innervates the premolars, canines, and incisors and their gingiva (Rodella et al. 2012)



CNV2 The maxillary division of the trigeminal nerve (Fig. 19a) is, like the ophthalmic division, wholly sensory. Its territory lies between the lower eyelids and the upper lip, excluding a midline strip of skin along the nose and parts of the nasal cavity. The maxillary nerve and its branches supply the palate, nasal mucosa, maxillary teeth, lacrimal gland, and skin. The maxillary nerve leaves the cranial fossa via the foramen rotundum (after giving off a small meningeal branch) and passes anteriorly through the pterygopalatine fossa. It leaves the fossa through the inferior orbital fissure, becoming the infraorbital nerve as it courses through the infraorbital groove, canal, and eventually emerging from the infraorbital foramen to the face, where it



Variations The inferior alveolar nerve may give multiple extra-osseous branches before entering the mandibular foramen. These will enter via accessory canals (Wolf et al. 2016). Bifid inferior alveolar canals show varying prevalence (0.1%–65% of individuals) depending on the study conducted (Rodella et al. 2012). The inferior alveolar nerve may split into two trunks intraosseously with one trunk innervating the molars and premolars and then becoming the incisive nerve. The other trunk becomes the mental nerve. The nerve may also split into three branches near the mandibular foramen: One for the molars and premolars, a second for canines and incisors, and finally a mental branch (Wolf et al. 2016). The inferior alveolar nerve may have varying associations with the maxillary artery (Rodella et al. 2012). See also the section on the auriculotemporal nerve. The mental nerve may also exit the mandible through more than one foramen and may innervate contralateral incisors (Rodella et al. 2012). The nerve to mylohyoid may give some branches to the inferior alveolar nerve (Rodella et al. 2012)



supplies the skin of the cheek, lateral nose, lower eyelid and associated conjunctiva, skin and mucosa of the upper lip, as well as adjacent gingiva up to the premolars. Before its emergence, when the nerve is within the infraorbital canal, it gives off the middle superior alveolar nerve (when present – see Table 7), responsible for innervating the upper premolars, and the mesiobuccal root of the first molar, as well as some mucosa of the maxillary sinus (McMinn 1995). Next, the infraorbital nerve gives off the anterior superior alveolar nerve and supplies some of the maxillary sinus and the upper incisors and canine, as well as the inferior lateral nasal wall, nasolacrimal duct, and anterior floor of the nose (McMinn 1995). A zygomatic branch leaves the maxillary nerve in the pterygopalatine fossa and enters the orbit through the inferior orbital fissure. It carries



Normal Variation in the Anatomy, Biology, and Histology of the Maxillofacial Region



postganglionic secretomotor fibers for the lacrimal gland that it passes to the lacrimal nerve. The zygomatic nerve eventually splits into the zygomaticofacial nerve which innervates the skin over the zygomatic bone and the zygomaticotemporal nerve innervating the skin over the temple. The posterior superior alveolar nerve is a single branch from the maxillary nerve in the pterygopalatine fossa. It divides into a number of branches that leave the fossa via the pterygomaxillary fissure. Two of these branches enter the posterior wall of the maxilla and innervate some of the maxillary sinus and the upper molars except for the anterior mesiobuccal root of the first molar, which is innervated by the middle superior alveolar nerve when present. One branch does not enter the maxilla, and it innervates the buccal gingiva of the molars. Ganglionic branches from the maxillary nerve join the maxillary nerve to the pterygopalatine ganglion within the fossa of the same name. These fibers pass through the ganglion without synapsing, but pick up postganglionic parasympathetic fibers as they go through the ganglion. These become branches of the ganglion and are: – The nasopalatine nerve innervating the posteroinferior nasal septum and then the palatal gingiva of the upper incisors after passing through the incisive canal. – The posterior superior medial and lateral nasal nerves supplying the corresponding nasal septum and lateral wall. – The greater palatine nerve, which enters the palatine canal between the maxilla and palatine bone and then exits to the hard palate through the greater palatine foramen (Fig. 9). It innervates some of the lateral nasal wall and adjacent floor of the nose, some of the maxillary sinus, and all of the hard palate except for the nasopalatine nerve territory. – The lesser palatine nerves emerge from the lesser palatine foramina, posterior to the greater palatine foramen, and innervate the mucosa of the soft palate and palatine tonsil. – A pharyngeal branch to supply the mucosa of the nasopharynx to the level of the pharyngotympanic tube.



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CNV3 The mandibular division of the trigeminal nerve (Fig. 19b) has a large sensory component and small somatomotor component. It enters the infratemporal fossa from the middle cranial fossa via the foramen ovale of the sphenoid bone. The foramen ovale has shown bilateral asymmetry in its size, which may be of clinical relevance (Berge and Bergman 2001). After entering the infratemporal fossa, it immediately gives off two branches, a recurrent meningeal branch to supply the dura that reenters the cranial cavity via the adjacent foramen spinosum (or reenters through the foramen ovale) (McMinn 1995) to innervate the cartilaginous auditory tube, dura mater, mastoid antrum, and air cells. The second branch is the nerve to the medial pterygoid innervating the medial pterygoid and sending a branch to tensor veli palatini and tensor tympani. The mandibular division of the trigeminal nerve then divides into its anterior and posterior branches.



Mandibular Division of the Trigeminal: Anterior Branch The anterior branch of CNV3 is predominantly motor. The only sensory branch being the buccal (or long buccal) nerve, discussed in the section on the oral cavity. The motor branches supply the remaining muscles of mastication including the deep temporal nerves to temporalis, nerve to masseter, and nerve to the lateral pterygoid. Mandibular Division of the Trigeminal: Posterior Branch The posterior branch of CNV3 is predominantly sensory with only one motor component. Its first branch is the auriculotemporal nerve, which courses posterior to the temporomandibular joint and through the parotid gland, giving sensory supply to the temporomandibular joint’s capsule before dividing to pass around the middle meningeal artery. Ultimately it supplies some skin over the ear and temple. It also carries postganglionic parasympathetic fibers from the otic ganglion. The lingual nerve provides sensory supply to mucosa of the oral cavity, discussed in a



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subsequent section of this chapter. The inferior alveolar nerve passes into the pterygomandibular fossa and enters the mandibular canal after giving off the motor branch to the mylohyoid and the anterior belly of the digastric muscle. After entering the mandibular canal, it gives branches to the mandibular teeth before dividing into its terminal incisive and mental branches. The mental branch exits the mandible via the mental foramen to supply the incisive labial gingiva and the skin of the chin and lower lip. The incisive branch continues in the mandibular canal to supply the anterior mandibular teeth. Variations in the branching pattern and course of the nerves supplying the structures of the upper and lower jaws can lead to inadequate effectiveness of local anesthesia during dental procedures or injury to the nerves during surgical procedures. For common variations in the course, distribution, and branching patterns of nerves, see Table 7.



Gross Anatomy of the Temporomandibular Joint The temporomandibular joints are specialized synovial joints, called ginglymoarthrodial synovial joints, providing articulation between the mandible and cranium. The joints function as modified hinge joints, enabling both rotation and Fig. 20 Components of the temporomandibular joint: C condyle, AE articular eminence, AT articular tubercle, EAM external auditory meatus, Cn coronoid process, An mandibular angle, R ramus



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translation, hence function in speech, mastication, respiration, and deglutition. It is one of the most often used joints in the human body. The bony articulation is between the condyle of the mandible and the glenoid fossa of the temporal bone (Fig. 20), located directly anterior to the external auditory meatus. The condyle of the mandible at rest articulates with the articular fossa via its anterior surface. There is an intervening biconcave articular disc constructed of dense fibrocartilage. The lining of joint surfaces is not hyaline cartilage as in other synovial joints; rather, it is fibrocartilage-like material to resist the constant forces acting on the joint during mastication and speech. The capsule of the joint follows the border of the articular surfaces (Fig. 21) and is attached to the anterior and posterior poles of the intraarticular disc. The capsule is thickened laterally to form the lateral capsular ligament of the joint, preventing lateral excursion of the condyle. The congruency of the joint is improved by an intra-articular fibrocartilaginous disc. The disc is concave and sits between the condyle of the mandible and articular eminence of the temporal bone. During movement of the temporomandibular joint, the condyle rotates against the disc during the first part of mandibular depression, but then the disc and condyle together slide anteriorly along the articular eminence in the latter part of joint movement to



Normal Variation in the Anatomy, Biology, and Histology of the Maxillofacial Region



Fig. 21 Left temporomandibular joint showing the outline of the attachment of the temporomandibular joint capsule



open the mouth. This part of the joint’s movement includes protrusion of the mandible. On closing the mouth, the disc and condyle are both retracted; elastic fibers attaching the posterior aspect of the disc to the posterior border of the glenoid fossa assist the disc in retracting with the condyle. An inferior inelastic set of fibers attach the disc to the posterior border of the condyle. The capsule of the temporomandibular joint forms a collar around the neck of the mandible and surrounds the articular surface of the glenoid fossa. It is reinforced by capsular ligaments that blend with the capsule and prevent lateral dislocation of the joint. Anteriorly, the intra-articular disc is attached to the smaller superior belly of the lateral pterygoid muscle via its attachment to the capsule. This attachment maintains the articulation between the disc and condyle during protraction of the mandible, which is performed by contraction of the lateral pterygoid muscle (Mohl 1988).



Muscles of Mastication The muscles acting on the temporomandibular joint are the muscles of mastication. They enable protrusion and retraction of the mandible as well as opening and closing of the mouth via rotation of the condyle against the intra-articular disc and gliding of the condyle and intra-articular disc



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against the articular eminence. The muscles of mastication are skeletal muscles which act mainly to produce retraction and elevation of the mandible via the temporomandibular joints (Mohl 1988). The muscles must act bilaterally, as the rami and body of the mandible join the two mandibular condyles to each other. The largest of the muscles of mastication is the temporalis muscle. Its belly is fan-shaped and located in the shallow temporal fossa, overlying the squamous part of the temporal bone. The muscle fibers converge on a tendinous insertion at the coronoid process of the mandible. The coronoid process is a traction epiphysis, having its growth directed by the tensional forces of the temporalis muscle. Because of the muscle’s fan-shaped structure, the temporalis produces elevation and retraction of the mandible. The muscle is covered with taut temporalis fascia that attaches superiorly to the pericranium forming part of the scalp. It is innervated by the deep temporal nerves (mandibular division of the trigeminal nerve) and receives vascular supply from the deep temporal arteries (from the maxillary artery). For attachments, actions, innervation, and variations of the muscles of mastication, refer to Table 8. The muscles of mastication are innervated by the anterior division or trunk of the trigeminal nerve (CNV3). Their common embryological origin as part of the first branchial arch dictates this common innervation. The most powerful of this group of muscles act to elevate and retract the mandible (close the mouth) and secondarily to stabilize the joints. Figures 22, 23, and 24 show bony attachments of these muscles on the mandible. A decrease in muscle function has been reported with increasing age (Cecílio et al. 2010).



Histology of the Temporomandibular Joint The histology of the temporomandibular joint demonstrates its adaptation to function. While other synovial joints in the human body have articular surfaces lined with hyaline cartilage, the temporomandibular joint is lined with



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Table 8 Muscles of mastication and variations Muscle Temporalis



Masseter



Attachments Temporalis attaches proximally to the floor of the temporal fossa and to the overlying temporal fascia. It inserts into the coronoid process of the mandible (Baker et al. 2015) Zygomatic bone and arch and mandibular ramus and angle (lateral surface)



Medial pterygoid



Maxillary tuberosity and palatine bone, medial surface of the lateral pterygoid plate, and the medial surface of the angle of the mandible (Baker et al. 2015)



Lateral pterygoid



Upper head: Infratemporal surface and crest of greater wing of sphenoid. Lower head: Lateral surface of lateral pterygoid plate. Upper head inserts into TMJ disc and capsule, lower head into pterygoid depression of mandible (Jorge et al. 2011) Mylohyoid line of the mandible, a midline raphe, and the body of the hyoid bone (Baker et al. 2015)



Mylohyoid



Digastric



Digastric fossa of the mandible, mastoid notch of the temporal bone, and to the body of the hyoid bone via a tendinous loop



Actions Vertical fibers elevate the mandible; horizontal fibers retract the mandible (Baker et al. 2015)



Innervation Deep temporal nerves (CNV3)



Variations See the entry for masseter muscle below



Elevates and helps with mandibular protrusion and lateral movement of the mandible. Acting with medial pterygoid, it provides a dynamic stability sling for the mandible Elevation of the mandible and protrusion (working with lateral pterygoid) (Baker et al. 2015). Acting with masseter, it provides a dynamic stability sling for the mandible Unilateral contraction: Lateral movement of mandible in contralateral direction. Bilateral: Protrusion/anterior projection of mandible (Jorge et al. 2011). Upper head is involved in elevation of the mandible especially with forceful closure



Masseteric nerve (CNV3)



Deeper fibers of masseter may contribute to temporalis (Bergman et al. 2006)



Nerve to medial pterygoid (CNV3)



None to mention



Nerve to lateral pterygoid (CNV3)



Elevates the floor of the mouth and moves hyoid bone and mandible during mastication and deglutition (Baker et al. 2015)



Mylohyoid branch (CNV3)



Elevates the hyoid bone and can depress mandible



Nerve to mylohyoid (anterior belly, from CNV3), facial nerve (posterior belly, CN VII)



Opinion is mixed as to whether there is direct attachment of the upper head to the articular disc of the TMJ or indirect attachment via the capsule (Tapia et al. 2011). A third head, attaching to the disc, has been reported to exist in 22% of individuals (Jorge et al. 2011) In some individuals (rate unknown), the muscle may consist of anterior and posterior portions. The sublingual gland may protrude to some extent through the gap between the anterior and posterior parts of the muscle in these cases (Malpas 1926) The posterior belly may be fused to stylohyoid (Bergman et al. 2006)



(continued)



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Table 8 (continued) Muscle Buccinator



Attachments Pterygomandibular raphe and molar alveolar processes. This muscle inserts into the lips, labial submucosa, and cheeks, as well as orbicularis oris



Actions Produces negative pressure in the oral cavity and moves oral contents from the vestibule to the occlusal plane. Unilaterally, buccinator draws the mouth ipsilaterally (Baker et al. 2015)



Innervation (see Table 4)



Variations None to mention



Fig. 22 Bony features relevant to the muscles of mastication and the superficial muscles in situ. (Original drawing by Dr Hala Al Janaby, Perth WA, Australia)



fibrocartilaginous-like material. Due to the high stress applied to these joints through mastication, and high frequency of movement, the articular surfaces have adapted to withstand effects of these stresses. The joint is further augmented by way of a biconcave intra-articular disc. This disc increases the articular surface of the joint, thereby increasing congruence and stability (especially dynamic stability). It further serves as a shock absorber. The disc is indirectly attached to the superior fibers of lateral pterygoid via the anterior



part of the capsule. Posteriorly the disc is attached to the posterior condyle by inelastic fibers of connective tissue and to the anterior wall of the petrotympanic fissure via elastic connective tissue fibers (Fig. 25). The intra-articular disc in healthy individuals decreases in thickness with increasing age. The decrease is usually even across its mediolateral dimension, however can show perforations in the lateral and centro-lateral regions as a consequence of physiological wear (Stratmann et al. 1996).



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Fig. 23 Locations of deeper muscles of mastication and other relevant landmarks. (Original drawing by Dr Hala Al Janaby, Perth WA, Australia)



Nose and Paranasal Sinuses Gross Anatomy of the Nose, Nasal Cavity, and Paranasal Sinuses The external nose, nasal cavity, and paranasal air sinuses form part of the respiratory system. The internal surfaces of the nose, nasal cavity, and paranasal air sinuses are lined by respiratory epithelium discussed separately below. The skeletal basis of the nasal cavity is formed by the maxillary bones, nasal bones, ethmoid, concha, nasal septum, and palatine bones. The external nose is only partially based on skeletal tissue; the remainder of the scaffold being formed by elastic cartilage (Fig. 26). The lateral wall of the nasal cavity is formed by the ethmoid superiorly and the maxilla and inferior concha inferiorly. There are three bony shelves projecting into the nasal cavity from the lateral wall. These are the superior and middle conchae formed by projections of the ethmoid



bone and the inferior concha, which is a small bony process attached to the maxilla. In almost half of the population, the middle concha may itself be pneumatized containing an air cavity (Capelli and Gatti 2016). This variation is called concha bullosa. The conchae create recesses: the sphenoethmoidal recess, superior to the superior concha; the superior meatus, inferior to it; the middle meatus, inferior to the middle concha; and, finally, the inferior meatus, inferior to the inferior concha. Each of these recesses has openings for communication with paranasal air sinuses or ducts (Fig. 27). The nasal cavity is surrounded by a number of paranasal air sinuses, some of which are bilaterally symmetrical, others that are subject to quite large variation. The largest paranasal air sinuses are the maxillary sinuses. These lie on either side of the nasal cavity extending throughout the body of the maxilla. They are pyramidal in shape, with the base lying anteriorly and the apex pointing posterosuperiorly. The maxillary ostium that



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Fig. 24 The mandible from the left, showing the attachment sites of most muscles of mastication: M masseter, T temporalis, LPt lateral pterygoid, and MPt medial pterygoid



Fig. 25 Masson’s trichrome stained cross-section of a temporomandibular joint. The condyle (C), temporal bone (T), and intra-articular disc (D) can be seen in articulation. To the right of the image (the anterior aspect of the joint) is the joint capsule (Cp) and lateral pterygoid (LPt.). To the left of the image (the posterior aspect of the joint) is the external auditory meatus (EAM) in close proximity, as well as the inelastic (Ie) and elastic (E) components of the connective tissue joining the disc to the temporal bone and posterior surface of the condyle, respectively. The condyle of the mature mandible (C) may contain some remnants of



the secondary cartilaginous growth component for subsequent remodelling of condylar morphology. This component forms a larger region of the mandibular condyle in infants and children. The capsule (Cp) is composed of dense fibrous tissue, thicker in the regions that form capsular ligaments. The intra-articular disc’s (D) biconcave shape is indicated here in cross-section. With increased age, the condyle may show a progressive, irregular remodelled surface, however with cartilage of normal appearance



drains the sinuses is found on the medial aspect, opening into the nasal cavity just beneath the middle meatus. This relatively high point for drainage can lead to a buildup of fluid and inflammatory or infectious material in the maxillary sinus. In approximately 40% of individuals, there is an accessory ostium of the maxillary



sinus (Capelli and Gatti 2016). Maxillary molar roots may project into the floor of the sinus, and the bony wall may be very thin inferiorly. Within the maxillary sinus, in almost half of the population, there is a thin wall of cortical bone separating the floor of the sinus into at least two separate basins (Kazunobu et al. 2014; Qian et al. 2016).



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Fig. 26 Anterior view of the face, highlighting skeletal components of the nasal cavity and external nose. NB nasal bones, MC middle concha, IC inferior concha, and NS nasal septum



Most maxillary sinuses with septae contain only one septum (approximately 84%). Two or three septae are less common, approximately 14% and 2%, respectively (Qian et al. 2016). Most septae are found in the anterior part of the sinus, in a buccopalatal orientation. The heights of the septae also vary, with the tallest found in the medial part of the sinus (Qian et al. 2016). Anteriorly, at the inferior aspect of the frontal bones, are the frontal sinuses. These vary greatly in size and distribution in the population. Some individuals have a thin intervening wall of the bone in the midline, in others the wall deviates to one side or the other, and in others there is an uneven distribution of sinus volume bilaterally. The morphology of the frontal sinuses is so unique that they are considered useful in postmortem/antemortem comparisons for identification purposes (Beaini et al. 2015). The ethmoidal air cells similarly vary in number and relative size, but are numerous and large enough that the ethmoid bone is filled with air cells. In approximately 45% of individuals (Capelli and Gatti 2016), there are extramural ethmoidal air cells, extending into the infraorbital region. The sphenoidal sinus is located primarily in the body of the sphenoid bone and is classified into



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four types depending on its posterior wall’s relationship with the sella turcica. The extent of the sinus can be limited to the body of the sphenoid, but can extend into the greater wing and even into the basi-occiput. This can be of clinical relevance because any neurovascular structures passing over the body of the sphenoid are then in close contact with the sinus cavity and can be damaged intraoperatively. These structures include the foramen rotundum and maxillary division of the trigeminal and the foramen ovale containing the mandibular division of the trigeminal nerve (Štoković et al. 2016). The courses of the optical nerve and internal carotid artery are particularly important to determine (Güldner et al. 2012). Paranasal air sinuses are thought to warm and humidify inhaled air before it reaches the deeper respiratory passages and ultimately the lungs, as well as decreasing the mass of skeletal tissue of the face and adding to the resonance of the human voice. Each of the paranasal air sinuses has an opening to the nasal cavity on its lateral wall. The sphenoidal sinus communicates with the nasal cavity via the sphenoethmoidal recess, the posterior ethmoid air cells via the superior meatus, the frontal and maxillary sinuses via the middle meatus, and the nasolacrimal duct via the inferior meatus. The interior surfaces of all paranasal air sinuses are lined with respiratory epithelium, discussed in detail below.



Histology of Respiratory Epithelium Respiratory epithelium is the epithelium lining the respiratory tract, characterized by the presence of cilia at the apex of pseudostratified columnar cells. Goblet cells, so called because of their morphology, are also present. These produce mucin that is released to the surface by vesicles and mixes with fluid to produce mucus. All paranasal air sinuses, as well as the nasal cavity itself, are lined by respiratory epithelium (Fig. 28). In healthy individuals, the respiratory epithelium of the maxillary sinus is less than 2 mm in thickness (Capelli and Gatti 2016). A gradual transition from respiratory epithelium to epidermal lining



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Fig. 27 Lateral wall of the nasal cavity and the openings between the nasal cavity and the paranasal sinuses and air cells. (Original drawing by Dr Hala Al Janaby, Perth WA, Australia)



is found at the nares, and a transition to the simple squamous epithelial lining of the alveoli is found in the lungs. The surface area of respiratory epithelium in the nasal cavity, from the nares anteriorly to the choanae posteriorly, is approximately 120cm2 (Schrödter et al. 2003). The submucosa of respiratory epithelium is highly vascularized to warm the inspired air in the upper respiratory



tract and to facilitate gas exchange in the lower parts of the tract (Gartner 2015; Young et al. 2013). The epithelium of the middle concha shows age-related changes, and other areas of respiratory epithelium most likely show age changes as well but are not well investigated. Ciliated epithelial cells decrease with age, but there is no correlation between goblet cell density



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Fig. 28 A cross-section of respiratory epithelium showing the pseudostratified ciliated layer (Ep) with a number of goblet cells (G) and the glandular tissue (Gl) in the underlying submucosa



and activity level with age (Schrödter et al. 2003). With increased age, there is a thickening of the basement membrane of the respiratory epithelium, with a corresponding increase in thin, atrophic epithelium and squamous metaplasia in individuals over the age of 40 years (Schrödter et al. 2003).



Oral Cavity and Tongue The oral cavity has unique structures to perform functions necessary for life including speech, respiration, mastication, special sensory functions (taste), digestion, and deglutition. Anatomical changes may have an impact on these functions (Waugh et al. 2014). Healthy, well-functioning oral structures warrant a healthy balanced diet (Scardina and Messsina 2012). Nutritional disorders may have a negative impact on oral structures. Specifically, poor diet is significantly associated with increased odds of oral disease and subsequently bad oral health (Scardina and Messsina 2012). Various oral mucosal diseases can arise due to various nutritional deficiencies. For example, micronutrient deficiencies of iron, folate, and vitamin B12 may cause changes such as swelling of the tongue, papillary atrophy, and surface ulceration (Thomas and Mirowski 2010). Diet has a direct impact on the development of the oral structures. Early or late nutritional imbalances result in different



presentations. The early nutritional imbalance leads to malformations. It is important to note that nutritional imbalance in a very active period of growth may cause greater damage (Scardina and Messsina 2012; Moynihan and Petersen 2004). Vitamin and mineral deficiencies in the prenatal phase influence the development of the embryo. It affects the odontogenesis, the growth of the maxilla, oral mucosa genesis, and skull/ facial development (Scardina and Messina 2012; Moynihan and Petersen 2004). Neurological impairment increases with advanced age. Taste and smell sensitivities often decline with aging and maybe associated with a reduction of appetite as the food becomes tasteless (McKenna and Burke 2010). This decline is thought to be due to apoptosis of cells in the taste buds of the oral cavity. This may affect nutritional status, as individuals may add abundant seasoning (particularly salt or sugar that have potential harmful effects on some people), or they may prefer very hot foods, which may burn the gingiva. At the same time, there are groups of elderly with certain disorders that affect their ability to taste either as a response to the prolonged use of medications or to the course of the disease itself. Examples of these disorders include mouth, nose, or sinus infections, gingivitis and periodontitis, cancer, and chronic kidney or liver disease. Medications to manage hypertension (such as captopril), hypercholesterolemia (such as the statins), and depression may also affect the sense



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of taste (Gueiros et al. 2009; McKenna and Burke 2010).



Dental Hard Tissues Teeth are composed of three distinct mineralized tissues: enamel, dentin, and cementum. The combination and apposition of these create a structure resilient to masticatory forces. Enamel is the highest mineralized tissue in the human body, consisting mostly of an inorganic matrix, 96% by weight and 89% by volume, (Avery et al. 2002) and arranged as enamel prisms (Fig. 29). It covers the anatomical crown of the teeth and protects them from masticatory forces (Berkovitz et al. 2016). Once enamel is formed and the crown of the tooth is completed, the cells forming the enamel matrix, the ameloblasts, degenerate into the reduced enamel epithelium. This epithelium merges with the oral mucosa as the tooth emerges into the oral cavity. Enamel has no reparative and little resorptive abilities. If the tissue is damaged, it cannot be regenerated.



Fig. 29 Hardground section of a tooth (left, also with inset) and a demineralized section of part of a tooth root (right; hematoxylin and eosin stain). In the hard ground section, dentin and enamel are seen in the crown (D and E, respectively), and in the demineralized section, dentin, cementum and part of the periodontal ligament are visible



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Dentin forms the bulk of the tooth structure, 70% inorganic component by weight and 47% by volume (Avery et al. 2002), and is formed by odontoblasts that retreat as they form the dentin, leaving a cell process within the dentinal tubule they have formed (Fig. 29). Odontoblasts line the internal surface of the dentin, adjacent to the pulp, and produce dentin throughout life (Provenza 1988). Odontoblasts are able to form secondary dentin and reparative dentin in response to damage to the tooth. Secondary and reparative dentins differ in structure from initially formed dentin. Cementum lines the external surface of the root of the tooth. Its structure is similar to that of the bone, but contains less mineral than the bone and dentin (Avery et al. 2002), and it is formed by cells similar to osteocytes: cementocytes (Fig. 29). The cemental layer ends beneath the crown, at the cemento-enamel junction. In 60% of individuals, the cemental layer overlaps enamel, in 30% of individuals the cemental layer and enamel layer meet at the cemento-enamel junction, and in 10% of individuals, there is a small gap between the enamel and



(D, C, and PDL). Dentinal tubules are visible in both images (DT). The dentino-enamel junction is seen in the left image (DEJ) as well as the neonatal line (NNL) – a temporary cessation or slowing of enamel production at the time of birth



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cementum (Avery et al. 2002). Cemental thickness varies along the length of the root. It is thickest at the root tip, 150–200 μm, and thinnest near the crown, 20–50 μm (Avery et al. 2002). The initially deposited layer of cementum is acellular, and subsequent layers alternate, with some being cellular and others not (Avery et al. 2002).



Gross Anatomy of the Tongue The tongue contributes effectively to the primary functions of the oral cavity and oropharynx (Madani et al. 2014). Skeletal muscles represent the bulk of the organ (Witt and Reuter 2015). The muscular structure of the tongue and its position on the floor of the mouth, as well as its muscular attachment to the hyoid bone, mandible, styloid processes, and pharynx allow it to perform the functions of deglutition, mastication, speech, and accessory manual functions. The specialized mucosa that covers the dorsal surface of the tongue has four types of papillae (epithelial specializations): circumvallate, foliate, filiform, and fungiform. Apart from the filiform papillae, lingual papillae contain taste buds that are responsible for the delivery of the sensory function of taste (Madani et al. 2014). The ventral and lateral surfaces of the tongue have no presence of lingual papillae. The lingual frenulum attaches the inferior surface of the tongue to the floor of the mouth via a fold of mucosal tissue. The tongue has two parts, from developmentally different origins. The movable anterior two thirds is termed the oral tongue and is separated from the non-movable posterior one third (pharyngeal part) by a V-shaped groove, the sulcus terminalis, which runs anterolaterally from a small midline pit, the foramen cecum (O’Rahilly and Müller 1983). The anterior wall of the oropharynx is formed by the base of tongue and can be examined by depressing the tongue with a mirror or spatula. The submucosa has lymphatic follicles known as the lingual tonsil (O’Rahilly and Müller 1983). The tongue has bilaterally symmetrical muscles of two types, extrinsic and intrinsic.



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The genioglossus, hyoglossus, styloglossus, and palatoglossus muscles are the extrinsic muscles that move the tongue in the oral cavity. However, the superior longitudinal, inferior longitudinal, transverse, and vertical muscles are intrinsic muscles and are responsible for changing the shape of the tongue (Norton and Netter 2012). Five cranial nerves contribute to the complex innervation of the tongue. The lingual nerve (one of the terminal branches of CNV3) innervates the anterior two thirds of the tongue for general sensation and by the chorda tympani (a branch of the facial nerve, CN VII) for taste. The glossopharyngeal nerve (CN IX) supplies the posterior third of the tongue for both general sensation and taste. The internal branch of the vagus (CN X) is responsible for general sensation and taste near the epiglottis. Thus, the nerves for taste are cranial nerves VII, IX, and X (Fehrenbach and Herring 2012; Norton and Netter 2012; Madani et al. 2014; O’Rahilly and Müller 1983). Motor innervation for all of the muscles of the tongue comes from the hypoglossal nerve (CN XII), with the exception of the palatoglossus, which is supplied by the pharyngeal plexus that are fibers from the cranial root of the spinal accessory nerve carried by the vagus nerve (CN X) (Norton and Netter 2012). Palatoglossus is often considered to be a muscle of the palate, rather than the tongue. The lingual artery, a branch from the external carotid artery, is the main arterial supply of the tongue. The lingual artery passes into the tongue deep to hyoglossus. It gives off dorsal lingual branches to supply the posterior tongue. The lingual artery also supplies a branch to the sublingual salivary gland as it passes toward the tip of the tongue. There is a midline fibrous septum along the length of the tongue that prevents all but minimal arterial anastomosis across the midline. Contrary to this, lymphatic drainage of the tongue is subject to a watershed overlying the midline, meaning that lymph can drain ipsi- or contralaterally from the tongue. The lingual veins are prominently seen on the ventral surface of the tongue and ultimately drain



Normal Variation in the Anatomy, Biology, and Histology of the Maxillofacial Region



into the internal jugular vein (Madani et al. 2014; O’Rahilly and Müller 1983). The lymphatic drainage of the tongue is important in the locoregional spread of carcinoma of the tongue to the submental, submandibular, and deep cervical nodes. Extensive communications take place across the median plane (O’Rahilly and Müller 1983). The appearance of the dorsal surface of the tongue is important clinically, as it may reflect an individual’s health status. However, there are wide variations in the normal appearance of the tongue that are discussed below and that must be considered during an oral examination when assessing the presence or absence of pathology.



Ankyloglossia Commonly known as a “tongue-tie,” ankyloglossia (Fig. 30a and b) is a condition in which the tongue has limited mobility due the restriction of the lingual frenulum as a result of an increase in its size (Canaan and Meehan 2005). Clinically, individuals with tongue-tie may not be able to protrude their tongue beyond the incisors or touch the palate. As this condition appears since birth, it may interfere with breastfeeding. It has also been proposed that the limited movement of the tongue may interfere with the ability to clear food debris and therefore enhance halitosis (Madani and Kuperstein 2014). In its most severe form, this condition may cause a speech impediment. Frenectomy is the treatment of choice if required.



Fig. 30 (a) Ankyloglossia, or tongue-tie, is present from birth and often observed in childhood (a) and is usually treated before adulthood (b). (Image (a) courtesy of



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Lingual Thyroid Lingual thyroid is a rare developmental entity of an ectopic thyroid gland that appears clinically as a submucosal mass on the midposterior dorsum of the tongue close to the foramen cecum (Canaan and Meehan 2005; Madani and Kuperstein 2014). The pathogenesis of this entity is unclear. However, some authors suggest that the failure of the thyroid anlage migration during embryogenic development may lead to the evolution of this lesion. The size of the lesion may interact with the functions of the mouth. The symptoms may range from mild dysphagia to severe upper airway obstruction. Females are mostly affected than males, with a ratio ranging from 4:1 to 7:1 (Amr and Monib 2011). The diagnosis is made by history, thyroid function tests, clinical examination, and advanced imaging including computed tomography and magnetic resonance imaging. A biopsy is preferably avoided because of the risks of the hemorrhage due to the vascular nature of such lesions. Treatment options vary from levothyroxine suppression therapy, radioactive iodine ablation, and lingual thyroidectomy (Amr and Monib 2011; Gallo et al. 2001). Hairy Tongue Hairy tongue is a relatively common temporary lesion that is found in nearly 13% of the population as a result of the elongation of the filiform papillae on the dorsal surface of the tongue resulting in hairlike appearance (Fig. 31). Smoking, poor oral hygiene, xerostomia, use of antibiotics, immunosuppressive drugs,



Dr Angus Cameron, Sydney NSW, Australia, and image (b) courtesy of Professor Camile Farah, Perth Oral Medicine & Dental Sleep Centre, Perth WA, Australia)



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Fig. 31 Hairy tongue caused by an elongation of the filiform papillae on the dorsal surface. (Image courtesy of Professor Camile Farah, Perth Oral Medicine & Dental Sleep Centre, Perth WA, Australia)



radiotherapy, excess use of mouthwashes containing peroxidase, and oral candidosis are the predisposing factors (Madani and Kuperstein 2014). The lesion is primarily confined to the posterior third of the dorsal surface of the tongue. The clinical color ranges from white, yellow, and brown to black due to the overgrowth of pigmentproducing bacteria or staining from food or tobacco. There is no need for a biopsy as the diagnosis is clinically based. Treatment requires enforcement of a high standard of oral hygiene, elimination of predisposing factors, and sparing use of a toothbrush or tongue scraper to promote the desquamation of the hyperkeratotic papillae without inducing hyperkeratosis (Madani et al. 2014).



Fissured Tongue Fissured tongue is characterized clinically by grooves on the dorsum of the tongue in varying arrangements (Canaan and Meehan 2005). It is relatively common with a prevalence rate that has been reported to range from 2% to 21% among the general population (Canaan and Meehan 2005). There are three well-recognized presentations of fissured tongue: (1) a prominent median groove as the sole presentation, (2) a prominent groove with accessory grooves radiating laterally (Fig. 32), and (3) multiple grooves arranged in an irregular, circinated pattern (Canaan and Meehan 2005). A strong link



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Fig. 32 Fissured tongue. (Image courtesy of Professor Camile Farah, Perth Oral Medicine & Dental Sleep Centre, Perth WA, Australia)



between geographic tongue and fissured tongue has been observed. Interestingly, fissured tongue has been reported to be more frequent in individuals with Down and Melkersson-Rosenthal syndromes. As this lesion is part of the normal anatomical variation of the tongue, no treatment is recommended. However, patients are encouraged to brush the tongue regularly to prevent food debris from entrapping in the lingual grooves (Madani and Kuperstein 2014).



Geographic Tongue Geographic tongue, also known as erythema migrans or benign migratory glossitis, is usually asymptomatic and mostly diagnosed incidentally during routine oral examination (Madani and Kuperstein 2014). Geographic tongue is fairly common with a prevalence of 1% to 3% of the population. Females are affected more than males with a ratio of 2:1. The etiology of this lesion is unknown; however, hereditary and environmental factors may play a role. Some evidence suggests a link between geographic tongue and psoriasis (Picciani et al. 2016), but this is not a commonly accepted proposition. Geographic tongue and fissured tongue commonly occur together. Geographic tongue has a distinctive clinical appearance of well-demarcated red zones secondary to the atrophy of the filiform papillae partially or entirely surrounded by a slightly



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Fig. 33 Geographic tongue. (Image courtesy of Professor Camile Farah, Perth Oral Medicine & Dental Sleep Centre, Perth WA, Australia)



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Fig. 34 Lingual tonsil. (Image courtesy of Professor Camile Farah, Perth Oral Medicine & Dental Sleep Centre, Perth WA, Australia)



elevated white scalloped border (Fig. 33). This lesion may appear on the dorsal, lateral, and ventral surfaces of the tongue and other mucosal surfaces such as labial and buccal mucosa. Treatment is symptomatic as some patients may complain from a burning sensation or sensitivity to hot or spicy foods. The use of mouthwashes with steroids or anesthetic agents may help the patients with such symptoms.



Lateral Lingual Tonsil The lymphoid tissue under stimulating conditions undergoes hyperplasia. Hyperplastic lymphoid tissue may present as non-tender, submucosal masses with a red-yellow color. Lymphoid hyperplasia appears more often asymptomatically as bilateral swellings on the posterior-lateral tongue, related to the foliate papillae, are known as lingual tonsils (Fig. 34) (Madani and Kuperstein 2014). This lesion does not necessitate treatment unless it has large asymmetrical presentation suggestive of lymphoma, and then further evaluation and management are warranted (Canaan and Meehan 2005). Lingual Varicosities Varices are abnormally dilated veins with unknown cause and may appear in the oral cavity primarily on the ventral surfaces of the tongue (Fig. 35) (Canaan and Meehan 2005). They present clinically as tortuous red-purple nodules with a remarkable transient blanching on pressure. These lesions are seen in elderly adults. Once the



Fig. 35 Lingual veins



diagnosis is confirmed by the clinical examination, no treatment is required.



Crenation of Lateral Tongue Tongue crenations (Fig. 36) are benign, relatively common incidental findings on the tip and lateral borders of the tongue as a result of stress-related prolonged contact with adjacent teeth (Canaan and Meehan 2005). Tongue crenations may appear in patients with either macroglossia, excessive lingual version of the teeth, tongue-sucking habits, or complete dentures. Other systemic factors can cause tongue crenations such as amyloidosis, nervous disorders, or impaired lingual lymphatic drainage secondary to malignancy. If a local factor is identified, no treatment is required; however, crenations not attributed to local factors require further investigation.



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Salivary Glands Major Salivary Glands Three major paired salivary glands are located in the oro-maxillary region: the parotid glands, submandibular glands, and sublingual glands. The parotid gland is located anterior to the ear, and it has an extensive fascial covering formed by the superficial layer of investing fascia. Its duct leads anteriorly over the surface of the masseter and enters the oral cavity opposite the second maxillary molar. The submandibular gland can be found medial to the angle of the mandible at the posterior border of mylohyoid. The submandibular duct runs



anteriorly from the gland along the floor of the mouth and opens into the sublingual papilla lateral to the frenulum of the tongue. The sublingual gland lies deep to the mucosa of the floor of the mouth. Its duct joins the submandibular duct, opening into the sublingual papilla. With increasing age, saliva production may decrease and some medications may have synergistic effects causing xerostomia. Xerostomia has several adverse reactions on oral structures and eventually oral health as it exacerbates dental caries, gingival disease, halitosis, and oral infections such as candidiasis (Yap and McCullough 2015). See Table 9 for anatomy and variations of the major salivary glands (Fig. 37).



Histology of Salivary Glands and Duct Systems



Fig. 36 Tongue crenations on lateral borders of the tongue as a result of stress-related prolonged contact with adjacent teeth. (Image courtesy of Professor Camile Farah, Perth Oral Medicine & Dental Sleep Centre, Perth WA, Australia)



Salivary glands are tubuloacinar structures that secrete modified fluid into the oral and pharyngeal spaces via a duct system. The saliva-producing cells are simple cuboidal structures but appear round to triangular in a stained histological section. The saliva-producing elements (parenchyma) are supported by connective tissue septa (stroma) that also contains the blood vessels and nerves of the salivary gland. Acini are wholly mucous, wholly serous, or mixed (Fig. 38). A mixed acinus appears to have



Table 9 Major salivary gland anatomy and variations Gland Parotid



Type Serous



Saliva production 25% of all saliva



Submandibular



Predominantly serous Predominantly mucous



60% of all saliva 5% of all saliva



Sublingual



Variations The parotid gland can vary greatly in dimensions and volume between individuals. The horizontal length and depth can vary by a factor of almost 3 and the vertical dimension by a factor of approximately 2. The shape of the parotid gland is irregular (Medbery et al. 2000). An accessory parotid gland of 5–10 mm diameter can be found at an average length of 6 mm along the parotid duct from the main gland. The incidence of accessory parotid gland is between 21 and 56% in the population (Zhu et al. 2016) None to mention The duct may have a separate opening rather than joining the submandibular duct. The sublingual duct may also join the sublingual duct at its distal extreme, forming a common opening into the oral cavity (Zhang et al. 2016)



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Fig. 37 The major salivary glands of parotid, submandibular and sublingual glands. (Original drawing by Dr Hala Al Janaby, Perth WA, Australia)



serous cells in a group outside mucous cells, in a serous “demilune” which is only an artifact of tissue processing (Fig. 39). A salivary duct leaves the acinus as an intercalated duct to lead saliva toward the oral/pharyngeal surface. The intercalated ducts are lined with simple squamous epithelium and are longest in the parotid gland. These join and lead to striated ducts. The epithelium of these ducts is simple cuboidal with a mid-placed nucleus. The basal cell membrane of these cells has many infoldings, giving it a striated appearance in a good histological section. The salivary secretion is modified in this part of the ductal system. Beyond the striated ducts, saliva enters the



collecting ducts. These ducts gradually change their epithelial morphology to stratified squamous epithelium as the ducts near the oral cavity (Hellquist and Skalova 2014). Myoepithelial cells project cell processes over acini (Tamgadge et al. 2013). These cells are epithelial cells with contractile properties that are thought to aid in the movement of saliva from the acini to the ducts and have roles in salivary gland architecture, histogenesis, and pathogenesis (Gartner and Hiatt 2013; Gudjonsson et al. 2005). They are rarely seen in light microscopy because of their morphology (squamous in shape, with a number of cell projections), but a nucleus is sometimes visible adjacent to an acinus (Fig. 40).



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Minor Salivary Glands There are numerous minor salivary glands that can be found in the oral cavity. These are usually



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located in the submucosa of lining oral mucosa and in some locations underlying masticatory mucosa.



Fig. 38 This image shows a section of parotid gland (x5, hematoxylin and eosin). The distinction between supporting tissue, stroma (S), and the active producing tissue, parenchyma (P) is clear. In one septum of the stroma, a nerve – fibers grouped (N) is visible in crosssection



Functional Variations in Salivary Glands Saliva has a significant role in the human body generally, and the oral cavity in particular (Yap and McCullough 2015; Tiwari 2011; Miletich 2010). The functions of saliva include lubricating and maintaining the integrity of the oral mucous membrane, soft tissue repair, balancing pH buffering, maintenance of ecological equilibrium, maintenance of tooth integrity, and physical and immunological protection. There is supporting evidence that the structure of the salivary parenchyma changes with age and is replaced with adipose and fibrovascular tissues (Nagler 2004; Gueiros et al. 2009). Measurement of salivary flow is essential in diagnosing salivary gland hypofunction. Stimulated and unstimulated whole saliva flow rate measurements are the primary methods to quantify salivary secretion. However, other specific tests can be undertaken and are discussed in the chapter on ▶ “Salivary Gland Disorders and Diseases.” There is variability in the threshold of salivary production among various populations and age groupings. Nonetheless, hyposalivation is classically defined as an



Fig. 39 The image above shows a section of submandibular gland (x20, hematoxylin and eosin) in which can be seen a mixed acinus (circled, MA) with a serous demilune surrounding mucous cells, an intercalated duct (ID) and



two (or possibly two parts of the same) striated duct (SD). Striations in the basal part of the duct lining cells can be seen in the left striated duct, at approximately the 5 o’clock to 7 o’clock position



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(Gueiros et al. 2009). Local and systemic diseases, medications, head and neck radiation, and chemotherapy severely affect saliva production (Yap and McCullough 2015). Recognizing the functional variations of salivary glands helps to better understand the health and disease of the oral cavity.



Histology of Oral Tissues



Fig. 40 Hematoxylin and eosin stained section of several mucous acini (MA). (Image courtesy of Professor Camile Farah, UWA Dental School, University of Western Australia, Perth WA, Australia)



unstimulated whole saliva values below 0.1 ml/ min and a stimulated salivary flow below 0.5 ml/ min, which corresponds to a 40–50% diminution of salivary gland secretion (Flink et al. 2005; Inoue et al. 2006). Although salivary flow is said to diminish as an age-related process, salivary production in healthy elderly patients remains stable (Tiwari 2011; Miletich 2010). Gender and weight can influence salivary flow as these factors are correlated with the size of salivary glands (Bergdahl 2000). Male and overweight healthy subjects have larger major glands and subsequently have higher salivary flow (Miletich 2010; Inoue et al. 2006). Increased body mass index is associated with larger salivary glands and increased salivary flow (Inoue et al. 2006). Gender-related salivary flow variations become more obvious with aging and beyond the age of 55 (Bergdahl 2000). It is important to note that hormonal changes in postmenopausal females reduce unstimulated salivary flow remarkably. However, controversy surrounds the impact of menopause on saliva production (Inoue et al. 2006; Eliasson et al. 2003). Interestingly, the use of hormone replacement therapy in postmenopausal females results in recovery of salivary flow (Eliasson et al. 2003; Laine and Leimola-Virtanen 1996). The qualitative and/or quantitative changes in saliva have a direct impact on the quality of life



Oral mucosa consists of a specialized epithelium lining the surfaces of the oral cavity. It is a stratified squamous epithelium, either keratinized, nonkeratinized, or parakeratinized, and protects the oral cavity from mechanical, microbial, and chemical damage (Winning and Townsend 2000). Keratinization of epithelium in the oral cavity protects the mucosa from potential injury from food items (Ciano and Beatty 2015), both physical and thermal injury. These regions are called masticatory mucosa, as opposed to the other regions that do not come into direct first contact with food and are covered by nonkeratinized lining mucosa, which is less resistant to damage, but more distensible (Winning and Townsend 2000). Parakeratinized epithelium retains nuclei in the superficial layers. This epithelium is common in gingival epithelium (Winning and Townsend 2000). The high turnover rate of cells in the oral mucosa, although variable between different parts of the oral cavity, is also a protective mechanism. Areas covered in masticatory mucosa include the hard palate, attached gingiva, and the anterior two thirds of the dorsum of the tongue (excluding the fungiform papillae). Lining mucosa is nonkeratinized and has submucosa deep to the lamina propria in most regions. Non-epithelial cells found in the mucosal epithelium include melanocytes, Langerhans cells, Merkel cells, and lymphocytes (Winning and Townsend 2000). More broadly, the epithelial layer is arranged into ridges and troughs against the underlying lamina propria. These papillae give mechanical strength to the oral mucosa by increasing the surface in contact between the epithelium and lamina propria. They are more numerous in masticatory mucosa compared with lining mucosa (Table 10).



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Table 10 Regional variations in oral mucosa and minor salivary glands (Berkovitz et al. 2016; Fehrenbach and Popowics 2015; Roed-Petersen and Renstrup 1969; Hiatt and Gartner 2010) Region Alveolus Hard palate



Mucosa type Nonkeratinized lining, thin mucosa Thick, keratinized, masticatory mucosa: 310  50 μm (Winning and Townsend 2000)



Lamina propria Short or absent



Minor salivary glands Seromucous



High number of connective tissue papillae (Ciano and Beatty 2015) 1.5 to 2.5 times more connective tissue papillae per mm2 compared with lining mucosa (Winning and Townsend 2000)



Pure mucous



Soft palate



Nonkeratinized, lining



Short papillae



Pure mucous



Floor of mouth



Nonkeratinized, lining, thin mucosa: 190  40 μm (Winning and Townsend 2000)



Low number of short, broad connective tissue papillae (seven times less per mm2 than in masticatory mucosa) (Winning and Townsend 2000)



Seromucous (Hand et al. 1999)



Vermilion zone Buccal mucosa



Keratinized, but thin



Labial mucosa



Gingiva



Nonkeratinized lining, thick mucosa: 580  90 μm (Winning and Townsend 2000). Ectopic sebaceous glands may be found in 80% of adults (Winning and Townsend 2000) Nonkeratinized, lining. Upper labial mucosa may contain ectopic sebaceous glands found in 80% of adults (Winning and Townsend 2000) Keratinized, masticatory epithelium – Gingiva facing oral surface. Crevicular gingiva is nonkeratinized sulcular gingiva (Winning and Townsend 2000). Attached gingiva appears pitted because of collagen fibers attaching the gingiva to underlying bone. The gingival sulcus between 0.5 and 2 mm



Submucosa Mobile Absent in midline – Lamina propria attaches to periosteum of hard palate (mucoperiosteum). Fat present in the posterolateral regions alters the color (Winning and Townsend 2000) Presence of varying amounts of fatty tissue alters the color (Winning and Townsend 2000) Loose submucosa



None High level of collagen organization (Ciano and Beatty 2015)



Mixed (predominantly mucous)



Varying amounts of fatty tissue alter the color (Winning and Townsend 2000)



High number of rete ridges in the region of incisors (Ciano and Beatty 2015)



Mixed (predominantly mucous)



Firm attachment to the underlying muscle tissue



Low number of rete ridges in the region of the incisors in lingual gingiva (Ciano and Beatty 2015). Attached gingiva has long, narrow papillae



None



Indistinguishable in attached gingiva



(continued)



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Table 10 (continued) Region



Tongue (ventral) Tongue (dorsal)



Mucosa type



Lamina propria



Minor salivary glands



deep in healthy individuals and is mildly inflamed due to the presence of oral microflora (Winning and Townsend 2000) Nonkeratinized, lining



Short, numerous papillae



Seromucous



Long papillae



Anterior: Mixed – Predominantly mucous Posterior: Pure mucous Circumvallate papillae: Pure serous



Specialized, see section on tongue



Submucosa



Indistinct. There is strong attachment to the underlying muscle Indistinct. There is strong attachment to the underlying muscle



Fig. 41 Mucosa of the hard palate and maxillary gingiva. Note the range of colors in the mucosa of the hard palate; presence of fatty tissue laterally gives a yellow appearance



Fig. 42 Mucosa of the floor of the mouth and gingiva, with some labial mucosa visible. Note the delicate blood vessels in the thin mucosa of the floor of the mouth-lining mucosa



A submucosa underlies the lamina propria in some regions of the oral cavity. Healthy oral mucosa is pink because the epithelium is semitransparent and the underlying connective tissue is well vascularized. Variations in epithelial thickness, subepithelial edema, connective tissue vascularization, and fiber thickness can cause clinical color changes (Berkovitz et al. 2016). Examples of healthy appearing oral mucosa can be seen in Figs. 41 and 42. Changes to the oral mucosa with aging are often unrecognizable; however aging makes the



mucosa more susceptible to local trauma and oral diseases. Age-related hyposalivation may alter the clinical appearance of oral mucosa substantially (Yap and McCullough 2015; McKenna and Burke 2010).



Dental Pulp Histologically, dental pulp resembles connective tissue, but it has two unique features; the first being that odontoblasts produce a layer between



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Fig. 43 This high power hematoxylin and eosin stained decalcified section of the pulp cavity shows the dentin of the tooth (D), including interglobular dentin (IgD) and predentin (PD) which is yet to be mineralized. Immediately



adjacent to the predentinal layer is the odontogenic zone (OgZ), comprised of odontoblasts. Deeper within the pulp tissue are fibroblasts (F), collagen fibrils (C), and blood vessels (BV)



the pulp and dentin, and the second is that this connective tissue is almost completely surrounded by hard tissue (dentin), making the normal inflammatory process a cause of pulp necrosis due to lack of space for swelling and edema (Fehrenbach and Popowics 2015) (Fig. 43). With increasing age, there is reduction in the size of the pulp chamber due to the continual production of dentin. This creates a change in the arrangement of the odontoblasts to a pseudostratified appearance, with histomorphometry changing from columnar cells to ovoid shorter cells (Daud et al. 2016). Pulp cell density also decreases with increasing age in both the crown and the root. The last cell population to decrease in density are coronal odontoblasts. Their density decreases after a decrease in fibroblast and subodontoblast densities (Daud et al. 2016).



thickness (Avery et al. 2002). This thickness decreases with increasing age. The periodontal ligament is highly vascular and has a rich nerve supply. It consists of collagen fibers organized into thick fibrous bands, arranged into distinguishable groups: oblique, apical, and horizontal fibers, alveolar crest fibers, and also interradicular fibers in multi-rooted teeth (Berkovitz et al. 1995). Odontogenic epithelial rests of Malassez can be found throughout the periodontal ligament, forming a “fishnet stocking” structure around the root. These cells, left after tooth formation, seem to prevent tooth ankylosis and certainly play a role in developing inflammatory odontogenic cysts.



Periodontal Ligament The periodontal ligament is the connective tissue found between the cementum of a tooth and the alveolar bone of the tooth socket (Fig. 44). Its function is partly to act as the periosteum of the alveolar bone. Although of uniform thickness, the periodontal ligament component of the tooth complex ranges from 0.15 mm to 0.38 mm in



Tongue The epithelium of the tongue is multifunctional. This is reflected in its composition and arrangement. The oral part (anterior two thirds) of the dorsum of the tongue is in contact with food and other items placed in the mouth. The mucosa on this part of the tongue forms a multitude of keratinized filiform papillae that aid in this gripping and protective function (Figs. 45 and 46). The keratinized layer helps to protect the tongue from abrasion and to some extent extreme



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Fig. 44 This high power hematoxylin and eosin stained decalcified section shows the periodontal ligament (P) attaching two teeth (on either side of the image) to alveolar bone (A). Cementum (C) and cementocyte lacunae can be seen covering the dentin (D) of the tooth on the left of the image. Epithelial rests (Er) can be seen within the periodontal ligament



Fig. 45 Dorsal surface of the tongue showing (a) keratinized filiform papillae; (b) slightly larger, nonkeratinized fungiform papillae; and (c) the chevron-shaped row of circumvallate papillae



Fig. 46 Hematoxylin and eosin stained section of the dorsal surface of the tongue showing keratinized filiform papillae (Fi) and nonkeratinized fungiform papillae (Fu) of the dorsum of the oral part of the tongue



temperature. Interspersed among the filiform papillae are slightly larger, nonkeratinized fungiform papillae (Figs. 45 and 46). These contain a small number of taste buds.



The dorsal surface of the posterior pharyngeal third of the tongue has glandular and lymphoid tissue deep to its epithelial surface, giving it a bumpy appearance.



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Separating the anterior two thirds and posterior one third is the sulcus terminalis and foramen cecum – a remnant of the migratory path of the thyroid gland. Immediately anterior to this is the chevron-shaped row of circumvallate papillae (Figs. 45 and 47). There are approximately 12 to 14 of these, and they are large enough to be easily distinguished with the naked eye. Histologically, these papillae have quite a number of taste receptor cells in their walls, as well as von Ebner glands, to produce fluid that flushes molecules away from the papilla’s furrow so that new taste molecules can enter. Taste perception is facilitated by receptors (T2R for bitter taste, T1R for sweet and umami taste, and vanilloid receptor TRPV1 for salty taste), ion channels (PKD1L3 and PKD2L1 for sour taste), and epithelial sodium channels (for salty taste). Genetic variation in these taste receptors (and therefore interindividual variation in taste perception) may be linked to diet and food choices, influencing nutritional and health status (Garcia-Bailo et al. 2009). Previously different regions of the dorsal surface of the tongue have been ascribed to the different tastes, sweet, bitter, sour, salty and umami. However, more recent evidence (Chandrashekar et al. 2006) supports the notion that taste buds consists of a variety of taste receptors cells capable of sensing all of the separate tastes, and this is not region specific. Fig. 47 Hematoxylin and eosin stained cross section of the dorsum of the tongue showing a circumvallate papilla (CV) with taste buds (Tb) in its lateral wall and a Von Ebner’s gland duct (VE) in the adjacent epithelial wall. Numerous serous acini are visible in the lower third of the image



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The final papilla type can be seen on the lateral surface of the tongue, the foliate papillae. There are a number of vertical grooves on the surface of the tongue. Foliate papillae also contain taste buds. The ventral surface of the tongue is covered with thin nonkeratinized lining mucosa, beneath which blood vessels are visible.



Lips While the core of both lips is mainly formed from skeletal muscle, the lip can be divided into three histological portions depending on their anatomical location (Fig. 48). The outer surface is covered by hairy skin, and sweat glands can be found in the dermis; the inner surface is covered by nonkeratinized mucosa and minor salivary glands replace the sweat glands. Finally, the vermilion zone is located between the two surfaces, it being covered by keratinized stratified squamous epithelium, rich in capillaries and free of both sweat and minor salivary glands (Kumar 2014).



Tonsillar Tissue Tonsillar tissue forming Waldeyer’s ring has an epithelial covering, folded into crypts or



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Tissue Spaces of the Maxillofacial Region Fascial Layers and Spaces of the Head and Neck



Fig. 48 Hematoxylin and eosin stained cross section of the lip showing epithelial types: epidermis (Ep), vermilion zone (Vz), and oral (lining) mucosa (Om). The muscle (M) orbicularis oris is also shown, as well as a hair follicle (Hf) and glandular tissue (G)



grooves. Tonsils contain a number of cell types, including lymphocytes, plasma cells, macrophages, and reticular cells, as well as extravasated erythrocytes and interdigitating cells (Perry 1994; Avery et al. 2002). The crypt lumina contain desquamated epithelial cells, bacteria, as well as living and dead lymphocytes. Encapsulation of the tonsil by a fibrous tissue capsule prevents the spread of any infection (Young et al. 2013). The epithelium of the palatine tonsil is covered by a 15–20 cell layer of non- or parakeratinized mucosa (Perry 1994). The crypts of the palatine tonsil are lined with nonuniform epithelium, with patches of stratified squamous and reticulated epithelium. Stratum spinosum cells are interspersed with non-epithelial cells, and the surface of the reticulated epithelium is stratified squamous but is interrupted by areas where non-epithelial cells pass into the crypt lumen.



The head and neck contain a number of fascial layers that surround structures and lie at the interface of movable components and so prevent friction from affecting the components in question. Where fascial layers lie adjacent to each other, they form potential spaces. These fascial spaces are of clinical relevance because they can both prevent and facilitate the spread of infections. Fascial compartments are also prone to compression when fluids and infectious substances accumulate within them. These are important in the head and neck region because of the respiratory passages that are present, as well as the conductive fascial spaces that lead to the middle and posterior mediastinum of the thorax. Knowledge of the extent, contents, and communications between these fascial spaces can aid in differential diagnosis of infections and masses palpated in the head and neck region (Shrestha et al. 2011; Warshafsky et al. 2012) The external-most layer of the neck fascia is the investing layer. It has some bony attachments inferiorly and superiorly. The investing layer of fascia can be imagined as a collar that surrounds the structures in the neck. It splits into a superficial and deep layer to surround the sternocleidomastoid, parotid gland, and trapezius. All other fascial layers are deep to this investing layer. The anterior-most of these is the pretracheal layer that contains the trachea and main bronchus more inferiorly, the esophagus, and the infrahyoid muscles. Note that the prefix “pre-” is used to denote fascia that surrounds structures named in the suffix. Sometimes the layer surrounding the muscles is referred to separately as the muscular layer and the layer surrounding the tubes as the visceral layer. The posteriormost fascial compartment is the prevertebral fascia that surrounds the pre- and post-vertebral muscles, the cervical spine, and the spinal cord. Components of these three fascial compartments combine to form the neurovascular compartment of the neck, the carotid sheath itself considered to be a fascial compartment. The carotid sheath contains the common



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carotid artery and its branches, the internal jugular vein, and the vagus nerve. Note that the vein is in the external-most orientation within the fascial layer due to its need to expand considerably in volume. The fascial spaces connected by these layers communicate with each other as well as distant anatomical compartments. These communications are part of what makes these compartments clinically important. Infections that are most commonly odontogenic in nature can spread by direct methods through these anatomical tissues and structures or indirectly using fascial compartments as infection routes. Where these compartments communicate with organs essential to life or are able to be constricted by products of infection and thereby compress essential anatomical structures, infections can be immediately lifethreatening. Three of the spaces in the head and neck region are considered to be particularly clinically relevant: the submandibular, lateral pharyngeal, and retropharyngeal-danger-prevertebral spaces (Reynolds and Chow 2007).



Retropharyngeal Spaces



Submandibular Space



Lymphatic Drainage of the Head and Oral Structures



The submandibular space is bounded by the body of the mandible and subdivided into two compartments separated by mylohyoid: the superior sublingual compartment and the inferior submylohyoid compartment. These two compartments communicate with each other at the posterior free border of mylohyoid. The submandibular space also communicates posteriorly with the parapharyngeal space through a gap created by the course of styloglossus through the pharyngeal constrictors.



Lateral Pharyngeal Space The lateral pharyngeal space is found, as the name suggests, lateral to the pharynx, specifically the buccopharyngeal fascia overlying the superior constrictor. It is medial to the mandible and medial pterygoid and parotid gland. The space is limited inferiorly at the hyoid bone and by the sphenoid bone superiorly. Posteriorly the space communicates directly with the retropharyngeal space.



The retropharyngeal space lies between the posterior pretracheal fascial layer and the anterior prevertebral fascial layer. The deep cervical lymph nodes are located bilaterally in the retropharyngeal space. Anteriorly, the prevertebral layer splits to create yet another fascial space – the danger space. The danger space extends from the base of the skull through to the posterior mediastinum to the level of the diaphragm. The prevertebral space encompasses the musculature surrounding the cervical spine and vertebral complex including the spinal cord. The three spaces, although delineated by fascia, readily communicate and allow for the spread of infections beyond the head and neck. Infections involving these spaces can lead to descending necrotizing mediastinitis (hence the term “danger” space given to the retropharyngeal spaces), involvement of the pericardium and/or pleural cavity, and even widespread retroperitoneal necrosis (Reynolds and Chow 2007).



The immune system includes the lymphatic component, composed of a network of lymphatic vessels and aggregates of lymphoid tissue known as lymph nodes (Fehrenbach and Herring 2012) (Fig. 49). An oral health care practitioner should have the competency to examine carefully for any palpable lymph nodes of the head and oral structures. The lymph nodes have the primary function of filtering interstitial fluids. They also produce lymphocytes that have a significant role in combating infections. Lymph vessels are present in most tissues, including dental pulp. Understanding the mechanical distribution of these vessels and the flow direction of lymph may help in the diagnosis of oral infections and potentially can be used to slow cancer spread (Fehrenbach and Herring 2012). The lymph nodes have a particular arrangement, stellate in small, interconnected clusters (Fehrenbach and Herring 2012). As each group of nodes drains fluids from designated anatomical locations,



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Fig. 49 Locations and relations of the cervical lymph nodes. (Original drawing by Dr Hala Al Janaby, Perth WA, Australia)



lymph nodes play a significant role in combating infections in these sites of the body. In the node, lymphocytes actively start fighting the infection. As a consequence, lymph nodes enlarge and are tender. In the case of strong control of the infection, the node will eventually subside. The opposing scenario is that the node fails to confine the infection, and it spreads through that lymph node or nodes to the next-proximal node or group of nodes (Fehrenbach and Herring 2012; Snell 2012).



Retropharyngeal Nodes Retropharyngeal nodes locate behind the upper part of the pharynx and in front of the arch of the



atlas, sitting in the buccopharyngeal fascia. They receive drainage from the nasal cavities, the nasal part of the pharynx, and the auditory tubes, and subsequently these drain to the superior deep cervical nodes. These nodes are commonly involved in throat infections (Fehrenbach and Herring 2012).



Submental Nodes The submental nodes are a small cluster of nodes and found inferior to the border of the chin. These nodes receive lymphatics from the mandibular incisors, the tip of the tongue, and the midline of the lower lip and chin. Tenderness and enlargement of



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these nodes are associated with any infection from the drained sites. These nodes tend to drain to the submandibular nodes or directly to the lower deep cervical nodes (Fehrenbach and Herring 2012; Waugh et al. 2014).



Submandibular Nodes The submandibular nodes are distributed around the submandibular gland near the ramus of the mandible and the commissures of the mouth. The easiest way to locate the gland and the nodes is to place a finger on the inferior border of the mandible near the angle. Run the finger back and forth until you feel the depression in the inferior margin of the mandible. Just medial to this depression is the submandibular gland, and the submandibular lymph nodes are grouped around it (Fehrenbach and Herring 2012). Lymphatics from all of the maxillary teeth and the maxillary sinus, the mandibular canines and all mandibular posterior teeth, the floor of the mouth and most of the tongue, the hard palate, the soft tissue of the buccal area, and the anterior nasal cavity are drained to this group of lymph nodes. Further, the submental nodes may drain to these nodes. Therefore, enlargement and tenderness of the submandibular nodes due to infections are relatively common as they receive lymph from many anatomical sites (Fehrenbach and Herring 2012; Waugh et al. 2014).



Upper Deep Cervical Nodes The upper deep cervical nodes are a group of lymph nodes that receive lymphatics from other groups of lymph nodes including the submandibular nodes, the retropharyngeal nodes, and the parotid nodes and from the third molar regions, the base of the tongue, the tonsillar area, the soft palate, and the posterior nasal cavity region. This important group of nodes is distributed on the lateral surface of the internal jugular vein and lie just deep to the anterior margin of the sternocleidomastoid muscle, about 2 inches below the ear (Fehrenbach and Herring 2012; Agur and Grant 2013).



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Lower Deep Cervical Nodes The lower deep cervical nodes drain the upper deep cervical nodes and many of the nodes of the posterior neck frequently referred to as occipital nodes, as well as glands in the anterior neck. This group of nodes is located on the lateral surface of the internal jugular vein and deep to the anterior margin of the sternocleidomastoid muscle. They are found superior to the clavicle. The lymphatic fluid drains from the lower deep cervical nodes to the junction of the subclavian and internal jugular veins (Fehrenbach and Herring 2012; Agur and Grant 2013).



Pharynx and Larynx Waldeyer’s Ring At the junction between the oral and nasal cavities and the oro- and nasopharynx are groups of lymphoid tissue, in the form of a circular band (Waldeyer’s ring). Tonsils forming Waldeyer’s ring are the lingual, palatine, pharyngeal, and tubal tonsils. The lingual tonsil is formed by the lymphoid follicles in the mucosa of the posterior third of the tongue. The palatine tonsil is located between the palatoglossal and palatopharyngeal folds, the tonsillar fossa. The floor of the fossa is formed by the superior constrictor of the pharynx. The fossa’s immune activities are improved by the presence of between 10 and 30 tonsillar crypts/infoldings of the epithelium (Perry 1994). The pharyngeal tonsil sits high on the posterior wall of the nasopharynx. It is particularly prominent in children and may affect breathing if hypertrophy is severe, leading to a characteristic facial expression (“adenoid face”) and altering the physical structure of the oral region (Nishimura and Suzuki 2003). The tubal tonsil is located around the opening of the auditory tube in the lateral wall of the nasopharynx. It consists of lymphoid tissue in the mucosa surrounding the cartilaginous auditory tube.



Normal Variation in the Anatomy, Biology, and Histology of the Maxillofacial Region



Gross Anatomy of the Pharynx and Larynx Including Anatomical Variations The neck has unique structure and geometry as it extends from the skull base and inferior mandibular margin to the superior thoracic aperture and includes relevant anatomical tissues and organs: the pharynx, larynx, trachea, esophagus, thyroid gland, and parathyroid glands (Fehrenbach and Herring 2012; Agur and Grant 2013). Several health problems can affect the neck including neck spasm and pain, whiplash, herniated disc, muscle sprain, laryngitis, airway obstruction, vocal cord polyps, primary and metastatic cancer, and other neoplasms. The neck contains seven vertebrae called the cervical vertebrae. They are the smallest and uppermost vertebrae in the body. The first cervical vertebra (atlas) articulates with the skull. The second cervical vertebra (axis) has an odontoid process that articulates anteriorly with the atlas and inferiorly with the third cervical vertebra (Fehrenbach and Herring 2012; Norton and Netter 2012; Agur and Grant 2013). The neck also has striking external feature, the laryngeal prominence that is commonly known as Adam’s apple. It is more evident in males than in females. At the level of the third cervical vertebra, there is mobile, disconnected bone known as hyoid bone that provides anatomical support to other muscles and ligaments that function during swallowing, mastication, and speech (Fehrenbach and Herring 2012; Agur and Grant 2013). There are two cervical muscles: sternocleidomastoid and trapezius (Fehrenbach and Herring 2012; Agur and Grant 2013). The major arterial supply comes from the carotid and subclavian arteries. The venous drainage is inconsistent and mostly to the internal, external, and anterior jugular vein (Norton and Netter 2012). The neck is richly innervated with motor and sensory nerve branches. The large bones and muscles in the neck divide it into anterior and posterior cervical triangles that can be subdivided into smaller triangles (Fehrenbach and Herring 2012; Agur and Grant 2013). The pharynx (throat) has a principle contribution to the functions of digestion and respiration. This 5-inch muscular



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tube connects the mouth and the nose to the esophagus and larynx. By doing so, it helps to regulate the passage of food and air (Norton and Netter 2012). It extends from the skull base to the lower border of the cricoid cartilage and is divided into three parts: the most superior, the nasopharynx, is involved only in breathing and speech. The other two parts, the oropharynx and the laryngopharynx, are used for both breathing and digestion. The pharynx is composed of the following structures: three constrictor muscles, three longitudinal muscles, cartilaginous part of the pharyngotympanic tube, and soft palate (Norton and Netter 2012; Agur and Grant 2013). The wall of the pharynx has five layers (inner to outer): mucous membrane, submucosa, pharyngobasilar fascia, muscular, and buccopharyngeal fascia (Norton and Netter 2012; Agur and Grant 2013; Waugh et al. 2014). The pharynx is richly vascularized and receives the arterial supply from the ascending pharyngeal, ascending palatine, tonsillar, pharyngeal arteries and superior and inferior thyroid arteries (Norton and Netter 2012). The pharyngeal plexus is responsible for the venous drainage of the pharynx. The motor and sensory innervation of the pharynx is by the pharyngeal branch of the glossopharyngeal nerve, the pharyngeal branch of the vagus nerve, and the cranial part of the spinal accessory nerve (Norton and Netter 2012; Waugh et al. 2014). The larynx has a significant role in connecting the pharynx to the trachea to prevent the entry of foreign bodies to the airways. It is also called the voice box as the larynx produces vocal sounds (phonation). Other functions of the larynx include coughing, the Valsalva maneuver, control of ventilation, and acting as a sensory organ (Fehrenbach and Herring 2012; Norton and Netter 2012; Agur and Grant 2013). The larynx is shorter in women and children than males and adults. Structurally the larynx has three large, unpaired cartilages (cricoid, thyroid, epiglottis), three pairs of smaller cartilages (arytenoids, corniculate, cuneiform), extrinsic and intrinsic ligaments, and muscles (cricothyroid, thyroarytenoid, posterior cricoarytenoid, lateral cricoarytenoid, transverse arytenoid, oblique arytenoid, aryepiglottis, thyroepiglottis) (Norton and Netter 2012; Waugh et al. 2014). Superior and inferior laryngeal arteries



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and veins are responsible for the blood supply (Norton and Netter 2012; Waugh et al. 2014). The anatomical structure of the larynx has four cavities (laryngeal cavity, laryngeal ventricles and saccules, rima vestibuli and rima glottidis, and piriform recesses) that facilitate the functions of the larynx (Norton and Netter 2012; Agur and Grant 2013). The lymphatic vessels that drain above the vocal folds drain to the deep cervical lymph nodes at the bifurcation of the common carotid artery. However, the lymphatic vessels that drain below the vocal folds drain to the upper tracheal lymph nodes (Agur and Grant 2013; O’Rahilly and Müller 1983).



Histology of Pharyngeal Mucosa The pharyngeal mucosa is a stratified squamous nonkeratinized epithelium that lines an elastic fibrous connective tissue; these elastic fibers are oriented longitudinally (Gartner 2015) and allow for distension of the pharynx when swallowing a solid or liquid bolus and also enable recoil of the tissue afterward to prevent obstruction of the gastrointestinal or respiratory tracts.



Histology of the Thyroid The thyroid, like other glands in the human body, contains mainly cuboidal simple secreting epithelium forming a follicle, but no ducts. The hormone secreted is stored in cavities and then absorbed into luminal spaces as colloid (Gartner 2015; Witt and Reutter 2015).



Fig. 50 The right orbit showing skeletal components: yellow – maxilla, pink – frontal bone, green – zygomatic bone, red – ethmoid, purple – lacrimal bone. G– greater orbital fissure, O – optic canal both within the sphenoid bone, NC – nasal cavity



The extraocular muscles are responsible for positioning the globes of the eye for functional vision. There are six distinct muscles for each eye: superior and inferior rectus muscles, medial and lateral rectus muscles, and the superior and inferior oblique muscles. These muscles are under somatic afferent control by cranial nerve IV (superior oblique), cranial nerve VI (lateral rectus), and cranial nerve III for the rest. The muscles all originate from a common tendon at the posterior aspect of the cone-shaped orbital cavity and then diverge to attach at various points around the globe of the eye (Kels et al. 2015).



Orbits Gross Anatomy of the Orbits



Vascular Supply of the Maxillofacial Region



The orbits form the containers for the eyes; extraocular muscles; optic, oculomotor, trochlear, and abducens nerves; lacrimal apparatus; and supporting tissues (Fig. 50). Each of the orbits is formed by the frontal bone, maxilla, lacrimal bone, zygomatic bone, ethmoid bone, and the greater and lesser wings of the sphenoid.



The head and neck are supplied by three main branches of the brachiocephalic trunk of the aorta on the right and the vertebral and common carotid branches of the aorta on the left (Gray et al. 1995). Orofacial structures are supplied by four main branches of the external carotid artery: the facial,



Normal Variation in the Anatomy, Biology, and Histology of the Maxillofacial Region



lingual, maxillary, and superficial temporal branches (Fig. 51). There is extensive vascular anastomosis in the orofacial region, and supply to any particular tissue is not hampered by the blockage or hemorrhage in just one vessel. The right common carotid (shorter than the left) arises from the brachiocephalic trunk, whereas the left originates directly from the aorta. This difference in origin is a consequence of embryological development.



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The common carotids ascend in the neck to the level of the superior border of the thyroid cartilage, where they divide into the external and internal carotids. At this level is the carotid sinus, a baroreceptor. On the internal wall of the artery at its bifurcation is the carotid body, a chemoreceptor. The external carotid is one of the branches of the bifurcation of the common carotid and begins its course at the level of L3/L4 intervertebral disc.



Fig. 51 The vascular supply of the maxillofacial region. (Original drawing by Dr Hala Al Janaby, Perth WA, Australia)



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The external and internal carotids are located in the carotid sheath, deep to the sternocleidomastoid muscle. The external carotid ultimately passes posterior to the angle of the mandible and anterior to the mastoid process to reach the parotid gland, within which it divides into its two terminal branches: the maxillary and superficial temporal arteries. The branches of the external carotid innervating orofacial structure are the facial artery, the lingual artery, and the superficial temporal artery.



The Facial Artery The facial artery branches from the external carotid artery at the greater horn of the hyoid bone. It courses anteriorly, crossing the border of the body of the mandible at the anterior border of masseter to reach the face. The artery’s pulse can be felt as it crosses the border of the mandible. The artery then travels obliquely superiorly to reach the angle between the eye and external nose. Here it supplies the lacrimal gland and anastomoses with the external nasal artery of the ophthalmic artery. It was once thought that the artery had a torturous course, but this is probably due to its appearance in cadaveric dissections. Occasionally there is a more superior origin of the facial artery (just inferior to the maxillary artery), and it then runs through the parotid gland to reach facial tissues. Even less frequently it may branch together with the lingual artery as the linguofacial trunk (Mangalgiri et al. 2015). The facial artery’s branches supply structures in the pharynx as well as the lower lip and chin, soft palate, and external nose.



The Lingual Artery The lingual artery is the main supply to the tongue and floor of the mouth. It enters the tongue at the root and branches into superior and inferior lingual arteries, supplying tongue musculature and overlying mucosa. Small branches from the



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lingual artery have been found to enter the superior genial spine foramen of the mandible (Jacobs et al. 2007), and this is an important consideration for implant surgery in the anterior mandible.



The Maxillary Artery The maxillary artery is one of the terminal branches of the external carotid artery. It arises within the parotid gland and eventually courses medially over lateral pterygoid before entering the pterygopalatine fossa. Variations of this have the artery coursing either between the superior and inferior heads of the lateral pterygoid or inferior to it. The course through the lateral pterygoid is used to divide the artery into three artificial sections: the first prior to lateral pterygoid, the second over lateral pterygoid, and the third beyond the lateral pterygoid. There are five branches from each of these three sections of the maxillary artery. These branches can be thought of as an aid to memory; the first part gives off bony branches, the second muscular branches, and the third nervous branches (Fig. 52). The largest branch of the first part is the middle meningeal artery. This artery enters the cranial cavity via the foramen spinosum together with the meningeal branch of the trunk of the mandibular division of the trigeminal nerve. Other branches are the anterior tympanic artery, the deep auricular artery, the accessory meningeal artery, and the inferior alveolar artery, which enters the mandibular foramen with the inferior alveolar nerve. Branches arising from the second part of the maxillary artery are the three temporal branches, medial pterygoid artery, masseteric artery, and buccal artery. The third part of the maxillary artery is within the pterygopalatine fossa. It gives off the posterior superior alveolar branch, infraorbital artery, greater palatine artery, pharyngeal artery, and artery of the pterygoid canal. All arteries branching from the maxillary within the pterygopalatine fossa accompany nerves. The final continuation of the maxillary artery is the sphenopalatine artery that enters



Normal Variation in the Anatomy, Biology, and Histology of the Maxillofacial Region



Fig. 52 The maxillary artery and its branches. (Original drawing by Dr Hala Al Janaby, Perth WA, Australia)



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the nasal cavity and divides into posterior medial and lateral nasal branches to supply mucosa of the nasal septum as well as the paranasal air sinuses and conchae of the lateral nasal cavity.



The Superficial Temporal Artery This is the other terminal division of the external carotid artery within the parotid gland. It courses superiorly through the parotid gland and runs as two branches, over the temporal region. It supplies the parotid gland, temporomandibular joint, and masseter. It gives off the transverse facial artery within the parotid gland.



Conclusions and Future Directions The normal variation of anatomical features can go unnoticed as the incidence of variations in the population might be very low, the variation may be located in a rarely imaged or investigated region, imaging techniques might not be sensitive enough to show certain variations, and the variation itself may not produce any symptoms or clinical significance. With increasing sophistication and availability of treatments, the presence of variations may become an important consideration for the clinician. The range of healthy gross and histomorphometries has to be taken into consideration when making a decision about clinical intervention. Surgical options must take into consideration the underlying anatomical features whose presence/absence/size might have an impact on patient outcomes after surgery. Three-dimensional imaging technologies in the oral and maxillofacial regions are beginning to enable better visualization of varying anatomical features. Techniques such as cone beam computed tomography can be used to make threedimensional measurements and assessments of anatomical features at high resolution and will hopefully draw attention to the range of anatomical variations in a way that previous techniques have not been able to do.



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The increasing average lifespan and average age of the population in many communities throughout the world should lead us to a better understanding of the healthy range of aging processes. Longitudinal studies of changes in oral and facial anatomical features would help clinicians understand normal variation compared with disease process or risk of onset of a disease. Again, imaging techniques that are noninvasive and repeatable over time will be crucial to revealing the variation of normal age changes in the population.



Cross-References ▶ Clinical Evaluation of Oral Diseases ▶ Clinical Evaluation of Orofacial Pain ▶ Cutaneous Pathology of the Head and Neck ▶ Head and Neck Tumors ▶ Neurophysiology of Orofacial Pain ▶ Neurosensory Disturbances Including Smell and Taste ▶ Odontogenic Pathology ▶ Pediatric Oral Medicine ▶ Pigmented Lesions of the Oral Mucosa ▶ Salivary Gland Disorders and Diseases ▶ Soft and Hard Tissue Operative Investigations in the Diagnosis and Treatment of Oral Disease



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64 Güldner C, Pistorius S, Diogo I, Bien S, Sesterhenn A, Werner J. Analysis of pneumatization and neurovascular structures of the sphenoid sinus using cone-beam tomography (CBT). Acta Radiol. 2012;53 (2):214–9. Gulsahi A. Osteoporosis and jawbones in women. J Int Soc Prev Community Dent. 2015;5:263–7. Hand A, Pathmanathan D, Field R. Morphological features of the minor salivary glands. Arch Oral Biol. 1999;44 (Suppl 1):S3–S10. Hand AR, Frank ME. Fundamentals of oral histology and physiology. Oxford: Wiley; 2014. Hanihara T, Ishida H. Frequency variations of discrete cranial traits in major human populations. IV. Vessel and nerve related variations. J Anat. 2001;199 (Pt 3):273–87. Hellquist H, Skalova A. Histopathology of the salivary glands, vol. 2014. Heidelberg: Springer; 2014. Hiatt JL, Gartner LP. Textbook of head and neck anatomy. Philadelphia: Wolters Kluwer Health/Lippincott William & Wilkins; 2010. Hung-Huey T. Panoramic radiographic findings of the mandibular foramen from deciduous to early permanent dentition. J Clin Pediatr Dent. 2004;28(3): 215. Hutto J, Vattoth S. A practical review of the muscles of facial mimicry with special emphasis on the superficial musculoaponeurotic system. Am J Roentgenol. 2015;204(1):W19–26. Inoue H, Ono K, Masuda W, Morimoto Y, Tanaka T, Yokota M, et al. Gender difference in unstimulated whole saliva flow rate and salivary gland sizes. Arch Oral Biol. 2006;51(12):1055–60. Iván S, Daniela Z. Age effect in the morphological traits performance for sex determination in human skulls and mandibles. Int J Morphol. 2012;1:296. Jacobs R, Lambrichts I, Liang X, Martens W, Mraiwa N, Adriaensens P, Gelan J. Oral and maxillofacial radiology: Neurovascularization of the anterior jaw bones revisited using high-resolution magnetic resonance imaging. Oral Surg Oral Med Oral Pathol Oral Radiol Endodontol. 2007;103:683–93. Jorge T, Mario C, Daniela Z, Iván S. Percentage of lateral pterygoid muscle inserted in the disc of human temporomandibular joint. Int J Morphol. 2011;3:965. Kazunobu S, Tatsurou T, Shinji K, Nao W, Shinobu M, Masafumi O, Shun N, Yasuhiro M. The significance of cone beam computed tomography for the visualization of anatomical variations and lesions in the maxillary sinus for patients hoping to have dental implant-supported maxillary restorations in a private dental office in Japan. Head Face Med. 2014;10(1): 3–28. Kaye EK, Vokonas P, Garcia RI. Metacarpal cortical bone area predicts tooth loss in men. JDR Clin Transl Res. 2017;2:179–86. Kels BD, Grzybowski A, Grant-Kels JM. Human Ocular Anatomy. Clin Dermatol. 2015;33:140–6.



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Interface Between Oral and Systemic Disease Michele D. Mignogna and Stefania Leuci



Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .



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Cardiovascular Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ischemic Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Congenital Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hypertensive Vascular Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Metabolic Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Disorders of Rhythm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Valvular Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Infective Endocarditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anticoagulant Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cardiac Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oral Manifestations of Cardiovascular Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .



69 69 75 75 77 77 78 80 81 82 85



Respiratory Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chronic Obstructive Pulmonary Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oral Manifestations of Respiratory Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .



85 85 86 87



Endocrine Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diseases of the Adrenal Glands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diseases of Parathyroid Glands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gonadal Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thyroid Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oral Manifestations of Endocrine Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .



88 88 89 91 93 95 98



Gastrointestinal Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dysphagia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gastroesophageal Reflux Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inflammatory Bowel Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hepatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alcoholic Liver Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .



98 98 100 101 104 108



M. D. Mignogna (*) · S. Leuci Oral Medicine Complex Unit, Department of Neuroscience, Reproductive and Odontostomatological Sciences, Federico II University of Naples, Naples, Italy e-mail: [email protected]; [email protected] # Springer Nature Switzerland AG 2019 C. S. Farah et al. (eds.), Contemporary Oral Medicine, https://doi.org/10.1007/978-3-319-72303-7_9



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68



M. D. Mignogna and S. Leuci Oral Manifestations of Gastrointestinal Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 Musculoskeletal Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Osteoporosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Osteoarthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fibromyalgia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oral Manifestations of Musculoskeletal Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .



109 110 111 111 112



Hematological Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Leukemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lymphomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oral Manifestations of Hematological Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .



112 114 115 116 117



Renal Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117 Oral Manifestations of Kidney Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119 Neurological Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Multiple Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Amyotrophic Lateral Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Parkinson’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dementia/Alzheimer’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oral Manifestations of Neurological Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .



120 120 121 122 123 124 124 125



Psychiatric Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anxiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Eating Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Substance-Related Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oral Manifestations of Psychiatric Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .



126 126 127 128 129 130



Conclusions and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131



Abstract



Oral medicine is a specialty of dentistry concerned with the oral health care of patients with chronic, recurrent and medically related disorders of the orofacial region and with their diagnosis and nonsurgical management. For these reasons, familiarity with medical conditions that correlate with the most common oral diseases is absolutely essential for specialists in oral medicine, as well as for all health care practitioners, to provide their patients with the best possible care. In internal medicine, medical professionals usually take a whole of person approach to diagnosis and treatment of systemic diseases. Similarly, oral medicine specialists should consider the orofacial region as a mirror to body



systems and “think systemically”. After all, oral health is part of general health. Careful examination of the oral cavity may reveal findings indicative of underlying systemic diseases. Further, local diseases may result from treatments and drugs with a profound impact on the patient’s health. This strong relationship between internal medicine and oral medicine mandates a comprehensive understanding of medicine for all oral medicine specialists. This chapter focuses on systemic diseases within an oral medicine context, specifically presenting diseases of cardiovascular, respiratory, endocrine, gastrointestinal, musculoskeletal, hematologic, renal, neurologic, and psychiatric disorders. This chapter is intended to offer a pathway for guidance of in depth



Interface Between Oral and Systemic Disease



medical information critical in contemporary oral medicine practice.



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Cardiovascular Diseases Ischemic Heart Disease



Keywords



Systemic evaluation · Systemic diseases · Systemic pathology · Internal medicine · Disseminated diseases · Localized diseases · Cardiovascular diseases · Respiratory diseases · Endocrine disorders · Gastrointestinal disorders · Musculoskeletal disorders · Hematological disorders · Renal diseases · Neurological disorders · Psychiatric disorders



Introduction This chapter addresses the complex, multifaceted relationship between oral and systemic health, and the deep link with medicine, as the oral cavity can be thought of as an expression of the homeostasis of the whole body. The focus is on the major systems, providing data on a selection of diseases and conditions regarding the definition, etiology, pathogenesis, and their management useful in oral medicine practice. This cannot substitute dedicated textbooks in internal medicine and does not include a complete and detailed description of all systemic diseases, as it is beyond the scope of this text. The major objective of this comprehensive chapter is to provide oral medicine specialists an overview with consistent information on the most frequent systemic diseases related to oral health and to review important aspects of systems pathology. The oral medicine clinician should be well versed in general and systemic pathology, systems pathology, and general and internal medicine, and should use this chapter as a starting point for further reading and exploration of systemic diseases and not as an exhaustive list of conditions. While this chapter highlights the oral manifestations of systemic conditions, it includes them for completeness, and not to delve into them in any great detail. A sole dedicated chapter titled ▶ “Oral Manifestations of Systemic Diseases and Their Treatments” explores these in much greater detail and is designed to complement the contents of this chapter.



Ischemic heart disease, also known as coronary artery disease, is a disease characterized by reduced blood supply to the heart. It is the most common cause of death worldwide (Murray et al. 2012); however, many patients survive acute myocardial infarction (MI), and many adults live with disabling symptoms of stable angina pectoris or ischemic heart failure. Ischemia is a condition in which the blood flow, and thus oxygen, is restricted or reduced to a part of the body, in this case the heart muscle and arteries. Myocardial ischemia is a consequence of reduced blood flow in coronary arteries due to a combination of fixed vessel narrowing and abnormal vascular tone as a result of atherosclerosis and endothelial dysfunction (Fig. 1). Other nonatherosclerotic causes of ischemia include (a) decreased coronary perfusion pressure due to hypotension, such as hypervolemia and septic shock; (b) decreased blood oxygen content, such as in marked anemia or pulmonary disease; (c) significant increase in myocardial oxygen demand, such as caused by rapid tachycardia, acute hypertension, or severe aortic stenosis; (d) unusual coronary abnormalities; (e) coronary emboli caused by endocarditis or artificial heart valves; (f) inflammation of the coronary arteries; (g) severe transient coronary spasm resulting from cocaine abuse; and (h) congenital abnormalities, trauma, or aneurysm of the coronary arteries (Davies 2000). Traditional and Framingham risk factors, such as hypertension, hyperlipidemia, diabetes, tobacco use, lifestyle, and diet, are modifiable both for women and men (Mahmood et al. 2014). Over the last decade the increased research focus of women at risk for ischemic heart disease has helped define and delineate some of the gender-specific factors at play, such as metabolic syndrome, pregnancy related disorders, autoimmune disorders, sleep apnea, chronic kidney disease, psychosocial factors such as depression, anxiety, low socioeconomic status, and work and marital stress (Mehta et al. 2015). The severity and duration of ischemia



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M. D. Mignogna and S. Leuci Table 1 Heart failure risk factors. (Adapted from Bui et al. 2011) Major clinical risk factors: Age, male gender, hypertension, LV hypertrophy, myocardial infarction, valvular heart disease, obesity, diabetes Minor clinical risk factors: Smoking, dyslipidemia, chronic kidney disease, albuminuria, sleep-disordered breathing, anemia, increased heart rate, dietary risk factors, sedentary lifestyle, low socioeconomic status, psychological stress Immune-mediated: Peripartum cardiomyopathy, hypersensitivity Infectious: Viral, parasitic (Chagas disease), bacterial Toxic risk precipitants: Chemotherapy (anthracyclines, cyclophosphamide, 5-FU), targeted cancer therapy (trastuzumab, tyrosine kinase inhibitors), cocaine, NSAIDs, thiazolidinediones, doxazosin, alcohol Genetic risk predictors: SNP (e.g., α2CDel322–325, β1Arg389), family history, congenital heart disease Morphological risk predictors: Increased LV internal dimension, mass, asymptomatic LV dysfunction Biomarker risk predictors: Immune activation (e.g., IGF1, TNF, IL-6, CRP), natriuretic peptides (e.g., BNP and NT-BNP), high sensitivity cardiac troponin



Fig. 1 Pathological specimen of advanced atherosclerosis with extensive thrombus (white arrows) and an aortic rupture (black arrow) at the base of the plaques. (Image courtesy of the Harry Brookes Allen Museum of Anatomy and Pathology, The University of Melbourne, Carlton VIC, Australia)



determines a spectrum of myocardial dysfunction, from stable angina to heart failure.



Heart Failure Heart failure (HF) is a major public health issue with a prevalence of over 5.8 million in the USA and over 37.7 million worldwide and rising. HF represents a considerable burden to the health-care system, responsible for costs of more than $39 billion annually in the USA alone, and high rates of hospitalization, readmission, and outpatient visits. It affects more men than women, and its prevalence greatly increases with advancing age and seems to be about 2–3% (Lloyd-Jones et al. 2010). Depending on the different groups of patients included in epidemiological studies, the incidence shows a great variation from 2–5 per 1000 person-years in USA to 10–19.3



BNP brain natriuretic peptide, CRP C-reactive protein, 5-FU 5-fluorouracil, HF heart failure, IGF insulin-like growth factor, IL interleukin, LV left ventricular, NSAIDs nonsteroidal anti-inflammatory drugs, NT-BNP N-terminal BNP, SNP single-nucleotide polymorphism, TNF tumor necrosis factor



per 1000 person-years in patients >65 years of age (Lloyd-Jones et al. 2002). The increasing incidence of HF in the elderly is consistent with trends in hypertension and ischemic heart disease. Although current therapeutic approaches have improved prognosis, HF mortality remains high, comparable to that of the most common cancers, with 16 breaths/min) Hepatomegaly Ascites Tissue wasting (cachexia)



Table 3 Symptoms of heart failure. (Adapted from McMurray et al. 2012) Typical Breathlessness Orthopnea Paroxysmal nocturnal dyspnea Reduced exercise tolerance



Fatigue, tiredness, increased time to recover after exercise, ankle swelling



Less Typical Nocturnal cough Wheezing Weight gain (>2 kg/ week) Weight loss (in advanced heart failure) Bloated feeling Loss of appetite Confusion (especially in the elderly) Depression Palpitations Syncope



Angina Pectoris “Angina” is a term used to describe clinical symptoms such as discomfort in the chest, jaw, shoulder, back, or arms that are induced by physical exertion or emotional stress and subside with rest or treatment with nitroglycerin. Angina pectoris (AP) is an important common condition with appreciable morbidity and mortality, caused by rapid, transient myocardial ischemia and hypoxia. Coronary artery disease is still highly prevalent worldwide, and stable angina pectoris is one of its more common presentations. An average of 3.4 million US adults older than 40 years of age experience angina each year. Among US adults,



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M. D. Mignogna and S. Leuci



Fig. 2 Photomicrograph of a histopathology specimen of a recent myocardial infarct (a;
20) showing the affected areas across the whole of the cardiac wall, and (b;
100) showing areas of necrosis (black arrows). Hematoxylin



and eosin stain. (Images courtesy of Professor Camile Farah, UWA Dental School, University of Western Australia, Perth WA, Australia)



Fig. 3 Photomicrograph of a histopathology specimen of an old myocardial infarct (a;
20) showing the affected areas becoming organized, and (b;
100) showing areas of fibrosis (black arrows). Hematoxylin and eosin stain.



(Images courtesy of Professor Camile Farah, UWA Dental School, University of Western Australia, Perth WA, Australia)



the age-adjusted prevalence of AP is higher among women than among men, while in those aged 60–79 years, it is higher in men than women (Mozaffarian et al. 2015). Communitybased studies suggest that people with diagnosed angina have a better 5-year survival than patients affected by myocardial infarction (MI; hazard ratios 3.5 and 6.8, respectively) (Figs. 2 and 3), compared with people without manifest ischemic heart disease (Lampe et al. 2000). The prognosis of each patient is related to individual factors and is strictly linked to the underlying



disease. Stable angina is a clinical expression of MI associated with fixed atherosclerotic coronary stenosis, which prevents the adaptation of coronary perfusion to an increased oxygen requirement. MI manifested by angina pectoris can be either acute or chronic. In addition, angina can occur in patients with a recent MI and termed postinfarction angina. Myocardial ischemia is the result of an imbalance between myocardial oxygen supply and myocardial oxygen demand. The inability of the coronary arteries to increase blood flow in response to increased cardiac



Interface Between Oral and Systemic Disease Table 4 Clinical classification of chest pain. (Adapted from Fox et al. 2006) Typical angina (definite)



Atypical angina (probable) Noncardiac chest pain



Meets three of the following characteristics Substernal chest discomfort (may be felt anywhere from the epigastrium to the lower jaw or teeth) with brief duration (< 10 min) Provoked by exertion or emotional stress Relieved by rest and/or nitroglycerin Meets two of the above characteristics Meets one or none of the above characteristics



metabolic demands is the baseline dysfunction instable angina. The majority of patients are symptomatic, but a certain percentage (25%) can be asymptomatic, with the clinical manifestations of myocardial ischemia being general chest discomfort (angina pectoris), arrhythmias, and left ventricular dysfunction (Conti 2007). The characteristics of discomfort related to myocardial ischemia have been extensively described and may be divided into four categories: location, character, duration, and relation to exertion, and other exacerbating or relieving factors (Table 4). For patients with stable angina, the Canadian Cardiovascular Society Classification divides the severity of symptoms using a grading system (Table 5). Initial diagnostic management of patients with suspected AP is electrocardiography, biochemistry exams, echocardiography, and chest x-ray. Treatments for AP include lifestyle changes, medicines, medical procedures, and cardiac rehabilitation. Different modalities of regimens with various drugs are described in the literature based on the needs of a heterogeneous patient population. Patients with recurrent angina pectoris most likely will require multidrug protocols, including beta-blockers, calcium channel blockers, nitrates, and new antianginal class molecules such as ranolazine, where different mechanisms may complement each other and result in a more efficacious strategy.



73 Table 5 Canadian Cardiovascular Society grading of angina pectoris. (Adapted from Campeau 2002) Grade Grade 1



Grade 2



Grade 3



Grade 4



Description Ordinary physical activity does no cause angina, such as walking and climbing stairs. Angina with strenuous or rapid or prolonged exertion at work or recreation Slight limitation of ordinary activity. Walking or climbing stairs rapidly, walking uphill, walking or stair climbing after meals, or in cold, in wind or under emotional stress, or only during the few hours after awakening. Walking more than two blocks on the level and climbing more than one flight of ordinary stairs at a normal pace and in normal conditions Marked limitation of ordinary physical activity. Walking one or two blocks on the level and climbing one flight of stairs in normal conditions and at normal pace Inability to carry out any physical activity without discomfort; angina may be present at rest There are four subgroups in CCS Grade 4. Groups A to D: (A) Admitted to hospital, becomes relatively asymptomatic with aggressive medical therapy, and may be managed on an outpatient basis (B) Admitted to hospital, continues to have angina despite aggressive medical therapy, and cannot be safely discharged home, but does not require IV nitroglycerin (C) Admitted to hospital and maximal medical therapy, including IV nitroglycerin, fails to control symptoms (D) Patient in shock



Cor Pulmonale Cor pulmonale is defined by the World Health Organization as “hypertrophy of the right ventricle resulting from diseases affecting the function and/or structure of the lungs, except when these pulmonary alterations are the result of diseases that primarily affect the left side of the heart, as in congenital heart disease” (WHO 1963) (Fig. 4). It is characterized by the presence of pulmonary hypertension (PH) resulting from diseases affecting the structure and/or the function of the lungs. PH results in right ventricular enlargement and may lead with time to right HF (Weitzenblum and Chaouat 2009). The development of cor pulmonale is generally associated with poor



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M. D. Mignogna and S. Leuci Table 6 Classification of pulmonary hypertension. (Adapted from Simonneau et al. 2004)



Fig. 4 Pathological specimen of right ventricular (RV) wall hypertrophy (black arrows) and dilation in a man of 59 years with a 15 year history of asthma and emphysema, diagnosed with Cor pulmonale and cardiac dysfunction. (Image courtesy of the Harry Brookes Allen Museum of Anatomy and Pathology, The University of Melbourne, Carlton VIC, Australia)



prognosis and increased death (Fig. 4). Cor pulmonale encompasses 6–7% of all types of adult heart disease in the United States where chronic obstructive pulmonary disease (COPD) is the major cause. Mortality in patients with concurrent COPD and cor pulmonale is higher than that in patients with COPD alone (Han et al. 2007). The global incidence is related to the geographic area depending on the prevalence of cigarette smoking, air pollution, and other risk factors for various lung diseases. Lung disorders cause PH by several mechanisms: (a) vasoconstriction caused by hypoxia; (b) hypercapnia, or both; (c) loss of capillary beds; (d) increased alveolar pressure; and (e) medial hypertrophy in arterioles. The causes of PH are copious and a classification is shown in Table 6. Dyspnea is the most common symptom; the development of additional symptoms such as chest pain, light-headedness, syncope, and lower extremity edema may prompt further evaluation. Physical findings commonly include a left parasternal systolic lift, a loud pulmonic component of



1. Pulmonary arterial hypertension 1.1. Idiopathic 1.2. Familial 1.3. Associated with: 1.3.1. Collagen vascular disease 1.3.2. Congenital systemic-to-pulmonary shunts 1.3.3. Portal hypertension 1.3.4. HIV infection 1.3.5. Drugs and toxins 1.3.6. Other (thyroid disorders, glycogen storage disease, Gaucher’s disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, chronic myeloproliferative disorders, splenectomy) 1.4. Associated with significant venous or capillary involvement 1.4.1. Pulmonary veno-occlusive disease 1.4.2. Pulmonary capillary hemangiomatosis 1.5. Persistent pulmonary hypertension of the newborn 2. Pulmonary hypertension with left heart disease 2.1. Left-sided atrial or ventricular heart disease 2.2. Left-sided valvular heart disease 3. Pulmonary hypertension associated with lung diseases and/or hypoxemia 3.1. Chronic obstructive pulmonary disease 3.2. Interstitial lung disease 3.3. Sleep-disordered breathing 3.4. Alveolar hypoventilation disorders 3.5. Chronic exposure to high altitude 3.6. Developmental abnormalities 4. Pulmonary hypertension due to chronic thrombotic and/or embolic disease 4.1. Thromboembolic obstruction of proximal pulmonary arteries 4.2. Thromboembolic obstruction of distal pulmonary arteries 4.3. Nonthrombotic pulmonary embolism (tumor, parasites, foreign material) 5. Miscellaneous Sarcoidosis, histiocytosis X, lymphangiomatosis, compression of pulmonary vessels (adenopathy, tumor, fibrozing mediastinitis)



the 2nd heart sound (S2), and murmurs of functional tricuspid and pulmonic insufficiency. Later, an RV gallop rhythm (3rd [S3] and 4th [S4] heart sounds) augmented during inspiration, distended jugular veins (with a dominant a wave unless tricuspid regurgitation is present), hepatomegaly, and lower-extremity edema may occur.



Interface Between Oral and Systemic Disease



Many treatment options are available depending on the medical conditions that cause PH, involving diuretics and oxygen therapy. Digitalis is used only in the case of an associated left HF or in the case of arrhythmia. Long-term oxygen therapy is at present the best treatment for PH in chronic respiratory failure. Future treatment may combine oxygen therapy and specific vasodilators (Weitzenblum and Chaouat 2009).



Congenital Heart Disease Congenital heart disease (CHD) is “a gross structural abnormality of the heart or intrathoracic great vessels that is actually or potentially of functional significance” (Mitchell et al. 1971). It is a general term for a range of birth defects that affect the normal workings of the heart. The term “congenital” means the condition is present at birth. CHD affects nearly 1% of – or about 40,000 – births per year in the United States (Reller et al. 2008). The most common type of heart defect is a ventricular septal defect. About 25% of babies with a CHD have a critical CHD and generally need surgery or other procedures in their first year of life. Certain chromosomal abnormalities, such as trisomy 21, trisomy 18, trisomy 13, and monosomy X (Turner syndrome), are strongly associated with CHD. However, these abnormalities account for only about 5% of patients with CHD. Many other cases involve microscopic deletions on chromosomes or single-gene mutations. The prevalence of CHD in adults is 3–6 per 1000 adults (Webb et al. 2015). Approximately 8–12% of CHD is attributed to environmental factors during pregnancy, such as alcohol consumption, rubella infection, hydantoin and thalidomide intake, phenylketonuria, and poorly controlled insulin-dependent diabetes (Bernier et al. 2010). Common complications of CHD are heart failure, arrhythmias, endocarditis, pulmonary arterial hypertension, and thrombotic events. CHD may be classified into acyanotic and cyanotic depending upon whether the patient clinically exhibits cyanosis. The acyanotic defects may further be subdivided into obstructive lesions (pulmonary stenosis, aortic stenosis, coarctation



75



of the aorta) and left-to-right shunt lesions (atrial septal defect, ventricular septal defect, patent ductus arteriosus). The cyanotic defects, by definition, affect right-to-left shunt (Tetralogy of Fallot, Transposition of the great arteries, Tricuspid atresia). One fifth of these patients undergo cardiac surgical procedures, 40% of whom have reoperations. Perioperative mortality varies according to basic anatomic diagnosis, age, presence of cyanosis, type of surgical procedure, and lastly reoperation. Not all patients require treatment; in some cases, surgery or cardiac catheterization may be needed to reduce the effects of and/or to repair the defect.



Hypertensive Vascular Disease Clinical hypertensive vascular disease is the result of complex alterations in the cellular components of the arterial wall. Changes in the endothelium, smooth muscle cell, extracellular matrix, and possibly the adventitia, contribute to complications of hypertension. An inflammatory state in the arterial wall mediated by reactive oxygen species is the main cause of damage through mechanical and humoral signaling pathways. Mechanical stimuli have three basic components: shear stress imposed by the flow of blood, wall stress as a result of pressure-induced wall deformation, and subsequent strain and the direct effects of pressure itself. The renin angiotensin system has been used as a prototypical model of altered humoral factors in hypertension.



Hypertension The National Heart Lung and Blood Institute (NHLBI) defines hypertension (high blood pressure) as a systolic pressure of 140 mmHg or greater, diastolic pressure of 90 mmHg or greater, or taking antihypertensive medication. Consensus recommendations for the management of hypertension in adults have recommended a systolic pressure threshold 150 mm Hg for initiation of drug therapy and a therapeutic target of 1 cm diameter and purple) Easy bruising Plethora Reproductive system Menstrual irregularity Amenorrhea Decreased libido Psychiatric and cognitive Depression Emotional lability Irritability Decreased memory Decreased concentration Skeleton and muscle Proximal muscle weakness Reduced bone mineral density Fractures Metabolism Impaired glucose tolerance Diabetes



Diseases of Parathyroid Glands Parathyroid glands are four small endocrine glands located behind the thyroid and control the homeostasis and balance of calcium and phosphorous in blood and bones through the production of parathyroid hormone (PTH) and calcitonin (produced by the thyroid gland). PTH is a polypeptide containing 84 amino acids that is a prohormone; effective hormonereceptor interaction requires solely the 34-N-terminal amino acids. The major target end organs for PTH action are the kidneys, skeletal system, and intestine in general. Secretion of PTH serves to increase blood calcium and decrease phosphate concentrations, which varies inversely with blood calcium concentration. PTH action on the bones can have a rapid or slow effect; in the first case, it acts on osteocytes to rapidly release exchangeable bone salts increasing extracellular calcium and phosphate levels within minutes, in the second case it activates osteoclasts and promotes



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M. D. Mignogna and S. Leuci



Decreased serum calcium



Increased serum calcium Parathyroid glands Bone Increased bone resorption Parathyroid hormone Kidney Increased calcium reabsorption



Increased calcium absorption in the gastrointestinal tract.



Intestine



Negative feedback/ decreased activity Positive feedback/ stimulation



Fig. 12 Parathyroid hormone (PTH) is secreted form the parathyroid glands in response to low blood serum calcium levels. PTH will act to increase resorption of Ca2+ from the



bones, increase absorption of Ca2+ in the intestines, and increase reabsorption of Ca2+ from the kidneys



development of new osteoclasts to resorb hydroxyapatite and release calcium and phosphate into the extracellular fluid within days to months. The effects of PTH on kidneys are realized through its action on the late distal tubule and collecting ducts to enhance resorption of tubular calcium and to increase urinary excretion of phosphate. Finally, PTH indirectly induces higher Vitamin D levels and biosynthesis (Fig. 12). Parathyroid disorders are usually classified into three groups: (i) hyperparathyroidism, (ii) hypoparathyroidism, and (iii) parathyroid cancer, commonly presenting with serum calcium abnormalities.



evaluation of serum electrolyte levels. This alteration can be derived from an intrinsic abnormal change altering excretion of PTH (primary or tertiary hyperparathyroidism) or from an extrinsic abnormal change affecting calcium homoeostasis stimulating production of PTH (secondary hyperparathyroidism). Primary hyperparathyroidism is a relatively common endocrine disorder, with prevalence estimates of 1–7 cases per 1000 adults (Adami et al. 2002). Secondary hyperparathyroidism is most commonly associated with chronic kidney disease or vitamin D deficiency (which may arise from malabsorption syndromes or chronic lack of exposure to sunlight); estimates report that as many as 90% of patients with kidney disease develop secondary hyperparathyroidism by the time hemodialysis is initiated (Memmos et al. 1982). Tertiary hyperparathyroidism occurs most commonly in the setting of renal transplantation where up to 30% of patients with secondary



Hyperparathyroidism Hyperparathyroidism is due to increased activity of the parathyroid glands with an unregulated overproduction of PTH resulting in hypercalcemia, often discovered incidentally during



Interface Between Oral and Systemic Disease



disease continue to have elevated PTH levels after receiving a renal allograft. Exceptionally in symptomatic patients, a diagnosis can be established on the basis of clinical data. Normal calcium level is 2.3–2.7 mmol/l; mild hypercalcemia (calcium 3 < mmol/l) is asymptomatic, but severe hypercalcemia can show different signs and symptoms including (a) general such as tiredness, malaise, dehydration, and depression; (b) renal such as renal colic from stones, polyurea, hematuria, and hypertension; (c) bone such as pain, cyst, Brown tumors (due to osteoclastic activity); and (d) abdominal pain, chondrocalcinosis and atopic calcification, and corneal calcification. Hyperparathyroidism must always be evaluated in patients with a clinical history of nephrolithiasis, nephrocalcinosis, osseous pain, subperiosteal resorption, and pathologic fractures, as well as in those with osteoporosisosteopenia, a personal history of neck irradiation, or a family history of multiple endocrine neoplasia syndrome (types 1 or 2). The diagnostic work-up is made with laboratory studies (such as total serum or ionized calcium, 24-h urine calcium, albumin level, PTH levels) and imaging studies. Treatment options are variable depending on the final diagnosis and clinical data; surgery is first line therapy to remove an overactive parathyroid gland in primary hyperparathyroidism. Patients who have mild primary hyperparathyroidism may not need immediate care or any surgery and can be safely monitored. Different classes of drugs namely calcimimetics, bisphosphonates, and hormone replacement therapy can be used in some cases if surgery is unsuccessful or not an option.



Gonadal Disorders Gonadal development is a complex process, which involves the tightly regulated differentiation of a bipotential embryonic gonad into either testes or ovaries. Once this has occurred, the phenotypic and gonadal sex of an individual is genetically determined.



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Ovaries are located on both sides of the uterus below the opening of the fallopian tubes. They produce estrogen and progesterone, the two major hormones that affect many of the female characteristics and reproductive functions. Testes are egg-shaped organs located in the scrotum outside the male body. They produce testosterone, which affects many of the male characteristics and sperm production. Women synthesize most of their estrogen in their ovaries and other reproductive tissues. Since men lack this female anatomy, they need to produce estrogen through a process involving an enzyme called aromatase that transforms testosterone into estradiol. In women, testosterone is produced in various locations: ovaries, adrenal glands, and peripheral tissues from the various precursors produced in the ovaries and adrenal glands. Gonadal function is determined by the activity of testes and ovaries through the regulation of the hypothalamic-pituitarygonadal axis. One of the multiple functions of the hypothalamus is the control of the pituitary gland (or hypophysis), which in turn, by releasing different kinds of hormones, influences the majority of the endocrine glands in the body – such as thyroid, adrenal, and gonads – as well as regulates growth, milk production, and water balance. It is a multilevel hormonal system involving the brain and pituitary regulated by a complex network of excitatory and inhibitory factors including gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), and follicle stimulating hormone (FSH). This axis is active in the embryonic and early postnatal stages of life and is subsequently restrained during childhood. Its reactivation culminates in puberty initiation. Female and male gonads produce sex hormones in different amounts: estrogen, progesterone, testosterone, androstenedione, and inhibin. The two major classes of gonadal diseases can be divided into hypogonadism and hypergonadism. Inadequate gonadal function is called hypogonadism, in which the hypothalamicpituitary-gonadal axis is interrupted at any level and may result in a reduction of sex hormone biosynthesis before and after the onset of puberty, both in males and females. Hypogonadism is increasingly common in the aging male



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population with a decrease in either of the two major functions of the testes: sperm and testosterone production (Wang et al. 2009). Hypogonadism is divided into primary and secondary hypogonadism. Primary hypogonadism is generally related to defects inherent within the gonad such as chromosomal abnormalities (Noonan Syndrome, Turner Syndrome, Klinefelter syndrome, XY females with SRY gene-immunity), orchitis, varicocele, trauma, drugs including chemo-radiotherapy, and autoimmune damage. Secondary hypogonadism is caused by various lesions and/or diseases involving either the hypothalamus or the pituitary (i.e., isolated idiopathic hypogonadotropic hypogonadism, Kallmann’s syndrome, sella or suprasellar tumors, trauma, surgery, radiation, meningitis, sarcoidosis, hemochromatosis). Signs and symptoms suggestive of male hypogonadism are related to androgen deficiency and involve musculoskeletal system (reduction of muscle strength, vigor and physical energy), sexuality (impotence, infertility, loss of libido), vasomotor and nervous system (hot flushes, sweating), mood disorder and cognitive function (depression, insomnia, difficulty with short-term memory). Often patients show gynecomastia, abdominal obesity, loss of body hair, infantile genitalia; they also have a wide spectrum of systemic complications because a low level of testosterone seems to be a risk factor for diabetes, metabolic syndrome, inflammation, dyslipidemia, and osteoporosis (Maggio and Basaria 2009). Diagnosis is based on the evaluation of the complete panel of hormone levels in blood and an MRI of the brain. Treatment includes testosterone replacement and the management of underlying disease. Diseases associated with the ovaries include ovarian cysts, ovarian cancer, menstrual cycle disorders, polycystic ovarian syndrome, and osteoporosis. Menopause is a form of hypogonadism that occurs naturally; the term derived from the Greek Meno (months) and Pause (cessation); the word means cessation of menstruation. Climacteric consists of physical and emotional change that precedes and accompanies menopause. These changes usually occur gradually and consist of



M. D. Mignogna and S. Leuci



three stages: premenopause (transition between fertility and the last menstrual period), menopause, and postmenopause (the years after the end of menstruation). Menopause is characterized by a dramatic decline in primordial follicle and increased levels of follicle stimulating hormone (FSH) and luteinizing hormone (LH) until complete anovulation. When there is a rapid decrease of estrogens, menstruation stops and symptoms of menopause start, even if the ovarian stroma continues to produce small amounts of androstenedione and testosterone. Ovarian hormones are necessary for the maintenance and health of most tissues in women. Alterations in these hormones can lead to osteoporosis, atrophy and inflammation of estrogen-deprived tissues (e.g., atrophic vaginitis), atherogenesis and alterations in cardiovascular compliance, and an increased risk of some forms of cancer (e.g., endometrial carcinoma as a consequence of estrogen excess). Symptoms of menopause encompass hot flushes, psychological changes, and nocturia. Vaginal mucosa experiences atrophic changes, with reduction of pH and lubrication; uterus, ovaries, and breasts are reduced in size and sometimes there is a prolapse of the pelvic floor. Diagnosis includes a complete serological assessment of estrogen, FSH, and LH levels. Some women can have benefits from estrogen therapy, especially those with premature ovarian failure; but a risk of breast cancer and heart disease when combined hormone therapy (estrogen plus progestin) is used for a long-term is described (Chlebowski and Anderson 2015). Hypergonadism is a rare condition where there is a hyperfunction of the gonads. The imbalance of the hormones can lead to puberty at an early stage, later in life or in the newborn. It can occur in both males and females, but is more common in males. In hypergonadism, the level of reproductive hormones increases and causes infertility in males and females. While there can be a multitude of causes for the development of hypergonadism (genetics, autoimmune disorders, anabolic steroids), tumors affecting the adrenal glands are a leading cause of this hormonal abnormality. It can manifest as precocious puberty, rapid growth in adolescents, high libido, acne, excessive hairiness, increased muscle mass, and mood swings.



Interface Between Oral and Systemic Disease



Thyroid Disease The thyroid gland consists of two lobes lying on either side of the ventral aspect of the trachea connected together by a thin band of connective tissue called the isthmus. It performs a vital function producing hormones that regulate metabolism. The understanding of thyroid disease requires an understanding of hypothalamic–pituitary–thyroid feedback control; the hypothalamic hormone, thyrotropin releasing hormone (TRH), all of which modulate the release of pituitary thyroid stimulating hormone (TSH). TSH interacts with specific receptors on thyroid follicular cells to stimulate thyroid hormone production, 80% of thyroxine (T4) and 20% of triiodothyronine (T3). T4 and T3 are transported blood bound to serum proteins. The 80% of T3 production comes from the conversion of T4 in peripheral tissues. The effects of thyroid hormones on virtually every cell in the body are manifest in the widespread clinical effects of their lack or excess. All forms of thyroid diseases are much more frequently observed in women than in men, although the reasons for this are not completely elucidated, and their manifestations are determined by dietary iodine availability. Thyroid diseases can be broadly classified as euthyroidism, hyperthyroidism, and hypothyroidism, clinical states reflecting normal, excessive, or defective levels of thyroid hormones respectively. Hormone levels can reflect a primary biosynthetic problem of the thyroid gland, or a destruction of thyroid cells with release of thyroid hormones, or iatrogenic causes, or changes resulting from target tissue abnormalities (Table 12). The most frequent causes of hyperthyroidism are various forms of thyroid dysfunction in elderly women or Graves’ disease, which occurs mostly in younger women. The causes of Graves’ disease include autoimmune stimulation to TSH receptor (80%), toxic multinodular goiter (15%), toxic adenoma (2%), thyroiditis (1%), and tumors (2%) (TSH secreting pituitary tumor, trophoblastic tumors, thyroid follicular carcinoma). It seems there exists a genetic background with a linkage to certain histocompatibility complex genes on



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chromosome 6 and associations with other diseases that are characterized by markers of autoimmunity (pernicious anemia, Sjogren’s syndrome, Addison’s disease, type 1 diabetes mellitus, and primary biliary cirrhosis). Graves’ disease is characterized by periods of remission and exacerbation; 10–15% of patients will progress to hypothyroidism or to Hashimoto’s thyroiditis (deBruin et al. 1988). Classical symptoms include weight loss despite increased appetite, heat intolerance, irritability, insomnia, sweatiness, diarrhea, palpitations, muscular weakness, and menstrual irregularity; clinical signs include diffuse goiter, fine resting tremor, tachycardia, hyperreflexia, eyelid lag, warm and smooth skin, and proximal myopathy and less commonly atrial fibrillation. A low serological level of TSH indicates likely suppression of the hypothalamic–pituitary axis and should be followed by the measurement of free thyroxine (T4) and free triiodothyronine (T3), both of which are usually elevated in Grave’s hyperthyroidism. Technetium-labeled thyroid scintigraphy may aid diagnosis when the cause of hyperthyroidism remains uncertain. Treatment strategies for Grave’s hyperthyroidism include the use of thionamides (antithyroid drugs), radioactive iodine therapy, or surgery. On the other hand, the most common causes of hypothyroidism are autoimmunity (Hashimoto’s thyroiditis), iodine deficiency, or following surgery or radioiodine therapy (Gessl et al. 2012). Hashimoto’s thyroiditis, also known as chronic lymphocytic thyroiditis, was first described by Hashimoto in 1912. It is characterized by gradual destruction of the thyroid gland, through autoimmune processes, due to a combination of genetic and environmental factors. Genes for human leukocyte antigen, cytotoxic T lymphocyte antigen4, protein tyrosine phosphatase nonreceptor-type 22, thyroglobulin, vitamin D receptor, and cytokines are considered to be of utmost importance (Zalatel and Gaberscek 2011). Environmental factors include iodine intake, drugs, infections, and different chemicals. Biochemical markers of the disease are thyroid peroxidase and/or serum thyroglobulin autoantibodies which are present with a higher prevalence in females than in males and increase with age.



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Table 12 Classification of thyroid diseases. (Adapted from Monaco 2003) I. Diseases characterized by (tissue) euthyroidism A. Euthyroid goiter (chronic) 1. Diffuse a. Sporadic b. Endemic (iodine deficiency) 2. Nodular a. Uninodular 1. Sporadic 2. Endemic (iodine deficiency) b. Multinodular 1. Sporadic 2. Endemic (iodine deficiency) 3. Euthyroid diffuse goiter (transient) a. Menarche, pregnancy, menopause (in iodine-deficient environments) b. Iatrogenic (antithyroid substances), iodide (deficiency/excess), environmental/diet (goitrogens, drugs, etc.) B. Tumors 1. Benign (single nodule) a. Adenoma b. Unusual tumors (teratoma, lymphoma, etc.) 2. Malignant a. Differentiated 1. Papillary 2. Follicular b. Undifferentiated (anaplastic) 1. Small cell 2. Giant cell c. Medullary d. Other malignant (lymphoma, sarcoma, metastatic tumors) C. Thyroiditis 1. Acute thyroiditis 2. Subacute thyroiditis (De Quervain’s) (in the euthyroid phase: polar disease) 3. Chronic autoimmune thyroiditis or Hashimoto’s disease (in the euthyroid phase: polar disease) 4. Postpartum and silent thyroiditis (in the euthyroid phase: polar disease) 5. Riedel’s thyroiditis II. Diseases characterized by (tissue) hyperthyroidism A. With thyroid gland hyperfunction 1. Diffuse hyperthyroid goiter with thyroid associated ophthalmopathy or Basedow-Graves’ disease 2. Multinodular hyperthyroid goiter or Plummer’s disease 3. Autonomous nodule (hyperthyroid) 4. Rare forms: excessive exogenous iodine, chronic autoimmune (i.e., Hashitoxicosis) and postpartum thyroiditis (in the hyperthyroid phase, polar diseases), pituitary resistance to thyroid hormones, TSH-secreting pituitary adenoma, chorionic gonadotrophin-secreting tumors (choriocarcinoma, hydatiform mole, embryonal carcinoma of the testis), follicular adenoma or carcinoma of the thyroid B. Thyrotoxicosis (without thyroid gland hyperfunction) 1. Excessive, exogenous thyroid hormones (thyrotoxicosis factitia, iatrogenic thyrotoxicosis) (see also transient hyperthyroidism) 2. Postinflammatory (subacute thyroiditis) or from destruction of the thyroid (see also transient hyperthyroidism) 3. Amiodarone induced (continued)



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Table 12 (continued) C. Transient hyperthyroidism 1. Adult forms (excessive exogenous iodine intake, excess of thyroid hormone intake, post-I therapy, hyperthyroid phase of polar diseases = postpartum, silent, and subacute thyroiditis) 2. Neonatal forms (maternal antibodies) III. Diseases characterized by (tissue) hypothyroidism A. With hypothyroidism 1. Primary hypothyroidism: a. Adult 1. Chronic autoimmune thyroiditis (with or without goiter) 2. Iatrogenic (surgery, I-therapy) 3. Diffuse and nodular goiter 4. Severe iodine deficiency b. Neonatal congenital (ectopia, agenesis, dyshormonogenesis (iodine metabolism, thyroglobulin biosynthesis, enzymatic defects)) 2. Pituitary (or secondary) hypothyroidism (tumor, inflammation, infiltration, trauma, TSH deficiency, isolated or panhypopituitarism) 3. Hypothalamic (or tertiary) hypothyroidism (tumor, inflammation, infiltration, trauma) B. Without hypothyroidism 1. Generalized and peripheral resistance to thyroid hormones (receptor and postreceptor defects) C. Transient hypothyroidism 1. Adult forms [iodine deficiency/excess, drug induced, environmental/diet, postpartum, and subacute thyroiditis (hypothyroid phase)] 2. Neonatal forms (iodine deficiency/excess, maternal goitrogen ingestion/antithyroid substances, maternal antibodies) IV. Thyroid associated ophthalmopathy 1. Only signs 2. Soft tissue involvement with signs and symptoms 3. Proptosis (exophthalmos) 4. Extraocular muscle involvement 5. Corneal involvement 6. Sight loss V. Abnormal thyroid parameters without thyroid diseases (non-thyroidal illness, deficit of TBG, etc.)



Autoantibodies (IgG) are directed against the two major thyroid antigens: thyroid peroxidase (TPO) and thyroglobulin (Tg); their action is the primary cause of the modification of the parenchyma, which is diffusely replaced by a lymphocytic infiltrate and a fibrotic reaction. Patients with Hashimoto’s thyroiditis are usually asymptomatic, and some patients develop goiters with or without hypothyroidism. Clinically patients present gradual enlargement of the thyroid gland (goiter) and gradual development of hypothyroidism; sometimes the thyroid gland may enlarge rapidly; rarely, it is associated with dyspnea or dysphagia from pressure on structures in the neck or mild pain and tenderness. Classical signs



and symptoms can vary from person to person and may include fatigue, weight gain, puffy face, cold intolerance, joint and muscle pain, constipation, dry skin and hair, decreased sweating, menstrual disorders/infertility, and depression. Diagnosis relies on the demonstration of circulating autoantibodies to thyroid antigens and reduced echogenicity on thyroid sonogram in a patient with clinical features. Treatment remains symptomatic and based on the administration of synthetic thyroid hormones to correct the hypothyroidism as required. Hashimoto’s thyroiditis is often associated with other organ specific diseases (e.g., pernicious anemia, vitiligo, celiac disease, type 1 diabetes



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mellitus, autoimmune liver disease, primary biliary cirrhosis, myasthenia gravis, alopecia areata, sclerosis multiplex, Addison’s disease), and nonspecific diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s syndrome, systemic sclerosis, mixed connective tissue disease). Both Hashimoto’s thyroiditis and Grave’s disease have been associated with diabetes mellitus: about 11% of patients affected by diabetes show thyroid dysfunction (Kadiyala et al. 2010). Thyroid hormones directly control insulin secretion; conversely type 1 and type 2 diabetes may induce a “low T3 state” characterized by low serum total and free T3 levels, but near normal serum T4 and TSH concentrations. Diabetes and thyroid disorders have been shown to mutually influence each other. In hypothyroidism, there is a reduction in glucose-induced insulin secretion by β cells, and the response of β cells to glucose or catecholamine is increased in hyperthyroidism due to increased β cell mass. Insulin resistance states may increase thyroid gland nodularity and coexisting diabetes may increase risk of vision loss in patients with Grave’s disease. Hypothyroidism can cause significant changes in blood glucose control and reduce the clearance of insulin from the bloodstream, so the dose of insulin may be reduced. Hyperthyroidism is typically associated with worsening blood glucose control and increased insulin requirements. The excessive thyroid hormone causes increased glucose production in the liver, rapid absorption of glucose through the intestines, and increased insulin resistance. Moreover, thyroid hormones may further alter carbohydrate metabolism through the interaction with leptin, adiponectin, and gut hormones, namely, ghrelin.



Oral Manifestations of Endocrine Disorders Oral and peri-oral melanotic pigmentation can occur in Addison’s disease and although this may be the first sign of the disease, it can also be seen later during the course of the disease. Hyperparathyroidism can cause central and peripheral giant cell tumors, also known as “Brown tumors.”



M. D. Mignogna and S. Leuci



Menopause has been associated with diminished salivation, mucosal atrophy, oral dysesthesia, and dysgeusia, while patients who are pregnant have an increased incidence of oral peripheral giant cell granuloma, angiogranuloma, and periodontal disease. Oral lichenoid lesions can be seen in patients with Hashimoto’s thyroiditis, and patients with diabetes, particularly poorly controlled diabetes, can present with mucosal atrophy and oral candidosis. These conditions are discussed in other chapters within this text, such as ▶ “Oral Manifestations of Systemic Diseases and Their Treatments,” ▶ “Oral Lichen Planus,” ▶ “Oral and Maxillofacial Fungal Infections,” ▶ “Pigmented Lesions of the Oral Mucosa,” and ▶ “Gingival Pathology.”



Gastrointestinal Disorders Gastrointestinal disorders (GD) may affect any section of the gastrointestinal tract, from the esophagus to the rectum, and the accessory digestive organs (liver, gall bladder, and pancreas). The term encompasses acute, chronic, recurrent, or functional disorders and covers a wide range of diseases, including inflammatory bowel disease and functional dyspepsia. From the mouth to the anus, the gastrointestinal tract allows for the digestion of food, through the action of muscles with the release of hormones and enzymes. It is conventionally divided into the upper (mouth to ileum) and lower (cecum to anus) gastrointestinal tracts. The global spectrum and classification of GD is very wide; and it is possible to divide diseases into (a) functional disorders (i.e., globus, functional dysphagia, and irritable bowel diseases); (b) motility disorders (i.e., gastroesophageal reflux disease, diarrhea, and achalasia); (c) other diseases (i.e., inflammatory bowel diseases, celiac disease, malabsorption, and diverticulosis).



Dysphagia The term dysphagia is commonly used to describe a symptom that manifests as (a) subjective awareness of swallowing difficulty during the passage



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of a liquid or solid bolus from the mouth to the stomach, or (b) the perception of obstruction during swallowing (Domenech Kelly 1999). It is included in the WHO’s classification of diseases; it can cause severe complications such as malnutrition, dehydration, respiratory infections, aspiration pneumonia, increased readmissions, institutionalization, and morbidity. Swallowing occurs in 3 phases: oral, pharyngeal, and esophageal, and it is possible to identify an oropharyngeal dysphagia (OD) typically as a result of neuromuscular disorders or hyposcialia caused by drugs or therapies and an esophageal dysphagia commonly caused by anatomic defects of the esophagus, motility disorders, or intrinsic or extrinsic obstructive lesions. More generally neurogenic causes of dysphagia include stroke, multiple sclerosis, amyotrophic lateral sclerosis, diabetic neuropathy, cerebral palsy, GuillainBarrè syndrome, dementia, and head trauma, while myogenic causes refer to muscular dystrophy, myasthenia gravis, and gastrointestinal resection. Other conditions that could represent potential causes of dysphagia encompass connective tissue disorders, rheumatologic (rheumatoid arthritis) and other connective tissue disorders (scleroderma, systemic lupus erythematous) (Ney et al. 2009). Pathologic conditions of the oral cavity, pharynx, esophagus, and proximal stomach can manifest with dysphagia. Patients



with dysphagia may experience the sensation of food getting stuck in the throat or chest, coughing or choking with swallowing, delayed or absent trigger to swallow discomfort, or the ability to “sense” the act of swallowing. In addition, patients with dysphagia may experience voice changes or wet voice, frequent throat clearing, otalgia, weight loss, abnormal lip closure and tongue movement, lingual dis-coordination, delayed oral and pharyngeal transit time, incomplete oral clearance, nasal regurgitation, pharyngeal pooling, dehydration, and/or pneumonia (Fig. 13). Patients reporting “swallowing problems” may be experiencing dysphagia, odynophagia, globus sensation, and/or heartburn (Perry and Love 2001). If oropharyngeal dysphagia is suspected, the patient should undergo initial testing with a water or semisolid bolus swallow test. If results are positive, the diagnosis can be confirmed with a videofluoroscopic swallowing study. If esophageal dysphagia is suspected, patients typically undergo endoscopic esophagogastroduodenoscopy; if obstruction or gastroesophageal reflux disease is suspected, biopsies can confirm the presence of esophagitis and provide specific pathologic identification of the obstructive lesion. In addition, therapeutic dilatation of a stricture and removal of foreign bodies can be accomplished as part of the evaluation procedure.



Fig. 13 Photomicrograph of a histopathology specimen of pneumonia of the lung (a;
20) showing a clear demarcation between the infected area on the top right with congestion of almost all the alveolar, and (b;
100)



showing the infected portion of the lung. Hematoxylin and eosin stain. (Images courtesy of Professor Camile Farah, UWA Dental School, University of Western Australia, Perth WA, Australia)



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Fig. 14 Photomicrograph of a histopathology specimen of colon adenocarcinoma (a;
20) showing extensive infiltration of the adenocarcinoma across the colon (black arrows) and (b;
100) showing nuclear atypia, pseudostratification, and hyperchromasia (yellow arrows) with the



neoplasm attempting to form glandular structures. Hematoxylin and eosin stain. (Images courtesy of Professor Camile Farah, UWA Dental School, University of Western Australia, Perth WA, Australia)



Gastroesophageal Reflux Disease



motility disturbances, fibrogenesis, and carcinogenesis (Fig. 15). The mechanisms of esophageal carcinogenesis associated with prolonged GERD remain obscure. Recent attention has focused on the role of nitrosating species and nitric oxide at the gastroesophageal junction (McColl 2005). Among the environmental factors, lifestyle factors, in particular being overweight/ obese, poor dietary habits, the lack of regular physical activity, and smoking, have frequently been suggested to be possible GERD risk factors (Kaltenbach et al. 2006). The falling prevalence of Helicobacter pylori infection and related diseases in developed countries during the twentieth century has been paralleled by an increase in GERD and its complications; there is circumstantial evidence that infection with H. pylori is relatively protective for the occurrence of GERD (Delaney and McKoll 2005). Heartburn and acid regurgitation are the most common symptoms of GERD, although pathologic reflux can result in a wide variety of clinical atypical presentations such as retrosternal chest pain without evidence of coronary artery disease, asthma, chronic cough, and hoarseness. Up to 70% of patients with complaints of GERD symptoms have been noted to have nonerosive reflux disease (NERD). Thus, NERD is the most common presentation of GERD. NERD patients are often considered to be afflicted with psychological comorbidity (Fass 2007).



Gastroesophageal reflux disease (GERD) is one of the most common problems encountered in clinical practice today, particularly in the Western world (about 10–20% in Western countries and under 5% in Asia) (Dent et al. 2005). The pathophysiology of GERD is complex and multifactorial involving gastric acid secretion, dysfunction of the antireflux barrier, gastric emptying disturbances, and abnormalities in esophageal defense mechanisms. How these different factors cause GERD is incompletely understood, but they all share one common initiating process: increased exposure of the esophageal squamous epithelium to gastric contents, namely, acid, pepsin, trypsin, and bile acids. Acid breakdown of the tissue defenses is what ultimately leads to symptom production, ulceration, strictures, columnar metaplasia (Barrett’s esophagus), and adenocarcinoma (Fig. 14) (Dodds et al. 1982). The pathogenesis of GERD is complex; essentially all nonimmune cell types of the esophagus, such as resident epithelial, mesenchymal, and endothelial cells, actively contribute to the initiation and perpetuation of the inflammatory response with the involvement of inflammatory cytokines, platelet activating factor, and reactive oxygen species. Once the inflammatory cascade with its inflammatory infiltrate described above fully unfolds, complications induced by pro-inflammatory mediators can occur, such as



Interface Between Oral and Systemic Disease



Pepsin



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Acid



Trypsin



Bacteria



Epithelial cells



Inflammatory mediators



Muscle cells Endothelial cells



Fibroblasts



Immune cells



Chronic Inflammation



Motility dysfunction



Fibrosis



Carcinogenesis



Fig. 15 Interactions between immune and nonimmune cells in gastroesophageal reflex disease



The diagnosis of typical GERD begins with a detailed clinical history to identify the characteristic symptom and define the intensity, duration, and frequency, uncover the triggering and relieving factors, and determine the pattern of evolution of the disorder over time, as well as its impact on the quality of the patient’s life. In this context, it is important to consider the patient’s age and the presence or absence of alarm manifestations, which include dysphagia, odynophagia, weight loss, GI bleeding, nausea and/or vomiting, and a family history of cancer. Confirmation is achieved using various preoperative evaluations including: ambulatory pH monitoring, esophageal manometry, upper endoscopy (esophagogastroduodenoscopy), and barium swallow. Currently, the main aim in the management of most patients with reflux symptoms is to achieve effective control of symptoms, which would be expected in turn to improve health-related quality of life. Because of the chronic evolution of the disease, the priority is



to find a treatment that is safe and effective for long-term use. Surgical intervention is often necessary in patients who fail medical therapy, are noncompliant or wish to discontinue long-term medical therapy, have complications secondary to GERD, or present with extra-esophageal symptoms.



Inflammatory Bowel Diseases Inflammatory bowel diseases (IBDs) represent a family of clinically diverse conditions that are characterized by chronic, primarily cell-mediated inflammation that leads to the damage of the gastrointestinal tract (Neuman and Nanau 2012). IBDs encompass ulcerative colitis (UC) (Fig. 16) and Crohn’s disease (CD) (Fig. 17), two chronic inflammatory diseases of uncertain etiology affecting the gut, characterized by alternating recurrence and alleviation periods (Fig. 18). In



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Fig. 16 Photomicrograph of a histopathology specimen of ulcerative colitis (a;
20) showing central area of ulceration and inflammation of mucosa and submucosa (dashed oval) and (b;
100) showing a highly inflamed region.



Hematoxylin and eosin stain. (Images courtesy of Professor Camile Farah, UWA Dental School, University of Western Australia, Perth WA, Australia)



Fig. 17 Photomicrograph of a histopathology specimen of Crohn’s disease (a;
20) showing inflammation of mucosa and submucosa and (b;
80) showing a highly inflamed region with obvious granulomas including giant



cells (black arrows). Hematoxylin and eosin stain. (Images courtesy of Dr Anitha Thomas, PathWest, Perth WA, Australia)



North America and Northern Europe (areas with highest IBD occurrence), the incidence of UC and CD is much higher than Southern Europe. IBD was traditionally thought to be of low occurrence in Eastern Europe, Asia, and Africa till recently (Molodecky et al. 2012). The development and course of IBDs is probably the result of the complex interactions between genetic susceptibility, environmental triggers (breast feeding, diet, smoking, drugs), and bacterial provocation, producing sustained inflammation supported by altered mucosal barrier and immune dysregulation. A defective mucosal barrier may result in increased intestinal permeability that promotes the exposure to luminal content and triggers



an immunological response that promotes intestinal inflammation. An imbalanced intestinal immune defense and intestinal immune tolerance is one of the risk factors for developing IBD. Alterations in gut microbiota, and specifically reduced intestinal microbial diversity, have been found to be associated with chronic gut inflammation in these disorders. Specific bacterial pathogens, such as virulent Escherichia coli strains, Bacteroides spp., and Mycobacterium avium subspecies paratuberculosis, have been linked to the pathogenesis of IBDs (Nitzan et al. 2016). The immunology of IBDs represents an imbalance between two types of T cell populations: regulatory T cells and pro-inflammatory T cells. Key



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Muscle hypertrophy



Crohn’s disease Characterized by chronic inflammation that affects any part of the gastrointestinal tract. Inflammation extends all the way through the intestinal wall from mucosa to serosa.



Cobblestone appearance



Fissures



Ulcerative colitis Characterized by inflammation in the large intestine. Only the innermost layer of the intestinal wall is affected.



Ulceration within the mucosa Fig. 18 Different anatomical locations affected by Irritable Bowel Disease



events that lead to the initiation of inflammatory changes include upregulation of various inflammatory pathways and persistent activation of mitogen-activation protein kinase and NF-kB signaling (Neuman and Nanau 2012). The subsequent release of proinflammatory cytokines leads to activation of T cells and other immune cells. TNF-α is a proinflammatory cytokine that plays a major role in the inflammation caused by IBDs. Levels of TNF-α are significantly increased in response to intestinal inflammation (Thomson et al. 2012). Although CD and UC share similar characteristics, they differ in terms of the location and nature of the inflammatory changes. The distinction between these two diseases is that in CD, inflammation can affect any part of the gastrointestinal tract, while UC is characterized by inflammation localized to the large intestine. Malnutrition affects 20–25% of individuals with IBDs with a major prevalence in CD. Oral and perioral lesions associated with CD can cause difficulty in eating and drinking; moreover, patients may reduce dietary intake due to fear of



abdominal pain and diarrhea. In CD, the most common complication is blockage of the intestine due to swelling, which results in thickening of the bowel wall. Patients affected by UC tend to experience pain in the lower left part of the abdomen as well as diarrhea. As a result, they may experience weight loss and blood on rectal examination. In contrast, patients with CD experience pain in the lower right abdomen, and bleeding from the rectum is less frequent than in UC. The European evidence-based consensus on the diagnosis and management of IBDs states that diagnosis should rely on physicians taking into account a number of factors including clinical and endoscopic evaluation as well as histologic, serologic, and radiologic assessment. There is no gold standard diagnostic tool (Dignass et al. 2012). Biopsies of the colon can be taken to confirm the diagnosis. In CD, mucosal damage is characterized by focal infiltration of leukocytes into the epithelium; granulomas and aggregates of macrophages are also found. The pathology in UC typically involves hemorrhage or inflammatory



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Fig. 19 Photomicrograph of a histopathology specimen of biliary cirrhosis (a;
20) showing the damage and inflammation across many bile ducts throughout the liver and (b;
100) showing the presence of plasma cells and intraepithelial lymphocytes within the bile duct (black



arrows) and the ductal cells presenting with more eosinophilic cytoplasm. Hematoxylin and eosin stain. (Images courtesy of Professor Camile Farah, UWA Dental School, University of Western Australia, Perth WA, Australia)



cells in the lamina propria and distortion of crypt architecture. Treatment of the disease involves use of immunosuppressive drugs that can significantly reduce the symptoms of the disease and help maintain its remission. IBD has no cure, and patients commonly require a lifetime of care; thus, effective management to reduce morbidity, hospitalization, and surgery are critical to improving disease-free remission and quality of life.



parenteral infection. These 5 types are of greatest concern because of the burden of illness and death they cause and the potential for outbreaks and epidemic spread (Table 13). The clinical features of viral hepatitis at the onset are similar regardless of the specific hepatotrophic virus involved. The symptoms may include fever, malaise, anorexia, arthralgia, vomiting, abdominal pain, headache, and possibly jaundice. Extrahepatic manifestations and complications may differ quantitatively, but qualitatively they are also common. The hepatitis A virus (Hep A) is a common cause of hepatitis worldwide where spread of infection is generally person to person or by oral intake after fecal contamination of skin or mucous membranes; less commonly, there is fecal contamination of food or water. Although it is rare, parenteral transmission of Hep A is possible due to use of contaminated blood products or needles during blood transfusion. Hepatitis A is endemic in developing countries, and most residents are exposed in childhood. Hep A infection stimulates both humoral immune response with production of antibodies and subsequent development of circulating immunocomplexes that are associated with signs and symptoms of the disease and cellular immune response, the major factor of the process of clearance of viral infection. Immunoglobulin M (IgM), IgG, and IgA antibodies directed against conformational surface epitopes on the Hep A particle are induced and can usually



Hepatitis Hepatitis is an inflammatory condition of the liver, an organ which performs many critical functions that affect metabolism including bile production essential to digestion, filtering of toxins from the body, excretion of bilirubin, cholesterol, hormones, and drugs, metabolism of carbohydrates, fats, and proteins, activation of enzymes, storage of glycogen, minerals, and vitamins (A, D, E, and K), synthesis of plasma proteins, such as albumin, and synthesis of clotting factors. Hepatitis can be self-limiting or can progress to fibrosis (scarring), cirrhosis (Fig. 19), or liver cancer (hepatocellular carcinoma). Hepatitis viruses are the most common cause of hepatitis, but other infections, toxic substances (e.g., alcohol, drugs), and autoimmune diseases can also cause hepatitis. There are 5 main hepatitis viruses (Fig. 20), referred to as types A and E for enteric infection and B, C, and D for



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Fig. 20 Photomicrograph of a histopathology specimen of viral hepatitis (a;
20) showing extensive damage across widespread areas of the liver and (b;
100) showing the presence of lobular inflammation, hepatocyte necrosis with rounded apoptotic bodies and importantly ground



glass hepatocytes (black arrows) indicative of hepatitis B. Hematoxylin and eosin stain. (Images courtesy of Professor Camile Farah, UWA Dental School, University of Western Australia, Perth WA, Australia)



Table 13 The major hepatitis viruses Virus HAV HBV HCV HDV HEV



Classification Picornaviridae, genus Hepatovirus Hepadnaviridae Flaviviridae, genus Hepacivirus Unclassified Caliciviridae, genus proposed



Genome RNA DNA RNA RNA RNA



be detected by the onset of clinical illness (Stapleton 1995). Although the disease is usually self-limiting, the severity of illness is age-dependent; in children, Hep A is usually asymptomatic, while in adults, symptomatic infection is characteristic, in which jaundice may (icteric in 70% of patients) or may not (anicteric) be present. Asymptomatic infection can be classified into two categories: subclinical and unapparent infection. In subclinical infections, only the biochemical features of hepatitis can be detected. Unapparent infection can be identified only by serological studies (Hadler and McFarland 1986). Fulminant hepatitis A is rare. The course of disease shows three phases: incubation (fecal Hep A excretion), symptomatic infection (presence of anti-Hep A IgM, main serological marker for diagnosis), and convalescence. The onset of Hep A is often abrupt and characteristic prodromal symptoms are followed, within a few days to a week, by dark urine and jaundice. Mild to moderate tenderness over an enlarged



Envelope Nonenveloped Lipid enveloped Lipid enveloped Lipid enveloped Nonenveloped



Spread Fecal-oral Parental Parental Parental (from HBV) Fecal-oral



liver is usually detected. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels usually both rise rapidly during the prodromal period, reach peak levels, and then decrease by approximately 75% per week. Several unusual clinical manifestations of Hep A are cholestatic hepatitis, relapsing hepatitis, and fulminant and subfulminant hepatitis (Lemon 1985). The hepatitis E virus (Hep E) infection is a worldwide disease, often under-diagnosed in part due to the use of serological assays with low sensitivity. In developing countries, Hep E is transmitted between humans by the fecal-oral route, usually via contaminated water, while in developed countries, it is transmitted zoonotically from animal reservoirs (Kamar et al. 2012). Hep E infection is usually an acute self-limiting disease, with symptomatic and biochemical recovery within 4 to 6 weeks, but in developed countries it causes chronic infection with rapidly progressive cirrhosis in organ transplant recipients, patients with hematological malignancy requiring



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chemotherapy, and individuals with human immunodeficiency virus (HIV). Jaundice occurs in about 75% of patients; the ALT level is usually 1000–3000 IU/liter, but the range is wide. There are two subgroup high risk patients in which the course of the infection and the prognosis are different: patients with preexisting chronic liver disease and immunocompromised individuals. A minority of patients develop extrahepatic manifestations: (1) neurological symptoms such as Guillain-Barré syndrome, Bell’s palsy, neuralgic amyotrophy, acute transverse myelitis, and acute meningoencephalitis (Cheung et al. 2012); (2) kidney injury; (3) pancreatitis; and (4) thrombocytopenia and aplastic anemia. Hep E infection can be diagnosed either indirectly by detecting serum anti-Hep E antibodies or directly by detecting the Hep E genome in blood or other bodily fluids; the presence of anti-Hep E IgM is a marker of acute infection. The hepatitis B virus (Hep B) infection is caused by a double-stranded DNA virus of the hepadnaviridae family. More than 400 million people worldwide are chronically infected with Hep B; 82% of the world’s 530,000 cases of liver cancer per year are caused by viral hepatitis infection, with 316,000 cases associated with hepatitis B and 118,000 with hepatitis C (Lai et al. 2003). The virus is transmitted via percutaneous or permucosal exposure to infected blood or body fluids and has an incubation period ranging from 40 to 160 days. In low prevalence areas such as Northern Europe and North America, Hep B infection is primarily acquired in adulthood through sexual contact or injecting drug use, whereas in high prevalence areas, Hep B infection is most commonly acquired perinatally or in early childhood (Alter 2003). There are seven major Hep B genotypes (A to H) prevailing in different parts of the world. The distribution of various genotypes is as follows: A is pandemic, B and C are found in Asia, D in Southern Europe, E in Africa, F in the USA, G in the USA and France, H in Central America. The majority of acute Hep B infections are asymptomatic; in adults, 30% will present with jaundice and 0.1–0.5% develop fulminant liver failure (Kao 2008). Hep B serologic testing involves measurement of several hepatitis



M. D. Mignogna and S. Leuci



B virus (Hep B)-specific antigens and antibodies. Different serologic markers or combinations of markers are used to identify different phases of Hep B infection and to determine whether a patient has acute or chronic Hep B infection, is immune to Hep B as a result of prior infection or vaccination, or is susceptible to infection (Table 14). The hepatitis C virus (Hep C) infection still represents a major public health threat, with a global diffusion, characterized by its propensity to chronicity. The most recent data of disease burden show an increase in seroprevalence over the last 15 years to 2.8% with an estimation of 130–170 million people chronically infected, equating to >185 million infections worldwide (Messina et al. 2015). Hep C is a member of the Flaviviridae family, naturally infecting only humans and chimpanzees, characterized by 7 major genotypes, further classified into 67 confirmed and 20 provisional subtypes. Studies suggest that specific genotypes, such as genotype 1, can be more cytopathic or can induce more rapid progression of the disease than do other genotypes (Smith et al. 2014). Hep C is primarily transmitted via the parentral route which includes injection drug use, blood transfusion, unsafe injection practices, other healthcare-related procedures, tattooing, perinatal and sexual transmission. Hep C is not directly cytopathic and liver lesions are mainly related to immune-mediated mechanisms, which are characterized by a predominant type 1 helper cell response. Co-factors influencing the outcome of the disease including age, gender, smoking, alcohol consumption, endovenous acquisition of Hep C coinfection with other viruses such as HIV, Hep B, and human T-cell lymphotropic virus are poorly understood, and other factors such as immunologic and genetic factors may play an important role. Hep C enters the liver cell and undergoes replication simultaneously causing cell necrosis by several mechanisms including immunemediated cytolysis in addition to various other phenomena such as hepatic steatosis, oxidative stress, and insulin resistance (Irshad and Dhar 2006). Whereas both innate and adaptive immunity are involved in the pathogenic action of



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Table 14 Possible interpretations of some common patterns of results in HBV infection Initial tests



Follow-up tests Hep B core antibody Hep B e (anti-HBc antigen IgM) (HBeAg) Not Not performed performed



Hep B e antigen (HBeAg) Not performed



Hep B e antigen (HBeAg) Not performed



Not performed Not performed



Not performed Not performed



Not performed Not performed



Not performed Not performed



Positive/or negative



Positive/ or negative



Negative



Negative



Detected or none detected



Negative



Positive



Positive



Positive



Positive



None detected



Positive



Positive



Positive



Negative



Negative



Negative



Detected



Positive



Negative



Positive



Negative



Negative



Positive



None detected or detected at very low level



Hep B surface antigen (HBsAg) Negative



Hep B surface antibody (antiHBs) Negative



Hep B Core antibody Total (antiHBc IgG + IgM) Negative



Negative



Positive



Negative



Negative



Positive



Positive



Positive



Negative



Negative



Hep C, cytotoxic lymphocytes are crucial in determining eradication or persistence of viral particles. Approximately 25% of patients exposed to Hep C surmount the infection naturally, but the remaining 75% face persistent or life-long Hep C infection. In most cases, acute infection is asymptomatic, until the disease reaches a late stage, with the development of liver cirrhosis, hepatocellular carcinoma, liver failure (leading to liver transplantation), and death. Hep C is the most common



Possible interpretation/stage of infection No active or prior infection; not immune – may be good candidate for vaccine; possibly in the incubation stage Immunity due to vaccination Infection resolved (recovery), virus cleared; immunity due to natural infection. However, if immunosuppressed, virus can reactivate Infection resolved (recovery), virus cleared; immunity due to natural infection. However, if immunosuppressed, virus can reactivate Acute infection is resolving (convalescent) Acute infection is resolving (convalescent) Chronic infection but low risk of liver damage – carrier state



cause of death in HIV-positive patients on highly active antiretroviral therapy. Hep C can also directly infect the lymphatic tissues, and its stimulation can lead to the development of B-cell lymphomas (Ferri et al. 1994). The WHO recommends offering the Hep C serology test to individuals from populations with high Hep C prevalence or those with a history of Hep C risk exposure/behavior (WHO 2015a) such as people who have received blood



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or blood components (red cells, platelets, fresh frozen plasma), injection drug users (past or present), people with associated HIV infection, hemophilia, on hemodialysis, with unexplained abnormal aminotransferase levels, children born to Hep C-infected mothers, healthcare workers after a needle stick injury or mucosal exposure to Hep C-positive blood, and current sexual partners of Hep C-infected persons. Diagnostic tests for Hep C can be divided into two broad categories: serologic assays that detect antibodies to Hep C and molecular assays that detect or quantify HCV Hep C RNA. The diagnostic tests used, including the presence of anti-Hep C antibodies in serum, cannot differentiate between acute and chronic Hep C infection because anti-Hep C IgM, used as a marker of acute infection, is variable in acute infectious disease and is also detected at high rates in patients with chronic Hep C infection. For this reason, reverse transcription polymerase chain reaction (RT-PCR) for the detection of Hep C RNA is necessary to confirm the diagnosis. Other investigations such as genotype testing, serum fibrosis panels, and liver biopsy may help to predict the response to treatment and prognosis. The serum fibrosis panel represents a pool of markers, divided into Class I (direct) and Class II (indirect), useful to identify different liver fibrosis stages related to Hep C virus (Valva et al. 2016).



Alcoholic Liver Disease



Fig. 21 Photomicrograph of a histopathology specimen of fatty changes in the liver with early changes and only small amounts of adipose tissue interspersed throughout the liver (a), and marked fatty changes with a large amount



of visible adipose tissue (b). Hematoxylin and eosin stain. (Images courtesy of Professor Camile Farah, UWA Dental School, University of Western Australia, Perth WA, Australia)



Alcoholic liver disease (ALD) is a broad term that encompasses a spectrum of phenotypes ranging from simple steatosis (fatty liver) (Fig. 21) in patients who consume over 80 mg of alcohol/ day to steatohepatitis (that can occur at any stage of the disease), progressive fibrosis in about 40% of cases, cirrhosis in approximately 15% of patients, and hepatocellular carcinoma in 1–2% of cases. One of the most important causative factors is represented by the amount and duration of alcohol consumption, the leading cause of the morbidity and mortality of liver disease. Alcohol is responsible for over 2.5 million deaths every year; in 2010, alcoholic cirrhosis caused half a million deaths worldwide, accounting for 50% of all cirrhosis-related mortality. An additional 80,000 deaths resulted from alcohol-related hepatocellular carcinoma (Cojocariu et al. 2014). Because the liver is the major organ responsible for alcohol metabolism, it is vulnerable to alcoholrelated injury. While fatty liver is usually reversible upon cessation of alcohol use, other forms of ALD tend to progress despite abstinence. Several risk factors for ALD have been identified: female gender, obesity, drinking patterns, dietary factors, non-sex-linked genetic factors, and cigarette smoking while comorbidities encompass: viral hepatitis, hemochromatosis, and HIV. The



Interface Between Oral and Systemic Disease



pathogenesis of ALD can be broadly divided into 3 steps, each of which with a multitude cascade of processes: (1) ethanol mediated liver injury, (2) inflammatory immune response, and (3) intestinal permeability and microbiome changes. The early step starts with the metabolism of ethanol to acetaldehyde with toxic effects on hepatocytes; these damaged cells in turn release damage-associated molecular patterns with the recruitment of innate and adaptive immune cells that perpetuate liver disease. Alcohol also has direct effects on intestinal microbiome and gut permeability through the action of bacterial products that reach the liver and stimulate an immune response and damage (Dunn and Shah 2016). The presence of symptoms and signs depends on the stage of the liver disease; fatty liver is often asymptomatic, and patients with alcoholic hepatitis may also be asymptomatic. Some patients show only hepatomegaly, or in association jaundice, fever, ascites and in the last stage hepatic encephalopathy, anorexia, and fatigue. There is no single laboratory or imaging study that can confirm the diagnosis, which is made by a combination of positive anamnesis of habitual alcohol intake in terms of duration and quantity, physical signs and laboratory evidence of liver disease (abnormal serum transaminases, particularly if the level of AST is greater than that of ALT and elevated levels of gamma-glutamyl transpeptidase (GGT)); in uncertain situations, it can be supported by imaging and liver biopsy results. Corticosteroids are the first-line therapy for severe alcoholic hepatitis; pentoxifylline is an alternative therapy, liver transplantation is the ultimate therapy for severe ALD, but generally requires 6 months of proven abstinence for eligibility.



Oral Manifestations of Gastrointestinal Disorders Patients suffering from dysphagia or gastroesophageal reflux disease can complain of oro-pharyngeal burning, erythematous lesions of the oropharyngeal region, hypersalivation, dysgeusia, and dental erosion. Inflammatory bowel disease can result in persistent oral ulceration, increase in



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recurrent aphthous stomatitis, cobblestoning of the buccal oral mucosa, mucosal hypertrophy and swelling of the gingiva, labial mucosa, mucosal tags, angular cheilitis, perioral erythema, and oral candidosis. Yellow oral mucosal pigmentation can be seen in patients suffering from hepatitis, and they can also present with oral mucosal atrophy, lichenoid lesions, hyposalivation, and parotid gland swellings. These lesions are extensively discussed in other chapters of this text, such as ▶ “Oral Lichen Planus,” ▶ “Salivary Gland Disorders and Diseases,” ▶ “Oral Ulcerative Lesions,” ▶ “Oral and Maxillofacial Viral Infections,” ▶ “Oral and Maxillofacial Fungal Infections,” in addition to ▶ “Oral Manifestations of Systemic Diseases and Their Treatments.”



Musculoskeletal Disorders Musculoskeletal disorders (MSDs) are injuries and disorders that affect the body’s movement or musculoskeletal system (muscles, tendons, ligaments, joints, nerves, discs, blood vessels). Muscle diseases can be classified into: regional syndrome (myofascial pain syndrome, tensionneck syndrome, rotator cuff syndrome, compartment syndrome), local muscle diseases (muscular rheumatism, fibrositis, myositis, myalgia, tender point, trigger point), and general syndromes (fibrositis syndrome, fibromyalgia syndrome related to chronic or psychopathologic diseases, idiopathic fibromyalgia, polymyalgia, polymyositis). Bone and joint diseases include osteopenia, osteoporosis, osteoarthritis, scoliosis, spondylolisthesis, ruptured or prolapsed disc, degenerative disc disease, and spinal stenosis (Bernard 2018). MSDs have many terms, such as repetitive motion injuries, repetitive strain injuries, cumulative trauma disorders, occupational cervicobrachial disorders, overuse syndrome, regional musculoskeletal disorders, and soft tissue disorders. MSDs can arise from the interaction of physical factors with ergonomic, psychological, social, and occupational factors. Typical symptoms can be acute or chronic and include pain, fatigue, inflammation, weakness, joint noises, stiffness, limited range of motion, lack of



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coordination, and sleep disturbances. The pain may be dull, sharp, radiating, or local and may be mild or severe. The causes of pain are multiple including trauma, postural strain, repetitive movements, overuse, and prolonged immobilization. Changes in posture or poor body mechanics may bring about spinal alignment problems and muscle shortening, therefore causing other muscles to be misused and become painful. Diagnosis is the result of the evaluation of symptoms and physical examination. Laboratory tests (i.e., erythrocyte sedimentation rate, creatinine kinase, rheumatoid factor, anticyclic citrullinated peptide antibody, antinuclear antibodies), imaging tests (radiographs, arthrography, dual-energy x-ray absorptiometry, computed tomography, magnetic resonance imaging, bone scan), and other diagnostic procedures (electromyography, arthroscopy, joint aspiration) are sometimes necessary to help the clinician establish or confirm a diagnosis (Gatchel and Kishino 2011).



Osteoporosis Osteoporosis is a skeletal condition characterized by a decline in bone mineral density (mass/volume) of normally mineralized bone. The reduced bone density leads to decreased mechanical strength, thus making the skeleton more likely to fracture. Bone strength is considered to be primarily due to bone density and quality (NIH 2001). Osteoporosis is responsible for more than 1.5 million fractures annually, including 300,000 hip fractures, approximately 700,000 vertebral fractures, 250,000 wrist fractures, and more than 300,000 fractures at other sites (Masi 2008). Mortality associated with osteoporotic fractures ranges from 15% to 30%, a rate similar to breast cancer and stroke. The decline in bone mineral content and the structural deterioration in osteoporosis are evident microscopically and upon bone imaging. The cortical layer becomes thin and the normally dense network of calcified trabeculae is disconnected. The bone appears porous and fragile. During adult life, the mechanical integrity of the skeleton is maintained by the process of bone remodeling, in which old bone is



M. D. Mignogna and S. Leuci



removed by osteoclasts and subsequently replaced by new bone, formed by osteoblasts in a series of coordinated or coupled actions. During middle age and in older adults, above all during menopause, there is an increase in bone turnover and a decrease in bone formation, the result of which is a progressive loss of bone mineral from osteopenia to osteoporosis. During menopause, this complex mechanism is caused mostly by the reduction of sex hormones (estrogen and testosterone) with subsequent loss of suppression of bone resorption. Estrogen deficiency induces a prolonged resorption phase with a reduction of osteoclast apoptosis and a shortened formation phase with an increase of osteoblast apoptosis (Manolagas 2000). A similar effect is caused by testosterone through different pathways. Osteoporosis can also develop as a consequence of diseases or pathological processes, and this is labeled secondary osteoporosis. However, regardless of the etiology, the initiating event in the process of osteoclastic activation is not yet completely understood. Common sites for osteoporotic fracture are the spine, hip, distal forearm, and proximal humerus. The presence of osteoporosis should be ascertained in all women aged 65 years. Men 65 years or women aged 65 years should be screened for the presence of risk factors such as early menopause ( 45 years), anorexia, smoking or alcohol abuse, chronic use of certain drugs, or diseases associated with an increased risk for osteoporosis (Cooper et al. 2011). Diagnosis is commonly based on the evaluation of bone mineral density (BMD) measurements, which provide prognostic information on the probability of future fractures and also on the evaluation of serological exams (erythrocyte sedimentation rate, blood cell count, protein electrophoresis, calcium/phosphorus, alkaline phosphatase, creatinine). There are a variety of procedures to assess BMD including dual energy x-ray absorptiometry, quantitative ultrasound, quantitative computed tomography, digital x-ray radiogrammetry, radiographic absorptiometry, and other radiographic techniques. Comprehensive treatment includes both a pharmacologic and non-pharmacologic approach. Current FDA-approved pharmacologic options



Interface Between Oral and Systemic Disease



include bisphosphonates, calcitonin, estrogen agonist/antagonist (raloxifene), estrogens and/or hormone therapy, tissue-selective estrogen complex (conjugated estrogens/bazedoxifene), parathyroid hormone (teriparatide), and receptor activator of nuclear factor kappa-B ligand inhibitor (denosumab). Nonpharmacologic approaches encompass limiting the risk of falls; maintaining adequate intake of calcium, vitamin D, and protein; performing adequate weight-bearing physical activity and exercise to maintain or improve balance and posture; and making appropriate lifestyle changes, such as smoking cessation and moderating alcohol intake.



Osteoarthritis Osteoarthritis (OA), the commonest arthropathy, also called osteoarthrosis or degenerative joint disease, is a progressive disorder of the joints caused by gradual loss of cartilage of one or more joints (usually knees, hips, and hands) typically with onset during middle or older age and resulting in the development of overgrowth of adjacent bone. The prevalence of OA varies depending on the specific joint(s) under study and the characteristics of the study population (i.e., 19.2% in knee OA in patients aged 45, 27.2% in hand OA, and 7% in hip OA) (Lawrence et al. 2008). OA is a multifactorial disease with systemic and local factors. Systemic factors are the cause of the onset of susceptibility of patients to have OA and include age, gender, ethnicity, bone density, congenital/developmental conditions, estrogen replacement therapy in postmenopausal women, nutritional factors, and genetics. Local factors include obesity, joint injury/surgery or deformity, occupation, muscle weakness, local biomechanical factors due to physical activity/sports or laxity or alignment. Although OA has been classified as a noninflammatory arthritis, increasing data on its pathogenesis show that multiple processes of inflammation occur, where different cytokines (i.e., interleukin-17) and metalloproteinases are released into the joint. These agents are involved in excessive matrix degradation that characterizes cartilage degeneration.



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Symptomatic OA is generally defined by the presence of pain, aching, stiffness, and locomotor restriction in a joint with radiographic evidence of OA. Signs of OA include coarse crepitus, bone enlargement (caused by bone remodeling, excessive osteophytosis, or joint subluxation), reduced range of movement, and joint-line tenderness. Muscle wasting and joint deformity occur with severe OA. Pain can derive from inflammatory processes with the stimulation of nociceptive fibers and mechanoreceptors in the synovium, subchondral bone, periosteum, capsule, tendons, or ligaments. Pain generally progresses through three stages: (a) early, with predictable sharp pain induced by mechanical insult and mild limitation of function; (b) mild/moderate where pain becomes regular with severe limitation of function during daily activities; and (c) advanced, where pain is constant and intense (Abhishek and Doherty 2013). Diagnosis is based on a history of joint pain worsened by movement; plain radiography may help in the diagnosis, but laboratory testing usually does not. Treatment strategies usually start with the use of nonsteroidal anti-inflammatory drugs associated with exercise, useful to reduce pain and disability, and glucosamine and chondroitin in combination. Other drug options include the use of corticosteroid and hyaluronic acid injections. Total joint replacement is recommended for symptomatic patients despite maximal medical therapy.



Fibromyalgia Fibromyalgia (FM) is a chronic pain syndrome characterized by dysregulation of pain-processing mechanisms and by widespread pain at multiple tender points, joint stiffness, and systemic symptoms (i.e., fatigue, sleep disturbances, mood disorders, and cognitive dysfunction). It affects 2–8% of the population; up to 85% of patients with FM are female, typically of childbearing age or older (Vincent et al. 2013). FM may arise de novo or evolve following nervous system sensitization after an identifiable triggering event or related to a peripheral pain generator such as osteoarthritis. The cause of fibromyalgia is not



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known; symptoms sometimes begin after physical trauma, surgery, infection, or significant psychological stress. In other cases, symptoms gradually accumulate over time with no single triggering event. However, many factors are known to aggravate existing symptoms. Cold, damp weather, mental health disturbance, physical or psychological stress, and also physical inactivity have all been associated with fibromyalgia. Familial studies have suggested an underlying genetic susceptibility on which environmental factors trigger the expression of symptoms (Buskila et al. 2007). Polymorphisms of serotonin transporters and dopamine receptors have also been evaluated in patients with FM; all these polymorphisms affect the metabolism or transport of monoamines, compounds that have a critical role in both sensory processing and the human stress response (Gürsoy et al. 2001; Buskila et al. 2004). Different studies confirm changes in neuroendocrine transmitters such as serotonin, substance P, growth hormone, and cortisol that suggest that the pathophysiology of the syndrome may be associated with autonomic and neuroendocrine regulation. Moreover, in FM the stress–adaptation response, modulated mostly by the hypothalamic-pituitary axis is disrupted, leading to stress-induced symptoms (Jahan et al. 2012). FM is a challenging diagnosis for many health care providers given the breadth of symptoms patients have on presentation and the paucity of specific objective findings. FM is often misdiagnosed because its symptoms are similar to other conditions like rheumatoid arthritis. There is no specific diagnostic laboratory test or biomarker available for the diagnosis of FM and diagnosis is made largely by clinical judgment. Medical care of FM and its comorbidities are quite difficult, time consuming, and costly; and this disorder also tends to be intractable. There is no reliable tool to predict treatment response in individual patients. There are currently no definitive treatments, but a combination of some medications (such as antidepressants, antiepileptic, anti-inflammatory agents), cognitive behavioral therapies/counseling, and lifestyle changes help relieve some of the symptoms and make the condition easier to live with.



M. D. Mignogna and S. Leuci



Oral Manifestations of Musculoskeletal Disorders Medications for the treatment of patients suffering from osteoarthritis may result in the development of oral lichenoid lesions. There can be a complex interplay between patients suffering fibromyalgia and the development of orofacial pain, particularly temporomandibular disorders, persistent idiopathic facial pain, and oral dysesthesia. These are discussed in detail in multiple chapters throughout this text, including ▶ “Arthritic Conditions Affecting the Temporomandibular Joint,” ▶ “Classification of Orofacial Pain,” ▶ “Diagnostic Imaging Principles and Applications in Head and Neck Pathology,” ▶ “Oral Dysesthesia,” and ▶ “Oral Manifestations of Systemic Diseases and Their Treatments.”



Hematological Disorders Blood diseases are collectively referred to as hematological disorders (HD) including a wide group of diseases, classified into four distinct categories: (i) hemoglobinopathy, (ii) anemia, (iii) hematological malignancies, and (iv) coagulopathies. Hemoglobinopathies are inherited disorders of globin, the protein component of hemoglobin (Hb); they are the most common genetic defect worldwide with an estimated 269 million carriers particularly in certain populations (South East Asia, sub-Saharan Africa and West Pacific region) (Angastiniotis and Modell 1998). Hemoglobinopathies are primarily grouped into thalassemia syndromes (α and β thalassemias) and structural hemoglobin variants (abnormal hemoglobins). They are caused by mutations affecting the production of α-globin chains and β-globin chains of the Hb molecule. The severity of the anemia and its consequences depend on the molecular defects that are involved in each affected individual. There are a number of clinically significant hemoglobins that do not alter the overall charge of the protein so are detected by other methods other than electrophoresis, e.g., isoelectric focusing, high-performance liquid chromatography, and immunologic techniques.



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Contact Phase Activation (Intrinsic Pathway)



PKa



Tissue Factor Pathway (Extrinsic Pathway)



PK



Tissue factor



HK



F VII



F VIIa F XI C1 Inhibitor F VIII



F XIa



Ca2+ F IX



Ca2+



F IXa



F VIIIa FX



FV



Ca2+



F Va



F Xa



Antithrombin III



Ca2+ prothrombin



Protein S



F Xa



TFPI



F XIIa



F XII



Protein C



Fibrinolysis



thrombin



fibrinogen



plasminogen



Fibrin monomer PAI-1



uPA, tPA



Fibrin ploymer F XIIIa TAFI



plasmin



Ca2+ Fibrin clot Clot lysis



α2-antiplasmin



Fig. 22 The blood coagulation cascade. (Adapted from Tapper and Herwald 2000)



The term “sickle-cell disease” includes all manifestations of abnormal Hb levels; these include homozygous sickle-cell disease and a range of mixed heterozygous hemoglobinopathies. It is a life-threatening genetic disorder characterized by chronic hemolytic anemia, vascular injury, and multiorgan dysfunction. The diagnosis of hemoglobinopathies in routine practice involves a red blood cell count with erythrocyte indices, and a hemoglobin test (hemoglobin electrophoresis and/or chromatography). Coagulophathies include various abnormalities of the coagulation system (Fig. 22), classified as: (1) disorders that affect primary hemostasis; (2) the coagulation pathways; and (3) the fibrinolytic system. Hemostasis is a complex physiological process, maintaining the fluidity of blood, and is regulated by the delicate balance existing between thrombogenic and antithrombogenic mechanisms present in the body. Defects of primary hemostasis may be due to abnormalities of



the vessel wall (i.e., Scurvy and Ehlers-Danlos syndrome, Henoch-Schonlein purpura, perivascular amyloidosis) or qualitative/quantitative defects of platelets that may cause bleeding in varying severity. A decreased platelet function can be inherited (Bernard-Soulier syndrome, Glanzmann thrombasthenia) or acquired (uremia, massive blood transfusion, drug-related); a reduced platelet number or thrombocytopenia can be caused by decreased production (common sign in hematological malignancies) or decreased survival (common in autoimmune diseases, in drug reactions, infections or hypersplenism). The normal coagulation pathway represents a balance between the pro-coagulant pathway that is responsible for clot formation and the mechanisms that inhibit the same beyond the injury site. Hence, coagulopathies can be categorized into disorders that lead to abnormal bleeding and those that lead to abnormal clotting (thrombophilia), in both cases acquired and hereditary (Table 15).



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M. D. Mignogna and S. Leuci



Table 15 Classification of coagulopathies Bleeding disorders Hereditary Von Willebrand disease Hemophilia A Hemophilia B Hemophilia C Factor V deficiency Factor X deficiency Factor VII deficiency Factor XIII deficiency Prothrombin deficiency Afribrinogenemia Acquired Consumptive Coagulopathies Disseminated intravascular coagulation Microangiopathic Hemolytic anemias Vitamin K deficiency Liver disease



Thrombotic disorders (thrombophilia) Hereditary Hereditary thrombophilia Antithrombin III deficiency Protein C deficiency Protein S Factor V Leiden (factor V mutation) Prothrombin mutation Factor II mutation (gene 20210 mutation)



Acquired Antiphospholipid antibody syndrome Increased levels of factors VIII, IX, XI or fibrinogen Fibrinolysis defects Homozygous homocystinuria



An excess of activation of the fibrinolytic system is associated with increased tendency to bleed, while deficiency of the same predisposes to thromboembolism. Excessive activation of fibrinolysis may be observed during cardiopulmonary bypass; hence, antifibrinolytics have a beneficial role in the prevention of same. Acquired hyperfibrinolysis may be seen in trauma, liver cirrhosis, amniotic fluid embolism, multiple myeloma, snake bite, and conditions associated with massive activation of tissue plasminogen activator, which can lead to disseminated intravascular coagulation (DIC) and hemorrhage.



Anemia Anemia (from the ancient Greek, anaimia, meaning “lack of blood”) is a common, multifactorial condition among older adults associated with a variety of adverse outcomes. It is defined by a decrease in the total amount of hemoglobin or



the number of red blood cells. According to the WHO, anemia is present if the blood concentration of hemoglobin (Hb) falls below 130 g/L in men or 120 g/L in women, except for infants, children, and pregnant women, who have their own lower limits of Hb concentration (WHO 1968). The WHO definition has not been adopted universally because Hb concentration in blood may vary depending on the population analyzed, age, gender, environmental conditions, and food habits (Beutler and Waalen 2006). For these reasons, epidemiological data can be largely different depending on the cut-off values of hemoglobin considered; definitive data towards differences between races need to be addressed. In line with the WHO definition and parameters, prevalence of anemia ranges from 9.2% to 23.9% in men, while in women the range is 8.1–24.7%. Anemia represents the first cause of medical visits in children and elderly people, where it is usually associated with nutritional deficiencies; on the other hand, anemia can be the first manifestation of a variety of systemic diseases. Anemia causes hypoxia and induces different compensating mechanisms. Signs and symptoms include fatigue, weakness, pale or yellowish skin, irregular heartbeats, shortness of breath, dizziness or lightheadedness, chest pain, cold hands and feet, and headache. Anemia can be classified from three points of view: pathogenesis, red cell morphology, and clinical presentation (Chulilla et al. 2009). In a diagnostic approach to the disease, it is mandatory firstly to distinguish if anemia is due to decreased red blood cell (RBC) production or to an increased RBC loss through the reticulocyte count. Reticulocytes are young RBC, usually present in the form of anemia due to hemolysis or bleeding. The reticulocyte count is used to assess the appropriateness of the bone marrow response to anemia. Anemia can be microcytic, macrocytic, and normocytic based on RBC size that can be small, large, or normal, respectively. RBCs are analyzed not only for size but also for morphology that in the normal state is characterized by a donut shape with the center third of the red cell being pale or without hemoglobin. Moreover, it is possible to recognize a hypochromic (decreased Hb per RBC) or



Interface Between Oral and Systemic Disease



normochromic (normal Hb per RBC) form of the disease. A complete blood cell count, Hb and hematocrit values, RBC indices, and peripheral blood smear constitute a baseline panel useful in the first step of diagnosis. The common causes of anemia are described in Table 16. Iron deficiency anemia is the most common subtype of anemia; it is a public health burden characterized by microcytic and hypochromic RBCs and reduction of iron stores, usually seen with low serum ferritin and low serum iron levels with high serum total binding capacity. Moreover, iron deficiency is associated with growth failure, immune system dysfunction, learning difficulties, and behavioral problems (Hurrell and Egli 2010). Generally, physiological iron levels are equal to 4–5 g with a complex balance and control of its absorption, mobilization, storage, and recycling, of which 25–30 mg daily are necessary for Hb synthesis. Iron recycling is carried out by spleen macrophages (90%) and about 10% is derived from diet (Zhang et al. 2014). Different causes may contribute to iron deficiency anemia such as genetic defects (Fanconi anemia), or increased iron demand not balanced by a correct supply (childhood, pregnancy, elderly). Another common cause of nutrition related anemia is the deficiency of vitamin B12 or cobalamin (less than 150 pmol/L). A correct daily dosage is 2.4 μg for men and nonpregnant women, 2.6 μg for pregnant women, 2.8 μg for lactating women, and 1.5–2 μg Table 16 Common causes of anemia Microcytic, hypochromic



Macrocytic



Normocytic, normal morphology Normocytic, abnormal morphology



Iron deficiency Thalassemia syndromes Sideroblastic anemia Transferrin deficiency Megaloblastic anemias Liver diseases Reticulocytosis Bone marrow failure Drugs Chronic diseases Infections Hemorrhage Hemoglobinopathies Hereditary Spherocytosis Autoimmune hemolytic anemia



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for children up to 18 years (Antony 2003). Diets free of animal products or patients affected by pernicious anemia (i.e., malabsorption) are the common causes of development of vitamin B12 deficiency. This causes a wide range of hematological, gastrointestinal, psychiatric, and in some cases permanent neurological disorders. Pernicious anemia is characterized by an increase of RBC mean corpuscular volume (MCV) and neutrophil hypersegmentation. Management of anemia is established based on the etiology of the disease; drugs, nutritional supplementation (iron, vitamins, folates), chemotherapy, surgery (splenectomy, bone marrow transplant), or blood transfusion are all potential strategies to treat the disease.



Leukemia The term leukemia, from the greek leukos “clear, white” and haima “blood,” encompasses a wide group of neoplasms involving the body’s blood-forming tissues, including the bone marrow and the lymphatic system with a final result of formation of abnormal white blood cells called “blasts.” The excessive number of abnormal cells can also interfere with the level of other cells, causing further harmful imbalance in the blood count. Leukemia represents 3.6% of all new cancer cases in the USA, most frequently diagnosed among people aged 65–74; the number of new cases is 13.5 per 100,000 men and women per year, while the number of deaths is 6.9 per 100,000 men and women per year (NIH-SEER 2016a). Didactically, leukemia is classified into four major categories: acute lymphoblastic leukemia (ALL) in adults and children, acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myelogenous leukemia (CML). In 2008, WHO in collaboration with the European Association for Haematopathology and the Society for Hematopathology revised and updated the classification based on genetics, morphologic, cytochemical, immunophenotypic, and clinical features of the disease (Vardiman et al. 2009). Common and general signs include



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enlarged lymph nodes, hypertrophic gingivitis, enlarged liver and spleen, fever, bleeding, bruising, fatigue, persistent mild or life-threatening infections, cutaneous rash (petechiae), headache, weight loss. Leukemic infiltration of the gingivae has been associated with monocytic variants of AML (M4) (Mani et al. 2008). Diagnosis involves a baseline blood test showing an abnormal white cell count and a consequent bone marrow biopsy may confirm and identify the specific type of leukemia (leukemic cells, DNA markers, and chromosome changes). The treatment and prognosis for leukemia depend on the type of blood cell affected and whether the leukemia is acute or chronic. In some patients, blood tests may not show variations, especially in the early stages of the disease or during remission. Anti-leukemic therapy in the acute forms of the disease is divided into 3 phases: (1) induction of complete remission with the use of different chemotherapies for reducing the leukemia mass in the shortest possible time and allowing growth of a normal bone marrow after aplasia; (2) consolidation of remission with the administration of drugs sequentially or alternatively, to eliminate leukemic cells resistant to the drugs used in induction and to reduce the risk of chemoresistance; and (3) maintenance phase (2–3 years), in which different drugs are used, either continuously or alternately, to eliminate residual leukemic cells in the cellular quiescent phase. Chemotherapy approaches with specific information on drugs and regimes for AML and ALL are described in Table 17. Allogenic heterologous transplantation is indicated in case of high risk of recurrence in patients