Essential Head and Neck Oncology and Surgery [Team-IRA] [1 ed.] 9798886974386, 9798886977462, 9781685072209, 9781685073893

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KJ Lee Essential Medicine Series

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KJ Lee Essential Medicine Series K. J. Lee, MD, FACS - Series Editor-in-Chief Yale University School of Medicine Quinnipiac University Netter School of Medicine Hamden, Connecticut, USA Hofstra University Zucker School of Medicine Hempstead, New York, USA

Essential Head and Neck Oncology and Surgery Maie A. St. John, MD, PhD, FACS (Editor) Benjamin L. Judson, MD, MBA (Editor) Josephine H. Nguyen, MD (Assistant Editor) 2023. ISBN: 979-8-88697-438-6 (Hardcover) 2023. ISBN: 979-8-88697-746-2 (e-book) Essential Sleep Medicine and Surgery Maria V. Suurna, MD, FACS (Editor) Stacey L. Ishman, MD (Editor) Josephine H. Nguyen, MD (Assistant Editor) 2022. ISBN: 978-1-68507-220-9 (Hardcover) 2022. ISBN: 978-1-68507-389-3 (e-book)

More information about this series can be found at https://novapublishers.com/productcategory/series/kj-lee-essential-medicine-series/

Maie A. St. John and Benjamin L. Judson Editors

Josephine H. Nguyen Assistant Editor

Essential Head and Neck Oncology and Surgery

Copyright © 2023 by Nova Science Publishers, Inc. DOI: https://doi.org/10.52305/WVLB7531 All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. We have partnered with Copyright Clearance Center to make it easy for you to obtain permissions to reuse content from this publication. Please visit copyright.com and search by Title, ISBN, or ISSN. For further questions about using the service on copyright.com, please contact:

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NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers’ use of, or reliance upon, this material. Any parts of this book based on government reports are so indicated and copyright is claimed for those parts to the extent applicable to compilations of such works. Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the Publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regards to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS.

Library of Congress Cataloging-in-Publication Data Names: St. John, Maie A., M.D., Ph.D., FACS, editor. | Judson, Benjamin L., editor. Title: Essential head and neck oncology and surgery / Maie A. St. John, MD, PhD, FACS (editor), Department of Head and Neck Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA, Benjamin L. Judson, MD, MBA (editor), Division of Otolaryngology, Department of Surgery, Yale School of Medicine, New Haven, CT, USA. Identifiers: LCCN 2023012174 (print) | LCCN 2023012175 (ebook) | ISBN 9798886974386 (hardcover) | ISBN 9798886977462 (adobe pdf) Subjects: LCSH: Head--Cancer--Treatment. | Neck--Cancer--Treatment. | Head--Cancer--Surgery. | Neck--Cancer--Surgery. Classification: LCC RC280.H4 E86 2023 (print) | LCC RC280.H4 (ebook) | DDC 616.99/491--dc23/eng/20230414 LC record available at https://lccn.loc.gov/2023012174 LC ebook record available at https://lccn.loc.gov/2023012175

Published by Nova Science Publishers, Inc. † New York

This book is affectionately dedicated to my patients whose courage is my guiding light. To my parents whose interest in this, as in all my ventures was never less than my own. To my dear husband Rick, whom I met in college, and who has made every single moment of my life better ever since. The final word of gratitude is to my incredible three sons for teaching me that indeed only from the heart can you touch the sky. Maie A. St. John

This book is dedicated to my wife Kara, and our sons Sam and Nate. I would like to thank my mentors, teachers, colleagues, and friends whose support and company have made travel along this career path possible and a joy. Finally, I hope readers gain something from this book that helps them care skillfully and compassionately for their patients. Benjamin L. Judson

Contents

Foreword and Acknowledgments ......................................................................................... xi Preface

.................................................................................................................... xiii

Additional Acknowledgments .............................................................................................. xv Chapter 1

Oral Cavity, Pharynx, and Larynx Anatomy, Physiology, and Other Basics .......................................................................................... 1 Sagar Kansara, MD, Dennis Kraus, MD and Patrick Ha, MD

Chapter 2

Temporal Bone and Skull Anatomy, Physiology, and Other Basics ........................................................................................ 11 Sujana S. Chandrasekhar, MD and Hosakere K. Chandrasekhar, MD

Chapter 3

Neck Spaces and Fascial Planes ................................................................ 31 Omar A. Karadaghy, MSCI, MD, Mia Jusufbegovic, MD, Jeffrey M. Blumberg, MD, FACS and Yelizaveta Shnayder, MD, FACS

Chapter 4

Thyroid and Parathyroid Glands ............................................................. 51 Tyler R. Halle, MD, Lindsay C. Boven, MD, Amr H. Abdelhamid Ahmed, Amy Y. Chen, MD and Gregory W. Randolph, MD

Chapter 5

Salivary Gland Diseases ............................................................................ 99 Rosh K. V. Sethi, MD, MPH, Wojciech K. Mydlarz, MD, David Eisele, MD and Daniel G. Deschler, MD

Chapter 6

Cysts and Neoplasms of the Mandible and Maxilla .............................. 123 Tara Aghaloo, MD, PhD, Ali Salehpour, MD, Brett A. Miles, MD and David Hirsch, MD

Chapter 7

Carotid Body Tumors, Paragangliomas and Vascular Anomalies ................................................................................................. 177 Paul Zolkind, MD, Tammara Lynn Watts, MD and Davud Sirjani, MD

Chapter 8

Leukoplakia, Erythroplakia, and Premalignant Lesions ..................... 189 Hunter Archibald, MD, Ashok Jethwa, MD and Frank Ondrey, MD, PhD

viii

Contents

Chapter 9

TNM Staging in Head and Neck Cancers .............................................. 207 Michael H. Berger, MD, Jose P. Zevallos, MD and William B. Armstrong, MD

Chapter 10

Overview of Guidelines and Evidence Based Care in Head and Neck Cancer ...................................................................................... 229 Saral Mehra, MD, MBA, Oded Cohen, MD and Babak Givi, MD

Chapter 11

Non-Melanoma Skin Cancers ................................................................. 241 Arielle Thal, MD, Thomas J. Ow, MD, MS, FACS and Cecelia E. Schmalbach, MD, MSc, FACS

Chapter 12

Malignant Melanoma of the Head and Neck ......................................... 257 Peter Yao Kelly Malloy, MD and Luc G. T. Morris, MD

Chapter 13

Tumors of the Oral Cavity and Oropharynx ........................................ 275 Danielle M. Bottalico, MD, Amy C. Hessel, MD and Richard Smith, MD

Chapter 14

HPV+ Oropharyngeal Cancers: Today and Tomorrow ....................... 313 Donovan Eu, MD, FAMS, Ameya A. Asarkar, MD, FACS and Jonathan Irish, MD, FRCS

Chapter 15

Tumors of the Larynx, Hypopharynx, and Cervical Esophagus ......... 331 Ameya A. Jategaonkar, MD, Timothy Blood, MD, Dinesh K. Chhetri, MD and David M. Cognetti, MD

Chapter 16

Skull Base and Sinonasal Tumors .......................................................... 347 Janet Chao, MD Thad Vickery, MD Michelle Chen, MD, MHS, R. Peter Manes, MD and Daniel M. Beswick, MD

Chapter 17

Minimally Invasive Surgical Techniques for the Management of Head and Neck Cancers ............................................... 367 Umamaheswar Duvvuri, MD, PhD and Benjamin L. Judson, MD, MBA

Chapter 18

Neck Dissection and Management of the Neck...................................... 383 Samuel Auger, MD, Gina Jefferson, MD, MPH, FACS and Nishant Agrawal, MD

Chapter 19

Head and Neck Reconstructive Surgery ................................................ 397 Kristen A. Echanique, MD, Joseph B. Meleca, MD, Heather Edwards, MD, Michael Fritz, MD, FACS and Rhorie P. R. Kerr, MD

Chapter 20

Chemotherapy, Targeted Therapy and Clinical Trials ........................ 425 Kartik Sehgal, MD, Deborah J. Wong, MD, PhD and Robert Haddad, MD

Contents

ix

Chapter 21

Immunosurveillance and Immunotherapeutic Approaches in Head and Neck Cancer........................................................................ 437 Vikash Kansal, PhD, Robert L. Ferris, MD, PhD and Nicole C. Schmitt, MD

Chapter 22

Targeted Radiation for Head and Neck Cancer: Specificity and De-Escalation.................................................................. 453 James H. Laird, MD Jie Deng, MD, PhD, Sumi Sinha, MD, Robert K. Chin, MD, PhD, Sue S. Yom, MD, PhD and Henry S. Park, MD, MPH

Chapter 23

Surviving and Thriving: Survivorship in the 21st Century .................. 469 Jymirah R. S. Morris, David A. Rapkin, PhD, Marci L. Nilsen, PhD and Jonas T. Johnson, MD

Chapter 24

It Takes a Village: State of the Art Multidisciplinary Care ................. 507 Kenric Tam, MD, Catherine T. Haring, MD, Carol R. Bradford, MD and Maie A. St. John, MD, PhD

Answers to Multiple Choice Questions.............................................................................. 5 About the Editors ................................................................................................................ 525 List of Contributors ............................................................................................................ 527 Index

................................................................................................................... 537

Foreword and Acknowledgments

As the knowledge of medicine has grown exponentially, it is necessary to have books each encompassing one subspecialty. I had the vision of creating a book for each subspecialty building from the formula and on the success of Essential Otolaryngology-Head and Neck Surgery, the inceptive book, which is in its 12th Edition, 49th year, and has been translated into several languages. It was cited as one of the most read texts in the field worldwide. Working with President Nadya S. Gotsiridze-Columbus, CEO of Nova Science Publishers, Inc., we developed K. J. Lee Essential Medicine Series, to host the subspecialty books. After a national search, we were fortunate to have Dr. Ben Judson and Dr. Maie St. John to be Editors of this book and Dr. Josephine Nguyen to be Assistant Editor to compile the ever important Practice Guidelines. We commend the scholarly contents of the chapter contributing authors. It is with great pleasure and honor for me to say they all worked very hard and have done a superb job. I thank them all and kudos to them. Like the inceptive book, I have no doubt this book will find its way to libraries, to the reference sections of emergency rooms, urgent care centers, as well as the dorm rooms, apartments, and homes of medical students, residents, fellows, young attendings, physician assistants, nurse practitioners and others. This book is not only a great text and reference for medical professionals, but it can also be of value for people outside the medical field to understand key concepts in order to better communicate with providers. K. J. Lee, MD, FACS, Editor-in-Chief KJ Lee Essential Medicine Series

Preface

This textbook presents a succinct yet comprehensive overview of the current essential topics in the multidisciplinary care of head and neck cancer patients. With each chapter written by experts in the many fields that comprise head and neck oncology and surgery, this compendium provides a unique, multidisciplinary perspective on the diagnosis and management of these patients. Information is presented in outline format to optimize the learning experience with multiple-choice questions to consolidate learning and practice guidelines to strengthen one’s grasp of the topics while presenting the opportunity for efficient reference. Finally, this textbook’s outline format, clear and concise language, and rich set of practice guidelines make it a trusted resource for nonmedical professionals hoping to learn more about head and neck cancer patients and their treatments.

Additional Acknowledgments

We wish to thank Penny Amescua and Christy Collins, whose tireless efforts, and unparalleled attention to detail, brought this book to fruition. We also would like to thank the chapter authors who have contributed their invaluable expertise and precious time which has made this book a reality. Finally, we wish to thank our inimitable mentor, Dr. K.J. Lee, who is the inspiration and foundation for this compendium. Dr. Lee, we are privileged to have had this opportunity to learn from you and count you as a lifelong friend and mentor.

Chapter 1

Oral Cavity, Pharynx, and Larynx Anatomy, Physiology, and Other Basics Sagar Kansara, MD Dennis Kraus, MD and Patrick Ha, MD Oral Cavity Anatomy (see Figure 1) – anatomic space from vermilion border to junction of hard/soft palate and circumvallate papillae

Figure 1. Oral cavity anatomy.

1. Subsites a. Vestibule i. Wet lip In: Essential Head and Neck Oncology and Surgery Editors: Maie A. St. John and Benjamin L. Judson

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ii. Labial and buccal gingiva and dentition iii. Buccal mucosa b. Oral cavity proper i. Oral tongue-ventral, dorsal, lateral border ii. Alveolar ridge iii. Mesial dentition and gingiva iv. Hard palate v. Floor of mouth vi. Retromolar trigone 2. Contents a. Minor salivary glands – hundreds scattered throughout mucosa, palate, oral tongue, base of tongue b. Salivary ducts i. Parotid duct (Stensen)-lateral to second molars ii. Wharton’s duct-midline floor of mouth, near the lingual frenulum c. Dentition − 32 adult teeth, numbered from superior right to superior left (116), inferior left to inferior right (17-32) d. Oral tongue i. Papillae − house taste buds, covers surface of anterior 2/3 of tongue e. Filiform f. Fungiform g. Foliate h. Circumvallate − V shape at the junction of anterior 2/3 and posterior 1/3, posterior to sulcus terminalis i. Lingual frenulum − mucosal fold attaching tongue to floor of mouth and gingiva. ii. Foramen cecum – see embryology iii. Lingual tonsil, vallecula – see oropharynx 3. Lymphatic drainage a. Oral cavity most often drains to level Ia, Ib, IIa, III. Midline structures such as anterior floor of mouth and tongue tip/posterior tongue often drain bilaterally. 4. Musculature a. Extrinsic tongue muscles (CN XII) i. Genioglossus ii. Hyoglossus iii. Styloglossus iv. Palatoglossus b. Intrinsic tongue muscles (CN XII) i. Longitudinal ii. Vertical iii. Transverse c. Floor of mouth musculature i. Mylohyoid (CN V-nerve to mylohyoid) ii. Geniohyoid (cervical plexus)

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iii. Anterior belly of digastric (CN V) 5. Arterial Supply a. Lingual artery branches i. Deep lingual ii. Dorsal lingual iii. Sublingual iv. Suprahyoid b. Facial artery branches i. Tonsillar ii. Labial iii. Ascending palatine c. Internal maxillary artery branches i. Descending palatine artery (via greater and accessory palatine foramen) 6. Innervation a. Anterior 2/3 tongue − CN V3 mediates pain, touch, temperature. Taste via chorda tympani. Lingual nerve -> chorda tympani -> geniculate ganglion -> nervus intermedius -> nucleus solitarius b. Greater palatine foramen-transmits descending palatine branch of V2 for sensory afferents, medial to upper second molar 7. Embryologic origin a. Fourth week of gestation, 1st-4th pharyngeal arches contribute b. Tuberculum impar (first arch) joins with lateral lingual swellings to form anterior 2/3 tongue c. Hypobranchial eminence develops concurrently to form posterior 1/3 d. Foramen cecum: invagination of the sulcus terminalis, origin of embryologic thyroid from which it descends into the neck.

Oropharynx 1. Anatomy − hard/soft palate junction to vallecula 2. Subsites a. Base of tongue (posterior 1/3 of tongue)/lingual tonsil b. Palatine Tonsil, lateral pharyngeal wall c. Posterior pharyngeal wall d. Uvula/soft palate e. Pharyngoepiglottic and glossoepiglottic folds f. Vallecula 3. Lymphatic drainage a. Level IIa, IIb, III, IV, rarely level I b. Midline structures such as base of tongue drain bilaterally 4. Musculature (via CN X, pharyngeal plexus) a. Palatoglossus (CN X) b. Palatopharyngeus (CN X)

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c. Musculus uvulae (CN X) d. Levator palatini (CN X) e. Tensor veli palatini (CN V3) f. Stylopharyngeus (CN IX) g. Superior constrictor (CN IX/X- pharyngeal plexus) 5. Arterial Supply a. Lingual artery branches (see oral cavity) b. Facial artery branches (see oral cavity) c. Ascending pharyngeal (via tonsillar branch) d. Maxillary (via descending palatine/tonsillar branch) 6. Innervation a. Posterior 1/3 tongue- visceral afferents (touch and gag) as well as sensation via CN IX to nucleus solitarius. Taste (base of tongue and valleculae papillae) also nucleus solitarius via CN IX. b. Palate: sensory afferents via nasopalatine and greater palatine nerves (CN V) 7. Embryologic origin a. Tonsil-second pharyngeal pouch. Tonsillar pillars arise from the second and third arches. (see Figure 2)

Figure 2. Branchial arch derivatives.

1. Oral Cavity, Pharynx, and Larynx Anatomy, Physiology, and Other Basics

Figure 3. Larynx and pharynx anatomy.

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Larynx and Hypopharynx 1. Anatomy (see Figure 3)-Lingual surface of epiglottis to esophageal inlet and cricoid a. Supraglottis i. Epiglottis (supra and infra-hyoid) • Quadrangular membrane – supporting fibroelastic membrane, extends from epiglottis to arytenoid/corniculate • Pre epiglottic space: bounded by hyoepiglottic ligament superiorly, thyrohyoid membrane anteriorly, epiglottis and thyroepiglottic ligament posteriorly ii. Aryepiglottic folds iii. Arytenoids iv. False vocal folds b. Glottis i. True vocal folds • Conus elasticus – supporting fibroelastic membrane, extends from cricoid to merge with vocal ligament • Reinke’s space – superficial lamina propria of true vocal fold • Paraglottic space: bounded by thyroid cartilage laterally, quadrangular membrane superomedially, ventricle medially, conus elasticus inferomedially, posteriorly by piriform sinus ii. Anterior commissure c. Subglottis/trachea i. Glottis to inferior border of cricoid d. Hypopharynx i. Post cricoid space ii. Piriform sinus 2. Lymphatic drainage a. Level IIa, IIb, III, IV, VI, VII b. Supraglottis, post cricoid space, anterior commissure – bilateral nodal drainage 3. Musculature a. Laryngeal musculature i. Intrinsic • Transverse arytenoid • Lateral cricoarytenoid • Posterior cricoarytenoid (only abductor of vocal cord) • Vocalis/Thyroarytenoid − Broyle’s tendon – insertion of vocalis tendon to thyroid cartilage • Cricothyroid-vocal fold tension-pitch. ii. Extrinsic • Suprahyoid musculature • Infrahyoid musculature • Stylopharyngeus • Arterial Supply

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− −

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Superior laryngeal artery (via superior thyroid arteryExternal carotid) – supraglottis Inferior laryngeal artery (via inferior thyroid arterythyrocervical trunk) – Glottis and subglottis

4. Innervation a. Superior laryngeal nerve (CN X) − internal – sensation of supraglottis, external-motor to cricothyroid b. Recurrent laryngeal nerve (CN X) − all intrinsic muscles of larynx except for cricothyroid (via external branch of SLN) i. Right – loops around subclavian ii. Left – loops around arch of aorta iii. Non recurrent nerve more common on the right – can result from aberrant subclavian artery, resulting in dysphagia lusoria. Rarely can occur on the left – associated with situs inversus. c. CN X/pharyngeal plexus – sensation to pharyngeal, esophageal inlet mucosa 5. Embryologic origin (see Figure 2) a. Supraglottis – third and fourth arch i. Glottis and subglottis – sixth arch

Physiology a.

ii.

Swallow i. Oral phase • Mastication - Muscles of mastication (CN V3) − Pterygoids (medial and lateral)-lateral pterygoid is the only muscle to protrude and open the jaw − Masseter − Temporalis • Salivation (visceral efferent) − Parotid gland o Inferior salivatory nucleus -> Glossopharyngeal -> Jacobson’s nerve -> Lesser petrosal nerve (pre ganglionic parasympathetic) -> Otic ganglion -> Auriculotemporal nerve to parotid − Submandibular and sublingual gland o Superior salivatory nucleus -> nervus intermedius -> facial nerve -> chorda tympani (pre ganglionic parasympathetic) -> submandibular ganglion -> gland • Control and preparation of bolus via buccinator, palate, tongue, lips, dentition, orbicularis Pharyngeal phase-bolus transit from oropharynx through upper esophageal sphincter into esophagus

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a.

iii.

Palate elevation (levator/tensor muscles) and posterior movement to contact posterior pharyngeal wall (Passavant ridge), thus preventing velopharyngeal insufficiency. b. Glottic closure, true and false fold as well as arytenoid contraction c. Hyoid and larynx move superiorly and anteriorly d. Bolus propulsion via tongue base and constrictor contraction e. Relaxation of upper esophageal sphincter, cricopharyngeus Esophageal phase a. Primary peristalsis and relaxation of lower esophageal sphincter

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References [1] [2]

[3]

Robbins, J., Hamilton, J. W., Lof, G. L. & Kempster, G. B. Oropharyngeal swallowing in normal adults of different ages. Gastroenterology 103, 823–829 (1992). Ferlito, A., Robbins K. T., Shah J. P., Medina J. E., Silver C. E., Al-Tamimi S., Fagan J. J., Paleri V., Takes R. P., Bradford C. R., Devaney K. O., Stoeckli S. J., Weber R. S., Bradley P. J., Suárez C., Leemans C. R., Coskun H. H., Pitman K. T, Shaha A. R., de Bree R., Hartl D. M., Haigentz Jr M., Rodrigo J. P., Hamoir M., Khafif A., Langendijk J. A., Owen R. P., Sanabria A., Strojan P., Vander Poorten V., Werner J. A., Bień S., Woolgar J. A., Zbären P., Betka J., Folz B. J., Genden E. M., Talmi Y. P., Strome M., González Botas J. H., Olofsson J., Kowalski L. P., Holmes J. D., Hisa Y., Rinaldo A. Proposal for a rational classification of neck dissections. Head Neck 33, 445–450 (2011). Hollingshead, W. Textbook of Anatomy. (Harper and Row, 1974).

Chapter 2

Temporal Bone and Skull Anatomy, Physiology, and Other Basics Sujana S. Chandrasekhar, MD and Hosakere K. Chandrasekhar, MD Temporal Bone Pneumatization, Bony (Osseous) Anatomy, and Muscular Attachments 1. The paired temporal bones are located at the lateral skull base in a pyramidal shape with the base laterally and apex medially and are pneumatized (aerated). a. The reasons for temporal bone pneumatization are postulated to include: i. pressure buffer ii. gas reserve iii. shock absorption spaces b. Spaces that are pneumatized are, from laterally to medially: i. Mastoid – the largest air space in the mastoid is called the antrum ii. Aditus ad antrum – connection between mastoid and tympanic cavities iii. Tympanic cavity (including epitympanum, hypotympanum, protympanum) iv. Petrous apex − can be aerated or filled with marrow bone c. Practice Guideline: Poor pneumatization of the temporal bone correlates with increased incidence and poor prognosis of: atelectasis, otitis media, cholesteatoma, and otic capsule injury in temporal bone fracture. 2. The temporal bone is comprised of six different bones: a. Squamous i. Is the largest part of the temporal bone, flat and plate-like, located anterosuperiorly ii. The external surface of the squamous bone is convex in shape and this temporal fossa and the lower part of the squamosa are the site of origin of the temporalis muscle iii. It articulates superiorly with the parietal bone and anteroinferiorly with the greater wing of the sphenoid bone

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b. Petrous i. Located posteriorly and medially ii. Is pyramid-shaped iii. Contains the inner ear and transmits the internal auditory canal and carotid artery c. Mastoid i. Located posteriorly and laterally ii. Lateral surface gives attachment to splenius capitis and longissimus capitis, overlain by sternocleidomastoid. iii. From the medial surface it gives attachment to the posterior belly of the digastric muscle iv. Its inferior portion is the mastoid process, which is absent or rudimentary at birth and only forms postnatally as the sternocleidomastoid muscle develops and pulls on the bone. • Practice Guideline: Because the extratemporal facial nerve is not protected by the mastoid bone at birth or in early childhood, it is susceptible to blunt trauma such as forceps delivery or a minor fall and is susceptible to laceration injury from a postauricular incision that extends inferiorly. d. Tympanic i. Lies inferiorly to the squamous, and anteriorly to the petromastoid ii. Reversed C-shaped • Posterior surface goes into the formation of the external auditory meatus • Anterior surface forms the posterior wall of the non-articular mandibular fossa e. Zygomatic Process i. Arises from the lower part of the squamous bone ii. Projects anteriorly, articulating with the temporal process of the zygomatic bone, to form the zygomatic arch iii. Posteriorly, it has a downward projection called the articular tubercle, which is the anterior boundary of the mandibular fossa, the articular part of the temporomandibular joint (TMJ) iv. The masseter muscle attaches to the inferior and medial surfaces of the zygomatic process f. Styloid Process i. Located immediately inferior to the opening of the auditory meatus ii. Acts as an attachment point for muscles and ligaments, such as the stylopharyngeus muscle and the stylomandibular ligament of the TMJ 3. The bony external auditory canal is nearly 2 cm long and arises from 4 bones: a. Its anterior wall and floor and the lower part of its posterior wall are formed by the tympanic bone

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b. The roof and upper part of the posterior wall are formed by the squamous bone c. Supero-posterior to the external opening is the suprameatal triangle with the spine of Henle d. Its inner end is closed by the tympanic membrane sitting in the bony annulus

External Ear Anatomy and Physiology 1. The external ear comprises the pinna and external auditory canal (EAC). Its function is to transmit sounds to the tympanic membrane. 2. The external 1/3 of the EAC is cartilaginous; the inner 2/3 is bony (see bony EAC above). The skin of the canal is thicker in the cartilaginous portion, includes a welldeveloped dermis and subcutaneous layer, and contains glands and hair follicles. The skin lining the osseous portion is thinner, firmly attached to the periosteum, and lacks a subcutaneous layer. 3. Cerumen is produced by the combination of secretions of two types of glands in the cartilaginous EAC and serves to clean, lubricate and has a slightly acidic pH that inhibits bacterial and fungal growth. Cerumen prevents epithelial maceration that can occur from residual moisture in the ear canal. The two glands and their products are: a. Sebaceous glands produce sebum b. Modified apocrine glands produce apocrine sweat 4. Sensory Innervation of the EAC: a. Greater auricular nerve and lesser occipital nerve (branches of the cervical plexus) innervate the skin of the auricle b. Auriculotemporal nerve (branch of the mandibular nerve) innervates the skin of the auricle and external auditory meatus. c. Branches of the facial and vagus nerves innervate the deeper aspect of the auricle and external auditory meatus i. Practice Guideline 1: the branch of the vagus nerve in the ear canal is called Arnold’s nerve, nicknamed Alderman’s nerve. Aldermen (town councilmen) were known to scratch their ear canals with their pen’s quills in order to stimulate this nerve and set of a coughing fit, enabling them to leave meetings early. ii. Practice Guideline 2: an early sign of vestibular schwannoma can be diminished sensation of the upper outer part of the EAC due to compression of the facial nerve in the internal auditory canal. This is called Hitselberger’s sign but it is primarily of historical significance. 5. Lymphatic Drainage is to the superficial parotid, mastoid, upper deep cervical and superficial cervical nodes

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Figure 1. Osseous temporal bone anatomy, medial view.

Figure 2. Osseous temporal bone anatomy, lateral view.

Middle Ear Anatomy and Physiology Overview The middle ear lies within the temporal bone and extends from the tympanic membrane to the lateral wall of the inner ear. The main function of the middle ear is to transmit vibrations from the tympanic membrane to the inner ear via the auditory ossicles. There are two shared

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but relatively distinct spaces: the mesotympanum (middle ear) and the epitympanum (attic). Subsets of the mesotympanum include the hypotympanum inferiorly and protympanum anteriorly. 1. Walls of the middle ear: The middle ear can be visualized as a closed space, with a roof and floor, medial and lateral walls and anterior and posterior walls. a. Roof (tegmen tympani) is formed by a thin bone from the petrous part of the temporal bone. It separates the epitympanic part of the middle ear from the middle cranial fossa i. It is contiguous with the roof of the mastoid, also called tegmen mastoidii or tegmen antrii (for roof of antrum) b. Floor contains the hypotympanic air cells, beneath which lies a thin layer of bone over the internal jugular vein (or jugular bulb) c. Lateral wall is made up of the tympanic membrane - pars tensa is defined by the tympanic ring and, superiorly, pars flaccida is defined by the notch of Rivinus d. Medial wall is formed by the promontory, which is the lateral wall of the otic capsule (inner ear) and contains a prominent bulge of the horizontal facial nerve canal and, anteriorly towards the protympanum, the semicanal of the tensor tympani muscle e. Anterior wall is a thin bony plate with superior openings for the Eustachian tube, the tensor tympani muscle and the chorda tympani nerve (iter chordae anterior). It separates the middle ear from the internal carotid artery f. Posterior wall (mastoid wall) consists of a lower bony partition between the tympanic cavity and the mastoid air cells i. Superiorly, there is an opening in this partition, the aditus ad antrum, which allows for air flow between the middle ear and mastoid. ii. Inferiorly, there is a potential space, the facial recess, between the vertical lie of the facial nerve medially and the chorda tympani nerve in iter chordae posterior (before it enters the middle ear space). • Practice Guideline: The facial recess is used surgically to enhance aeration pathways in canal wall up surgery, to define the level when taking the canal wall down in chronic ear disease, or to provide access for implantation of hearing devices such as cochlear implants and active middle ear implants. 2. Mucosal lining of the middle ear: a. The middle ear is lined with squamous and ciliated columnar cells. b. The posterior mucosal lining is composed of non-secretory flat squamous epithelium. The number of ciliated columnar epithelial cells in the mucosal lining progressively increases toward the eustachian tube to constitute about 80% of the cells adjacent to the eustachian tube entrance. c. These histomorphological changes evidence the progressive transformation from flat, nonsecretory squamous epithelium to respiratory epithelium that is

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pseudostratified, ciliated columnar cells just proximal to the eustachian tube entrance. d. The changing cellular architecture of the middle ear cavity facilitates function of an organized mucociliary transportation system from primarily the epitympanum and hypotympanum to the eustachian tube.

Tympanic Membrane 1. The tympanic membrane (TM) is the medial wall of the EAC and lateral wall of the middle ear. The larger surface area is called the pars flaccida and the smaller, superior, portion is called the pars tensa. The membranous annulus of the TM sits within the bony annulus of the tympanic ring and holds the membrane in place to allow for its vibration in response to sound. 2. Sound vibrations in air are captured by the EAC and cause a movement in the TM which then creates oscillation of the ossicles. This movement helps to transmit the sound waves from the tympanic membrane to the oval window at the internal ear. 3. Its diameter is about 8–10 mm and its shape is that of a flattened cone with its apex directed inward. The ratio of the surface area of the TM to the oval window is 20:1, and that serves to allow adequate energy transfer between air and the inner ear fluids, preserving approximately 98% of the sound energy. 4. Structure of the TM is three-fold: a. The lateral or outer or epithelial layer arises from the first branchial arch embryologically b. The middle, fibrous layer, has two layers within it: one circular array and one radial array of fibers, giving the TM its strength. i. Practice Guideline: Calcium depositions in the TM are in the fibrous layer, called myringosclerosis if only involving the TM and tympanosclerosis if also involving other middle ear structures, and are secondary to infection and inflammation. c. The medial or inner or mucosal layer arises from the first branchial pouch embryologically. 5. Practice Guideline: Congenital cholesteatoma is caused when, in the developing TM, the lateral (epithelial) layer gets pinched inside into the medial (mucosal) layer as the first branchial arch and pouch meet. That small ‘knuckle’ of epithelium is then trapped inside the middle ear and is often seen as a small white ball or pearl just anterior to the neck of the malleus. It may be missed and only identified after it has grown or disrupted its sac.

Ossicles 1. The bones of the human middle ear are the malleus (hammer), incus (anvil) and stapes (stirrup). They are connected via two joints: a. The incudomallear joint is a synovial joint in the epitympanum between the head of the malleus and the body of the incus.

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4.

5.

6.

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b. The incudostapedial joint is a ball-and-socket synovial joint between the lenticular process of the incus and the head of the stapes. Malleus has no body; incus has no head; stapes has no neck. The malleus is the largest and most lateral of the ear bones, attaching to the tympanic membrane, via its handle or manubrium. The head of the malleus lies in the epitympanic recess, where it articulates with the body of the incus. The inferior most end of the malleus is the umbo, which is attached to the TM at the apex of its mediallyfacing cone. a. The average weight of the malleus is 23 mg. The average length of the malleus is 8.23 to 8.53 mm, with 4.72 mm for head and neck and 4.17 mm to 5.20 mm for the manubrium. The incus consists of a body and two limbs. The body articulates with the head of the malleus in the attic. The shorter limb is the short process and extends posteriorly from the body to the aditus ad antrum. The longer limb is the long process which extends into the posterior middle ear. It ends in a right angle at the small lenticular process of the incus, which then articulates with the head of the stapes. a. The average weight of the incus is 27 mg. The average total length (body to end of long process) of the incus is 7.04 mm. The average width (body to end of short process) is 5.31 mm. The average length of the long process in 3.27 mm. The average angle between the two limbs of the incus is 97.230. The stapes is the smallest bone in the human body. It is stirrup-shaped, with a head, two limbs (the anterior and posterior crura), and a base (footplate). The head articulates with the incus, and the base joins the oval window of the inner ear. a. The average weight of the stapes is 2.5 mg. Its mean total height is 3.44 mm. The footplate length is an average of 3.04 mm and its width is 1.10 mm. The angle between the crura is 51.010. b. The footplate of the stapes is thicker at the poles (anterior crus (AC) and posterior crus (PC)) than in the middle. i. In the normal stapes, the footplate thickness is 0.61 mm at AC, 0.46 mm at the midpoint, and 0.64 mm at the PC. ii. In a series of patients with otosclerosis, the footplate was significantly thicker: 0.94 mm at the AC, 0.60 mm at the midpoint, and 0.72 mm at the PC. iii. The distance from the udersurface of the footplate to the saccular membrane is 1 to 1.5 mm. iv. Practice Guideline: When performing stapes surgery, neither the instrument used to perforate the footplate nor the prosthesis should be allowed to enter more than 0.25 mm past the footplate, to minimize risk of post-stapes surgery sensorineural hearing loss. The malleus and incus arise from the first branchial arch. The stapes arises from the second branchial arch. The stapes footplate has a dual origin, from the second arch laterally and the otic capsule medially.

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From: https://simple.wikipedia.org/wiki/Ossicles. Figure 3. Auditory ossicles.

From: https://emedicine.medscape.com/article/1290547-overview#a2. Figure 4. Intratemporal course and branches of the facial nerve.

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Muscles and Nerves in the Temporal Bone 1. Facial Nerve a. The facial nerve (CN VII) is a mixed nerve with both motor and visceral components. i. The motor nerve has its origin in the lower pons and then the fibers run dorsally to reach the floor of the fourth ventricle, where the fibers make their first genu (bend) on the surface of the abducens nucleus, then exit the pons just above the olive and pass laterally toward the cerebellopontine angle (CPA). ii. The sensory nerve is called nervus intermedius, originates in the pons and the medulla and joins the motor portion in the CPA. b. The facial nerve then enters the internal auditory canal (IAC) and has a complex course in the temporal bone. i. In the IAC, CN VII runs in the anterior-superior aspect of the canal for 10 mm. ii. Leaving the fundus of the IAC it takes a sharp anterior turn in the narrow 3mm long labyrinthine segment. • Practice Guideline: This is the narrowest portion of the Fallopian canal and the most common site of inflammatory damage in Bell’s or idiopathic/viral facial paralysis. iii. At this point the nervus intermedius enlarges into the geniculate ganglion (GG) and the motor and sensory parts have fused into one nerve. The GG is the first surgical but second anatomical genu (bend) of the facial nerve, after which the nerve turns and runs posteriorly. iv. The nervus intermedius gives off: • The greater petrosal nerve that sends secretomotor fibers that join the parasympathetic fibers of the deep petrosal nerve to become the vidian nerve, pass through the pterygoid canal and enter the sphenopalatine ganglion. It then innervates five territories: 1. Nasal septum 2. Lateral nasal wall 3. Hard palate 4. Soft palate 5. Nasopharynx • The lesser petrosal nerve which gathers the tympanic branch of CN IX (Jacobson’s nerve) to reach the otic gangion (attached to V3). From here, secretomotor fibers reach to the parotid gland. • Sensory fibers to the posterosuperior EAC and the mucosa of the contiguous supratonsillar fossa. • Chorda tympani nerve (see below) v. In the middle ear, the facial nerve runs horizontally from the GG anteriorly, crossing the middle ear just superior to the oval window and

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turns inferiorly at the second anatomical genu posteriorly (just inferior to the horizontal semicircular canal) and then runs vertically down in the mastoid to exit the bone at the stylomastoid foramen. • The motor facial nerve gives off: − In its vertical lie, a branch to the stapedius muscle − At the stylomastoid foramen, a communicating branch to the auricular branch of CN X that then gives 3 more branches to: o Occipital belly of the occipitofrontalis muscle o Posterior belly of the digastric muscle o Posterior belly of the stylohyoid muscle c. Practice Guideline: When approaching the facial nerve in the middle ear, the cochleariform process is a useful landmark for the anterior-most extent of the horizontal facial nerve. d. Practice Guideline: The Fallopian canal (the bony canal of the facial nerve) has areas of dehiscence in 20 to 50 percent of cases. e. Practice Guideline: The most common site of iatrogenic facial nerve injury is drill trauma at the second genu of the facial nerve. In order to avoid this catastrophic outcome, the surgeon must be familiar with the relational anatomy of the short process of the incus, the lateral (horizontal) semicircular canal, the posterior bony EAC wall, and the facial nerve. 2. Chorda Tympani Nerve a. The chorda tympani nerve is a branch of the facial nerve (previously considered a hitchhiker) that joins the lingual nerve, which is the third branch of the mandibular nerve (V3) to supply secretomotor innervation to salivary glands in the floor of the mouth and taste to the ipsilateral anterior tongue. b. It leaves the descending (vertical) facial nerve superior to the stylomastoid foramen and enters the middle ear posteriorly via the iter chordae posterior. It then flies between the long processes of the incus and malleus to exit the middle ear anteriorly at the iter chordae anterior, emerging at the petrotympanic fissure. c. Practice Guideline: The chorda tympani nerve is a useful landmark in chronic otitis media surgery. As it is always medial to the malleus and lateral to the incus, preservation of the nerve can facilitate safe middle ear surgery even in the presence of significant inflammation or granulation. 3. Jacobson’s Nerve a. Jacobson nerve is the tympanic branch of the glossopharyngeal nerve (CN IX) and arises from the inferior ganglion of the glossopharyngeal nerve. It also carries preganglionic parasympathetic fibers, from the inferior salivary nucleus, which eventually enter the otic ganglion. b. It enters the tympanic cavity via the inferior tympanic canaliculus and contributes to the tympanic plexus located on the cochlear promontory. The parasympathetic fibers leave the plexus as the lesser petrosal nerve. c. Practice Guideline: The neuroendocrine cells related to this nerve give rise to glomus tympanicum tumors.

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4. Tensor Tympani Muscle a. The tensor tympani is a striated muscle innervated by the mandibular branch of the trigeminal nerve (CN V). b. It attaches from the greater wing of the sphenoid, forms connections with the bony and cartilaginous Eustachian tube (ET) in its semicanal superiorly and medially in the ET, passes through the cochleariform process, and inserts onto the neck of malleus. c. During contraction, it functions to open the ET and pull the malleus medially, to stiffen the TM and decreases the propagation of sound throughout the ossicular chain. However, this is considered inadequate in terms of speed for noise protection. 5. Stapedius Muscle a. The stapedius muscle is the smallest skeletal muscle in the body and its tendon attaches to the stapes, the smallest bone in the body. It is innervated by the facial nerve (CN VII). b. The stapedius muscle varies between 9 and 11 mm, with a maximum breadth of 2-3 mm, and its tendon is about 2 mm long. It begins 3 mm superior to the stylomastoid foramen and runs medial to midportion of vertical facial nerve. It ends at the pyramidal process at the posterior wall of the middle ear, where the tendon attaches to the posterior aspect of the head (capitulum) of the stapes. c. Practice Guideline: The acoustic reflex test (ART) is a cranial nerve VII and VIII reflex arc that can be used to identify otosclerosis (stapes fixation) or for facial nerve site-of-lesion testing. The reflex arc is likewise considered too slow for adequate noise protection.

Inner Ear Anatomy and Physiology 1. The inner ear is housed inside the densest bone in the body, the otic capsule. It lies within the petrous part of the temporal bone. The geometry of the inner ears is precise, to allow for complex movements that include pitch, yaw and roll. a. On each side the three semicircular canals (SCCs) are perpendicular to each other, and the vertical canals (superior and posterior, or anterior and inferior) are coplanar to the opposite vertical canals of the other side. b. The horizontal (lateral) SCCs are parallel to the ground with the anterior, ampullated end 30 degrees higher than the posterior, non-ampullated end. c. Otolith organs – the utricle is in the same plane as the ipsilateral LSCC; the saccule is at 90 degrees to that. d. The neurosensory units within the ampulla of each SCC and in the macules of the otolith organs also have a strict geometrical orientation. 2. Each bony labyrinth is composed of the cochlea, vestibule and three semicircular canals. There are five bony openings into the vestibule, as the bony non-ampullated canals of the superior and posterior canals merge into a common crus (crus commune),

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and it houses the utricle and saccule. The bony labyrinth is lined internally with periosteum and contains perilymph. a. Perilymph has a composition similar to cerebrospinal fluid (CSF): rich in sodium (140mM) and poor in potassium (5mM) and calcium (1.2mM).

Figure 5. Spatial orientation of the semicircular canals.

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3. The membranous labyrinth lies almost completely within the bony labyrinth. It consists of the cochlear duct, three semicircular ducts, two otolith organs (utricle and saccule), and the endolymphatic duct and sac. The sac is outside of the bony labyrinth. There are six membranous openings into the vestibule (3 ampullated and 3 nonampullated ends) per ear. The membranous labyrinth is filled with endolymph. a. Endolymph has a unique composition: very rich in potassium (150mM), very poor in sodium (1mM) and almost completely lacking in calcium (20-30 µM). b. Endolymph has a positive potential (+80mV) compared to perilymph. 4. The inner ear has two openings into the middle ear, both covered by membranes. The oval window membrane (OWM) lies between the middle ear and the vestibule and houses the footplate of the stapes. The round window separates the middle ear from the end of the cochlear duct (scala tympani) and is referred to in older literature as the ‘secondary tympanic membrane.’ The RWM is inside the RW niche, and the RWM lies perpendicular and inferior to the OWM. a. Practice Guideline: The electrode array of a cochlear implant can be inserted directly via an incision in the RWM or via a cochleostomy drilled in the nearby promontory. All approaches access the basal turn of the cochlea. The bony overhang of the RW niche often must be drilled away to expose the entire RWM. b. Practice Guideline: From a surgical perspective, the cochlea curves to the right in a left ear and to the left in a right ear. This information is useful when inserting an electrode with modiolus-facing electrodes. 5. Cochlear microanatomy and physiology a. Scala vestibuli – contains perilymph b. Scala media – contains endolymph, organ of Corti c. Scala tympani – contains perilymph d. Stria vascularis – produces endolymph and releases it into the cochlea e. Scala tympani and scala media are separated by the basilar membrane, on which the organ of Corti sits f. Scala vestibuli and scala media are separated by Reissner’s membrane g. Organ of Corti consists of: i. 3 rows of outer hair cells – for a total of 12,000 per ear ii. 1 row of inner hair cells – for a total of 3,500 per ear iii. Inner and outer sulcus supporting cells iv. Tunnel of Corti h. Rosenthal’s canal transmits the nerve from the organ of Corti to the ganglion i. Modiolus – contains the cochlear nerve ganglion j. The basal turn of the cochlea processes high frequency sounds while the apical turn processes low frequency sounds. 6. Vestibular neuroepithelial anatomy a. Semicircular Canals are responsible for angular acceleration and deceleration i. The vertical SCCs are named either as superior and posterior or anterior and inferior, in order to emphasize that they are perpendicular to each other on the same side. The horizontal SCC is also called the lateral SCC. ii. The ampullated end of each SCC is its anterior end.

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iii. Hair cells in the vestibular system contain one tall kinocilium and several stereocilia each. • Bending the stereocilia toward the kinocilium depolarizes the cell and results in increased afferent activity. • Bending the stereocilia away from the kinocilium hyperpolarizes the cell and results in a decrease in afferent activity. iv. There are two types of vestibular hair cells. Type II hair cells are innervated by bouton terminals of vestibular primary afferents; they occur in all vertebrates. Type I hair cells are innervated by cup-like, calyceal terminals; they occur only in amniotes (reptiles, birds, and mammals). Type I hair cells have significantly higher stereocilia numbers than type II hair cells. v. The crista is the sensory epithelial mound in the ampulla that contains the hair cells. The cupula is a gelatinous matrix that extends from the hair cell cilia to the opposite side of the SCC wall and is deflected based on endolymph movement, resulting in either depolarization or hyperpolarization of the hair cells. • Type 1 hair cells are more dense at the apex • Type 2 hair cells are more dense on the slopes • All hair cells are oriented in the same direction on each crista vi. Orientation of the kinocilium is towards the utricle (utriculopetal) in the vertical SCCs and away from the utricle (utriculofugal) in the horizontal SCCs. b. Otolithic Organs are responsible for linear acceleration and deceleration and are gravity receptors i. The utricle and saccule are the two otolothic organs. The saccule may also be a rudimentary hearing organ. ii. They lie perpendicularly to each other and lie within the vestibule between the SCCs and the cochlea. The saccular membrane is directly deep to the oval window, about 1 - 1.5 mm away. • Practice Guideline: In cases of endolymphatic hydrops (ELH), the saccular membrane can be ballooned out and may, in cases, touch the undersurface of the stapes footplate. This puts the inner ear at risk with footplate manipulation. Most stapes replacement prosthesis enter about 0.25mm into the vestibule. If contemplating stapedectomy/stapedotomy surgery in patients with active symptoms of ELH, control the ELH first to minimize risk of saccular membrane damage from the drill/pick/laser and prosthesis.

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iii. The macula is the neuroepthelial unit of each otolithic organ. Each macula is bisected by a central line called the striola. The hair cells are aligned in relation to the striola: The kinocilia point toward the striola in the utricle and away from the striola in the saccule. Because hair cells are oriented in different directions, tilts in any direction will activate some afferents. iv. The otolithic membrane is denser than the cupula in the SCCs, and embedded with calcium carbonate crystals called otoconia. Thus, with any position of the head, gravity will bend the cilia of some hair cells, due to the weight of the otoconial membrane which is attached to the cilia. • Practice Guideline: Benign paroxysmal positional vertigo (BPPV) occurs when one or a few otoconia are knocked off of the otolithic membrane and become free-floating in the endolymph. In certain head positions, the weight of these crystals will then move a SSC cupula, causing a sensation of whirling vertigo that abates only when the head is moved in the opposite direction, releasing the weight on the cupula. Because it is the most dependent crista, the posterior SCC is the site of BPPV in 80% of cases.

Figure 6. Inner ear as gyroscope.

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The Eighth Cranial Nerve 1. CN VIII has two divisions, the anterior cochlear (or acoustic) nerve and the posterior vestibular nerve. The vestibular portion of CN VIII is further divided into a superior (SVN) and inferior (IVN) nerve. a. The SVN innervates the utricle, as well as the superior and lateral SSCs. b. The IVN innervates the posterior SCC and the saccule. i. The singular nerve carries information from the posterior SCC crista and joins the IVN in the internal auditory canal (IAC). 2. Cochlear Nerve: The ganglion of the cochlear nerve is in the modiolus of the cochlea. a. There are 35,000 neurons in each cochlea. i. 95% are type 1 neurons which are large, bipolar, and connect with inner hair cells (IHCs). Each IHC is innervated by 10 to 20 type 1 neurons. ii. 5% are type 2 neurons which have very small fibers and connect to outer hair cells (OHCs). Each type 2 neuron innervates several OHCs. 3. Afferent auditory pathways: The orderly spatial arrangement of the cochlear neurons is maintained in the cochlear nerve trunk and continues into the cochlear nuclei. a. The nerve fibers from the basal turn (high frequencies) are peripherally located; those from the apical turn (low frequencies) are in the central region of the nerve trunk. b. The fibers end in the cochlear nucleus of the brainstem, mostly to the ventral cochlear nucleus. c. Fibers from the dorsal nucleus cross to enter the lateral lemniscus and the on to the inferior colliculus and then to the medial geniculate body (MGB). Fibers from the ventral nucleus go to both contralateral and ipsilateral superior olive. d. Each cochlea has nearly equal bilateral neuronal connections to the MGBs and thus to the auditory cortices. 4. Efferent cochlear pathways: There are 40,000 efferent cochlear fibers. They originate as 500-600 crossed and uncrossed fibers as the olivocochlear bundle (of Rasmussen) in the superior olivary complex. Collaterals go to the ventral cochlear nucleus and emerge from the brainstem in the IVN. The bundle then joins the cochlear nerve. Efferent fibers ramify numerously at almost every level before ending on the nerve chalice of IHCs and on cell bodies of OHCs. 5. Vestibular Nerve: The ganglion of the vestibular nerve is named Scarpa’s ganglion and lies in the IAC. The SVN and IVN have separate ganglions. There are 18,000 vestibular fibers per ear. 6. Afferent vestibular pathways: Medial to the vestibular ganglion, the SVN and IVN merge into a single trunk. They end in four major vestibular nuclei: superior, medial, lateral, and descending, which are in a single oval mass medial to the cochlear nucleus in the brainstem. a. Fibers from the maculae reach the medial and lateral vestibular nuclei b. Fibers from the SCCs reach the superior, medial and lateral vestibular nuclei

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c.

Vestibulo-ocular fibers arise from the superior, medial and lateral nuclei, pass via the medial longitudinal bundle and make connections with the oculomotor nuclei (CN III, IV and VI). d. Vestibulo-spinal fibers arise from the lateral, medial and descending nuclei, reach the anterior horns of the spinal cord, and mediate trunk and limb muscle reflexes. 7. Efferent vestibular pathways: There are 200-300 efferent vestibular fibers per ear. They travel with cochlear efferents until meeting up with the IVN and then dispersing as scattered fibers to supply the maculae and cristae.

Structures of the Vestibular Apparatus. This work by Cenveo is licensed under a Creative Commons Attribution 3.0 United States (http://creativecommons.org/licenses/by/3.0/us/). Figure 7. Structural anatomy of the vestibular apparatus.

From: https://www.wikiwand.com/en/Endolymph. Figure 8. Microanatomical cross-section of the cochlea.

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Figure 9. Neuroepithelial orientation of the ampulla of the semicircular canal.

Figure 10. Neuroepithelial orientation of the maculae of the otolith organs.

Table 1. Comparison of composition of endolymph and perilymph Composition Perilymph Na (mM) 140 K (mM) 4-5 Cl (mM) 110 Ca (mM) 1.2 Proteins (g/l) 1 Glucose (mM) 4 pH 7.4 Osmolarity (mosm/l) 290 Potential (mV) 0 Adapted from Delprat B, Irving S. http://www.cochlea.eu/en/cochlea/cochlear-fluids.

Endolymph 1 150 130 0.02 0.15 0.5 7.4 315 80

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Questions 1. The auricle and external auditory canal receive sensory innervation from all of the following nerves EXCEPT: a. Trigeminal nerve b. Facial nerve c. Cochleovestibular nerve d. Vagus nerve e. Cervical plexus 2. The heaviest ossicle by weight is the: a. Malleus b. Incus c. Stapes d. Stapes footplate 3. The most common site of iatrogenic injury to the intratemporal facial nerve is: a. Geniculate ganglion b. Horizontal (tympanic) segment c. Second surgical genu d. Vertical (mastoid) segment e. Stylomastoid foramen 4. Which of these pairings is INCORRECT?: a. Scala vestibuli – perilymph b. Cupula - crista c. Scala media – endolymph d. Macula - striola e. Scala tympani – endolymph

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References Akazawa Y, Ganaha A, Higa T, Kondo S, Oyakawa Y, Hirakawa H, Suzuki M, Yamashiro T. Measurement of stapes footplate thickness in otosclerosis by ultra-high-resolution computed tomography. Acta Otolaryngol. 2020 Nov;140(11):899-903. Chandrasekhar SS, Chandrasekhar HK, editors. Temporal Bone Histology and Radiology Atlas, Plural Publishing, 2018. Delprat B, Irving S. http://www.cochlea.eu/en/cochlea/cochlear-fluids. Accessed 12/4/21. Gray L. Neuroscience Online, Chapter 10. https://nba.uth.tmc.edu/neuroscience/m/s2/chapter10.html Reviewed and revised 07 Oct 2020. Accessed 12/4/21. Kang TK, Ha R, Oh JH, Sunwoo W. The potential protective effects of temporal bone pneumatization: A shock absorber in temporal bone fracture. PLoS One. 2019;14(5):e0217682. Published 2019 May 31. doi:10.1371/journal.pone.0217682. Keidar E, De Jong R, Kwartowitz G. Tensor Tympani Syndrome. [Updated 2021 Jul 25]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK519055/. Kumar IDV, Chaitanya DK, Singh V, Reddy DS. A morphometric study of human middle ear ossicles in cadaveric temporal bones of Indian population and a comparative analysis. J Anatom Soc India 2018; 67:12-17. Massa HM, Lim DJ, Kurono Y, Cripps AW. Middle Ear and Eustachian Tube Mucosal Immunology. Mucosal Immunology. 2015;1923-1942. doi:10.1016/B978-0-12-415847-4.00101-4. Mogra K, Gupta S, Chauhan S, Panwar L, Rajuram. Morphological and morphometric variations of malleus in human cadavers. Int J Healthcare Biomed Res. Apr 2014;2(3):186-192. Moravec WJ, Peterson EH. Differences Between Stereocilia Numbers on Type I and Type II Vestibular Hair Cells. J Neurophys Nov 2004;92(5):3153-3160. https://doi.org/10.1152/jn.00428.2004. Prasad KC, Azeem Mohiyuddin SM, Anjali PK, Harshita TR, Indu Varsha G, Brindha HS. Microsurgical Anatomy of Stapedius Muscle: Anatomy Revisited, Redefined with Potential Impact in Surgeries. Indian J Otolaryngol Head Neck Surg. 2019;71(1):14-18. doi:10.1007/s12070-018-1510-5. Rask-Andersen H, Schart-Moren N, Stromback K, Linthicum F, Li H. Special anatomic considerations in otosclerosis surgery. Otolaryngol Clin NA. April 2018, 51(2):357-374. Roeser RJ, Ballachanda BB. Physiology, pathophysiology, and anthropology/epidemiology of human ear canal secretions. J Am Acad Audiol. 1997 Dec;8(6):391-400. PMID: 9433685. Schuknecht HF, Gulya AJ. Anatomy of the Temporal Bone with Surgical Implications, Lea & Febiger, Philadelphia, 1986.

Chapter 3

Neck Spaces and Fascial Planes Omar A. Karadaghy, MSCI, MD Mia Jusufbegovic, MD Jeffrey M. Blumberg, MD, FACS and Yelizaveta Shnayder, MD, FACS Objectives 1. To describe the anatomy of the neck allowing for enhanced understanding of the pathophysiology of deep space neck infections and pathology. 2. To succinctly describe the anatomic boundaries and relationships of key cervical structures with the aid of supplemental illustrations. 3. To understand the anatomic boundaries and spaces of the neck as they relate to surgical management of both benign and malignant pathology of the head and neck via transoral and transcervical approaches.

Introduction 1. Comprehension of complex head and neck anatomy is imperative for understanding the etiology and management of diseases affecting this region. 2. Pathophysiology of deep space neck infections and its potential propagation to adjacent regions such as the mediastinal or intracranial regions require a foundational understanding of the subunits within the neck. 3. Knowledge of important structures of the head and neck is necessary to reduce morbidity when surgical intervention is required.

Anatomy 1. Triangles of the Neck a. Anterior Cervical Triangle i. Formed by the mandible, the sternocleidomastoid muscle (SCM), and the midline In: Essential Head and Neck Oncology and Surgery Editors: Maie A. St. John and Benjamin L. Judson

ISBN: 979-8-88697-438-6 © 2023 Nova Science Publishers, Inc.

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ii. Further subdivided into the digastric, carotid, muscular and submental triangles • Digastric (Submaxillary) Triangle − Formed by mandible, anterior belly and posterior belly of the digastric muscle • Carotid Triangle − Formed by posterior belly of digastric, superior belly of omohyoid, and SCM • Muscular Triangle − Formed by superior belly of omohyoid, midline, and SCM • Submental Triangle − Formed by hyoid, mandible, and bilateral anterior bellies of digastric muscles − Posterior Cervical Triangle iii. Formed by SCM, trapezius, and clavicle iv. Further subdivided into the occipital and subclavian triangles • Occipital Triangle − Formed by SCM, trapezius, and omohyoid • Subclavian Triangle − Formed by omohyoid, SCM, and clavicle 2. Levels of the Neck (Figure 1) a. Level I i. Level Ia • Submental lymph nodes • Midline structure

Figure 1. Levels of the neck.

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•

• a.

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Bound by hyoid bone inferiorly, bilateral anterior bellies of the digastric laterally, and the mylohyoid muscle as the deep boundary Contents: submental artery and vein

Level Ib • • •

Submandibular lymph nodes Bound by the inferior border of the mandible, anterior and posterior bellies of the digastric Contents: marginal and cervical branches of the facial nerve, facial artery and facial vein, submandibular gland, lingual nerve, submandibular ganglion, hypoglossal nerve

b. Level II i. Upper jugular lymph nodes ii. Divided by the spinal accessory nerve into levels IIa (inferior) and IIb (superior) iii. Extends from the skull base superiorly to the level of the carotid bifurcation inferiorly. Radiographically the hyoid bone defines the inferior extent. iv. Laterally bound by the posterior border of the SCM and medially by the stylohyoid muscle v. The deep boundary is created by the cervical muscular floor vi. Contents: spinal accessory nerve, occipital artery, carotid sheath structures, cervical plexus rootlets c. Level III i. Middle jugular lymph nodes ii. Extends from the carotid bifurcation superiorly to the junction of the omohyoid with internal jugular vein. Radiographically, level III extends from the level of the hyoid bone to the lower border of the cricoid arch. iii. Laterally bound by the posterior border of the SCM and medially by the sternohyoid muscle iv. The deep boundary is created by the cervical muscular floor v. Contents: Carotid sheath structures, cervical plexus rootlets d. Level IV i. Lower jugular lymph nodes ii. Extends from the omohyoid muscle superiorly to the clavicle inferiorly iii. Laterally bound by the posterior border of the SCM and medially by the sternohyoid muscle iv. The deep boundary is created by the cervical muscular floor v. Contents: Carotid sheath structures, cervical plexus rootlets, thoracic duct, transverse cervical vessels

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e.

Level V i. Posterior triangle ii. Level Va and Vb are divided by a plane extending horizontally from the inferior border of the cricoid iii. Extends superiorly from the junction of the SCM and trapezius muscles at the skull base to the level of the clavicle inferiorly iv. Bound by the posterior border of the SCM anteriorly and anterior border of the trapezius posteriorly v. Contents: omohyoid, spinal accessory nerve, transverse cervical vessels, thoracic duct, external jugular vein, cervical plexus rootlets f. Level VI i. Anterior compartment of the neck ii. Extends from the hyoid to the suprasternal notch iii. Lateral boundary is formed by the medial border of the carotid sheath on either side iv. Contents: superior and inferior thyroid arteries, thyroid veins, recurrent laryngeal nerve, parathyroid glands g. Level VII i. Superior mediastinal lymph nodes ii. Bound superiorly by edge of manubrium to the superior border of the aortic arch inferiorly iii. Laterally bounded by the common carotid on the left and innominate on the right iv. Contents: thymus, recurrent laryngeal nerve 3. Fascial Planes of the Neck (Figure 2) a. Cervical fascia encases the contents of the neck forming potential head and neck spaces and consequently constituting anatomic limitations to the spread of disease b. Superficial Cervical Fascia i. Extends from the superior aspect of the head to the shoulders, axilla, and thorax inferiorly ii. Contiguous with the SMAS and Galea Aponeurosis iii. Envelops the platysma, external jugular vein, and muscles of facial expression iv. Infections superficial to this plane generally take the form of cellulitis; fascia serves as a barrier to prevent the spread of cellulitis to deeper neck structures. c. Deep Cervical Fascia: divided into superficial, middle and deep layers i. Superficial Layer (Investing Fascia) • Originates from the posterior spinous processes of the vertebrae and inserts anteriorly on the sternum, hyoid, mandible, and zygomatic arches • Envelopes SCM, trapezius, and muscles of mastication, as well as the submandibular and parotid glands • Contains the parotid and masticator spaces

3. Neck Spaces and Fascial Planes

• •

Forms the stylomandibular ligament that separates the parapharyngeal and submandibular spaces Forms the floor of the submandibular space

(a)

(b) Figure 2. Cervical Fascia. (a) Axial, (b) Sagittal.

ii. Middle Layer • Further subdivided into the muscular and visceral divisions − Muscular division surrounds the infrahyoid strap muscles

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o

Extends from hyoid to sternum, clavicle, scapulae − Visceral division surrounds the trachea, larynx, pharynx, esophagus, thyroid, parathyroids, and constrictor muscles of the pharynx o Extends from the pharyngeal constrictor muscles and hyoid to the anterior mediastinum • Buccopharyngeal fascia − Created from the posterior superior aspect of the middle layer − Forms the anterior/medial boundary of the retropharyngeal space − Forms the pterygomandibular raphe − Envelops the constrictor muscles o It is the lateral margin of a radical tonsillectomy iii. Deep Layer • Originates from the vertebral spinous processes and envelops the posterior contents of the neck • Further subdivided into the alar and prevertebral divisions − Alar division forms the posterior wall of the retropharyngeal space and anterior wall of the danger space − Prevertebral division adheres to the vertebral bodies and transverse processes laterally, cervical muscles, brachial plexus, and phrenic nerve. It serves as the posterior wall of the danger space. d. Carotid Sheath i. All three layers of the deep cervical fascia contribute to the carotid sheath ii. It is intimately associated with the parapharyngeal space in particular iii. Contains the internal jugular vein, internal/external/common carotid arteries, and the vagus nerve 4. Neck Spaces – Table 1 a. Temporal Fossa i. Lateral depression within in the skull containing the temporalis muscle ii. Communicates with the infratemporal fossa and pterygomaxillary fissure iii. Source of infection: rare and usually secondary to odontogenic causes or sinusitis

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Table 1. Neck spaces Space Temporal Fossa

Infratemporal Fossa

Pterygopalatine Fossa

Masticator Space

Parotid Space

Peritonsillar Space

Buccal Space

Parapharyngeal Space

Boundaries Superior: Temporal line Inferior: Zygomatic Arch Anterior: Temporal line Posterior: Temporal line Medial: Cranium Lateral: Temporalis Fascia Superior: Temporal fossa and infratemporal surface of sphenoid bone Inferior: Lateral pterygoid Anterior: Inferior orbital fissure/infratemporal surface of maxilla Posterior: Temporal bone/Styloid process Medial: Lateral pterygoid plate Lateral: Mandibular ramus and coronoid process Superior: Sphenoid body Inferior: Palatine bone Anterior: Posterior wall of maxillary sinus Posterior: Greater wing of the sphenoid bone Medial: Palatine bone Lateral: Pterygomaxillary fissure Superior: Temporal fossa Inferior: Junction of pterygoid muscles to mandible Anterior: Superficial layer of deep cervical fascia Posterior: Mandibular ramus Medial: Medial pterygoid muscle Lateral: Masseter muscle Space contained between the parotid gland and the surrounding superficial layer of deep cervical fascia circumferentially Superior: Superior constrictor Inferior: Superior constrictor Anterior: Palatoglossus Posterior: Palatopharyngeus Medial: Palatine tonsil Lateral: Superior constrictor Superior: Zygomatic Arch Inferior: Mandible Anterior: Oral commissure Posterior: Pterygomandibular raphe Medial: Buccopharyngeal fascia overlying buccinator muscle Lateral: Cutaneous cheek Superior: Skull base Inferior: Hyoid bone Anterior: Pterygomandibular raphe Posterior: Prevertebral fascia Medial: Buccopharyngeal fascia overlying superior constrictor Lateral: Superficial layer of deep cervical fascia over the medial pterygoid and parotid gland

Content Temporalis muscle and temporal fat pad

Medial/lateral pterygoid muscles, insertion of temporalis onto coronoid process, internal maxillary artery, pterygoid venous plexus, Mandibular nerve (V3) with otic ganglion

Maxillary nerve (V2), sphenopalatine ganglion, internal maxillary artery

Masseter, pterygoid muscles, ramus of mandible, inferior alveolar nerve (V3), internal maxillary artery

Facial nerve, external carotid, retromandibular vein, and lymph nodes Loose connective tissue, tonsillar arterial branches (lingual, facial, and ascending pharyngeal origin)

Buccal fat, Stenson’s duct, facial artery, buccal branch of facial and trigeminal nerves, possible accessory parotid gland

Prestyloid compartment: internal maxillary artery, maxillary nerve, adipose tissue, deep lobe parotid gland, lymph nodes, inferior alveolar nerve, lingual nerve, auriculotemporal nerve, medial/lateral pterygoid muscles Poststyloid compartment: carotid artery, internal jugular vein, sympathetic chain, and cranial nerves IX, X, XI, XII

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Table 1. (Continued) Space Submandibular/Sublingual Spaces

Boundaries Superior: Mucosa of the floor of mouth Inferior: Digastric muscle Anterior: Mylohyoid and anterior belly of digastric at the mandibular symphysis Posterior: Posterior belly of the digastric muscle,stylomandibular ligament Medial: Hyoglossus and mylohyoid muscle Lateral: Mandible, platysma

Content Sublingual space: sublingual glands, Wharton’s duct, geniohyoid, lingual and hypoglossal nerves Submandibular space: digastric muscle, submandibular glands, portions of the hypoglossal nerve, facial vein/artery, marginal mandibular branch of the facial nerve, lymph nodes

Retropharyngeal Space

Superior: Skull base Inferior: Cervical fascia fusion at the 2nd thoracic vertebrae Anterior: Buccopharyngeal fascia Posterior: Alar fascia Medial: Midline raphe of the superior constrictor Lateral: Carotid Sheath Superior: Skull base Inferior: Diaphragm Anterior: Alar fascia Posterior: Prevertebral fascia Medial: Open Lateral: Carotid Sheath Superior: Skull base Inferior: Coccyx Anterior: Prevertebral fascia Posterior: Vertebral bodies Medial: Open Lateral: Transverse process of vertebrae Superior: Skull base Inferior: Mediastinum Anterior: Sternocleidomastoid muscle Posterior: Prevertebral space Medial: Visceral space Lateral: Sternocleidomastoid muscle Superior: Hyoid bone Inferior: Mediastinum over the fibrous pericardium and aortic arch Anterior: Superficial layer of the deep cervical fascia Posterior: Prevertebral fascia Medial: Open Lateral: Parapharyngeal space

Lymph nodes, connective tissue

Danger Space

Prevertebral Space

Carotid Space

Visceral Space

Loose areolar tissue

Dense areolar tissue, paraspinal and prevertebral muscles, phrenic nerve, brachial plexus, vetebral artery and vein

Carotid artery, jugular vein, vagus nerve, ansa cervicalis

Thyroid gland, larynx, trachea, pharynx, esophagus

b. Infratemporal Fossa i. Complex space medial to the ramus of the mandible and the zygomatic arch ii. Communicates with the orbit, temporal fossa, and pterygomaxillary fossa iii. Source of infection: rare and usually secondary to odontogenic causes or sinusitis c. Pterygopalatine Fossa i. Complex 3-dimensional space containing the sphenopalatine ganglion

3. Neck Spaces and Fascial Planes

•

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Can be conceptualized as a box with several foramina at each border (Figure 3)

Figure 3. Pterygopalatine fossa.

ii. Communicates with the infratemporal fossa, parapharyngeal space, masticator space, and temporal fossa iii. Source of infection: orbit, odontogenic causes, sinusitis d. Masticator Space i. Potential space encased by the superficial layer of the deep cervical fascia and containing the muscles of mastication ii. Communicates with the buccal, submandibular, parotid, and parapharyngeal spaces iii. Source of infection: posterior mandibular molars, trauma, iatrogenic (surgery) • Often accompanied by trismus e. Parotid Space i. Pyramidal space encompassing the parotid gland and encased by the superficial layer of the deep cervical fascia ii. Communicates with temporal fossa, parapharyngeal, and masticator spaces iii. Source of infection: parotitis, suppurative lymphadenitis f. Peritonsillar Space i. Potential space between the palatine tonsil and superior constrictor muscle ii. Communicates with the parapharyngeal space iii. Source of infection: pharyngeal infections, trauma • Trismus suggests medial pterygoid involvement g. Buccal Space i. Potential space between the platysma and buccinator muscles and encased by the superficial layer of the deep cervical fascia

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ii.

Communicates with submandibular space, pterygopalatine fossa, infratemporal fossa, parapharyngeal space iii. Source of infection: odontogenic origin • Involvement of masseter posteriorly can result in trismus h. Parapharyngeal Space i. Space extending from the skull base to the hyoid, taking the shape of an inverted pyramid (Figure 4) • Divided by the styloid process into prestyloid and poststyloid compartments ii. Communicates with the peritonsillar, submandibular, retropharyngeal, parotid, masticator, carotid, and visceral spaces iii. Source of infection: most often pharyngeal or odontogenic origin

Figure 4. Parapharyngeal space.

i.

Submandibular/Sublingual Spaces i. The mylohyoid muscle separates this space horizontally into the sublingual space superiorly and the submandibular space inferiorly • The posterior edge of mylohyoid allows communication between the two subdivisions • The space between the two anterior bellies of the digastric is referred to as the submental space ii. Communicates with the parapharyngeal and visceral spaces

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iii. Source of infection: odontogenic origin, sialadenitis, lymphadenitis, trauma • The roots of the 2nd and 3rd mandibular molars lie below the attachment of the mylohyoid and therefore communicate directly with the submandibular space j. Retropharyngeal Space i. Midline potential space extending from the skull base to the mediastinum • The fascial layers fuse at the midline dividing it into a left and right side ii. Communicates with the carotid sheath, superior mediastinum, parapharyngeal and danger spaces iii. Source of infection: pharyngeal origin, suppurative lymphadenitis, trauma k. Danger Space i. Potential space between the alar and prevertebral fascia containing loose areolar tissue and allowing rapid spread of infection to the thorax • Can be a source of mediastinitis or empyema ii. Communicates with the mediastinum and retropharyngeal and prevertebral spaces iii. Sources of infection: trauma, local spread from neighboring spaces l. Prevertebral Space i. Potential space between the prevertebral division of the deep layer of deep cervical fascia and the vertebral bodies, extending from the skull base to the coccyx • Dense fibrous attachments help mitigate the spread of infection ii. Communicates with the danger space iii. Source of infection: spinal osteomyelitis and inflammatory pathology, trauma, local spread from neighboring spaces m. Carotid Space i. The carotid sheath is formed by the confluence of all three layers of the deep cervical fascia and extends from the skull base to the aortic arch • Termed “The Lincoln Highway of the Neck” as it is a potential avenue allowing rapid spread of infection ii. Communicates with the parapharyngeal, retropharyngeal, and visceral spaces iii. Source of infection: intravenous drug use, iatrogenic causes, spread from adjacent neck compartments • Infections can result in Horner’s syndrome, vocal cord paralysis, Lemierre’s Syndrome, or carotid artery pseudoaneurysm

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n. Visceral Space i. Midline space extending from the hyoid to the mediastinum ii. Communicates with the submandibular, parapharyngeal, retropharyngeal spaces iii. Source of infection: trauma, thyroiditis

Deep Neck Space Infections 1. Etiology a. Most common: Odontogenic or Pharyngeal (specifically teeth, tonsils, salivary glands) i. Generally mixed flora including aerobic, anaerobic, Gram +, and Gram - bacteria ii. Streptococcus pyogenes, Staph aureus, Strep viridans, Strep pneumoniae, Strep pyogenes, Prevotella, Enterobacteriaceae, Peptostreptococcus, and Fusobacterium species are all commonly seen b. Although the incidence has decreased with widespread use of antibiotics, deep neck space infections remain morbid with 10-40% mortality rates due to sepsis and organ failure c. Risk factors for deep neck space infections include age >55 years, cardiopulmonary comorbidities, poor nutritional status, and immunocompromised status (diabetes mellitus, etc.) d. Abscess formation is most commonly found in the submandibular, parapharyngeal, and carotid spaces e. Pattern of spread is related to the origin of infection i. Dental – submandibular/masticator spaces ii. Tonsil – parapharyngeal/carotid spaces iii. Salivary – parotid, submandibular, carotid spaces 2. Clinical Evaluation a. History - recent dental, sinus, or otologic infection, trauma, or procedure b. Symptoms − inflammatory symptoms including pain, fever, swelling, dysphagia, odynophagia, shortness of breath, hoarseness, otalgia i. Flexible fiberoptic evaluation should be performed for any airway related concerns including dyspnea, stridor, odynophagia, and dysphonia/changes to voice without obvious cause c. Signs − trismus, “Hot Potato Voice,” neck swelling, drooling, crepitus, tenderness, discharge from Wharton or Stenson’s ducts, edema of the floor of mouth/tongue, tonsillar swelling versus soft palate swelling d. Blood tests − complete blood count, basic metabolic panel e. Imaging: i. Plain Film Radiography • Inexpensive but of limited utility • Panorex may aid in identifying an odontogenic source

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•

Lateral neck view may identify thickening of arytenoids or epiglottis (thumbprint sign) ii. Ultrasound • Inexpensive • Can aid in investigating superficial abscesses iii. CT • Ideally completed with contrast • Allows for the best visualization of neck spaces and structures • Can help differentiate between an organized fluid collection versus phlegmon iv. Magnetic Resonance Imaging • Helpful in evaluating select concerns, including intracranial extension and vertebral body involvement • Often difficult to obtain in the acute setting 3. Treatment a. Airway Management i. Should be evaluated immediately with a low threshold to perform a flexible fiberoptic exam ii. Loss of airway is a significant source of mortality from deep neck infection iii. Temporizing measures including oxygen, cool humidification, steroids, heliox, and/or epinephrine nebulizers can be considered iv. Cases of significant respiratory distress should be managed in a timesensitive manner • If time allows, proceeding to the operating room allows for optimal conditions • Awake nasotracheal versus orotracheal intubation if possible • Awake tracheostomy should be considered if the patient has features concerning for difficult intubation b. Empiric Antibiotics Choices i. Should cover gram-positive and gram-negative bacteria ii. PCN in combination with a beta lactamase inhibitor or beta lactamase resistant antibiotic in combination with anaerobic coverage is recommended • Can consider Unasyn or Clindamycin for community acquired infections • Pseudomonas and/or MRSA coverage should be considered iii. Empiric treatment for necrotizing fasciitis should include Ceftriaxone + Clindamycin + Metronidazole iv. Steroids aid not only in reducing airway concerns but may decrease edema/inflammation and progression of cellulitis into abscess c. Surgical versus Medical Treatment i. Exact surgical indications are debated; however, most authors agree that the presence of an abscess >2cm, airway concerns, or failure to

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respond after 48-72 hours of medical management are indications for surgical intervention ii. Surgery can provide immediate relief of certain symptoms, microbiologic samples for culture guided therapy, and can potentially be associated with decreased antibiotic duration and decreased hospitalization time iii. Exact time frame from diagnosis to surgical intervention vs watchful waiting duration is debated iv. Need for regular wash-outs is debated v. Transoral vs transcervical surgical approach is not clearly delineated and is often at the discretion of clinicians 4. Selected Presentations of Deep Neck Infections a. Ludwig’s Angina i. Classically described as rapidly progressing cellulitis/edema/abscess of the submandibular/sublingual space ii. Generally, occurs after dental procedures iii. Involvement of this space can posteriorly displace the oral tongue leading to dysphagia, odynophagia, drooling, and is a potential airway concern iv. Management involves early airway protection through oral versus nasal intubation, intravenous antibiotics, and surgical drainage of abscess if indicated b. Lemierre Syndrome i. Suppurative thrombophlebitis of the internal jugular vein ii. Usually due to extension from carotid space disease iii. Symptoms include spiking fevers (“picket fence”), pain along SCM, thrombosis of IJ on ultrasound, CTA or MRA iv. Classically caused by Fusobacterium necrophorum v. Treatment includes prolonged antibiotics with anticoagulation remaining a controversial topic c. Mediastinitis i. Usually, a result of downward extension of infection, often from pharyngeal involvement ii. Variable microbiological sources iii. Symptoms include chest pain and dyspnea iv. Imaging may demonstrate a widened mediastinum or pneumomediastinum v. Intervention may require transthoracic drainage d. Retropharyngeal Abscess i. Presents with neck pain, swelling, and limited cervical range of motion due to irritation of paraspinal muscles within the alar division of the deep cervical fascia ii. Other symptoms include dysphagia, drooling, and pharyngeal edema which may impact airway status iii. Given the midline fusion, these infections are generally unilateral iv. Imaging can be used to ascertain degree of involvement

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e.

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v. Management includes early airway securement followed by intravenous antibiotics and surgical drainage if amenable Peritonsillar Abscess i. Presents with fever, odynophagia, cervical adenopathy, muffled voice, uvular deviation, and soft palate/unilateral tonsillar bulging ii. Diagnosis is clinical; however, imaging can be used as an adjunct if there is severe trismus or if there is failure to clinically improve iii. CT with contrast is the preferred imaging modality iv. Treatment requires distinction between phlegmon vs abscess formation • Needle aspiration can be both diagnostic and therapeutic • Incision and drainage is often the treatment of choice for a large abscess • Small abscess/phlegmonous changes can be managed conservatively with IV antibiotics, steroids, and symptomatic management • Outpatient tonsillectomy can be considered following resolution of the acute infection, especially if multiple episodes have occurred

Surgical Approaches 1. Transcervical a. Approached with a skin incision through the neck i. Location of incision can be modified by location of pathology ii. Similar to a cervical lymphadenectomy, a linear incision located within a neck crease is well suited for access while also seeking to camouflage scarring iii. If lesions are laterally based, an incision centered along the anterior border of the SCM can be considered iv. Midline abscesses can be approached through an appropriately placed midline incision v. Care should be taken placing a more superior incision to account for the course of the marginal mandibular nerve b. Provides access to a number of potential spaces including parapharyngeal space, masticator space, submandibular/submental spaces, retropharyngeal space, danger space, prevertebral space, carotid space, and visceral space c. Advantages include wider exposure, better visualization of critical structures, and the ability to obtain better proximal control of important blood vessels d. Disadvantages include scarring, poor surgical planes due to acute infection leading to difficulty identifying critical structures including cranial nerves, potential fistula formation, and/or possible chyle leak depending on the level of dissection required

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e.

It is important to distinguish the level of the disease in parapharyngeal, retropharyngeal, prevertebral, or danger spaces as they can be approached transorally if the pathology is in a favorable anatomic location f. When approaching superiorly based pathology, including within the parapharyngeal, retropharyngeal, prevertebral, or danger spaces, key structures to identify include the submandibular gland, marginal mandibular branch of the facial nerve, hypoglossal nerve, facial artery and vein, and digastric muscle i. The Hayes Martin Maneuver (division and superior reflection of the facial vein) can be employed to protect the marginal mandibular nerve g. More inferiorly and laterally based pathology contained within the carotid, retropharyngeal, prevertebral, and danger spaces should utilize the digastric muscle, anterior border of sternocleidomastoid muscle, and omohyoid muscle as helpful landmarks i. Important structures to consider include the hypoglossal nerve, spinal accessory nerve, ansa cervicalis, and contents of the carotid sheath h. When approaching the visceral space important structures to consider include the recurrent and superior laryngeal nerves, parathyroid glands, esophagus, and vascular supply to the thyroid gland i. Placement of a either a passive (more frequently utilized) or suction drain at the surgical site recommended i. The decision of drain type is dependent on location and depth of cavity ii. The authors’ preference is generally to place a passive drain such as a Penrose in a gravity dependent position to aide further drainage iii. Red rubber catheters can be utilized as a means to irrigate into the cavity if there are concerns of reaccumulating purulent debris. iv. In cases where excessive bleeding is encountered, a suction drain may be considered 2. Transfacial/Transparotid a. Approached through a facial skin incision, such as a modified Blair incision b. There should be a low threshold to utilize facial nerve monitoring if there is any concern about the safety of the nerve. c. The authors’ advocate for facial nerve monitoring in all transparotid approach, and select transfacial approaches if the abscess is felt to be deep to the SMAS d. Provides access to a number of potential spaces of the neck including temporal fossa, infratemporal fossa, parapharyngeal space, pterygopalatine fossa, masticator space, parotid space, and/or buccal space e. This can be used in combination with a transcervical approach to obtain wide access to the parapharyngeal space or pterygopalatine fossa f. Similar to a transcervical approach, the advantages of this approach include better ability to visualize critical structures g. Deep dissection generally requires identification and dissection of the facial nerve, which can both increase the incidence of postoperative paresis but also serve as a way to protect distal divisions

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h. More superficial dissection can be utilized to approach the buccal space without increased morbidity to the facial nerve 3. Transoral a. Approached through a mucosal incision within the oral cavity or oropharynx b. Provides access to a number of potential spaces including the peritonsillar space, masticator space, buccal space, submandibular/submental space, retropharyngeal space, danger space, or prevertebral space, especially if the pathology is midline c. Advantages to this approach include avoiding an external incision, as well decreased concern for cranial nerve injury due to less invasive nature d. Disadvantages include decreased visualization (often limited by trismus), the inability to place a drain, and, if the pathology is sufficiently lateral, greater concern for internal carotid artery injury i. Caution should be taken when dissecting beyond the lateral pharyngeal wall to avoid injury to the internal carotid artery e. Exposure can be enhanced using a Crowe-Davis or McIvor mouth retractor f. A peritonsillar abscess can often be approached without the need for general anesthesia g. If an odontogenic etiology is suspected, extraction of the diseased tooth should be considered at the time of drainage for source control of the infection

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Questions 1. A 3-year-old female presents to the emergency room for evaluation of progressive swelling of a lateral neck lump. The family reports that approximately 2 weeks ago the patient had an episode of runny nose, congestion, cough, and multiple bilateral neck lymph nodes. While the remainder of the symptoms have improved, a prominent swelling along the left lateral neck has progressed and become erythematous. In the past two days, the parents have noticed new onset fever. A CT scan with contrast was obtained in the ED demonstrating a suppurative lymph node deep to the sternocleidomastoid at a level between the hyoid bone and cricoid cartilage. Which of the following levels of the neck is the abscess most likely contained in: a. Level Ia or Ib b. Level II c. Level III d. Level IV 2. The trachea is enveloped by which layer of cervical fascia? a. Superficial Cervical Fascia b. Superficial Layer of Deep Cervical Fascia c. Middle Layer of Deep Cervical Fascia - Muscular division d. Middle Layer of Deep Cervical Fascia - Visceral division e. Deep Layer of Deep Cervical Fascia 3. A 56-year-old-male presents to the ENT clinic for evaluation of an oral mass. Patient reports that this was identified by his primary care physician, and presents for evaluation and treatment. The mass is asymptomatic, but the patient notes a gradual increase in size over the past year. On exam, there is a laterally based lesion causing medial displacement of the right tonsillar pillars. Outside MRI was performed demonstrating a parotid mass within the deep lobe that is located deep to the superior constrictor muscle and buccopharyngeal fascia. The neck space corresponding to the location of the mass is most likely: a. Peritonsillar Space b. Parapharyngeal Space c. Buccal Space d. Retropharyngeal Space 4. A 48-year-old female with a history of diabetes and poor dental care presents to the emergency room with rapidly progressive facial and submandibular swelling. The husband reports that the patient underwent some form of dental procedure the day before presentation. On exam, the patient is upright and leaning forward. There is palpable firmness noted along the floor of mouth and the tongue appears posteriorly displaced. The patient is not actively stridulous, but is reporting increasing difficulty breathing. Which of the following is the best next step? a. Initiation of antibiotics +/- steroids b. Obtain contrasted imaging

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c. Securing the airway d. Admission for observation on the floor 5. The midline neck space located between divisions of the deep layer of deep cervical fascia is known as: a. Retropharyngeal Space b. Danger Space c. Prevertebral Space d. Visceral Space

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References Biron, V. L., Kurien, G., Dziegielewski, P., Barber, B., and Seikaly, H. (2013). Surgical vs ultrasound-guided drainage of deep neck space abscesses: a randomized controlled trial: surgical vs ultrasound drainage. J Otolaryngol Head Neck Surg, 42. 18. Blumberg, J. M., and Judson, B. L. (2014). Surgical management of parapharyngeal space infections. Oper Tech Otolaryngol, 25, 304-309. Boscolo-Rizzo, P., Marchiori, C., Montolli, F., et al. (2006). Deep neck infections: a constant challenge. ORL J Otorhinolaryngol Relat Spec, 68, 259-265. Boscolo-Rizzo, P., Stellin, M., Muzzi, E., et al. (2012). Deep neck infections: a study of 365 cases highlighting recommendations for management and treatment. Eur Arch Otorhinolaryngol, 269, 1241-1249. Celakovsky, P., Kalfert, D., Smatanova, K., Tucek, L., Cermakova, E., Mejzlik, J., et al. (2015). Bacteriology of deep neck infections: analysis of 634 patients. Aust Dent J, 60(2), 212–215. Chan, Y., and Goddard, J. C. (2019). KJ Lee’s Essential Otolaryngology, 12th edition. McGraw-Hill Education. Crespo, A. N., Chone, C. T., Fonseca, A. S., et al. (2004). Clinical versus computed tomography evaluation in the diagnosis and management of deep neck infection. Sao Paulo Med J, 122, 259-263. Duggal, P., Naseri, I., and Sobol, S. E. (2011). The increased risk of community-acquired methicillin-resistant Staphylococcus aureus neck abscesses in young children. Laryngoscope, 121, 51-55. Dulin, Michael, F.., Timothy P. Kennard, and Laura Leach. (2008). “Management of cervical lymphadenitis in children.” Clinical Inquiries, (MU) (2008). Flint, Paul, W., and Charles, W. (2020). Cummings. Cummings Otolaryngology Head & Neck Surgery. Gehrke, T., Scherzad, A., Hagen, R., and Hackenberg, S. (2021). Deep neck infections with and without mediastinal involvement: treatment and outcome in 218 patients. Eur Arch Otorhinolaryngol. Greenberg, S. L., et al. (2007). Surgical management of Ludwig’s angina. Aust N Z J Surg, 77, 540-543. Huang, T. T., Liu, T. C., Chen, P. R., Tseng, F. Y., Yeh, T. H., and Chen, Y. S. (2004). Deep neck infection: analysis of 185 cases. Head Neck, 26(10), 854–860. Karkos, P. D., Leong, S. C., Beer, H., et al. (2007). Challenging airways in deep neck space infections. Am J Otolaryngol, 28, 415-418. Lawrence, R., and Bateman, N. (2017). Controversies in the management of deep neck space infection in children: an evidence-based review. Clin Otolaryngol., 42(1), 156-163. Neff, L., Newland, J. G., Sykes, K. J., et al. (2013). Microbiology antimicrobial treatment of pediatric cervical lymphadenitis requiring surgical intervention. Int J Pediatr Otorhinolaryngol, 77, 817-820. Ovassapian, A., et al. (2005). Airway management in adult patients with deep neck infections: a case series and review of the literature. Anesth Analg, 100, 585-589. Plaza Mayor, G., Martinez-San Millan, J., and Martinez-Vidal, A. (2001). Is conservative treatment of deep neck space infections appropriate? Head Neck, 23(2), 126–133. Potter, J. K., Herford, A. S., and Ellis, E. (2002). Tracheotomy versus endotracheal intubation for airway management in deep neck space infections. J Oral Maxillofac Surg, 60, 349-354. Rega, A. J., Aziz, S. R., Ziccardi, V. B., et al. (2006). Microbiology and antibiotic sensitivities of head and neck space infections of odontogenic origin. J Oral Maxillofac Surg, 64, 1377-1380. Ridder, G. J., Technau-Ihling, K., Sander, A., and Boedeker, C. C. (2005). Spectrum and management of deep neck space infections: an 8-year experience of 234 cases. Otolaryngol Head Neck Surg, 133(5), 709–714. Shimizu, Y., Hidaka, H., et al. (2017). Clinical and bacteriological differences of deep neck infection in pediatric and adult patients: review of 123 cases. Int J Pediatr Otorhinolaryngol, 99, 95-99. Vieira, F., Allen, S. M., Stocks, R. M., and Thompson, J. W. (2008). Deep neck infection. Otolaryngol Clin North Am., 41(3), 459-483, vii. Wang, L. F., Kuo, W. R., Tsai, S. M., and Huang, K. J. (2003). Characterizations of life-threatening deep cervical space infections: a review of one hundred ninety-six cases. Am J Otolaryngol, 24(2), 111–117.

Chapter 4

Thyroid and Parathyroid Glands Tyler R. Halle, MD Lindsay C. Boven, MD Amr H. Abdelhamid Ahmed Amy Y. Chen, MD and Gregory W. Randolph, MD “The extirpation of the thyroid gland for goiter typifies perhaps better than any operation the supreme triumph of the surgeon’s art.” —Halsted, 1920

Embryology and Anatomy Embryology 1. Thyroid medial anlage arises as a ventral diverticulum from endoderm of first and second pharyngeal pouches at the foramen cecum. 2. Diverticulum forms at 4 weeks gestation, descends through midline anterior path, the thyroglossal duct tract, reaching adult pretracheal position by 7 weeks. 3. Complete arrest of migration results in a lingual thyroid without normal tissue in the orthotopic location. 4. Persistence of inferior portion of thyroglossal duct tract results in a pyramidal lobe. 5. Persistence of thyroid tissue along the rest of the thyroglossal duct tract can develop into a thyroglossal duct cyst. 6. Lateral thyroid primordia develop from the fourth and fifth pharyngeal pouches and join medial anlage as it descends in the neck. 7. Parafollicular C cells arising as ultimobranchial bodies from the neural crest of the fourth pharyngeal pouch migrate into the developing lateral thyroid lobes.

Anatomy 1. General a. Thyroid gland is composed of two lateral lobes connected by an isthmus that rests at second to fourth tracheal cartilages. In: Essential Head and Neck Oncology and Surgery Editors: Maie A. St. John and Benjamin L. Judson

ISBN: 979-8-88697-438-6 © 2023 Nova Science Publishers, Inc.

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b. Each lobe measures approximately 4.5 cm high x 1.5 cm wide x 2 cm deep. c. Pyramidal lobe present in up to 40% of patients. d. A fusion anomaly of the thyroglossal duct in the midline leads to two independent lobes with no isthmus. Isthmus agenesis is very uncommon. 2. Fascia a. The cervical viscera—including trachea, larynx, and thyroid—are ensheathed by middle (visceral) layer of the deep cervical fascia. b. Important to distinguish true thyroid capsule from loose areolar tissue between the true thyroid capsule and strap muscles (ie, the perithyroidal sheath). i. True thyroid capsule: tightly adherent to thyroid parenchyma and continuous with fibrous septa that divide the gland’s parenchyma into lobules. ii. Perithyroidal sheath: thin cobweb-like tissue encountered as strap muscles are elevated from the ventral surface of the thyroid; typically easily lysed and occasionally associated with small bridging vessels from undersurface of the strap muscles to the true thyroid capsule. 3. Ligament of Berry a. Thyroid is attached to laryngotracheal complex by anterior and posterior suspensory ligaments, causing gland to elevate with larynx during deglutition. b. Anterior suspensory ligament arises from anterior aspect of the first several tracheal rings and inserts on undersurface of the isthmus and is less robust than the posterior ligament. c. Posterior suspensory ligament (ligament of Berry) is condensation of middle layer of deep cervical fascia and connects the posterior thyroid to the cricoid cartilage and first two tracheal rings. Ligament is vascularized by a branch of the inferior thyroid artery. d. Recurrent Laryngeal Nerve (RLN) penetrates the thyroid within the ligament of Berry in significant percentage of patients, putting the RLN at risk of injury in this location. 4. Lymphatics a. Extensive regional intra- and periglandular lymphatic network. Isthmus and medial lobes drain initially to Delphian, pretracheal, and superior mediastinal nodes. Lateral thyroid drains initially to the internal jugular chain. Inferior pole drains initially to paratracheal, peri-RLN nodes. Superior thyroid drains into the superior pretracheal and cervical nodes. 5. Vasculature a. Arterial supply is superior thyroid artery, a branch of the external carotid artery, and the inferior thyroid artery, a branch of the thyrocervical trunk. b. The thyroid ima artery is a separate unpaired inferior vessel which may rise from the innominate artery, carotid artery, or aortic arch directly and is present in 1.5% to 12% of cases. c. Venous drainage is via superior, middle, and inferior thyroid veins (Figure 1). Superior thyroid vein is branch of the internal jugular vein and travels with the superior thyroid artery in the superior pole vascular pedicle. Middle thyroid vein travels without arterial complement and drains into the internal

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jugular vein. Inferior thyroid vein travels without arterial complement, extending from the inferior pole to the internal jugular or brachiocephalic vein.

Figure 1. Posterior view of thyroid showing superior and inferior thyroid arteries and their relationship to the RLNs.

6. Recurrent and Superior Laryngeal Nerves a. The cervical branches of vagus nerve that are of concern during thyroid surgery include both internal and external branches of the superior laryngeal nerve (SLN) as well as the RLN (Figure 2). b. SLN i. SLN’s internal branch supplies sensation (general visceral afferents) to lower pharynx, supraglottic larynx, and base of tongue, and special visceral afferents to epiglottic taste buds. ii. SLN’s external branch provides motor innervation (branchial efferents) to inferior constrictor and cricothyroid muscle. Contraction of cricothyroid is important for increasing vocal fold length and tension, which is important for production of high-frequency phonation. iii. SLN arises from upper vagus nerve and descends medial to carotid sheath dividing into internal and external branches ~ 2 to 3 cm above superior pole. iv. Internal branch travels medially to carotid system, entering posterior aspect of thyrohyoid membrane, providing sensation to ipsilateral supraglottis.

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Figure 2. Recurrent and superior laryngeal nerves.

v.

vi.

c.

RLN i.

ii.

External branch descends to region of superior pole and traverses medially along inferior constrictor muscle to enter cricothyroid muscle. In ~ 20% of cases, external branch travels subfascially on inferior constrictor, making visualization difficult, but is identifiable with neural stimulation. As external branch slopes downward on inferior constrictor musculature, it is closely associated with superior thyroid pedicle. Typically, external branch diverges from superior pole vascular pedicle 1 cm or more above superior aspect of superior thyroid pole. However, in ~ 20% of cases external branch crosses the vessels within 1 cm of the superior thyroid pole, and in 15% of cases (up to 50% in large goiters) the external branch crosses over the actual thyroid parenchyma, putting nerve at risk during ligation of superior pole vessels. The RLN provides motor innervation (branchial efferents) to inferior constrictor and all intrinsic laryngeal muscles except for cricothyroid muscle. The RLN supplies sensation (general visceral afferents) to larynx (vocal cords and below), upper esophagus, and trachea, and parasympathetic innervation to lower pharynx, larynx, trachea, and upper esophagus.

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iii.

iv.

v.

vi.

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Left RLN emerges from underneath aortic arch and enters thoracic inlet in a paratracheal position and extends upward in or near tracheoesophageal groove, ultimately crossing the distal branches of the inferior thyroid artery. Typically, for last centimeter prior to laryngeal entry, nerve travels close to lateral border of the trachea. Right RLN branches from vagus nerve and wraps behind the subclavian artery, ascending into the neck more laterally than left RLN. Right RLN ascends the neck traveling from lateral to medial, crossing inferior thyroid artery. The right RLN ascends into the paratracheal region in more obliquely compared to more directly cranially trajectory of left RLN. Non-recurrent right laryngeal nerve occurs in ~ 0.5 to 1.0% of patients and is usually associated with retroesophageal subclavian artery. Non-recurrent left laryngeal nerves are exceptionally rare with estimated prevalence of 0.004% and is associated with situs inversus. In ~1/3 of patients, the RLN branches prior to laryngeal entry (Figure 3).

Figure 3. Superior thyroid and inferior thyroid arteries (left figure) and superior, middle, and inferior thyroid veins (right figure).

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Physiology Hormones 1. Thyroid gland composed of follicles that absorb and store iodine for production of thyroid hormones (TH). Follicles have single layers of thyroid cells that secrete hormones triiodothyronine (T3) and thyroxine (T4). 2. Thyroid stimulating hormone (TSH) released by anterior pituitary regulates thyroid hormone production and secretion. As TH decreases, TSH increases to stimulate thyroid to maintain TH at preexisting set point. Increased TSH levels stimulate gland size and vascularity. High TH suppreses TSH release. 3. T3 a. Several times more physiologically potent than T4. b. 10% of the thyroid gland’s production of TH. c. Half-life is 1 day, so reassessment of thyroid function tests after dose change of exogenous T3 is performed after 1 to 2 weeks. d. 80% of circulating T3 is created from conversion of T4 in the periphery. e. Exogenous T3 (levotriiodothyronine) is available as liothyronine. 4. T4 a. Strongly correlates with thyroid-stimulating hormone (TSH) level and is believed to play predominant role in TSH negative feedback. b. About 90% of the thyroid gland’s production of TH. c. Half-life is 6 to 7 days; therefore, with change in exogenous T4 dose, thyroid function tests are reassessed after 5 to 6 weeks. d. Exogenous T4 is available as levothyroxine and is predominant method of thyroid hormone replacement for patients. 5. Both T4 and T3 a. Stimulate calorigenesis, potentiate epinephrine, lower cholesterol levels, and have roles in normal growth and development. b. Iodine is actively transported into the thyroid follicular cell and oxidized to thyroglobulin-bound tyrosine residues. Four iodinizations result in the formation of T4; removal of one residue results in the formation of T3. c. Subsequently stored bound to thyroglobulin in colloid. The stored hormone is taken up from colloid, cleaved off thyroglobulin, and released into circulation. d. Predominately protein bound (mainly to thyroid-binding globulin), with less than 1% representing free (ie, unbound) hormone.

Pathophysiology Benign Thyroid Disease Thyroid Function Tests (Table 1) 1. TSH assays (third generation ultrasensitivity assays capable of detecting 0.01 mU/L) often are the only test needed to sensitively diagnose hypo- or hyperthyroidism.

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2. TSH measurements used to monitor replacement therapy and post-treatment suppressive therapy for thyroid carcinoma. 3. If TSH is high and T4 is normal, subclinical hypothyroidism is diagnosed. This pattern is typically seen in early Hashimoto’s thyroiditis. 4. If TSH is low and T4 and T3 are normal, subclinical hyperthyroidism is diagnosed. This can be seen in multinodular goiter, with progressive hyperfunctional regions in the thyroid, which can move to frank hyperthyroidism. 5. Total T4 and total T3 laboratory tests measure total amount of protein-bound and free hormone. Can have significant fluctuation in these total measures with changes in thyroid-binding globulin level. a. T3 resin uptake test: Allows for correction of total T4 level for fluctuation in thyroid-binding globulin. T3 resin uptake measures the binding capacity of existing thyroid-binding globulin. The more available binding sites on native thyroid-binding globulin, the less resin uptake of radio-tagged T3. Thus, in states of thyroid-binding globulin excess, T3 resin uptake is low. i. High levels of thyroid-binding globulin occur in pregnancy or with use of birth control pills. ii. Low thyroid-binding globulin levels can occur in hypoproteinemic states, acromegaly, Cushing syndrome, and certain drugs such as androgens and anabolic steroids. Table 1. Patterns of Thyroid Function Tests Euthyroid

Hyperthyroid

Hypothyroid

States of High TBG Normal  

States of Low TBG Normal  

TSH Normal   Total T4 Normal   T3 resin uptake (or Normal   THBR) Free T4 index Normal Normal Normal   TBG, thyroid-binding globulin; TSH, thyroid-stimulating hormone; T4, thyroxine; T3, triiodothyronine.

Hypothyroidism 1. Hypothyroidism is functional state characterized by decreased TH. In primary gland failure, decreased TH results in increased TSH. In central hypothyroidism (rare), TSH is decreased with resultant decreased TH. 2. Hypothyroidism has a variety of causes and can present with a multitude of symptoms. (Table 2). 3. Treatment for hypothyroidism is typically started at a low dose to avoid abrupt correction, especially in elderly patients or patients with coronary artery disease. 4. Typically, T4 is started at 0.05 mg PO per day and is slowly increased, titrated to TSH level. 5. Myxedema refers to non-pitting edema secondary to increased glycosaminoglycan in tissue in severe hypothyroidism.

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Table 2. Hypothyroidism Differential Diagnosis 1. Primary gland failure (common) A. Hashimoto thyroiditis B. Iodine deficiency C. Associated with thyroiditis (lymphocytic/postpartum, subacute) D. Radiation-induced (I131 or external beam) E. Postsurgical F. Drugs (lithium, iodine) G. Hereditary metabolic defects in hormonogenesis 2. Central hypothyroidism (rare)

Clinical Manifestations Fatigue, slow mentation, change in memory, depression, cold intolerance, hoarseness, brittle hair, dry skin, thick tongue, weight gain, constipation/ileus, menstrual disturbance, bradycardia, nonpitting edema, hyporeflexia, psychosis, hyponatremia, hypoglycemia, coma. In infants, mental retardation/cretinism.

Hyperthyroidism 1. Hyperthyroidism is physiologic state of increased TH biosynthesis and secretion. In primary hyperthyroidism, this leads to TSH suppression. 2. Hyperthyroidism can occur as a result of several pathologic entities and presents with characteristic symptoms (Table 3). 3. Graves’ disease and toxic nodular goiter (aka Plummer’s disease) account for most cases of hyperthyroidism. Hyperthyroidism caused by thyroiditis is typically selflimiting. 4. Thyrotoxicosis refers to the clinical syndrome of TH excess. Table 3. Hyperthyroidism Differential Diagnosis 1. Graves’ disease 2. Toxic nodule/multinodular goiter 3. Thyroiditis 4. Exogenous hyperthyroidism/struma ovarii/functional thyroid cancer 5. Thyrotropin, thyrotropin-like secreting tumor (pituitary, trophoblastic, other)

Clinical Manifestations Weight loss, fatigue, nervousness, tremor, palpitations, increased appetite, heat intolerance, muscle weakness, diarrhea, sweating, menstrual disturbance

Graves’ Disease 1. Autoimmune disease, accounts for 60% of clinical hyperthyroidism. 2. Activating autoantibodies bind to the TSH receptor, resulting in TSH-like activity. 3. More common in females, often presents in the third to fourth decades. 4. Physical examination shows diffusely enlarged gland with increased metabolic activity and increased blood flow which can result in thyroid bruit. 5. Thyroid histology shows scattered lymphocytic infiltration. 6. Can cause infiltrative ophthalmopathy with exophthalmos. Although considered a part of Graves’ disease, ophthalmopathy typically follows an independent course relative to the thyroid disease and does not occur in all patients. 7. Patients may exhibit infiltrative dermopathy, resulting in localized myxedema (e.g., pretibial) and rarely thyroid acropachy, characterized by digital clubbing and edema of the hands and feet. 8. Iodine-123 (I123) scanning shows a diffuse increased gland uptake.

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9. Treatments include radioactive iodine ablation, antithyroid drugs, or surgery. Treatment in the United States, except in children and young adults, most often involves radioactive iodine.

Toxic Multinodular Goiter 1. Hyperthyroidism arising from one or more toxic nodules. Unlike Graves’ disease, hyperfunctional tissue is restricted to one or more regions within the gland, which are enlarged in nodular pattern. 2. Accounts for 5-15% of cases of hyperthyroidism but is most frequent cause of thyrotoxicosis in the elderly. 3. Develops from a preexisting nontoxic nodular goiter. 4. More frequent in endemic goiter, occurring in iodine-deficient regions, and more common in females. 5. No eye or skin findings like those with Graves’ disease. 6. Progressive formation of nodules and hyperfunctional regions. Excess TH results in suppression of TSH. Lower TSH results in the adjacent normal gland becoming less active on I123scans, with hyperfunctional areas being hot. 7. In early stages, the hyperfunctional region is not autonomous and a suppression I123 shows no uptake. Pre-hyperthyroid pattern of suppressed TSH but normal T4 and T3 is labeled subclinical hyperthyroidism. 8. Jod-Basedow phenomenon is development of overt hyperthyroidism with exogenous iodine administration (eg, iodine CT contrast) in these patients. 9. With time, hyperfunctional regions become autonomous, secreting TH despite significant TSH suppression. When true autonomy occurs, I123 scanning shows focal hot regions with complete absence of adjacent normal gland. Suppression scanning at this time shows ongoing focal uptake, demonstrating autonomy despite TSH suppression. Uninodular Toxic Goiter 1. Hyperthyroidism typically does not occur until the nodule is larger than 2.5 cm. 2. Such nodules usually characterized by enhanced T3 production relative to T4. 3. Unlike Graves’ disease, there is a low rate of spontaneous remission after antithyroid drug therapy is withdrawn. 4. Treatment is either surgery or radioactive iodine; antithyroid medications are considered only as pretreatment prior to more definitive surgical or radio ablative treatment. 5. Surgery is typically unilateral, quickly and definitively corrects hyperthyroidism, and is associated with low morbidity. Treatment of Hyperthyroidism 1. Antithyroid drugs can be used to render patient euthyroid until definitive treatment 2. Radioiodine ablation, with orally administered I131, can be used as definitive treatment. Areas of increased uptake are preferentially injured by beta-radiation. Contraindicated in women who are pregnant or lactating.

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Antithyroid Medications 1. Propylthiouracil (PTU) and methimazole: a. Block iodine organification and TH synthesis, PTU also blocks peripheral conversion of T4 to T3. b. PTU is given q3d; methimazole qd. c. Typically takes 6 to 8 weeks to render a patient euthyroid. d. Side effects include rash, fever, lupus-like reaction, and bone marrow suppression (0.3%-0.4% of cases), which is reversible if detected early. PTU has been associated with liver failure, especially in children, so methimazole is typically considered the first-line therapy for hyperthyroidism except during pregnancy and lactation. e. While both methimazole and PTU cross the placenta equally, there have been rare reports of birth defects with methimazole and so PTU is preferred. PTU also shows less concentration in breast milk than methimazole. 2. Iodides: a. Potassium iodide and Lugol solution inhibit organification and prevent TH release. b. Given preoperatively to decrease thyroid gland vascularity. c. Antithyroid effect is transient, with escape within 2 weeks, and is termed Wolff-Chaikoff effect. d. Prolonged high-dose iodides, especially in the setting of toxic nodular goiter, can result in hyperthyroidism. 3. Beta-adrenergic blockers a. Examples include propranolol or nadolol. b. Block peripheral TH effects (do not alter TH production). c. Useful in symptomatic control while other treatments are initiated and also in transient forms of hyperthyroidism associated with thyroiditis (see later). d. Contraindicated in patients with asthma, chronic obstructive pulmonary disease (COPD), cardiac failure, insulin-dependent diabetes, bradyarrhythmias, and those taking monoamine oxidase inhibitors. 4. Advantages in the treatment of hyperthyroidism: a. Quick onset of action b. May facilitate remission with ongoing euthyroid status after discontinuation of the medicine 5. Disadvantages a. Risk of agranulocytosis b. High rate of hyperthyroid relapse (74% of patients relapsed if followed over a period of 5 years) c. Liver failure with PTU Radioactive Iodine Ablation 1. Advantages: Represents an effective, relatively inexpensive, safe, and definitive treatment option. 2. Disadvantages: a. Up to 80% of patients with Graves’ disease and up to 50% of those with toxic nodules treated with radioactive iodine ultimately become hypothyroid.

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b. Risk of developing malignancy including breast. c. Teratogenic effects (conception must be delayed more than 6 months after radioactive iodine treatment) d. Can worsen Graves’ ophthalmopathy (especially in smokers) e. Less rapid normalization of TH levels than surgery (typically 6-8 weeks). 3. D. Some reluctance to treat young patients with radioactive iodine ablation given potential for long-term development of second malignancies.

Surgical Treatment of Hyperthyroidism 1. Advantages: a. Correction of the hyperthyroid state faster than radioactive iodine and without the risks of antithyroid drugs b. Especially suited for toxic nodules, where one discrete region of the thyroid may be resected with preservation of contralateral normal tissue c. Many studies show that when properly done, surgery poses a lower risk of hypothyroidism than radioactive iodine ablation. 2. Surgery for Graves’ is considered when there is: (1) failure or significant side effects after medical treatment, (2) need for rapid return to euthyroidism, (3) massive goiter, (4) a wish to avoid radioactive iodine, (5) concern regarding RAI and eye disease or, (6) Graves’ with nodules. 3. Preoperative endocrinologic management is essential to return patient to euthyroid state and avoid perioperative thyroid storm. This is usually accomplished with antithyroid drugs for 6 weeks prior to surgery with or without beta-adrenergic blockers. 4. When euthyroid, a 2-week course of preoperative iodide (super saturated potassium iodide [SSKI] or Lugol solution), is believed to decrease vascularity and gland friability, although efficacy is controversial. 5. Goal of surgery for hyperthyroidism is to remove the hyperfunctional tissue, which typically means total thyroidectomy for Graves’ disease. Implicit is that it is preferable to render the patient hypothyroid than to provide inadequate resection with recurrent hyperthyroidism. 6. Surgical treatment for Graves’ disease: a. Total thyroidectomy with resection of any existing pyramidal lobe. b. In the past, subtotal resection was considered, but generally not used now. 7. Surgical treatment for toxic nodule(s): a. Resection of the involved portion of the gland (lobectomy) b. Consider both scintillographic and sonographic information in developing surgical plan. Hot regions may not correspond to the areas of ultrasonic nodularity.

Thyroiditis Hashimoto’s Thyroiditis (Chronic lymphocytic thyroiditis) 1. Most common form of thyroiditis and most common single thyroid disease in iodinesufficient countries.

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2. Autoimmune disease with increased thyroid peroxidase antibodies in 70% to 90% of patients. 3. More common in females and often presents in third to fifth decades. 4. At presentation patients are typically euthyroid but hypothyroidism symptoms are present in ~ 20% of cases. 5. Firm, symmetric goiter and regional pain may be reported; typically both lobes are enlarged. 6. Histologically, there is lymphocytic infiltration with germinal center formation, follicular acinar atrophy, Hürthle cell metaplasia, and fibrosis. 7. Iodine123 scanning typically contributes little information to the workup. 8. If patient is hypothyroid, treatment with TH resolves symptoms and may decrease the size of the goiter. 9. Surgery is only considered if the goiter is large or symptomatic. 10. Development of a discrete palpable abnormality not part of the diffuse goiter process (ie. a discrete nodule) should be evaluated with fine-needle aspiration (FNA) despite a preexisting diagnosis of thyroiditis. 11. Lymphoma is rare complication. Rapidly enlarging mass within a Hashimoto’s gland warrants biopsy.

Subacute Granulomatous Thyroiditis (aka De Quervain’s thyroiditis) 1. Most common cause of enlarged painful thyroid. 2. Viral in etiology, often preceded by upper respiratory tract infection, frequently with fever and malaise. 3. Pain can radiate to the angle of the jaw and ear. Pain and enlargement may only involve a portion of the gland and later migrate to opposite side. 4. About 50% present with hyperthyroidism, elevated TH and sedimentation rate. Painful phase typically resolves in 3 to 6 weeks. 5. I123 scanning typically shows less than 2% uptake - this low uptake distinguishes the transient hyperthyroidism of SGT from that of Graves’ disease or toxic multinodular goiter. 6. About 50% have hypothyroid phase lasting several months, with most reverting to euthyroid, only 5% permanent hypothyroidism. 7. Self-limiting − treat as needed with nonsteroidal anti-inflammatory drugs (NSAIDs) and rarely steroids. Subacute Lymphocytic Thyroiditis 1. Also termed silent, painless, or postpartum thyroiditis 2. Etiology unknown but believed to be an autoimmune process 3. Painless with course otherwise similar to subacute thyroiditis 4. Occurs sporadically but is common in postpartum females (up to 5%) 5. Presents as painless, symmetric thyroid enlargement and reversible hyperthyroidism 6. Thyrotoxicosis is generally self-limiting with no treatment needed, although permanent hypothyroidism can result in approximately 20%.

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Acute Suppurative Thyroiditis 1. Rare thyroid infection often with abscess formation. 2. Most often bacterial (commonly due to Staphylococcus, Streptococcus, or Enterobacter) but can be fungal or even parasitic. 3. Typically presents in the setting of an upper respiratory tract infection (URTI). 4. Treatment is with antibiotics and often incision and drainage in the case of abscess. 5. A left pyriform sinus fistula has been found to be one cause of suppurative thyroiditis. Recurrent episodes, after acute treatment, should be evaluated with CT, endoscopy, and/or barium swallow. Riedel Struma (Invasive fibrous thyroiditis) 1. Rare inflammatory process of unknown etiology – the thyroid equivalent to sclerosing cholangitis or retroperitoneal fibrosis. 2. Large, nontender goiter with a woody consistency fixed to surrounding structures. 3. Clinical course characterized by progressive regional symptoms including dysphagia, tracheal compression, and possibly RLN paralysis. 4. Typically euthyroid at presentation but can progress to hypothyroidism. 5. Thyroid histology: extensive fibrosis, the hallmark of which is extrathyroidal extension of fibrosis into surrounding neck structures. 6. Can be confused with malignancy and requires biopsy, such as isthmusectomy. Aggressive surgery is usually avoided because of the loss of surgical planes. Treatment with steroids can be helpful. Drug-Induced Thyroiditis 1. Common drugs: amiodarone, interferon-alpha, interleukin-2, lithium, minocycline 2. Thyroid abnormalities usually resolve when the offending drug is stopped. 3. Amiodarone: can produce thyrotoxicosis through either drug-induced thyroid hormone overproduction (type 1 treated with antithyroid meds) or destructive thyroiditis (type 2 treated with steroids) Euthyroid goiter (nontoxic diffuse and multinodular goiter) 1. Thyroid enlargement without significant functional derangement may occur with diffuse enlargement (nontoxic diffuse goiter) or through multinodular formation (multinodular goiter). 2. Goiter development can be sporadic or associated with iodine deficiency, inherited metabolic defects, or exposure to goitrogenic agents. 3. Thyroid function tests are normal for nontoxic diffuse goiter. For multinodular goiter, thyroid function tests may show a normal T4 and T3, with TSH low normal (subclinical hyperthyroidism) as some of the nodules slowly grade toward autonomy. 4. Goiter may be stable over a period of years or can slowly grow. Nodules within multinodular goiter may also undergo rapid, painful enlargement secondary to hemorrhage. Such a rapid increase in size may be associated with pain and an increase in regional symptoms, including airway distress. 5. From 15% to 45% of patients with large cervical goiters or substernal goiters may be asymptomatic. Patients may be asymptomatic and yet have radiographic evidence of tracheal compression.

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6. When patients with goiter are symptomatic, they may present with chronic cough, nocturnal dyspnea, choking, dysphagia, and difficulty breathing in different neck positions or in recumbent position. Up to 20% of patients with large cervical and retrosternal goiters may present with acute airway distress, with up to 10% requiring intubation. 7. Surgery should be considered for symptomatic patients, those with significant radiographic evidence of airway obstruction, or substernal goiter (with substernal tissue representing abnormal thyroid tissue unavailable for routine physical exam, monitoring, or FNA). Consideration can be given for significant cosmetic defect as well. 8. The physical examination of such patients should include evaluation of respiratory status, tracheal deviation, and substernal extension. The development of venous engorgement or subjective respiratory discomfort with the arms extended over the head (Pemberton sign) can suggest obstruction of the thoracic inlet from a large or substernal goiter. 9. All patients should have vocal cord mobility assessed. 10. All patients should have TSH test to rule out subclinical hyperthyroidism. This should be done prior to CT scanning with contrast (Jod-Basedow effect). 11. Ultrasound should be performed with consideration of FNA of nodules (see thyroid nodule work up below). 12. If there is concern for tracheal deviation, compression or substernal extension CT scan should be performed. 13. Thyroxine suppression can reduce goiter size and has been found to be more helpful in diffuse than in multinodular goiter. The reduction in goiter size is, however, unpredictable. Goiter growth typically resumes after T4 discontinuation. 14. During surgery for goiter, nerve identification is necessary as in all cases of thyroidectomy. It may be necessary to use a superior approach with identification of the nerve at the laryngeal entry point after superior pole dissection and then retrograde dissection of the nerve. 15. Multiple surgical series suggest that sternotomy for large cervical and substernal goiters is rarely needed. The surgery for cervical and substernal goiter can include lobectomy to total thyroidectomy. The incidence of carcinoma (usually small intrathyroidal papillary carcinomas) in such multinodular goiters is approximately 7.5%.

Thyroid Nodules Background 1. Discrete lesions radiographically distinct from surrounding thyroid parenchyma. Prevalence of palpable nodules is ~ 5% in women and ~1% in men. Prevalence on ultrasound is 19-68% and increases with age. 2. Usually asymptomatic, but require evaluation given risk of malignancy, which is ~ 815% in nodules >1 cm. The incidence of thyroid cancer is increasing throughout the world and in the United States, from 4.9 cases per 100,000 in 1975 to 14.2 per 100,000

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in 2014. Over 56,000 new cases of thyroid cancer estimated in 2017. Much of the increase is attributed to increased detection. 3. Ninety-five percent of thyroid nodules are colloid nodules, adenomas, thyroid cysts, focal thyroiditis, or cancer. However, less likely entities are possible (see Table 4). 4. Colloid or adenomatous nodule is a nodule within a gland affected by multinodular goiter. Represents a focal hyperplastic disturbance in thyroid architecture and generally not a true clonal neoplasm. 5. Follicular adenomas are monoclonal tumors and can be autonomous or nonautonomous. It is unknown if some follicular adenomas have the capability of evolving into follicular carcinoma. Table 4. Differential diagnosis of the thyroid nodule

95%

Colloid nodule—MNG Adenoma Cyst Focal thyroiditis Carcinoma S/P hemithyroidectomy Hemiagenesis Metastasis to thyroid Thyroglossal duct cyst

Non-thyroid: Lymph node Parathyroid cyst Cystic hygroma, dermoid, teratoma Laryngocele MNG, multinodular goiter; S/P, status post.

Evaluation and Management of Thyroid Nodules History and physical examination are first steps in thyroid cancer risk assessment and providing clinical context for interpretation of further diagnostic studies including ultrasound and fine needle aspiration (Table 5). Table 5. Degree of clinical concern for carcinoma in a thyroid nodule based on history and physical examination Less Concern Chronic stable examination Evidence of a functional disorder (e.g., Hashimoto’s, toxic nodule) Multinodular gland without dominant nodule

More Concern Age < 30 or > 60 years Males Rapid growth, pain History of radiation exposure Family history of thyroid carcinoma Hard, fixed lesion Lymphadenopathy Vocal cord paralysis Size > 4 cm Aerodigestive tract compromise (eg, stridor, dysphagia)

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History 1. Age: Patients < 30 years of age have a higher risk of carcinoma. In patients > 60 years of age, nodular disease is more common and malignant disease, if found, is thought to have a worse prognosis. 2. Gender: Males have an increased risk of a thyroid nodule being malignant, up to double that of females in some studies. 3. Radiation exposure: Exposure to ionizing radiation (e.g., Chernobyl incident) increases risk of papillary thyroid cancer and more aggressive malignant behavior. Low-dose radiation therapy (eg, 200-500 rads) was given prior to 1955 for adenoidal and tonsillar hypertrophy, thymic enlargement, facial acne, and tinea of the head and neck. Approximately 1.8%-10% of patients exposed to low-dose radiation eventually develop thyroid carcinoma. Nodules may develop with a latency of up to 20-30 years, requiring ongoing vigilance. 4. Significant family history of thyroid cancer, especially medullary carcinoma or MEN 2, increases the risk of carcinoma. Physical Examination 1. Technique: orient to the thyroid gland by using adjacent cartilaginous laryngeal reference points. Once thyroid cartilage notch is identified, the anterior ring of the cricoid can be easily found. One fingerbreadth below the cricoid, the isthmus can be palpated on the underlying upper cervical trachea. When identifying the isthmus in the midline or the bilateral thyroid lobes laterally, it is useful to have the patient swallow in order to have the thyroid roll upward underneath the thumb. With such an examination, nodules of 1 cm or greater can often be detected. 2. Risk of malignancy: a. Size of nodule: The risk of follicular malignancy is higher in larger nodules. Larger nodules, particularly > 4 cm, are also more difficult to assess given a higher false negative rate with FNA. Generally, nodules 7mm. Intermediate suspicion features include hypoechogenicity, and low suspicion features include hyper- or isoechogenicity, solid nodule with regular margins, and mixed solid/cystic. Very low suspicion features include spongiform appearance, and purely cystic nodules are thought to be benign. 2. Evaluation of lymph nodes: sensitive technique to identify number, size, and shape of cervical nodes surrounding and distant from the thyroid. Concerning ultrasound features of lymph nodes suggestive for malignancy include microcalcifications, irregular borders, hypervascularity, and loss of the lymph node hilum. 3. Useful in screening for small lesions in patients presenting with metastatic thyroid cancer and for the evaluation of the thyroid in patients with a history of head and neck radiation. 4. Elastography: U/S elastography (USE) has been applied to study the stiffness/elasticity of nodules as a means to help identify risk of malignancy. USE is a relatively new diagnostic tool that evaluates the degree of distortion of US beam under the application of an external force and is based upon the principle that the softer parts of tissues deform easier than the harder parts under compression, thus allowing a semi-

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quantitative determination of tissue elasticity. While USE may prove to be a useful noninvasive risk assessment tool, its performance is highly variable and operator dependent and has not yet been recommended for widespread use in thyroid nodule work-up.

TiRads Scoring System 1. The diagnostic sensitivity and specificity of ultrasound features vary, and no single feature has proved capable of reliably distinguishing malignant lesions from those that are benign. To address these shortcomings, several national and international professional organizations have developed US-based risk-stratification systems (often referred to as Thyroid Imaging Reporting and Data System or TIRADS) that assign thyroid nodules to categories characterized by increasing risks (or risk ranges) for cancer, based on the presence or absence of the above-mentioned nodule features. 2. The American College of Radiology, for instance, has developed the Thyroid Imaging, Reporting, and Data System (TIRADS) algorithm that ascribes malignancy risk to thyroid nodules based on nodule composition, echogenicity, shape, size, and margins and can provide useful additive information to Bethesda cytology results. 3. The scoring systems have been evaluated by a meta-analysis of 10,437 nodules which found that on the average TIRADS had a good sensitivity and specificity of 79 and 71%, respectively. 4. The EU-TIRADS 1 category refers to a US examination where no thyroid nodule is found and has a risk of malignancy of 0% 5. The EU-TIRADS 2 category has a risk of malignancy of close to 0%. This category includes two patterns: pure/anechoic cysts and entirely spongiform nodules. FNA is not indicated unless to relieve compressive symptoms. 6. The EU-TIRADS 3 category has a risk of malignancy of 2-4%. This category includes patterns of oval shape, smooth margins, isoechoic or hyperechoic, without any features of high risk. FNA should usually be performed only for nodules >20 mm. Table 6. EU-TIRADS categories and risk of malignancy Category EU-TIRADS 1: normal EU-TIRADS 2: benign

US features Malignancy risk, % No nodules None Pure cyst 0 Entirely Spongiform EU-TIRADS 3: low risk Ovoid, smooth isoechoic/hyperechoic 2-4 No features of high suspicion EU-TIRADS 4: intermediate Ovoid, smooth, mildly hypoechoic 6-17 risk No features of high suspicion EU-TIRADS 5: high risk At least 1 of the following features of high suspicion 26-87 - Irregular shape - Irregular margins - Microcalcifications - Marked hypoechogenicity (and solid) EU-TIRADS, European Thyroid Imaging Reporting and Data System; US, ultrasound. Table from the Russ et al., 2017.

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7. The EU-TIRADS 4 category has a risk of malignancy of 6-17%. This category includes patterns of oval shape, smooth margins, mildly hypoechoic, without any features of high risk. FNA should usually be performed for nodules >15 mm. 8. The EU-TIRADS 5 category has a risk of malignancy of 28-87%. This category includes nodules with at least 1 of the following high-risk features: non-oval shape, irregular margins, microcalcifications, and marked hypoechogenicity. FNA should usually be performed for nodules >10 mm.

Fine-Needle Aspiration Biopsy 1. Fine-needle aspiration (FNA) biopsy is the diagnostic procedure of choice for the evaluation of thyroid nodules (Table 7). Ultrasound guidance is strongly recommended because of the improvement in overall sensitivity, specificity, and accuracy of FNA compared to palpation-guided FNA. Effectiveness of FNA is, in turn, related to the skill of both aspirator and cytopathologist. FNA has decreased the number of patients being sent to surgery by 20% to 50% and has increased the yield of carcinoma in surgical specimens by 10%-15%. 2. FNA is recommended for nodules suspicious for malignancy. In general, this risk increases for larger nodules and for nodules with more suspicious sonographic features (as discussed above). Guidelines suggest proceeding with FNA if a nodule is: > 1 cm with high or intermediate suspicion features > 1.5 cm with low suspicion features > 2.0 cm with very low suspicion features No biopsy recommended for purely cystic nodules 3. The Bethesda classification system is the recommended standardized diagnostic terminology/classification system for reporting thyroid FNA results. This is a sixtiered system for separating FNA results based on risk of malignancy (Table 8). While risk of malignancy is estimated for each of the six categories, variability in institutionspecific estimated risk is recognized and should be understood by practitioners. a. Nondiagnostic: Accounts for about 15% of cases, with 2-4% of these ultimately showing malignancy. Such aspirates should be repeated under ultrasound guidance. In the event of two nondiagnostic results, patients should be considered for surgical excision if the nodule demonstrates a suspicious sonographic pattern or there are clinical risk factors for malignancy. Low risk nodules may be monitored with surveillance. b. Benign: Because the risk of malignancy is very low (0-3%), no additional immediate work up is recommended. Options for management of nodules reported “benign” include (1) following the patient with repetitive examinations and sonograms; (2) administering suppressive therapy (uncommon); and rarely (3) surgery (such as with large nodules >4 cm). Larger nodules have a higher risk of false negative results, and the risk of malignancy may be higher.

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Table 7. Algorithm for the evaluation of thyroid nodules 1. All patients with suspected thyroid nodule(s) should undergo thyroid ultrasound. 2. Patients found to have thyroid nodules >1 cm should undergo a complete history, physical examination, and measurement of serum TSH. 3. If low TSH, then I123 or Tc99 scanning; if uniform increased uptake or “hot” then evaluate and treat for hyperthyroidism. 4. If no nodule is seen sonographically and TSH is high then evaluate and treat hypothyroidism. If TSH is normal then no further workup. 5. Based on the combination of nodule size and sonographic characteristics, U/S-guided FNA should be considered. For intermediate and high suspicion features, nodules > 1 cm should be biopsied. For low and very low suspicion features, nodules > 1.5 to 2 cm should be considered for biopsy. 6. FNA results: A. Nondiagnostic/inadequate: repeat U/S-guided FNA; if nondiagnostic again, then close follow-up or surgery based on ultrasonographic features and clinical risk B. Malignant: surgery C. Indeterminate: Consider repeat FNA with molecular testing for supplemental information regarding risk of malignancy. If suspicious for carcinoma, then surgery. If low suspicion for carcinoma, can consider surveillance. D. Benign: It is recommended that nodules found to be benign on FNA and are easily palpable be followed clinically at 6-18 month intervals. Benign nodules not easily palpated should be followed with U/S at the same follow-up intervals. If there is evidence of benign nodule growth, repeat FNA with U/S guidance is recommended. 7. Purely cystic nodules are considered to be very unlikely to be malignant and diagnostic FNA is not routinely recommended. Aspiration is considered as a therapeutic option and if performed, cytology should be sent. Surgery is sometimes recommended for large or recurrent cysts. Data from Cooper DS, Doherty GM, Haugen BR, et al. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2006 Feb; 16(2):109-142. Haugen DS, Alexander EK, Bible KC, et al. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association task force on thyroid nodules and differentiated thyroid cancer. Thyroid. 2016 Jan; 26(1):1-133.

d. Indeterminate: i. Atypia of Undetermined Significance or Follicular Lesion of Undetermined Significance (AUS/FLUS): shows architectural and/or nuclear atypia precluding a “benign” categorization but not sufficient for higher risk category. Risk of malignancy is estimated at 5-15% but is variable across centers. Management options include (1) repeat FNA with consideration for molecular testing to help further supplement cancer risk assessment, (2) diagnostic/therapeutic surgical excision, or (3) close clinical surveillance. ii. Follicular Neoplasm or Suspicious for Follicular Neoplasm (FN/SFN): One of the main difficulties with FNA in the identification of malignancy is the differentiation of follicular adenoma from follicular carcinoma. This diagnosis hinges on a histologic finding of pericapsular vascular invasion. In order to definitively differentiate follicular adenoma from follicular carcinoma, histologic evaluation of the entire capsule is necessary. This cannot be obtained with FNA. The FNA of follicular adenomas is graded as to several cytopathologic features ranging from macrofollicular to

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microfollicular. The least worrisome finding on FNA of a follicular lesion is described as a macrofollicular lesion or as a colloid adenomatous nodule. A microfollicular lesion with little colloid and a few follicular sheets, has increased risk of carcinoma. The overall estimated risk of malignancy in this category is 15-30%. Management options for this category include most commonly (1) repeat FNA [with consideration for molecular testing to help further supplement cancer risk assessment] or (2) diagnostic/therapeutic surgical excision • Hürthle cell neoplasm or suspicious for Hürthle cell neoplasm is a subset of this category with presence of Hürthle cells − large polygonal follicular cells with granular cytoplasm. A Hürthle cell-predominant aspirate may indicate an underlying Hürthle cell adenoma or Hürthle cell carcinoma. Hürthle cells can also be present as metaplastic cells in a variety of thyroid disorders, including multinodular goiter and Hashimoto thyroiditis. Because of the risk of an underlying Hürthle cell carcinoma, patients with FNAs described as Hürthle cellpredominant may have repeat biopsy with molecular testing versus diagnostic surgical excision. Table 8. The Bethesda System for reporting thyroid cytopathology: Implied risk of malignancy and recommended clinical management Diagnostic Category Nondiagnostic or unsatisfactory

Risk of Malignancy (%) 5-10b

Benign Atypia of undetermined significance or follicular lesion of undetermined significance Follicular neoplasm or suspicious for a follicular neoplasm Suspicious for malignancy

0-3c 10-30d

25-40e 50-75

Usual Managementa Repeat FNA with ultrasound guidance Clinical and sonographic follow-up Repeat FNA, molecular testing or lobectomy Molecular testing, lobectomy

Near-total thyroidectomy or lobectomyg,h Malignant 97-99 Near-total thyroidectomy or lobectomyg a Actual management may depend on other factors (eg, clinical and sonographic) besides the FNA interpretation. b The risk of malignancy varies with the type/structure of the nodule, i.e., solid vs. complex vs. ≥50% cystic. c Estimate extrapolated from studies showing correlation between biopsied nodule and surgical pathology follow-up. d Estimates extrapolated from histopathologic data from large case cohorts (including repeat atypi-cal FNAs) and meta-analysis of the post 2007 literature. e Includes cases of follicular neoplasm with oncocytic features (aka Hürthle cell neoplasm). f Estimates extrapolated from histopathologic data from large case cohorts and meta-analysis of the post 2007 literature. g Some studies have recommended molecular analysis to assess the type of surgical procedure (lobectomy vs. total thyroidectomy). h In the case of “suspicious for metastatic tumor” or a “malignant” interpretation indicating meta-static tumor rather than a primary thyroid malignancy, surgery may not be indicated. Data from Ali Sz and Cibas ES: The Bethesda System for Reporting Thyroid Cytopathology definitions, criteria, and explanatory notes. Second ed. Springer, 2017.

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4. Suspicious for malignancy: Specimens with cytologic features strongly suspicious for malignancy but not conclusive; confers a 60-75% risk of malignancy and is generally managed with thyroid lobectomy or total thyroidectomy. a. Malignant: When FNA is read as malignant, the chance of malignancy is very high, with a false-positive rate of only 1%. Medullary carcinoma of the thyroid can have a variety of histologic and cytologic forms. Once medullary carcinoma is suspected, calcitonin immunohistochemistry can confirm the FNA diagnosis. Anaplastic carcinoma is often easily identified based on the degree of anaplasia. Lymphoma can be suggested by FNA, but additional tissue with open biopsy is often required to confirm the diagnosis. Aspirates read as primary thyroid malignancy are treated with surgery. 5. FNA false-negative rate ranges from 1%-6%. False negatives occur with greater frequency in small lesions < 1 cm or large lesions > 3-4 cm.

Molecular Testing 1. Background: Molecular testing of thyroid FNA specimens is primarily used diagnostically among patients with nodules that are cytologically indeterminate (i.e., Bethesda III and Bethesda IV). a. Traditionally, these patients underwent repeat biopsy or diagnostic thyroid lobectomy. Molecular testing allows for more detailed risk stratification and preoperative counseling in appropriately selected patients. b. Various molecular biomarkers associated with increased or decreased risks of thyroid malignancy have been identified. Specific molecular tests & techniques vary widely and may include assessment for point mutations, genomic translocations, gene fusions, insertions/deletions, copy number variation, and RNA-based gene expression profiling. 2. Indications: Molecular testing is primarily reserved for cytologically indeterminate thyroid nodules (i.e., Bethesda III/IV). a. Molecular testing does not definitively identify lesions as malignant or benign. Rather, it provides additional information to further characterize the risk of malignancy to guide shared decision-making between physicians and patients. 3. Molecular tests must be evaluated in the context of their sensitivity & specificity, which are immutable characteristics of the test in question, as well as positive predictive value (PPV) and negative predictive value (NPV), which vary based on disease prevalence within the population. a. Previously, molecular tests tended to optimize sensitivity and NPV to “rule out” malignancy, or they optimized specificity and PPV to “rule in” malignancy. As molecular testing evolves, the advantages & disadvantages of one test over another are becoming less stark. b. Example of a “rule out” test is gene expression classification, which measures the expression of various gene transcripts in an FNA sample. The material is classified as either benign or suspicious based on a priori results to maximize sensitivity and NPV for malignancy.

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Example of a “rule in” test is a multi-gene panel assessing for the presence of numerous genetic lesions (e.g., BRAFV600E) that are not typically seen in benign aspirates and that are associated with high specificity and high PPV for malignancy. 4. Long-term data is still needed, highlighting the importance of informed consent and acknowledgement of patient preference, pretest probability, and feasibility when molecular testing of FNA specimens is being considered. c.

Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Features (NIFTP) 1. NIFTP is a very low risk thyroid neoplasm that was previously called non-invasive encapsulated follicular variant papillary thyroid carcinoma. In 2017, it was reclassified as NIFTP to reflect its indolent behavior and low-risk natural history. 2. Diagnosis can only be made after invasion has been excluded, which requires examination of the entire tumor capsule following thyroidectomy. 3. NIFTP is a borderline malignant or premalignant lesion. It is defined by: a. Encapsulation or clear demarcation of tumor from adjacent thyroid tissue. b. Follicular growth pattern c. Nuclear features of PTC d. Lack of (i) vascular or capsular invasion, (ii) well-formed papillae or psammoma bodies, (iii) >30% solid/trabecular/insular growth pattern, (iv) tumor necrosis or high mitotic rate; AND (v) microscopic features of other PTC variants 4. Patients diagnosed with NIFTP should be surveilled annually for at least a decade following thyroidectomy. Surveillance practices are likely to evolve as longitudinal data becomes available over time.

Well-Differentiated Thyroid Carcinoma (WDTC) Papillary Thyroid Carcinoma 1. Histopathology: Papillary thyroid carcinoma (PTC) is characterized histologically by the formation of papillae and unique nuclear features such as nuclear grooves and intranuclear inclusions. The nuclei of the neoplastic epithelium are large, with prominent nucleoli giving “Orphan Annie eye” appearance. Lesions with any papillary component, even if follicular features predominate, are believed to follow a course consistent with PTC. Unfavorable histologic forms of PTC include diffuse sclerosing, tall-cell, and columnar cell variants. 2. Clinical behavior and spread: PTC is strongly lymphotropic, with early spread through intrathyroidal lymphatics as well as to regional cervical lymphatic beds. Nodal metastases from PTC can often undergo cystic formation and may be black in color. 3. PTC has a tendency for multifocality within the thyroid gland. 4. At presentation, approximately 30% of patients harbor clinically evident cervical nodal disease with a rate of distant metastasis at presentation of approximately 3%. In the pediatric population the nodal metastatic rate is as high as 60%.

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5. The presence of cervical lymph node metastasis may increase the subsequent rate of nodal recurrence, particularly with macroscopic nodal disease. Most studies suggest that the presence of microscopic cervical lymph node metastasis does not have significant prognostic implications. 6. Etiology and demographics: PTC occurs in all ages, including children, and occurs three times more frequently in women. The peak incidence in women is 40-50 years of age with a peak incidence 10-20 years later in men. The incidence of PTC has been increasing although mortality levels are stable. The majority of PTC arise spontaneously. Ionizing radiation exposure is a widely studied causative factor of PTC and the incidence of PTC was increased after the Chernobyl accident. A very small subset of thyroid cancer is associated with syndromes such as Familial Adenomatous Polyposis, Cowden Syndrome and Gardner’s syndrome. 7. Molecular alterations: The mitogen-activated protein kinase (MAPK) pathway is central to malignant transformation. In 70% of all cases alteration in this pathway is found. Specific genetic alterations known to be associated with PTC include RET/PTC, NTRK1, RAS and BRAF. The BRAF mutation is the most common genetic event in PTC accounting for approximately 50% of all cases. The presence of a BRAF mutation appears to be a negative prognosticator with a higher frequency of extrathyroidal invasion, cervical lymph node and distant metastasis as well as a higher recurrence rate. 8. Prognosis: The ten-year survival rates of PTC are over 90% but age >40 is associated with increased recurrence and mortality rates. This rate increases even more after age 60. Children are more likely to have an advanced stage at the time of diagnosis. Risk stratification, as discussed later in this chapter, is important for prognosis.

Follicular Thyroid Carcinoma 1. Histopathology: Follicular carcinoma is a well-differentiated thyroid malignancy, with follicular differentiation lacking features typical of PTC. Follicular lesions are differentiated into benign follicular adenomas, minimally invasive carcinoma or widely invasive follicular carcinomas by examination of the tumor capsule. Capsular or vascular invasion is the most reliable indication of malignancy. The degree of invasiveness is variable but correlates with the prognosis. 2. Clinical behavior and spread: Follicular carcinoma is less likely present with nodal metastasis than papillary carcinoma as the spread is typically hematologic. The rates of distant metastasis at presentation are higher and are estimated at 16% overall. Follicular carcinoma is typically a unifocal lesion. The incidence of contralateral disease for follicular carcinoma approaches zero. 3. Etiology and demographics: Follicular carcinoma occurs more commonly in females than in males and in an older age group than PTC, with the median age in the sixth decade. The molecular pathogenesis of follicular carcinoma involves RAS genetic mutations or gene rearrangements of PAX-PPARγ. 4. Prognosis: Follicular carcinomas tend to present in an older age group with a higher rate of distant metastatic disease, and therefore have a worse prognosis than PTC. The tumor size and especially the degree of invasiveness are key factors in the prognosis. 5. Hürthle cell carcinoma is considered a subtype of follicular carcinoma. It is also known as follicular carcinoma, oxyphilic type. Hurthle cells have abundant granular

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cytoplasm with a round nucleus and prominent nucleolus. Hemosiderin-laden histiocytes may be present. Hurthle cell carcinomas are believed to follow a more aggressive course than follicular carcinoma overall, especially with respect to distant metastasis. Metastasis usually occurs hematogenously, but lymph node metastasis is also not uncommon. Radioactive iodine uptake is generally reduced, with greater reliance being placed on surgery. The overall mortality rate is 30% - 70%.

Prognostic Risk Grouping for Well Differentiated Thyroid Carcinoma (WDTC) 1. The identification of key prognostic variables makes it possible to segregate patients with WDTC into a large low-risk group and a small high-risk group. Mortality in the low-risk group is approximately 1% to 2%, while in the high-risk group it is approximately 40% to 50%. Segregation of patients into high- and low-risk groups permits appropriately aggressive treatment in the high-risk group with avoidance of excess treatment and its complications in patients in low-risk category. 2. The key elements of existing prognostic schema for WDTC include: a. Age: Typically, for younger females, < age 50 and for males > age 40 prognosis is good. b. Degree of invasiveness/extrathyroidal extension: Increased invasiveness increases the risk of local, regional, and distant recurrence and decreases survival. c. Metastasis: The presence of distant metastasis increases mortality. d. Sex: Males generally have a poorer prognosis than females. e. Size: Lesions > 5 cm have a worse prognosis and lesions < 1.5 cm have a better prognosis. There is controversy as to the exact cutoff, some describing decreased prognosis with lesions > 4 cm. 3. The two best-known prognostic schema: Hay scheme for papillary carcinoma is summarized by the mnemonic AGES—for age, gender, extent, and size. Cady prognostic schema is for PTC and follicular carcinoma and is summarized by the mnemonic AMES—for age, metastasis, extent, and size.

Guidelines for Preoperative Staging of WDTC 1. It is recommended that patients with malignant cytologic findings on FNA, being treated with thyroidectomy, undergo preoperative neck ultrasound for evaluation of the contralateral lobe and cervical lymph nodes. CT scanning of the neck can be considered.

Specific Guidelines for Appropriate Operative Management of WDTC 1. Recommendations for extent of thyroidectomy: a. Total thyroidectomy is indicated in patients with large thyroid cancers, tumors with extrathyroidal extension and in patients with metastases. In addition, those with suspicious cytology with bilateral nodules may prefer total

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thyroidectomy to avoid the possibility of requiring a future surgery on the contralateral lobe. b. A total thyroidectomy should be performed if radioactive iodine therapy is anticipated. c. Lobectomy alone may be sufficient only for small, low-risk, isolated, intrathyroidal PTC without cervical nodal disease. 2. Level VI neck dissection should be performed in patients with clinically evident lymph node involvement and in patients with advanced stage PTC. a. Systematic evaluation of the central neck nodal beds should be performed (including Delphian, perithyroid, pretracheal, RLN/paratracheal, upper mediastinal, and perithymic regions), with resection of grossly enlarged lymph nodes. b. Prophylactic central neck dissection without clinical disease evidence by either radiologic means or physical examination is controversial. A higher rate of hypoparathyroidism occurs with central neck dissection and there is a potential to upstage patients due to micrometastatic lymph node disease. Proponents of central neck dissection believe the routine removal of the central nodal beds will remove a potential recurrence source and the potential re-operative morbidity associated with it, permit accurate long-term surveillance, and improve staging accuracy to intensify treatment with radioactive iodine. 3. Total thyroidectomy without central node dissection may be appropriate for follicular cancer. 4. In patients with biopsy-proven metastatic cervical lymphadenopathy a lateral neck compartmental lymph node dissection should be performed. If nodal disease is evident in the lateral neck, a selective neck dissection sparing all structures encompassing levels 2-4, ± 5 depending on imaging findings, rather than “berry picking” is recommended. Such a systematic neck dissection seems to decrease subsequent nodal recurrence and the need for complicated reoperation, but has an unclear impact on survival.

Invasive Disease 1. RLN: When disease is focally adherent to a functioning RLN, it should be dissected off, removing gross disease and preserving the functioning nerve. An infiltrated RLN can be resected if preoperative paralysis is present or if gross disease cannot be removed from the nerve. 2. Strap Muscles: Extracapsular disease involving the strap muscles is usually easily managed with resection of the involved musculature. 3. Laryngotracheal complex: Disease invasive to the larynx and trachea is managed with resection of gross disease, with preservation of vital structures when possible. Neartotal excision with postoperative adjuvant treatment is equivalent with respect to survival to more radical resection.

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Postoperative Follow-up for WDTC 1. Thyroid hormone, usually T4, is given to suppress TSH to 0.1-0.3 mU/L in high-risk patients and 0.5-2.0 mU/L in low risk patients. 2. I131 can be given post-thyroidectomy based on the patient’s risk grouping and likelihood of harboring metastatic disease. Typically, high-risk patients with PTC and most patients with follicular carcinoma are considered for treatment. a. I131 is given in ablative doses ranging from 30-100 mCi if patients have undergone less than total thyroidectomy and have greater than 2% uptake on regional neck scanning. b. If adjuvant treatment is necessary or disease is identified on whole body scans, or in high risk patients, doses of I131 (100-150 mCi) are given. 3. External beam radiation (typically using from 50-60 Gy) has been employed to palliate extensive laryngotracheal disease, prolong local control, and improve quality of life in inoperable cases or where gross disease persists postoperatively. It has also been used to palliate bony and central nervous system (CNS) metastasis. 4. Thyroglobulin is produced by normal and malignant thyroid tissue and can serve as a marker of well-differentiated thyroid cancer after thyroidectomy. If thyroglobulin is low (< 2 ng/mL on T4 suppression) or unmeasurable after total thyroid ablation and whole body scanning is negative, patients rarely harbor clinically significant metastatic disease. 5. Cervical ultrasound (US) at 6 and 12 months and then annually for 3-5 years is recommended to evaluate the thyroid bed as well as central and lateral cervical nodal compartments for disease recurrence or metastasis. 6. PET/CT scanning may be performed and useful on patients with WDTC who have a negative I131 scan who have thyroglobulin > 10 ng/mL.

Medullary Thyroid Carcinoma (MTC) 1. Histopathology: This lesion arises from parafollicular C cells (not thyroid follicular cells). Calcitonin is secreted by normal parafollicular C cells, and calcitonin elevation occurs in C-cell hyperplasia and all forms of medullary carcinoma of the thyroid (MTC). This tumor marker has proven extremely useful in establishing a diagnosis in asymptomatic relatives of hereditary cases and in postoperative surveillance. RET oncogene point missense germ-line mutations have been identified in patients with inherited MTC. 2. Etiology and demographics: MTC represents approximately 5% to 10% of all thyroid cancers. Approximately 75% of MTC occurs as a sporadic neoplasm, typically presenting in the fourth decade as a unifocal lesion. Hereditary MTC accounts for the remaining 25%, occurring in a younger age group with multifocal lesions (Table 9). All three forms of hereditary MTC are inherited as autosomal dominant traits and proceeded by C cell hyperplasia. 3. Clinical behavior and spread: MTC has a strong tendency toward paratracheal and lateral neck nodal involvement. MTC tends to recur locally and may metastasize

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hematogenously to lung, liver, or bone. For all types of MTC, the 5-year survival rate is between 78% and 91%; the 10-year survival rate is between 61% and 75%. 4. RET-inhibitors: as of December 2021, 2 RET-inhibitors (Selpercatinib & Pralsetinib) were FDA approved for treating patients with advanced or metastatic RET- mutant MTC who are ≥12 years old. Table 9. Subtypes of Medullary Thyroid Carcinoma (MTC)

Pheochromocytoma

Hyperparathyroidism

Mucosal Neuromata Marfanoid Habitus

Negative Positive or negative

Likelihood of Regional LN Involvement

— Autosomal dominant

Age at Presentation (Decade)

Sporadic MEN IIa

Family History

Mode of Transmission

Subtypes of MTC

Fourth Third

High High if Dx with mass

No Yes

No Yes

No No

Low if Dx with screen Autosomal Usually First or High Yes No Yes dominant negative second Autosomal Positive or Fourth Low No No No dominant negative LN, lymph node; MEN, multiple endocrine neoplasia; FMTC, familial nonmultiple endocrine neoplasia medullary carcinoma of the thyroid (now FMTC is considered a nonpenetrant form of MEN 2A). MEN IIb FMTC

5. Surgical treatment: Surgery remains the mainstay option for management of medullary carcinoma of the thyroid. a. The surgical recommendation is total thyroidectomy with central neck dissection for all MTC cases. b. Given the high incidence of microscopic lateral neck disease, all patients with palpable MTC should have ipsilateral level II to V neck dissections with a consideration for bilateral dissection.

Lymphoma 1. Histopathology: Primary thyroid lymphomas are typically of the non-Hodgkin type. Primary thyroid Hodgkin disease is extremely rare. 2. Clinical behavior and spread: Lymphomas are highly curable malignancy if diagnosed promptly and managed correctly. Treatment is based on the lymphoma subtype and the extent of disease and is similar to the treatment of non-Hodgkin lymphoma (NHL) at other sites. Radiation therapy and chemotherapy are the main treatments, surgery is mainly restricted to biopsy. 3. Etiology and demographics: Thyroid lymphomas constitute only 3% of all NHLs and approximately 5% of all thyroid neoplasms. Thyroid lymphoma usually occurs in women in the sixth decade of life, presenting typically as a rapidly enlarging firm,

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painless mass. Patients may present with evidence of RLN paralysis, dysphagia, and regional adenopathy. Often, there is a history of preexisting hypothyroidism (30%40% of cases). The incidence of primary thyroid lymphomas in patients with Hashimoto thyroiditis is markedly increased.

Anaplastic Thyroid Carcinoma (ATC) 1. Epidemiology & Clinical Features a. Highly aggressive thyroid malignancy generally affecting patients >60 years of age. b. Median survival is about 5 months and 1-year survival is ~20%. c. Patients often present with a rapidly enlarging lower neck mass that is fixed to the laryngotracheal complex. Hoarseness, dyspnea, dysphagia, and pain are common and may reflect invasion of surrounding structures (70% incidence at presentation), including the larynx (13%), trachea (46%), laryngeal nerves (27%), esophagus (44%), or muscles (65%). 2. Diagnosis & Workup a. Biopsy: FNA biopsy is sufficient for diagnosis in most (~60%) of cases, but additional tissue may be necessary to perform immunohistochemical (IHC) and/or molecular studies that are important for identification of tumor-specific mutations that may be targetable therapeutically. Core needle biopsy usually provides sufficient tissue for these purposes. Rarely, open surgical biopsy is required. Sufficient biopsy material should be obtained to rule out lymphoma, which is readily treatable. b. Histopathology: Undifferentiated follicular cells characterized by a high mitotic rate, significant nuclear pleomorphism, extensive tumor necrosis, and widely invasive growth pattern. ATC are thought to arise in most cases from pre-existing well-differentiated thyroid cancers. c. Molecular studies: i. Molecular profiling should be performed at the time of ATC diagnosis to inform decisions related to the use of targeted therapies. Several mutation-specific therapies have shown promise and been approved for the treatment of ATC. ii. p53: Somatic mutations resulting in loss of p53 tumor suppressor functions is a molecular hallmark of ATC. iii. BRAF: Somatic mutations affecting BRAF are seen in 40-70% of ATC. BRAFV600E is a targetable mutation that may be seen in ATC as well as PTC. Expedited testing for BRAF V600E should be performed when ATC is suspected. iv. Thyroid-specific markers including thyroglobulin (TG) and thyroidtranscription factor 1 (TTF-1) are typically absent due to the undifferentiated nature of the tumor. One exception is PAX8, which is expressed in 40-60% of ATC but may also be seen in renal and ovarian carcinomas.

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v.

Ki-67 IHC can be used to assess proliferation rates when mitotic activity cannot be reliably assessed. ATC show a high Ki-67 proliferation index of ≥30%.

Table 10. IHC and common pathologic markers useful in ATC IHC marker PAX-8

Staining pattern / comment - Positive in 40-60% of ATC, at least focally - Most specific marker of primitive thyroidal differentiation - Supports a diagnosis of ATC in the proper morphological and clinical context of an otherwise undifferentiated high-grade neoplasm

Pan-cytokeratins

- Supports epithelial nature of ATC - May be positive focally - Positive in up to 70% of ATC - Typically indicates underlying papillary thyroid carcinoma - Can also serve as a surrogate for molecular testing preoperatively and in the immediate post diagnostic period and thus can be used therapeutically for targeted BRAF inhibition

BRAFV600E

Ki-67 p53

Lymphoid markers (CD20, CD34, CD45 and others) Chromogranin Calcitonin and Carcinoembryonic antigen (CEA) Thyroglobulin (Tg)

- ATC should display high proliferation index (at least > 30% but most often significantly higher) - p53 overexpression is seen in over half of ATC - Abnormal p53 immunoreactivity (either complete loss of p53 expression or markedly increased p53 expression) can support a diagnosis of ATC in the proper histological and IHC context - Typically negative in ATC

- Typically negative in ATC - Typically negative in ATC

- Typically negative in ATC

Thyroid- Usually negative in ATC but focal/weak staining transcription can be seen in 10-30% of ATC factor-1 (TTF-1) Table from the Karcioglu et al. 2021.

Differential / possible pitfalls - Large B cell lymphomas (PAX8 antibodies (polyclonal) can cross-react with PAX5) - Entrapped benign thyroid follicular cells and C-cells - May be weakly positive in some medullary thyroid carcinomas - Metastatic carcinomas (kidney, pancreas, gynecological/Mullerian) - Some neuroendocrine tumors (due to cross reactivity) - Some sarcomas, including Ewing sarcoma (80%) - Absence does not rule out ATC - Also expressed in a wide variety of tumors including: - Papillary thyroid carcinoma (especially tall cell variant) and some poorly differentiated thyroid carcinomas - Metastatic melanoma - Some metastatic carcinomas (lung, colon, etc…) - Langerhans cell histiocytosis,

- Also expressed in many high-grade neoplasms including carcinomas and sarcomas

- Large cell lymphoma, especially diffuse large B cell lymphoma

- Expressed in medullary thyroid carcinoma - Expressed in medullary thyroid carcinoma

- May be positive if co-existing differentiated thyroid carcinoma - May be positive if co-existing differentiated thyroid carcinoma

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d. Laboratory tests: CBC with differential, comprehensive metabolic panel, thyroid function tests (TSH, free thyroxine), thyroglobulin / antithyroglobulin should be obtained. e. Imaging: i. Ultrasound of the thyroid & neck provides meaningful information about the primary tumor and regional lymph nodes. ii. Cross-sectional contrasted CT imaging of the neck & chest should be obtained to help guide planning for surgery and radiation. iii. Whole body 18F FDG PET/CT is the preferred modality to evaluate for regional and distant metastatic disease. CT, MRI, and bone scans are alternatives for assessing for distant disease where PET is unavailable. iv. MRI brain with and without contrast (or CT if MRI unavailable) should be considered to evaluate for central metastases. f. Airway & Vocal Cord Assessment: Vocal cord mobility and airway patency should be assessed via flexible fiberoptic laryngoscopy at diagnosis and as indicated based on symptoms thereafter. g. Staging: All ATC is Stage IV at presentation—stage IVa disease is limited to the thyroid, stage IVb reflects extrathyroidal extension or regional nodal involvement, and stage IVc is defined by distant metastasis. 3. Treatment a. ATC is best managed by a multidisciplinary team including specialists in endocrinology, radiation & medical oncology, thyroid surgery, nuclear medicine, and palliative care. b. The poor overall prognosis must be discussed with the patient/family at the earliest appropriate time. Goals of care and palliative / hospice care options should be reviewed soon after diagnosis and revisited as needed. c. Treatment for ATC is typically multimodal with surgery, targeted, immunotherapy, and/or radiation. d. Surgery: i. Surgical treatment is often limited to debulking or biopsy, frequently in the setting of tracheotomy for impending airway compromise. In general, procedures should not generate a wound or result in complications that would delay or prevent initiation of chemoradiation. ii. Patients with stage IVa and IVb disease (i.e., no distant metastatic disease) may be considered for may be considered for surgical treatment for locoregional disease. Total thyroidectomy with central and lateral neck dissections should be performed in this situation. Surgery should not be performed if complete visible tumor resection (R0 or R1) is not anticipated. iii. Aggressive surgery involving resection of major vascular or visceral structures should generally be avoided. There is a lack of data supporting an association between increased extent of surgery and improved survival outcomes in patients with stage IVb ATC.

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e.

f.

Chemoradiation: i. External beam radiation and systemic chemotherapy may have a role in ATC treatment in the neoadjuvant, primary, adjuvant, and palliative settings depending on patient & tumor characteristics, functional status, and patient preference. ii. The most well supported use is as an adjuvant therapy to surgical resection in patients without distant disease where concurrent chemotherapy is recommended to begin as soon as possible and no later than 6 weeks after surgery. iii. Primary chemoradiation may be considered in patients with unresectable locoregional disease. In the setting of metastatic disease, radiation offers little benefit beyond palliation. Radioactive iodine is ineffective. iv. The role of standard chemotherapy is shrinking in favor of targeted therapies and immunotherapy. The chemotherapy regimen typically includes a taxane (paclitaxel or docetaxel), with or without anthracyclines (doxorubicin) or platin (cisplatin or carboplatin). Targeted therapies i. Dabrafenib (BRAF inhibitor) and Trametinib (MEK inhibitor) combination therapy has shown significant survival benefit and disease regression among patients with BRAFV600E-mutated disease. Patients with this mutation and unresectable or distant disease should be offered this therapy. ii. Other therapies targeting rarer mutations and other pathways are under evaluation and may be considered in patients with unresectable or distant disease, typically as part of a clinical trial. Examples include TRK inhibitors (Larotrectinib, entrectinib), RET inhibitors (selpercatinib, pralsetinib), multkinase inhibitors (Lenvatinib), and others. iii. The role of immune therapy in ATC management is also currently under evaluation. PD1/PD-L1 inhibitors (e.g., nivolumab, pembrolizumab) may be considered in patients with high PD-L1 expression. iv. The importance of timely molecular analysis of biopsy specimens is highlighted by these therapies.

Thyroidectomy: Surgical Anatomy 1. A horizontal neck incision is made, within a natural skin crease, typically 1-2 finger breadths above the sternal notch. A subplatysmal skin flap may be raised. 2. The strap muscles raphe is divided, and the sternohyoid and sternothyroid are elevated in one layer off the ventral surface of the thyroid lobe. 3. Through primarily blunt dissection, the lobe is dissected and mobilized. As this is done, the thyroid gland is retracted medially, and the strap muscles are retracted

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laterally. The middle thyroid vein should be ligated, providing lateral exposure of the mid lobe (Figure 4).

Figure 4. Middle thyroid vein division provides for greater lateral exposure.

4. The inferior pole is dissected with attention toward identifying and preserving the inferior parathyroid, which is typically located within 1 cm inferior or posterior to the thyroid’s inferior pole. 5. The RLN can be identified through the lateral approach at the midpolar level just below the ligament of Berry and its laryngeal entry point or medial to the tubercle of Zuckerkandl. The RLN is identified as a white, wave-like structure with characteristic vascular stripe. Extralaryngeal branching can occur in about one-third of patients above the crossing point of the RLN and inferior thyroid artery. On the right, the RLN takes a more oblique course than on the left. Nerve stimulation can be used to facilitate nerve identification. The laryngeal entry point is indicated by the inferior cornu of the thyroid cartilage. The possibility of a nonrecurrent RLN on the right should be kept in mind. 6. The RLN should be identified visually in all cases and confirmed electrically through neural monitoring. 7. The distal branches of the inferior and superior thyroid arteries should always be ligated as close to the thyroid as possible in order to optimize parathyroid preservation (Figure 5). If the parathyroid has turned black as a result of its dissection or has a questionable vascular pedicle, it can be biopsied, confirmed as parathyroid, and then minced and placed into several muscular pockets in the sternocleidomastoid muscle (SCM).

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Figure 5. Laterally, the inferior thyroid artery and superiorly, the superior thyroid artery are followed to identify inferior and superior parathyroid glands.

8. Downward and lateral retraction of the superior pole allows dissection in the interval between the thyroid cartilage medially and the superior pole laterally (cricothyroid space). The superior polar vessels are then ligated at the level of the thyroid capsule. In approximately 20% of cases, the external branch of the SLN is closely related to the superior pole vessels at the level of the thyroid capsule and is thereforevulnerable to injury. The external branch of the SLN can be electrically identified with a neural monitor.

Surgical Complications 1. RLN paralysis rates vary because many studies do not perform postoperative laryngeal examination, which is essential for determination of accurate postoperative paralysis rates. Many reports reveal rates of 6% to 7%, while some report as high as 23%. The incidence of RLN paralysis increases with bilateral surgery, revision surgery, surgery for malignancy, surgery for substernal goiter, and in patients brought back to surgery for bleeding. RLN paralysis causes hoarseness, dysphagia and aspiration. Bilateral RLN paralysis may result in a nearly normal voice but respiratory insufficiency with postoperative stridor. Temporary RLN paralysis generally resolves within 6 months. 2. SLN external branch paralysis occurs in 0.4% to 3% of cases and results in reduction of cricothyroid vocal cord tensing with loss of high vocal registers. Therefore, damage

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can result in loss of projection and high pitch tones while singing. The affected cord will be lower and bowed, with laryngeal rotation. 3. Hypoparathyroidism can result in hypocalcemia post-operatively with the calcium decrease being most apparent on the second post operative day. Symptoms may include perioral and digital paresthesias. Progressive neuromuscular irritability results in spontaneous carpopedal spasm, abdominal cramps, laryngeal stridor, mental status changes, QT prolongation on the electrocardiogram, and ultimately tetanic contractions. Chvostek sign is the development of facial twitching with light tapping over the facial nerve. This sign must be assessed preoperatively, as approximately 5% of the normal population has a positive Chvostek sign in the setting of eucalcemia. Trousseau sign is induced carpal spasm through tourniquet-induced ischemia. Temporary hypoparathyroidism, defined as being of less than 6 months duration, occurs in from 17% to 40% of patients after total thyroidectomy. Permanent hypoparathyroidism after total thyroidectomy occurs in approximately 10% of patients. 4. Post-operative hematoma occurs in less than 2% of thyroid surgeries and can occur immediately or several days postoperatively. A hematoma may cause airway obstruction and should be treated as a surgical emergency. Endotracheal intubation may be difficult in these patients due to edema and compression of the glottis. The use of a drain postoperatively has not been shown to decrease hematoma rates.

Remote-Access Thyroid and Parathyroid Surgery 1. Some patients wish to avoid a cervical scar because of keloids, hypertrophic scarring, for cosmetic reasons, or due to cultural values. Several approaches to the thyroid and parathyroid glands have been developed to avoid the typical cervical collar incision (“scarless” thyroidectomy). 2. Careful patient selection is critical. Oncologic control and risks to the laryngeal nerves, parathyroid glands, and other vital structures must always be prioritized over cosmetic considerations. 3. Absolute contraindications to remote-access approaches include: thyroid cancer with extrathyroidal extension or lymph node involvement; Graves’ disease; substernal extension; and previous neck surgery. In general, the optimal patient has a unilateral nodule 1 mg/dL above the upper limit of normal b. Patients < 50 years of age c. Creatinine clearance < 60cc/min, kidney stones, nephrocalcinosis, or hypercalciuria. d. Osteoporosis (defined by bone mineral density score ≤2 standard deviations below the mean corrected for age, gender, and race) or history of fracture.

Parathyroid Localization Studies 1. Imaging does not have a role in the diagnosis of PHPT. It is principally for surgical planning. Preoperative localization studies help in identification of candidates for minimally invasive parathyroidectomy and in revision cases or where an ectopic gland is suspected. (Figure 6). 2. Ultrasound: a. Parathyroid adenomas are typically oval, homogeneous, hypoechoic, and have a feeding vessel. b. Advantages: Inexpensive. Non-invasive and no radiation or contrast exposure. Also evaluates for concomitant thyroid nodules. c. Disadvantages: Very operator-dependent with sensitivities ranging from 5196%. US is poor at detecting lesions behind the larynx/trachea and in the

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mediastinum. Lastly, US is a non-physiologic study—i.e., not specific for abnormal parathyroid glands vs small lymph nodes or other lesions

Figure 6. Parathyroid localization tests: parathyroid adenoma seen on Ultrasonogram, CT, MRI, (top), and planar sestamibi scanning, gross pathology, and SPECT/CT of parathyroid adenoma (bottom).

3. Sestamibi (Technetium 99m, Tc99MIBI) Scan a. Sestamibi is initially taken up by both thyroid and parathyroids. Tracer uptake in the thyroid washes out more quickly than adenomatous parathyroid glands. Two-hour interval scans show tracer retained within adenomatous parathyroid glands. The uptake and retention of sestamibi is related to cellular mitochondrial content. Single photon emission computerized tomography (SPECT) scanning increases the accuracy of sestamibi scanning by combining scintigraphy with CT imaging for improved 3D localization. b. Advantages: Useful for detecting single adenomas with a sensitivity of 89%. May detect ectopic adenomas. c. Disadvantages: Low sensitivity for multi-gland disease, hyperplasia, and small adenomas. 4. Four-Dimensional CT (4D-CT) a. Contrasted CT protocol that assesses contrast uptake at multiple points in time to allow for differentiation of tissues by contrast retention over time. The scan typically includes a non-contrast phase, an arterial phase (25-30s after contrast injection), and a delayed phase (60-80s after contrast injection). b. Advantages: Provides both anatomic and physiologic information. High sensitivity (≥85%) in localizing parathyroid adenomas to a single side. Excellent in identifying ectopic glands.

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c.

Disadvantages: Radiation and contrast exposures. Decreased specificity relative to ultrasound.

Surgical Theory for Hyperparathyroidism 1. Although a single adenoma is more likely, hyperplasia must always be kept in mind when creating the surgical plan. Unilateral exploration augmented by preoperative localization studies should allow shorter operative times, a decrease in postsurgical complications, and resultant cost savings. 2. The trend is toward unilateral surgery and minimally invasive approaches with increased reliance on preoperative localization testing and intraoperative PTH assays. Given the short half-life of PTH, approximately 10 minutes after resection of an adenoma, the PTH should fall to within normal limits. Once sufficient PTH fall occurs, the surgery can be successfully halted. Exploration of other parathyroid glands should be performed if PTH does not normalize after removal of the suspected source lesion. Rapid PTH assays are available and are beneficial for unilateral approaches. 3. In cases of four-gland hyperplasia, surgical strategies include three and one half-gland subtotal resection to four-gland resection with autotransplantation. In general, the aggressiveness of the surgical approach should relate to the clinical severity of the subtype of four-gland hyperplasia.

Parathyroid: Surgical Anatomy 1. Parathyroid glands have been described as flat-bean or leaf-like shaped yellow-tan, caramel, or mahogany in color and thus may be distinguished from the brighter, less distinct yellow fat with which the parathyroids are typically closely associated. They can be observed as discrete bodies gliding within the more amorphous fat surrounding them as this fat is gently manipulated (the gliding sign). 2. The vast majority of humans have four parathyroid glands, but approximately 5% of patients will have more than four glands. 3. Mirror-image symmetry occurs for the upper parathyroids as well as for the lower parathyroids which can assist in finding a contralateral parathyroid.

Superior Parathyroid: Surgical Anatomy 1. The superior parathyroid derives from the fourth branchial pouch and is associated with the lateral thyroid anlage/C-cell complex. 2. The final adult position of the superior parathyroid is less variable than that of the inferior parathyroid because of its shorter embryologic migratory path. 3. The superior parathyroid typically occurs at the level of the cricothyroid articulation of the larynx, approximately 1 cm above the intersection of the RLN and inferior thyroid artery. It is closely related to the posterolateral aspect of the superior thyroid

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pole, often resting on the thyroid capsule in this location. The superior parathyroid is located at a plane deep (dorsal) to the plane of the RLN in the neck.

Inferior Parathyroid: Surgical Anatomy 1. The inferior parathyroids derive from the third branchial pouch and migrate with the thymus anlage. Due to their longer path of migration, the inferior parathyroid has a more variable adult position. 2. The inferior parathyroid is found in close association with the inferior pole of the thyroid, often on the posterolateral aspect of the capsule of the inferior pole or within 1 to 2 cm. It is often closely associated with the thyrothymic tongue. 3. The inferior parathyroid is generally located superficial (ventral) to the RLN and the superior gland is deep (dorsal). 4. The most common ectopic locations for parathyroid adenomas include retroesophageal, retrotracheal, anterior mediastinal, intrathyroidal and in the carotid sheath.

Parathyroid Surgery 1. Patients should be positioned supine with slight neck extension. 2. A small midline incision is made in a natural skin crease through skin, subcutaneous tissue and the platysma. 3. The strap muscles are separated in the median raphe then taken off the ventral surface of the thyroid gland. The thyroid gland is then mobilized and retracted medially. 4. The enlarged parathyroid is identified, circumferentially dissected and the vascular pedicle is controlled with care not to damage the RLN.

Complications of Parathyroid Surgery 1. Reasons for failure (ie, persistent or recurrent hypercalcemia) in surgery for HPT include failure to find the adenomatous gland in a normal cervical location, failure to find a second adenoma, failure to recognize four-gland hyperplasia, failure to identify a supernumerary gland (ie, fifth gland), regrowth of adenoma from the unresected stump of an adenoma, unrecognized parathyroid carcinoma, or incorrect diagnosis (eg, BFHH). 2. Permanent hypoparathyroidism occurs after surgery in approximately 5% of cases adenoma cases overall and in about 10% to 30% cases of hyperplasia or secondary HPT. 3. RLN paralysis rates are low, ranging from 0.4-4%.

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Pediatric Thyroid Nodules: Workup and Management 1. Thyroid nodules a. Prevalence of thyroid nodules is estimated to be 0.2–5% in children compared with 19–35% in adults. Risk factors for developing nodules in children include head and neck irradiation, female gender, iodine deficiency, age of puberty, and family or personal history of thyroid disease. Thyroid nodules are more common in females, with a female/male ratio of 3:1. The incidence of thyroid cancer is higher in children. b. Pediatric thyroid nodules are more likely to be malignant when compared with those in adults (25% versus 10%, respectively). Thyroid cancers in children are generally larger and have a greater incidence of lymph node and lung metastases. Pediatric thyroid cancers are also characterized by a higher recurrence rate, though the overall prognosis for cancer-related death is much better. According to the 2015 ATA guidelines on management for children with thyroid nodules and differentiated thyroid cancer, the upper age limit for pediatrics should be defined as patients ≤ 18 years of age, since most children have completed development by this age. 2. Risk factors a. Risks associated with the development of thyroid nodules in children include iodine deficiency, prior radiation exposure, a history of antecedent thyroid disease, and several genetic syndromes, such as APC-associated polyposis, the Carney complex, the DICER1 syndrome, the PTEN hamartoma tumor syndrome, Werner syndrome, Beckwith–Wiedemann syndrome, the familial paraganglioma syndromes, Li–Fraumeni Syndrome, McCune–Albright syndrome, and Peutz–Jeghers syndrome. An annual physical examination is recommended in children at high risk for thyroid neoplasia. Additional imaging should be pursued if palpable nodules, thyroid asymmetry, and/or abnormal cervical lymphadenopathy are found on examination. 3. Diagnosis a. Characteristics of a thyroid nodule include its size, consistency, tenderness or pain, changes over time, growth, and fixation to surrounding structures. Patients may also present with cervical lymph nodes due to metastasis. Compressive symptoms such as dysphagia, hoarseness, discomfort, or shortness of breath may also be present in children with thyroid nodules. b. Ultrasonography (US) is recommended as the first diagnostic imaging modality in all children with thyroid nodules as it is non-invasive and inexpensive. US features such as hypoechogenicity, irregular margins, increased intranodular blood flow, microcalcifications and abnormal cervical lymph nodes are more commonly seen in malignant nodules. c. Scintigraphy differentiates between functioning and nonfunctioning nodules and classifies nodules as either “cold” or “hot” depending on their iodinetrapping function. This is not very effective for differentiating a benign from a malignant nodule in the pediatric population. A hot nodule may represent a follicular adenoma, an adenomatous goiter hyperplasia, a chronic lymphocytic thyroiditis, a colloid goiter, or, rarely, a carcinoma. Cold nodules

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are often benign and the incidence of malignancy ranges from 20% to 60%. Scintigraphy is not routinely used in the workup of thyroid nodules. d. FNA is not warranted for the evaluation of a nodule < 1 cm in size unless the patient is at high-risk for malignancy, i.e exposure to radiation, or the nodule is associated with pathologic regional lymph nodes. A size criterion is less commonly used in children because thyroid volume changes with age and the size of the nodule alone does not predict malignant histology. US characteristics, clinical context, and family history should be used more to determine which nodules need FNA. All FNA in children should be performed for nodules with high-risk features and under US guidance. Preoperative FNA of a hyperfunctioning nodule in a child is not warranted as hyperfunctioning nodules in children will be surgically removed. e. For both children and adults, The Bethesda System is used for reporting FNA results of a thyroid nodule. 4. Management: a. If a patient has benign cytology without suspicious nodules and has no risk factors for cancer, surgical resection can be avoided. Serial ultrasound in 6-12 months may be used to follow up thyroid nodules. Surgery may be considered for nodules that are increasing in size, associated with compressive symptoms, cosmetic reasons or patient/parent choice. b. For non-diagnostic nodules on FNA, repeat FNA should be performed within 3-6 months. c. For euthyroid patients with solitary or suspicious nodules, or patients with hypo-functioning nodules on nuclear thyroid scintigraphy, FNA is indicated. d. A hot nodule, hyperfunctioning nodule, usually corresponding to a toxic adenoma can be symptomatic. If it is isolated to the gland, thyroid lobectomy is recommended. e. For nodules with indeterminate cytology, lobectomy plus isthmusectomy is favored over repeat FNA. f. If a nodule increases in size during the follow-up or exceeds 4 cm in size, reevaluation with FNA or surgical removal is indicated, i.e lobectomy for isolated unilateral lesions. g. FNA of nodules > 4 cm has decreased sensitivity for detection of malignancy. Given the high false-negative rate of FNA in large lesions, surgery should be considered especially if they are solid. If surgery is undertaken, lobectomy is preferred to minimize the risk for complications. h. For children with a unilateral nodule suspicious for follicular neoplasm, a lobectomy is recommended as the initial procedure, followed by total thyroidectomy if the diagnosis of cancer is confirmed by intraoperative pathology. i. In cases when cancer is clinically suspected and cytologically confirmed, a total thyroidectomy is recommended. j. For patients with Papillary Thyroid Cancer (PTC) i. Total thyroidectomy (TT) is the recommended initial surgical approach. Alternatively, in patients with a small unilateral tumor confined to the thyroid gland, a near-total thyroidectomy should be

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ii.

iii.

performed, (deep parotid lobe) intraglandular as well as periglandular lymph nodes

Sublingual and Minor Salivary Glands 1. The sublingual glands are paired, located opposite the lingual frenulum, superior to the mylohyoid muscle, and drain individually in the floor of mouth via multiple ducts of Rivinus or via the submandibular duct via the Bartholin duct 2. Mucoceles of the sublingual glands are called ranulas 3. Minor salivary glands are located throughout the upper airway, but are concentrated in the oral cavity, especially the palate, and number 600 to 1000

Imaging Neoplasms 1. Imaging studies in small, mobile, superficial parotid lesions are elective. Ultrasound to distinguish solid from cystic mass and for fine-needle aspiration (FNA) guidance 2. Ultrasound a. Cost-effective, often available in office setting, no radiation exposure (especially important in the pediatric population) b. Loss of fatty hilum, round lymph nodes, and abnormal peripheral vascularity can suggest malignancy c. Less information than computed tomography (CT) and magnetic resonance imaging (MRI) in deep lobe lesions, retromandibular lesions, and extraparotid extension d. Useful for obtaining image-guided biopsies when needed 3. Magnetic resonance imaging (MRI) is the best study for lesions suspect for neoplasm (noninflammatory)

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a.

4.

5. 6.

7.

8.

Fat (the parotid gland has a high fat content) is hyperintense (bright) on unenhanced T1-weighted images b. Almost all neoplasms are visualized as hypointense (dark) on T1 images. c. T1 images can determine invasion of bone (skull base extension) d. Tissue with abundant water content is hypointense (dark) on T1 images and hyperintense on unenhanced T2-weighted images e. Less cellular differentiated masses (benign and low-grade malignancy) tend to be hyperintense on T2 unenhanced images as they may have more water content than their malignant counterpart which are more likely hypointense f. Cellular benign mixed tumors are hypointense on T1; hyperintense on T2 g. Warthin tumors are isointense/hyperintense on T1 (cysts containing cholesterol); variable/heterogeneous intensity on T2 h. Gadolinium-enhanced images can be hyperintense with inflammatory lesions or neoplasms and can help distinguish a purely cystic from solid tumor i. Distinguishing between benign and malignant lesions by MRI is not reliable but malignancy can be suspected with irregular margins or extraglandular infiltration of tumor j. Diffusion-weighted imaging may provide additional information as hypercellular neoplasms demonstrate restricted water motion CT scan is useful in some settings a. Most neoplasms have a similar appearance on CT; contrast allows discerning between a purely cystic lesion, lipoma, and a neoplasm b. Inferior to MRI in determining the extent of soft tissue disease c. Early cortical involvement of the mandible or skull base is better determined by CT; MR is better at determining bone marrow and intracranial involvement d. CT-guided FNA can be diagnostic in nonpalpable lesions e. Noncontrast CT reliably detects sialoliths Nuclear scintigraphy (rarely used): Tc-99m pertechnetate is rarely used but may help in diagnosing Warthin tumor PET fluorodeoxyglucose (PET-FDG) for initial evaluation is not reliable, not anatomic, and expensive. Pleomorphic adenoma and Warthin tumors are FDG-avid, while many malignant cancers are low grade so can’t reliably distinguish between adenoma and carcinoma Parapharyngeal tumors a. Deep lobe parotid tumors and ectopic salivary gland tumors in the prestyloid space b. Poststyloid space lesions are usually schwannomas and paragangliomas Inflammatory lesions a. Ultrasound or unenhanced CT for calculi, but, plain radiographs are also used b. Sialography is contraindicated in the acute setting of sialadenitis, but may be useful in evaluating for stones, ductal strictures, penetrating trauma, and inflammatory disorders c. MR sialography can image the salivary ducts and does not require cannulation of the duct

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9. Systemic diseases a. Ultrasound or CT may identify calcifications in Sjögren disease or sarcoidosis b. CT or MRI can show multifocal tissue involvement of IgG4-related disease spectrum c. Sialography or MRI sialography may help stage Sjögren disease d. MRI is most sensitive in determining a mucosa-associated lymphoid tissue (MALT) lymphoma in Sjögren patients. Biopsy should be performed on any solid masses in Sjögren patients e. Bilateral parotid cysts can be identified with imaging and may suggest an HIV-positive patient (lymphoepithelial cysts)

Physiology and Related Topics 1. Embryology a. Parotid glands develop in the seventh embryonic week near the eventual duct orifice near the angle of the stomodeum b. The parotid anlage grows posterior and the facial nerve grows anterior c. A true capsule is not formed d. Salivary secretion starts after birth e. Intraparotid lymph nodes form within the pseudocapsule of the parotid but lymph nodes do not form within other salivary glands 2. Physiology − autonomic nervous system a. Flow of saliva is regulated by the autonomic nervous system b. Parasympathetic cholinergic stimulation is dominant and uses mostly the neurotransmitter acetylcholine to activate phospholipase C which activates second messenger Ca-2+. Its functions include fluid formation, and transport activity in the acinar and ductal cells c. Sympathetic beta-adrenergic neurotransmitter is predominantly norepinephrine using G-protein–activated second messenger, cyclic adenosine monophosphate (cAMP). Its functions include exostosis and protein metabolism d. In the acinar cell Na+, Cl-, and HCO3- are secreted into the acinar lumen after the parasympathetic neurotransmitter attaches to the parasympathetic M3 muscarinic receptor e. Water is drawn into the acinar lumen by the osmotic gradient of NaCl f. Water impermeable ductal cells in the ductal lumen reabsorb NaCl and secrete KHCO3, (and a small amount of protein) making saliva less isotonic and more alkaline 3. Physiology − sialochemistry a. Saliva is 99.5% water and the remainder proteins and electrolytes b. Humans secrete about a liter of saliva per day c. Saliva becomes more viscous in the following order; parotid, submandibular gland, sublingual gland, minor salivary gland d. Ca2+ concentration is twice as high in the submandibular gland.

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e.

Parotid gland secretion is proteinaceous, watery, and serous and is the predominant saliva that is stimulated f. Gustatory and olfactory stimulation induce predominantly parotid secretion g. Submandibular gland secretion has a higher mucin content and a higher basal flow rate and is the predominant unstimulated saliva h. Alpha-amylase is the most abundant protein with 40% of the body amylase produced by salivary glands i. Salivary osmolality increases during stimulation (NaCl is not reabsorbed as much) 4. Physiology − sialometry a. Flow of saliva can be measured by volumetric techniques or with dynamic radionucleotide scintigraphy using Tc-99m pertechnetate b. Normal values are difficult to establish because of variability of the flow rates in healthy individuals c. No substantial age-related effect on stimulated salivary flow d. Decreased basal salivary flow with age e. Unilateral salivary gland resection does not usually result in subjective xerostomia 5. Physiology − salivary gland function a. Amylase starts the digestion of starch b. Saliva lubricates the food bolus with mucous glycoproteins assisting with speech, mastication, swallowing, and taste c. Saliva buffers with bicarbonate (HCO3-) d. Antimicrobial proteins include secretory immunoglobulin A, mucins, lysozyme, histamine, lactoferrin, and amylase e. Salivary proteins have a dental protective function preventing dental plaque formation and promoting remineralization f. Excretory function includes viruses (HIV) and inorganic elements (lead) g. Oral epidermal growth factor is reduced with loss of salivary gland function and impedes oral wound healing 6. Pathologic states a. Cystic fibrosis results in abnormal chloride regulation with failure of reabsorption of NaCl in the ductal cells resulting in more viscous saliva with decreased flow rates and sludging of saliva b. Prescription and nonprescription drugs are the most common sources of xerostomia, in particular anticholinergic medications (antihistamines and antidepressants) c. Aging results in loss of acinar cells, and decreased salivary flow combined with other systemic disease and medications leads to xerostomia

Histology 1. Parotid gland a. Acinar cells are pyramidal shape with a basal nucleus and secretory granules at the apex

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b. The serous cells of the parotid are interposed by myoepithelial cells that have a contractile function c. Acinar duct leads to the intercalated duct, the intralobular striated duct, and the excretory duct d. The intercalated and striated ducts can modify the salivary composition. e. Adipose cells in the parotid parenchyma increase with aging 2. Submandibular gland − predominantly serous with 10% mucous cells often surrounded by serous cells in a demilune pattern 3. Sublingual glands and minor salivary gland a. Mucous acinar cells with an even higher percent of mucous acini in minor salivary glands, which are unencapsulated b. Ebner glands are serous minor salivary glands located posteriorly on the tongue 4. Ultrastructure a. Secretory granules are prominent on the apical (facing the acinar lumen) aspect of the acinar cell b. Protein production occurs mostly in acinar cells, starts in the mitochondria and endoplasmic reticulum of the acinar cell, with further posttranslational protein modification in the Golgi complex and storage in the secretory granules c. Water permeable acinar cells are highly polarized and the apical and basolateral membranes are separated by tight junctions d. The extracellular matrix separates the acinar cells from the interstitium e. Myoepithelial cells are located between connective tissue and acinar basal membranes (as well as intercalated duct cells) and contain both smooth muscle and epithelial cells and are rich in adenosine triphosphate (ATP)

Non-Inflammatory Salivary Gland Disease 1. Adenomatoid hyperplasia a. Idiopathic asymptomatic nodule generally on the hard palate b. Biopsy reveals normal minor salivary gland with excision being curative 2. Sialadenosis/Sialosis a. Painless enlargement of the salivary glands b. Enlarged acinar cells c. Myoepithelial atrophy and degenerative changes in neural elements 3. Oncocytic metaplasia a. Mitochondria are enlarged and more numerous b. Idiopathic and associated with aging and most common in the parotid 4. Sebaceous metaplasia a. Sebaceous cells found in normal salivary glands, most commonly parotid. b. Fordyce granules: sebaceous cells in the oral mucosa c. Metaplasia occurs with sebaceous cells replacing cells of the intercalated or striated duct

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5. Necrotizing sialometaplasia (unilateral or midline ulcer on the posterior hard palate or at the junction of the hard and soft palates) a. Exuberant squamous metaplasia b. Inflammatory response in minor salivary glands c. Can be misinterpreted as a malignant process 6. Accessory and heterotopic salivary gland tissue (SGT) a. Accessory SGT i. Ectopic salivary gland tissue with a duct system, most commonly located anterior to the main parotid gland ii. Drains into the main parotid duct iii. Adjacent to the buccal branch of the facial nerve b. Heterotopic SGT: i. Acini in an abnormal location without a duct system ii. Most commonly in cervical lymph nodes with rare examples in the middle ear, thyroid, and pituitary 7. Amyloidosis a. Rarely reported in salivary glands b. Positive Congo red staining (apple-green birefringence on polarized view) c. Painless salivary gland enlargement 8. Immunoglobulin G4 (IgG4)–related disease a. Systemic disease characterized by abundant infiltration of IgG4-positive plasma cells and lymphocytes with associated fibrosis i. Elderly men ii. Serum IgG4 levels may be elevated b. Definitive diagnosis requires histopathologic analysis and IgG4 staining c. IgG4-related spectrum of disease (Table 1): most commonly in salivary glands d. Multiorgan involvement is common and can be seen in the pancreas, bile ducts, gall bladder, kidneys, retroperitoneum, mesentery, lungs, gastrointestinal tract, and blood vessels e. CT or MRI to evaluate head and neck and other possible regions of involvement f. PET/CT with bright FGD uptake when active and resolution when in responds to medical treatment g. Excellent response to corticosteroid therapy 9. Lipomatosis a. Tumor-like accumulation of intraparenchymal fat tissue b. Fibrous capsule, discreet mass c. Associated with aging, diabetes, alcoholism, and malnutrition 10. Cheilitis glandularis a. Nodular swollen lower lip of adult males b. Can express saliva c. Nonspecific histologic finding, hyperplasia, fibrosis, and ectasia

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Table 1. Head and neck locations and manifestations of IgG4-related disease Salivary glands Mikulicz disease Chronic sialadenitis (Küttner tumor) Orbits Lacrimal glands Mikulicz disease Chronic dacryoadenitis Idiopathic orbital inflammation (pseudotumor) Lymphoid hyperplasia Perineural spread (trigeminal nerve branches) Sinonasal cavities Thyroid gland Hashimoto thyroiditis Riedel thyroiditis Pituitary gland Hypophysitis (pituitary stalk/gland) Larynx (submucosal lesion) Lymph nodes

Inflammatory Salivary Gland Disease Sialadenitis 1. Acute suppurative sialadenitis a. Elderly, debilitated, and postsurgical (abdominal and hip) patients most commonly involves the parotid gland b. Parotid is less mucinous and has less antimicrobial activity than submandibular gland c. Sialoliths more commonly involve the submandibular gland d. Etiology: salivary stasis i. Staphylococcus aureus is most common pathogen (monitor for MRSA) ii. Streptococcus viridans anaerobes e. Parotitis presents with typically unilateral painful gland swelling and purulence from Stensen’s duct f. Ultrasound or CT may identify stone or abscess; sialography is contraindicated as it results in more inflammation g. Treatment: Usually beta-lactamase and anaerobic sensitive antibiotics, (unless case is mild), hydration, posterior to anterior massage and decompression, and sialogogues h. Parotid abscess can be difficult to diagnose clinically with anaerobic infections i. Drainage of abscess involves elevation of facial flap and radial incisions in the parotid parenchyma in the direction of the facial nerve

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2. Chronic sialadenitis a. Sialolithiasis may result in scarred, stenotic ducts, and sialectasia leading to diminished secretory function of the gland. b. Rx: Antibiotics, hydration, sialogogues, manual decompression—50% improve c. Removal of sialolith can return gland function, obviate gland removal d. Kuttner tumor—heavy lymphoid infiltrate in submandibular gland, may mimick neoplasm 3. Mumps a. “Epidemic” parotitis, paramyxovirus, prevent with measles, mumps, and rubella (MMR) vaccine b. Peak age 4 to 6 years c. Most common viral infection, mostly bilateral parotid involved, also fevers, malaise, orchitis, encephalitis, or sensorineural hearing loss d. Dx: clinical, serologic; Rx: supportive 4. Human Immunodeficiency Virus (HIV) a. Parotid enlargement from lymphoid hyperplasia, infection, lymphoma b. May be presenting sign of HIV c. Lymphoepithelial cysts only in parotid but not in other salivary glands because of the incorporation of lymph nodes in parotid embryology d. May develop a sicca syndrome similar to Sjögren syndrome—diffuse infiltrative lymphocytosis syndrome (DILS) e. Dx: HIV+ serology, associated cervical adenopathy, and nasopharyngeal lymphoid hypertrophy f. Deforming bilateral cysts can form, cyst unlikely malignant, Rx: antiretroviral meds and in select patients sclerotherapy; surgery rarely recommended g. Solid mass—40% risk of malignancy 5. Granulomatous diseases a. Tuberculosis increasing secondary to HIV and immigrant population i. Primary is through intraglandular lymph nodes, mostly parotid ii. Secondary; after infection of lungs with hematogenous spread iii. Dx: Purified protein derivative (PPD), FNA–acid-fast bacilli, culture, Langerhans giant cells b. Atypical mycobacteria—children 16 to 36 months i. Violaceous hue of skin, sinus tracts ii. Chest x-ray (CXR) negative, PPD nonreactive iii. Dx: serology iv. Rx: incision and curettage, surgical excision of gland c. Actinomycosis—gram-positive anaerobic actinomyces, sulfur granules i. Risk factors—poor oral hygiene, impaired immunity ii. Sinus tracts, multiloculated abscesses iii. Rx: Penicillin G IV × 6 weeks, then PO erythromycin or clindamycin d. Cat scratch disease—Bartonella henselae, rickettsial pathogen i. Associated with lymphatics of parotid

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7.

8.

9.

10.

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ii. Dx: serology and polymerase chain reaction (PCR), lymphadenopathy, positive Warthin-Starry stain reaction, pathologic features iii. Rx: observation, azithromycin e. Toxoplasmosis—Toxoplasmosis gondii, protozoan parasite, increased incidence with HIV epidemic, under cooked meats, and cat feces i. Dx: culture, acute and convalescent titers ii. Rx: pyrimethamine and sulfadiazine, plus folinic acid f. Sarcoidosis: systemic, unknown etiology, noncaseating granulomas i. Heerfordt disease/syndrome—acute parotitis, uveitis, polyneuritis (facial nerve palsy) ii. Rx: steroids Sjögren syndrome—autoimmune disease, destruction acinar, and ductal cells a. Xerophthalmia, xerostomia—primary b. With collagen vascular disease (rheumatoid arthritis)—secondary c. More common in women, immune-mediated disease, alleles HLA-B8, HLADr3 genetic predisposition d. Parotid hypertrophy e. Dx: (+) anti-Ro (SS-A) and anti-La (SS-B) serologies, minor salivary gland biopsy can demonstrate increased lymphocyte infiltration f. Higher rate of non-Hodgkin lymphoma from prolonged stimulation of autoreactive B cells g. Histology—benign lymphoepithelial lesion with proliferation of epimyoepithelial islands h. Rx: oral hygiene, salivary substitutes, pilocarpine, and cevimeline Sialolithiasis a. Sialoliths - exact etiology unknown. Typically cause pain and swelling with meals. Tend to enlarge over time b. Sialolith imaging includes plain and dental (submental vertex) x-rays, sialography (determines strictures, dilations, and filling defects), ultrasound (can detect stones and ductal dilation), noncontrast CT, scintigraphy (secretory function), and MR sialography c. Intraoral sialolithotomy - incise floor of mouth mucosa, removes stone, heals by secondary intention or suturing of duct d. Transoral proximal Wharton duct stone excision - gland sparing e. Incision of Stensen duct can lead to duct stenosis f. Submandibular sialoliths often in the duct, parotid often in the parenchyma Sialendoscopy for diagnosis of salivary gland swelling without obvious cause (occult sialolith, stricture, or kink) and removal of select small sialoliths a. Stones larger than 5 mm are not able to be removed with a basket b. Wharton duct is more difficult to cannulate than Stensen duct Extracorporeal lithotripsy—not FDA approved in United States. Compressive shock waves brought to focus through acoustic lenses results in stone fragmentation. Residual stone fragments can be removed by sialendoscopy Intracorporeal lithotripsy delivers laser energy through a fiberoptic cable

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Pediatric Salivary Gland Disease 1. Hyposalivation—dehydration, radiotherapy (XRT) for malignancy, anticholinergic drugs 2. Parotitis a. Neonatal suppurative parotitis—preterm, male neonates. Staphylococcus aureus most common b. Recurrent parotitis of childhood—more common in boys, age 3 to 10, recurs weekly or monthly, no pus from duct, imaging shows ectasia of ducts, Rx: antibiotic for Staphylococcus aureus, dilation of Stensen’s duct, and sialendoscopy c. Viral—mumps (paramyxovirus), HIV, cytomegalovirus d. Bacterial—uncommon 3. Congenital cysts a. Parotid dermoid: an isolated midline cystic structure b. Dermoid floor of mouth: midline, unlike a ranula c. Branchial: associated with frequent infections, less than 5% of branchial anomalies are first branchial cleft abnormalities, present from the external auditory canal to the angle of the mandible i. Type I has a tract to the membranous external auditory canal ii. Type II without tract to external auditory canal; Rx: complete surgical resection iii. Polycystic parotid gland has multiple cysts, primitive or mature ducts, remnant acini 4. Acquired cysts a. Ranula - extravasation, not a true cyst; blue translucent swelling, simple type in sublingual space; plunging type posterior to mylohyoid, extending into the neck, Rx: complete resection of sublingual gland b. Mucocele - pseudocyst, lower lip most common location 5. Neoplasms - vascular neoplasm most common salivary neoplasms of children (20%) a. Hemangiomas present at birth usually involute between age 2 and 5 (50% by 5 years, 70% by 7 years) i. Most commons salivary gland neoplasm in children ii. 80% single lesion, 20% multiple lesions iii. Surgery only if impending complications, otherwise can remove postinvolution sparing facial nerve iv. Rx with propranolol b. Lymphangiomas mostly present in the first year of life, rarely involute; Rx— surgery: can be difficult with involvement of nerves and deep tissue planes, OK-432 sclerosing agent c. Most common benign solid neoplasms: pleomorphic adenoma d. Fifty percent of solid salivary gland neoplasms malignant (higher rate than in adults), most common malignancy is mucoepidermoid carcinoma 6. Sialorrhea a. Children with cognitive and physical disabilities, cerebral palsy, metal poisoning

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b. Conservative Rx—glycopyrrolate, scopolamine, Botox c. Surgery—bilateral parotid duct ligation (risks: sialadenitis and fistulization) and submandibular gland excision 7. Recurrent aspiration of saliva from ptyalism/sialorrhea a. Tracheotomy often unsuccessful in prevention b. Laryngotracheal separation is successful; reversible in select patients

Benign Tumors and Cysts (Table 2) Table 2. Benign salivary gland tumors and lesions Pleomorphic adenoma Myoepithelioma Basal cell adenoma Warthin tumor Oncocytoma Lymphadenoma Cystadenoma Sialadenoma Ductal papillomas Sebaceous adenoma Canalicular adenoma and other ductal adenomas Non- neoplastic epithelial lesions Sclerosing polycystic adenosis Nodular oncocytic hyperplasia Lymphoepithelial sialadenitis Intercalated duct hyperplasia Benign soft tissue lesions Hemangioma Lipoma/sialolipoma Nodular fasciitis Hematolymphoid tumors Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) (Adapted from 2017 WHO Classification of Head and Neck Tumors).

1. Benign mixed tumor (pleomorphic adenoma) a. Most common benign salivary gland neoplasm in adults and children (60-70% of all benign tumors) b. Most frequently arise in the parotid gland (70%), typically in the superficial lobe c. Most common minor salivary gland site is the palate followed by upper lip d. Slight predominance for females (M:F ratio of 1:1.4) e. Histology: epithelial and myoepithelial cells, frequently separating to form a chondromyxoid stroma f. Pleomorphic adenomas lack infiltrative growth but contain “pseudopods” that project beyond the tumor capsule (incomplete fibrous capsule) which has important implications for surgical resection strategies

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3.

4.

5.

6.

7.

g. Most tumors have rearrangements in HGMA2 or PLAG1 h. Malignant transformation is rare however risk of transformation is 1.5% within first 5 years of diagnosis, increasing to 10% if observed for >15 years Papillary cystadenoma lymphomatosum (Warthin tumor) a. Occur almost exclusively within the parotid gland (95%) b. Second most common benign salivary gland tumor (15-36% of all benign tumors) c. Strongly associated with smoking (irritation of ductal epithelium by tobacco smoke), predilection for males in 4th-7th decade of life d. Often bilateral (7-10%), either metachronously (90%) or synchronously (10%) e. Histology: tripartite histology with cyst formation, bilayered oncocytic epithelium, and lymphoid stroma Myoepithelioma a. Less than 1.5% of all salivary gland tumors b. Commonly occur in the parotid (40-90%) or palate c. Histology: Plasmacytoid or spindled myoepithelial cells d. Clinically difficult to distinguish from pleomorphic adenoma Oncocytoma a. Less than 1% of all salivary gland tumors b. Most commonly found in parotid gland c. Predilection for 5th to 6th decade of life, associated with prior radiation exposure d. Often enhance on radionucleotide scans e. Histology: Oncocytic predominance (Large epithelial cells with granular eosinophilic cytoplasm due to mitochondrial hyperplasia) Basal cell adenoma a. 1-3% of all salivary gland neoplasms b. Most commonly occur in adults, 5th – 6th decades of life c. Most common site is parotid gland d. Usually solid though can be cystic e. Histology: Basaloid cells organized with prominent basal cell layer and distinct basement membrane-like structure. Four growth patterns: solid, trabecular, tubular and membranous. Can be difficult to distinguish from solid adenoid cystic carcinoma but basal cell adenomas lack true invasion and peripheral palisading Canalicular adenomas a. Less than 1% of all salivary gland tumors b. Mostly occur in minor salivary glands, usually the upper lip c. Histology: Cells arranged in parallel rows forming duct-like structures Sebaceous adenoma a. Less than 0.1% of all salivary gland neoplasms b. 50% occur in parotid gland c. Histology: Nests and islands of sebaceous cells without atypia

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8. Sclerosing polycystic adenosis a. Described in 1996 and newest inclusion in WHO Classification of Salivary Gland Tumors b. Typically occur in parotid gland c. Wide age range: 9-84 years d. Similar to fibrocystic change and sclerosing adenosis of the breast e. 1/3 of patients develop recurrence after resection 9. Non-neoplastic epithelial lesions a. See WHO list above b. Intercalated duct hyperplasia often found incidentally, thought to be precursor to basal cell adenoma and epithelial-myoepithelial carcinoma c. Nodular oncocytic hyperplasia similar to oncocytoma, but without dominant encapsulated lesion 10. Soft tissue lesions a. Hemangiomas: most common in infancy with rapid growth phase 1-6 months and involution over next 1-12 years. Surgical excision reserved for lesions that do not regress b. Lipomas: rare in salivary glands, but if present typically found in parotid gland c. Nodular fasciitis: spindle cell proliferations arising from superficial fascia, 3-4th decades of life 11. Sialoblastoma a. Borderline tumor of uncertain malignant potential b. Arise in perinatal to neonatal period c. Histology: primitive basaloid cells

Malignant Tumors (Table 3) 1. General considerations a. Malignant salivary gland tumors are rare (3% of all head and neck cancers) with an estimated incidence of 0.9 per 100,000 in the United States b. Less than 5% of tumors arise in pediatric age group c. Inverse relationship between incidence of tumors by site and percentage malignant: majority of tumors occur in parotid but only 15% malignant compared to minority of tumors arising in minor salivary glands with 46% malignant d. Tumor behavior closely associated with histologic type and grade e. Primary treatment is surgical followed by adjuvant radiation if indicated (close or positive margins, high-grade histology, perineural invasion, multiple involved lymph nodes) 2. Mucoepidermoid carcinoma a. Most common salivary gland malignancy in adults and children b. Majority occur in major salivary glands, rarely can arise in minor glands or intraosseously

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Histology: Solid and cystic components with presence of mucous, squamoid (epidermoid) and intermediate cell types d. Low grade lesions typically more cystic with little atypia, high grade lesions more solid with greater squamoid/intermediate cells e. Low grade rarely metastasize 3. Adenoid cystic carcinoma a. Infiltrative, indolent, progressive growth b. Recurrence often many years later c. Histology: three growth patterns – tubular, solid and cribriform d. Solid type predominance portends poorer prognosis e. Frequently associated with perineural invasion (70-75% of cases) f. Metastases may be delayed and often occur distantly (lungs) g. Uncommonly associated with metastasis to regional nodes Table 3. Malignant salivary gland tumors Mucoepidermoid carcinoma Adenoid cystic carcinoma Acinic cell carcinoma Polymorphous adenocarcinoma (formerly polymorphous low-grade adenocarcinoma) Clear cell carcinoma Basal cell carcinoma Adenocarcinoma, not otherwise specified Salivary duct carcinoma Myoepithelial carcinoma Epithelial-myoepithelial carcinoma Carcinoma ex-pleomorphic adenoma Secretory carcinoma (formerly mammary analogue secretory carcinoma) Sebaceous adenocarcinoma Carcinosarcoma Poorly differentiated carcinoma Undifferentiated carcinoma Large cell neuroendocrine carcinoma Small cell neuroendocrine carcinoma Lymphoepithelial carcinoma Squamous cell carcinoma Oncocytic carcinoma Salivary gland neoplasm of uncertain malignant potential (SUMP) Sialoblastoma (Adapted from 2017 WHO Classification of Head and Neck Tumors).

4. Polymorphous adenocarcinoma a. Formerly known as polymorphous low grade adenocarcinoma (PLGA) b. Majority arise in minor salivary glands making them the second most common minor salivary gland carcinoma (palate most common) c. Histology: concentric whirling of nests around each other in single-file arrangement d. Generally low grade malignancy, lymph node metastasis is uncommon

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5. Acinic cell carcinoma a. 1-3% of all tumors and 10% of all malignant salivary gland tumors b. Wide age range, peak in 3rd decade of life c. Second most common childhood salivary gland malignancy d. Majority occur in parotid (90%) e. Histology: Characteristic acinic cell (blue cytoplasm with abundant seroustype granules with blue, central nucleus) and dense lymphoid infiltrate with germinal centers f. FNA can be difficult due to ACC resembling normal salivary tissue g. Tumor recurrence in 1/3 of cases despite negative margins h. Associated with long clinical course due to delayed recurrence 6. Carcinoma Ex Pleomorphic Adenoma a. Mixed tumor with presence of carcinoma b. Most patients in 6-7th decade of life (10 years after peak of incidence of pleomorphic adenoma) c. Often present with sudden transformation and rapid growth of an existing mass d. Any form of carcinoma can be found in the mixed tumor e. Widely invasive tumors require local and regional surgical management and adjuvant radiation therapy 7. Carcinosarcoma a. Also known as true salivary gland malignant mixed tumor b. Rare (1% of all salivary gland malignancies) c. Sarcomatous component typically spindle cell sarcoma d. Aggressive with 2/3 patient dying from local recurrence or distant metastasis within 30 months 8. Salivary duct carcinoma a. Aggressive salivary gland tumor with male predominance b. Similar to high grade ductal carcinoma of the breast c. Histology: ductal carcinoma in situ component with cribriform pattern, often with comedo-type necrosis d. Most are negative for estrogen and progesterone receptors 9. Low-grade tumors a. Epithelial-myoepithelial carcinoma: mostly in parotid gland (80%), recurrence rate of 40% b. Secretory carcinoma (formerly mammary analogue secretory carcinoma): identical to secretory carcinoma of the breast, typically in parotid gland, most cured with local resection c. Basal cell adenocarcinoma: malignant version of basal cell adenoma, prognosis is good d. Myoepithelial carcinoma: malignant version of myoepithelioma with varied prognosis 10. Lymphoma a. Primary salivary gland lymphoma represents 5% of all extranodal lymphomas

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b. Marginal zone B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) is most common type c. Association with Sjögren disease 11. Metastases a. Parotid has average of 20 intraparenchymal lymph nodes, majority in superficial lobe b. Metastasis to intraparotid lymph nodes typically from cutaneous squamous cell carcinoma and melanoma (80-90%) and less commonly Merkel cell carcinoma c. Rarely, metastasis to parotid parenchyma from non-head and neck primaries (e.g., lung, kidney, breast, prostate) d. Conversely, metastasis to submandibular gland parenchyma most commonly from non-head and neck primary tumors (85%)

Clinical Management 1. History a. b. c. d. e. f. g.

Age and gender Location of disease (gland involved) Presence/absence of pain (higher suspicion of malignancy with pain) Temporal trend of growth Cranial nerve deficits (facial nerve/trigeminal nerve) Episodic vs progressive swelling Other symptoms i. Xerostomia/xerophthalmia ii. Malocclusion, dental caries, trismus iii. Otalgia iv. Fever v. Unintentional weight loss vi. Neck mass h. Social history: tobacco and alcohol exposure, travel, infectious exposure i. Family history: autoimmune disorders, head and neck malignancy, lymphoma, genetic disorder/syndrome 2. Physical examination a. General i. Facial symmetry ii. Cranial nerves (facial/trigeminal) iii. Location, mobility, tenderness, and quality of mass iv. Regional lymph node examination v. Signs of systemic disease vi. Examination of eyes/lacrimal glands b. Parotid gland i. Palpation of gland, overlying skin, bimanual palpation of buccal space, examination of Stenson’s duct

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ii. Examination of oropharynx and/or nasopharynx for submucosal bulging from deep lobe parotid tumors in pre-styloid space iii. Trismus can occur with posteromedial extension of parotid tumors into infratemporal fossa c. Submandibular gland i. Asymmetry between paired glands ii. Bimanual palpation of submandibular gland iii. Cranial nerves: hypoglossal, lingual, marginal mandibular branch of facial nerve iv. Intraoral examination of Wharton’s duct d. Minor salivary glands i. 500-1000 glands along upper aerodigestive tract ii. Most common site involved with salivary gland tumors is hard palate where majority of minor glands located 3. Laboratory studies a. Consider lab work for diagnosis or exclusion of infectious, granulomatous, metabolic, autoimmune, hormonal or other systemic disorders i. Complete blood count ii. Erythrocyte sediment rate (ESR) iii. Serum calcium and angiotensin-converting enzyme elevation (sarcoidosis) iv. Autoantibodies-rheumatoid factor (RF), antinuclear antibodies (ANA), anti-SSA and anti-SSB (Sjögren syndrome) v. Thyroid stimulating hormone (thyroid dysfunction) vi. Complete metabolic panel (hepatic or renal dysfunction) vii. Human immunodeficiency virus test viii. Nutritional or vitamin deficiencies 4. Radiology (see imaging section earlier in chapter) a. MRI most useful for assessment of salivary gland neoplasms b. T1 weighted imaging useful to distinguish tumors from fatty parenchyma of salivary glands c. Benign lesions typically T1 hypointense, T2 hyperintense d. MRI helpful to assess for perineural spread 5. Biopsy a. Fine-needle aspiration (FNA) is mainstay of diagnostic workup b. Commonly paired with ultrasound to improve diagnostic accuracy c. Minimal risk to facial nerve, tumor seeding extremely rare d. Important limitations: overlapping histologies, malignancy often requires assessment of growth pattern which cannot be determined with limited sample e. FNA overall highly sensitive (85.5%-99%) and specific (96.3%-100%) f. FNA Sensitivity (68%) < specificity (91%) for malignant tumor identification g. If initial FNA non-diagnostic, repeat FNA indicated to improve rate of diagnosis

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h. FNA results classified according to Milan System for Reporting Salivary Gland Cytopathology i. Goal is to avoid ambiguity often seen in FNA interpretation of salivary gland tumors ii. Cellular or nuclear atypia raise suspicion of early malignant transformation or malignancy and now typically reported as Salivary gland neoplasm of uncertain malignant potential (SUMP) iii. SUMP classification carries increased risk of malignancy and necessitates careful patient evaluation and discussion i. Surgical excision often required for definitive diagnosis j. Intraoperative frozen section useful to assess extent of tumor spread, nerve involvement, margins, confirmation of diagnosis, inform need for neck dissection k. Diagnostic lower lip biopsy of minor salivary glands for tissue sampling in diagnosis of inflammatory disorders (e.g., Sjögren) l. Incisional biopsy may be necessary for diffuse or inflammatory diseases such as amyloidosis, sarcoidosis

Salivary Gland Surgery 1. General principles a. Remove tumor with adequate margin to avoid local recurrence b. Extent of dissection is limited by size, location and histology of tumor 2. Parotidectomy a. Modified Blair incision (incision in preauricular crease, extending around lobule and curving into natural skin crease in upper neck) b. May consider facelift approach to hide incision in hairline c. Types of parotidectomy: i. Partial – removal of tumor with cuff of normal parotid tissue ii. Superficial – removal of entire superficial lobe iii. Total – removal of superficial and deep lobes iv. Extracapsular – removal of tumor with preservation of capsule only d. Great auricular nerve preservation can be considered though it can be associated with dysesthesia and minimal quality of life improvement e. Anterograde facial nerve identification: i. Tragal pointer (main trunk 1-1.5cm deep and inferior) ii. Tympanomastoid suture line (main trunk 6-8mm deep) iii. Posterior belly of digastric define plane of nerve iv. Stylomastoid foramen v. Retrograde facial nerve dissection may be helpful when tumor overlies main trunk of nerve

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119 Sialolithiasis Viral

Acute sialadenitis Bacterial Radiation-induced Inflammatory Obstructive Granulomatous Chronic sialadenitis Autoimmune HIV-associated Non-neoplastic Trauma Acute

Necrotizing sialometaplasia

Pneumoparotitis

Salivary Gland Disorders

Aging Non-Inflammatory Sialadenosis Benign (Table 1) Nutritional disorder

Neoplastic Malignant (Table 2) Chronic

Behavioral Medications Amyloidosis Idiopathic

Figure 1. Classification of salivary gland disorders.

3. Submandibular gland excision a. Curvilinear incision in favorable neck crease two fingerbreadths below mandible b. Identification of marginal mandibular nerve is critical: nerve lies beneath cervical fascia and crosses anterior facial vein. It can be ptotic in older patients c. Nerve can be protected by ligating facial vein lower in the neck and retracting it superiorly d. Mylohyoid muscle retraction anteriorly will reveal submandibular ganglion, lingual and hypoglossal nerves, and submandibular duct which overly hyoglossus muscle e. Facial nerve can be preserved or ligated as it courses through the gland 4. Parapharyngeal salivary gland tumor excision a. Most commonly approach transcervical, or with a combined transoral approach b. Deep lobe parotid tumors can be approached with a parotidectomy incision with cervical extension c. Stylohyoid muscle and posterior belly of digastric can be divided or retracted

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d. Stylomandibular ligament division is necessary to allow anterior retraction of the mandible access to the parapharyngeal space e. Mandibulotomy approach may be required for superiorly located tumors adjacent to skull base f. Nasal intubation may facilitate greater mandibular retraction and exposure, obviating the need for mandibulotomy 5. Complications and management a. Facial nerve paresis/paralysis: facial nerve injury is rare if anatomic integrity is preserved. Neuropraxia is the most common type of injury b. Facial nerve sacrifice: nerve repair with direct neurorrhaphy or cable graft should be performed immediately. If immediate repair is not performed, static or dynamic reanimation should be considered c. Ear lobe numbness: often results from injury or sacrifice of the great auricular nerve; overall quality of life among patients with nerve sacrifice is not significantly impaired d. Frey’s syndrome: gustatory sweating due to cross-reinnervation of postganglionic parasympathetic fibers to parotid and postganglionic sympathetic fibers supplying exocrine glands of the skin; incidence of 35-60% e. Sialocele: Risk of accumulated can be mitigated with surgical drain, pressure dressing; treatment options include compression, drainage, anticholinergics, and botulinum toxin injection

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Practice Guidelines Patient Characteristic Patient has intermittent painful parotid swelling with meals. Patient is afebrile without white blood count elevation. There is decreased salivary production. Noncontrast CT with parotid swelling and small calcification in duct. Conservative measures (warm compresses, sialogogues, gland milking) and avoidance of food triggers do not resolve the symptoms. Patient with initial intermittent progressed to chronic submandibular gland swelling with meals. Painful tenderness with mild inflammation but no obvious infection. CT shows large 2cm sialolith within hilum of gland. Conservative sialadenitis measures and medical therapy with antibiotic and steroid improved did not resolve symptoms. Patient has chronic parotitis but increasing dry eyes and dry mouth not relieved by improved hydration. Labs show weak SS-A and SS-B serology.

Patient with suspicion for salivary gland cancer based on clinical exam or diagnostic evidence of malignancy Patient with suspicion for salivary gland neoplasm

Qualified Option Patient should be referred for evaluation and management with sialendoscopy

Patient should be counseled regarding sialolithiasis leading to sialadenitis. Surgical removal of submandibular gland should be planned and considered.

Multidisciplinary evaluation and discussion with Rheumatology should be obtained. Diagnostic lower lip biopsy can be considered for Sjögren syndrome to identify lymphocytic infiltration Computed tomography (CT) with intravenous contrast, and/or magnetic resonance imaging (MRI) of the neck and primary site as well as the chest Fine needle aspiration biopsy or coreneedle biopsy should be performed to support the diagnosis of malignant vs benign salivary gland neoplasm

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References Berg EE, Moore CE. Office-based sclerotherapy for benign parotid lymphoepithelial cysts in the HIV-positive patient. Laryngoscope. 2009;119:868-870. Iro H, Zenk J, Escudier MP, Nahlieli O, Capaccio P, Katz P, Brown J, McGurk M. Outcome of minimally invasive management of salivary calculi in 4,691 patients. Laryngoscope. 2009;119:263-268. Prendes BL, Orloff LA, Eisele DW. Therapeutic sialendoscopy for the management of radioiodine sialadenitis. Arch Otolaryngol Head Neck Surg. 2012;138(1):15-19. Seikaly H, Jha N, Harris JP, Barnaby P, Liu R, Williams D, McGaw T, Rieger J, Wolfaardt J, Hanson J. Longterm outcomes of submandibular gland transfer for prevention of postradiation xerostomia. Arch Otolaryngol Head Neck Surg. 2004;130:956-961. Thackray A, Lucas R. Tumors of the major salivary glands. Atlas of Tumor Pathology, Series 2, Fascicle 10. Washington, DC: Armed Forces Institute of Pathology; 1974:107-117. Deschler DG, Kozin ED, Kanumuri V, Devore E, Shapiro C, Koen N, and Sethi Rosh KV. Single-surgeon parotidectomy outcomes in an academic center experience during a 15-year period. Laryngoscope Investig Otolaryngol. 2020;4:1096-1103. El-Naggar AK, Chan JKC, Grandis JR, Takata T, Slootweg PJ. WHO Classification of Head and Neck tumors, 4th Edition. World Health Organization. 2017.

Chapter 6

Cysts and Neoplasms of the Mandible and Maxilla Tara Aghaloo, MD, PhD Ali Salehpour, MD Brett A. Miles, MD and David Hirsch, MD Part I: Odontogenic Cysts (OCs) and Benign Cysts of the Maxilla and Mandible 1. A cyst is an epithelial-lined pathological cavity that can be filled with liquid, semiliquid, or gas. [1, 2] 2. Odontogenic cysts can be split into two categories – those arising from inflammatory processes and those arising from developmental processes. Developmental OCs arise from odontogenic epithelial remnants. Inflammatory OC arise from the rests of Malassez after an inflammatory stimulus. The most widely accepted theory of growth is due to hydrostatic and osmotic pressure, as the cyst lining is semi-permeable. [3-8] 3. Prevalence is 11.26%, more common in men vs. women, with a ratio of 1.6:1. [9, 10] 4. Odontogenic cysts are 2.25 times more frequent than odontogenic tumors. [1]

Inflammatory Odontogenic Cysts Periapical Cyst (Radicular Cyst) 1. Definition a. Inflammatory cyst associated with a nonvital tooth. They can be caused by an infected non-vital pulp, failed root canal treatment, root fracture with perforation, or retained root – first leads to a periapical granuloma as a protective mechanism. With persistent inflammation, epithelial rests of Malassez at PDL are stimulated and leads to cyst formation. Associated with high levels of inflammatory cytokines such as IL-1α and TNF α. [2, 4, 6, 9] 2. Description & Clinical Features a. Most common cyst of the jaw; found to be over 50% of all jaw cysts. [1, 11]

In: Essential Head and Neck Oncology and Surgery Editors: Maie A. St. John and Benjamin L. Judson

ISBN: 979-8-88697-438-6 © 2023 Nova Science Publishers, Inc.

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b. Most common in the third and fourth decade of life with a male predominance, almost always in permanent teeth, and most common in anterior maxilla (60%). [2, 12] c. Often asymptomatic and discovered incidentally on imaging. Clinical findings on symptomatic patients include pain (typically secondary to infection), swelling, tenderness to palpation, and drainage. [2, 9, 12] d. Unicortical plate expansion with eggshell cracking on palpation due to bone resorption; when enough bone is resorbed, it appears like a bluish fluctuance. [4, 12, 13] 3. Diagnosis & Imaging a. Always associated with nonvital teeth (necrotic pulp), so they do not respond to thermal or electric pulp testing. [14] b. Radiograph shows a periapical radiolucency with loss of the lamina dura; typically appears as a well-defined, well-circumscribed radiolucency with a sclerotic border. Usually does not displace adjacent teeth. Can also be found on lateral aspects of roots due to accessory root canals, which can mimic other lesions. Regional lymph node exam can show ipsilateral lymphadenopathy. [2, 4, 12-15] c. Histologically, present as chronic inflammatory lesions lined by nonkeratinized stratified squamous epithelium which can show cholesterol clefts and Rushton bodies. [2, 4, 11, 16, 17] d. Residual cysts – these are related to radicular cysts: they are inflammatory cysts that remain in the jaw after extraction of non-vital tooth, when periapical inflammatory tissue is not debrided. [2, 4, 11, 18] 4. Management: a. Small lesions (3000 mm3 being histologically confirmed as OKC. [44] 4. Management. [45-48] a. No general consensus on how to best treat the OKC b. The treatment options are 1) simple enucleation, 2) enucleation with a combination of peripheral ostectomy, 5-FU, cryotherapy, and Carnoy’s solution, 3) decompression via marsupialization with delayed enucleation, electrocautery, and 4) segmental resection. [49] c. Enucleation alone with the highest recurrence rate. [49] d. Ideal timeframe for marsupialization is 4.5 months, though many surgeons usually wait for 6-9 months; marsupialization thickens the cyst lining, making enucleation easier without as much rupture of the cyst lining. Also has been shown to change the lesion from parakeratinized to orthokeratinized. Leads to new bone formation in the resorbed areas. [38, 50-52]

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Carnoy’s solution has a recurrence of only 2.5%, and only needs to be applied for 5 minutes to penetrate 1.5mm into cancellous bone. It has the lowest rate of recurrence but has chloroform as an active ingredient and is labeled by the FDA as a carcinogen, limiting its availability in many centers. [49] f. Cryotherapy has shown recurrence rates of 20% after enucleation. It is difficult to gauge the depth of penetration and can lead to wound dehiscence, unintended soft tissue damage, or nerve damage. The most common technique is to spray for 1 minute and let thaw for 5 minutes and repeat 2-3 times. [49] g. Topical 5% 5-FU is an antitumor antimetabolite analog of uracil that downregulates the hedgehog signaling. It is placed in the cavity for ~24 hours on a cotton gauze and removed the day after surgery. Very small amounts are absorbed when placed topically, so it has a very high toxic dose and can be used safely. Need for studies to evaluate long term follow-up, but current studies show exceptionally low recurrence rates. There are reports of transient paresthesia that fully resolved. This is a very effective option with minimal cost and no functional or cosmetic deficits. [49, 53, 54] 5. Prognosis a. OKC has recurrence rate around 7-28% after 5 years. [39, 53, 54] b. Often need life-long follow-up, as any remaining cells can lead to recurrence. Enucleation and curettage alone lead to highest rates of recurrence, with some studies showing rates as high as 25-30%. Overall, besides local bony destruction and risk of recurrence, OKC has a good prognosis. [2, 49] c. Rarely can transform into primary intraosseous carcinoma in situ, with rates estimated to be 0.13-3%. If transformation, surgical resection is the definitive treatment, with almost half of all cases also using adjuvant radiation. [55, 56] d. Anyone with multiple OKCs should consider testing for NBCCS. [33] e.

Lateral Periodontal Cyst (LPC) (Botryoid Odontogenic Cyst) 1. Definition: a. Non-inflammatory developmental odontogenic cyst found along the lateral tooth root surface, originates from rests of the dental lamina epithelium in the alveolar bone. It is the hard tissue variant of the gingival cyst of the adult. [2, 8, 9, 47] 2. Description & Clinical Features: a. Uncommon lesion - represents 0.4% of odontogenic cysts. [5, 8, 47] b. Highest incidence in the 6th decade of life, with the mean age of 46.8, higher in men, almost 70% found in mandible, most frequently in the mandibular premolar and canine region. [2, 5, 8, 47] c. Almost always asymptomatic (88%) and discovered during routine radiographs; typically measure 4 weeks • Absence of pus, fistula, sequestrum • Unknown origin • Diffuse sclerosing osteomyelitis (DSO) is the largest subtype of PCO iv. Mean age of 53. 87% of cases are found in the mandible and 90% of all cases are from dental origin. The main clinical features are pain, trismus, paresthesia, and swelling. Can lead to lymphadenopathy, periodontal disease, fistulas, and pathologic fractures. Poor oral hygiene and smoking are two of the largest risk factors. [102, 104, 106] 3. Diagnosis & Imaging: a. Generally, presents as a mixed pattern of radiolucent and sclerotic changes with sequestration and periosteal reaction. Medullary bone sclerosis is common and correlates with progression of disease. [102, 106]

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b. Empty osteocytic lacunae, absence of osteoblast rimming, and empty Haversian canals, with inflammatory cells with microabscesses and fibrous stroma in the marrow space. [107] c. CT best for subtle early trabecular demineralization and cortical perforation and thinning. MRI can be used to evaluate marrow space and extention of disease to adjacent soft tissue. [108] d. Soft tissue and bone specimens should be sent to microbiology lab for speciation and sensitivities. [108] e. Most common bacterial isolate is -hemolytic streptococcus, followed by coagulase-negative staphylococcus, Propionibacterium acnes, and actinomyces. [102] f. Generally, vital signs and laboratory studies are normal at time of presentation. [103] 4. Management & Prognosis: a. Initial treatment is typically medical – antibiotics guided by cultures, antiinflammatory, surgical debridement. Resection and reconstruction will follow if no resolution. [104] b. Surgical treatment is typically sequestrectomy, debridement, or resection depending on extent of lesion, may need reconstruction depending on size of defect. [108] i. Need antibiotics in conjunction with surgical treatment

Fungal & Granulomatous Infections of the Jaw Mucormycosis 1. Definition: a. A rare, aggressive, rapidly spreading fungal infection that affects the maxillofacial region. [109, 110] b. There are major and minor isolates isolated from patients with Mucormycosis: Most common genera are Rhizopus, Rhizomucor, Absidia. Rhizopus. It is the third most common opportunistic fungal infection. [111] 2. Description & Clinical Features: a. Main transmission is via inhalation of fungal spores or direct cutaneous penetration b. Typically seen in patients with uncontrolled diabetes (especially with ketoacidosis), IV drug use, trauma/burns, malnutrition, neutropenia, malignancy, or any immunocompromised state. [112] c. Can lead to sinus, orbital, rhino, CNS, and pulmonary involvement i. Most common maxillofacial lesion is rhinocerebral mucormycosis that involves the oral cavity, maxilla, palate, nose, sinuses, orbits, and CNS with characteristic necrotic eschar • Symptoms – rapidly progressive facial cellulitis, periorbital edema, nasal inflammation, palatal eschar with rapid tissue necrosis. [112]

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•

Cranial nerve involvement signals a poor prognosis, signifying cavernous sinus or carotid disease that can lead to vision loss, stroke, and trigeminal, facial, orbital, and optic nerve involvement. [109, 112]

3. Diagnosis & Imaging: a. CT is used to show extent and spread of disease. [113] b. MRI useful to evaluate intracranial, cavernous sinus, internal carotid, and perineural spread. [113] c. Histology shows extensive tissue necrosis with numerous branching (90 degrees) and nonseptate hyphae. [113] 4. Management and Prognosis: a. Early debridement of all necrotic and non-viable tissue with early (within day 4-6) initiation of amphotericin B is the best treatment. Surgery can include partial or total maxillectomy, mandibulectomy, and orbital exoneration. [113, 114] b. Fatality rate for severe infection is close to 100%. [115] c. Though late disease has an extremely poor prognosis, early treatment with amphotericin has shown survival up to 72%. [113, 116]

Histoplasmosis 1. Definition: a. A common endemic fungal infection in the USA. Caused by Histoplasma capsulatum spores in most, warm soil in the Mississippi and Ohio River Valley. Highest rates in the Midwest. [109] 2. Description & Clinical Features: a. Primarily an acute pulmonary infection, but often has disseminated spread to extrapulmonary sites such as the oral cavity. Transmitted through aerosolization and inhaling spores into the lungs. [117] b. Disseminated histiocytosis much more common in immunocompromised individuals and can lead to multi-organ disease. [118, 119] i. Oral manifestations most often found in disseminated cases. [118] c. Oral lesions are extremely painful solitary granulomatous, nodular ulcerative or vegetative lesions with gray/yellow pseudomembranous appearance. [117] i. Most common oral sites are the tongue, palate, gingiva, buccal mucosa 3. Diagnosis & Imaging: a. Imaging for oral disease not routinely done. [109] b. Biopsy and culture are needed for tissue diagnosis. c. Histopathology: Dense inflammatory infiltrate with granulomas, giant cells, and psudohyphae. GMS and periodic acid-Schiff stains can be used to find budding yeasts with peripheral pale zone “halo” in the cytoplasm of the histiocytes. [109, 116] 4. Management & Prognosis a. Mild to moderate disease treatment is with oral itraconazole. [117] b. Severe disseminated disease can be treated with IV amphotericin B followed by itraconazole as condition improves. [117]

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Blastomycosis 1. Definition: a. Fungal infection caused by Blastomyces dermatitidis – most concentrated in the Ohio and Mississippi River valleys, Great Lakes, and Saint Lawrence River. Also known as Gilchrist disease. [120] 2. Clinical Features: Fever, unexplained weight loss, productive cough. a. Maxillofacial manifestations include small oral ulcers that may look like epidermoid carcinoma. Also can appear on the lips or skin. Bone is second most common site for dissemination. [113, 121] b. Can also lead to verrucous lesions, granulomas, and abscesses in the mandible with bone loss and mobile teeth. 3. Imaging & Diagnosis: a. Histology: Inflamed connective tissue with multinucleated giant cells and granulomas with central necrotic core. [120] b. Imaging may show radiolucent bone lesions or abscesses in the mandible. [109, 113] 4. Treatment & Prognosis: a. Most cases are treated with oral itraconazole. Severe cases are first started on amphotericin B. [121] b. Prognosis is very good, with a case fatality rate between 4.3-6.3%. [121] Cryptococcosis 1. Definition: a. Opportunistic fungal infection caused by Cryptococcus neoformans which is an encapsuled yeastlike fungus that typically affects immunocompromised individuals with AIDS, cancer, receiving steroids, or chemotherapy. [113] 2. Description & Clinical features: Primarily a pulmonary infection that can lead to disseminated spread in immunocompromised individuals. a. Primary disease of the lungs leads to a mild flu-like illness, whereas disseminated disease can involve the CNS, skin, and bone. [122] b. Oral lesions are rare and typically appear as tender nonhealing ulcers or friable plaques. 3. Diagnosis and imaging: a. Oral manifestations are typically only seen with significant dissemination in immunocompromised individuals. [122] b. Histopathology shows granulomatous inflammatory disease with giant cells and round yeasts. [123] 4. Management and prognosis: a. In patients with AIDS, antiretroviral treatment to increase the CD4 and neutrophil count is crucial. [124] b. Amphotericin B is the still the gold standard treatment. Long term oral fluconazole has also been effective is less severe cases. [124]

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Aspergillosis 1. Definition: a. Fungal infection caused by Aspergillus species, which is a mold with hyaline hyphae. [125] 2. Description & clinical features: a. Ubiquitous in the environment and typically reside in the respiratory tract. Route of infection is through inhalation of spores. Vast majority of cases are in immunocompromised individuals, as the spores disseminate. [109, 125] b. Maxillofacial clinical features include aspergilloma, mycetoma or aspergillus sinusitis. [109, 113] c. Rapidly progressive acute sinusitis can occur in immunocompromised individuals and presents with pain, swelling, purulent rhinorrhea, and nasal obstruction. Also associated with perineural invasion around cranial nerves. [126] d. Spores can also enter the sinus after dental procedure such as extraction or root canal. [109] e. Deep necrotic ulcers can be found on the palate and gingiva, typically as an extension of sinus disease. Maxillofacial osteomyelitis has also been reported from aspergillosis. [109, 127] 3. Imaging & diagnosis: a. CT and MRI are the gold standard for imaging. A dystrophic calcification of a fungal hyphae show up as a radiopaque antrolith in the sinus. [113] b. Histopathology: septate hyphae with angioinvasion, necrotic bone, and chronic granulomatous inflammation. [128] c. Culture and microscopy are the imperfect gold standard. PCR is now available for more accurate and rapid diagnosis. [129] 4. Management and prognosis: a. Treated with antifungals and local debridement, with minimization of immunosuppression if possible. [125] Autoimmune Rheumatoid Arthritis 1. Definition: a. Chronic, immune-mediated inflammatory disease with synovial inflammation and swelling that can lead to destruction of cartilage and bone and lead to joint damage and disability. [130] b. Pediatric variant is known as idiopathic juvenile arthritis (JIA). [131] 2. Clinical features and description: a. 1% of the world population has RA, and affects women 3:1, most commonly in the years between 35-45. [132] b. Bilateral symmetric inflammatory polyarthritis involving small and large joins. [130]

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c.

TMJ involvement is difficult to treat and includes pain, swelling, limited range of motion. It can also lead to incomplete development that leads to micrognathia, malocclusion, facial deformity, and ankylosis. [130, 132] d. 40-96% of children with IJA have TMJ involvement. IJA is the most common type of arthritis in the pediatric population with incidence rate of 12.8 to 15/100,000 in some populations. [131, 133] e. Resorption of the condyle leads to reduction in joint space and hypomobility with shortening of the ramus. [130] 3. Imaging and diagnosis a. Plain radiographs, CT, and MRI are regularly used to image the TMJ. CBCT is more diagnostic than traditional CT and is very useful due to the lower radiation dose. Condylar flattening and erosion and osteophyte formation are frequently seen. Bone scintigraphy is also used to determine which joint is more affected. [131, 134] b. Autoantibody testing for RF and anti-citrullinated protein antibody is also diagnostic 4. Management and Prognosis a. Medical management with disease modifying anti-rheumatic drugs (DMARD) is initiated. [130, 134] b. Intraarticular steroid injection and orthodontic devices are used to preserve facial and jaw growth in children. [130] c. If disease progresses, arthroplasty and finally total joint replacement is the definitive treatment. [131]

Systemic Sclerosis (Scleroderma) 1. Definition: a. immune-mediated rheumatic disease that is characterized by fibrosis of the skin and internal organs and vasculopathy. [135] 2. Clinical features and description: a. Highest mortality of any other rheumatic disease. More common in females, incidence 2-10/one million, with survival of only 66% at 10 years. [135, 136] b. Systemic presentation includes Raynaud phenomenon, pulmonary hypertension, skin thickening, esophageal dysmotility, arthralgia, and renal insufficiency. [137] c. Roughly one-third of patients with RA suffer from secondary SS. 158 d. Skin and subcutaneous tissue fibrosis and atrophy eliminate wrinkles and leads to microcheilia (thin lips) and limited mouth opening (microstomia). Also associated with xerostomia, periodontal disease, and TMD. [136, 138] e. Can lead to condylar fibrosis and resorption with significant functional limitations via chronic collagen deposition. Mandibular resorption can become so bad as to result in pathologic fracture. Condylar resorption can also get so bad as to lead to open bite or retrognathia. [136, 138, 139] 3. Imaging and diagnosis: a. Radiographs and CT shows bone resorption of the condyles and the mandibular angle. Can also see widening of the PDL of teeth. [138] b. Criteria for diagnosis includes: [135]

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i.

Proximal skin involvement, skin thickening of the fingers, abnormal nailfold capillaries, and systematic sclerosis related antibodies. [135] c. Histology: dense collage deposition within and around normal structures d. Lab studies to detect anticentromere antibodies or anti-Scl 70 (topoisomerase I) 4. Management and Prognosis: a. Difficult disease to treat with only 66% survival after 10 years. [135, 136] i. Methotrexate is effective in early diffuse cutaneous systemic sclerosis and best choice for inflammatory arthritis. Low-dose prednisone and biologics are also effective. [135] b. Great care must be taken to ensure good oral hygiene, even though it’s quite difficult with the sclerotic changes in the hands and fingers as well as microstomia. [135]

Part III: Systemic Conditions Of The Jaws Langerhans Cell Histiocytosis (Histiocytosis X) 1. Definition: a. Langerhans Cell Histiocytosis (LCH) is a bone-marrow derived inflammatory neoplasia of myeloid precursor cells (Langerhans cells). [140] 2. Description and clinical features: a. Historically broken down into three subtypes: [141] i. Letterer-Siwe disease – subacute or acute disseminated form ii. Hand-Schüller-Christian disease – disseminated chronic form iii. Eosinophilic granuloma – localized chronic form b. 5 cases per million annually, with 50% of all cases in people age 15 or younger. Much more rare in adults, with 1 case per million annually. Median age of diagnosis is age 3.5. Highest incidence rate before 1 year old. 2:3 male:female ratio. [141-143] c. Most frequently involved organs are skeleton (80%), skin (33%), pituitary (25%), hematopoietic (15%), and the lungs (15%). [144] i. Isolated cutaneous disease in 2% of those affected. In patients who present with cutaneous disease, 87-93% of involvement of other organs. [143] d. Bone lesions are osteolytic in more than 50% of cases and have the characteristic “punched out” appearance. [145, 146] i. 75% of bone involvement is unifocal. Typically presents as a soft tissue mass with swelling and pain. [143, 147] ii. The skull, jaws, long bones of upper extremities, ribs, pelvic bones, and vertebrae are most common bones affected. [148] • Skull 27%, femur 13%, mandible 11%, pelvis 10%. [149] iii. Orbital involvement can lead to exophthalmos; middle ear involvement can lead to deafness; mandibular lesions can lead to facial swelling, pathologic mandibular fractures, and tooth mobility.

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Bone marrow involvement can lead to pancytopenia and hepatosplenomegaly, which has a worse prognosis. [148] e. Posterior mandible is most common location. [142, 150, 151] 3. Diagnosis and imaging: a. Stain positive for CD1a, CD207 and S-100. Also have characteristic cytoplasmic Birbeck granules on electron microscopy. [141, 143] b. Histopathology: inflammatory infiltrate with Langerhans cells, macrophages, lymphocytes, eosinophilic granulocytes, and giant cells. c. CT and radiographs show lytic, punched out lesions without marginal sclerosis or periosteal reaction. [149] d. Panoramic radiograph will show poorly defined unilocular or multilocular radiolucent lesions. With alveolar involvement, floating teeth and tooth displacement also seen. [141, 142, 152] 4. Management a. Depending on the number of organs affected, chemotherapy, radiotherapy, and surgery are options. [148] i. Isolated bone lesions typically resected with good prognosis. [148, 153]. Furthermore, unifocal small lesions typically do not need any treatment as they resolve spontaneously. [154] ii. Localized mandibular lesions can be treated with surgical curettage. If resection is done and it leaves a large defect, autologous bone grafts can be used to fill the defect. [154] iii. Asymptomatic focal small lesions can be surveilled. Intralesional steroids, ACTH, antibiotics, chemotherapy, and radiotherapy have also been described. [142, 155] 5. Prognosis a. Single organ involvement such as skin, one bone, lymph node has the best prognosis, with a mortality rate of less than 10%. [142] b. Multiple organ involvement – such as liver, spleen, lung, hematopoietic, have mortality from 30-50%. [142]

Gorlin Syndrome (Nevoid Basal Cell Carcinoma Syndrome – NBCCS) 1. Definition: a. Autosomal dominant neurocutaneous disease caused by germline mutations in the PCTH1/SUFU genes that is mainly characterized by multiple OKCs, multiple BCCs, skeletal abnormalities such as vertebral and rib anomalies, palmar and plantar pits, early calcification of the falx cerebri, and extracutaneous tumors. [156-158] 2. Clinical features and description: a. Incidence is approximately 1/15,000 and associated with multiple phenotypes that typically include coarse facial appearance, macrocephaly, and hypertelorism. Macrocephaly is evident with head circumference >60cm, and frontal bossing seen in 25%. [159, 160]

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b. ~75% of individuals with Gorlin syndrome have a first degree relative with the syndrome, with the other 25% thought to be de novo germline mutations. [160] c. OKCs start to form at around age 10 and are often the first notable symptom. [161] i. Some studies show that 36% of children presenting with their first OKC had undiagnosed Gorlin syndrome. [162] ii. OKCs in Gorlin syndrome have a higher recurrence rate (60%) compared to non-syndromic OKCs (28%). [163] d. Around age 20, BCCs start to develop, and increase drastically with age. The frequency in people >20yo is 51.4%, and >40yo is up to 71.7%. [161] e. Intellectual disability seen in up to 5% of patients. [158] 3. Imaging and diagnosis: a. Diagnosis is based on two major diagnostic criteria (BCCs, OKCs, palmar or plantar pitting, falx cerebri calcification, medulloblastoma, affected first degree relative) and one minor diagnosis criterion (rib abnormalities, macrocephaly, cleft lip/palate, ovarian/cardiac fibroma, ocular abnormalities, lymphomesenteric cysts, skeletal malformations), or one major and three minor criteria b. Can also be based on identifying heterozygous germline PTCH1 or SUFU pathologic variant on molecular testing. [157] 4. Management and prognosis a. Radiotherapy is strongly discouraged in Gorlin patients, as the ionizing radiation can exacerbate BCCs. [156]. In patients with many BCCs, excisions can become extensive and cause significant disfigurement. 5-FU and imiquimod has been shown to be effective. [159] b. of OKCs i. The treatment options are enucleation without peripheral ostectomy, enucleation with some combination of peripheral ostectomy, 5-FU, cryotherapy, and Carnoy solution, decompression via marsupialization with delayed enucleation, electrocautery, and segmental resection. [49]

Gardner’s Syndrome 1. Definition: a. Autosomal dominant subtype of familial adenomatous polyposis (FAP) syndrome, characterized by many adenomas in the colon and rectum that also presents with extraintestinal maxillofacial findings such as numerous osteomas, odontomas, supernumerary teeth, and impacted teeth. [164, 165] 2. Description and clinical features: a. Caused by a mutation in the adenomatous polyposis coli (APC) gene on chromosome 5q21 which promotes fibroblastic proliferation. [164]. b. Almost 100% of individuals will develop colorectal carcinoma around age 40 with no treatment. [166]

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c.

Dental abnormalities are present in 30-75% of individuals, and osteomas are present in 68-82% of patients. [167]. Odontomas equal in the maxilla and mandible. [168] d. Supernumerary teeth seen in 11-27% of patients, which is much higher than normal population (0-4%). [168] e. Frontal bones and maxilla are most frequent site. [166] f. Mandibular osteomas at the angle, lingual alveolar process, lower edge of body, coronoid, and condylar processes. Maxillary osteomas in the sinus and alveolar margin. [169] These osteomas are typically asymptomatic but painful on palpation. They can impair mouth opening if on the condyle or coronoid process, and cause narrowing of the palate and speech defects in the maxilla. [168] g. There are reports of extremely difficult extractions due to ankylosis. [170] 3. Diagnosis and imaging: a. Panoramic radiograph shows focal radiopaque osteomas in 80% of cases and widespread osteomas much less frequently. They also show odontomas and many impacted, unerupted supernumerary teeth in the mandible and maxilla. Can also lead to adjacent root resorption. [164, 168]. Also can see multiple radiopacities throughout the mandible and maxilla (enostoses) – most frequently in the premolar-molar region. b. Overall appearance is often cotton-wool with osteomas with high mineral content. [164] c. On histology, osteomas have minimal marrow spaces and only occasional Haversian canals. [171] d. CT imaging shows sclerotic masses with radiodensities similar to teeth. 4. Management and prognosis: a. Osteomas on the condyle or coronoid process than impair mouth opening can be treated with resection. [168] b. Osteomas that cause a significant esthetic concern can also be excised. Forehead osteomas via a coronal approach and mandibular osteomas via extraoral approach depending on the location. [172, 173] c. Often times, the dentist will see early signs of disease such as impacted teeth or osteomas, which can lead to early GI workup and a much more favorable prognosis. [171]. d. Orofacial manifestations are esthetic and functional with no reported cases of malignant transformation of osteomatous lesions. [169]

Renal Osteodystrophy & Brown Tumor 1. Definition: a. Pathologic bone lesions secondary to chronic kidney disease and hyperparathyroidism. [174] 2. Description and clinical features: a. Mechanisms

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i.

Hyperphosphatemia in CKD leads to hypocalcemia and hyperparathyroidism. Damaged kidneys cannot make active form of vitamin D, so less calcium absorption in the gut and leads to higher PTH secretion with bone resorption. [175] b. Clinically presents osteitis fibrosa cystica, which is the replacement of calcified bone with fibrous tissue, is caused by increased bone turnover activity and increased PTH. [176] c. Brown tumors are a severe form of osteitis fibrosa cystica – these are benign unifocal or multifocal rapidly growing bone lesions that are present in 1.51.75% of patients with secondary hyperparathyroidism. Seen in the ribs, clavicles, pelvis, spine, tibia, humerus, skull, maxilla, and mandible. [176] i. Name comes from gross anatomy: it is a dark brown tissue mass due to its high vascularity, hemorrhage, and hemosiderin deposit. [177] ii. Brown tumor caused by bone tissue replacement with vascularized fibrous connective tissue. Hyperparathyroidism also leads to osteoclast activation, leading to resorption over areas of bone neoformation. [178] iii. Cortical bone is primarily affected with decreased cortical width, cortical density, and increased cortical porosity. [179] d. Most common clinical presentation in the maxillofacial region are expanding bone lesions, and some studies showed 95% of patients reported facial asymmetry or swelling. [177] i. Can lead to pain, difficulty speaking, eating, breathing, and malocclusion ii. Can also lead to pathologic mandible fracture. [178] e. Brown tumor affects women more than men, 3:1. More common in the mandible, and most common in anterior mandible. [178] 3. Imaging and diagnosis: a. Orthopantograms and CT scans show unilocular or multilocular osteolytic radiolucencies with loss of lamina dura, root resorption. [177, 180] b. Histology is very similar to central giant cell granuloma with proliferation of spindle cells with extravasated blood multinucleated giant cells with osteoclasts, cellular fibrovascular tissue, and hemosiderin deposits. [178, 180] c. Diagnosis of brown tumor and secondary hyperparathyroidism is based on elevated serum calcium, alkaline phosphatase, PTH, low serum phosphate, and histology. d. CT, panoramic radiographs, and bone scintigraphy are also helpful to identify extent of the lesion. [181] i. Can see ground-glass bone secondary to trabecular atrophy and delineate how large the osteolytic defect is. [178] 4. Management and prognosis: a. Management is almost always first aimed towards normalizing the PTH levels by treating the underlying cause, which leads to resolution of the bone lesions in many cases. [182] i. Some refractory jaw lesions do not resolve after normalization of PTH and can be excised. Furthermore, if the lesion is very large, it

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may cause pathologic fracture and can be treated with surgery. [180, 182-184]

Cleidocranial Dysplasia (Cleidocranial Dysostosis) 1. Definition: a. Cleidocranial dysplasia is a rare autosomal dominant skeletal dysplasia of both intramembranous and endochondral ossification, caused by the runtrelated gene RUNX2. [185] 2. Description & Clinical Features: a. Affects 1/1,000,000 individuals. [186] b. RUNX2 is located on chromosome 6p21. 30-40% caused by de novo mutations. 30% of cases do not have pathogenic RUNX2 gene. [187, 188] c. Associated with absent or hypoplastic clavicles, short stature, wormian bones, widened pubic symphysis. [186, 187] d. Craniofacial features include: open fontanelles, short stature, retention of primary teeth, delayed eruption of permanent teeth, supernumerary teeth, and multiple impacted teeth. Supernumerary teeth due to incomplete resorption of tooth bud formation. [189, 190] e. Can also have hypertelorism, midface retrusion with relative mandibular prognathism, and class III malocclusion. Nasal bones can also be missing or hypoplastic. [187, 189] f. Zygomatic arch can be thin with a downward bend. [189] g. No associated cognitive or intellectual deficits. [190] h. Mandible has a narrow ascending ramus with slender and pointed coronoid process. [189] 3. Diagnosis & Radiographic Findings: a. Chest radiograph will show clavicle aplasia or hypoplasia, and can be unilateral or bilateral. Can also see scoliosis of the thoracic spine and incomplete closure of the neural arches of the cervical vertebrae. [189] b. Lateral cephalometric radiograph will show frontal, parietal, and occipital bossing with open skull sutures. [189] c. Panoramic radiograph will show multiple supernumerary and impacted teeth, retained primary teeth, hypoplastic maxillary sinus, downward zygomatic tilt, narrow ascending ramus, and a pointed coronoid process with a distal curvature. [189] d. Will also see course trabecular patterns of the maxilla and mandible with dense alveolar crestal bone in the anterior mandible. [189] e. Cone-beam CT used to localize supernumerary and impacted teeth. [189] 5. Management/Prognosis: a. Multidisciplinary team effort including maxillofacial surgeon, orthodontist, prosthodontist, geneticist, orthopedic surgeon, and pediatrician. b. The most approved orthodontic-surgical protocols are the TorontoMelbourne, Jerusalem, Bronx, and Belfast-Hamburgh methods. [187]

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c.

Jerusalem is a 2-stage protocol that is most commonly followed: [187, 191, 192] i. Age 10: extract anterior primary teeth and supernumerary teeth and exposure of permanent anterior teeth with orthodontic bonding with chains ii. Age >13: extract posterior primary teeth, exposure unerupted canines and premolars, and complete ortho traction d. Bone overlying supernumerary teeth should be removed because histologically it has abnormally dense trabeculation. [189] e. Orthognathic surgery and dental implant placement are some of the final treatment steps to restore ideal functional and esthetic occlusion. [186, 187] f. Maxillary distraction is recommended for movements >1cm. [186] g. Septorhinoplasty can be done after orthognathic surgery to restore facial balance and nasal breathing. [187]

Part IV: Odontogenic Benign Tumors Odontogenic tumors can be broadly categorized based on their embryologic tissue of origin [Epithelial, Ectomeschyme and Epithelial with Ectomeschyme (Mixed)]. These different tissues retain their ability to proliferate and have the potential to generate cysts/tumors. [193]

Epithelial Origin Ameloblastoma 1. Definition: a. Slow growing locally invasive odontogenic tumor formed from odontogenic epithelium in a mature fibrous stroma devoid of odontogenic ectomesenchyme. [194] 2. Description/Clinical features: a. 2nd most common type of odontogenic tumor. [194] b. Typically presents as a painless lesion within the mandible. [194] c. Progressively enlarging causes expansion and erosion of the bony cortices, ultimately leading to infiltration of the adjacent soft tissue. [Figure 2]. [194] d. Rarely causes paresthesia, but can cause tooth mobility, displacement and root resorption. [194] e. Histologically resembles developing tooth without the necessary components to form dental hard tissue. [194] f. In general, no significant sex predilection, typically seen 3rd- 6th decade of life and increased incidence with African American population. [194] g. Ameloblastoma can be divided into three main categories: Multi-cystic/Solid, Unicystic and Peripheral which impacts the management and prognosis of the lesion.

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Figure 2. CT of Ameloblastoma of the Mandible. Axial CT demonstrating the cortical expansion of the left mandible. Marked buccal expansion with thinning of the lingual cortex.

3. Multi-cystic/Solid (also referred to as Conventional) a. ~91% of Ameloblastomas. [194] b. Majority occur in the posterior mandible often involving the ascending ramus. Also can be found in posterior maxilla. [195] c. Several different microscopic subtypes exist within Multi-cystic/Solid. Follicular, Plexiform, Acanthomatous, Granular cell, Desmoplastic*, Basal Cell) but have little bearing on behavior the tumor. [194] d. Follicular pattern is the most common and recognizable subtype presenting with islands of epithelium resembling the enamel organ (stage seen in normal tooth development). Single layer of tall columnar Ameloblast-like cells surround a central core with their nuclei arranged in reversed polarity (nuclei at opposite pole to basement membrane). [193] e. Desmoplastic variant has unique radiographic presentation on plain film displaying radiolucent and radiopaque pattern. [194] Histological stromal dysplasia is pathognomonic. [194] 4. Unicystic a. 5-15% of Ameloblastomas. [194] b. Younger patients within their 2nd decade of life. [194] c. Majority lesions can be found in posterior mandible. [194] d. Histopathologic variants of Unicystic exist Luminal (confined cyst wall lining), Intraluminal (in the lumen of cyst) and Mural which impact prognosis. [194]

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5. Peripheral (also referred to as Extraosseous) a. ~1% of Ameloblastomas. [194] b. Soft tissue variant of multi-cystic/solid ameloblastoma. [194] c. Present similarly as painless non-ulcerated, exophytic, sessile posterior gingival or posterior alveolar mucosal lesion. [194] d. Due to pressure resorption may experience saucerization, but rarely exhibit bony involvement. [194] 6. Diagnosis/Imaging: a. Histopathologic evaluation can demonstrate different microscopic subtypes. [194] b. Several radiographic modalities can be utilized such as plain film radiograph, magnetic resonance and conventional CT (gold standard). [194] c. Plain film radiography can demonstrate lesion with ‘soap bubble’ (for large radiolucent loculations) or ‘honeycombed’ (when loculations are small). [194] d. Unicystic ameloblastoma are usually well circumscribed lesion around the crown of an unerupted mandibular 3rd molar. [194] e. Desmoplastic Ameloblastoma can present as a mixed radiopaque radiolucent lesion and typically occurs in anterior jaw of maxilla. [194] 7. Management: a. In general, marginal resection is the most common treatment. [194] b. Some may argue that performing an additional peripheral ostectomy ~ 1 – 1.5 cm past radiographic margins is necessary to prevent recurrence. [196] c. Location can impact ability to obtain surgical margins such as proximity orbit. d. These lesion are rarely life threatening unless they expand to vital organs. [194] 8. Prognosis: a. > 5 year disease periods do not indicate cure and will require lifelong follow up. [194, 197] b. Has the potential for malignant transformation, however metastatic spread is uncommon. [194] c. More than 50% of recurrences occur within 5 years of primary surgical intervention. Recurrences have been seen 45 years later. [196] i. Multi-cystic/Solid after marginal resection has been shown to demonstrate a recurrence rate of 15%-25%. Conservative treatment (enucleation, curettage, surgical excision with peripheral osteotomy or other adjuvant treatment) has shown recurrence rates 55-90%. [198] ii. Unicystic has been shown to have lower recurrence than multicystic/solid when treated with enucleation (30%), however marginal resection has been shown to have the lowest chance of recurrence (3.6%). [197] iii. Peripheral after local surgical excision resection has been shown to demonstrate a recurrence rate of 16 -19%. [199]

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Adenomatoid Odontogenic Tumor (AOT) 1. Definition: a. Noninvasive lesion of odontogenic epithelium with variation in histologic patterns embedded in a mature connective tissue stroma. [200] 2. Description/Clinical features: a. Rare asymptomatic large lesion that can cause cortical expansion with slow and progressive growth. [200] b. Can cause tooth mobility and displacement. [200] c. Affects younger patients in 2nd decade of life and shown to have female predominance (2:1). [200] d. “Two-thirds tumor”: occurrence in maxilla in two third of cases, in younger patient’s in in two third of cases, unerupted tooth and affected teeth in two third of cases (are often canines). [200, 201] 3. Diagnosis/Imaging: a. 3 main variants: i. Follicular type (73%) - Plain film radiography demonstrates well circumscribed unilocular radiolucencies that involve crown unerupted/impacted tooth extending below the cemento-enamel junction (occasionally with fine calcifications) [Figure 3A, Figure 3B]. [201] ii. Extrafollicular type (24%) - Has also been observed between the roots of teeth. [201] iii. Peripheral type (3%) - located in the gingival mucosa. [201]

Figure 3A. CT of Adenomatoid odontogenic Tumor of the Maxilla. Axial CT demonstrates large expansile adenomatoid odontogenic tumor of the maxilla with involvement into the right maxillary sinus. In the center of the adenomatoid odontogenic tumor an impacted right maxillary canine tooth can be visualized.

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Figure 3B. Orthopantomogram of Adenomatoid odontogenic tumor of the Maxilla. Orthopantomogram demonstrates well circumscribed lesion of the right maxilla encompassing a displacing a right maxillary canine.

b. Histopathology may have duct like structures owing to the adenomatoid name, however these are not true ducts or glandular structures. [201] 4. Management: a. Encapsulated lesion, so enucleation is treatment of choice and often if tooth is involved can be spared. [200] 5. Prognosis: a. Unlikely to recur. [200]

Squamous Odontogenic Tumor (SOT) 1. Definition: Locally infiltrative neoplasm well differentiated squamous epithelium in fibrous stroma. [202] 2. Description/Clinical features: a. Can exist intraosseous or peripheral. [202] b. Extremely rare. [203] c. Painless +/- painful gingival swelling associated cortical expansion with tooth mobility. [203] d. Mandible affected more than maxilla. [203] 3. Diagnosis/Imaging: a. Nonspecific. Radiolucent defect that can be triangular in shape between roots of teeth. [203] b. Histopathology varying islands of bland squamous epithelium in mature fibrous connective tissue. [203, 204] 4. Management: a. Local excision or curettage. [204] b. Maxillary squamous odontogenic tumors more likely to invade adjacent structures (due to the porous nature of maxillary bone compared to mandible). [204] 5. Prognosis: a. Typically do not recur after conservative surgical treatment and extraction of teeth. [204]

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Calcifying Epithelial Odontogenic Tumor (CEOT)/Pindborg Tumor 1. Definition: a. Locally invasive epithelial odontogenic neoplasm with presence of amyloid that can become calcified. [205] 2. Description/Clinical features: a. Less than 1% of odontogenic tumors. [205] b. No sex prediction. [205] c. Mean age of presentation is 40. [205] d. Often painless slow growing lesion of the posterior mandible. [205] 3. Diagnosis/Imaging: a. Unilocular or multilocular radiolucent defect. [205] b. Scalloped well defined margins +/- calcifications. [205] c. Large areas of amorphous eosinophilic hyalinized extracellular material present (Positive staining for Congo Red). [205] d. May present as intraosseous (central) which is more common than extraosseous (peripheral)[205] 4. Management: Local resection with peripheral ostectomy of normal bone. [205] a. Prognosis: Recurrence 14%. [205] Treatment with curettage have highest incidence of recurrence. [205] b. Long term follow up due to rare potential for malignant transformation. [205]

Epithelial with Ectomeschyme (Mixed) Origin Ameloblastic Fibroma Definition: Odontogenic ectomesenchyme resembling the dental papilla and epithelial stands/nests resembling the dental lamina and enamel organ. 11 Description/Clinical features: Uncommon tumor with unknown incidence. [206, 207] Occurs in younger patients in the first two decades of life. [206, 207] Slightly more common in males than females. [206, 207] Solid soft tissue mass that can cause expansion as it increases in size commonly in posterior mandible. [206, 207] Diagnosis/Imaging: Unilocular or multilocular radiolucent lesion. [206, 207] Typically with well-defined cortical margins. [206, 207] Has been shown to be associated with calcifying odontogenic cyst. [206, 207] Often associated with an unerupted/impacted tooth (~75%). [206, 207] Management: Controversial, initially thought to be treated with curettage only, however reports have indicated higher incidence of recurrence. [206, 207] Recent recommendation conservative initial therapy with aggressive therapy for recurrence. [206, 207]

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Prognosis: Range for recurrence is variable depending on study. Although uncommon the possibility of malignant transformation to ameloblastic fibrosarcoma is well documented. [207]

Ameloblastic Fibro-Odontoma 1. Definition: a. Ameloblastic fibroma with enamel and dentin. [206, 208] 2. Description/Clinical features: a. Difficult to distinguish between developing odontoma. [206, 208] b. Common seen in children 1st and 2nd decade of life. [206, 208] c. Most often affecting the posterior mandible. [206, 208] d. Presenting as an asymptomatic swelling of the posterior mandible that can cause expansion and is often associated with an unerupted tooth. [206, 208] e. No sex predilection. [206, 208] 3. Diagnosis/Imaging: a. Well circumscribed with variable amounts of calcified material. Often unilocular. [206, 208] 4. Management: a. Treatment is conservative curettage or enucleation. [208] 5. Prognosis: a. Rare recurrence and is not associated with malignant transformation to ameloblastic fibrosarcoma. [208] Odontoma 1. Definition: a. Hamartoma where enamel, dentin and occasionally cementum is present. [209] b. Two main subtypes include Compound (multiple tooth like structures) and Complex (gnarled mass no resemblance to tooth). [209] Occasionally have a mixture, but this is rare. [209] 2. Description/Clinical features: a. Most common odontogenic tumor. [209, 210] b. Considered to be hamartomas rather than true neoplasm. [209, 210] c. Varying levels of enamel, dentin pulp and cementum. [209, 210] d. Large odontomas can cause bony expansion. [209, 210] 5. Diagnosis/Imaging: a. Diagnosed typically first two decades of life. [210] b. More common in maxilla than mandible. [210] c. An unerupted tooth is often associated with odontoma. [210] d. Complex odontomas can display mature tubular dentin. [210] 6. Management: a. Enucleation and curettage. [210] 7. Prognosis: a. Uncommon to recur. [210]

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Odontoameloblastoma 1. Definition: a. Aggressive odontogenic tumor with combination of features from an Odontoma and an Ameloblastoma. [211] 2. Description/Clinical features: a. Slight male and mandibular predilection. [211] b. Predominately affects young patients with mean age of 20 c. Bony expansion, Root resorption, Tooth displacement and +/- pain commonly seen. [211] 3. Diagnosis/Imaging: a. Well-defined unilocular or multilocular radiolucent lesion with radiopaque material seen throughout the lesion. [211] b. Histologically, the epithelium demonstrates follicular and plexiform patterns (similar to ameloblastoma) with mineralized dental tissue (similar to odontoma). [211] 4. Management: a. Local curettage has been shown to have multiple recurrences. [211] b. Similar to ameloblastoma will require marginal resection with peripheral ostectomy and long term follow up. [211] 5. Prognosis: a. Similar to conventional ameloblastoma. [211]

Ectomesenchyme Origin Odontogenic Fibroma 1. Definition: a. Proliferation of inactive odontogenic epithelium embedded in a mature fibrous stoma. [212] 2. Description/Clinical features: a. More common in females. [212] b. More common to affect mandible. [212] c. In the maxilla often anterior and mandible often posterior. [212] d. Often asymptomatic, however larger lesion can be associated with bony expansion. [212, 213] e. Soft tissue counterpart for this lesion peripheral odontogenic fibroma. [212, 213] f. Clinically looks similar to peripheral ossifying fibroma differing by histopathology presentation. [212, 213] 3. Diagnosis/Imaging: a. Small lesion tend to be well defined unilocular radiolucencies. [212, 213] b. Can exhibit radiopaque spots within lesion. [212, 213] a. Consists of fibrous tissue. [212, 213] 4. Management: a. Treatment with enucleation and thorough curettage. [212, 213]

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5. Prognosis: a. Responds well and recurrence unlikely. [212, 213]

Odontogenic Myxoma 1. Definition: a. Locally aggressive intraosseous neoplasm with stellate and spindle cells embedded in myxoid/mucoid extracellular matrix. [214] 2. Description/Clinical features: a. Often young adults 2nd to 3rd decade. [214] b. Mandible more often affected. [214] c. Often painless expansion leads to bone destruction that can sometimes be rapid and can cause soft tissue infiltration. [214] d. No sex predilection. [214] 3. Diagnosis/Imaging: a. Unilocular or multilocular margins with irregular scalloped can displace and resorb bone. [214] b. Radiographic pattern characteristically described as “soap bubble.” [214] c. At time surgery gelatinous specimen is often observed. [214] 4. Management: a. Smaller lesion curettage and long term follow up. [214] b. Larger lesion will require more extensive resections because they are not encapsulated. [214] 5. Prognosis: a. Often infiltrates surrounding bone recurrence rate 25%. [214] b. Metastasis does not occur. [214] c. Death can occur by involvement of vital structures. [214] Cementoblastoma 1. Definition: a. Odontogenic neoplasm of cementoblasts. [215] 2. Description/Clinical features: a. Majority arise in mandible often involving posterior molar and premolar areas. [215] b. Impacted or unerupted teeth are often not affected. [215] c. These lesions rarely affect deciduous teeth. [215] d. Occurs predominately in children/young adults. Pain and swelling are often present. [215] 3. Diagnosis/Imaging: a. Radiopaque lesion that fused to one or more tooth roots surrounded by rim radiolucent. [215] b. Similar to osteoblastoma, except fusion of lesion to tooth. [215] 4. Management: a. Surgical extraction of tooth together with attached lesion. [215] 5. Prognosis: a. Recurrence can occur with incomplete removal. [215]

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b. Completeness of removal most closely related to success, however this does not guarantee no recurrence. [215]

Part V: Odontogenic Malignant Tumors Ghost Cell Odontogenic Carcinoma 1. Definition: a. Ghost cell odontogenic carcinoma (GCOC) is characterized by ghost-cell (keratinizing cells with aberrant terminal differentiation) with dentinoid deposition. [216] 2. Description: a. Extremely rare, with Asian predominance. More common in maxilla. [216] 3. Clinical features: a. May arise from existing benign cystic lesion. 4. Diagnosis/Imaging: a. Histological diagnosis with high rates of p53 mutation. [216] 5. Management: a. Primarily surgical excision, role of radiation and chemotherapy is unclear. [216] 6. Prognosis: a. Natural history and prognosis unclear because of rarity. [216]

Odontogenic Sarcoma 1. Definition: a. Group of mixed odontogenic malignancies characterized by a benign epithelial component and malignant mesenchymal component. 2. Description: a. Ameloblastic fibrosarcoma (AFS) is the most common type, (malignant counterpart to ameloblastic fibroma, AF). [217] 3. Clinical features: a. Thought to arise from either de-novo or from pre-existing AF. [216] Mandibular predominance in the posterior jaw. [216] b. Low-intermediate grade malignancy, presenting with mass-effect. 4. Diagnosis/Imaging: a. Always radiolucent. b. On IHC, Ki-67, p53 and PCNA may be positive. [218] 5. Management: a. Segmental resection is the most recommended therapy for AFS, but there are no consensus guidelines of management. [217] 6. Prognosis: a. Distant metastases is low, high rate of local recurrence. [218]

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Part VI: Malignant Primary Tumors of the Jaw Malignant Bone and Cartilage Malignancy Chondrosarcoma and Mesenchymal Chrondrosarcoma 1. Definition: a. Malignant bone tumor of that is defined by production of cartilaginous matrix. [216] 2. Description/Clinical Features: a. The occurrence of these tumors is rare and most are located in the mandible or maxilla. [219, 220] b. Any age is affected, with a slight male predisposition. [221] c. Indolent behavior, less aggressive, more slowly growing than osteosarcoma. [220, 222] d. Mesenchymal subtype is much more rare, and is more aggressive with a poorer prognosis. [220, 223] e. Majority present as early stage tumors, with low rates of regional (5.6%) and distant (6.8%) involvement. [220] 3. Diagnosis/Imaging: a. On histology, these tumors show osteodestructive growth. Differentiated tumors resemble hyaline cartilage surrounded by a cartilaginous matrix, with small nuclei. b. IHC is of limited value in diagnosing this tumor. Typical staining pattern for this tumor consists of S100, SOX9 and podoplanin. [216] c. A large proportion (~60%) of these tumors harbor IDH1/2 mutations. [224] Mesenchymal type does not have IDH mutations, but instead HEY1-NCOA2 fusions. [225] d. On imaging, they appear as soft tissue masses with ring or crescent calcification. MRI findings are heterogeneous and similar to osteosarcoma. [226] 4. Management: a. Surgical excision with clear margins is the primary treatment modality. b. Low rates of regional nodal (5.6%) involvement may obviate the need for elective neck dissection in low-risk cN0 disease. [220] c. Adjuvant radiation is an option in high-risk or advanced disease. [223] d. Historically, treatment of the mesenchymal type utilizes higher rates of adjuvant radiation and chemotherapy. [223] 5. Prognosis: a. Generally indolent behavior with better prognosis (5-yr DSS 91.4%) [220] compared to osteosarcoma (5-yr DSS 59.7%). [222] b. Mesenchymal (5-yr DSS 53.2%) subtypes have poorer survival.

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Osteosarcoma 1. Definition: a. Malignant bone tumor with characteristic neoplastic feature of bone production. 2. Description/Clinical Features: a. It is a rare, aggressive, high-grade tumor. Periosteal subtype is of intermediate grade, and parosteal subtype is of low-grade. [216] b. Primarily in children and adolescents, no sex predilection. c. Affects the long bones more frequently than the facial bones or mandible. d. Risk factors include prior radiation therapy and Paget’s disease of bone (osteitis deformans). [216] e. Associated with syndromes associated with tumor formation, including LiFraumeni syndrome, retinoblastoma, Werner syndrome, and RothmundThomson syndrome. 3. Diagnosis/Imaging: a. Histologically, defined by highly atypical cells producing neoplastic osteoid. [216] Tumors exhibit osteodestructive features, frequently replacing marrow spaces. b. Low-grade osteosarcoma is positive for MDM2 and CDK4 which differentiates it from benign mimics. [216] c. On imaging, they appear as ill-defined soft tissue masses which are generally radiolucent but may also incorporate radio-opaque features signifying bone production. [226] d. Characteristic “Sunburst” appearance on CT. [226] e. MRI shows heterogeneous signal intensity. [226] 4. Management: a. Surgical excision with clear margins is the primary treatment modality. [222] b. The role of adjuvant radiation and neoadjuvant/adjuvant chemotherapy is controversial. [227] c. Generally, multimodality approach has been used for high-grade or unresectable or advanced disease. [227, 228] d. There are no guidelines for management of the neck in patients with osteosarcoma, but previous studies have shown nodal involvement anywhere between 5.6-13.2%. [222] 5. Prognosis: a. Prognosis is poor with (5-yr DSS 59.7%). [222] b. Poor prognostic factors include size and stage, age, osteoblastic subtype, positive margins, and nonsurgical therapy. [222] Angiosarcoma 1. Definition: a. Defined as malignant tumors of the vascular endothelium. Primary angiosarcoma of the oral cavity and salivary glands is very rare at jugulotympanic paraganglioma > vagal paraganglioma > laryngeal paraganglioma > other rare sites (sinonasal, orbit, trachea) Sporadic a. 90% of carotid body tumors b. Rarely bilateral (4-5%) Familial a. 10% of carotid body tumors b. 30-40% bilateral or multifocal, increased risk of pheochromocytoma c. Genetics: i. RET, VHL, NF1 and SDH (succinate dehydrogenase) subunits: SDHB, SDHC, and SDHD. SDHD and SDHB ii. Associated syndromes: Von Hippel-Lindau, Neurofibromatosis type I, MEN 2A, MEN 2B iii. SDHB malignancy rate can be as high as 38%. Hyperplastic a. Associated with chronic hypoxia b. Higher prevalence in populations living at high altitude and patients with chronic lung disease Physical Exam a. Typically presents as painless, enlarging mass deep in neck at the level of the hyoid b. Tethered vertically but mobile horizontally (Fontaine’s sign) c. May be pulsatile or have a bruit d. Rarely presents with cranial neuropathy (5%) with CNX and XII most common Growth rate is typically about 1-2 mm per year

Diagnosis and Management 1. Radiology a. CT: well defined, contrast-enhancing soft tissue mass at the carotid bifurcation b. MRI: hyperintense on T2. Demonstrates characteristic “salt and pepper” appearance indicative of hemorrhages (salt) and signal voids from high-flow vessels (pepper) c. U/S: hypoechoic mass, hypervascular with low-resistance flow pattern d. Angiography commonly performed demonstrating a highly vascular tumor arising within the carotid bifurcation and causing splaying of the internal and external carotid arteries (Lyre sign) e. Ascending pharyngeal artery main contributing artery

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f.

Shamblin classification: Predicts operative time, need for vascular repair, and risk of peripheral neurological deficits. i. Type 1: localized tumor, easily separated from the carotid. ii. Type 2: tumor is larger, adherent to the vessels, or partially encases ECA or ICA iii. Type 3: tumor completely encases at least one carotid artery (ICA or ECA) g. If carotid sacrifice is a possibility, internal carotid balloon occlusion study with postocclusion single-photon emission computed tomography is indicated to evaluate adequacy of cerebral perfusion

TYPE 1

TYPE 2

TYPE 3

Figure 2. Shamblin Classification. Illustrated by Megan Llewellyn, MSMI, CMI; copyright Duke University; with permission under a CC BY-ND 4.0 license.

2. Pre-operative workup a. Biopsy - should be avoided due to risk of bleeding or triggering a hypertensive crisis if functional b. Embolization - May be considered in select, larger tumors but is not correlated with reduced operative time, blood loss or postoperative cranial nerve deficits c. Serum or 24 hr Urine Catecholamine/Metanephrine studies are commonly used to screen for functional (secreting) tumors d. Functional tumors require close blood pressure monitoring by anesthesia and commonly receive preoperative alpha- and beta- adrenergic blockade 3. Surgery a. Only curative option and recommended treatment modality for smaller tumors in healthy patients. i. Local control achieved in 94-100% of patients ii. Tumors 5 cm associated with cranial nerve deficit rate 67% b. Symptomatic, fast-growing, and concern for malignancy also support surgical intervention

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c.

Transcervical approach typically with identification of CN IX, X, XI, XII, and sampling of level 2 and 3 lymph nodes d. External carotid artery may be ligated to improve tumor mobilization e. Vascular surgery should be immediately available due to potential risk of injury to the internal carotid artery 4. Complications of Surgery a. Iatrogenic injury to cranial nerves or vascular injury b. First bite syndrome - poorly understood. Brief, sharp pain within the parotid on initiating eating due to injury to cervical sympathetic chain, tends to improve with time. Frequently treated with NSAIDS, anticonvulsants, calcium channel blockers or anticholinergics c. Baroreflex failure - tachycardia and blood pressure lability due to loss of carotid sinus reflex mediated by Hering nerve (branch of CN IX); more significant for patients with bilateral surgery 5. Radiation a. Predominant treatment option for unresectable tumors or patients unsuitable for surgery b. Associated with good local control (80-100%) and stable or improved symptoms in 60-70% c. Risk of radiation-related adverse effects including osteoradionecrosis, cranial nerve deficit and radiation-induced secondary malignancy 6. Observation a. Appropriate for small, nonfunctional, and non-growing tumors or patients who are not good surgical or radiation candidates b. Yearly CT or MRI to monitor tumor growth

Vagal Paragangliomas Presentation and Natural History 1. Originate from one of three ganglia along the course of the vagus nerve (most commonly nodose ganglion) 2. Presentation is typically neck mass or hoarseness, with ¼ to 1/3 patients presenting with a CNX palsy 3. Frequently located in post-styloid parapharyngeal space and anteromedially displace the carotid artery 4. Higher malignancy rate than other head and neck paragangliomas (16%) 5. Same histopathology as carotid body tumors

Diagnosis and Management 1. Contrast enhanced CT or MRI i. Vascular tumor displacing the carotid sheath vessels anteromedially

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ii. “Salt and pepper” appearance on MRI iii. Can splay carotid arteries and mimic carotid body tumor iv. May extend up to skull base or intracranially 2. Surgery i. Essentially guarantees post-operative vagal paralysis (>95%) ii. Typically reserved for aggressive tumors invading the skull base and for patients with preexisting vagal paralysis iii. Associated with worse tumor control and higher complication rates and cranial nerve deficits than radiation iv. Cervical, transparotid, or trans-temporal approach commonly utilized v. If diagnosis of vagal paraganglioma is made intra-operatively when carotid body or other tumor suspected, it is appropriate to abort the case and proceed with radiation or observation 3. Radiation i.

Typically first line treatment for growing tumors in patients without pre-existing vagal nerve deficit ii. 90% local control rate 4. Observation i.

Considered in patients with stable tumor size, not suitable radiation or surgical candidates

Schwannomas Presentation and Natural History 1. Benign, slow-growing, often asymptomatic tumor derived from nerve sheath cells with very low risk of malignant transformation 2. Similar presentation to carotid body tumors 3. Nerve weakness may indicate nerve of origin (e.g., Horner’s syndrome from a sympathetic chain tumor) or may be secondary to compression of the nerve from a growing tumor in close proximity 4. Classically grows within a capsule that is peripherally attached to the nerve of origin 5. Genetics: a. No gender predilection, 3rd-5th decade b. Associated with alterations in neurofibromatosis type 2 (NF-2) gene and can rarely be associated with the NF-2 syndrome. c. Approximately 90% sporadic 6. Histology: a. Antoni A cells: Highly cellular interlacing bundles of spindle-shaped schwann cells b. Antoni B cells: Hypocellular, disorganized with loose stroma 7. 50% of parapharyngeal space schwannomas arise from vagal nerve, can also arise from sympathetic chain, CN IX, XI, XII, cervical or brachial plexus

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Diagnosis and Management 1. Radiology a. CT: Well-defined, higher attenuation than muscle with contrast enhancement b. MRI: Intermediate on T1, increased signal intensity on T2, homogeneous (typically no “salt and pepper” appearance) c. Anterior displacement of common or internal carotid arteries 2. Surgery: a. Treatment modality of choice for growing tumors b. Intracapsular enucleation may be preferred over extracapsular resection for function sparing c. 25-40% risk of vocal cord immobility with this technique in vagal schwannomas

Congenital Vascular Anomalies Presentation and Natural History 1. Classification − hemangiomas and vascular malformations 2. Hemangiomas − true vascular tumors composed of rapidly dividing endothelial cells a. Two types: congenital (10%) and infantile (90%) b. Congenital hemangioma is a rare tumor which is present at birth i. Can be rapidly involuting (RICH) or noninvoluting (NICH) ii. GLUT1 negative iii. Surgery often required for NICH c. Infantile hemangioma (IH) is the most common vascular anomaly in the head and neck. i. Presents after birth and can be cutaneous, subcutaneous, or transcutaneous. ii. Classically is a red, well-demarcated lesion iii. GLUT 1 (glucose transporter-1) is specific and diagnostic for IH d. Three phases of growth which occur independent of the growth of the child i. First phase is growth or proliferation for 9-12 months. ii. Second phase is quiescence variably lasts 3 to 10 years. iii. Third phase is the involuted phase. May see residual sequela of skin iv. atrophy and telangiectasia if the skin was involved. 3. Classically, lesions reach 80% of final size by 3 months 4. 50%, 70%, and 90% of the hemangioma occurs by 5, 7, and 9 years of age with some variability 5. Hemangiomas have three distributions: a. Focal − is a solitary lesion, which is usually red and vascular b. Multifocal − multiple lesions − if 5 or more lesions are present, it is common to have liver or GI involvement

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Segmental distribution − usually follows trigeminal nerve dermatomes and can involve large areas of the face. 10-65% of children with V3 (beard) distribution have subglottic hemangioma involvement. PHACES syndrome - anomalies of Posterior cranial fossa, Hemangiomas-segmental, major intracranial or cervical Arteries, Cardiac (heart and aorta) Eyes, Sternum Subglottic hemangioma: Must be ruled out as a cause of stridor in an infant with cutaneous hemangioma Parotid hemangioma: most common parotid tumor of infancy. Presents as a deep, firm mass within the substance of the gland c.

6. 7. 8. 9.

Diagnosis and Management 1. Diagnosis is made clinically and rarely by biopsy; the history of manifesting after birth and a rapid proliferation phase is common 2. Observation appropriate if tumor is small, not rapidly growing, no eye/lip/nose involvement, subcutaneous only, and no subglottic involvement 3. Early therapeutic intervention is commonly recommended with initiation of treatment between 1-3 months associated with best outcomes 4. Absolute indication for intervention: ulceration, bleeding, significant size, functional deficit, congestive heart failure with exceptional tumor size, Kasabach-Merritt Phenomenon (consumptive coagulopathy) 5. Treatment options include: a. Propranolol: Thought to be due to vasoconstriction/decreased VEGF expression, b. 90% experience improvement within 5 weeks c. Other treatment options: i. Selective beta-blockers or corticosteroids for non-responsive tumors ii. Topical beta-blockers for superficial lesions iii. Pulsed-dye laser: can be used for superficial lesions, or for ulcerated lesions to promote resurfacing, or for telangiectasia after involution. iv. Excisional surgery: Localized lesions, residual scars or removal of fibrofatty remnants (residuum) of involuted hemangiomas

Vascular Malformations 1. Benign lesions defined by progressively growing, aberrant and ectacic vessels 2. As opposed to hemangiomas, vascular malformations tend to grow with the patient, rarely regress 3. Slow flow (capillary, venous, lymphatic) vs. fast flow (AVM) 4. Capillary a. Port-wine stain b. Telangiectasias

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Sturge-Weber Syndrome (port-wine stain of face with ipsilateral intracranial angiomas/AVMs) Presents in childhood with soft, compressible, bluish/purple mass Commonly misdiagnosed as a hemangioma Tendency to occur in skin, oral cavity, airway, muscle groups Genetics i. Syndromes: blue rubber bleb nevus syndrome, glomuvenous malformation, multiple cutaneomucosal venous malformation ii. Hereditary: Autosomal dominant with locus on chromosome 9 Symptoms: Pain, swelling from clot formation

Diagnosis and Management 1. 2. 3. 4. 5. 6.

Ultrasound and color doppler common first line MRI to evaluate extent of disease Angiography useful for deep lesions Coagulation labwork Early intervention often ideal Observation/head of bed elevation/warm compresses/ibuprofen for venous malformations 7. Laser therapy: Skin and mucosal venous malformations a. ND:Yag, KTP or CO2 b. Typically require serial procedures every 3-6mo until adequate disease clearance c. Can be used for airway malformations to resurface vesicles, excise redundant tissue f. Sclerotherapy commonly used i. May cause skin necrosis, systemic toxicity ii. Induces inflammation, thrombosis and fibrosis g. Surgery: i. Preoperative sclerotherapy common to reduce intraoperative bleeding ii. Localized lesions, lesions resistant to sclerotherapy or residual after sclerotherapy, or intended to improve efficacy of sclerotherapy

Lymphatic 1. Usually diagnosed shortly after birth or during childhood 2. Can be identified on prenatal ultrasound- if concern for airway compromise may be an indication for EXIT procedure 3. May enlarge and become symptomatic secondary to local infection, or during puberty 4. Commonly cervicofacial, may be along aerodigestive tract

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5. Fluid-filled and non-compressible (distinguishable from venous malformation) 6. Macrocystic a. Easier to treat (Sclerotherapy vs. surgery) and better prognosis b. Occasionally regress without intervention 7. Microcystic (not candidate for sclerotherapy) 8. Focal, multifocal or diffuse 9. Can lead to abnormalities of cranio-maxillofacial skeleton, dental occlusion 10. Infections can be life threatening and need urgent and aggressive management

Diagnosis and Management 1. 2. 3. 4.

MRI- can determine extent of disease and macrocystic vs microcystic disease Sclerotherapy: mainstay of treatment for macrocystic lymphatic malformations Ethanol or sotradecol most commonly, also Bleomycin, OK-432, doxycycline utilized CO2 laser- superficial mucosal lesions or those not amenable to surgery, safe and efficacious but recurrence is common 5. Surgery: a. Offers curative option, easier for focal disease b. Depends on size and extent c. May be difficult due to intraoperative bleeding, poorly defined borders

Arterio-Venous Malformations (AVMs) 1. 2. 3. 4. 5.

High-flow, destructive lesions composed of dilated and convoluted vascular channels. Grow with the patient but may experience bursts of rapid growth and progression Commonly occur in the midface and oral cavity May be focal or diffuse Low-resistance “nidus” of dilated capillaries connects supplying arteries and draining veins 6. Lesions may present as spongy, warm with palpable pulsations and indistinct borders

Diagnosis and Management 1. Arteriography and embolization 2. Surgery indicated for focal disease or debilitating, life-threatening lesions due to bleeding or tissue invasion, cardiac morbidity due to high flow lesions 3. Recurrence is common and may occur several or more years later

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References Buckmiller, L. M., G. T. Richter, and J. Y. Suen. “Diagnosis and management of hemangiomas and vascular malformations of the head and neck.” Oral diseases 16.5 (2010): 405-418. Cavallaro, G., Pattaro, G., Iorio, O., Avallone, M., & Silecchia, G. “A literature review on surgery for cervical vagal schwannomas.” World journal of surgical oncology 13.1 (2015): 1-4. Cox, Joshua A., Erica Bartlett, and Edward I. Lee. “Vascular malformations: a review.’ Seminars in Plastic Surgery. Vol. 28. No. 02. Thieme Medical Publishers, 2014. Davila, V. J., Chang, J. M., Stone, W. M., Fowl, R. J., Bower, T. C., Hinni, M. L., & Money, S. R. “Current surgical management of carotid body tumors.” Journal of vascular surgery 64.6 (2016): 1703-1710. Gilbo, P., Morris, C. G., Amdur, R. J., Werning, J. W., Dziegielewski, P. T., Kirwan, J., & Mendenhall, W. M. “Radiotherapy for benign head and neck paragangliomas: A 45‐year experience.” Cancer 120.23 (2014): 3738-3743. Khafif, A., Segev, Y., Kaplan, D. M., Gil, Z., & Fliss, D. M. “Surgical management of parapharyngeal space tumors: a 10-year review.” Otolaryngology—Head and Neck Surgery 132.3 (2005): 401-406. Kuet, M. L., Kasbekar, A. V., Masterson, L., & Jani, P. “Management of tumors arising from the parapharyngeal space: a systematic review of 1,293 cases reported over 25 years.” The Laryngoscope 125.6 (2015): 1372-1381. Kruger, A. J., Walker, P. J., Foster, W. J., Jenkins, J. S., Boyne, N. S., & Jenkins, J. “Important observations made managing carotid body tumors during a 25-year experience.” Journal of vascular surgery 52.6 (2010): 1518-1523. Metheetrairut, C., Chotikavanich, C., Keskool, P., & Suphaphongs, N. “Carotid body tumor: a 25-year experience.” European Archives of Oto-Rhino-Laryngology 273.8 (2016): 2171-2179. Moore, M. G., Netterville, J. L., Mendenhall, W. M., Isaacson, B., & Nussenbaum, B. “Head and neck paragangliomas: an update on evaluation and management.” Otolaryngology—Head and Neck Surgery 154.4 (2016): 597-605. Offergeld, C., Brase, C., Yaremchuk, S., Mader, I., Rischke, H. C., Gläsker, S., Schmid, K. W., Wiech, T., Preuss, S. F., Suárez, C., Kopeć, T., Patocs, A., Wohllk, N., Malekpour, M., Boedeker, C. C., & Neumann, H. P. “Head and neck paragangliomas: clinical and molecular genetic classification.” Clinics 67 (2012): 19-28. Riffat, F., Dwivedi, R. C., Palme, C., Fish, B., & Jani, P. “A systematic review of 1143 parapharyngeal space tumors reported over 20 years.” Oral oncology 50.5 (2014): 421-430. Suárez, C., Rodrigo, J. P., Mendenhall, W. M., Hamoir, M., Silver, C. E., Grégoire, V., Strojan, P., Neumann, H. P. H., Obholzer, R., Offergeld, C., Langendijk, J. A., Rinaldo, A., & Ferlito, A. “Carotid body paragangliomas: a systematic study on management with surgery and radiotherapy.” European Archives of Oto-Rhino-Laryngology 271.1 (2014): 23-34. Taïeb, D., Kaliski, A., Boedeker, C. C., Martucci, V., Fojo, T., Adler, J. R., & Pacak, K. “Current approaches and recent developments in the management of head and neck paragangliomas.” Endocrine reviews 35.5 (2014): 795-819.

Chapter 8

Leukoplakia, Erythroplakia, and Premalignant Lesions Hunter Archibald, MD Ashok Jethwa, MD and Frank Ondrey, MD, PhD Global Impact of Head and Neck Cancer – Introduction 1. Head and neck cancer represents a significant burden of worldwide morbidity and mortality. a. Approximately 800,000 new cancers are diagnosed annually. b. A higher stage confers a lower cancer-specific survival rate. 2. Many head and neck cancers may be preceded by preneoplastic lesions. a. Monitoring and treatment of these lesions represents an area for early intervention against head and neck malignancy. 3. Head and neck mucosal lesions (like leukoplakia) have potential to transform into malignancy. a. Worldwide incidence of leukoplakia is 1-2% b. Average age of development between 45 and 54 years old c. Overall transformation rate to cancer is approximately 1% annually i. Rate varies on a number of factors including anatomic subsite. d. The main risk factors for developing preneoplasia are tobacco and alcohol usage. e. Treatment generally involves serial examination, biopsy, and excision. f. These lesions represent a small but significant risk of transformation to cancer and require close clinical monitoring.

Lesions and Definitions 1. A variety of terminologies exist regarding mucosal lesions of the upper aerodigestive tract. Clarifying the meaning of each term helps convey and define the risk associated with each.

In: Essential Head and Neck Oncology and Surgery Editors: Maie A. St. John and Benjamin L. Judson

ISBN: 979-8-88697-438-6 © 2023 Nova Science Publishers, Inc.

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Common Benign Lesions 1. Benign alveolar ridge keratosis (also called morsicato mucosae oris or friction ridge keratosis) a. Hyperkeratotic lesion that forms from chronic trauma of the mucosa on the alveolar ridges. i. It is most common in older males who wear dentures. ii. It presents as a white, slightly rough patch, usually less than a centimeter in largest dimension. iii. The risk of malignant transformation is minimal. 2. Candidiasis a. This is a mucosal infection caused by Candida albicans and is frequently associated with altered immunity, such as HIV infection or steroid usage. i. In contrast to leukoplakia, it is scrapable with an inflamed erythematous base, and may be painful. b. It can present in the oral cavity, oropharynx, larynx, hypopharynx, and esophagus. i. Symptoms depend on anatomic subsite, but dysphagia and hoarseness are notable laryngeal and hypopharyngeal symptoms. c. Treatment is with topical nystatin or oral fluconazole. d. There is no risk of malignant transformation, but some malignancies may have superimposed candidiasis. 3. Oral hairy leukoplakia a. This is an exophytic or shaggy white lesion that most commonly affects the lateral tongue. b. Caused by Epstein-Barr virus in an immunocompromised patient. i. It may be the initial presentation of HIV. c. It has no risk of malignant transformation.

Pre-Neoplastic Lesions 1. Leukoplakia − Leukoplakia is a lesion with malignant potential that presents as a nonscrapable mucosal white plaque in the oral cavity, oropharynx, or larynx. a. It may harbor underlying histologic dysplasia. b. It is a diagnosis of exclusion: the World Health Organization (WHO) defines it as a white lesion having “questionable risk having excluded (other) known diseases or disorders that carry no increased risk for cancer.” c. Leukoplakia may be categorized by a variety of modifiers that are associated with different risks of malignant transformation: i. Homogeneous: Thin, flat, uniform, and has at least one area that is well-defined against the surrounding mucosa. It is associated with a lower risk of transformation to malignancy. • In oral leukoplakia there is a 0.6-5% chance of transformation to cancer.

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ii. Nonhomogeneous: Predominantly white or red and white lesion that may be speckled, nodular, exophytic, or verrucous. It is associated with a higher risk of transformation to malignancy: • Risk of transformation in oral cavity: 20-25%. • Proliferative verrucous leukoplakia is sometimes categorized as a third entity outside of leukoplakia and erythroplakia. • Nodular: slightly raised, rounded, red and or white excrescences • Exophytic: irregular sharp or blunt projections • Proliferative verrucous: (see below) iii. Size: larger than 200 mm2 has been found to be associated with a risk of malignant transformation iv. Dysplasia (see below) 2. Oral leukoplakia: Leukoplakia of the oral cavity (see Figure 1.) a. More common in older males and tobacco and alcohol users. b. risk of dysplasia of 15.6-39.2% in oral leukoplakic lesions. c. Overall risk of transformation 0-25%.

Figure 1. Nonhomogeneous leukoplakia of the buccal mucosa.

3. Oropharyngeal leukoplakia: This entity is less-commonly described than oral or laryngeal leukoplakia. It can theoretically occur in any oropharynx subsite and may precede development of oropharyngeal SCC. 4. Laryngeal leukoplakia: This lesion is located most commonly on the true vocal folds at the medial and superior edges and anterior commissure.

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a.

Annual incidence is estimated at 4.2:100,000 in the United States and is more common in men. b. Tobacco smoking is the main risk factor. c. Overall risk of malignant transformation is 14.1%. More specifically, the risk of transformation is 3.7% in laryngeal leukoplakia without dysplasia on initial biopsy, 10.1% with mild to moderate dysplasia, and 18.1% with severe dysplasia. 5. Erythroplakia: Red lesion that may be flat or depressed, atrophic, and nonkeratinized. The red coloration comes from underlying vascularity. a. Oral and oropharyngeal erythroplakia occur most commonly on the soft palate, floor of mouth, ventral tongue, and tonsillar fossae. b. Risk factors include tobacco and alcohol usage. c. It is less common than leukoplakia (prevalence rate reported 0.02-0.2%) d. Significant risk of underlying dysplasia (90%) and a high risk of malignant transformation. e. Risk of transformation is estimated to be 7 times higher than oral leukoplakia with an overall rate of 14-50%. i. In the larynx, erythroplakia has a 4 fold risk of malignancy compared to leukoplakia. 6. Proliferative Verrucous Leukoplakia (PVL): Oral PVL lesions initially appear as solitary, flat, homogeneous white patches. They progress to thickened multifocal lesions, with exophytic papillary and later verrucous stages. (See Figure 2.) a. PVL is more common in women and nonsmokers. b. It has a very high risk of transformation to malignancy (43.87-63.9%) and high risk of recurrence (71.2%).

Figure 2. Proliferative verrucous leukoplakia of the mandibular gingiva. Periprobe for lesion measurement.

7. Submucous fibrosis: Fibrotic process that begins in the lamina propria of the oral cavity and presents with stiffening and blanching of the oral mucosa. a. Overactive fibroblasts lead to increased deposition of extracellular matrix,

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especially Type I collagen. b. Affects the lips, cheeks, and soft palate. c. It is caused by areca nut chewing and exposure and is most common in patients from Southeast Asia. d. Patients can suffer from trismus e. The risk of malignant transformation has been reported to be 7.6% over 17 years with up to a 33-37% lifetime risk. 8. Lichen planus: Oral lichen planus (OLP) is an inflammatory chronic mucocutaneous disorder. (see Figure 3) a. The lesions are characterized by hyperkeratotic oral mucosa with a striated, annular, or lacy appearance. b. They are most commonly found on the buccal mucosa, gingiva, and ventral or lateral tongue. c. Lesions are typically bilateral d. More common in older females. e. Associations with HPV and HCV have been described. f. Histologically, lichen planus demonstrates increased subepithelial lymphohistiocytes, intraepithelial lymphocytes, and degenerating basal keratinocytes resulting in colloid called “civatte bodies”. g. A large review reported a rate of malignant transformation of about 1% over an average period of follow-up of 54 months. i. Erosive and ulcerative forms of lichen planus are associated with a greater risk of transformation.

Figure 3. Oral lichen planus of the buccal mucosa. Lacy reticular pattern referred to as Wickham’s striae.

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9. Oral lichenoid lesions: Oral lichenoid lesions (OLL) are clinically and histologically similar to lichen planus but are associated with an identifiable etiology. a. Three etiologies have been described: drug reactions, contact allergy, and graft versus host disease (GVHD). i. Antimalarials and antihypertensives are the two most commonlydescribed drug classes ii. Dental amalgam is a risk factor for contact allergy b. Acute and chronic GVHD can commonly result in oral lesions. c. Some authors have described histological differences between OLP and OLL, including greater perivascular inflammatory infiltrate in OLL and fewer mast cells in OLL, while others report no histological differences. d. If an inciting agent like a drug is identified, it should be removed, as there is a risk of malignant transformation. i. One prospective study showed an annual transformation rate of 0.77%. Chronic oral GVHD has also been associated with development of head and neck SCC.

Risk Factors and Etiopathogenesis 1. Tobacco (smoking and chewing) a. 20% of the world’s population uses some form of tobacco. b. Odds ratio of oral leukoplakia associated with tobacco usage is 5.42-7, with a positive dose response relationship. c. After tobacco cessation, the incidence of oral leukoplakia dropped by twothirds in a large study. d. Smoking 20 or more cigarettes daily was associated with a 44% chance of laryngeal leukoplakia and 47% chance of vocal cord dysplasia. 2. Alcohol a. The odds ratio of oral leukoplakia associated with frequent alcohol usage is 8.66. b. 35.2% percent of patients with laryngeal leukoplakia were reported to be heavy alcohol users. 3. Field cancerization − This concept, introduced by Slaughter in 1953, asserts that multiple malignancies can arise in a given mucosal space due to the fact that a combination of factors, generally chronic exposure to tobacco and alcohol, has resulted in the mucosa being “condemned.” a. This means it is able to achieve the development of cancer, and able to achieve multiple and recurrent malignancies. 4. Betel nut − Betel nut is associated with a 26 fold higher risk of oral leukoplakia and a relative risk of submucous fibrosis of 109-175. 5. Fanconi anemia − Fanconi Anemia (FA) is an autosomal recessive syndrome characterized by bone marrow failure, congenital anomalies, and blood and solid tumors. a. Head and neck squamous cell carcinoma is the most common solid tumor in this population. Fanconi Anemia is caused by mutations in 22 genes that are

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part of the FA pathway. Patients have inability to repair DNA damage and genomic instability. b. Children with FA have a high incidence of oral leukoplakia (12% in one paper.) 6. Dyskeratosis congenita − DC is an inherited bone-marrow failure disorder. a. Patients may present with skin hyperpigmentation, nail dystrophy, and oral leukoplakia. b. Clinicians should consider DC in any child with leukoplakia. c. It is caused by mutations in telomere maintenance (e.g., DKC1.) d. The risk of leukoplakic to malignant transformation is 30%. 7. Syphilis − tertiary syphilis is associated with leukoplakia a. High rate (30-100%) of malignant transformation.

Diagnosis 1. Physical examination and biopsy: the gold standard for oral, oropharyngeal, and laryngeal premalignancy diagnosis is examination and tissue biopsy. a. Oral and oropharyngeal lesions should be examined directly and palpated for thickness, tenderness, or friability. b. If concerning, a biopsy should be performed. i. Oral cavity and some anterior oropharyngeal biopsies may be completed in clinic under local anesthesia. ii. The tissue should be evaluated by a trained head and neck pathologist. iii. In-clinic laryngeal biopsy has been described but may be technically challenging and is associated with a high false-negative rate. iv. Any questionable lesion that is inaccessible in clinic warrants an exam under anesthesia, direct laryngoscopy, and biopsy. • Some studies have shown that multiple-site biopsies decrease the false negative rate of diagnosis. Some other technologies exist to aid in evaluating lesions:

Oral Cavity 1. Optical Coherence tomography − OCT is a noninvasive method of obtaining crosssectional images of tissue in vivo using non-infrared light. a. Attached to an endoscope, the beam penetrates 1-3 mm into the mucosa. b. Images allow the investigator to measure the epithelial thickness and potentially visualize basement membrane invasion. c. It may help guide suitable biopsy location. 2. Autofluorescence − This technique relies on differential fluorescence of normal and diseased mucosa. Bifluorophores in normal tissue fluoresce when excited by 400-460 nm light, but do so less strongly with diseased tissue.

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a.

Some studies show a high sensitivity for oral premalignancy (85%,) but low specificity (15%.) 3. Vital stains − Topical agents that bind to dysplastic or abnormal mucosa have been described to aid in premalignancy diagnosis. a. Toluidine blue is a cationic metachromic dye that binds to acidic structures (e.g., DNA, RNA) in vivo and preferentially stains dysplastic epithelium and epithelium undergoing rapid proliferation. b. Sensitivity for dysplastic lesions is reported 56-74%, and the stain may be used to guide biopsy location. 4. Biomarkers − The sampling accessibility of saliva and brush biopsy have prompted many investigators to evaluate for biomarkers predictive of malignant transformation. a. Mehotra et al. reported high positive predictive value (PPV) and negative predictive value, 84 and 98% respectively, for brush biopsy of the oral mucosa. b. Several investigators have shown that presence of specific miRNA in saliva may be predictive of leukoplakia progression. c. In standard histological biopsy, loss of heterozygosity of leukoplakic lesions at chromosome 3p, 9p, and 17p are each associated with a risk of oral cancer development. d. Loss of p53 expression and eIF4 upregulation may each predict transformation. e. Unfortunately, despite the promise of biomarkers, thus far none have proven to be clinically useful.

Larynx 1. Laryngoscopy − Flexible and rigid laryngoscopy are the mainstay methods for directly evaluating the larynx, oropharynx, and hypopharynx. a. Any voice complaint should be evaluated at least with flexible laryngoscopy. b. If a lesion is appreciated and cannot be ruled out for malignancy, the surgeon will need to complete direct laryngoscopy with biopsy in the operating room under general anesthesia. i. This remains the gold standard. 2. Stroboscopy − A mucosal lesion like leukoplakia may show stiffening of the mucosal wave. a. It is most useful when leukoplakic lesions are located at the medial border of the cords. 3. Narrow band imaging − Narrow band imaging (NBI) uses optical interference technology using two wavelengths to pierce the superficial and deep mucosa layers to highlight the mucosal microvasculature. a. High-risk lesions will have intraepithelial papillary capillary loops (IPCLs.) Vessels that are oriented perpendicularly to the orientation of the true cords are considered higher-risk. Interestingly, leukoplakia itself hinders evaluation of underlying microvasculature.

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4. Contact endoscopy − A rigid endoscope with high magnification (60x-150x) is put into direct contact with the mucosal surface to evaluate for dysplastic change. a. Images are taken before and after staining with methylene blue. b. Advantages over biopsy include immediate results and a larger surface area to evaluate than in traditional tissue biopsy. c. Disadvantages include using rigid scopes, no tissue for biopsy, and examination of only the superficial mucosa.

Dysplasia 1. Histopathology: Histopathologic evaluation on biopsy is important for prognosis and treatment. a. A higher degree of dysplasia confers a greater risk of transformation to malignancy. b. Severe dysplasia and carcinoma in situ (CIS) should be excised and moderate dysplasia may be observed. i. Excision does not prevent lesion recurrence or alter invasive cancer risk in a given individual (see below in Treatment.) ii. Interobserver variability does exist between pathologists. 2. Oral cavity dysplasia: Characterized by “architectural and cytonuclear changes of epithelium with hyperchromasia and nuclear enlargement, decreased N-C ratio, mitoses in suprabasal layers and loss of differentiation of keratinocytes towards the surface.” a. The degree of dysplasia (e.g., mild, moderate, severe/CIS) is determined by the level of dysplastic cells. For example, mild dysplasia reaches no further than the lower third of the epithelium, moderate reaches the middle third, et cetera. b. A newer subtype of dysplasia called differentiated dysplasia has been described: “a basal layer of small cells with hyperchromatic or open nuclei with small nucleoli with an abrupt transition to suprabasal large cells with abundant, eosinophilic cytoplasm with differences in eosinophilia, intercellular edema, with clearly visible desmosomes, and large open nuclei with prominent nucleoli.” i. This has been shown to be more sensitive for lesions at risk of transformation to malignancy. 3. Laryngeal dysplasia − laryngeal dysplasia may be reported by a pathologist similarly to oral cavity dysplasia. However, in 2017 the WHO recommended adopting a twotier (low or high grade) dysplasia.

Treatment General Principles of treatment: Treatment for upper aerodigestive premalignancy can be challenging and elusive. Following a diagnostic biopsy, it is generally recommended that

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severely dysplastic lesions and CIS should be treated. Some authors recommend treatment of moderate dysplasia. 1. Wide local excision a. Excision of mucosal premalignant lesions with wide local excision is a common method of treatment. i. The surgeon may use electrocautery or cold knife. ii. There are no accepted margin guidelines, but > 2 mm is described. iii. Regardless of treatment modality, a recurrence rate of over 30% should be expected in oral leukoplakia. b. Effects of surgical resection: retrospective studies have shown that oral lesion excision does not prevent transformation to malignancy. 2. Microflap (larynx) technique with preservation of underlying superficial lamina propria has better voice outcomes than vocal cord stripping. a. Cuts may be made with a laser or microsurgical instrument. b. Anterior commissure disease should be staged to avoid webbing. 3. Laser a. Oral cavity i. CO2 laser is often employed for lesion ablation, but with this technique the lesion is not completely interrogated and can be misdiagnosed. ii. There is theoretically less tissue contraction and may improve oral mobility post-resection compared to electrocautery. 1. Recurrence risk factors include smoking and nonhomogeneous leukoplakia. b. Larynx i. CO2 laser (10,600 nm) is a “coagulative scalpel” used for dividing epithelium and basement membrane. ii. PDL (585 nm) and KTP (532 nm) lasers are angiolytic, resulting in coagulation of the microvasculature. iii. In-office serial laser ablation is possible. 4. Photodynamic therapy (PDT) a. Photosensitizers, e.g., aminolevulinic acid (ALA,) are taken up preferentially by dysplastic mucosal cells. When exposed to a light source, the molecule creates reactive oxygen species, leading to apoptosis and death of aberrant cells. b. PDT may be more useful with widespread lesions, and causes less damage to collagenous tissue. Recurrence rates are similar to surgical resection (0-66%.) 5. Chemoprevention – Chemoprevention is based on the concept of preventing or reversing dysplastic changes to avoid lesion transformation to cancer. a. Thus far there have been no strong clinical studies showing durable effects in chemoprevention, but work continues. i. Retinoids: early studies with retinoids showed some efficacy and were advanced to larger randomized trials. In a Phase III trial published in 1990, Hong et al. showed that oral isotretinoin is effective for prevention of second primary tumors in HNSCC. However, the majority of patients treated with retinoids required

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dose-reduction due to toxicity and there was ultimately no effect on overall survival. A more recent Phase III trial failed to confirm any effect of 13-cis-retinoic acid on second primary formation. ii. Tacrolimus: topical tacrolimus has shown efficacy for treatment of oral lichen planus. iii. Steroids: Topical clobetasol, fluocinolone, and triamcinolone may be used for treatment of oral lichen planus. iv. Metformin, pioglitazone, COX-2, berry-extracts, topical curcumin, green teas, among others have shown some antineoplastic activity.

Observation, Active Surveillance, Risk Factor Reduction 1. Leukoplakia, especially with dysplasia, represents a premalignant lesion that indicates close, long-term follow-up. a. In a large retrospective study on oral leukoplakia, transformation of leukoplakia occurred most commonly in the second year of follow-up (5% rate,) but that at least 1% of lesions transformed to cancer annually subsequently, with a mean time to transformation of 8.1 years. b. Given the low but unceasing risk for transformation, the authors recommend that leukoplakia requires “constant observations, regardless of how long it has existed or how benign it appears.” 2. Patients with leukoplakic and dysplastic lesions should be cared for and examined regularly in a Head and Neck cancer clinic. a. Patients should be educated on risk factors, provided counseling for tobacco and alcohol cessation, and have access to clinical trials. b. While work on biomarkers and chemoprevention continues, regular followup remains the gold standard for care.

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Key Points • • • •

Leukoplakia and erythroplakia represent lesions with malignant potential and should be biopsied to rule out dysplasia and underlying malignancy Higher risk lesions include nonhomogeneous leukoplakia, erythroplakia, proliferative verrucous leukoplakia, and erosive lichen planus Severe dysplasia and CIS should be removed by wide local excision and sent for complete pathological review. Risk factor reduction and close follow-up are the mainstays of management.

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Questions 1. A 65M with COPD and smoking history presents with discomfort while swallowing and hoarseness for two weeks. Three weeks ago he was treated for COPD exacerbation at an urgent care. Flexible laryngoscopy demonstrates a white membrane with inflamed erythematous base of the base of tongue, epiglottis, and true cords. The patient is prescribed oral fluconazole and nystatin mouthwash. At follow-up 6 weeks later the patient says he feels completely better. Flexible laryngoscopy demonstrates a 7mm flat white lesion of the anterior commissure. Appropriate management is: a. Reassurance and primary care follow up b. Continued treatment with antifungals c. Microdirect laryngoscopy with vocal cord stripping d. Microdirect laryngoscopy with unilateral microflap biopsy 2. The lesion at greatest risk of malignant transformation is: a. 2 cm2 nonhomogeneous leukoplakia of floor of mouth b. 2 cm2 erythroplakia of buccal mucosa c. 2 cm2 proliferative verrucous leukoplakia of the hard palate d. 2 cm2 erosive lichen planus of the mandibular buccal gingiva 3. The main described associations with proliferative verrucous leukoplakia are: a. Tobacco b. Alcohol c. Betel quid d. Female sex 4. A 14-year-old male presents with a nontender non-scrapable white plaque of the oral tongue. He has abnormal thumbs and several tan patches on his skin. Appropriate management should include: a. Topical corticosteroids for oral lesion b. CT w/ IV contrast of head and neck c. Reassurance and followup with pediatrics d. Biopsy, flexible laryngoscopy exam, and referral to Medical Genetics and pediatric Heme-Onc 5. This treatment for oral leukoplakia has been prospectively shown to decrease the risk of transformation to cancer. a. Wide local excision b. CO2 laser ablation c. Oral cis-retinoic acid d. Photodynamic therapy e. None of the above

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Chapter 9

TNM Staging in Head and Neck Cancers Michael H. Berger, MD Jose P. Zevallos, MD and William B. Armstrong, MD Introduction 1. The American Joint Committee on Cancer (AJCC) in coordination with the International Union Against Cancer (UICC) has published a unified staging the AJCC/UICC staging TNM classification system since 1987. 2. The 8th edition of the AJCC staging system was published in 2016 and is proposed to be used for all tumors diagnosed from 2018 until a subsequent edition is published 3. The AJCC staging system utilizes the TNM classification a. T describes the primary tumor i. Generally, refers to size of tumor, but may include extent of local invasion into surrounding structures, depth of invasion (oral cavity), vocal cord mobility (larynx) b. N refers to regional lymph node metastasis i. Generally dictated by size of affected lymph nodes, location of affected lymph nodes (i.e., unilateral versus bilateral/contralateral), extranodal extension ii. Most head and neck cancers share a common N classification system. Notable exceptions include HPV-positive oropharyngeal cancer, nasopharyngeal carcinoma, thyroid/parathyroid carcinoma, melanoma, and sarcoma c. M refers to the presence or absence of distant metastases, categorized as Mx (metastatic workup not completed by likelihood of metastasis low), M0 (no distant metastases), M1 (presence of distant metastases)

In: Essential Head and Neck Oncology and Surgery Editors: Maie A. St. John and Benjamin L. Judson

ISBN: 979-8-88697-438-6 © 2023 Nova Science Publishers, Inc.

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Overview of Changes Included in AJCC 8th Edition 1. Nodal (N) categories a. Extranodal extension (ENE) is incorporated into the N category for almost all head and neck subsites, including oral cavity, HPV-negative oropharynx, larynx, major salivary glands, unknown primary, non-melanoma skin, nasal cavity, and paranasal sinuses. b. ENE is not included in the N category for HPV-positive oropharynx, nasopharynx, thyroid/parathyroid, melanoma, and sarcoma i. Clinical ENE designated cN3b, requiring unambiguous evidence of gross ENE on clinical exam (e.g., skin invasion, muscular infiltration, nerve invasion with dysfunction, or supported by strong radiographic evidence). ii. Pathological ENE increases pN category by one full category; defined as tumor extending through node capsule into surrounding connective tissue with or without associated stromal reaction. iii. Pathologic ENE classified as minor (≤2mm) or major (>2mm) extension beyond node capsule 2. Oral Cavity a. Depth of invasion (DOI) included in the T-classification. DOI is measured from adjacent normal basement membrane plane to deepest extent, and not tumor thickness which varies for ulcerative or exophytic tumors b. The cutaneous lip is no longer included as an oral cavity subsite; it is instead included in cutaneous carcinoma of the head and neck 3. Nasopharyngeal Cancers (NPC) a. Addition of separate dedicated chapter owing to unique tumor biology of NPC b. Inclusion of T0 category with patients with Epstein Barr virus - positive cervical lymph node and no identification of primary tumor 4. Oropharyngeal cancer a. Human papillomavirus (HPV)-associated oropharyngeal cancers now have separate T and N categories, as well as unique overall prognostic stage grouping, compared to HPV-negative oropharyngeal cancers 5. Cutaneous carcinoma of head and neck a. New chapter included in AJCC 8th edition, with unified staging system incorporating non-melanoma, non-Merkel cell cutaneous malignancies of the head and neck 6. Thyroid a. Age cutoff in prognostic staging changed to 55 years (previously was 45) i. All patients < 55 years old are Stage I, unless there is distant metastasis, in which case, they are Stage II b. Nodal status has less of effect on overall staging than prior editions i. In AJCC 7th edition, lateral lymph node involvement staged patients as Stage IV

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ii. In AJCC 8th edition, patients ≥ 55 years old with tumors ≤ 4 cm are Stage I if no extrathyroidal extension or Stage II if there is any lymph node involvement (central or lateral) iii. Patients ≥ 55 years old, with tumors > 4 cm without extrathyroidal extension are considered Stage II, regardless of lymph node involvement c. In AJCC 8th edition, degree of extrathyroidal extension upstages patients ≥ 55 years old i. Patients ≥ 55 years old are Stage II if there is limited gross extrathyroidal extension (only strap muscles involved) ii. Patients ≥ 55 years old are Stage III if there gross invasion of subcutaneous tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve are iii. Patients ≥ 55 years old are Stage IVa if there is gross invasion of the prevertebral fascia or of the great vessels iv. Stage IVb is restricted to patients ≥ 55 years old with presence of distant metastasis d. T category for anaplastic thyroid carcinoma now same as differentiated thyroid carcinoma. However anaplastic thyroid carcinoma still has its own unique prognostic staging system 7. Parathyroid a. New chapter included in AJCC 8th edition (Table 1) 8. Sarcoma a. Soft tissue of sarcoma in head and neck now has unique staging system in AJCC 8th edition (Table 2 and Table 3)

Tumor Category 1. Tumor (T category) varies across the different anatomic regions, but the most common theme for classifying is size of the tumor a. The use of tumor size illustrated in Table 1 is the foundation for T category for oral cavity, p16 negative oropharynx, hypopharynx and major salivary glands with additional characterization of depth of invasion, anatomic subsites, or anatomic structures invaded incorporated in staging for each anatomic region. Table 1. General rules for T category in head and neck Tx Tis T1 T2 T3 T4

Primary tumor cannot be assessed Carcinoma in situ Tumor size ≤ 2 cm Tumor size > 2 cm, ≤ 4 cm Tumor > 4 cm Advanced local disease (specifics based on adjacent local structures invaded and is dependent on subsite

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Nodal Category 1. Nodal (N) category consistent for oral cavity, HPV-negative oropharyngeal, hypopharyngeal, laryngeal, major salivary gland, cervical metastasis from unknown primary carcinoma and non-melanoma cutaneous carcinomas a. HPV-positive oropharyngeal cancer, nasopharyngeal carcinoma, thyroid/parathyroid carcinoma, melanoma, and sarcoma have unique N categories. Table 2. Nodal (N category) for oral cavity, HPV-negative oropharyngeal, hypopharyngeal, laryngeal, major salivary gland, nasal cavity and paranasal sinuses, cervical metastasis from unknown primary carcinoma and non-melanoma cutaneous carcinomas Clinical (cN) Category cNX Regional lymph nodes cannot be assessed cN0 No regional lymph node metastasis cN1 Metastasis in a single ipsilateral lymph node, ≤ 3 cm, no extranodal extension cN2a Single ipsilateral lymph node > 3 cm and ≤ 6 cm, no extranodal extension cN2b Multiple ipsilateral lymph nodes, ≤ 6 cm, no extranodal extension cN2c Bilateral or contralateral lymph nodes, ≤6 cm, no extranodal extension cN3a Metastasis in lymph node > 6 cm, no extranodal extension cN3b Metastasis in any lymph node, with positive extranodal extension (clinically)* Pathologic (pN) Category pNX Regional lymph nodes cannot be assessed pN0 No regional lymph node metastasis pN1 Metastasis single ipsilateral lymph node, ≤ 3 cm, no extranodal extension pN2a Single ipsilateral lymph node ≤ 3 cm, with positive extranodal extension OR Single ipsilateral node > 3 cm, but ≤ 6 cm, no extranodal extension pN2b Multiple ipsilateral lymph nodes, none > 6 cm, no extranodal extension pN2c Bilateral or contralateral lymph nodes, none > 6 cm, no extranodal extension pN3a Metastasis in lymph node > 6 cm, no extranodal extension pN3b Metastasis in single ipsilateral lymph node > 3 cm, with positive extranodal extension+ OR Multiple ipsilateral, contralateral, or bilateral nodes, any of which have positive extranodal extension * Clinical ENE defined as unambiguous evidence of gross ENE on clinical exam (e.g., skin invasion, muscular infiltration, nerve invasion with dysfunction, or supported by strong radiographic evidence). + Pathological ENE defined as tumor extension through node capsule into surrounding connective tissue with or without associated stromal reaction. Pathologic ENE may be sub-classified as minor (≤2 mm) or major (>2mm) extension beyond node capsule.

Metastasis Category Metastatic disease is characterized as absent (M0), present (M1), or undetermined (Mx).

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Prognostic Stage Grouping TNM classification is utilized to divide patients into five staging groups 0-IV for each anatomic site. Table 3. Prognostic Stage Groups for oral cavity, HPV-negative oropharyngeal, hypopharyngeal, laryngeal, major salivary gland, and nonmelanoma cutaneous carcinomas T Class Tis T1 T2 T3 T1-T3 T4a T1-T4a Any T T4b Any T

N Class N0 N0 N0 N0 N1 N0-N1 N2 N3 Any N Any N

M Class M0 M0 M0 M0 M0 M0 M0 M0 M0 M1

Stage 0 I II III III IVA IVA IVB IVB IVC

Oral Cavity Table 4. Mucosal lip and oral cavity T category Tx Tis T1 T2

T3

T4a

T4b

Primary tumor cannot be assessed Carcinoma in situ Tumor size ≤ 2 cm, depth of invasion ≤ 5 mm Tumor size ≤ 2 cm, depth of invasion > 5 mm and ≤ 10 mm OR Tumor size > 2 cm, ≤ 4 cm, and depth of invasion ≤ 10 mm Tumor > 4 cm OR Depth of invasion > 10 mm Moderately advanced local disease Lip: Invasion through cortical bone or involves inferior alveolar nerve, floor of mouth, or skin of face Oral cavity: Tumor invades adjacent structures only (such as through cortical bone of mandible/maxilla, or involves maxillary sinus or skin of the face Very advanced local disease Tumor invades masticator space, pterygoid plates, or skull base and/or encases the internal carotid artery

1. Epithelial and minor salivary gland cancers of the oral cavity and the mucosal lip a. Cutaneous lip cancers are staged separately with cutaneous squamous cell carcinoma. 2. Sites included: mucosal lip, buccal mucosa, lower and upper alveolar ridge, retromolar trigone, floor of mouth, hard palate, anterior two-thirds of tongue (oral tongue) 3. Summary of changes included in AJCC 8th edition.

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Nasopharynx 1. Staging system used for epithelial tumors of the nasopharynx a. Does not include mucosal melanoma, lymphomas, soft tissue sarcomas 2. Nasopharyngeal cancer with new specifically designated chapter in AJCC 8th edition, due to unique tumor biology Table 5. Nasopharynx T category Tx T0 Tis T1 T2

T3 T4

Primary tumor cannot be assessed No evidence of primary tumor, but Epstein Barr Virus positive in cervical lymph node(s) Carcinoma in situ Tumor confined to nasopharynx, or presence of extension to oropharynx/and or nasal cavity without parapharyngeal involvement Tumor extends to parapharyngeal space AND/OR Invades adjacent soft tissues (medial pterygoid, lateral pterygoid, prevertebral muscles) Tumor invades bony structures of skull base, cervical vertebra, pterygoid structures, and/or paranasal sinuses Intracranial extension, involvement of cranial nerves, hypopharynx, orbit, parotid gland, and/or extensive soft tissue infiltration beyond lateral surface of lateral pterygoid

Table 6. Nasopharynx regional lymph node (N) category Nx N0 N1

N2 N3

Regional lymph nodes cannot be assessed No regional lymph node metastasis Unilateral metastasis in cervical lymph node(s) AND/OR Unilateral or bilateral metastasis in retropharyngeal lymph node(s), ≤6 cm, above caudal border of cricoid cartilage Bilateral metastasis in cervical lymph node(s), ≤ 6 cm, above the caudal border of cricoid cartilage Unilateral or bilateral metastasis in cervical lymph node(s), ≥ 6 cm AND/OR Extension below the caudal border of the cricoid cartilage

Table 7. Nasopharyngeal carcinoma prognostic stage grouping T Class Tis T1 T0-T1 T2 T2 T0-T1 T2 T3 T3 T3 T4 T4 T4 T4 Any T Any T

N Class N0 N0 N1 N0 N1 N2 N2 N0 N1 N2 N0 N0 N1 N2 N3 Any N

M Class M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1

Stage 0 I II II II III III III III III IVa IVa IVa IVa IVa IVb

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Human Papillomavirus-Associated (P16+) Oropharyngeal Cancer 1. New independent classification system included in the AJCC 8th edition, in response to the recognition of the distinct clinical and biologic behavior as well as prognosis for oropharyngeal squamous cell carcinoma associated with human papillomavirus (HPV). Table 8. HPV-associated oropharyngeal cancer T-category T0 Tis T1 T2 T3

T4

Primary tumor cannot be assessed, but there is p16+ cervical lymph node(s) Carcinoma in situ Tumor ≤ 2 cm Tumor > 2 cm and ≤ 4 cm Tumor > 4 cm OR Extension to lingual surface of epiglottis Moderately advanced local disease; Invades larynx, extrinsic muscle of tongue, medial pterygoid, hard palate, or mandible or beyond

Table 9. HPV-associated oropharyngeal cancer nodal category Clinical (cN) Category cNX Regional lymph nodes cannot be assessed cN0 No regional lymph node metastasis cN1 One or more ipsilateral lymph nodes ≤ 6 cm cN2 Contralateral or bilateral lymph nodes ≤ 6 cm cN3 Lymph node(s) > 6 cm Pathologic (pN) Category pNX Regional lymph nodes cannot be assessed pN0 No regional lymph node metastasis pN1 Metastasis in 4 or fewer lymph nodes pN2 Metastases in more than 4 lymph nodes

Table 10. HPV-associated oropharyngeal cancer prognostic stage grouping Clinical prognostic stage groups: T Class N Class T0-2 N0-1 T0-2 N2 T3 N0-N2 T0-T4 N3 T4 N0-N3 Any T Any N Pathologic prognostic stage groups: T Class N Class T0-T3 N0 -N1 T0-T2 N2 T3-T4 N0-N1 T3-T4 N2 Any T Any N

M Class M0 M0 M0 M0 M0 M1

Stage I II II III III IV

M Class M0 M0 M0 M0 M1

Stage I II II III IV

2. In order to utilize this classification system, p16 immunotesting is mandatory. However, HPV in situ hybridization may be used as an alternative

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Determination of p16 positivity based on immunotesting is defined as ≥ 75% of tumor cells showing at least moderate staining intensity 3. Extranodal extension not incorporated into N category of HPV-associated cancers at this site a.

Human Papillomavirus-Negative (P16-) Oropharyngeal Cancer 1. Staging system used for epithelial tumors of the oropharynx that are HPV or p16 negative 2. Included subsites: soft palate/uvula, base of the tongue, tonsillar pillars, pharyngeal tonsils, glossotonsillar sulcus, lateral and posterior pharyngeal walls Table 11. HPV-negative oropharyngeal cancer T category Tx Tis T1 T2 T3

T4a T4b

Primary tumor cannot be assessed Carcinoma in situ Tumor ≤ 2 cm Tumor > 2 cm and ≤ 4 cm Tumor > 4 cm OR Extension to lingual surface of epiglottis Moderately advanced local disease; Invades larynx, extrinsic muscle of tongue, medial pterygoid, hard palate, or mandible Very advanced local disease Invades lateral pterygoid muscle, pterygoid plates, lateral nasopharynx, or skull base or encases carotid artery

Hypopharynx 1. Staging system used for epithelial tumors of the hypopharynx. Table 12. Hypopharynx T category Tx Tis T1

T2

T3

T4a T4b

Primary tumor cannot be assessed Carcinoma in situ Tumor limited to one subsite of hypopharynx AND/OR Tumor size ≤ 2 cm Tumor invades > 1 subsite of hypopharynx or an adjacent site OR Tumor > 2 cm and ≤ 4 cm, without fixation of hemi larynx Tumor > 4 cm OR Fixation of hemi larynx OR Extension in esophagus Moderately advanced local disease; Invades thyroid/cricoid cartilage, hyoid bone, thyroid gland, or central compartment soft tissue Very advanced local disease Invades prevertebral fascia, encases carotid artery, or involves mediastinal structures

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2. Three subsites included: 1. pyriform sinuses, 2. Lateral and posterior pharyngeal walls (from level of superior aspect of hyoid bone or vallecula to the lower border of cricoid cartilage), and 3. postcricoid region

Larynx Table 13. Supraglottic larynx T category Tx

Primary tumor cannot be assessed

Tis

Carcinoma in situ

T1

Tumor limited to one subsite of supraglottis, with normal vocal cord mobility

T2

Tumor invades > 1 subsite of hypopharynx or glottis or a region outside the supraglottis, without fixation of hemi-larynx Tumor limited to larynx with vocal cord fixation AND/OR Invades any of following: postcricoid region, pre-epiglottic space, paraglottic space, and/or inner cortex of thyroid cartilage Moderately advanced local disease; Invades through outer cortex of thyroid cartilage AND/OR Invades tissue beyond larynx (trachea, soft tissue of neck, deep extrinsic muscle of base of tongue, strap muscles, thyroid gland, or esophagus) Very advanced local disease Invades prevertebral space, encases carotid artery, or involves mediastinal structures

T3

T4a

T4b

Table 14. Glottic larynx T category Tx

Primary tumor cannot be assessed

Tis

Carcinoma in situ

T1a

Tumor limited to one vocal cord AND Normal vocal cord mobility Tumor involves both vocal cords AND Normal vocal cord mobility Tumor extends to supraglottis and/or subglottis AND/OR Impaired vocal cord mobility Tumor limited to larynx with vocal cord fixation AND/OR Invades paraglottic space and/or inner cortex of thyroid cartilage Moderately advanced local disease; Invades through outer cortex of thyroid cartilage AND/OR Invades tissue beyond larynx (trachea, cricoid cartilage, soft tissue of neck, deep extrinsic muscle of base of tongue, strap muscles, thyroid gland, or esophagus) Very advanced local disease Invades prevertebral space, encases carotid artery, or involves mediastinal structures

T1b

T2

T3

T4a

T4b

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1. Distinct T categories used for malignancies of the supraglottis, glottis, and subglottis within the larynx a. Staging system not used for nonepithelial tumors of lymphoid tissue, soft tissue, bone, or for mucosal melanoma, all of which have unique staging systems 2. Subsites: a. Supraglottis: suprahyoid epiglottis, infrahyoid epiglottis, laryngeal side of aryepiglottic folds, arytenoids, false vocal cords b. Glottis: True vocal cords, including anterior and posterior commissure extending 10mm inferior to the plane of the vocal fold at the floor of ventricle c. Subglottis: from inferior boundary of glottis to inferior margin of cricoid cartilage Table 15. Subglottic larynx T category Tx

Primary tumor cannot be assessed

Tis

Carcinoma in situ

T1

Tumor limited to subglottis

T2

Tumor extends to supraglottis and/or subglottis AND/OR Impaired vocal cord mobility Tumor limited to larynx with vocal cord fixation AND/OR Invades paraglottic space and/or inner cortex of thyroid cartilage Moderately advanced local disease; Invades cricoid or thyroid cartilage AND/OR Invades tissue beyond larynx (trachea, soft tissue of neck, deep extrinsic muscle of base of tongue, strap muscles, thyroid gland, or esophagus) Very advanced local disease Invades prevertebral space, encases carotid artery, or involves mediastinal structures

T3

T4a

T4b

Nasal Cavity and Paranasal Sinuses 1. Staging system used for malignancies arising from mucosa of the nasal cavity and paranasal sinuses a. Does not include mucosal melanoma, sarcoma, or lymphomas 2. Nasal cavity subsites: septum, nasal floor, lateral nasal wall, and edge of naris to mucocutaneous junction 3. Nasal cavity and ethmoid sinuses utilize same T staging system 4. Separate T category for maxillary sinus

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Table 16. Nasal cavity and ethmoid sinus T category Tx Tis T1 T2

T3 T4a

T4b

Primary tumor cannot be assessed Carcinoma in situ Tumor confined to any 1 subsite, with or without bony invasion Invades 2 subsites in a single region OR Extends to involve an adjacent region within the nasoethmoid complex, with or without bony invasion Tumor extends to invade the medial wall or floor of orbit, maxillary sinus, palate, or cribriform plate Moderately advanced local disease Invades any of the following: anterior orbital contents, skin of nose/cheek, minimal extension to anterior cranial fossa, pterygoid plates, sphenoid/frontal sinuses Very advanced local disease Invades any of the following: orbital apex, dura, brain, middle cranial fossa, cranial nerves (other than V2), nasopharynx, or clivus

Table 17. Maxillary sinus T category Tx Tis T1 T2 T3 T4a

T4b

Primary tumor cannot be assessed Carcinoma in situ Limited to maxillary sinus mucosa with no bony erosion/destruction Tumor causes bony erosion/destruction, including extension into hard palate, and/or middle nasal meatus, except extension to posterior wall of maxillary sinus and pterygoid plates Invades any of the following: posterior maxillary sinus wall, subcutaneous tissue, orbital floor, medial wall of orbit, pterygoid fossa, ethmoid sinuses Moderately advanced local disease Invades any of the following: anterior orbital contents, skin of cheek, minimal extension to anterior cranial fossa, pterygoid plates, sphenoid/frontal sinuses Very advanced local disease Invades any of the following: orbital apex, dura, brain, middle cranial fossa, cranial nerves (other than V2), nasopharynx, or clivus

Major Salivary Glands 1. Staging system used for cancers arising in the major salivary glands a. Lymphomas not included b. Minor salivary gland tumors are staged based on their primary site, utilizing same systems as squamous cell carcinoma Table 18. Major salivary glands T category Tx T0 Tis T1 T2 T3

T4a T4b

Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ Tumor size ≤ 2 cm, without extra parenchymal extension Tumor size > 2 cm and ≤ 4 cm, without extra parenchymal extension Tumor > 4 cm AND/OR Presence of extra parenchymal extension Moderately advanced local disease Invasion of surrounding skin, mandible, ear canal, and/or facial nerve Very advanced local disease Invasion of skull base and/or pterygoid plates, and/or carotid artery

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Non-Melanoma Cutaneous Carcinoma of the Head and Neck 1. Staging system used for nonmelanoma skin cancers of the head and neck a. Includes 82 types of skin cancers, including squamous cell carcinoma, basal cell carcinoma, and adnexal carcinomas, but excludes melanoma and Merkel cell carcinoma b. Excludes eyelid skin cancer c. Includes vermilion of lip, which is not included in oral cavity 2. New classification system included in the AJCC 8th edition Table 19. Cutaneous carcinomas of the head and neck T category Tx Tis T1 T2 T3

Primary tumor cannot be assessed Carcinoma in situ Tumor size ≤ 2 cm Tumor size > 2 cm and ≤ 4 cm Tumor > 4 cm OR Minor bone erosion OR Perineural invasion a OR Deep invasion b T4a Tumor with gross cortical bone/marrow invasion T4b Tumor with skull base invasion and/or skull base foramen invasion a Perineural invasion defined in AJCC as tumor cells within nerve sheath of a nerve lying deeper than the dermis or measuring 0.1 mm of larger in caliber or presenting with clinical or radiographic involvement of named nerves without skull base invasion or transgression. b Deep invasion defined in AJCC as invasion beyond subcutaneous fat or < 6 mm (measured from granular layer of adjacent normal epithelium to base of tumor).

Mucosal Melanoma 1. Staging system used for mucosal melanomas involving the nasal cavity, paranasal sinuses, oral cavity, oropharynx, nasopharynx, larynx, or hypopharynx 2. Given the aggressive nature of mucosal melanoma, T category starts with T3 (i.e., there is no T1 or T2 for mucosal melanomas) Table 20. Mucosal melanoma of the head and neck T category T3 T4a T4b

Tumor limited to the mucosa and immediately underlying soft tissues, regardless of thickness or size Moderately advanced local disease; Involves deep soft tissue, cartilage, bone, or overlying skin Very advanced local disease Involves brain, dura, skull base, lower cranial nerves (IX, X, XI, XII), masticator space, carotid artery, prevertebral space, or mediastinal structures

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Table 21. Mucosal melanoma of the head and neck N category Nx N0 N1

Cannot be assessed No regional lymph node metastases Regional lymph node metastases present

Merkel Cell Carcinoma Table 22. Merkel cell carcinoma of the head and neck T category Tx Tis T1 T2 T3 T4

Primary tumor cannot be assessed Carcinoma in situ Tumor size ≤ 2 cm Tumor size > 2 cm and ≤ 5 cm Tumor > 5 cm Tumor invades fascia, muscle, cartilage, or bone

Table 23. Merkel cell carcinoma of the head and neck N category Clinical (cN) Category cNX Regional lymph nodes cannot be assessed cN0 No regional lymph node metastasis cN1 Metastasis in regional lymph node(s) cN2 In-transit metastasis (discontinuous from primary tumor; located between primary tumor and draining regional nodal basin, or distal to the primary tumor), without lymph node metastasis cN3 In-transit metastasis (discontinuous from primary tumor; located between primary tumor and draining regional nodal basin, or distal to the primary tumor), with lymph node metastasis Pathologic (pN) Category pNX Regional lymph nodes cannot be assessed pN0 No regional lymph node metastastasis pN1a Clinically occult regional lymph node metastasis following lymph node dissection pN1b Clinically and/or radiologically detected regional lymph node metastasis, microscopically confirmed pN2 In-transit metastasis (discontinuous from primary tumor; located between primary tumor and draining regional nodal basin, or distal to the primary tumor), without lymph node metastasis pN3 In-transit metastasis (discontinuous from primary tumor; located between primary tumor and draining regional nodal basin, or distal to the primary tumor), with lymph node metastasis

Table 24. Merkel cell carcinoma of the head and Neck M category Clinical (cM) Category cM0 No distant metastasis cM1a Distant metastasis detected on clinical and/or radiologic examination cM1b Metastasis to lung cM1c Metastasis to all other visceral sites Pathologic (pM) Category pM0 No distant metastasis pM1a Distant metastasis confirmed microscopically to distant skin, distant subcutaneous tissue, or distant lymph node(s) pM1b Distant metastasis confirmed microscopically to lung pM1c Distant metastasis confirmed microscopically to all other distant sites

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Table 25. Merkel cell carcinoma prognostic stage grouping Clinical prognostic stage groups: T Class N Class Tis N0 T1 N0 T2-3 N0 T4 N0 T0-4 N1-3 T0-4 Any N Pathologic prognostic stage groups: Tis N0 T1 N0 T2-3 N0 T4 N0 T1-4 N1a T0 N1b T1-4 N1b-3 T0-4 Any N

M Class M0 M0 M0 M0 M0 M1

Stage 0 I IIA IIB III IV

M0 M0 M0 M0 M0 M0 M0 M1

0 I IIA IIB IIIA IIIA IIIB IV

Thyroid Carcinoma 1. Same T and N and M category system used for all histologies, (papillary, follicular, poorly differentiated, Hürthle cell, medullary, and anaplastic thyroid a. Definition of extrathyroidal extension (ETE) modified to remove microscopic extrathyroidal extension from classification of T3 tumors and record only gross ETE b. Overall prognostic staging in differentiated thyroid cancers incorporates age of patient c. Medullary thyroid cancer has separate overall prognostic staging system d. Given aggressive nature and poor prognosis associated with anaplastic thyroid cancer, there is designated AJCC prognostic staging system specifically for anaplastic thyroid cancer Table 26. Papillary, follicular, poorly differentiated, Hurthle cell, medullary and anaplastic thyroid carcinoma T category Tx T0 T1a T1b T2 T3a T3b T4a

Primary tumor cannot be assessed No evidence of primary tumor Tumor size ≤ 1 cm, no extrathyroidal extension Tumor > 1 cm but ≤ 2 cm, no extrathyroidal extension Tumor > 2 cm and ≤ 4 cm, no extrathyroidal extension Tumor > 4 cm, no extrathyroidal extension Any size tumor with gross extrathyroidal extension, invading only strap muscles Any size tumor with gross extrathyroidal extension, invading subcutaneous soft tissue, larynx, trachea, esophagus, or recurrent laryngeal nerve T4b Any size tumor, with gross extrathyroidal extension, invading prevertebral fascia or encasing carotid artery or mediastinal vessels Note that in multifocal tumors of the thyroid, the largest tumor determines the classification

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Table 27. Papillary, follicular, poorly differentiated, Hürthle cell, medullary and anaplastic thyroid carcinoma Nodal (N) category Nx N0a N0b N1a N1b

Regional lymph nodes cannot be assessed ≥1 cytologically or histologically confirmed benign lymph nodes No radiologic or clinical evidence of locoregional lymph node metastasis Metastasis to level VI or VII lymph nodes, unilateral OR bilateral Metastasis to unilateral, bilateral, or contralateral lateral neck lymph nodes or retropharyngeal lymph nodes

Table 28. Differentiated thyroid cancer (papillary, Hurthle cell, follicular) prognostic stage grouping Age < 55 years old ≥ 55 years old

T Class Any T Any T T1 T1 T2 T2 T3a/b T4a T4b Any T

N Class Any N Any N N0/Nx N1 N0/Nx N1 Any N Any N Any N Any N

M Class M0 M1 M0 M0 M0 M0 M0 M0 M0 M1

Stage I II I II I II II III IVa IVb

Table 29. Anaplastic thyroid cancer prognostic stage grouping T Class T1 – T3a T1 – T3a T3b T4 Any T

N Class N0/Nx N1 Any N Any N Any N

M Class M0 M0 M0 M0 M1

Stage IVa IVb IVb IVb IVc

Table 30. Medullary thyroid cancer prognostic stage grouping T Class T1 T2 T3 T1-3 T4a T1-3 T4b Any T

N Class N0 N0 N0 N1a Any N N1b Any N Any N

M Class M0 M0 M0 M0 M1 M0 M0 M1

Parathyroid Carcinoma 1. Staging system used for parathyroid carcinoma a. New classification system added in the AJCC 8th edition 2. Regional lymph node category (N) same as in thyroid cancer

Stage I II II III IVA IVA IVB IVC

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3. There is no overall prognostic staging classification for parathyroid carcinoma, due to lack of sufficient data Table 31. Parathyroid carcinoma T category Tx T0 Tis T1 T2 T3 T4

Primary tumor cannot be assessed No evidence of primary tumor Atypical parathyroid neoplasm (uncertain malignant potential) Localized to the parathyroid gland with extension limited to soft tissue Direct invasion into thyroid gland Direct invasion into recurrent laryngeal nerve, esophagus, trachea, skeletal muscle, adjacent lymph nodes, or thymus Direct invasion into major blood vessel or spine

Head and Neck Soft Tissue Sarcomas 1. Staging system used for sarcomas of the head and neck a. Excludes rhabdomyosarcoma (alveolar and embryonal subtypes), Kaposi sarcoma, dermatofibrosarcoma protuberans, angiosarcoma 2. New classification system added in the AJCC 8th edition 3. There are no overall prognostic stage groups, as this is new classification system and prospective data needs to be obtained 4. M category a. M0, no distant metastases or M1, distant metastases present Table 32. Head and neck sarcoma T category Tx T1 T2 T3 T4a T4b

Primary tumor cannot be assessed Tumor size ≤ 2 cm Tumor size > 2 cm, ≤ 4 cm Tumor > 4 cm Tumor invades orbit, skull base/dura, central compartment viscera, facial skeleton, or pterygoid muscles Tumor invades brain parenchyma, prevertebral muscles or encases carotid artery or involves central nervous system via perineural spread

Table 33. Head and neck sarcoma N category N0 N1

No regional lymph node metastases or unknown lymph node status Regional lymph node metastasis

Cervical Lymph Nodes and Unknown Primary Tumor 1. T0 assigned for unknown primary in head and neck 2. Presumptions: a. Nasopharynx source if EBV present b. Oropharynx source if p16+ (HPV) c. Salivary glands: unique histology

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3. N category: Same as nodal category for most head and neck subsites (Table 2) 4. M category a. M0, no distant metastases or M1, distant metastases present Table 34. Prognostic stage grouping for metastatic cervical adenopathy and unknown primary* T Class N Class M Class T0 N1 M0 T0 N2 M0 T0 N3 M0 T0 Any N M1 *This classification system is not used for EBV-related and HPV-related tumors.

Stage III IVA IVB IVC

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Key Clinical Points • •

•

•

Appropriate and up-to-date oncologic staging is critical in the management of patients with tumors of the head and neck. The AJCC 8th edition of the Cancer Staging Manual introduced novel dedicated algorithms for head and neck sarcoma, parathyroid carcinoma, nonmelanoma head and neck cutaneous carcinoma, cancers of unknown primary, and HPV-associated oropharyngeal cancers. The AJCC 8th edition of the Cancer Staging Manual additionally introduced alterations to existing algorithms, including adding a T0 classification for nasopharyngeal carcinoma, incorporation of depth of invasion into T staging for oral cavity cancers, incorporation of extranodal extension into for almost all head and neck subsites, including oral cavity, HPV-negative oropharynx, larynx, major salivary glands, unknown primary, non-melanoma skin, nasal cavity, and paranasal sinuses. Utilization of a common and accurate set of staging principles allows practitioners to more effectively assess and communicate a given patient’s disease status, prognosis, and best treatment options.

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Questions 1. A 46 year old female is evaluated with a left thyroid mass, measuring 4.8 cm in largest diameter. Fine needle aspiration reveals papillary thyroid cancer. A total thyroidectomy and central neck dissection was performed. There was no extrathyroidal extension on pathologic examination. Central neck dissection (level VI) pathologic evaluation revealed 2 out of 10 lymph nodes positive for papillary thyroid cancer. No distant metastasis noted on further work up. Which answer best describes the patient’s TNM staging? a. T2N1aM0, Stage I b. T2N1bM0, Stage II c. T3aN1aM0, Stage I d. T3aN2M0, Stage II e. T3bN1bM0, Stage III 2. All of the following head and neck subsites utilize extranodal extension within their nodal (N) staging system EXCEPT: a. HPV-negative oropharynx b. HPV-positive oropharynx c. Nasal cavity d. Larynx e. Oral cavity 3. A 77 year old man with extensive smoking history presents with a left oral tongue squamous cell carcinoma. He undergoes a left hemiglossectomy and left neck dissection. His pathology reveals a primary tumor from the oral tongue, measuring 3.5 x 2.2 cm with depth of invasion of 12 mm. Neck dissection revealed no regional metastasis. PET/CT revealed no signs of distant metastasis. Which answer best describes the patient’s TNM staging? a. T1N0M0 b. T2N0M0 c. T3N0M0 d. T4aN0M0 e. T4bN0M0 4. A 62 year old female smoker presents with three-month history of voice changes. Flexible laryngoscopy in the office reveals a mass centered on the right arytenoid with extension to the right false vocal cord. There is right sided vocal cord fixation noted. In-office biopsy confirmed squamous cell carcinoma. CT neck reveals a right sided level III lymph node measuring 3.5 cm, as well as a left sided level III lymph node measuring 3.0 cm. Neither lymph node appeared to have extranodal extension based on imaging or physical examination. PET/CT revealed no signs of distant metastasis. Which of the following best describes the patient’s clinical TNM staging? a. T2N2aM0 b. T3N1M0 c. T3N2aM0

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d. T3N2bM0 e. T3N2cM0 5. A 49-year-old male presents a small pigmented lesion of the nasal cavity along the medial aspect of the inferior turbinate. The lesion is biopsied and is confirmed to be mucosal melanoma. According to the AJCC TNM staging guidelines, what is the lowest T category for mucosal melanoma, regardless of size or thickness? a. T1 b. T2 c. T3 d. T4a e. T4b

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References Amin MB, Edge SB, Greene FL, Byrd DR, Brookland RK, Washington MK, Gershenwald JE, Compton CC, Hess KR, Sullivan DC, Jessup JM, Brierley JD, Gaspar LE, Schilsky RL, Balch CM, Winchester DP, Asare EA, Madera M, Gress DM, Meyer LR. eds. AJCC Cancer Staging Manual. 8th ed. New York: Springer; 2017. Karassawa Zanoni D, Patel SG, Shah JP. Changes in the 8th Edition of the American Joint Committee on Cancer (AJCC) Staging of Head and Neck Cancer: Rationale and Implications. Curr Oncol Rep. 2020;21(6). Karia PS, Morgan FC, Califano JA, Schmults CD. Comparison of tumor classifications for cutaneous squamous cell carcinoma of the head and neck in the 7th vs 8th edition of the AJCC cancer staging manual. JAMA Dermatology. 2018;154(2):175–81. Lydiatt WM, Patel SG, O’Sullivan B, Brandwein MS, Ridge JA, Migliacci JC, Loomis AM, Shah JP. Head and Neck Cancers - Major Changes in the American Joint Committee on Cancer Eighth Edition Cancer Staging Manual. CA Cancer J Clin. 2017;67(2). Machczyński P, Majchrzak E, Niewinski P, Marchlewska J, Golusiński W. A review of the 8th edition of the AJCC staging system for oropharyngeal cancer according to HPV status. Eur Arch Oto-RhinoLaryngology. 2020;277(9):2407–12. Tuttle RM, Haugen B, Perrier ND. Updated American joint committee on cancer/tumor-node-metastasis staging system for differentiated and anaplastic thyroid cancer (Eighth Edition): What changed and why? Thyroid. 2017;27(6):751–6. Yang XL, Wang Y, Liang SB, He SS, Chen DM, Chen HY, Lu LX & Chen Y. Comparison of the seventh and eighth editions of the UICC/AJCC staging system for nasopharyngeal carcinoma: Analysis of 1317 patients treated with intensity-modulated radiotherapy at two centers. BMC Cancer. 2018;18(1):1–11.

Chapter 10

Overview of Guidelines and Evidence Based Care in Head and Neck Cancer Saral Mehra, MD, MBA Oded Cohen, MD and Babak Givi, MD Introduction 1. Several evidence-based and expert-based guidelines have been developed to improve quality and consistency in the treatment of head and cancer throughout the world. 2. Examples of current leading guidelines include: a. The National Comprehensive Cancer Network (NCCN) [1] b. The American Society of Clinical Oncology (ASCO) [2-5] c. The European Society for Medical Oncology (ESMO) [6-7] d. Regional and other national guidelines (Pan Asian [8], United Kingdom [9], etc.) 3. Adherence with guidelines is associated with improved overall survival among patients with advanced head and neck cancer [10] 4. In the United States, the NCCN is the primary guideline utilized for a number of reasons: a. NCCN Guidelines are reviewed and updated at least annually. b. Include both caregiver and patient focused guidelines c. Provides Discussions regarding many aspect of cancer management (NCCN principles)

General Management Considerations [1, 6, 9] 1. A multidisciplinary team including surgery, radiation and medical oncology is considered standard of care 2. Early-stage disease is defined as either T1-2N0 (Stage I and II). a. Treatment aim for most sites of disease should be for single-modality treatment whenever possible to limit treatment-related side effects

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b. In early-stage disease, tri-modality therapy should be avoided and requires careful pre-treatment assessment and multi-disciplinary discussion. Advanced disease is defined as Stage III or IV cancer without distant metastasis. a. In most cases, treatment will require at least dual modality (Surgery/RT or Systemic/RT) b. Tri-modality treatment may be necessary for advanced disease with adverse features. Management of the neck a. The neck should be addressed in all advanced disease to increase regional control b. Management of N0 neck is site dependent and may include observation, elective neck dissection/radiation, or (according to at least one guideline) sentinel lymph node biopsy (in oral cavity) c. Bilateral neck management is recommended in suspicious involvement of contralateral nodes and primary tumor that approach midline d. An adequate neck dissection should include at least 18 lymph nodes [2, 11] Adjuvant therapy a. Considerations: i. Extranodal extension (ENE), pT3 or pT4, positive margins, close margins, multiple positive nodes, perineural/lymphatic/vascular invasion (PNLVI). b. Triple modality treatment (Surgery/Systemic/RT): i. ENE and positive margins are two indications for adjuvant Systemic/RT treatment ii. Preoperative surgical assessment for feasibility of negative margin surgery is crucial iii. Complete resection (or re-resection) should be the goal of surgery in an attempt to avoid giving tri-modality treatment whenever feasible (especially for pharynx and larynx cancers) c. For patients with T1-T2 and only one lymph node involved (N1), with no adverse pathologic features, adjuvant radiation can be considered or withheld after multidisciplinary and patient-centered discussion of risks versus benefits. Very advanced disease is defined as very advanced local tumor (T4b), regional nodal disease with gross ENE, metastatic disease at presentation (M1), and recurrent or persistent disease: a. Treatment should be done after multidisciplinary discussion, goals of care discussion, and early involvement of palliative medicine services b. Clinical trials are preferred c. Neoadjuvant systemic therapy may be considered d. Treatment options can be stratified based on performance status

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Cancer Surveillance and Follow-Up [1, 6] 1. Risk of relapse is estimated 40-60% with locally advanced disease 2. Most recurrences occur in the first 2 years (approx. 80%) and are identified by the patients. 3. Recommended follow-up interval: a. Year 1 - up to 3 months interval b. Year 2 - up to 6 months interval c. Year 3-5, every 4-8 months d. >5 years, every 12 months 4. Additional checks include TSH (6-12 months if treated with RT), dental evaluation (yearly, if radiated) 5. Head and neck imaging for advanced disease a. Follow-up is based on clinical assessment at 4-8 weeks after completion of treatment b. Recommended 3 months after completion of primary treatment c. Consider FDG-PET/CT at 12 weeks to assess regional response and need for neck dissection i. If FDG PET/CT is not available, a Contrast CT or MRI at 8-12 weeks post treatment can be considered ii. On high suspicion for persistent disease, biopsy followed by resection should be performed when feasible d. Routine interval imaging can be carried based on recurrence risk stratification and/or based on clinical assessment alone (new onset of symptoms or signs) 6. Supportive care and rehabilitation including: a. Speech/hearing/swallowing evaluation and rehabilitation as indicated b. Nutritional evaluation and rehabilitation until nutrition status stabilized c. Lymphedema and physical therapy evaluation and rehabilitation as needed d. Ongoing surveillance for depression e. Smoking cessation and alcohol counseling as indicated 7. Integration of survivorship care and care plan within 1 year is ideal, as complementary to involvement of head and neck oncology team [1, 12]

Treatment Recommendations by Site Oral Cavity [1, 2, 6] 1. Standard of care is surgical excision as primary modality 2. If surgery is not feasible: a. Radiation can be considered for early-stage cancer b. Clinical trials can be considered for locally advanced cancer c. Brachytherapy can be considered for selected T1 patients [7]

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3. Neck management: a. For select reliable patients with cT1, cN0, close surveillance can be considered2; otherwise, the neck should be addressed in most oral cavity cancers b. Sentinel lymph node is considered an alternative to elective neck dissection in early-stage disease (T1-2, N0) c. Elective neck dissection (for N0) should include levels 1-3 d. For N+ disease, neck dissection should include levels 1-4 ± 5 e. For oral cavity cancer, lymph node yield may impact prognosis, and minimal thresholds in oral cavity cancer should be >16 for N0 neck, and >26 for N+ neck [13] f. Bilateral neck dissection should be considered for lesions at or approaching midline, and for T3-T4 oral tongue/floor of mouth cancer 4. Positive margins should be re-resected whenever feasible. 5. Advanced disease: a. Availability and planning for reconstructive surgery should be part of the multidisciplinary treatment discussion 6. Adjuvant therapy: a. See general considerations above

Oropharynx [1, 2, 6] 1. Human papilloma virus (HPV) testing by p16 immunohistochemistry is required, for accurate staging of disease 2. Currently, despite significant differences in staging and prognosis there are no major differences in the management of HPV-negative and HPV-positive oropharyngeal cancers. 3. Early-stage cancer can be managed with single modality treatment (surgery or radiation). 4. Consideration for surgical treatment: a. Surgical treatment should be considered as primary modality if there is high likelihood of achieving negative margins, very low or no suspicion for extranodal extension, and absence of carotid involvement. b. Transoral surgery (direct, transoral laser microsurgery, or transoral robotic surgery) can decrease the functional impact of treatment by sparing selected patients chemotherapy and possibly allowing for lower radiation doses [14] c. Ligation of at-risk feeding blood vessels should be performed before transoral endoscopic surgery to decrease the severity and incidence of postoperative bleeding [2] d. For early-stage cancers, re-resection should be considered for positive margins. 5. Neck management: a. Management of the neck in HPV-positive cancer may vary based on the number and size of involved lymph nodes

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b. For N0 disease, levels 2-4 should be addressed, with consideration of bilateral management for lesions at or approaching midline. 6. Advanced disease: a. Systemic/RT is sometimes preferred over surgery depending on functional considerations and likelihood of tri-modality treatment b. Surgery remains a management option, and should be offered to patients as part of a multidisciplinary treatment team c. Induction chemotherapy and clinical trials may also be considered d. There are many ongoing treatment de-intensification trials for HPV-positive disease that may change treatment paradigms

Hypopharynx [1, 6] 1. Clinical trials should be considered for all stages of hypopharyngeal cancer 2. The two major consideration in choosing treatment modality are the extent of disease and the ability to preserve a functioning larynx after completion of treatment 3. For N0 disease levels 2-4 should be included, and bilateral for lesions approaching midline. 4. Early-stage cancer (T1 and selected T2, N0) a. In the absence of adverse features, single modality treatment should be pursued (RT or surgery). b. Surgery should include partial laryngopharyngectomy (open or endoscopic) + neck dissection + hemithyroidectomy + pretracheal and ipsilateral paratracheal node dissection c. For positive margin after surgery, if re-resection can be done with confidence, this should be pursued, otherwise RT (or consideration of Systemic/RT). 5. All other disease stages a. Surgery followed by risk stratified adjuvant therapy, or concurrent Systemic/RT are typical treatment options b. For T4a (laryngeal invasion) or non-functional larynx, surgical treatment with total laryngopharyngectomy and associated procedures should be considered [6], but induction chemotherapy and Systemic/RT are also possible. c. Induction chemotherapy can be considered for all cases: i. Responsive tumors should be followed by radiation alone (complete response) or Systemic/RT (partial response) ii. Unresponsive tumor (primary or regional progression) should be followed by surgery when amenable

Nasopharynx [1, 5, 7] 1. The primary treatment is non-surgical 2. For all patients, intensity-modulated radiotherapy (IMRT) with daily image guidance should be offered.

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3. Elective nodal volumes should cover the bilateral neck from the retropharyngeal lymph nodes to level IV and V. Level 1b may be omitted in selected cases [5]. 4. In T1, N0 disease, RT alone is recommended 5. In T2,N0 disease, the role of Systemic/RT versus RT alone is controversial [1, 5] 6. For all other stages a. Clinical trials are preferred b. Treatment options include induction chemotherapy followed by Systemic/RT OR Systemic/RT ± adjuvant chemotherapy 7. Follow-up for EBV-associated nasopharynx cancer includes routine imaging up to 3 years from treatment and plasma EBV DNA (yearly) [7]

Larynx [1, 6] 1. Early staged cancer (T1-2, N0): a. Should be treated with a single modality (RT or Surgery) with emphasis on function preservation b. Partial laryngectomy may be endoscopic or open c. For carcinoma in situ, endoscopic resection is preferred d. Management of the neck differs by site: i. The neck should be treated electively in levels 2-4 in all supraglottic cancer ii. Early glottic cancer does not require neck dissection or neck RT. e. Selected T3 may be managed as early staged cancer as indicated above 2. Advanced disease a. The neck should be treated electively (levels 2-4 and additional central nodes) in most cases, though for T3N0 glottic cancer it can be considered b. In general, treatment options can include: i. Systemic/RT or Surgery or Induction chemotherapy ii. Surgery should include laryngectomy, ipsilateral thyroidectomy as indicated, pre-tracheal and ipsilateral paratracheal lymph node dissection • For N0 disease, lateral (or bilateral when indicated) neck dissection should be done for T4a tumors, T1-4 supraglottic tumors, and can be considered for T3N0 glottic tumors. • For N+ disease, lateral (or bilateral when indicated) neck dissection should be done iii. Induction chemotherapy: • Responsive tumors (complete response or partial response) should be followed by radiation alone or Systemic/RT. • Patient with unresponsive tumors should go on to surgery. c. In patients amenable to total laryngectomy, with T3, N0-1 disease there are various treatment options:

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i.

RT alone for patients who are not candidates for systemic treatment can be considered, particularly for patients non amenable to total laryngectomy d. For T3, N2-3 tumors, there are various treatment options: i. Systemic/RT or Surgery or Induction chemotherapy e. T4a tumors: i. Surgery is the preferred modality of treatment ii. For patients who are unfit for surgery or decline surgery, clinical trials and induction systemic treatment can be considered, or Systemic/RT

Paranasal Sinus Tumors [1, 15, 16] 1. Paranasal sinus tumors include a variety of tumors, therefore appropriate multidisciplinary management is critical based on specific pathology. 2. For non-SCC tumors (neuroendocrine, small cell, high-grade olfactory esthesioneuroblastoma, etc.): a. Referral to a major medical center that specializes in these diseases is recommended b. Systemic therapy should be a part of the overall treatment. c. Clinical trials should be considered 3. Neck management: a. Elective neck management in clinically N0 necks in nasal and paranasal sinus cancer has been controversial. b. Elective neck management is recommended for patients with T3 to T4 squamous cell carcinoma and poorly differentiated carcinoma of the maxillary sinus. 4. Maxillary sinus tumors a. Surgical resection is the preferred modality of treatment b. Surgery is also preferred in cases of previous incomplete resections c. Observation could be offered for T1-2 following complete resection, unless adenoid cystic histology, in which adjuvant RT is recommended d. Adverse features for Maxillary Sinus Tumors include positive margins, close margins, or extranodal extension (ENE). 5. Ethmoid sinus cancer a. Surgical resection is the preferred modality of treatment b. Surgery is also preferred in cases of previous incomplete resections c. Observation could be offered for selected T1 following complete resection. Otherwise, adjuvant therapy is recommended d. Neoadjuvant systemic therapy can be considered for advanced cancer. Complete response should be followed by adjuvant therapy (systemic/RT or RT). Otherwise, resection should be attempted. e. Adverse features for ethmoid sinus tumors include: i. Positive margins/ close margins

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ii. iii. iv. v.

Location of tumor - tumors adjacent to cribiform plate and/or medial wall or orbit Unfavorable histology (high grade, adenoid cystic) Intracranial and/or intraorbital extension Perineural invasion (PNI) / lymphovascular space invasion.

Salivary Gland Tumors [1, 4] 1. Pre-operative imaging: a. All suspected lesions should undergo pre-operative imaging b. If bone invasion is suspected, then contrast CT should be done c. If neural involvement is suspected, then contrast MRI should be done to assess extent 2. Surgical resection is the preferred modality of treatment 3. Surgery is also preferred in cases of previous incomplete resections 4. For T1-2: a. Low grade with complete resection, follow-up as clinically indicated b. Low grade w spillage or perineural invasion, consider RT 5. For T3-4 /high grade cancer: a. Surgeons should perform at least a superficial parotidectomy with consideration of a total or subtotal parotidectomy (for parotid primary) 6. Neck management: a. N-positive neck - levels 1-5 b. Elective neck management in clinically N0 differs between sites: c. For major salivary glands − consider elective neck dissection for T3-4 and high-grade tumors d. For parotid malignancies - levels 2-4 7. Adjuvant RT therapy: a. Adenoid cystic carcinoma should receive adjuvant RT b. Adverse features i. Intermediate or high grade ii. Close/positive margins iii. Lymph node metastases iv. Neural/perineural/lymphatic/vascular invasion

Occult Primary [1, 3] 1. Work-up to include fine-needle aspiration or core biopsy assessing for lymphoma, thyroid, melanoma, squamous cell carcinoma, adenocarcinoma, anaplastic/ undifferentiated tumors. 2. Additional staining: a. HPV (oropharynx) - especially for level 2 nodes b. EBV (nasopharynx) - if HPV testing is negative c. Thyroglobulin, calcitonin, PAX8, TTF (thyroid origin).

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3. Repeat FNAB, or core biopsy, or open biopsy may be necessary for uncertain or nondiagnostic histology. a. If open biopsy is performed, surgeon and patient should be prepared for neck dissection at the same time based on frozen section result. 4. CT neck followed by PET-CT should be performed to evaluate primary site 5. Planned surgery: a. Advanced visualization techniques (narrow band imaging, HD cameras) may be used intraoperatively to improve localization b. Random biopsies of nonsuspicious areas should be performed judiciously as they carry a low yield c. For a node in level 1-3, upper 5: i. EUA, palpation and inspection, biopsy of areas of clinical concern, tonsillectomy +/- lingual tonsillectomy, direct laryngoscopy and nasopharynx survey ii. Bilateral palatine tonsillectomy after bilateral lingual tonsillectomy should be avoided d. For node level 4, lower 5: i. EUA including direct laryngoscopy, esophagoscopy, bronchoscopy, whole body CT with contrast (or FDG PET/CT if not previously performed) e. For level 5: i. Perform extensive skin and scalp examination for skin cancer 6. Treatment (primary not found after appropriate work-up): a. There should be emphasis on multidisciplinary discussion b. Having HPV-positive finding on neck FNA, should be managed as oropharynx primary if no primary is specifically identified c. Having EBV-positive finding on neck FNA, should be managed as nasopharynx primary if no primary is specifically identified d. For N1 disease without adverse features: i. Neck dissection + RT (consider parotid coverage for node 1-3) e. For N2-3, there are various treatment options including surgery, radiation, or induction chemotherapy: i. For clinical ENE, systemic/RT is preferred

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Questions 1. Which of the following is an important principle in the care of patients with very advanced head and neck cancer: a. Treatment should be done after multidisciplinary discussion, goals of care discussion, and early involvement of palliative medicine services b. Clinical trials should be avoided so as not to delay starting treatment c. Neoadjuvant systemic therapy should not be considered d. Surgical debulking should be done prior to other treatment in most cases 2. Which of the following is a recommended intervention in the surveillance and followup guidelines for patients with head and neck cancer? a. Routine PET Scan imaging every 12 months in asymptomatic patients b. Annual head and neck examination after the first year post treatment. c. Screening for Depression d. Routine MRI imaging in Salivary gland tumors surveillance. 3. Which feature in oral cavity cancers is an indication for adding systemic therapy to adjuvant radiotherapy? a. Bone invasion in alveolar tumors with negative margin resection. b. T3 tumors with negative margin resection c. Perineural, lymphatic, and vascular invasion d. Extranodal extension 4. A 47 year old man comes to see you for a single 2.8cm left-sided well encapsulated cystic level II neck mass without additional nodal disease. Fine needle aspiration biopsy indicates squamous cell carcinoma, and there is no apparent primary on imaging. Following guideline adherent evaluation (including exam under anesthesia, palpation and inspection, biopsy of areas of clinical concern, direct laryngoscopy and nasopharynx survey, and tonsillectomy), a 1cm primary P16-positive squamous cell carcinoma is identified in the left tonsil that is completely removed with negative margins. There are no clinical trials easily accessible to the patient. Which could you offer to this patient based on the current evidence? a. Neck dissection, with or without adjuvant therapy depending on pathologic findings b. Chemotherapy with platinum based agents c. Excision of the involved node d. Definitive RT alone 5. A 64 year old woman is seen with a 3 cm right submandibular gland mass that is completely removed with the entire submandibular gland (negative margins). Pathology reveals adenoid cystic carcinoma. Which of the following is evidence-based adjuvant treatment. a. Systemic/RT b. RT c. Neck dissection d. Observation

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National Comprehensive Cancer Network. Head and Neck. (2021, November 27). https://www.nccn. org. Koyfman SA, Ismaila N, Crook D, D'Cruz A, Rodriguez CP, Sher DJ, Silbermins D, Sturgis EM, Tsue TT, Weiss J, Yom SS, Holsinger FC. Management of the Neck in Squamous Cell Carcinoma of the Oral Cavity and Oropharynx: ASCO Clinical Practice Guideline. J. Clin. Oncol. 2019 Jul 10;37(20):17531774. doi: 10.1200/JCO.18.01921. Epub 2019 Feb 27. PMID: 30811281; PMCID: PMC7098829. Maghami E, Ismaila N, Alvarez A, Chernock R, Duvvuri U, Geiger J, Gross N, Haughey B, Paul D, Rodriguez C, Sher D, Stambuk HE, Waldron J, Witek M, Caudell J. Diagnosis and Management of Squamous Cell Carcinoma of Unknown Primary in the Head and Neck: ASCO Guideline. J. Clin. Oncol. 2020 Aug 1;38(22):2570-2596. doi: 10.1200/JCO.20.00275. Epub 2020 Apr 23. PMID: 32324430. Geiger JL, Ismaila N, Beadle B, Caudell JJ, Chau N, Deschler D, Glastonbury C, Kaufman M, Lamarre E, Lau HY, Licitra L, Moore MG, Rodriguez C, Roshal A, Seethala R, Swiecicki P, Ha P. Management of Salivary Gland Malignancy: ASCO Guideline. J. Clin. Oncol. 2021 Jun 10;39(17):1909-1941. doi: 10.1200/JCO.21.00449. Epub 2021 Apr 26. PMID: 33900808. Chen YP, Ismaila N, Chua MLK, Colevas AD, Haddad R, Huang SH, Wee JTS, Whitley AC, Yi JL, Yom SS, Chan ATC, Hu CS, Lang JY, Le QT, Lee AWM, Lee N, Lin JC, Ma B, Morgan TJ, Shah J, Sun Y, Ma J. Chemotherapy in Combination With Radiotherapy for Definitive-Intent Treatment of Stage II-IVA Nasopharyngeal Carcinoma: CSCO and ASCO Guideline. J. Clin. Oncol. 2021 Mar 1;39(7):840-859. doi: 10.1200/JCO.20.03237. Epub 2021 Jan 6. PMID: 33405943. Machiels JP, René Leemans C, Golusinski W, Grau C, Licitra L, Gregoire V; EHNS Executive Board. Electronic address: [email protected]; ESMO Guidelines Committee. Electronic address: [email protected]; ESTRO Executive Board. Electronic address: [email protected]. Squamous cell carcinoma of the oral cavity, larynx, oropharynx and hypopharynx: EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2020 Nov;31(11):1462-1475. doi: 10.1016/j.annonc.2020.07.011. Epub 2020 Oct 23. PMID: 33239190. Bossi P, Chan AT, Licitra L, Trama A, Orlandi E, Hui EP, Halámková J, Mattheis S, Baujat B, Hardillo J, Smeele L, van Herpen C, Castro A, Machiels JP; ESMO Guidelines Committee. Electronic address: [email protected]; EURACAN. Nasopharyngeal carcinoma: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2021 Apr;32(4):452-465. doi: 10.1016/j.annonc.2020.12.007. Epub 2020 Dec 25. PMID: 33358989. Keam B, Machiels JP, Kim HR, Licitra L, Golusinski W, Gregoire V, Lee YG, Belka C, Guo Y, Rajappa SJ, Tahara M, Azrif M, Ang MK, Yang MH, Wang CH, Ng QS, Wan Zamaniah WI, Kiyota N, Babu S, Yang K, Curigliano G, Peters S, Kim TW, Yoshino T, Pentheroudakis G. Pan-Asian adaptation of the EHNS-ESMO-ESTRO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with squamous cell carcinoma of the head and neck. ESMO Open. 2021 Dec;6(6):100309. doi: 10.1016/j.esmoop.2021.100309. Epub 2021 Nov 26. PMID: 34844180; PMCID: PMC8710460. Paleri V, Urbano TG, Mehanna H, Repanos C, Lancaster J, Roques T, Patel M, Sen M. Management of neck metastases in head and neck cancer: United Kingdom National Multidisciplinary Guidelines. J. Laryngol. Otol. 2016 May;130(S2):S161-S169. doi: 10.1017/S002221511600058X. PMID: 27841133; PMCID: PMC4873907. Cohen O, Brauer PR, Judson BL, Burtness BA, Earles J, Mehra S. Guideline - Adherence in advanced stage head and neck cancer is associated with improved survival - A National study. Oral Oncol. 2022 Feb;125:105694. doi: 10.1016/j.oraloncology.2021.105694. Epub 2021 Dec 28. PMID: 34971883. Divi V, Chen MM, Nussenbaum B, Rhoads KF, Sirjani DB, Holsinger FC, Shah JL, Hara W. Lymph Node Count From Neck Dissection Predicts Mortality in Head and Neck Cancer. J. Clin. Oncol. 2016 Nov 10;34(32):3892-3897. Cohen EE, LaMonte SJ, Erb NL, Beckman KL, Sadeghi N, Hutcheson KA, Stubblefield MD, Abbott DM, Fisher PS, Stein KD, Lyman GH, Pratt-Chapman ML. American Cancer Society Head and Neck Cancer Survivorship Care Guideline. CA Cancer J. Clin. 2016 May;66(3):203-39. doi: 10.3322/caac. 21343. Epub 2016 Mar 22. Erratum in: CA Cancer J. Clin. 2016 Jul;66(4):351. PMID: 27002678.

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Chapter 11

Non-Melanoma Skin Cancers Arielle Thal, MD Thomas J. Ow, MD, MS, FACS and Cecelia E. Schmalbach, MD, MSc, FACS Non-Melanoma Skin Cancer (NMSC) 1. NMSC includes >80 histologic subtypes of cutaneous cancer but the most common are: a. Basal Cell Carcinoma (BCC) accounts for 75% of NMSC, most common cancer b. Cutaneous Squamous Cell Carcinoma (cSCC) accounts for 20% of NMSC, 2nd most common cancer c. Merkel Cell Carcinoma (MCC) accounts for 5% of NMSC, rare neuroendocrine tumor 2. Epidemiology a. BCC and cSCC are considered Keratinocyte Carcinomas (KCs) b. KCs are common: 40-50% of Americans will have 1 or more by age 65 i. Incidence difficult to accurately assess because most are not tracked by a formal registry, ~3.3 million Americans affected per year ii. Increasing incidence related to artificial UVR exposure (tanning booths), reduction in atmospheric ozone concentration and increased UVB penetration, improved detection 3. Prognosis a. Excellent for KCs: >90% 5-year overall survival (OS), local recurrence rate is 10% b. Subset of aggressive KCs: regional metastasis rate 3-5% (cSCC most commonly), mortality rate 0.7/100,000 per year in the US c. MCC is more aggressive with worse prognosis (~5-year OS for localized disease as low as 50%)

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NMSC Risk Factors 1. Environmental a. Ultraviolet Radiation (UVR) i. Chronic/cumulative exposure ii. Single tanning booth session will increase risk of SCC and BCC iii. Fitzpatrick skin type I (fair skin/light hair) more susceptible iv. Tanning booth use 2. History of radiation exposure (environmental, occupational, treatment-related) 3. Genetics: a. Xeroderma Pigmentosa (XP): Autosomal Recessive (AR), due to mutations involved in nucleotide excision repair (NER) including XPC and ERCC2, increased risk of KCs and melanoma b. Fanconi Anemia: AR, chromosome instability, poor DNA repair mechanisms due to mutations in genes FANCA, FANCC, FANCG c. Nevoid BCC syndrome (Gorlin Syndrome): AD, mutation in PTCH1 gene on chromosome 9q, encodes PTCH sonic hedgehog receptor, tumor suppressor gene i. Syndrome consists of BCC in adolescence, jaw cysts, bifid ribs, scoliosis, intellectual disability, frontal bossing 4. Immunosuppression: solid organ transplant (SOT), lymphoproliferative disorders, HIV/AIDS a. Immunosuppressed patients with head and neck (H&N) cSCC are ~2x as likely to develop recurrence and ~3.5x as likely to die of H&N cSCC than immunocompetent counterparts. b. SOT patients are at particularly high risk c. Current AJCC staging does not include immune status, but it is an important risk factor that impacts prognosis 5. Human Polyomavirus 5 (Merkel Cell Polyomavirus) has been implicated in MCC a. dsDNA virus that causes asymptomatic infection, transmitted during childhood b. Merkel cell polyomavirus is being investigated as a biomarker for recurrence 6. BRAF-Inhibitors: increase risk of cSCC during treatment 7. Chronic inflammation/scarring lesions (Marjolin ulcer): increased risk of cSCC 8. Arsenic is risk factor for cSCC and BCC 9. Prior non-melanoma skin cancers increase the risk of future lesions

Workup 1. History a. b. c. d.

Change in lesion color, size, shape Presence of bleeding, ulceration, pain Personal/family history of skin cancer/lesions History sun exposure

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e. History of tanning booth use f. Immunosuppression 2. Physical Exam a. Head and neck exam with attention to high sun exposed areas (ears, nose, lips, scalp) and cervical nodes b. Cranial nerve exam to assess for perineural spread c. Location of NMSCs impact risk of recurrence, metastasis, and overall prognosis (Figure 1) i. L zone (low risk lesions) includes trunk/limbs ii. M zone (medium risk lesions) includes cheek, forehead, scalp, neck iii. H zone (high risk lesions) includes central face, eyelids/brows, periorbita, nose, cutaneous lips, chin, mandible, pre/postauricular region, temple, ear 3. Biopsy a. Shave biopsies for non-pigmented superficial lesions b. If more than superficial lesion, include deep reticular dermis (i.e., punch biopsy) c. Excisional biopsy: i. Narrow margin (6 mm) T4 T4a: gross cortical bone/marrow invasion T4b: skull base or skull base foramen involvement

b. N Stage i. N1: Single ipsilateral node 6 cm and ENE• N3b: clinically overt ENE+ c. M Stage: i. M1: distant metastasis 4. Treatment a. Non-invasive: topical 5-FU, topical imiquimod, photodynamic therapy (PDE), cryotherapy i. Can be considered for low risk/superficial lesions, lower cure rate than C&E b. Intralesional Interferon alpha-2B i. Effective for low risk, superficial BCC ii. Rarely used due to expense/regimen (3 injections per week for 3 weeks) iii. Side effects: flu like symptoms c. Curettage and electrodessication (C&E): scrape away tumor down to normal dermis, then denature involved area with electrodessication i. Only for low-risk, superficial BCC ii. Advantages: • Fast/cost effective • Tissue sparing iii. Disadvantages: • No histologic assessment • Healing by secondary intention can lead to scarring • Operator dependent (must be able to recognize normal dermal layer) • Not applicable in hair bearing regions (risk of invasion extending along follicular structures that would not be removed) iv. Cure rate 91-97% in properly selected patients

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d. Mohs micrographic surgery (MMS) i. Preferred treatment for high-risk BCC, can also be used for positive margin clearance of previously resected low-risk BCC when necessary ii. Advantage: comprehensive 360° assessment of margin affords lower recurrence rate compared to traditional surgical excision with wide margins iii. Disadvantage: more costly • Relative contraindications/considerations for MMS: • Patient inability to tolerate procedure under local anesthesia • Bony invasion • Large nerve involvement (CNV, CNVII) iv. Technique performed by trained MMS surgeon: • Typically performed under local anesthesia with patient awake • Tumor outlined and debulked • Tumor excised at 45-degree beveled edge to facilitate tissue mounting • Specimen oriented, tumor mapped to patient • Tissue mounted and frozen section performed • Margins analyzed, any area of positivity is marked on the map and additional tissue serially removed • Process repeated until all margins are negative e. Wide Surgical Resection i. Wide local excision (WLE) with 3-5 mm margins ii. Reconstruction requiring advancement, rotation or tissue transfer should be delayed until margins evaluated (confident clearance on frozen section pathology, or wait for evaluation of permanent section) to avoid alteration of anatomy which may complicate further resection iii. Therapeutic neck dissection if clinically node positive (cN+) • Indicated with grossly positive and/or pathologically confirmed metastasis • Resect involved nodal basin along with draining nodal basin: − Level I-IV and parotidectomy if affecting temple, high cheek, forehead − Level V/suboccipital and retroauricular nodes if posterior scalp and neck disease f. Radiation Therapy (RT) i. Primary RT can be considered for advanced BCC with 70-80% complete response rate; consider primary RT when surgery is contraindicated, not feasible or cosmetically unacceptable ii. Adjuvant RT should be considered if margins are positive/unresectable, if PNI is noted, and for any patient with N+ disease

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iii. Contraindicated for patients with genetic conditions predisposing to cutaneous cancers, patients with connective tissue disorders, recommend against RT in patients 2 cm 4. Treatment a. Non-invasive options for diffuse AK/field cancerization with superficial lesions, and cSCC in situ include (in order of efficacy): topical 5-FU, PDE, topical imiquimod, ingenol mebutate, cryotherapy b. Curettage & Electrodessication i. Indicated for diffuse AK/field cancerization, cSCC in situ, superficial low risk cSCC ii. 96% cure rate for low-risk lesions c. MMS i. Preferred treatment for high-risk, recurrent cSCC or any cSCC in high-risk patients ii. Lower local recurrence rate compared to traditional surgery iii. Cure rates: 96% for primary cSCC, 77% for recurrent cSCC iv. Local recurrence rate: 3.1% for primary cSCC, 10% for recurrent cSCC

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d. Wide Surgical Resection i. Wide Local Excision: ~0.5-1 cm margin (correlate to tumor diameter) ii. Reconstruction requiring advancement, rotation or tissue transfer should be delayed until margins evaluated (confident clearance on frozen section pathology, or wait for evaluation of permanent section) to avoid alteration of anatomy which may complicate further resection iii. Therapeutic neck dissection if clinically node positive (cN+) • Indicated with grossly positive and/or pathologically confirmed metastasis • Resect involved nodal basin along with draining nodal basin: − Level I-IV and parotidectomy if affecting temple, high cheek, forehead − Level V/suboccipital and retroauricular nodes if posterior scalp and neck disease iv. Elective neck dissection (with or without parotidectomy) is not routine due to low overall risk of LN metastases v. SLNB has potential benefit for cN0 patients at high-risk of nodal metastasis but survival benefit and indication/selection criteria not well established. e. RT i. Primary RT can be considered when surgery is contraindicated, not feasible or cosmetically unacceptable • Recurrence rates following primary RT for primary and recurrent cSCC, 6.7% and 10% respectively. ii. Primary RT can be considered for extensive Bowen disease over large surface area iii. Adjuvant RT indicated if: • one node >3 cm or > = 2 positive nodes • any ENE • incompletely excised or unresectable nodal disease • unresectable positive surgical margin iv. Adjuvant RT considered if • One positive node 90% b. Recurrence rate 75 years of age, primary tumor >2 cm, immunosuppression, lip lesions, LVI d. Occurs in elderly (90% of diagnoses occurs in patients >50 years of age), Caucasian populations 2. Histology: a. Small round blue cells, neuroendocrine granules, intercellular junctions, rigid spinous processes, paranuclear intermediate filaments b. Diagnosis requires specific immunohistochemical staining: CK20, CD117, S100, CD45, panCK c. Must differentiate from small cell lung cancer (SCLC) which is positive for thyroid transcription factor (TTF-1), MCC is negative

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3. Staging according to AJCC 8th Edition a. T Stage i. T1: 5 cm iv. T4: invades bone, muscle, fascia, cartilage b. N Stage i. N1: metastasis to regional LNs ii. N2: in transit metastasis (metastasis between primary and draining nodes, not incontinuity with primary) without LN metastasis iii. N3: in transit metastasis with LN metastasis c. M Stage i. M1 • M1a: metastasis to distant skin sites, subcutaneous tissue and LNs • M1b: metastasis to lung • M1c: metastasis to all other sites 4. Treatment a. Wide Surgical Resection i. Wide local excision with 1-2 cm margin ii. MMS can be considered as an alternate to WLE iii. Reconstruction: • When RT is indicated - primary closure is optimal to allow for expeditious initiation of RT within 3-4 weeks • If RT not indicated, reconstruction should be delayed until negative margins are confirmed histologically iv. SLNB is indicated for all cN0 patients • Most sensitive staging modality for regional metastasis • ~33% of patients who are cN0 at presentation will have +SLNB • Positive SLNB requires neck dissection and/or RT to the nodal basin • Negative SLNB can be observed − RT should be considered in high-risk or immunosuppressed patients with negative SLNB due to higher risk of false negative SLNB and regional recurrence v. Therapeutic neck dissection if clinically node positive (cN+) • Indicated with grossly positive and/or pathologically confirmed metastasis • Resect involved nodal basin along with draining nodal basin: − Level I-IV and parotidectomy if affecting temple, high cheek, forehead − Level V/suboccipital and retroauricular nodes if posterior scalp and neck disease

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b. RT i.

Primary RT can be considered when surgery is contraindicated, not feasible or cosmetically unacceptable ii. Adjuvant therapy indicated if: • Tumor >1cm, narrow/positive margins, PNI/LVI, +SLNB, multiple positive nodes, ENE+, immunosuppressed patients • If adjuvant RT is indicated at time of diagnosis based on above risk factors, then proceed with narrow margin excision to reduce morbidity and post-operative time to RT • Palliative therapy for unresectable or extensive disease c. Systemic therapy: i. Pembrolizumab, nivolumab and avelumab for locoregional disease or M+ disease when curative surgery/RT is not feasible ii. Neoadjuvant/adjuvant chemotherapy with cisplatin/carboplatin +/etoposide has been studied; evidence does not suggest survival benefit; can be considered for M+ disease when checkpoint immunotherapy is contraindicated d. Multidisciplinary Tumor Board discussion recommended for all patients diagnosed with MCC 5. Prognosis: a. 5-year MCC-specific survival is 41-77% b. 25%-36% present with locoregional disease, 50% develop locoregional disease, 33% develop metastasis c. Local recurrence rate similar to other NMSC; distant metastatic rate is high ~33% i. Local recurrence/dermal metastasis via neurotropic spread (PNI) ii. Distant metastasis to skin, lung, CNS, bone, liver d. Immunosuppression is poor prognostic factor

NMSC Prevention and Oncologic Follow up 1. Primary Prevention: a. Patient education: self-exam, sunscreen, sun avoidance, avoid tanning booths 2. Secondary Prevention: a. Whole body skin exams (WBSE) i. Value of WBSE not well established for general population ii. High risk patients should perform routine self-skin exams as well as annual WBSE to assess for suspicious/new lesions b. Oncologic Follow Up: i. BCC: clinic exam every 6-12 months for 5 years, then annually for life ii. cSCC: clinic exam q3 months for 2 years, then q6-12 months for 3 years, then annually for life

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iii. MCC: clinic exam every 3-6 months for 3 years, then every 6-12 months for life c. Imaging as clinically indicated i. Routine post treatment imaging recommended for MCC-CXR and CT neck at 3 months post-treatment, then annually 3. Tertiary Prevention: a. Nicotinamide under investigation - may be effective in preventing KC growth, 30% reduction in new cSCCs and 20% reduction in new BCCs over 12 months b. High Risk Patients: i. Retinoids reduce incidence of new cSCCs in transplant patients or patients at high risk of cSCC with multiple actinic keratoses or diagnosis of Xeroderma Pigmentosum ii. Work with transplant team to decrease level of immune suppression, consider switching from other immunosuppressants to mTOR inhibitors to reduce likelihood of new cSCCs

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Questions 1. Which of the following is considered primary treatment for a high-risk BCC without evidence of locoregional disease? a. Primary radiation therapy b. Mohs Micrographic Surgery (MMS) c. Wide local excision with sentinel lymph node biopsy d. Sonidegib 2. Which of the following is true about immunosuppression in the setting of cutaneous carcinomas? a. Immunosuppressed patients have a higher risk of developing advanced BCC than cSCC b. Switching to mTOR inhibitors increases the risk of developing cSCC for immunosuppressed patients c. Immunosuppression does not impact recurrence or prognosis d. Solid organ transplant patients with cSCC have the worst prognosis compared to those with other causes of immunosuppression 3. Which of the following risk factors is accurately matched to its malignancy? a. Marjolin Ulcer - Merkel Cell Carcinoma b. Polyomavirus - Basal Cell Carcinoma c. PTCH 1 gene mutation - Basal Cell Carcinoma d. Xeroderma Pigmentosa - Merkel Cell Carcinoma 4. What is considered a “high risk” feature of keratinocyte carcinomas? a. 8mm lesion on the forehead b. Clark level IV depth of invasion for a cSCC c. Adenoid variant cSCC d. Well differentiated cancer 5. Curettage and electrodessication is used to treat the majority of which of the following types of skin cancer? a. Low risk BCC b. High risk cSCC c. Merkel Cell d. Melanoma

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References Elghouche AN, Pflum ZE, Schmalbach CE. Immunosuppression Impact on Head and Neck Cutaneous Squamous Cell Carcinoma: A Systematic Review with Meta-analysis. Otolaryngol. Head Neck Surg. 2019 Mar;160(3):439-446. doi: 10.1177/0194599818808511. Epub 2018 Oct 23. PMID: 30348055. Miles BA, Goldenberg D; Education Committee of the American Head and Neck Society (AHNS). Merkel cell carcinoma: Do you know your guidelines. National Comprehensive Cancer Network Guidelines (Version 2. 2021). https://www.nccn.org/guidelines/ category_1#site. October 31, 2021. Ow TJ, Grethlein SJ, Schmalbach CE; Education Committee of the American Head and Neck Society (AHNS). Do you know your guidelines? Diagnosis and management of cutaneous head and neck melanoma. Head Neck. 2018 May;40(5):875-885. doi: 10.1002/hed.25074. Epub 2018 Feb 27. PMID: 29485688. Porceddu SV, Bressel M, Poulsen MG, Stoneley A, Veness MJ, Kenny LM, Wratten C, Corry J, Cooper S, Fogarty GB, Collins M, Collins MK, Macann AMJ, Milross CG, Penniment MG, Liu HY, King MT, Panizza BJ, Rischin D. Postoperative Concurrent Chemoradiotherapy Versus Postoperative Radiotherapy in High-Risk Cutaneous Squamous Cell Carcinoma of the Head and Neck: The Randomized Phase III TROG 05.01 Trial. J. Clin. Oncol. 2018 May 1;36(13):1275-1283. doi: 10.1200/JCO.2017.77.0941. Epub 2018 Mar 14. PMID: 29537906.

Chapter 12

Malignant Melanoma of the Head and Neck Peter Yao Kelly Malloy, MD and Luc G. T. Morris, MD Epidemiology 1. 106,110 estimated new cases of melanoma in USA in 2021 (5th most common cancer) [1] a. Incidence rising at 1.4% per year (2009-2018) b. Melanoma in situ incidence has risen more dramatically c. Much of the rapid rise in melanoma incidence over the past 40 years may be attributable to more biopsies being performed and higher diagnostic scrutiny by dermatopathologists (increasing diagnosis, not solely increasing incidence of disease) [2] 2. 7,180 estimated deaths from melanoma in USA in 2021 [1] a. Death rate falling at 3.4% per year (2010-2019) 3. 15%-25% of melanoma is located in the head and neck [3–6] 4. More cases in white persons than any other racial/ethnic group 5. Men are 1.6 times more likely to develop melanoma than women 6. Median age at diagnosis is 65 years

Risk Factors 1. Sun/UV exposure is the most important environmental risk factor, though level of relative risk (RR) varies by exposure pattern with intermittent sun exposure and history of sunburn carrying the highest RR a. Intermittent sun exposure has a RR of 1.61 [7] b. History of sunburn has a RR of 2.03 [7] c. Total sun exposure has a RR of 1.34 [7] d. Chronic sun exposure has RR of 0.95 [7] e. Sunbed/tanning bed use has a RR of 1.20 [8] f. These RRs are much lower than for smoking and lung cancer (10-20).

In: Essential Head and Neck Oncology and Surgery Editors: Maie A. St. John and Benjamin L. Judson

ISBN: 979-8-88697-438-6 © 2023 Nova Science Publishers, Inc.

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2. Sunscreen may be modestly protective, but this has not been definitively proven, with the only randomized controlled trial showing a non-statistically significant reduction in melanoma risk with daily sunscreen use [9] 3. Geographic location a. Higher incidence in lower latitudes 4. Number of nevi 5. Dysplastic nevi 6. Family history of melanoma 7. Immunosuppression 8. Sun sensitivity or inability to tan 9. Light skin, red or blond hair, blue or green eyes

Etiology 1. Hereditary syndromes a. Familial Atypical Multiple Mole Melanoma (FAMMM) syndrome i. Autosomal dominant ii. Commonly due to mutations in CDKN2A gene iii. High total body nevi count (>50) and family history of melanoma iv. 90% risk of melanoma by age 90 [10] b. Xeroderma pigmentosa i. Autosomal recessive ii. Caused by defect in any of 9 genes in the nucleotide excision repair pathway, which prevents repair of DNA damage caused by UV exposure iii. 10,000-fold increased risk for skin cancer [11] iv. Freckling of sun-exposed areas by age 2 v. Without sun protection, 50% develop first skin cancer by age 10 [12] 2. Molecular biology of sporadic melanoma a. Mitogen-Activated Protein Kinase (MAPK) (Ras-Raf-MEK-ERK) pathway i. Important pathway that regulates cell proliferation ii. Pathway is activated in most melanomas via driver mutations in: • BRAF – proto-oncogene (40-50%) [13] − BRAF mutations result in constitutive activation of kinase function independent of upstream signaling from RAS • NRAS – proto-oncogene (15-20%) [13] − NRAS mutations constitutively active MAPK, PI3K, and other cell signaling pathways causing cell proliferation • NF1 – tumor suppressor (10-15%) [13] − NF1 mutations cause MAPK activation through loss of ability to downregulate RAS

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b. KIT mutations i. Receptor tyrosine kinase on cell membrane, which on binding stem cell factor, activates cell growth pathways ii. Most commonly mutated in mucosal (15-20%) and acral melanomas (15-20%) [13] c. UV signature i. Mutation pattern from UVA and UVB exposure with a threshold of 60% of C > T mutations and 5% of CC > TT mutations [14] ii. Due to chronic exposure of head and neck to sun, melanomas in this area often have a UV signature [15] d. Molecular profile of HN melanomas i. Most frequent mutations: NF1 (41.4%), BRAF V600E (14.8%), NRAS (11.7%), BRAF class 1 (10.5%) [16] ii. Highest tumor mutational burden of all melanoma subsites [16] iii. Enrichment of NF1 tumors and depletion of NRAS and BRAF V600E tumors compared to cutaneous melanomas overall [16]

Diagnosis and Evaluation 1. History a. Color change, growth, or development of itching, bleeding, pain, or ulceration of a previously present lesion b. Assess risk factors for melanoma (see risk factors above) c. 70% of melanomas are discovered by patients or family members with a minority discovered by medical providers [17] 2. Physical Exam a. ABCDE checklist for assessing pigmented lesions with concern for melanoma: i. Asymmetry ii. Border irregularities iii. Color variation (within lesion or over time) iv. Diameter (> 6mm or increase in size) v. Evolution (changes over time) b. Perform a thorough head and neck exam with special attention to: i. Subsite is a predictor of prognosis ii. Face (best) > neck > scalp > ear (worst) [17] iii. Signs of aggressive/advanced disease: iv. Ulceration v. Nodularity vi. Satellite lesions iv. Examine draining lymph node basin with attention to patterns of spread by location vii. Parotid lymph nodes, especially for anterior scalp, temple, or cheek melanomas

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viii. Occipital lymph nodes, especially for retroauricular or posterior scalp lesions 3. Subtypes of melanoma a. Superficial spreading – 70% i. Prolonged radial growth prior to vertical invasion ii. Likely to be associated with pre-existing nevus iii. Variably pigmented macules or thick plaque with irregular borders iv. 60% are thin (2mm thick at time of diagnosis [19] c. Acral lentiginous – 5-10% i. Most common melanoma in dark-skinned people (62-70% of melanomas in black persons and 29-46% in Asian persons) ii. Dark irregularly pigmented macules or patches with irregular borders iii. Commonly occurs on palms, soles, and nail beds d. Lentigo maligna melanoma – 10-15% i. Common in chronically sun-damaged areas (face, ears, scalp, neck) of elderly ii. Begins as tan or brown macules iii. Grows slowly and sudden change in size or bleeding may indicate vertical growth and invasion iv. Lentigo maligna melanoma is distinct from lentigo maligna, which is another term for melanoma in situ, which is precancerous 4. Differential diagnosis a. Seborrheic keratosis b. Pigmented actinic keratosis c. Benign melanocytic lesions d. Atypical (dysplastic nevus) e. Basal cell carcinoma f. Keratoacanthoma g. Squamous cell carcinoma h. Sebaceous carcinoma i. Merkel cell carcinoma j. Hemangioma 5. Biopsy a. Excisional/complete biopsy i. For small lesions ii. Excise with 1-3 mm margins and to extending to a depth encompassing thickest portion of lesion b. Incisional biopsy i. For large lesions or lesions in challenging anatomical locations such as face or ear ii. Partial sampling should include the thickest part of the lesion

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c.

Needle or shave biopsy are not recommended as they may miss the full depth of the lesion d. Histopathology i. The following histologic factors should be included in the pathology report, with the 3 bolded factors being the dominant histologic predictors of outcome: ii. Size of specimen iii. Tumor thickness (Breslow) iv. Ulceration v. Dermal mitotic rate vi. Peripheral and deep margin status vii. Microsatellitosis viii. Breslow Thickness Stage I Stage II Stage III Stage IV

6. Labs a.

0.75 mm or less 0.76-1.50 mm 1.51-4.0 mm 4.1 mm or greater

Serum LDH, a nonspecific screening test for distant metastasis, is incorporated into AJCC8 guidelines for classification of stage IV disease, and should be tested in patients with stage IV disease

7. Imaging a. No routine imaging is recommended for patients with clinical stages I and II disease without signs or symptoms of metastasis b. For patients with stage III or IV disease, baseline imaging may include CT neck, chest, abdomen, and pelvis vs. whole body PET/CT and brain MRI

Staging 1. The current standard for evaluation and prognostication is the staging system by the American Joint Committee on Cancer (AJCC, 8th edition) 2. The AJCC8 staging system for cutaneous melanoma is detailed in Tables 1 and 2 3. The AJCC8 staging system for mucosal melanoma of the head and neck is detailed in Tables 3 and 4 Table 1. Cutaneous melanoma TNM definitions, AJCC8 Primary tumor (T) T category TX: Primary tumor thickness cannot be assessed (e.g., diagnosis by curettage) T0: No evidence of primary tumor (e.g., unknown primary or completely regressed melanoma) Tis (melanoma in situ)

Thickness Not applicable

Ulceration status Not applicable

Not applicable

Not applicable

Not applicable

Not applicable

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Table 1. Continued) Primary tumor (T) T category T1 T1a T1b T2 T2a T2b T3 T3a T3b T4 T4a T4b Regional lymph nodes (N) N category

NX

N0 N1

N1a N1b N1c N2

N2a N2b N2c N3

N3a

T category ≤1.0 mm 1 to 2 mm >1 to 2 mm >2 to 4 mm >2 to 4 mm >2 to 4 mm >4 mm >4 mm >4 mm

T category Unknown or unspecified Without ulceration With ulceration With or without ulceration Unknown or unspecified Without ulceration With ulceration Unknown or unspecified Without ulceration With ulceration Unknown or unspecified Without ulceration With ulceration

Extent of regional lymph node and/or lymphatic metastasis Number of tumor-involved regional lymph Presence of in-transit, satellite, nodes and/or microsatellite metastases Regional nodes not assessed (e.g., SLN No biopsy not performed, regional nodes previously removed for another reason). Exception: Pathological N category is not required for T1 melanomas, use cN. No regional metastases detected No One tumor-involved node or in-transit, satellite, and/or microsatellite metastases with no tumor-involved nodes One clinically occult (i.e., detected by SLN No biopsy) One clinically detected No No regional lymph node disease Yes Two or three tumor-involved nodes or intransit, satellite, and/or microsatellite metastases with one tumor-involved node Two or three clinically occult (i.e., detected No by SLN biopsy) Two or three, at least one of which was No clinically detected One clinically occult or clinically detected Yes Four or more tumor-involved nodes or intransit, satellite, and/or microsatellite metastases with two or more tumorinvolved nodes, or any number of matted nodes without or with in-transit, satellite, and/or microsatellite metastases Four or more clinically occult (i.e., detected No by SLN biopsy)

12. Malignant Melanoma of the Head and Neck T category N3b

Thickness Four or more, at least one of which was clinically detected, or presence of any number of matted nodes Two or more clinically occult or clinically detected and/or presence of any number of matted nodes

N3c

Distant metastasis (M) M category M0 M1 M category

M criteria Anatomic site No evidence of distant metastasis Evidence of distant metastasis M criteria Anatomic site Distant metastasis to skin, soft tissue including muscle, and/or nonregional lymph node Distant metastasis to lung with or without M1a sites of disease

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Ulceration status No

Yes

LDH level Not applicable See below

LDH level M1a Not recorded or unspecified M1a(0) Not elevated M1a(1) Elevated M1b Not recorded or unspecified M1b(0) Not elevated M1b(1) Elevated M1c Distant metastasis to non-CNS visceral sites Not recorded or unspecified with or without M1a or M1b sites of disease Not elevated M1c(0) M1c(1) Elevated M1d Distant metastasis to CNS with or without Not recorded or unspecified M1a, M1b, or M1c sites of disease M1d(0) Normal M1d(1) Elevated Suffixes for M category: (0) LDH not elevated, (1) LDH elevated. No suffix is used if LDH is not recorded or is unspecified. AJCC: American Joint Committee on Cancer; TNM: tumor, node, metastasis; SLN: sentinel lymph node; LDH: lactate dehydrogenase; CNS: central nervous system.

Table 2. Cutaneous melanoma TNM prognostic stage groups, AJCC8 Clinical (cTNM) When T is... Tis T1a T1b T2a T2b T3a T3b T4a T4b Any T, Tis Any T Pathological (pTNM) Tis T1a T1b T2a T2b T3a T3b T4a T4b T0 T0

And N is... N0 N0 N0 N0 N0 N0 N0 N0 N0 ≥N1 Any N

And M is... M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1

Then the clinical stage group is... 0 IA IB IB IIA IIA IIB IIB IIC III IV

N0 N0 N0 N0 N0 N0 N0 N0 N0 N1b, N1c N2b, N2c, N3b, or N3c

M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0

0 IA IA IB IIA IIA IIB IIB IIC IIIB IIIC

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Table 2. (Continued) Clinical (cTNM) When T is... T1a/b-T2a T1a/b-T2a T2b/T3a T1a-T3a T3b/T4a T4b T4b Any T, Tis

And N is... N1a or N2a N1b/c or N2b N1a-N2b N2c or N3a/b/c Any N ≥N1 N1a-N2c N3a/b/c Any N

And M is... M0 M0 M0 M0 M0 M0 M0 M1

Then the clinical stage group is... IIIA IIIB IIIB IIIC IIIC IIIC IIID IV

Table 3. Mucosal melanoma of the head and neck TNM staging, AJCC8 Primary tumor (T) T category T criteria T3 Tumors limited to the mucosa and immediately underlying soft tissue, regardless of thickness or greatest dimension; for example, polypoid nasal disease, pigmented or nonpigmented lesions of the oral cavity, pharynx, or larynx T4 Moderately advanced or very advanced T4a Moderately advanced disease. Tumor involving deep soft tissue, cartilage, bone, or overlying skin. T4b Very advanced disease. Tumor involving brain, dura, skull base, lower cranial nerves (IX, X, XI, XII), masticator space, carotid artery, prevertebral space, or mediastinal structures. Regional lymph nodes (N) N category N criteria NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastases N1 Regional lymph node metastases present Distant metastasis (M) M category M criteria M0 No distant metastasis M1 Distant metastasis present

Table 4. Mucosal melanoma of the head and neck TNM prognostic stage groups, AJCC8 T T3 T4a T3-T4a T4b Any T

N N0 N0 N1 Any N Any N

M M0 M0 M0 M0 M1

Stage Group III IVA IVA IVB IVC

Treatment 1. Surgery a. Primary Lesion i. Wide local excision with adequate margins (Table 5) ii. Adequate margins have been extrapolated from studies of melanoma of non-head and neck sites and 1-2 cm margin recommendations must

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often be balanced with aesthetic and functional considerations in the head and neck Head and neck site specific considerations: Scalp – deep margins commonly extend through galea and may include periosteum and calvarium for extensive/deep disease Facial – resection may extend to deep layer of subcutaneous fat Lesions over parotid – excised down to the parotidomasseteric fascia. If fascia is invaded, consider performing a superficial parotidectomy Auricular – may require partial or complete auriculectomy in advanced disease. Lesions extending into external auditory canal may require temporal bone resection

Table 5. Recommended margins for surgical excision based on Breslow thickness Thickness of Melanoma Recommended Clinical Margins [44] In situ 0.5–1.0 cm ≤1.00 mm 1.0 cm 1.01–2.00 mm 1–2 cm 2.00 mm 2.0 cm RCT, randomized controlled trial.

Strength of Recommendation Weak Strong Strong Strong

Evidence Consensus RCT RCT RCT

b. Regional lymph nodes i. Lymphadenectomy ii. Indication: patients with lymph node metastases noted on physical exam or imaging and confirmed with biopsy iii. Sentinel lymph node biopsy (SLNB) iv. Indication: offer to patients with thin melanomas that are T1b (0.8 to 1.0 mm Breslow thickness or 1.0 to 4.0 mm), and thick melanomas (T4; >4.0 mm in Breslow thickness) v. Procedure • Radioactive dye (technetium Tc-99m sulfur colloid or Tc-99m tilmanocept) is injected into the skin around the site of the original melanoma • Lymphoscintigraphy is used to image lymphatic drainage and identify sentinel node(s) • SPECT-CT can be added to lymphoscintigraphy for additional anatomic detail • Blue dye (isosulfan blue or methylene blue) may also be injected into the melanoma at the time of surgery to improve visual identification of lymph nodes during surgery • During surgery, handheld gamma probe can identify “hot” nodes with high radiotracer activity. A “hot” node is usually defined based on a ratio of ex vivo sentinel node counts:in vivo nodal basin counts of 10:1

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•

Additional sentinel lymph nodes, defined as nodes that are grossly suspicious, harbor blue dye, or have a radioactivity count of >10% of the hottest node value, are surgically removed • Nodes are removed until the surgical bed returns to background radioactivity levels, usually less than 10% of hottest node vi. SLN status is the most important prognostic factor for relapse/survival in patients with intermediate (1.2-3.5 mm) or thick (>3.5 mm) primary melanomas (MSLT-1 trial) [20] vii. In patients with a positive SLN, completion lymph node dissection vs. active nodal basin surveillance with serial ultrasound should be offered and discussed • there is no difference in overall survival between CLND and nodal observation (MSLT-2 [21] and DeCOG-SLT [22] trials) • immediate CLND improves the rate of regional disease control by decreasing future nodal recurrences but at the cost of additional morbidity (MSLT-2 trial) [21] c. Reconstruction i. Wait until margin status is confirmed on final pathologic report before performing a complex reconstruction (local, regional, or free flap) 2. Radiation a. Adjuvant radiation after lymph node dissection decreases the rate of nodal field relapse but offers no survival benefit (TROG 02-01 study in H&N melanoma). [23] Adjuvant RT after therapeutic nodal dissection may be considered for: i. Multiple positive nodes ii. Extranodal spread iii. Large involved nodes iv. Positive margins v. Recurrent disease after previous surgery 3. Cytotoxic Chemotherapy a. Role of cytotoxic chemotherapy is limited to patients who have progressed after optimal treatment with other systemic therapy options b. Dacarbazine and temozolomide (prodrug) i. Alkylating agents with oral cavity, 25% > paranasal sinuses, 15% [38– 40] 3. 40% are amelanotic [41] 4. Poor prognosis, 5-year overall survival is 25% [37] 5. Staging differs from that for cutaneous melanoma (see staging above), with staging beginning at stage III as the most limited form of disease to reflect poor prognosis 6. Treatment: a. Surgical resection b. Therapeutic neck dissection for clinically positive lymph nodes c. Primary RT can be considered for unresectable tumors [42] d. Role of adjuvant RT has not been definitively established in clinical trials but may improve local-regional control [43]

Follow-Up 1. There is no consensus on optimal follow-up strategy and intervals 2. At minimum, typical follow-up may include a detailed history and physical exam with attention to regional recurrences every 3-12 months after definitive treatment 3. In light of new and more effective systemic therapies, the role of PET/CT in the follow-up of high-risk patients is being further evaluated. PET/CT may be considered every 6 months in very high-risk melanoma patients (clinical stage III and IV)

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Questions 1. The rapid rise in melanoma incidence over the past 40 years is most attributable to: a. More biopsies being performed and higher diagnostic scrutiny by dermatopathologists b. Increasing exposure to UV radiation c. Decreased use of sunscreen d. Population migration to lower latitudes 2. Which of the following patterns of sun/UV exposure carries the highest level of relative risk for melanoma? a. Intermittent sun exposure b. History of sunburn c. Total sun exposure d. Chronic sun exposure 3. A 56-year-old man presents for evaluation of a lesion on the left neck suspicious for melanoma. Aside from a small, pigmented lesion on the left neck, the remainder of the head and neck exam is unremarkable. Biopsy demonstrates a cutaneous melanoma 0.3mm in depth, with no ulceration. What is the next step in treatment? a. Observation b. Wide local excision c. Wide local excision and sentinel lymph node biopsy d. Primary radiotherapy 4. Which of the following concerning sentinel lymph node biopsy (SLNB) is true? a. SLN status is the most important prognostic factor for relapse/survival in patients with intermediate (1.2-3.5 mm) or thick (>3.5 mm) primary melanomas b. In patients with a positive SLN, completion lymph node dissection (CLND) demonstrates survival benefit over nodal observation c. In patients with a positive SLN, immediate CLND does not improve the rate of regional disease control compared to nodal observation d. SLNB should be offered to patients with T1a melanomas 5. Which is the following concerning mucosal melanoma is false? a. A majority of mucosal melanomas arise in the head and neck b. The staging of mucosal melanoma differs from the staging for cutaneous melanoma c. The most common site for mucosal melanoma in the head and neck is the oral cavity d. Overall, mucosal melanoma has a worse prognosis than cutaneous melanoma

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Reinhard Dummer, Axel Hauschild, Mario Santinami, Victoria Atkinson, Mario Mandalà, John M Kirkwood, Vanna Chiarion Sileni, James Larkin, Marta Nyakas, Caroline Dutriaux, Andrew Haydon, Caroline Robert, Laurent Mortier, Jacob Schachter, Thierry Lesimple, Ruth Plummer, Kohinoor Dasgupta, Eduard Gasal, Monique Tan, Georgina V Long, Dirk Schadendorf. Five-Year Analysis of Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma. N Engl J Med. 2020;383(12):1139-1148. doi:10.1056/NEJMOA2005493. Lisa Zimmer, Elisabeth Livingstone, Jessica C Hassel, Michael Fluck, Thomas Eigentler, Carmen Loquai, Sebastian Haferkamp, Ralf Gutzmer, Friedegund Meier, Peter Mohr, Axel Hauschild, Bastian Schilling, Christian Menzer, Felix Kieker, Edgar Dippel, Alexander Rösch, Jan-Christoph Simon, Beate Conrad, Silvia Körner, Christine Windemuth-Kieselbach, Leonora Schwarz, Claus Garbe, Jürgen C Becker, Dirk Schadendorf. Adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet (London, England). 2020;395(10236):1558-1568. doi:10.1016/S0140-6736(20)30417-7. Chang AE, Karnell LH, Menck HR. The National Cancer Data Base Report on Cutaneous and Noncutaneous Melanoma A Summary of 84,836 Cases from the Past Decade. 1998. doi:10.1002/(SICI)1097-0142(19981015)83:8. Gideon Bachar, Kwok Seng Loh, Brian O'Sullivan, David Goldstein, Stephen Wood, Dale Brown, Jonathan Irish. Mucosal melanomas of the head and neck: experience of the Princess Margaret Hospital. Head Neck. 2008;30(10):1325-1331. doi:10.1002/HED.20878. Snehal G Patel, Manju L Prasad, Margarita Escrig, Bhuvanesh Singh, Ashok R Shaha, Dennis H Kraus, Jay O Boyle, Andrew G Huvos, Klaus Busam, Jatin P Shah. Primary mucosal malignant melanoma of the head and neck. Head Neck. 2002;24(3):247-257. doi:10.1002/HED.10019. Nandapalan V, Roland NJ, Helliwell TR, Williams EMI, Hamilton JW, Jones AS. Mucosal melanoma of the head and neck. Clin Otolaryngol Allied Sci. 1998;23(2):107-116. doi:10.1046/J.13652273.1998.00099.X. Carvajal RD, Spencer SA, Lydiatt W. Mucosal melanoma: a clinically and biologically unique disease entity. J Natl Compr Canc Netw. 2012;10(3):345-356. doi:10.6004/JNCCN.2012.0034. Hitoshi Wada, Kenji Nemoto, Yoshihiro Ogawa, Masato Hareyama, Hiroshi Yoshida, Akio Takamura, Keiichi Ohmori, Yasushi Hamamoto, Tadashi Sugita, Mari Saitoh, Shogo Yamada. A multi-institutional retrospective analysis of external radiotherapy for mucosal melanoma of the head and neck in Northern Japan. Int J Radiat Oncol Biol Phys. 2004;59(2):495-500. doi:10.1016/J.IJROBP.2003.11.013. Abraham J Wu, Jennifer Gomez, Joanne E Zhung, Kelvin Chan, Daniel R Gomez, Suzanne L Wolden, Michael J Zelefsky, Jedd D Wolchok, Richard D Carvajal, Paul B Chapman, Richard J Wong, Ashok R Shaha, Dennis H Kraus, Jatin P Shah, Nancy Y Lee. Radiotherapy after surgical resection for head and neck mucosal melanoma. Am J Clin Oncol. 2010;33(3):281-285. doi:10.1097/ COC.0B013E3181A879F5. Susan M Swetter, John A Thompson, Mark R Albertini, Christopher A Barker, Joel Baumgartner, Genevieve Boland, Bartosz Chmielowski, Dominick DiMaio, Alison Durham, Ryan C Fields, Martin D Fleming, Anjela Galan, Brian Gastman, Kenneth Grossmann, Samantha Guild, Ashley Holder, Douglas Johnson, Richard W Joseph, Giorgos Karakousis, Kari Kendra, Julie R Lange, Ryan Lanning, Kim Margolin, Anthony J Olszanski, Patrick A Ott, Merrick I Ross, April K Salama, Rohit Sharma, Joseph Skitzki, Jeffrey Sosman, Evan Wuthrick, Nicole R McMillian, Anita M Engh. NCCN Guidelines® Insights: Melanoma: Cutaneous, Version 2.2021. J Natl Compr Canc Netw. 2021;19(4):364-376. doi:10.6004/JNCCN.2021.0018.

Chapter 13

Tumors of the Oral Cavity and Oropharynx Danielle M. Bottalico, MD Amy C. Hessel, MD and Richard Smith, MD Anatomy The anatomy of the oral cavity and pharynx are reviewed in Chapter 1.

Benign Tumors of the Oral Cavity and Oropharynx Oral Cavity 1. Congenital – products of errors in embryogenesis (malformations) or results of intrauterine events that affect embryonic and fetal growth (deformations and disruptions). Lesions in the oral cavity that appear as “tumors” are usually related to soft tissue anomalies that arise from errors in the embryonic fusion of the anterior tongue, tongue-base anlagen, and the origin of the thyroglossal duct in the area of the foremen cecum. a. Cysts or Pseudocysts – Arise from the primitive foregut and major or minor salivary glands. Most commonly, they are seen in the floor of mouth. b. Mucoceles – Pseudocysts from the minor salivary glands arising as the secretions dissect into the soft tissues. These present as submucosal swellings primarily in the along the occlusal surface of the buccal mucosa. Treatment is usually unroofing, marsupialization or excision. c. Ranulas – Pseudocysts from the sublingual glands and the submandibular ducts. Probably arise from improper drainage or after trauma. Present in floor of the mouth as blue fluctuant submucosal swelling. Large ranulas may present as neck masses, when the extend through the mylohyoid muscle (plunging ranula). These do not have true cyst walls so complete removal is not necessary. However, it is important to remove the sublingual gland with is usually the source. Large ranulas can be treated with intracystic sclerotherapy of OK-432. In: Essential Head and Neck Oncology and Surgery Editors: Maie A. St. John and Benjamin L. Judson

ISBN: 979-8-88697-438-6 © 2023 Nova Science Publishers, Inc.

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2. Neoplasms a. Teratoma and epithelial choristomas − Mass of normal cells in an abnormal location. These tend to be from gastric or enteric origin presenting in the mouth or tongue. Surgical excision is the treatment. b. Epulis and Granular cell tumor − Arise from the mucosal of the gingiva (usually anterior maxillary alveolar ridge). If presenting in the newborn, it is called an epulis and is seen more commonly in girls than boys. They are benign, present as an oral mass and are treated with surgical excision. 3. Vascular a. Hemangiomas – Vascular tumors typically seen as red or bluish. They tend to be raised and firm to palpation. They occur on any oral soft tissue, but are most common on the lips, dorsum of the tongue, gingiva and buccal mucosa. Not well-defined and can rapidly enlarge in infancy but will regress in childhood. They are painless but may bleed if traumatized. b. Lymphangiomas – Tumors of lymphatic vessels. They tend to be soft, superficial and are compressible. May not present at the mucosal surface. Most common sites are tongue, lips and buccal mucosa. If they involve the floor of mouth and neck, they are called cystic hygromas. c. Many of the oral hemangiomas will involute without treatment. Only 10-20% require treatment and can include cautery, cryotherapy, laser therapy, sclerotherapy and surgery. Sclerotherapy and laser therapy can result in tissue irritation and sloughing, scarring and potential recurrence is common and may be fraught with complications. 4. Trauma-related a. Fibroma – Chronic irritation resulting in reactive connective tissue hyperplasia. These are pink, smooth, firm, and usually less than 1cm. They may be pedunculated. Common sites are tongue, lip, palate, buccal mucosa. Treatment is surgical excision, if symptomatic. Recurrence is rare. b. Peripheral ossifying fibroma – Chronic irritation along the gingiva. Presents as red, swollen, gingival mucosa. Generally, presents in the third or fourth decade, but the juvenile form will arise in young males under 15 years old. These are encapsulated and well circumscribed, containing mineralized tissues thus appear to be bone-like on imaging. Treatment is surgical excision. Recurrent is low. c. Pyogenic granuloma (lobular capillary hemangioma) – Rapidly appearing small ( females 2:1 up to 4:1 c. Generally seen in people > 50 years old. But about 6% occur in patient 35 years were high risk factors. b. Smokeless tobacco – has increased risk for oral cavity and pharynx cancer. The use of snuff had an odds ratio of 3.01 for oral cavity cancer and chewing tobacco had an odds ratio of 1.81. c. Second-hand smoke exposure may be a contributing factor particularly for women and for oral cavity cancer d. Marijuana is difficult to assess due to reporting biases e. Alcohol – Alcohol consumption does appear to increase the risks of head and neck cancer independently, but probably has an additive effect with tobacco use. The relative risk of head and neck cancer with alcohol use seems to be dose dependent, with more alcohol consumption having a higher risk. In addition, there may be an association with genetic susceptibility around the alcohol dehydrogenase and aldehyde dehydrogenase enzymes. f. Viral exposures – Human papilloma virus – While the human papilloma virus (particularly HPV 16) is commonly associated with cancers of the oropharynx (base of tongue and tonsil), it is not frequently seen in squamous cell carcinomas of the oral cavity. The incidence HPV or P16 positivity in the biopsies of oral cavity cancer is around 10-15%. Thus, routine HPV testing is not recommended for cancers in the mouth. g. Immunodeficiency – HIV infection does have an increased risk of head and neck cancers, including oral cavity cancers. In addition, solid organ transplant recipients have an increased risk for head and neck cancer. While this is primarily in the cutaneous cancers, there is about a 3% increased risk of oral cavity cancer. h. Betel nut chewing – the practice of chewing betel nut products is widespread in Asia and is an independent risk factor for development of head and neck cancers, primarily oral cavity. This is also synergistic with tobacco and alcohol. i. Radiation – There may be a link to prior radiation and salivary gland malignancies as well as thyroid cancer and sarcoma. However, there is a significant lag time between the radiation exposure and the development of cancer as well as a relatively low risk. j. Genetic factors – P53 disorders. 4. Pathology a. Mucosa – The majority of oral cavity cancers are mucosal-based squamous cell carcinomas. Epithelium can develop a spectrum of abnormal changes (cytologic atypia) that is graded on a spectrum that can eventually lead to malignant transformation. Histologic findings that account for diagnosing dysplasia include:

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Architecture • Irregular epithelial stratification, loss of polarity of basal cells, drop-shaped rete ridges, increased number of mitotic figures, abnormal superficial mitoses, premature keratinization in single cells, keratin pearls in the rete pegs ii. Cytology • Abnormal variation in nuclear size, abnormal variation in nuclear shape, abnormal variation in cell size, abnormal variation in cell shape, increased nuclear to cytoplasm ratio, increased nuclear size, atypical mitotic figures, increased number and size of nucleoli, hyperchromasia. iii. Leukoplakia/Erythroplakia • White (or red) plaque of questionable risk in any mucosal site in the oral cavity. It can be homogenous (thin and flat) or nonhemogenous (irregularly flap or nodular). Histologically may contain dysplastic epithelium. Malignant transformation is around 1%. (14) (See Chapter 8) iv. Dysplasia • Histological spectrum of epithelial precursor lesions. Often a progression of malignant changes ranging from mild dysplasia (top 1/3 of epithelium) to severe dysplasia (>2/3 cytologic atypia). Rate of malignant transformation is 2.4 more likely with severe dysplasia. v. Carcinoma in situ • Once the dysplasia and cellular atypia extends the entire depth of the epidermis. vi. Invasive carcinoma • Malignant cells are seen crossing the basal layer into the dermis. Squamous cell carcinomas are often more involved than the clinical exam reveals so pathology evaluation should be focused on depth of invasion (DOI). b. Minor and Sublingual Salivary Glands i. These oral cavity tumors are very rare; only 10-15% of all salivary gland tumors present in the mouth and have an overall incidence of 0.4/100,000 population. Most are seen in patients younger than 60yo (56%) and the tumors usually present early ( 4cm (T3) and those with deep invasion into surrounding structures such as bone and skin (T4a) or extensive invasion of muscles or skull base (T4b). ii. The tumor staging of oral cavity squamous cell carcinomas also includes the depth of invasion (DOI) which is the new changes for the AJCC 8th edition as DOI has an impact on overall treatment planning, prognosis, and survival. In general, a small squamous cell carcinoma with a DOI > 5mm will get upstaged to T2, and a previously T2 or T3 tumors with DOI > 10mm are considered moderately advanced and will be reclassified as T3 or T4, respectively. (17) (27) iii. For salivary gland and other non-squamous tumors, the depth of invasion does not apply so the AJCC staging by size remains as described. [AJCC table] c. Nodal (N) stage. i. The regional disease is staged clinically by the number, size and location of the lymph nodes. ii. If the patient has a single ipsilateral lymph node that is 3m but < 6cm is an N2a, multiple ipsilateral lymph nodes under 6cm are considered N2b, and contralateral lymph nodes under 6cm is N2c. And N3 disease includes any lymph nodes > 6cm, and any clinically evident lymph node (N3a) with extra-nodal extension (N3b). d. Clarifying unknown disease (T0 or N0) or unable to assess (Tx or Nx) i. T0 - When a tumor is not identified (unknown primary) but has a diagnosis of cancer via other source such as FNA of lymph adenopathy. ii. Tx - If a primary tumor has been previously biopsied or removed such that the examining provider can no longer assess the site iii. Sometimes it is possible to determine the prior size of the altered tumor by measurements from imaging report or from pathology report such that the stage can be reported with all the information available such as Tx (T1). iv. N0 - If the patient has no evidence of clinically (+) lymph nodes on exam or imaging v. Nx – Prior excisional biopsy or dissection that makes it unable to assess the lymph node status vi. If imaging or pathology reports give a clinical picture prior to the procedure, then the stage can be reported with clarification such as Nx (N2c).

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Clinical stage vs Pathologic stage i. Clinical staging should take place at the completion of the initial evaluation and before treatment has begun. This stage will utilize the clinical information (exam, imaging, biopsy) and will be designated with a small “c” in front of the stage (example: cT1, N2a, M0). ii. Pathologic staging occurs if the surgical pathology report provides new information that will change the previous stage and will be designated with a small “p” in front of the stage (example: pT2, N2b, M0). 9. Treatment a. Primary Tumor i. For the most part, oral cavity malignancy will be considered for surgery and/or radiation therapy. The decision to do one over the other is dependent on location, stage and overall co-morbidities and medical health. ii. Surgery is preferred as the primary treatment modality for long-term morbidity reasons as well as the pathology staging which may lead to adding combined therapy. The goal for oral cavity cancer surgery should be negative margins. Traditionally this would be >5mm, but there is some evidence that pathologically >2.2mm is enough. In addition, the goal is to maintain function such as speech and swallowing. Reconstruction should be considered when the resection impacts function, cosmetics or will cause wound healing problems. iii. Definitive radiation is an option for early staged oral cavity cancers, primarily squamous cell carcinomas of the tongue and floor of mouth. This can be with traditional conformal techniques or brachytherapy. However, there appears to be a decrease in overall survival with primary radiation, but may be a selection bias for those patients unable to have surgery. • These options do not treat the regional lymphatics, so patient selection should be based on low risk for occult metastasis. • The early and late side effects include mucositis, skin reaction, loss of taste, dysphagia xerostomia and fibrosis, osteoradionecrosis, trismus and lymphedema, respectively. b. Primary Treatment considerations for oral cavity subsites i. Lip (squamous cell carcinoma) breaks down into inner mucosa which is oral cavity cancer and outer vermillion which is classified as skin. About 25% of all oral cavity cancers occur on the lip. Surgery is considered the treatment of choice, though radiation can be used for small lesions with equal cure rates (85-95%). Lower lip is most likely squamous cell carcinoma and has a relatively low risk for metastasis (2%) and is based on tumor size and depth of invasion. Upper lip and oral commissure have worse prognosis as they tend to grow faster, invade and metastasize earlier. The goal of surgery on the lip is to obtain a negative margin (>5mm) and to preserve function, primarily oral competence, and facial expression. MOHS micrographic surgery

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has been used for lip cancer, however the narrow margin standard for this type of surgery may be ineffective for lips cancers T2 or higher. Reconstruction options should consider dynamic reconstruction whenever possible and include a variety of local flaps such as the Fan flap, Abbe-Eastlander and Karapandzic flaps. [See Chapter 19] ii. Lower alveolar ridge and retromolar trigone subsite involves the mucosa directly over the top of the mandible extending along the body to the ramus. Because this site blends into the buccal mucosa, maxillary tuberosity, floor of mouth and even the soft palate, it is often fraught with larger defects than expected and higher recurrence rates due to the microscopic extension into the bone. Surgery is the preferred treatment modality compared to primary radiation (locoregional control 89% vs 51%). Exposure for these tumors can be difficult especially when attempting mucosal margins of > 10mm. Attempts should be made to determine bone invasion prior to surgery with imaging and clinical assessment, taking into consideration the dental status of the patients. Patients with recent extraction are more likely to have bone erosion than dentate patients. Small tumors with superficial invasion can be resected with skin grafting. Larger defects (T2 and up), replacement with pedicled flaps or soft tissue transfer should be considered to prevent trismus. With known bone erosion, then surgical management should include a segmental removal of the mandible which subsequently would require reconstruction. In most cases where the bone is removed, plans should be made for microvascular reconstruction of the bone using fibula, scapula, iliac crest etc. Cadaver bone or plate reconstruction with rotational flaps should be avoided as neither option will likely be cosmetically or functionally acceptable, especially in the face of post-operative radiation therapy. iii. Upper alveolar ridge and maxilla involves the hard palate and the upper dentition. Using the same surgical principles with margins, the superficial tumors involving the upper gum and teeth will require dental extraction and even removal of the alveolar bone. Because the soft tissue enveloping the maxillary bone is not thick, it is likely that tumors in this location will be adherent to and erode into the bone. Therefore, surgical management of these tumors must include the possibility of entering into the nasal cavity or the maxillary sinus. This oroantral fistula must be managed with a surgical obturator and or reconstruction flap, so the appropriate pre-op consults and planning should be considered. iv. Buccal mucosa is a site where deep extension may be more than expected. Again, removal of the tumor with 10mm margins is the goal of surgery. The tumors, however, can be much deeper than expected and can enter the buccal space. In addition, the loss of the surface area on the cheek needs to be considered to maintain adequate mouth opening. For small superficial lesions, skin grafting or

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artificial substances such as Alloderm or Integra may work well. But there should be a plan for microvascular soft tissue flap reconstruction is recommended for any lesion greater than a few centimeters in the hopes to avoid severe trismus. v. Oral tongue is a site where en bloc resection can be difficult due to the 3-dimensional structure and functionality of the organ. It is necessary to think about resulting defect on speech and swallowing. Again, 10mm margins are recommended, not only radially on the mucosa but also depth-wise into the tongue musculature. Clearance on the deep margin can be tricky as the muscle can retract into the organ after resection. Pathologically close margins need to be interpreted with a high degree of caution. In addition, the final defect and its impact on function needs to be anticipated. If surgery leads to the loss of more than a third of the functional tongue, extending to the floor or mouth or base of tongue, reconstruction should be considered. Microvascular soft tissue free flaps may offer the best restoration of the tongue bulk and function. The goal of reconstruction should be to create a healthy wound that does not fistulize into the neck, recreate the size and shape of the tongue, and to allow for regaining the overall function of speech and swallowing. vi. Floor of mouth is a difficult location for cancers to be assessed as the surrounding structures can impair the ability to see the whole tumor. The depth of invasion may be underestimated due to the bone as well as the inability to palpate completely. Tumors can often extend to the lingual surface of the mandible or into the geniohyoid musculature and deep muscles of the tongue. Superficial lesions can be resected locally with primary closure or skin grafting. However, the deeper lesions may encroach on the lingual nerve, the sublingual glands, submandibular ducts and even the mylohyoid muscle of the neck. Tethering of the tongue to the floor of mouth is common with the loss of mucosa in this area. Pedicles or microvascular free flaps may be necessary to help with avoiding the tethering as well as preventing fistulation into the neck. Neck and Regional Lymphatics i. The regional lymphatics are a major consideration in oral cavity. The development of regional lymph nodes is the most reliable predictor of treatment outcomes; with the presence of metastatic lymph nodes decreasing both disease-free survival and overall survival. It is critically important to identify lymph node disease in the work-up and staging to plan appropriately for the successful treatment. In oral cavity, up to 35% of the N0 necks will have occult disease pathologically. ii. In early-stage disease (T1 and T2), there are options regarding how to address the regional lymphatic based on the location, size, and depth of invasion. However, once the oral cavity primary (T3 and T4) is advanced or if regional metastasis has been determined on staging,

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then surgical management must include the regional lymphatics. Combined modality therapy is often necessary for the treatment of these advanced cancers. There is a debate among the experts for managing the clinically node negative neck (N0) which has been outlined in the clinical guidelines by the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN). iii. Observation. Observation of the N0 neck should be offered only when the risk of microscopic metastasis is considered less than 3-4mm and are in locations that carry a high risk for occult metastasis. The levels that are included in the neck dissection are based on the location of the primary tumor, but for the most part include level I through level III or IV. The decision to include level IV should be based on the location of the primary and positive regional lymphatics. The rate of skip metastasis is low in the clinically N0 neck (T2 sized tumor. Larger tumors should have elective neck dissection with special attention to the level Ib lymph nodes including the facial lymph nodes. Levels dissected should include Level Ib through III. v. Oral tongue and floor of mouth – These two locations are where the depth of invasion is more valuable in the assessment of metastasis risks. It is felt that a tumor with DOI of > 3mm has an increased risk of occult metastasis going from less than 10% to greater than 20%. It is important to pathologically evaluate the regional lymphatics in the higher risk tumors. In advanced tumors (T3 and T4), elective neck dissection should be performed (level I through III or IV) and bilaterally, if the primary is midline. In T1 and T2 primary tumors, sentinel node biopsy and elective neck dissection (level I through III) have been equally effective in identifying and staging the neck for oral cavity cancers. SNLB can identify occult regional lymphatics in tumors that are intermediate in risk (DOI 1-3mm), midline tumors for which END would be bilateral, and low risk primary sites that don’t require reconstruction. Neck Treatment considerations for non-squamous cell pathology i. Salivary gland malignancy • Lymph node metastasis is one of the most important prognostic factors in these tumors. Generally, the regional lymphatic involvement is at low risk (14-20%). But lymph nodes should be addressed with high grade pathology, advanced T-stage and in the presence of extracapsular extension, bone invasion, or named-nerve invasion. • If neck dissection is needed, levels dissected should be based on primary site of involvement. ii. Sarcoma • Oral cavity sarcoma is an exceedingly rare tumor type with a wide range of histopathologies. In general, the risk of occult

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regional metastasis is low, but should be assessed by a caseby-case basis. • Decision to treat the neck should be based on the staging of the regional lymphatics with exam and imaging. Multidisciplinary discussion with a sarcoma oncology team to determine the risks of metastasis may be warranted. 10. Adjuvant therapy (see Chapter 20 and 22) a. Neoadjuvant − The standard of care for oral cavity tumors remains surgery. However, in advanced disease, chemotherapy (or immunotherapy) has been used to reduce the tumor burden and perhaps the complexity of the surgery. Investigations have shown that most of the patients had clinical response to chemotherapy (80%), but there has not been a significant disease-free or overall survival benefit. However, if a tumor has a strong response to chemotherapy ( 4mm. In the regional lymphatics, more than one positive lymph node or a positive lymph node that is more than 2cm in size. c. The addition of concurrent chemotherapy with radiation therapy, this is also driven by the pathologic features and used to augment the adjuvant radiation. It has been shown to improve locoregional control in high-risk tumors. The effect on disease-free survival and overall survival is felt to be improved, but the studies are difficult to interpret due to including all head and neck disease sites. The indications for adjuvant chemotherapy including positive final margins, extensive nodal disease (N3) and extra-nodal extension (ENE) in the positive lymph nodes. 11. Surveillance (see Chapter 23) a. The rationale for cancer surveillance is to have early detection of recurrent or metastatic disease. In addition, the risk factors for head and neck cancer remain throughout life, so surveillance can be used for identifying second primary tumors in nearby locations. However, it is not entirely clear if early detection of recurrent cancer versus waiting for symptomatic recurrence affects the overall prognosis. Survival after recurrent oral cavity cancer is

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related to the location of the original tumor, the original stage, the extent of prior treatment as well as the timing of the recurrence and not to the frequency of surveillance. While asymptomatic surveillance may not improve overall survival, frequent follow-ups can allow early identification of treatment related side effects and allow for early interventions. b. For oral cavity cancer, the most likely timing for recurrent disease is in the first 2 years. So, the most intensive surveillance schedule should be in the initial 24 months. But there is no consensus to the timing or technique of appropriate surveillance. c. A general example of surveillance for oral cavity cancer i. 4-8 weeks after completion of treatment: Clinical exam to assess for healing as well as functional recovery. ii. For the first year, routine follow up every 3 months: comprehensive exam and baseline post-treatment imaging (CT scan or MRI scan). • If there are any discrepancies on imaging or exam, PET scan can be used, but this should not be used as screening imaging. • Ultrasound is another way to follow the regional lymphatics and avoids IV contrast and radiation exposure. • Each subsequent visit should have a clinical exam and discussion of post-treatment side effects and overall function. These visits may include imaging, however there is a role of using imaging on a symptomatic basis only. d. Second year of follow up is every 3-4 months e. Third to Fifth year is every 6 - 12 months f. For the tobacco users, annual screening CT chest should be considered as laid out by the American Thoracic Society. g. Any patient receiving radiation to the neck should have thyroid function screening (TSH, T4) once or twice a year.

Oropharynx (Non-HPV related) 1. Introduction a. The oropharynx includes four subsites as previously described b. Squamous cell carcinoma (SCC) accounts for approximately 90% of all carcinomas of the oropharynx i. It is important to note that HPV mediated oropharyngeal cancer is a distinct disease entity (see Chapter 14). Here we will focus on HPV negative oropharyngeal cancer. c. The oropharynx is part of Waldeyer’s ring and is abundant in lymphoid tissue. Therefore, lymphoma is the second most common malignancy. d. The oropharynx is rich in lymphatics i. Depending on the subsite involved, 15-75% of patients with oropharyngeal SCC will present with lymph node involvement.

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Soft palate − Bilateral drainage primarily to level I and II − Can also drain to retropharyngeal lymph nodes • Palatine tonsils − Ipsilateral drainage to level II and III − Can also drain to retropharyngeal lymph nodes • Base of tongue − Bilateral drainage to level II and III • Posterior pharyngeal wall − Bilateral drainage to level II-IV − Can also drain to retropharyngeal nodes e. Additionally, minor salivary glands are present within the oropharynx and can undergo malignant transformation (see Chapter 5) i. Adenoid cystic carcinoma ii. Mucoepidermoid carcinoma iii. Acinic cell carcinoma iv. Myoepithelial carcinoma v. Secretory carcinoma vi. Clear cell carcinoma vii. Adenocarcinoma viii. Carcinoma ex-pleomorphic adenoma ix. Epithelial-myoepithelial carcinoma 2. Etiology a. SCC arises from the accumulation of multiple genetic mutations in genes responsible for cell cycle regulation and cell death b. These genetic changes can be inherited, but more often are acquired from environmental exposures such as tobacco and alcohol i. Genetic causes include Li-Fraumeni syndrome and Fanconi anemia c. The concept of “field cancerization” applies to all mucosal head and neck cancers and provides explanation for the high rate of second primaries in patients with oropharyngeal cancer i. Prolonged exposure of the upper aerodigestive tract to carcinogens leads to molecular alterations, giving rise to pre-malignant lesions. With time, certain areas can undergo further transformation giving rise to malignant lesions. d. Genetic alterations occur via inactivation of tumor suppressor genes or activation of proto-oncogenes to oncogenes i. Tumor suppressor genes: p53, retinoblastoma, p16 ii. Proto-oncogenes: RET, EGFR, RAS e. Heavy tobacco users have a 5 to 25-fold increased risk of developing head and neck cancer compared to nonsmokers i. The effect of tobacco is dose related f. Alcohol consumption is also associated with a dose-dependent increased risk of developing head and neck cancer ranging from 2.7 to 8.8-fold increase g. Concurrent exposure to tobacco and alcohol is synergistic

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3. Workup a. History i. It is important to obtain a complete history including review of systems and past medical, social and family history ii. Specifically, inquire about alcohol consumption and quantification of tobacco use (pack years) iii. Common presenting symptoms can include: • Pain • Dysphagia • Unilateral otalgia • Odynophagia • Painless neck mass • Dysphonia • Hemoptysis • Respiratory distress b. Physical Exam i. A thorough head and neck examination should be performed on all patients ii. Assess for trismus iii. Assess dentition • This is important because restoration or extraction are often necessary prior to the initiation of treatment iv. Systematic visualization of all mucosal surfaces in the oropharynx is important • Mirror exam • Fiberoptic laryngoscopy v. Palpation of primary tumor • This is important to assess for tumor fixation and to approximate extent of submucosal spread vi. Cranial nerve exam • Cranial nerve deficits indicate extension into the mandible, parapharyngeal or masticator spaces vii. Nodal enlargement c. Biopsy of primary lesion or fine-needle aspiration (FNA) of neck node i. Image-guided (US or CT) needle biopsy or core biopsy of neck nodes may offer better diagnostic yield than FNA by palpation alone ii. Tumor human papillomavirus (HPV) testing by p16 immunochemistry is required • P16 expression is highly correlated with HPV status and prognosis − However, p16 is not completely specific for HPV o Can be positive in 10-20% of hpv-negative oropharyngeal SCC • Can also perform DNA in situ hybridization or PCR

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d. Imaging studies i. CT with contrast and/or MRI with contrast • CT should be obtained with contrast and will evaluate the extent of primary tumor size and involvement of adjacent structures (carotid artery, base of skull, floor of neck, bone) − It aids in staging and determining nodal status − Radiographic criteria for nodal malignancy are lesions greater than 1cm and presence of central necrosis o CT up-stages nodal disease 10-20% • MRI is best for evaluating soft tissue involvement such as the tongue base. It is preferred over CT if cranial nerve deficits are noted or if tumors encroach upon the skull base • Imaging should extend from the skull base to the thoracic inlet ii. CT chest with contrast or CXR • CXR can be used as screening for pulmonary metastasis or primary pulmonary cancer − If suspicious findings on CXR, CT chest with contrast is recommended • However, for patients who are 50 years of age or older with a significant smoking history (20 pack-years or more), low dose chest CT is the preferred primary screening modality iii. PET CT • If imaging fails to reveal an obvious primary, PET/CT should be ordered before any surgical intervention • Indicated for Stage III and stage IV disease iv. Panoramic dental x-ray • Recommended when post-operative radiation is anticipated e. Staging endoscopy i. Exam under anesthesia (EUA) to look for second primaries • The percentage of patients with synchronous second primaries is approximately 8% and most commonly occurs in the upper aerodigestive tract and esophagus ii. Assess submucosal spread, mandibular invasion and tumor fixation f. Additional evaluation/consultation i. Laboratory evaluation • Complete blood count, blood chemistry, liver function tests, electrocardiogram • Can also include thyroid function tests ii. Dental evaluation iii. Nutrition, speech and swallowing evaluation • Important for all patient with particular emphasis for patients with speech or swallow dysfunction as well as those whose treatment is expected to impair or alter speech or swallow iv. Audiogram v. Smoking cessation

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4. Staging a. Tumor staging (Table 1) b. Clinical staging system of regional lymph nodes (cN) (Table 2) i. Clinically overt extra nodal extension (ENE) is defined as invasion of skin or dense tethering to adjacent structures or evidence of dysfunction of adjacent cranial nerves, brachial plexus, sympathetic chain and/or phrenic nerves c. Pathologic staging system of regional lymph nodes (pN) (Table 3) d. Overall stage (Table 4) Table 1. Tumor staging for oropharynx Tx TO Tis Tl T2 T3 T4a T4b

Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ Tumor 2cm or less in greatest dimension Tumor between 2 and 4 cm in greatest dimension Tumor greater than 4cm in greatest dimension or extension to lingual surface of epiglottis Moderately advanced local disease. Tumor invades the larynx, deep/extrinsic muscle of the tongue, medial pterygoid, hard palate or mandible Very advanced local disease. Tumor invades the lateral pterygoid muscle, pterygoid plates, lateral nasopharynx, or skull base or encases the carotid artery

Table 2. Clinical staging for regional lymph nodes (cN) NX NO N1 N2a

Regional lymph nodes cannot be assessed No regional nodes metastasis Metastasis in a single ipsilateral lymph node, 3cm or less in greatest dimension, ENE(-) Metastasis in a single ipsilateral lymph node, greater man 3cm but not more than 6cm in greatest dimension, ENE (-) N2b Metastasis in multiple ipsilateral lymph nodes, none more man 6cm in greatest dimension, ENE (-) N2c Metastasis in bilateral or contralateral lymph node(s), none more than 6cm in greatest dimension, ENE(-) N3a Metastasis in a lymph node more man 6cm in greatest dimension, ENE (-) N3b Metastasis in a lymph node with clinically overt ENE(+) ENE = extranodal extension

Table 3. Pathologic staging for regional lymph nodes (pN) NO Nl N2a N2b N2c N3a N3b

No regional nodes metastasis Metastasis in a single ipsilateral lymph node, 3cm or less in greatest dimension, ENE(-) Metastasis in a single ipsilateral lymph node, greater than 3cm but not more than 6cm in greatest dimension and ENE (-) or single ipsilateral node 3cm or smaller in greatest dimension and ENE (+) Metastasis in multiple ipsilateral lymph nodes, none more than 6cm in greatest dimension, ENE (-) Metastasis in bilateral or contralateral lymph node(s), none more than 6cm in greatest dimension, ENE(-) Metastais in a lymph node larger than 6cm in greatest dimension and ENE (-) Metastasis in a single ipsilateral node larger than 3cm in greatest dimension and ENE(+), or multiple ipsilateral, contralateral or bilateral nodes any with ENE(+) or a single contralateral node of any size and ENE(+)

5. Treatment a. Early stage disease (T1-2, N0-N1) i. 2 treatment options

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Resection of primary tumor with neck dissection − Resected tumors are assessed for adverse features including extranodal extension (ENE), positive margins, close margins, perineural invasion, nodal disease in level IV or V, vascular invasion and lymphatic invasion o No adverse features → no further treatment o Adverse features: ▪ Positive margin → re-resection if feasible ▪ If there is ENE, concurrent systemic therapy/RT is recommended ▪ Post-operative systemic therapy/RT ➢ Cisplatin is recommended systemic therapy o For positive margins that cannot be re-resected as well as adverse features other than ENE, RT with or without concurrent systemic therapy can be considered Definitive radiation therapy (RT)* (See Chapter 22) − *For T1-2, N1 disease, concurrent systemic therapy/RT is recommended − Intensity-Modulated Radiation Therapy (IMRT) or three dimensional conformal radiation therapy (3DCRT) is recommended for oropharynx to minimize the dose to critical structures o IMRT is preferred. ▪ This is a computer 3D-modeled therapy based on the size and location of the primary tumor where higher doses of therapy are delivered to the tumor bed ▪ Uninvolved structures are spared by using a combination of several intensity modulated fields from different beam directions o 3D- CRT ▪ This uses imaging technology to creased a three-dimensional image of the patient’s tumor and nearby structures and tissues ▪ Multiple treatment fields are arranged to maximize radiation dose to the target area while achieving maximal sparing of normal tissue − Proton therapy is an area of active investigation and may be considered when normal tissue constraints cannot be met by photon therapy − Fractionation scheme

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o

66 (2.2Gy/fraction) to 70Gy (2Gy/fraction) 5 days/week for 6-7 weeks • For tumors approaching the midline (base of tongue, soft palate, posterior pharyngeal wall, tonsil invading the tongue base), there is a risk of contralateral metastasis and bilateral treatment is warranted. b. Locally advanced resectable disease (T3-T4a, N0-N3) i. 3 treatment options • Concurrent systemic therapy/RT (See Chapter 20 and 22) − Preferred systemic therapy o High-dose cisplatin (Preferred) ▪ Single dose cisplatin given every 3 weeks at 100mg/m2 + standard fractionation o Carboplatin/Infusional 5-FU ▪ 3 cycles of carboplatin + 5FU + standard fractionation • Resection of primary with neck dissection − No adverse features→ RT − Adverse features o ENE and/or positive margins→ concurrent systemic therapy/RT o Other adverse features→ RT or concurrent systemic therapy/RT • Induction chemotherapy followed by RT or systemic/RT Table 4. Staging for HPV-negative oropharyngeal cancer

Tl T2 T3 T4a T4b Ml

NO I II III

N2

N3

III

IVA

IVB

IVA IVB IVC

−

c.

Nl

Preferred agent and regimen o Docetaxel/cisplatin/5-FU • 3 cycles followed by definitive RT Surgical options i. Trans Oral Surgery (TOS) • Transoral case selection − Anatomic considerations o Adequate mouth opening o Low mallampati score o Adequate width of mandibular arch

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o Presence of dentition − Tumor characteristics o Exophytic, mobile tumors are more ideally suited for transoral removal ▪ Tumors that grow in the deep intrinsic muscles of the tongue, the extrinsic muscles of the tongue or the latera pharyngeal wall constrictor muscles become less mobile and more difficult to expose and excise transorally o Tumors that require removal of more than 50% of the base of tongue or more than 75% of the soft palate are contraindicated for transoral surgery Direct Transoral Resection (DTR) − The tumor must be accessible without the benefit of laryngoscopy, microscopy or endoscopy − Lesions amendable to DTR include small tonsil tumors, tumors of the soft palate and tumors of the posterior pharyngeal wall Transoral Laser Microsurgery (TLM) − For tumors that are difficult to access using other techniques, TLM using specialized laryngoscopes and the CO2 laser can be helpful o The laser is more precise than standard cautery technique o Additionally, the laser and microscope can be used to resect tumor that are otherwise difficult to access transorally ▪ This includes tumors of the lateral and posterior pharyngeal walls, posterior tongue base and vallecula Transoral Robotic Surgery (TORS) − TORS offers several advantages including improved optics, three-dimensional tumor visualization, 540 degrees of wristed instrumentation, tremor reduction, and the ability to access distal oropharyngeal tumors or base of tongue tumors − To determine if a patient’s anatomy is amenable to TORS, access should be evaluated including evaluation of teeth, mandible, trismus, tori, tongue, size and extent of tumor as well as flexibility of neck − Tumors not amenable to TLM may still be possible with TORS and visa versa.

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ii. Open approaches • Mandibular swing or composite resection • Median manidbuloglossotomy − This involves division of the mandible at the symphysis and the tongue along the medial raphe o Allows access to small tumors isolated to the mid-portion of the tongue base. Lateral exposure is limited. • Suprahyoid pharyngotomy − A neck incision is used to enter the pharynx superior to the hyoid to allow for tongue base access. This is useful for smaller tongue base tumors without extension to other sites. • Lateral pharyngotomy − Pharynx is entered posterior to the thyroid ala on the least affected side − There is limited superior exposure and risk of injury to the hypoglossal and superior laryngeal nerves iii. Reconstruction • Small defects of pharynx and tongue base (less than 3 cm of pharyngeal wall involvement in greatest dimension and less than 1/3 the volume of the tongue base) − Healing by secondary intention o Associated with slightly increased pain o Often utilized after TOS resection − Primary closure o Ideal method of reconstruction if a tension-free closure can be obtained − Skin graft o Allows resurfacing with good functional outcome o Does not provide tissue bulk − Transfer of buccal fat pad for pharyngeal defects to protect the internal carotid • Small defects of the soft palate − Partial thickness defect − Full thickness defect − Velopharyngeal insufficiency o The soft palate is the most important component of the velopharyngeal mechanism which includes the lateral and posterior pharyngeal walls o Adequate velopharyngeal function can be obtained if reconstruction allows for the closure

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of the nasopharynx with swallowing and an opening of no more than 20mm2 during speech o More common with full thickness resection • Larger defects of oropharynx − Regional pedicled flaps o Pectoralis major o Trapezius o Sternocleidomastoid o Latissumus dorsi o Platysma o Deltopectoral o Superior-constrictor advancement-rotation (SCARF) − Free tissue transfer o Soft tissue defects ▪ Radial forearm ▪ Anterolateral thigh o Bony defects ▪ Osseocutaneous flaps ➢ Fibula ➢ Iliac crest ➢ Scapula ➢ Lateral arm 6. Follow-up and Surveillance (see Chapter 23) a. Oropharyngeal cancer patients require close observation initially to detect recurrence and lifelong follow-up to identify second primaries. Follow-up intervals are not standardized. However, (Table 5) is a suggested surveillance interval for patients who have completed treatment i. Recurrences usually presented in the first 2 years after treatment ii. Metachronous second primaries remains constant at about 4-5% per year iii. Distant metastasis develops in approximately 15% of patient with head and neck cancer Table 5. Recommended follow-up status post treatment Years Post-treatment 1 2 3 4 and 5 after 5

Follow-up 1-3 mo 2-4mo 3-6mo 4-6mo every 12 mo

b. Annual TSH and Chest x-ray i. As noted above, low-dose CT scan instead of CXR should be considered for heavy smokers

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Key Clinical Points 1. SCC accounts for the majority of oral cavity and oropharyngeal malignancies. Tobacco and alcohol remain significant risk factors for both oral cavity and HPV-negative oropharyngeal SCC. It is important to remember HPV-positive and HPV-negative oropharyngeal SCC are separate diseases entities with HPV-negative SCC portending a decreased survival. The five-year overall survival for oropharyngeal HPV-positive and HPV-negative disease is 74% and 44%, respectively. 2. Early-stage oral cavity and oropharyngeal SCC can often be treated with single modality therapy. Locally advanced resectable disease requires multi-modality therapy. High-risk features in oral SCC include close or positive margins, bone invasion and perineural invasion. Similarly, high-risk features for oropharyngeal SCC include close or positive margins and perineural invasion. Patients with high-risk features require adjuvant therapy. 3. There is a high rate of clinically positive nodes as well as occult nodal metastasis at initial presentation of both oral cavity and oropharyngeal cancer. Therefore, most patients require treatment of the neck. 4. Appropriate reconstruction of the oral cavity and oropharynx requires consideration of multiple factors including location of tumor, size of defect as well as patient-related factors. The least complex, invasive reconstructive option to restore function and form is preferred. 5. Both oral cavity and oropharyngeal cancer patients require close follow-up and surveillance to detect recurrences as well as lifelong follow-up to detect second primaries.

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Questions 1. What is the most common location of pyogenic granuloma in the oral cavity? a. Gingiva b. Buccal mucosa c. Floor of mouth d. Hard palate 2. Which of the following is considered a risk factor for the development of oral cavity cancer? a. HPV infection b. Chewing betel nut c. EBV infection d. Previous dental surgery 3. A 54 year old man presents with a white lesion on his left lateral tongue that has been present for approximately 8 months. He denies pain or discomfort and has no tobacco or alcohol history. On examination, a patchy white infiltrate is noted on the left lateral tongue and it cannot be scraped. He has no lymphadenopathy on exam. You biopsy the lesion and pathology reveals severe hyperkeratosis and acanthosis. What is the diagnosis? a. Erythoplakia b. Leukoplakia c. Lichen planus d. Oral candidiasis 4. Which of the following is the appropriate surgical treatment for a T2N0M0 hpvnegative cancer of the right tonsil? a. Transoral excision of the primary alone b. Transoral excision of the primary with right neck dissection levels I-IV c. Transoral excision of the primary with right neck dissection levels II-IV d. Transoral excision of the primary with bilateral neck dissection levels II-IV 5. A 54 year old male is found to have cT1N1 HPV-negative SCC of the right base of tongue. He undergoes surgical resection of the primary tumor as well as bilateral neck dissections. The tumor has negative margins, however, 1 of the lymph nodes is noted to have ENE. What is the appropriate adjuvant therapy? a. No additional treatment b. Radiation alone c. Contralateral neck dissection d. Concurrent systemic therapy with radiation

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6. A 74 year old male presents with a floor of mouth mass. A biopsy confirms the diagnosis of squamous cell carcinoma. CT shows gross involvement of the anterior mandible. There is no evidence of nodal disease or distant metastasis on PET CT. What surgical procedure is recommended for the primary site? a. Segmental mandibulectomy and floor of mouth resection b. Chemotherapy and radiation c. Mandibulotomy with floor of mouth resection d. Marginal mandibulectomy

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Chapter 14

HPV+ Oropharyngeal Cancers: Today and Tomorrow Donovan Eu, MD, FAMS Ameya A. Asarkar, MD, FACS and Jonathan Irish, MD, FRCS Abstract The incidence of Human Papillomavirus-associated oropharyngeal cancers has increased significantly in the past 2 decades and is amongst the most common cancers in the head and neck. These cancers have a better overall survival and therefore there are ongoing efforts to investigate treatment de-escalation that aims to minimize the acute and long-term side effects of treatment while maintaining high cure rates. This chapter outlines the workup and management of patients with HPV related oropharyngeal cancers and discusses the potential of future de-escalation of treatment for these patients.

Keywords: oropharyngeal cancer, p16 cancers, human papilloma virus (HPV), transoral robotic surgery (TORS)

Introduction 1. Human papillomavirus (HPV) is a family of papillomaviruses that account for more than 100 different subtypes. 2. Fourteen subtypes are associated with oncogenesis and over the past decade, there has been an increased understanding of HPV related cancers of the head and neck and more specifically of the oropharynx.

Oropharynx Anatomy The oropharynx (Figure 1 and 2) lies between the nasopharynx superiorly and the hypopharynx inferiorly.

In: Essential Head and Neck Oncology and Surgery Editors: Maie A. St. John and Benjamin L. Judson

ISBN: 979-8-88697-438-6 © 2023 Nova Science Publishers, Inc.

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Boundaries 1. Between level of the junction of hard-soft palate to the level of the hyoid bone/vallecula. 2. Separated from the hypopharynx laterally by the pharyngoepiglottic fold 3. Anteriorly it is bounded by the circumvallate papillae and is contiguous to the oral tongue 4. Posteriorly it is bounded by the posterior pharyngeal wall Subsites 1. Soft palate and uvula 2. Palatine tonsil/tonsillar fossa 3. Lateral and posterior pharyngeal walls 4. Base of tongue

Figure 1. Transoral view of oropharynx.

Figure 2. Sagittal view depicting boundaries of the oropharynx.

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Epidemiology 1. There has been an exponential increase in the incidence of oropharyngeal squamous cell carcinoma (OPSCC), especially Human papilloma virus (HPV) associated, in the past several decades. 2. 14 sub-types of HPV have been identified in the oral and anogenital tract. However, the most studied high-risk subtypes are 16 and 18. Studies have shown that sub-type 16 is identified in approximately 90% of HPV associated OPSCC. 3. HPV related OPSCC is: (i) more common in a younger age group (40-60 years) (ii) associated with sexual practices including oro-genital and oro-anal sex, (iii) more common in individuals with high number of sexual partners. These features are in contrast to the known etiological risk factors associated with HPV negative OPSCC, including smoking, alcohol consumption, chewing tobacco and betel nut 4. Several studies have shown that patients with HPV positive OPSCC have improved survival when compared to patients with HPV negative OPSCC. In comparable tumors, Ang et al. reported 3-year survival at 82.4% in HPV positive patients versus 57.1% in HPV negative patients. 5. HPV positivity has been reported to have a risk reduction (for death) of 58% (HR 0.42; 95% CI 0.27-0.66) 6. Smoking in HPV positive OPSCC is associated with poorer overall survival (OS) and disease specific survival (DFS). A recent systematic review reported that patients who are heavier smokers have a 0.55-5.2 times increased hazard of locoregional recurrence compared to never smokers.

General Presentation History 1. The most common initial presentation of HPV+ patients is painless cervical lymphadenopathy. 2. Other frequent symptoms include: Visible mass within the oropharynx Dysphagia Odynophagia Nonspecific pain Nonspecific weight loss

Soreness of throat Globus sensation Otalgia Changes in voice Fatigue

3. Unlike HPV negative head and neck cancer patients, HPV positive patients do not have significant risk factors such as smoking/heavy alcohol consumption.

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Physical Assessment 1. Most patients present with painless cervical lymphadenopathy commonly in the level II distribution, but lymphadenopathy may involve multiple nodal levels and both sides of the neck. 2. A visible mass is commonly identified in the lingual and/or palatine tonsils. 3. Palpation and visualization of the oropharynx is important in identifying submucosal occult primaries. 4. Carcinoma of Unknown Primary (CUP) may be seen in a small subset of patients presenting with nodal disease without any localizing primary within the oropharynx.

Diagnosis Tissue Biopsy 1. Biopsy of the primary site is often required to confirm diagnosis. 2. Biopsy of the lymph node by fine needle aspiration cytology (FNAC) or a core biopsy may also be performed in cases where the primary tumor is not accessible/visible. 3. Adequate tissue should be obtained to allow for p16 immunohistochemistry staining. 4. p16, a tumor suppressor gene which is a cyclin-dependent kinase 2A (CDK 2A), is a robust surrogate marker for HPV positive OPSCC. The cut-off defined for p16 positivity is the presence of over expression of p16 (Figure 3) both intranuclear and cytoplasmic with at least moderate (+2/3) staining intensity.

Figure 3. Intracytoplasmic and intranuclear p16 staining in HPV+ base of tongue SCC.

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Imaging 1. Cross-sectional imaging is necessary to further delineate the primary lesion and regional disease for treatment planning and staging. a. Computed tomography with contrast (CT) b. Magnetic resonance imaging (MRI) of the head and neck. Pros of CT vs MRI More readily available compared to MRI Shorter imaging acquisition time

Cons of CT vs MRI Poorer soft tissue definition compared to MRI particularly for primary tongue base cancers CT associated with more streak artifact compared to MRI for patients with dental hardware

Less likely to have motion artifacts Better bony cortex delineation for locally advanced tumors compared to MRI Adequate for staging in most cases

2. Functional imaging further aids to evaluate for regional and distal spread of disease. a. Functional imaging commonly utilizes fluorodexoygluocse (18F-FDG), a glucose analog radiotracer which acts as a maker for tissue metabolism. b. PET-CT has high sensitivity in detection of primary tumor and allows for a single modality for staging for regional and distal metastasis.

Carcinoma Unknown Primary (CUP) If no primary lesion is identified after a thorough clinical examination of the head and neck, the suspicion of an occult primary is entertained. 1. Biopsy of the enlarged node often aids to confirm diagnosis and to further determine the likely source of the primary. a. Immunohistochemical staining for p16 and other markers such as EBER (nasopharynx), CD20 (lymphomas) and thyroglobulin (thyroid) may assist in subsequent management for the primary. 2. Functional imaging using PET CT. a. Useful in up to 44% of patient cases for identifying a potential primary within the oropharynx. 3. Panendoscopic examination with tonsillectomy and targeted biopsies under general anesthesia. a. Ipsilateral tonsillectomy may be performed, but bilateral tonsillectomy has been advocated due to the incidence of synchronous and contralateral primaries. 4. Transoral robotic surgery or transoral laser surgery with lingual tonsillectomy a. Improves diagnostic yields in up to 67% of patients that have no findings on physical exam, radiological imaging and panendoscopy.

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5. Localization of the primary site allows for greater precision in radiation therapy targeting and contouring thereby reducing the sequalae of treatment.

Staging 1. Recognizing the differences in prognostic outcomes between patients with HPV positive and negative OPSCC, The American Joint Commission on Cancer (AJCC) updated the 8th edition AJCC staging system with a distinct TNM staging for HPV+ OPSCC. AJCC 8th edition TNM Staging T stage T0 T1 T2 T3 T4 N stage Nx N0 N1 N2 N3 Pathological N stage Nx pN0 pN1 pN2 M stage M0 M1

Findings No primary tumor identified Tumor ≤2 cm in largest dimension Tumor >2 cm but ≤4 cm in largest dimension Tumor >4 cm in largest dimension or extension to epiglottic lingual surface Tumor invading to larynx, extrinsic muscle of tongue, medial pterygoid, hard palate or mandible/beyond Findings Regional nodal status unknown No nodal metastasis Nodal metastasis to ipsilateral neck and ≤6 cm Nodal metastasis to contralateral/bilateral neck and ≤6 cm Nodal metastasis >6 cm in size Findings Regional nodal status unknown No nodal metastasis ≤4 positive lymph nodes >4 positive lymph nodes Findings Distal metastasis absent Distal metastasis present

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2. Important changes to the 8th edition include: (i) the omission of the carcinoma in situ (Tis) stage and (ii) no distinction between the T4a and T4b stages as is seen in HPV negative OPSCC. a. Omission of the Tis change was warranted due to the absence of a distinct basement membrane in HPV positive OPSCC. b. Studies have shown that there was no statistically significant difference between tumors staged as T4a and T4b when staged as per the 7th edition of AJCC. c. Studies have shown that the number of lymph nodes have a higher correlation with survival in HPV positive OPSCC rather than the size or laterality d. With increasing numbers of patients being offered Transoral robotic surgery (TORS) with neck dissection, a distinct pathological staging system was proposed with N1 encompassing 1 to 4 lymph nodes and N2 for >5 nodes. e. TNM staging now assigns only Stage IV as designating distant metastatic disease (M1). f. All patients with CUP whose LN biopsy overexpressing p16 or positive HPVISH are staged as per the staging for OPSCC.

Treatment Radiotherapy with or without Chemotherapy 1. Traditionally, the treatment of choice for OPSCC has been radiation therapy with or without chemotherapy depending on the stage of the tumor, with surgery reserved in the salvage setting. With the advancement of radiation techniques like intensitymodulated radiotherapy treatment (IMRT), radiation related adverse effects have decreased considerably. 2. Initial trials did not stratify patients by their HPV status but showed that adding chemotherapy to standard radiotherapy added a 6.6% overall survival benefit at 5 years in patients with OPSCC. A meta-analysis by Pignon et al. reported an absolute benefit of 6.5% at 5 years in trials with concomitant chemotherapy. Since then, several studies have reported the addition of chemotherapy in locally advanced tumors improves the survival outcomes.

Surgical Treatment While open surgery had been limited to salvage cases prior to HPV stratification, now Transoral LASER microsurgery (TLM) and Transoral robotic surgery (TORS) play an important role in the treatment of patients with HPV+ OPSCC.

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Conventional open approaches: The advent of TORS has decreased the role of open surgical approaches in the treatment of OPSCC, especially in HPV+ patients primarily due to the better prognosis associated with HPV+ OPSCC following radiotherapy with or without chemotherapy and significant morbidity associated with open approaches. 1. Open approach with a lip split mandibulotomy to access base of tongue or tonsillar tumors. Locally advanced tumors may require a composite mandibular resection 2. A lateral pharyngotomy approach may be used to approach tonsillar or glossotonsillar sulcus tumors. 3. Transcervical approach with lingual release may be required for patients requiring total glossectomy. Total glossectomy with laryngectomy may be required in tumor extending into the vallecula or the epiglottis 4. Reconstruction with pedicled flaps like the pectoralis or free flaps like antero-lateral thigh flap is usually required for large defects.

Minimally Invasive Approaches 1. Transoral LASER microscopy (TLM) a. TLM is described to allow better visualization and precise cuts compared to monopolar cautery available in TORS. However, access and maneuverability have now been circumvented with the improved retractors and articulated arms. 2. Transoral robotic surgery (TORS) a. TORS has led to the resurgence of surgery playing an important role in the management of early-stage and intermediate stage HPV+ OPSCC. An important advantage of surgical resection is that these patients can potentially be stratified according to their pathological risk further aiding in treatment deescalation and thereby reducing treatment associated morbidity and toxicity without compromising oncologic outcomes. b. Early stage OPSCC can be effectively treated with TORS. Patient selection is the key to achieve optimum oncologic and functional outcomes. Adequate exposure and access are critical for en bloc resection of the primary tumor with adequate margins in all planes. c. Functionally, any tumor which may require resecting more than 50% of the tongue musculature or resection crossing the midline and epiglottis are contraindications to TORS. d. TORS is contraindicated in unresectable neck disease, mandible or hyoid involvement, or tumor extending laterally into the neck, internal carotid artery involvement and prevertebral fascia involvement.

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Surgical vs Nonsurgical Treatment of p16 Oropharyngeal Cancers ORATOR Trial 1. To date, the ORATOR trial has been the only prospective trial comparing surgical treatment to non-surgical treatment. This trial is summarized below: Aim Study type Patient population Treatment

Outcomes

Results

Evaluation of differences in quality of life (QOL) 1 year after treatment International multicenter phase 2 randomized study Early oropharyngeal cancers (T1-2, N0-2, M0) [Not restricted to p16 OPSCC] 68 patients recruited Randomized to surgery (TORS and neck dissection) with adjuvant treatment vs RT with/without chemotherapy Primary: • Swallowing-related QOL at 1 year (MD Anderson Dysphagia Inventory [MDADI] score) - 10-point change considered clinically meaningful • Other QOL index, i.e., EORTC, H&N35, FOIS, VHI-10 Secondary: • Overall survival • Recurrence free survival • 1-year MDADI scores were in favor of nonsurgical modalities compared to surgery (86.9 vs 80.1) • 100% of patients taking oral diet with no restrictions in RT group vs 84% in the surgical group • Equivalent overall survival/recurrence free survival in both groups

2. ORATOR was a pioneer prospective surgical trial that demonstrated equivalent disease specific outcomes of both surgical and nonsurgical treatment for HPV + oropharyngeal cancers. 3. While this trial favored nonsurgical modalities, a small sample size, clear indications for adjuvant treatment, and the utility of a 10-point difference in MDADI scoring have resulted in ongoing discussion.

De-Escalation Strategies with Cetuximab RTOG 1016 1. The results of RTOG 1016 comparing Radiotherapy (RT) + cetuximab vs. Radiotherapy + cisplatin were published by Gillison et al. in 2019. This was a multicenter non-inferiority randomized controlled trial. Estimated 5-year survival rates were higher in the RT + cisplatin cohort at 84.6% (80.6-88.6) versus 77.9% (73.4-82.5) in the RT + cetuximab group (p = 0.02). Similarly, the progression-free survival was significantly better in the RT + cisplatin cohort [hazard ratio 1.72 (1.29-2.29); onesided log-rank p = 0.0001] compared to in the RT + cetuximab group (with 5-year

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estimates of 78.4% (73.8-83.0) vs. and 67.3% (62.4-72.2) respectively). There was no difference in the toxicity profile between the two groups.

De-ESCALate Trial 1. Another trial which was conducted in Europe by Mehanna et al. reported similar results when comparing cisplatin and radiotherapy versus cetuximab and radiotherapy in patients with HPV-positive OPSCC. A statistically significant difference was observed in patients receiving radiotherapy with cisplatin versus cetuximab with an overall survival (OS) at 2 years of 97.5% versus 89.4%, respectively (HR 5.0, 95% CI 1.714.7, p = 0.001). The 2 year recurrence rate was higher at 16.1% in the cetuximab group versus 6.0% in cisplatin group. (HR 3.4 [1.6-7.2, p = 0.0007]). The toxicity rate was similar in the two groups.

De-Escalation Trials in HPV+ Oropharyngeal Cancers Given the better response rates and survival of patients with HPV + OPSCC, treatment paradigms have shifted towards de-escalation of treatment with greater emphasis on survivorship. Broadly, these approaches may be divided into surgical and nonsurgical deescalation trials and a summary of these trials are attached in the table below.

Biomarkers for p16 Oropharyngeal Cancers Biomarkers allow for detection, characterization, and monitoring of disease at every phase of management. They can help predict disease response to treatment and are often useful in detecting primary tumors or recurrent disease. Some biomarkers currently being studied for HPV + OPSCC include: 1. Plasma cell-free HPV DNA 2. HPV DNA in oral rinse 3. Serum HPV antibodies Many of these tools have shown promise in the management of OPSCC. The use of an oral rinse to detect HPV DNA allows for a noninvasive method to screen for disease in high-risk populations. Quantification of both plasma cell-free HPV DNA and HPV DNA obtained from oral rinses have been shown in some studies to predict recurrent disease. The utility of serum HPV antibodies in prognostication is remains equivocal. While more studies are required to further support their utility in clinical management, HPV biomarkers demonstrate tremendous potential to screen, diagnose and prognosticate patients with p16 positive OPSCC.

Ongoing study

N Lee et al.

SS Yom et al.

Single arm phase II adjuvant therapy deescalation for adequately resected OPSCC

MC1273 D Ma et al.

De-escalation of adjuvant treatment

FMISO-based deescalation approach

30 ROC trial

Pilot study

FMISO PET for selection of deescalation

Randomized phase II trial

NRG HN002

De-escalation of CRT Study/Study type Author

Adequately resected (margin negative) p16 OPSCC with 3 cm, multiple LN, ENE, LVI, PNI Int risk pt: absence of ENE High risk pt: ENE present

T0-2, N1-2c (7th TNM edition) HPV-related OSCCs Resection of primary tumor (margin status unimportant)/Core biopsy of LN in unknown primary

RT 30 Gy/36 Gy (ENE) and Docetaxel

F-FMISO PET prior to radiation and at second week of radiation if hypoxia noted in pre-treatment study. De-escalation - 30 Gy with 2 cycles chemo if absent tumor hypoxia at baseline or after 2 weeks of CRT

18

80 pts (37 Int risk, 43 high risk)

Preliminary report: 158pts

33 pts

Assessment of early tumor hypoxia response 1 week into chemoradiation via 18F-FMISO PET De-escalation treatment for metastatic lymph nodes to a total dose of 60 Gy in absence of hypoxia

Stage III-IVB HPV + OPC patients

306 pts

De-escalate CRT (IMRT 60 Gy + weekly cis) vs RT (IMRT 60Gy)

OPC p16 positive T1-T2 N1-N2b M0 T3 N0-N2b M0 (AJCC 7th ed) ≤10 pack-years of smoking)

Pt numbers

De-escalation

Criteria

Table 1.

2yr LRC 96.2% 2yr PFS 91.1% 2yr OS 98.7% Rates of grade 3 or worse toxicity at pre-RT and 1 and 2 years post-RT were 2.5%, 0%, and 0%. PHASE III ongoing - DART-HPV

Preliminary results: 128 patients de-escalated 1-year LRC, DMFS & OS were 94%, 100%, and 100%, respectively none failed in the primary site. 8 patients had recurrent nodal disease underwent successful salvage surgery.

10/33 patients met criteria for de-escalation After a median follow-up of 32 months, both 2-year LRC and 2-year OS were 100%.

Results 2-year PFS • IMRT alone: 87.6% • IMRT with chemotherapy: 90.5% IMRT with chemotherapy met study endpoint (Historical control rate of 85%) Ongoing HN005 compares current standard of care IMRT with high dose Cisplatin to 60 Gy IMRT with reduced dose Cisplatin and 60 Gy IMRT with Nivolumab.

R Ferris et al.

Ongoing trial

Ongoing trial

Phase II deescalation of p16 OPSCC pts with intermediate risk

PATHOS trial

Phase II/III RCT in whom the choice of adjuvant treatment depends on pathological risk factors after resection

ECOG 3311

De-escalation of adjuvant treatment Study/Study type Author

519 pts enrolled

Phase II completed 242 patients. Currently undergoing Phase III transition plan for 1100 patients (international accrual)

Low risk T1-2, N0-1: No adjuvant Intermediate risk clear/close margins, ECE 1 mm ECE/≥5 LN: CRT (Cis + 66 Gy)

Intermediate risk factors such as LN metastases, LVI or PNI or close resection margins are randomized between adjuvant dose-deescalated radiotherapy (50 Gy) …

OPSCC pts (cT1-2 stage III/IV AJCC7 without matted neck N+) treated with TORS

HPV-related OPSCCs (T1-3, N0-2b) and a negative smoking history

…or standard adjuvant radiotherapy (60 Gy). High-risk factors (incomplete resection or ECE), patients are randomized between postoperative radiotherapy and postoperative chemoradiation with 60 Gy

Pt numbers

De-escalation

Criteria

Table 1. (Continued)

Expected conclusion 2027

To date no preliminary results

Results 2yr PFS Arm A (Low risk): 93.9% Arm B (Int risk - 50Gy): 95% Arm C (Int risk - 60 Gy): 95.8% Arm D (High risk): 90.5% 2 yr LRC Low risk: 93.9% Int risk (50 Gy): 95% Int risk (60 Gy): 95.9% High risk: 90.5%

OPTIMA 2 evaluated response following Nivolumab, nabpaclitaxel and carboplatin for adaptive de-intensified

OPTIMA II

OPTIMA Phase II trial …

A Rosenberg et al.

TY Seiwert et al.

De-escalation of adjuvant treatment Study/Study type Author De-escalation by induction OPTIMA TY Seiwert Phase II trial et al. stratifying patients for de-escalation based on risk stratification and response to induction chemotherapy

Arm B: HR with ≥50% shrinkage OR LR with 50% radiological response received radiotherapy only to a dose of 50 Gy. 30-50% radiological response were treated with dose de-escalated chemoradiation (45 Gy plus concomitant paclitaxel, 5-FU and hydroxyurea) Patients with N2c, >10 pack years): Pts with ≥50% response received 45 Gy plus concomitant paclitaxel, 5-FU and hydroxyurea Pts with lesser response received 75 Gy plus concomitant paclitaxel, 5-FU and hydroxyurea Nivolumab, nab-paclitaxel, and carboplatin were administered for 3 cycles Arm A: LR with ≥50% post-induction shrinkage - received single-modality RT to 50 Gy OR TORS.

HPV-related OPSCC (T1-4, N2-3) according to the 7th TNM edition

Locoregionally advanced HPV+ OPC. High-risk (HR) included any of the following: T4, N2c-N3 (AJCC 7th ed) 20 pack yr smoking hx Non-HPV16 subtype All others were low-risk (LR).

De-escalation

Criteria

73 pts

62 pts

62 pts

Pt numbers

The DRR following induction was 70.8% (95% CI 60.3%, 81.3%). Median follow-up 23.1 months. LR 47.9%, and HR 52.1%. De-escalated treatment was administered in 84.9%. Arm A N = 28, Arm B N = 34, and Arm C N = 10. 2-year PFS for full cohort was 90.4% (95% CI = 79.3%, 95.7%). 2-year PFS for Arms A, B, and C were 96.3%, 85.8%, and 100.0% respectively.

Within low-risk group: 71% underwent RT50 21% underwent CRT45 2 yr PFS - 95%, 2 yr OS - 100% Within high-risk group: 71% received CRT45 29% received CRT75 2 yr PFS - 94%, 2 yr OS - 97% Overall 2 yr PFS 94.5% Within 11% non-inferiority margin of historic control (85%) 82% of patients in the high-dose chemoradiation arm (75 Gy) received a gastrostomy tube compared to 0% in the de-escalated group (radiotherapy with 50 Gy).

Results

De-escalation of adjuvant treatment Study/Study type Author De-escalation by induction treatment for locoregionally advanced HPV+ OPC Criteria Arm C: All others - received regular dose CRT to 70-75 Gy. Adjuvant Nivolumab was administered for 6 months. The primary endpoint was deep response rate (DRR) ≥50% shrinkage to induction therapy

De-escalation

Table 1. (Continued) Pt numbers

2-year overall survival (OS) for full cohort was 93.3% (95% CI = 82.4%, 97.5%). 2-year OS for Arm A, B, and C were 96.0%, 91.9%, and 100.0% respectively Among TORS (N = 9), pathologic complete response was 66.7%. G-tube rates in Arms A, B, and C were 7.1%, 44.1%, and 75.0% respectively (p = 0.0001). 1 Death during induction reported There were 3 local failures and no distant failures.

Results

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Prevention Vaccination 1. Standardized screening tests and validated biomarkers are not currently available for HPV+ OPSCC. Increasing the awareness and improving vaccination rates are extremely important in preventing this entity. 2. The FDA recently approved the use of Gardasil-9 for females and males between the ages 9 and 45 years in OPSCC. 3. In a study by Herrero et al., the vaccine had an efficacy of over 93% in preventing oral HPV infection, compared to the control group.

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Questions 1. What is the most common presentation of HPV positive OPSCC? a. Odynophagia b. Otalgia c. Painless cervical lymphadenopathy d. Dysphagia 2. The diagnosis of a p16 positive OPSCC is confirmed by which of the following? a. Identification of HPV DNA within the biopsy specimen b. HPV detection on plasma c. HPV detected on the biopsy specimen by in-situ hybridization d. 70% positive staining with p16 immunohistochemistry 3. The findings of ECOG 3311 supported which one of the following de-escalation strategies? a. De-escalation of adjuvant radiation in patients with intermediate risk b. TORS as a single modality is an effective treatment for all patients with HPV positive OPSCC c. TORS and adjuvant radiation alone effectively treats all patients with HPV positive OPSCC d. Induction treatment prior to TORS shows equivalent results compared to chemoradiation. 4. All the following are contraindications for Trans-oral robotic surgery except? a. Hyoid involvement b. Tumor extending to the mandible c. Internal carotid artery involvement d. Anterior tonsillar pillar involvement 5. According to the AJCC 8th edition of the TNM staging which of the following is no longer a recognized T stage in HPV+ OPSCC? a. T2 b. Tis c. T4 d. T3

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References Ang, K. K., Harris, J., Wheeler, R., Weber, R., Rosenthal, D. I., Nguyen-Tân, P. F., Westra, W. H., Chung, C. H., Jordan, R. C., Lu, C., Kim, H., Axelrod, R., Silverman, C. C., Redmond, K. P., & Gillison, M. L. Human papillomavirus and survival of patients with oropharyngeal cancer. N. Engl. J. Med. 2010;363:2435. Bourhis, J., Calais, G., Lapeyre, M., Tortochaux, J., Alfonsi, M., Sire, C., Bardet, E., Rives, M., Bergerot, P., Rhein, B., & Desprez, B. Concomitant radiochemotherapy or accelerated radiotherapy: analysis of two randomized trials of the French Head and Neck Cancer Group (GORTEC). Semin. Oncol. 2004;31:822826. Calais, G., Alfonsi, M., Bardet, E., Sire, C., Germain, T., Bergerot, P., Rhein, B., Tortochaux, J., Oudinot, P., & Bertrand, P. Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. J. Natl. Cancer Inst. 1999;91(24):2081-6. Chen, S. Y., Massa, S., Mazul, A. L., Kallogjeri, D., Yaeger, L., Jackson, R. S., Zevallos, J., & Pipkorn, P. The association of smoking and outcomes in HPV-positive oropharyngeal cancer: A systematic review, American Journal of Otolaryngology, Volume 41, Issue 5, 2020, 102592, https://doi.org/10.1016/j. amjoto.2020.102592. Dahlstrom KR, Anderson KS, Cheng JN et al. HPV serum antibodies as predictors of survival and disease progression in patients with HPV-positive squamous cell carcinoma of the oropharynx. Clin. Cancer Res. 2015, 21, 2861-2869. D Dahlstrom, K. R., Li, G., Hussey, C. S., Vo, J. T., Wei, Q., Zhao, C., & Sturgis, E. M. Circulating human papillomavirus DNA as a marker for disease extent and recurrence among patients with oropharyngeal cancer. Cancer 2015, 121, 3455-3464. Evans M, Knott S, Hurt C et al. PATHOS: A phase II/III trial of risk-stratified, reduced intensity adjuvant treatment in patients undergoing transoral surgery for human papillomavirus (HPV)-positive oropharyngeal cancer. Journal of Clinical Oncology 2018; 36:TPS6097-TPS6097. Ferris RL, Flamand Y, Weinstein GS et al. Phase II Randomized Trial of Transoral Surgery and Low-Dose Intensity Modulated Radiation Therapy in Resectable p16+ Locally Advanced Oropharynx Cancer: An ECOG-ACRIN Cancer Research Group Trial (E3311). J. Clin. Oncol. 2021:JCO2101752. Fu TS, Foreman A, Goldstein DP, de Almeida JR. The role of transoral robotic surgery, transoral laser microsurgery, and lingual tonsillectomy in the identification of head and neck squamous cell carcinoma of unknown primary origin: a systematic review. J. Otolaryngol. Head Neck Surg. 2016; 45:28. Gillison, M. L., Trotti, A. M., Harris, J., Eisbruch, A., Harari, P. M., Adelstein, D. J., Jordan, R. C. K., Zhao, W., Sturgis, E. M., Burtness, B., Ridge, J. A., Ringash, J., Galvin, J., Yao, M., Koyfman, S. A., Blakaj, D. M., Razaq, M. A., Colevas, A. D., Beitler, J. J., … Le, Q. T. Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): A randomised, multicentre, non-inferiority trial. Lancet 2019; 393: 40-50. Gipson, B. J., Robbins, H. A., Fakhry, C., & D’Souza, G. Sensitivity and specificity of oral HPV detection for HPV-positive head and neck cancer. Oral Oncol. 2018, 77, 52-56. Herrero, R. et al. Reduced prevalence of oral human papillomavirus (HPV) 4 years after bivalent HPV vaccination in a randomized clinical trial in Cost Rica. PLoS One (2013) 8, e68329. Lee, N. Y., Sherman, E. J., Schöder, H., McBride, S. M., Yu, Y., Kang, J., Tsai, C. J., Gelblum, D. Y., Boyle, J., Singh, B., Cohen, M., Cracchiolo, J. R., Ganly, I., Dunn, L., Kriplani, A., Fetten, J. V., Michel, L. S., Wong, R. J., Pfister, D. G., & Riaz, N. The 30 ROC trial: Precision intra-treatment imaging guiding major radiation reduction in human papillomavirus related oropharyngeal cancer. Journal of Clinical Oncology 2021; 39:6019-6019. Lydiatt, W. M., Patel, S. G., O’Sullivan, B., Brandwein, M. S., Ridge, J. A., Migliacci, J. C., Loomis, A. M., & Shah, J. P. Head and Neck cancers-major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J. Clin. 2017; 67: 122-137. Ma, D. J., Price, K. A., Moore, E. J., Patel, S. H., Hinni, M. L., Garcia, J. J., Graner, D. E., Foster, N. R., Ginos, B., Neben-Wittich, M., Garces, Y. I., Chintakuntlawar, A. V., Price, D. L., Olsen, K. D., Van Abel, K. M., Kasperbauer, J. L., Janus, J. R., Waddle, M., Miller, R., … Foote, R. L. Phase II Evaluation of

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Aggressive Dose De-Escalation for Adjuvant Chemoradiotherapy in Human Papillomavirus-Associated Oropharynx Squamous Cell Carcinoma. J. Clin. Oncol. 2019; 37:1909-1918. Mehanna, H., Robinson, M., Hartley, A., Kong, A., Foran, B., Fulton-Lieuw, T., Dalby, M., Mistry, P., Sen, M., O’Toole, L., Al Booz, H., Dyker, K., Moleron, R., Whitaker, S., Brennan, S., Cook, A., Griffin, M., Aynsley, E., Rolles, M., … Evans, M. Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): An open-label randomised controlled phase 3 trial. Lancet 2019; 393: 51 60. Nichols, A. C., Theurer, J., Prisman, E., Read, N., Berthelet, E., Tran, E., Fung, K., de Almeida, J. R., Bayley, A., Goldstein, D. P., Hier, M., Sultanem, K., Richardson, K., Mlynarek, A., Krishnan, S., Le, H., Yoo, J., MacNeil, S. D., Winquist, E., … Palma, D. A. Radiotherapy versus transoral robotic surgery and neck dissection for oropharyngeal squamous cell carcinoma (ORATOR): an open-label, phase 2, randomised trial. Lancet Oncol. 2019; 20:1349-1359. Pignon, J., Bourhis, J., Domenge, C., & Designé, L. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet. 2000;355(9208):949-55. Riaz N, Sherman E, Pei X et al. Precision Radiotherapy: Reduction in Radiation for Oropharyngeal Cancer in the 30 ROC Trial. J. Natl. Cancer Inst. 2021; 113:742-751. Rosenberg, A., Agrawal, N., Pearson, A. T., Seiwert, T. Y., Gooi, Z., Blair, E. A., Ginat, D., Howard, A., Chin, J., Kochanny, S., Izumchenko, E., Juloori, A., Haraf, D. J., & Vokes, E. E. Nivolumab, nabpaclitaxel, and carboplatin followed by risk/response adaptive de-escalated locoregional therapy for HPV-associated oropharyngeal cancer: OPTIMA II trial. Journal of Clinical Oncology 2021; 39:6011-6011. Seiwert, T. Y., Foster, C. C., Blair, E. A., Karrison, T. G., Agrawal, N., Melotek, J. M., Portugal, L., Brisson, R. J., Dekker, A., Kochanny, S., Gooi, Z., Lingen, M. W., Villaflor, V. M., Ginat, D. T., Haraf, D. J., & Vokes, E. E. OPTIMA: a phase II dose and volume de-escalation trial for human papillomavirus-positive oropharyngeal cancer. Ann. Oncol. 2019; 30:297-302. Yom, S. S., Torres-Saavedra, P., Caudell, J. J., Waldron, J. N., Gillison, M. L., Xia, P., Truong, M. T., Kong, C., Jordan, R., Subramaniam, R. M., Yao, M., Chung, C. H., Geiger, J. L., Chan, J. W., O’Sullivan, B., Blakaj, D. M., Mell, L. K., Thorstad, W. L., Jones, C. U., … Le, Q. T. Reduced-Dose Radiation Therapy for HPV-Associated Oropharyngeal Carcinoma (NRG Oncology HN002). J. Clin. Oncol. 2021; 39:956965. Zhu L, Wang N. 18F-fluorodeoxyglucose positron emission tomography-computed tomography as a diagnostic tool in patients with cervical nodal metastases of unknown primary site: a meta-analysis. Surg. Oncol. 2013; 22:190-194.

Chapter 15

Tumors of the Larynx, Hypopharynx, and Cervical Esophagus Ameya A. Jategaonkar, MD Timothy Blood, MD Dinesh K. Chhetri, MD and David M. Cognetti, MD Larynx Introduction Malignancies of the larynx tend to arise from the mucosal surfaces of the larynx and the vast majority of these cancers are squamous cell carcinoma. Most laryngeal malignancies are thought to arise from precancerous/dysplastic lesions [1-3]. Carcinogen exposure, e.g., tobacco and alcohol are thought to drive the vast majority of these cancers [1-3]. In recent years human papilloma virus (HPV) has increasingly been identified in laryngeal cancers, though the implications of HPV status on laryngeal cancer treatment and prognosis remain unclear [4].

Laryngeal Anatomy 1. Cartilages: The larynx is comprised of nine total cartilages. Three paired and three unpaired cartilages. a. The arytenoid, corniculate, and cuneiform are the three paired cartilages of the larynx b. Three unpaired cartilages are the cricoid cartilage, thyroid cartilage, and the epiglottis 2. Membranes: Various membranes span the cartilages and can serve as barriers to tumor spread. a. Conus elasticus arises from the cricoid arch and extends to the superior aspect of the thyroid cartilage. Posteriorly the conus elasticus attaches at the vocal processes In: Essential Head and Neck Oncology and Surgery Editors: Maie A. St. John and Benjamin L. Judson

ISBN: 979-8-88697-438-6 © 2023 Nova Science Publishers, Inc.

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b. The quadrangular membrane spans between the arytenoids and the epiglottis. And forms the aryepiglottic fold superiorly and the false cords inferiorly c. The thyrohyoid membrane spans the superior aspect of the thyroid cartilage to the posterior aspect of the hyoid 3. Spaces: Several spaces surround the larynx and invasion of tumor into these spaces can affect the staging, treatment, and prognosis of laryngeal malignancies. a. Preepiglottic space i. lymphatically rich space ii. lies between the epiglottis and the thyrohyoid membrane and extends from the hyoepiglottic ligament superiorly to the attachment of the epiglottis to the thyroid cartilage inferiorly b. Paraglottic Spaces i. These lie laterally to the preepiglottic space ii. Bound inferomedially by the conus elasticus and superomedially by the quadrangular membrane iii. Thyroid cartilage forms the anterior border iv. Bound posteriorly by the pyriform sinus 4. Laryngeal cancer subsites: Larynx cancer is diagnosed and staged based on the primary subsite that is involved. a. Supraglottis is comprised of the laryngeal surface of the epiglottis, the aryepiglottic folds, the arytenoids, and the false cords i. Rich lymphatic drainage to levels II, III, and IV of the lateral neck b. Glottis includes the true vocal folds and both the anterior and posterior commissures i. Little to no lymphatic drainage c. Subglottis exends from below the vocal folds to the inferior limit of the cricoid cartilage i. Lymphatic drainage is primarily to pretracheal (level VI) and mediastinal nodes

Patient Evaluation 1. Presenting symptoms can vary greatly based on tumor subsite, pattern of growth, and the stage of disease a. Glottic tumors can present with hoarseness and dysphonia even with very early stage tumors b. Supraglottic tumors may present with a variety of symptoms ranging from dysphonia to dysphagia and stridor i. Early supraglottic tumors may present with nodal metastases 2. Patient evaluation must be centered around a thorough head and neck examination a. Assessment for impending airway collapse is paramount b. Carcinogen exposure such as tobacco or alcohol should be identified c. Indirect or flexible laryngoscopy can assist in visualization and characterization of the laryngeal mass

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3. Imaging, especially contrast enhanced CT or MRI assists in tumor characterization and assessment for regional metastases a. PET scans can be useful in evaluating for second primary malignancies and distant metastases 4. Operative endoscopy and biopsy confirm the tissue diagnosis a. Operative laryngoscopy is also important for tumor characterization and treatment planning especially when considering transoral or partial laryngeal surgical techniques

Laryngeal Cancer Staging Tumors are staged according to the American Joint Committee on Cancer 8th Edition Staging Manual [6]. Tumors staging is somewhat distinct based on the subsite (see Table 1). Table 1. Laryngeal cancer tumor staging (T Stage) Subsite Glottis

Tumor Stage T1a T1b T2

Description

Tumor limited to 1 vocal cord Tumor involves both vocal cords Tumor extends to the supraglottis and/or subglottis, and/or with impaired vocal cord mobility T3 Tumor limited to the larynx with vocal cord fixation and/or invasion of the paraglottic space and/or inner cortex of the thyroid cartilage T4a Tumor invades through the outer cortex of the thyroid cartilage and/or invades tissues beyond the larynx (e.g., trachea, cricoid cartilage, soft tissues of the neck including deep extrinsic muscle of the tongue, strap muscles, thyroid, or esophagus) T4b Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures Supraglottis T1 Tumor limited to 1 subsite of the supraglottis, with normal vocal cord mobility T2 Tumor invades mucosa of more than 1 adjacent subsite of the supraglottis or glottis or region outside the supraglottis (e.g., mucosa of base of the tongue, vallecula, medial wall of pyriform sinus), without fixation of the larynx T3 Tumor limited to the larynx, with vocal cord fixation, and/or invades any of the following: postcricoid area, pre-epiglottic space, paraglottic space, and/or inner cortex of the thyroid cartilage T4a Tumor invades through the outer cortex of the thyroid cartilage and/or invades tissues beyond the larynx (e.g., trachea, soft tissues of the neck, including deep extrinsic muscle of the tongue, strap muscles, thyroid, or esophagus) T4b Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures Subglottis T1 Tumor limited to the subglottis T2 Tumor extends to vocal cord(s), with normal or impaired mobility T3 Tumor limited to the larynx with vocal cord fixation and/or invasion of paraglottic space and/or inner cortex of the thyroid cartilage T4a Moderately advanced local disease; Tumor invades cricoid or thyroid cartilage and/or invades tissues beyond the larynx (e.g., trachea, soft tissues of the neck including deep extrinsic muscles of the tongue, strap muscles, thyroid, or esophagus) T4b Very advanced, local disease; Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures Table modified from the AJCC 8th Edition guidelines [6].

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Table 2. Regional nodal staging (N Stage) Clinical (cN)

N Stage N0 N1 N2a N2b N2c

Pathological (pN)

N3a N3b N0 N1 N2a N2b N2c N3a N3b

Description No regional lymph node metastasis Metastasis in a single ipsilateral lymph node ≤ 3 cm in greatest dimension and no extranodal extension (ENE) Metastasis in a single ipsilateral lymph node > 3 cm but not more than 6 cm in greatest dimension and without ENE Metastasis in multiple ipsilateral lymph nodes, none > 6 cm in greatest dimension and without ENE Metastasis in bilateral or contralateral lymph nodes, none > 6 cm in greatest dimension and without ENE Metastasis in a lymph node > 6 cm in greatest dimension and without ENE Metastasis in any node(s) with clinically overt ENE No regional lymph node metastasis Metastasis in a single ipsilateral lymph node ≤ 3 cm in greatest dimension and without ENE Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension with ENE, or a single ipsilateral node between 3 and 6 cm in greatest dimension without ENE Metastasis in multiple ipsilateral lymph nodes, none > 6 cm in greatest dimension and without ENE Metastasis in bilateral or contralateral lymph node, all no more than 6 cm in greatest dimension and without ENE Metastasis in a lymph node > 6 cm in greatest dimension without ENE Metastasis in a single ipsilateral node > 3 cm in greatest dimension with ENE, or a single contralateral node with ENE, or multiple ipsilateral, contralateral, or bilateral nodes, any with ENE

Note that this is essentially unchanged for hypopharynx cancers as well. Table modified from the AJCC 8th Edition guidelines [6].

1. Tumor stage (T) a. Tis – Tumors that do not invade the basement membrane are considered insitu. This is true for all subsites b. T1 supraglottis – limited to a single subsite in the supraglottis c. T1 subglottis – limited to the subglottis alone d. T1 Glottis: i. T1a – Isolated to a single vocal fold ii. T1b – Involvement of both vocal folds e. T2 Supraglottis – involving more than one subsite or extension to the glottis f. T2 Subglottis – tumor extension to the glottis g. T2 glottis – tumor resulting in impaired vocal fold mobility h. T3 All subsites – invasion into the paraglottic or pre-epiglottic spaces i. Tumors that result in vocal fold fixation are considered T3 i. T4a – these represent locally advanced tumors that have spread beyond the larynx. Invasion can extend through the outer cortex of the thyroid cartilage, strap muscles, trachea, esophagus, extrinsic tongue musculature and/or surrounding neck tissues. j. T4b – Tumors that traditionally are considered unresectable and involve the prevertebral fascia, mediastinal structures, and/or encase the carotid

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2. Nodal Stage (N) a. Laryngeal cancer nodal staging is similar to that of other head and neck malignancies (see Table 2)

Laryngeal Cancer Treatment Surgery, radiation therapy (RT), and chemotherapy are mainstays of treatment of laryngeal cancer. Open and transoral techniques have been developed for the treatment of early and advanced laryngeal cancers. RT alone or concurrent chemoradiotherapy (CRT) have also been used as organ preserving approaches to treat cancers of the larynx. Clinical trials such as the Departments of Veterans Affairs Laryngeal Cancer Study and RTOG 91-11 resulted in a significant shift towards non-surgical treatments for locally advanced laryngeal cancers [7, 9]. However recent studies looking at long term laryngectomy free survival and overall survival in these patients have resulted in a renewed interest in primary surgical treatments for laryngeal cancers [9-12]. Ultimately the treatment for laryngeal cancer is guided by the tumor subsite, stage, and patient factors including comorbid conditions and functional considerations. 1. Early stage supraglottic cancers may be amenable to surgical treatment or RT alone. a. Surgery can be either transoral (robotic or laser) or open supraglottic laryngectomy [13-16] b. Both surgical approaches have demonstrated excellent long term functional and oncologic results with the transoral techniques showing lower rates of temporary tracheostomy and feeding tube use and shorter hospitalization c. Generally, supraglottic tumors will need to have the neck addressed either with neck dissection or radiation due to the higher rate of occult metastases with supraglottic tumors 2. Definitive CRT or total laryngectomy is typically necessary for advanced supraglottic cancers 3. Early glottic cancers may be treated with surgical treatment or RT alone. a. Treatment can be limited to the primary site alone given the lack of lymphatic drainage b. Conservation laryngeal surgery includes endoscopic and open partial laryngectomy techniques [16, 17]. Several studies have demonstrated excellent oncologic and functional results with transoral laser microsurgery (TLM) 4. Advanced glottic cancers (T3 and T4) are not ideally suited for partial laryngectomy alone a. Local control rates for T4 glottic tumors with RT alone have been poor b. Generally advanced glottic tumors are treated with definitive CRT or total laryngectomy 5. Primary subglottic malignancies are rare a. Partial laryngeal approaches may be attempted in select cases b. Vascularized composite grafts for cricotracheal reconstruction in patients with partial laryngeal defects from malignancy have been described [18]

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c.

Given the integral role of the crico-arytenoid unit in laryngeal function, total laryngectomy is often needed when the cricoid is compromised by tumor (or by oncologic margins) d. Adjuvant treatment with radiation and/or chemotherapy is often utilized to maximize locoregional control. 6. Rates of surgical salvage following laryngeal cancer recurrence are relatively high and close surveillance in previously treated patients is paramount a. TLM and partial laryngeal surgery may be possible in select cases b. Surgical salvage often requires total laryngectomy or laryngopharyngectomy. i. Vascularized regional or free tissue reconstruction is often utilized for pharynx reconstruction in these cases to minimize risk of salivary fistula [19, 20]

Uncommon Laryngeal Malignancies While an exhaustive list of laryngeal malignancies is beyond the scope of this chapter, it is important to understand the various malignancies that may present as a laryngeal mass. 1. Squamous cell carcinoma represents the most common laryngeal malignancy. Variants of squamous cell carcinoma may also be present in the larynx. These variants include: a. Verrucous carcinoma i. Less radiosensitive than traditional squamous cell cancers ii. Upfront surgical therapy is typically favored in these cases iii. HPV may be associated with verrucous cancers b. Basaloid squamous cell carcinoma c. Spindle cell variant of squamous cell carcinoma d. Papillary squamous cell carcinoma 2. Salivary gland malignancies may also present in the larynx as there are minor salivary glands within the larynx, especially the supraglottis a. Mucoepidermoid carcinoma b. Adenoid cystic carcinoma c. Other salivary gland cancers such as adenocarcinomas 3. Neuroendocrine tumors of the larynx a. Carcinoid b. Paragangliomas c. Small cell carcinoma 4. Non-epithelial connective tissue malignancies of the larynx a. Chondrosarcoma is the most common of these cancers i. Generally arises from the cricoid cartilage b. Liposarcoma (most commonly in the supraglottis) c. Kaposi’s sarcoma i. Associated with immunocompromise states, e.g., Acquired Immunodeficiency Syndrome (AIDS)

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Hypopharynx Anatomy 1. Spans the region from the oropharynx to the cervical esophagus, (from the level of the hyoid bone to the inferior border of cricoid cartilage) and is divided into 4 subsites [21] a. Pyriform sinuses i. inverted triangles with the apex at the cricoid and the base at the pharyngoepiglottic fold b. Lateral pharyngeal walls i. reside in the area between pyriform sinuses and the posterior pharyngeal walls bilaterally c. Posterior pharyngeal wall d. Post-cricoid region i. posterior to the cricoid overlying the posterior cricoarytenoid muscles and lies between the medial aspects of the pyriform sinuses 2. Deep extension from the subsites results in tumor upstaging a. can present with earlier symptoms (dysphonia from laryngeal invasion, neck mass from nodal metastasis, etc.). 3. The hypopharyngeal lymphatic network is robust and results in nodal metastasis most commonly to neck levels II-IV and retropharyngeal lymph nodes [22-29].

Tumors of the Hypopharynx 1. Comprise 3-4% of all head and neck cancers [22, 23], 2. Tumors tend to present late with advanced T stage tumors resulting in one of the worst prognoses for head and neck cancers with a 30-35% 5-year overall survival [24, 25] 3. 75-77% of patients with hypopharyngeal cancer present with stage III or IV disease [31, 45] 4. Historically, hypopharyngeal cancer occurs in male heavy tobacco and alcohol users in their 60s [30] a. Other documented risk factors for hypopharyngeal cancer include PlummerVinson syndrome and gastroesophageal reflux disease [33] 5. Majority of hypopharyngeal cancer (95%) is squamous cell carcinoma a. adenocarcinomas, sarcomas, and lymphomas responsible for the remainder of the tumors in this region [21]

Patient Evaluation 1. Presenting symptoms are noted to differ with the stage of the tumor

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a.

2. 3. 4. 5.

6. 7.

8. 9.

Stage I/II patients present most commonly with symptoms easily attributable to GERD and pharyngitis b. Higher stage tumors most commonly present with neck mass, dyspnea, dysphagia and otalgia [31] Careful physical examination focusing on cervical lymphadenopathy and flexible office laryngoscopy are mainstays of office examination Office based fine needle aspiration of an enlarged cervical lymph node can facilitate a diagnosis Primary site is typically not accessible for office biopsy unless via channeled scope, which may be considered Direct laryngoscopy and esophagoscopy under general anesthesia allows for biopsy of the hypopharynx and to define the extent of the tumor (inferior extent) involvement Assessment of tumor slide on the posterior pharyngeal wall can indicate if the tumor involves the prevertebral fascia CT neck with contrast is used to define the extent of the primary tumor, to assess cartilaginous involvement and to identify regional spread. PET/CT scanning is often used to augment the local and regional assessment while also evaluating for distant metastatic disease Incidence of synchronous tumors is 16-18%, thus careful evaluation with imaging and examination under anesthesia is critically important [32] MRI is generally reserved for when CT imaging is equivocal with respect to cartilage invasion or for prevertebral fascia involvement [23]

Staging 1. Tumors are staged according to the American Joint Committee on Cancer 8th Edition Staging Manual [6] (the below T/N staging is adapted from AJCC and NCCN guidelines) a. Tumor staging i. Tumors which do not invade the basement membrane of the mucosa are termed carcinoma in situ (Tis) ii. T1 tumors are 2 cm or smaller and limited to one subsite of the hypopharynx iii. T2 tumors invade more than 1 subsite, are larger than 2 cm but under 4 cm and are not fixed to the underlying larynx iv. T3 tumors are over 4 cm or with fixation of the hemi-larynx, or extension to the esophageal mucosa • T4a tumors invade the larynx (thyroid/cricoid cartilage/hyoid bone), thyroid gland, esophageal muscle or strap muscles • T4b tumors are unresectable with extension to the prevertebral fascia, encasing the carotid artery or involving mediastinal structures

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b. Clinical nodal staging i. Nx- lymph nodes cannot be assessed ii. N0- no regional lymph node metastasis iii. N1- Metastasis to a single ipsilateral lymph node 3cm or smaller and extra-nodal extension negative ENE(-) iv. N2a- Metastasis in a single ipsilateral node larger than 3 cm but smaller than 6 cm in greatest dimension and ENE(−) v. N2b- Metastases in multiple ipsilateral nodes, none larger than 6 cm in greatest dimension and ENE(−) vi. N2c- Metastases in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest dimension and ENE(−) vii. N3a- Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE(−) viii. N3b- Metastasis in any node(s) and clinically overt ENE(+) c. Pathologic nodal staging i. Nx- Regional lymph nodes cannot be assessed ii. N0- No regional lymph node metastasis iii. N1- Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension and ENE(−) iv. N2a- Metastasis in single ipsilateral node 3 cm or smaller in greatest dimension and ENE(+); or a single ipsilateral node larger than 3 cm but smaller than 6 cm in greatest dimension and ENE(−) v. N2b- Metastases in multiple ipsilateral nodes, none larger than 6 cm in greatest dimension and ENE(−) vi. N2c- Metastases in bilateral or contralateral lymph node(s), none larger than 6 cm in greatest dimension and ENE(−) vii. N3a- Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE(−) viii. N3b- Metastasis in a single ipsilateral node larger than 3 cm in greatest dimension and ENE(+); or multiple ipsilateral, contralateral or bilateral nodes, any with ENE(+) or a single contralateral node of any size and ENE(+)

Treatment 1. Management falls into two approaches: surgical and non-surgical primary therapy. a. Surgical management is subdivided into laryngeal sparing procedures and laryngectomy b. Laryngeal sparing surgery can again be subdivided into transoral laser microsurgery (TLM), transoral robotic surgery (TORS), and open techniques. c. Organ preservation surgical approaches are reserved for T1, T2 and select T3 tumors [21] d. Lateral hypopharyngeal wall tumors are generally accepted as more favorable candidates for transoral resection

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e.

Open surgical resections, including partial laryngectomies (hemilaryngectomy, supracricoid laryngectomy), total laryngectomies, and total laryngopharyngectomies are generally offered for patients with T3-T4 tumors, and generally require some sort of reconstruction (regional, or free tissue transfer reconstruction) f. Neck dissection (levels II-IV, VI) is also recommended in surgically managed patients due to the high rate of occult positive lymph nodes in a clinically N0 neck [35, 36] i. A contralateral neck dissection should also be considered as the rate of positive contralateral lymphadenopathy was found to be 13% with increased risk to the contralateral neck if the tumor is on the medial aspect of the pyriform sinus versus the lateral pharyngeal wall [37, 38] 2. Definitive radiation therapy can be used to treat select T1/T2 tumors and to concurrently treat the at-risk neck lymph nodes 3. Chemotherapy alone is not used as a primary treatment except in the palliative setting 4. Concurrent CRT is the mainstay of nonsurgical treatment supported by a number of clinical trials [39-42]

Cervical Esophageal Cancer Anatomy 1. The esophagus extends from 6th cervical vertebra to the 11th thoracic vertebra [43] 2. Cervical esophagus begins at the upper esophageal sphincter, (composed of the cricopharyngeus muscle and investing fibers from the superior esophagus and the inferior constrictors) and continues to the thoracic inlet where it becomes the thoracic esophagus [44] 3. The esophagus has two layers of muscles, an inner circular layer and an outer longitudinal layer 4. The upper third of the esophagus is composed mainly of skeletal muscle while the lower two thirds of the esophagus consist of smooth muscle

Patient Evaluation 1. Cervical esophageal tumors present late with 75-77% presenting with stage III or stage IV disease 2. Endoscopic examination and biopsy are necessary to both diagnose, define extent of disease and delineate gross invasion by the tumor 3. Smoking and alcohol intake are well established risk factors for cervical esophageal cancer and should be elicited on history [47, 48, 49, 50]

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4. Secondary to the anatomic location of the cervical esophagus, bronchoscopy should be considered to evaluate the trachea for invasion [58]

Esophageal Malignancies 1. Cervical esophageal cancer accounts for 5.3% of all esophageal cancers 2. Squamous cell carcinoma accounts for 95% of cases [45] 3. The majority of the remainder of cervical esophageal malignancies are adenocarcinomas

Treatment 1. In the past, surgical extirpation involving a total laryngo-pharyngo-esophagectomy was commonly performed for cancers of the cervical esophagus. Reconstruction of the surgical defect was performed using regional flaps (gastric pull up, pectoralis major flap, deltopectoralis flap) or free flaps (jejunal, colon) [57, 55] a. Unfortunately, such surgeries involved a large and morbid surgery with a significant risk for mortality [51-54, 56] 2. Multiple authors have evaluated the most appropriate treatment for cervical esophageal cancers in the past decades 3. While exact treatment protocols vary between sites, definitive chemoradiation (CRT) now is the accepted treatment of choice for these cancers, given no significant survival differences between surgical resection and CRT [57] 4. Surgical resection now is mainly limited to patients with a very aggressive tumor with no expectation of organ preservation with CRT [29] 5. Interestingly, resection was found to result in a survival benefit in patients who did not have a complete response after CRT and may be considered in this circumstance [56]

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Questions 1. Which of the following is true regarding cancers of the larynx? a. Tumors of the glottis often present as a neck mass before other symptoms b. Tumors of the supraglottis readily metastasize to the lateral neck c. Tumors of the subglottis readily metastasize to the lateral neck d. Invasion of the extrinsic tongue muscles suggests T3 staging 2. Which of the following is most accurate regarding the treatment of laryngeal cancers? a. Verrucous cancers may respond more favorably to primary surgical therapy b. HPV status is important in the treatment planning for laryngeal malignancies c. Voice outcomes are generally far poorer for early glottic cancers that are treated with TLM d. When primary CRT has failed, total laryngectomy is the only reliable option for surgical salvage 3. Which of the following is true regarding surgical salvage for recurrent laryngeal cancer? a. Surgical salvage rates are generally very poor in cases of recurrent laryngeal cancer b. TLM and other partial laryngeal techniques are not viable options in the previously radiated patient c. Reconstruction with vascularized tissue is often necessary in cases of salvage total laryngectomy d. Pharyngeal/salivary fistulas after salvage laryngectomy are rare 4. Which of the following is false regarding hypopharyngeal cancer? a. Medial piriform sinus tumors have an increased risk of contralateral lymph node metastasis b. Neck dissection is recommended in surgically managed patients c. Small lateral pyriform sinus tumors may be considered for transoral resection d. 5-year survival rates tend to be better than most other head and neck cancers 5. Which of the following is false regarding cervical esophageal cancer? a. The majority of cancers are adenocarcinoma b. The majority of cancers present with late stage disease c. Chemoradiation and surgical resection confer equivalent survival outcomes d. Smoking and alcohol are well established risk factors

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Chapter 16

Skull Base and Sinonasal Tumors Janet Chao, MD Thad Vickery, MD Michelle Chen, MD, MHS R. Peter Manes, MD and Daniel M. Beswick, MD Introduction 1. Presenting symptoms for sinonasal tumors (benign and malignant) a. Unilateral nasal obstruction and watery rhinorrhea—most common b. Epiphora c. Cheek swelling (may indicate infratemporal fossa involvement) d. Proptosis (orbit) e. Diplopia (orbit) f. Headache (cranial fossa) 2. Unilateral nasal obstruction as a presenting symptom should prompt assessment with endoscopy and potentially imaging (MRI vs. CT with contrast enhancement) a. CT can delineate the soft tissue abnormality as well as better evaluate for bone remodeling/invasion (Figure 1) b. MRI can differentiate tumor from retained secretions and suggest the soft tissue nature of the tumor c. Biopsy only after a vascular lesion and encephalomeningocele (Figure 2) have been ruled out with imaging 3. Most common benign sinonasal tumors are osteoma and inverted papilloma a. Inverted papilloma is the most common surgical indication for benign sinonasal tumors 4. Sinonasal malignancies are categorized by their histology. Basic classifications include squamous cell carcinomas, sarcomatous/mesenchymal tumors, neuroectodermal tumors, salivary neoplasms, respiratory epithelial lesions, hematolymphoid tumors, and tumor-like entities. New entities are being continually added to the WHO classification (Table 1)

In: Essential Head and Neck Oncology and Surgery Editors: Maie A. St. John and Benjamin L. Judson

ISBN: 979-8-88697-438-6 © 2023 Nova Science Publishers, Inc.

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Figure 1. Non-contrasted coronal computed tomography image demonstrates a soft tissue density mass in the left nasal cavity. This individual presented with epistaxis and left nasal obstruction.

Figure 2. Histologic images from an encephalocele at 100x magnification using an haemotoxylin and eosin stain (top) and glial fibrillary acidic protein (GFAP) stain (bottom). Do not biopsy a skull base mass before imaging rules out an encephalocele.

5. Most common malignant sinonasal tumor is squamous cell carcinoma 6. Sinonasal malignancies often present at advanced stage at initial diagnosis 7. Most common site of paranasal sinus malignancies are: a. Maxillary sinus (45-70%) b. Nasal cavity (15-35%)

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c. Ethmoid sinus (10-20%) d. Frontal and sphenoid sinus tumors are rare ( 3 cm but ≤ 6 cm in greatest dimension and ENEMetastasis in multiple ipsilateral lymph nodes, none > 6 cm in greatest dimension and ENEMetastasis in bilateral or contralateral lymph node(s), none > 6 cm in greatest dimension and ENEMetastasis in a lymph node that is > 6 cm in greatest dimension and ENEMetastasis in: • Single ipsilateral lymph node, > 3 cm and ENE+ or • Multiple ipsilateral, contralateral, or bilateral lymph nodes, any with ENE+ or • Single contralateral lymph node of any size and ENE+

2. Adenocarcinoma: a. Second most common sinonasal malignancy accounting for 13%-19% of all cases b. Histologically there are three subtypes: 1. low grade and 2. high grade nonintestinal type and 3. intestinal type adenocarcinoma. c. Wood dust exposure is a risk factor, specifically for the intestinal type. d. 60% overall 5-year survival e. 6:1 male:female predominance f. Most commonly occur in the olfactory groove g. Treatment consists of complete surgical resection with negative margins. Adjuvant radiation for high grade lesions 3. Sinonasal undifferentiated carcinoma: a. Rare, poorly differentiated and rapidly growing to invade the skull base, orbit, and brain b. 60% of cases start in the paranasal sinuses (ethmoids most common) and 40% in the nasal cavity c. Typically presents with T3 or T4 disease d. Distant metastases are common even with good local control e. Poor prognosis with 40% 5-year survival f. Histologically contain sheets, nests and ribbons of small cells without glandular or squamous differentiation g. Treatment typically involves aggressive surgical resection followed by chemoradiation 4. NUT (midline) carcinoma: a. Recently defined highly aggressive carcinoma genetically defined by the presence of a reciprocal chromosomal translocation NUT (nuclear protein in testis) gene on chromosome 15q and the BRD4 (bromodomain- containing protein 4) gene on 19p. b. Rare (2% of all sinonasal carcinomas), more common in younger adults

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c.

Similar histologic appearance to SNUC with demonstration of chromosomal translocation via RT-PCR or FISH. d. Treatment protocols are similar to SNUC

Malignant Salivary Gland Tumors 1. Adenoid cystic carcinoma: a. Arises from minor salivary glands within the respiratory mucosa b. Classified by tubular (low-grade), cribriform (most common), solid (high grade with worse prognosis), or mixed patterns c. Insidious growth, locally destructive with propensity for perineural invasion (50%) without lymphatic spread d. Distant (most commonly to lung or bone) and late (5-20 years after initial diagnosis) metastasis are common even with good locoregional control. e. Adenoid cystic carcinoma of the paranasal sinuses is often diagnosed late (invasion of the skull base, orbit, and central nerves is common) making negative surgical margins challenging f. Primary surgery with endoscopic or open approaches is the mainstay treatment. Radiation therapy is given in cases with advanced disease or positive margins. 2. Mucoepidermoid carcinoma: a. Arises from minor mucoserous glands in the submucosa b. Most common in the nasal cavity and maxillary sinus c. Histologically demonstrate mucous, intermediate and epidermoid cells, with columnar, clear cell or oncocytic elements. Tumors are graded from I-IV d. Surgical resection is the mainstay of treatment and is definitive for low grade tumors (grade I-II). Radiation is reserved for advanced disease (Grade III-IV) or positive margins.

Neuroectodermal Malignancies 1. Esthesioneuroblastoma (olfactory neuroblastoma): a. 2-7% of new sinonasal malignancies diagnosed in the United States b. 75% 2-year survival for Kadish A or B; drops to 25% with Kadish C disease c. Most often originates from the ethmoid roof and cribriform plate d. Histopathologically characterized by small blue cells with lobular architecture and Homer-Wright pseudorosettes (tumor cells grouped around a central neurophil) and Flexner-Wintersteiner rosettes (tumor cells surrounding a central lumen that contains acid mucopolysaccharide)

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The Hyams histologic criteria grades tumors from I to IV depending upon pathologic features such as mitotic activity and necrosis. e. Positive for neuronal differentiation staining negative for cytokeratin (CK) and positive for neuron-specific enolase, S-100, chromogranin, and synaptophysin f. Arises from the olfactory groove and may invade locally with locoregional metastasis to the neck and distant spread to the lungs and bones g. Modified Kadish staging: A. Tumor confined to nasal cavity B. Nasal cavity and paranasal sinuses C. Extends beyond nasal cavity and/or paranasal sinuses D. Metastatic disease h. Treatment i. Complete surgical resection with negative margins (sample dura or olfactory bulb if tumor demonstrates leptomeningeal enhancement) ii. Single modality treatment may be considered for low grade and Kadish A where margins are negative iii. Endoscopic approaches to the skull base are generally preferred for Kadish A and B tumors whereas combined endoscopic and craniofacial approaches for tumors extending beyond the paranasal sinuses (Kadish C), though approaches are evolving and specific surgical plan depends on expertise of treating teams. iv. Radiation alone is generally reserved for patients that are poor surgical candidates or for unresectable tumors v. Surgery plus radiation is associated with superior outcomes and is generally recommended for patients with Kadish C disease or positive margins vi. Chemotherapy remains of unclear benefit and is not routinely used 2. Mucosal melanoma: a. Rare, only 1% of all melanomas (5-10% of sinonasal malignancies). More common in females. 20% multifocal. 40% amelanotic b. Poor prognosis. Distant metastasis common regardless of margins on surgical resection. Overall 5-year survival is 25% (compared with 80% for cutaneous melanoma) i. All classified as T3 and Stage 3 at a minimum based on AJCC staging c. Often ulcerative and necrotic d. Histopathology is characterized with small, uniform blue cells in a nesting pattern e. S100 positive and frequently positive for melanocytic markers, including MART-1/melan-A, tyrosinase, HMB-45, Mitf, and SOX10 (Figure 4) f. Most common sites within the head and neck include the nasal cavity, paranasal sinuses and oral cavity i.

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Non-Epithelial Sinonasal Malignancies 1. Rhabdomyosarcoma a. Most common pediatric sinonasal malignancy b. Embryonal variant is most common in pediatric patients. Alveolar variant is more aggressive and also more common in adults.

Figure 4. Histologic images from a sinonasal melanoma showing strong SOX10 positivity (top) and focal S100 positivity (bottom).

c.

Subclassified as orbital parameningeal and non-orbital/non parameningeal. Parameningeal disease is more likely to be unresectable given propensity to invade critical structures. d. Histologically, tumors demonstrate primitive cells with skeletal muscle differentiation and scattered rhabdomyoblasts e. Treatment includes different combinations of surgery, chemotherapy, and radiation depending on the ability to obtain negative margins and involvement of the skull base or presence of metastases. 2. Angiosarcoma a. Rare, high grade, malignant vascular malignancies accounting for 0.1% of all sinonasal malignancies b. Slight male predominance c. Epistaxis and nasal congestion most common presenting symptoms

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d. May see metastatic angiosarcomas to the sinonasal cavities in KasabachMerritt Syndrome e. Histologically, angiosarcomas demonstrate vasoformative neoplastic cells that infiltrate into adjacent soft and hard tissues with abundant mitotic figures. f. Positive immunostaining for vimentin, CD31, CD34, and Factor VIII-RA g. Mainstay of treatment is radical surgery if negative margins are possible h. Radiation is beneficial in patients with advanced disease. Chemotherapy protocols are not standardized with several different cytotoxic medications in use. Give the rarity of these malignancies this remains an area of active research 3. Chondrosarcoma a. Rare malignancies representing 10-20% of all primary bone tumors of which 5-10% are located in the head and neck (most commonly in the larynx, maxilla, mandible and skull base). Rare to present in the paranasal sinuses. b. Histologically demonstrate atypical chondrocytes with enlarged hyperchromatic nuclei with multinucleate cells infiltrating the bone. c. Three grades depending on the degree of cellularity, nuclear size and atypia, and mitotic activity d. Treatment is complete surgical resection. Chondrosarcomas are radiation resistant and radiation is only reserved for palliation of non-resectable tumors. e. 5-year survival reported 50-80% with high rates of local recurrence (up to 60%). f. Metastasis possible to lungs and bone (up to 20%)

Lymphoproliferative/Hematogenous Malignancies 1. Lymphoma a. Rare, 1.5% of all lymphomas b. Most common types are Non-Hodgkin’s lymphomas including diffuse large B- cell lymphoma (DLBCL) (50%) followed by extranodal natural killer/Tcell lymphoma (25%) c. Less common types are follicular lymphoma, mucosal associated lymphoid tissue lymphoma (MALT), and mantle cell lymphoma d. Treatment of sinonasal lymphoma includes referral to oncology for chemotherapy depending on tumor type e. 50% overall 5-year survival. f. No role for surgical intervention beyond biopsy for tissue diagnosis in suspected cases. 2. Plasmacytoma a. Proliferation of monoclonal plasma cells outside of the bone marrow b. Mean age 55 with male predominance 2.3:1 c. 11-33% conversion to multiple myeloma over 10 years with the highest rates of conversion within the first 2 years – therefore, long term follow-up indicated

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d. Extramedullary plasmacytomas represent 1% of all head and neck tumors. 80% of head and neck plasmacytomas present in the nasal cavity and paranasal sinuses. e. Treatment is most often radiation therapy alone as plasmacytomas are highly radiosensitive. Chemotherapy may be considered for high grade tumors or in cases where progression to multiple myeloma has occurred. f. Surgery has similar outcomes to radiation where disease is localized and can be completely excised with negative margins.

Management and Treatment of Sinonasal Malignancies 1.

2.

3. 4.

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6.

7.

Importance of multidisciplinary management 1. Optimal approaches and treatment strategies often include a team approach with input from head and neck surgeons, oculoplastic surgeons, neurosurgeons, and medical and radiation oncologists. Surgery with curative intent is the mainstay treatment when possible a. Ohngren’s line is an imaginary plane from the medial canthus to the angle of the mandible i. Lesions inferior and anterior to this line tend to present earlier and are more likely to be completely resected ii. Lesions superior and posterior to the line present at more advanced stages and are more challenging to fully resect, likely involving critical structures (ex: orbit, carotid, skull base, infratemporal fossa) Radiation as the sole modality of treatment is recommended for unresectable cases, poor surgical candidates, or lymphoreticular tumors For advanced tumors (T3 and T4), positive surgical margins, perineural spread, perivascular invasion, cervical lymph node metastasis, and recurrent tumors, a combination of surgery and adjuvant radiotherapy with and without chemotherapy is recommended Traditional open approaches for resection a. Caldwell-Luc b. Midface degloving c. Lateral Rhinotomy d. Weber-Fergusson e. Craniofacial resection f. Bicoronal craniotomy Extended endoscopic approaches to the skull base a. Transodontoid b. Transclinoid c. Transtuberculum d. Transplanum e. Transcribiform f. Transmaxillary-transpterygoid Hybrid cranioendoscopic

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Questions 1. A patient presents with unilateral nasal obstruction and a polypoid mass is seen in the right nasal cavity on endoscopy. What do you do next? a. In-office Biopsy b. Reassurance – most likely a benign polyp c. Schedule for intra-operative biopsy, frozen section analysis, and possible resection d. Imaging – MRI or CT 2. The most common benign tumor of the paranasal sinuses is: a. Osteoma b. Imaging Fibrous dysplasia c. Inverted papilloma d. Lobular capillary hemangioma 3. You are discussing management options for a patient with sinonasal inverted papilloma. You recommend surgical excision, based in part on the rate of transformation to squamous cell carcinoma for this lesion. What is the approximate frequency of malignant transformation for this neoplasm? a. 1-2% b. 3-5% c. 5-15% d. 35% 4. The most common sinonasal malignancy is: a. Adenocarcinoma b. Squamous cell carcinoma c. Sinonasal undifferentiated carcinoma d. Mucoepidermoid carcinoma 5. The most common site of a paranasal sinus malignancy is the: a. Nasal cavity b. Maxillary sinus c. Ethmoid sinus d. Sphenoid sinus

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References Bignami, M., Dallan, I., Terranova, P., Battaglia, P., Miceli, S., and Castelnuovo, P. (2007). Frontal sinus osteomas: the window of endonasal endoscopic approach. Rhinology, 45(4), 315-320. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/18085027. Bishop, J. A. (2017). OSPs and ESPs and ISPs, Oh My! An Update on Sinonasal (Schneiderian) Papillomas. Head Neck Pathol, 11(3), 269-277. doi:10.1007/s12105-017-0799-9. Danesi, G., Panciera, D. T., Harvey, R. J., and Agostinis, C. (2008). Juvenile nasopharyngeal angiofibroma: evaluation and surgical management of advanced disease. Otolaryngol Head Neck Surg, 138(5), 581-586. doi:10.1016/j.otohns.2008.01.011. Dulguerov, P., Allal, A. S., and Calcaterra, T. C. (2001). Esthesioneuroblastoma: a meta-analysis and review. Lancet Oncol, 2(11), 683-690. doi:10.1016/S1470-2045(01)00558-7. El-Naggar, A. K., Chan, J. K. C., Grandis, J. R., Takata, T., and Slootweg, P. J. (2017). WHO Classification of Head and Neck Tumours, International Agency for Research on Cancer. Ellington, C. L., Goodman, M., Kono, S. A., Grist, W., Wadsworth, T., Chen, A. Y., . . . Saba, N. F. (2012). Adenoid cystic carcinoma of the head and neck: Incidence and survival trends based on 1973-2007 Surveillance, Epidemiology, and End Results data. Cancer, 118(18), 4444-4451. doi:10.1002/cncr.27408. Erdogan, N., Demir, U., Songu, M., Ozenler, N. K., Uluc, E., and Dirim, B. (2009). A prospective study of paranasal sinus osteomas in 1,889 cases: changing patterns of localization. Laryngoscope, 119(12), 23552359. doi:10.1002/lary.20646. Fatterpekar, G. M., Delman, B. N., and Som, P. M. (2008). Imaging the paranasal sinuses: where we are and where we are going. Anat Rec (Hoboken), 291(11), 1564-1572. doi:10.1002/ar.20773. Fu, Y. S., and Perzin, K. H. (1974). Non-epithelial tumors of the nasal cavity, paranasal sinuses, and nasopharynx. A clinicopathologic study. II. Osseous and fibro-osseous lesions, including osteoma, fibrous dysplasia, ossifying fibroma, osteoblastoma, giant cell tumor, and osteosarcoma. Cancer, 33(5), 12891305. doi:10.1002/1097-0142(197405)33:53.0.co;2-p. Ganly, I., Patel, S. G., Singh, B., Kraus, D. H., Bridger, P. G., Cantu, G., . . . Shah, J. P. (2005). Craniofacial resection for malignant paranasal sinus tumors: Report of an International Collaborative Study. Head Neck, 27(7), 575-584. doi:10.1002/hed.20165. Gotte, K., and Hormann, K. (2004). Sinonasal malignancy: what’s new? ORL J Otorhinolaryngol Relat Spec, 66(2), 85-97. doi:10.1159/000077801. Hong, S. L., Kim, B. H., Lee, J. H., Cho, K. S., and Roh, H. J. (2013). Smoking and malignancy in sinonasal inverted papilloma. Laryngoscope, 123(5), 1087-1091. doi:10.1002/lary.23876. Jethanamest, D., Morris, L. G., Sikora, A. G., and Kutler, D. I. (2007). Esthesioneuroblastoma: a populationbased analysis of survival and prognostic factors. Arch Otolaryngol Head Neck Surg, 133(3), 276-280. doi:10.1001/archotol.133.3.276. Kaufman, M. R., Brandwein, M. S., and Lawson, W. (2002). Sinonasal papillomas: clinicopathologic review of 40 patients with inverted and oncocytic schneiderian papillomas. Laryngoscope, 112(8 Pt 1), 13721377. doi:10.1097/00005537-200208000-00009. Lawson, W., Schlecht, N. F., and Brandwein-Gensler, M. (2008). The role of the human papillomavirus in the pathogenesis of Schneiderian inverted papillomas: an analytic overview of the evidence. Head Neck Pathol, 2(2), 49-59. doi:10.1007/s12105-008-0048-3. Ledderose, G. J., Betz, C. S., Stelter, K., and Leunig, A. (2011). Surgical management of osteomas of the frontal recess and sinus: extending the limits of the endoscopic approach. Eur Arch Otorhinolaryngol, 268(4), 525-532. doi:10.1007/s00405-010-1384-y. Lin, E. M., Sparano, A., Spalding, A., Eisbruch, A., Worden, F. P., Heth, J., . . . Marentette, L. J. (2010). Sinonasal undifferentiated carcinoma: a 13-year experience at a single institution. Skull Base, 20(2), 6167. doi:10.1055/s-0029-1236165. Lombardi, D., Tomenzoli, D., Butta, L., Bizzoni, A., Farina, D., Sberze, F., . . . Nicolai, P. (2011). Limitations and complications of endoscopic surgery for treatment for sinonasal inverted papilloma: a reassessment after 212 cases. Head Neck, 33(8), 1154-1161. doi:10.1002/hed.21589.

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Malempati, S., and Hawkins, D. S. (2012). Rhabdomyosarcoma: review of the Children’s Oncology Group (COG) Soft-Tissue Sarcoma Committee experience and rationale for current COG studies. Pediatr Blood Cancer, 59(1), 5-10. doi:10.1002/pbc.24118. Nicolai, P., Castelnuovo, P., Lombardi, D., Battaglia, P., Bignami, M., Pianta, L., and Tomenzoli, D. (2007). Role of endoscopic surgery in the management of selected malignant epithelial neoplasms of the nasoethmoidal complex. Head Neck, 29(12), 1075-1082. doi:10.1002/hed.20636. Nudell, J., Chiosea, S., and Thompson, L. D. (2014). Carcinoma ex-Schneiderian papilloma (malignant transformation): a clinicopathologic and immunophenotypic study of 20 cases combined with a comprehensive review of the literature. Head Neck Pathol, 8(3), 269-286. doi:10.1007/s12105-014-05277. Overdevest, J. B., Amans, M. R., Zaki, P., Pletcher, S. D., and El-Sayed, I. H. (2018). Patterns of vascularization and surgical morbidity in juvenile nasopharyngeal angiofibroma: A case series, systematic review, and meta-analysis. Head Neck, 40(2), 428-443. doi:10.1002/hed.24987. Patel, S. G., Singh, B., Polluri, A., Bridger, P. G., Cantu, G., Cheesman, A. D., . . . Shah, J. P. (2003). Craniofacial surgery for malignant skull base tumors: report of an international collaborative study. Cancer, 98(6), 1179-1187. doi:10.1002/cncr.11630. Qiu, Q. H., Liang, M. Z., Liu, H., Chen, S. H., Zhang, H. B., and Zhang, Q. H. (2010). [Nasal endoscopic surgical treatment for chondrosarcoma of paranasal sinus and the skull base]. Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi, 45(7), 551-554. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/ 21055050. Schick, B., Plinkert, P. K., and Prescher, A. (2002). [Aetiology of Angiofibromas: Reflection on their Specific Vascular Component]. Laryngorhinootologie, 81(4), 280-284. doi:10.1055/s-2002-25322. Schreiber, A., Villaret, A. B., Maroldi, R., and Nicolai, P. (2012). Fibrous dysplasia of the sinonasal tract and adjacent skull base. Curr Opin Otolaryngol Head Neck Surg, 20(1), 45-52. doi:10.1097/MOO.0b013e32834e901c. Shuman, A. G., Light, E., Olsen, S. H., Pynnonen, M. A., Taylor, J. M., Johnson, T. M., and Bradford, C. R. (2011). Mucosal melanoma of the head and neck: predictors of prognosis. Arch Otolaryngol Head Neck Surg, 137(4), 331-337. doi:10.1001/archoto.2011.46. Tiwari, R., Hardillo, J. A., Mehta, D., Slotman, B., Tobi, H., Croonenburg, E., . . . Snow, G. B. (2000). Squamous cell carcinoma of maxillary sinus. Head Neck, 22(2), 164-169. doi:10.1002/(sici)10970347(200003)22:23.0.co;2-#. Zanation, A. M., Ferlito, A., Rinaldo, A., Gore, M. R., Lund, V. J., McKinney, K. A., . . . Devaiah, A. K. (2010). When, how and why to treat the neck in patients with esthesioneuroblastoma: a review. Eur Arch Otorhinolaryngol, 267(11), 1667-1671. doi:10.1007/s00405-010-1360-6.

Chapter 17

Minimally Invasive Surgical Techniques for the Management of Head and Neck Cancers Umamaheswar Duvvuri, MD, PhD and Benjamin L. Judson, MD, MBA Introduction This chapter covers trans-oral surgical approaches to treating head and neck cancers and tumors. There are three primary modalities for performing trans-oral tumor resections of upper aerodigestive tract tumors, which include: 1. Direct Transoral Surgery (DTS) which is performed with a headlight and possibly loupes 2. Trans-oral robotic surgery (TORS) 3. Transoral laser microsurgery (TLM). Specifics of each of these approaches will be covered below along with general principles for trans-oral surgeries.

Anatomy 1. Trans-oral surgery requires familiarity with anatomy from an inside-out perspective. 2. Consider layer by layer anatomic relationships of key structures starting from mucosa of the upper aerodigestive tract and working outwards towards the skin. 3. Knowledge should include: a. Anatomic orientation and landmarks including major structures, musculature, and fascial planes (e.g., submandibular gland, digastric, styloglossus, and stylopharyngeus muscles, thyrohyoid membrane). b. Location and relationships of vascular structures (e.g., branches of lingual and superior laryngeal arteries). c. Course and function of nerves (e.g., CN’s V, IX, XII).

In: Essential Head and Neck Oncology and Surgery Editors: Maie A. St. John and Benjamin L. Judson

ISBN: 979-8-88697-438-6 © 2023 Nova Science Publishers, Inc.

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See chapter 1 for a review of oropharyngeal, hypopharyngeal, and laryngeal anatomy. ii. Patient and tumor specific anatomic considerations are reviewed with each trans-oral approach.

Treatment Selection 1. Careful consideration in choosing when to use a trans-oral treatment approach is paramount to success. 2. With each treatment approach, tumor and patient considerations can be used to determine a patient’s candidacy for trans-oral surgery. 3. Consideration of open surgical and non-surgical treatment options is important. Multidisciplinary team evaluation and discussion is highly recommended for treatment decisions. Just because you can do a trans-oral surgery on a particular patient does not mean that it is the best treatment for them. 4. Each minimally invasive treatment approach has indications that overlap in some areas and have relative advantages and disadvantages. There are situations where one or another or multiple trans-oral approaches may be appropriately considered. 5. Although these techniques are “minimally invasive” in their approach, they can result in large defects that require significant healing and recovery. They also have the potential to have a large impact on a patient’s ability to speak and swallow. 6. Specific treatment selection considerations for oropharynx, larynx, and hypopharynx tumors are covered in Chapters 13, 14, and 15.

Management of the Neck 1. Depending on tumor histology and clinical situation, DTS, TORS, TLM surgeries are often combined with management of the neck with neck dissection when there is a clinically evidence neck disease, or based on the risk of occult disease when the neck is clinically negative. 2. Squamous cell carcinoma of the oropharynx, both HPV+ and HPV-, generally requires elective or therapeutic treatment of the neck. 3. Ipsilateral neck needs to be treated for tonsil cancers and lateralized cancers. 4. Bilateral neck dissection needs to be performed for all but the most lateralized base of tongue tumors. 5. Ligation of branches of the external carotid artery or the entire external carotid artery on the side of the primary tumor can be performed during neck dissection to reduce the risk of large volume bleeds. The vessels do not need to be transected but only need to be clipped or tied. This is primarily a consideration for TORS surgeries and is not routinely done either for DTS or TLM. 6. Neck dissection can be staged or combined and done at same time as the trans-oral tumor resection.

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Staged

Combined

Anesthetic

Multiple

One

Allows for more efficient use of equipment that cannot be moved to another OR, such as a robot Vessel ligation performed at the time of neck dissection to reduce risk of bleeding can only be done if neck dissection surgery is done prior to the transoral surgery Staging allows for improvement in airway edema, which is usually only a major consideration during laryngeal surgery

Equipment that cannot be moved to another OR is occupied for the entire length of the surgery

Equipment

Vessel ligation

Airway edema

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Vessel ligation can be performed when neck dissection is done first as part of a combined surgery

Edema of the upper aerodigestive tract may be greater with combined surgeries

Complications Bleeding 1. Can vary from minor nuisance bleeding to major bleeding requiring return to the operating room and even the risk of death. 2. Methods to reduce risk of bleeding: a. Careful hemostasis with electrocautery and bipolar cautery, including use of these modalities when surgery is primarily done using a laser. b. Use of endoscopic clips for discrete vessels. c. Larger vessels, such as the superior laryngeal artery, should be intentionally identified, and are best managed with clipping. d. Use of ties is possible when performing DTR. e. During neck dissection portion of surgery, identification and ligation of vessels feeding the tumor site. 3. Management of bleeding. a. Sentinel minor bleeding can precede more significant bleeding and should be assessed carefully. b. Assess and secure airway if needed. c. Resuscitate with fluids and blood as needed. d. Return to the OR for persistent bleeding and consider the OR for significant bleeding that has resolved spontaneously. e. Consider monitoring based on the amount of bleeding if source has not been identified and treated. f. CT angiogram can be used if the source of a more significant bleed has not been identified.

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Dysphagia and Aspiration 1. Pre-operative swallowing function should be assessed through history and physical, and preferably also with formal evaluation by a Speech Language Pathologist. This can be done with: a. Modified barium swallow (MBS), or b. Functional Endoscopic Evaluation of Swallow (FEES). 2. Pre-operative and post-operative swallow therapy and techniques can improve swallow recovery following endoscopic surgery. 3. Nasogastric feeding immediately post-operatively can be used if a patient is aspirating or has initial dysphagia that prevents adequate nutritional intake. 4. Assessment of pulmonary function and reserve should be considered when aspiration is expected, such as with more extensive supraglottic resections.

Direct Trans-Oral Surgery (DTS) Equipment 1. Head light – good illumination is critical. a. Battery powered lights allow more freedom of movement. b. Corded lights can work well for DTS if they provide bright focused light. 2. Loupes –utilization of 2.5x loupes for magnification are used by some surgeons. 3. Monopolar cautery a. Spatula tip is primary instrument. b. Insulated tip is needed to avoid injury to lips or other surrounding structures. c. Extended length tip is often needed. d. Suction cautery is usually not utilized and is inferior to bipolar for control of mucosal or muscle small vessel perforator bleeding. e. Newer cautery handpieces with smoke evacuators are useful for removing smoke from surgical field but are more likely to need extended tip to avoid clashes of handpiece with lips and teeth. 4. Bipolar cautery a. Long and insulated bipolars forceps. b. Foot pedal control. 5. Handheld CO2 laser a. Laser beam is delivered via flexible fiber. b. Handpieces of different lengths and angles are available. c. Effective for thin tumors limited to the mucosa or with limited depth of invasion. d. Can be used as an alternative to monopolar cautery for cutting which results in less thermal effect to tissue but does not have the same coagulative ability as monopolar cautery.

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6. Other instruments a. Long DeBakey forceps and other instruments. b. Extended length clip appliers, either reusable or disposable. c. Red-rubber catheter placed through nose for smoke evaluation.

Patient Selection General Medical Condition 1. 2. 3. 4. 5. 6.

Ability to undergo general anesthesia. Not taking anticoagulants. No underlying coagulopathy. Normal healing function. Normal immune system. Lung function is important if surgery is expected or has potential to worsen swallowing function and lead to aspiration.

Anatomy 1. Good transoral exposure of the tumor target is needed. Exposure is usually determined by: a. Good mouth opening. b. Low Mallampati score. c. No dental barriers such as loose teeth. d. Tongue that is not too large or obstructive. e. Absence of narrow mandible or mandibular tori. f. No retropharyngeal carotid or other large vessel that is immediately adjacent to the tumor.

Tumor Selection 1. DTS can be used for tumors of the: a. Tonsils. b. Lateral oropharynx including tonsillar pillars. c. Posterior pharyngeal wall of the oropharynx. d. Soft palate. 2. Tumors that are exophytic, pedunculated, mobile or smaller are more amenable to DTS. 3. Tumors that are endophytic, fixed, or with invasion into underlying structures tend to be less amenable to DTS. 4. Palate tumors can result in velopalantine insufficiency (VPI) if there is not sufficient soft palate to close off the pharynx.

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a.

Single sided closure of the pharynx on the side of the tumor resection can be used in some cases. b. If VPI results, this can be a difficult problem to address.

Anesthesia 1. Larger and exophytic tumors can create a difficult airway, requiring management with careful intubation approaches to avoid loss of the airway or trauma to the tumor with resultant bleeding. a. Video laryngoscope intubation (e.g., GlideScope or others) is appropriate and effective in most patients. b. Some patients require flexible fiberoptic intubation because of tumor or other patient factors. c. Collaboration and communication with an experienced anesthesia team is important. 2. Oral and nasal intubation are the preferred approaches and should be selected based on the tumor location and specifics. 3. Tracheostomy is not needed for DTS except in exceedingly rare cases. 4. Oral intubation can help with exposure of tonsil tumors by aiding in retraction of the base of tongue. 5. Nasal intubation via nostril contralateral to the tumor can place endotracheal tube away from the tumor. 6. Precautions for airway fires must be carefully adhered to during DTS. This includes: a. Low fiO2 - should be less than 30% if tolerated by the patient, and definitely lower than 50% fraction inhaled of oxygen. b. Monitoring for and addressing gas leaks around the endotracheal tube balloon. c. Avoiding contacting the endotracheal tube with electrocautery or laser. d. If airway fire occurs, immediate steps should be taken: i. Disconnect the ETT before extubating the patient to avoid “flame thrower” effect on the airway. ii. After extubation, place saline in the airway. iii. Patient should be reintubated and endoscopy performed. iv. Hospital regulations generally require fire alarm activation for any type of fire in the OR. 7. Airway is generally improved after tumor resection and extubation at the end of the case is usually safe and preferred.

Retraction 1. Having a variety of different retractors immediately available and trying different exposure techniques is useful for getting the best exposure possible. a. McIvor b. Crowe-Davis c. Dingman

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d. Sweetheart retractor, Hurd retractor, or other retractors held by the primary surgeon or by a bedside assistant. e. Red rubber catheter to retract soft palate, looped through the nose and out through the mouth and secured with a clamp. 2. Tongue retraction can be important and supplemented with additional measures that include: a. Thick silk stitch through the tongue can be used to retract the tongue and pull it forward if necessary. b. If pulling the tongue forward over the lower teeth, a lower tooth guard should be used to prevent a bite injury to the tongue from compression against the lower teeth.

Procedures Depending on patient anatomy, the oropharynx except for the base of tongue is usually available for DTR. 1. Radical tonsillectomy. a. Lateral cut along the retromolar trigone, anterior/lateral to the anterior tonsillar pilar. b. Superior cut above the tonsillar fossa, just below or including a portion of the soft palate. c. Inferior cut just above or involving some of the base of tongue. Depending on how far inferiorly and anteriorly dissection is performed, sometimes the medial aspect of the submandibular gland and the posterior belly of the digastric muscle are vizualized. d. Cuts are made through the superior constrictor muscle and dissection is performed lateral to the muscle leaving the parapharyngeal fat as the lateral border posterior, which is a relatively avascular plane. e. Posteriorly, a cut is made through the pharynx to mobilize the specimen. f. The longus coli muscles can be visualized posteriorly. g. Care must be taken with the parapharyngeal space as this contains the carotid and internal jugular vessels. h. Pre-operatively it is important to make sure that there is not a retropharyngeal carotid. 2. Soft palate excisions. a. The limitation with resection of soft palate tumors is primarily due to the velopharyngeal insufficiency (VPI). This occurs when there is insufficient soft palate or insufficient soft palate mobility for this to reach the posterior pharyngeal wall and close of the nasopharynx during speech and swallow. This results in hyper-nasal speech and nasal regurgitation of liquids and foods.

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Trans-Oral Robotic Surgery (TORS) Robot Systems 1. DaVinci FDA approved for transoral use in 2009 for T1 and T2 tumors. a. Xi system is not FDA approved for TORS but its use for TORS has been published. b. SP (Single Port) system was approved for TORS in 2019. 2. Flex Robotic system was FDA approved for transoral use, for which it was primarily designed, in 2015. 3. There are other robotic technology and systems both in development and that have been FDA approved for uses other than TORS, with the expectation that additional systems will be coming to TORS in the future.

Patient Selection General Medical Condition 1. 2. 3. 4. 5.

Ability to undergo general anesthesia. No coagulopathy or anticoagulants. Normal healing function. Normal immune system. Lung function is important when surgery has the potential or expectation of worsening swallowing function and leading to aspiration.

Anatomy 1. Good transoral exposure of the tumor target is needed. Exposure is usually determined by: a. Good mouth opening. b. Low Mallampati score. c. No dental barriers such as loose teeth. d. Tongue that is not too large or obstructive. e. Absence of narrow mandible or mandibular tori. f. No retropharyngeal carotid or other large vessel that is immediately adjacent to the tumor.

Tumor Anatomy 1. TORS is primarily used for tonsil or base of tongue tumors. 2. Soft palate tumors can be addressed with TORS, but arguably does not provide an advantage over a non-robotic transoral technique. 3. Supraglottic tumor and nasopharyngeal tumor resections are possible in very select cases and have been described in the literature.

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Exophytic tumors are better targets than endophytic tumors. Tumors with some mobility are better than more fixed tumors. Invasion into underlying musculature can make excision more difficult. Tonsil tumors are usually easier to access than base of tongue tumors. Assessment of both tumor anatomy and access to the tumor should be carefully assessed in the clinic with history and physical. A direct laryngoscopy with use of operative retractors for exposure can also be used in borderline or difficult cases.

Anesthesia 1. Larger and exophytic tumors can create a difficult airway, which needs to be managed with careful intubation approaches to avoid loss of the airway or trauma to the tumor with resultant bleeding. a. Video laryngoscope intubation (e.g., GlideScope or others) is appropriate and effective in most patients. b. Some patients require flexible fiberoptic intubation because of tumor or other patient factors. c. Collaboration and communication with an experienced anesthesia team is important. 2. Oral and nasal intubation are the preferred approaches and should be selected based on the tumor location and specifics. 3. Tracheostomy can be used but is very rarely required for TORS. 4. Oral intubation can help with exposure of tonsil tumors by aiding in retraction of the base of tongue. 5. Nasal intubation is often helpful with base of tongue tumors so that the endotracheal tube does not block access. 6. Precautions for airway fires must be carefully adhered to during TORS. This includes the same preventive measures and management as described in the DTS section above. Specific considerations for TORS include: a. Avoiding contacting the endotracheal tube with electrocautery. b. Consider using a reinforced or protected ETT to avoid damage to the tube as a result of trauma by the robotic instruments. c. Use ETT position (endonasal or to one side or held by a retractor) to reduce risk of ETT damage.

Retraction 1. Having a variety of different retractors immediately available and trying different exposure techniques is useful for getting the best exposure possible. a. McIvor – closed loop tooth retractor usually restricts access of robotic arms. b. Crowe-Davis – allows robotic arms more mobility than McIvor and can be useful for both tonsil and base of tongue exposure. c. Dingman – more open than McIvor. d. Feyh-Kastenbauer – has more adjustments possible than other retractors and in particular has a variety of blades for retracting and exposing the base of tongue.

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2. Retractors can be suspended for exposure. Options include: a. Mayo stand – can conflict with patient habitus or other instruments. b. Martin arm – attaches to bedside and more adjustable than Mayo. c. Feyh Kastenbauer – has suspension arm that attaches to the bedside, similar to the Martin arm. 3. Tongue retraction can be an important maneuver for exposure and supplemented with additional measures that include: a. Thick silk stitch through the tongue can be used to retract the tongue and pull it forward if necessary. b. If pulling the tongue forward over the lower teeth, using a lower tooth guard should be used to prevent a bite injury to the tongue from compression against the teeth by the retractor.

Procedures 1. Radical tonsillectomy. a. This is as descried in the DTR section above. b. TORS expands exposure for radical tonsillectomy, particularly to the inferior anatomy such as the base of tongue. 2. Base of tongue resection. a. This includes excision of base of tongue tumors, vallecular masses, and lingual tonsillectomy. b. Exposure is more difficult than with the radical tonsillectomy. c. Pre-operative ipsilateral ligation of the lingual artery is particularly useful in reducing nuisance bleeding during the procedure as well as major bleeding post-operatively. d. The key step with base of tongue resections is exposure. Sometimes, the entire resection site cannot be exposed at once and sequential repositioning is required for complete access. e. Depth of resection can vary from just below the lingual tonsillar tissue, leaving the underlying muscular intact, to deeper resections of the muscular tissue. f. Resection of any portion of the epiglottis comes with significantly increased risk of dysphagia and aspiration.

Treatment Decision Making 1. Decisions should be made in collaboration with a multidisciplinary team that specializes in the management of head and neck cancers. 2. Most patients have non-operative management options. 3. For HPV associated oropharyngeal cancers, there are multiple trials exploring deintensification with the use of trans-oral surgery. 4. Patients should not be treated outside of standard of care if not supported by a randomized clinical trial or as a part of a trial. 5. Detailed discussion of management of oropharynx cancer is covered in Chapters 12 and 13.

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Trans-Oral Laser Microsurgery (TLM) History of TLM 1. Techniques for TLM were developed with the introduction of microscopic surgery, advanced laryngoscopy, and the CO2 laser. They were first pioneered in Germany where they became more established and have been promulgated and refined by TLM proponents in the United States. Overall, adoption in the United States has been more limited with lower utilization relative to radiation for the treatment of laryngeal cancers, compared to Europe. Unique aspects of the TLM approach include: a. Transection of tumors is encouraged to better assess tumor depth and improve access with bulkier tumors. This results in piecemeal resection. b. Frozen section margin control requires careful orientation of specimens and communication with the pathologist. c. Defects following TLM are allowed to heal by secondary intention which can contribute to slow recovery during the healing process.

Equipment 1. Microscope with high quality optics, with: a. Adjustable focus. b. Adjustable working distance, usually set at 400 mm. 2. CO2 laser with: a. Adjustable power to different Wattage levels. b. Targeting beam. c. Different modes such as continuous or repeating pulse. d. Some systems offer programed cutting shapes. 3. Micromanipulator to connect laser to the microscope enabling line-of-site use of the laser. 4. CO2 laser that can be used via flexible fibers. a. Not necessary but can be useful. b. Allows laser to be delivered via handheld instruments. 5. True Blue laser (455 nm). a. Increasingly used for ablation of early glottic cancers. b. Minimizes disruption of underlying normal tissue. 6. Variety of laryngoscopes to enable access to different targets and provide enough room for use of instruments and the laser through the scope. Laryngoscopes should be designed for laser use with a dull low-reflective surface. a. Dedo i. Overall good balance of exposure and working space. b. Hollinger i. Aka anterior commissure laryngoscope. ii. Smaller working channel restricts operative mobility, good for exposing hard to reach small targets.

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c.

Lindholm i. Designed for blade to go into vallecula and expose supraglottic larynx. ii. Large amount of working space. d. Weerda i. Bivalve with adjustable upper and lower blades. Longer versions used for exposure of Zenker’s diverticulum; shorter versions can provide good exposure of supraglottic larynx. e. Hinni i. Adjustable in multiple dimensions, useful for exposure of base of tongue and supraglottic larynx, sometimes also endo-larynx. 7. Suspension system. a. Two primary systems: i. Pilings. ii. Storz. b. Suspension arms that rest on patient’s chest. i. Must be careful of amount of pressure applied. ii. Can get in way of microscope. c. OR bed mounted suspension systems.

Procedures 1. Cordectomy. a. Classified into the following types by the European Laryngeal Society: i. Type I: Subepithelial cordectomy. ii. Type II: Subligamental cordectomy. iii. Type III: Transmuscular cordectomy. iv. Type IV: Total or Complete cordectomy. b. Voice outcomes for type III and IV are generally poor. c. Type I and II should be considered as a treatment option for early T stage glottic cancer (T1 and T2 tumors). d. Given the very low propensity of early stage glottic cancers for nodal metastasis, this is one of the few endoscopic surgeries that is not combined with neck dissection. 2. Supraglottic laryngectomy. a. Treatment option for T1, T2, and some T3 supraglottic cancers. b. Preferred treatment for tumors that are not radiosensitive, such minor salivary gland and sarcoma. c. Classified into the following types by the European Laryngeal Society: i. Type I: Limited excision – Excision of small superficial tumors on the free border of the epiglottis, the aryepiglottic fold, the arytenoids or the ventricular fold or any other part of the supraglottis. ii. Type II: Medial supraglottic laryngectomy with partial resection of the pre-epiglottic space.

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iii. Type III: Medial supraglottic laryngectomy with resection of the preepiglottic space. iv. Type IV: Lateral supraglottic laryngectomy. d. Swallowing therapy and rehabilitation is critical and takes time following surgery. 3. Hypopharynx resection. a. Because most hypopharynx tumors present with high T stage, candidates for endoscopic resection are rare.

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Questions 1. Effective strategies for reducing the risk of airway fire during TLM surgery include all the following EXCEPT: a. Use of laser safe endotracheal tube. b. Maintaining FiO2 below 65%. c. Maintaining adequate ETT balloon inflation. d. Use of saline soaked pledgets to protect surrounding structures. 2. Advantages of the KTP laser in treating larynx cancers include all the following EXCEPT: a. Useful in ablation techniques for glottic cancers. b. Limits thermal injury to underlying structures. c. Delivered via a fiber which can be used through flexible laryngoscopes. d. Preferred for treating T3 and T4 laryngeal cancers. 3. Which of the following is a potential reason to NOT perform TORS? a. Mallampati class II. b. T2 tonsil cancer. c. HPV+ oropharyngeal cancer with gross extra-nodal extension. d. Minor salivary gland cancer of the tonsil. 4. Strategies for avoiding bleeding complications include all of the following EXCEPT: a. Red blood cell resuscitation. b. Endoscopic clipping of named vessels. c. Ligation of tumor feeding vessels during neck dissection. d. Stopping anticoagulants pre-operatively. 5. Which of the following statements about margin control is CORRECT? a. En-bloc tumor resection during TLM is encouraged as a strategy to improve margin control. b. Margin control is an important reason to select between DTR and TORS. c. Direct communication and collaboration with the pathologist is an important contributor to successful TORS surgery. d. It is important to take margins with the electrocautery during TORS.

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References Ambrosch P, Kron M, Steiner W: Carbon dioxide laser microsurgery for early supraglottic carcinoma, Ann. Otol. Rhinol. Laryngol. 107:680–688, 1998. Ambrosch P, Brinck U, Fischer G, Steiner W: Special aspects of histopathologic diagnosis in laser microsurgery of cancers of the upper aerodigestive tract, Laryngorhinootologie 73:78–83, 1994. American Society of Anesthesiologists Task Force on Management of the Difficult Airway: Practice guidelines for management of the difficult airway: an updated report by the American Society of Anesthesiologists Task Force on Management of the Difficult Airway, Anesthesiology 98:1269–1277, 2003. Ferlito A, Silver C, Howard D, Silver C E, Howard D J, Laccourreye O, Rinaldo A,Owen R. The role of partial laryngeal resection in current management of laryngeal cancer: a collective review, Acta Otolaryngol. 120:456–465, 2000. Flint P W: Minimally invasive techniques for management of early glottic cancer, Otolaryngol. Clin. North Am. 35:1055–1066, 2002. Friedman A D, Hillman R E, Landau-Zemer T, Burns J A, Zeitels S M. Voice outcomes for photoangolytic KP laser treatment of early glottic cancer, Ann Otol Rhinol Laryngol 122(3):151–158, 2013. Hinni M L, Zarka M A, Hoxworth J M: Margin mapping in transoral surgery for head and neck cancer, Laryngoscope 123:1190–1198, 2013. 97. Batsakis JG: Surgical excision margins: a pathologist’s perspective, Adv. Anat. Pathol. 6:140–148, 1999. Iyer N G, Nixon I J, Palmer F, Kim L, Whitcher M, Katabi N, Ghossein R, Shah J P, Patel S G, Ganly I. Surgical management of squamous cell carcinoma of the soft palate: factors predictive of outcome, Head Neck 34:1071–1080, 2011. Jako G J, Vaughan C W, Strong M S, Polanyi T G: Surgical management of malignant tumors of the aerodigestive tract with carbon dioxide laser microsurgery, Int. Adv. Surg. Oncol. 1:265–284, 1978. Jepsen M C, Gurushanthaiah D, Roy N, Smith M E, Gray S D, Davis R K. Voice, speech, and swallowing outcomes in laser-treated laryngeal cancer, Laryngoscope 113:923–928, 2003. Kennedy J T, Paddle P M, Cook B J, Chapman P, Iseli T A. Voice outcomes following transoral laser microsurgery for early glottic squamous cell carcinoma, J. Laryngol. Otol. 20:1–5, 2007. Kirchner J A: One hundred laryngeal cancers studied by serial section, Ann. Otol. Rhinol. Laryngol. 78:689, 1969. Moore E J, Olsen K D, Kasperbauer J L: Transoral robotic surgery for oropharyngeal squamous cell carcinoma: a prospective study of feasibility and functional outcomes, Laryngoscope 119:2156–2164, 2009. Remacle M, Eckel H E, Antonelli A, Brasnu D, Chevalier D, Friedrich G, Olofsson J, Rudert H H, Thumfart W, de Vincentiis M, Wustrow T P. Endoscopic cordectomy. A proposal for a classification by the Working Committee, European Laryngological Society, Eur. Arch. Otorhinolaryngol. 257:227–231, 2000. Roy S, Smith L P: What does it take to start an oropharyngeal fire? Oxygen requirements to start fires in the operating room, Int. J. Pediatr. Otorhinolaryngol. 75:227–230, 2011. Schuller D E, Trudeau M, Bistline J, LaFace K. Evaluation of voice by patients and close relatives following different laryngeal cancer treatments, J. Surg. Oncol. 44:10–14, 1990. Steiner W, Ambrosch P: The role of the phoniatrician in laser surgery of the larynx. In Steiner W, Ambrosch P, editors: Endoscopic laser surgery of the upper aerodigestive tract, New York, 2000, Thieme, pp 124– 129. Steiner W: Results of curative laser microsurgery of laryngeal carcinomas, Am. J. Otolaryngol. 14:116–121, 1993. Weinstein G S, O’Malley B W, Cohen M A, Quon H. Transoral robotic surgery for advanced oropharyngeal carcinoma, Arch. Otolaryngol. Head Neck Surg. 136:1079–1085, 2010. Zeitels S M, Burns J A: Oncologic efficacy of angiolytic KTP laser treatment of early glottic cancer, Ann. Otol. Rhinol. Laryngol. 123(12):840–846, 2014. Zeitels S M, Vaughan C W, Domanowski G F: Endoscopic management of early supraglottic cancer, Ann. Otol. Rhinol. Laryngol. 99:951–956, 1990.

Chapter 18

Neck Dissection and Management of the Neck Samuel Auger, MD Gina Jefferson, MD, MPH, FACS and Nishant Agrawal, MD Background 1. Surgical management of the neck in mucosal squamous cell carcinoma (SCC) of the head and neck is a critical part of a head and neck surgeon’s armamentarium. 2. Crile described the radical neck dissection in 1906 and the field has since moved toward balancing oncologically sound treatment with reduction of morbidity [1]. 3. Anatomic sites of the head and neck have predictable lymphatic drainage patterns, and defined rates of occult regional metastases considered for neck dissection to reduce rates of regional recurrence. A comprehensive neck dissection, with at least 18 lymph nodes removed, can increase prognostic accuracy, and decrease rates of persistence or recurrence in the neck [2]. 4. Cervical node status is a crucial prognostic factor.

Anatomy Six defined nodal levels: 1. Ia: defined by anterior bellies of digastric muscles below mandible, above hyoid. 2. Ib: triangle between anterior and posterior bellies of digastric muscles and mandible. 3. II: skull base to inferior border of hyoid, strap muscles to posterior SCM. IIa; anterior to CN XI, IIb; posterior to CN XI. 4. III: Inferior border of hyoid to inferior border of cricoid, strap muscles to posterior SCM. 5. IV: Inferior border of cricoid to clavicle, strap muscles to posterior SCM. 6. V: Posterior border of SCM to anterior border of trapezius. Va: above level of cricoid, Vb; below. 7. VI: Hyoid to suprasternal notch, between lateral borders of sternohyoid muscles. In: Essential Head and Neck Oncology and Surgery Editors: Maie A. St. John and Benjamin L. Judson

ISBN: 979-8-88697-438-6 © 2023 Nova Science Publishers, Inc.

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Figure 1. Levels of the neck (Illustration ©Chris Gralapp).

Work-Up Metastatic Cervical Lymphadenopathy 1. Physical exam – palpation of the neck for lymphadenopathy is important but subject to high rates of error due to skill level, patient habitus, and treatment-related changes. 2. Flexible laryngoscopy – allows visualization of mucosal surfaces to evaluate for ulceration, asymmetry, lesions, fullness. 3. Biopsy – obtain biopsy +/- U/S guidance for suspicious neck mass. FNA is first line; consider core biopsy if inadequate sample for p16 or other molecular testing. 4. Ultrasound – useful in mapping extent of cervical LN involvement and characterizing high-risk features; inadequate for HNC where retropharyngeal nodes at risk. 5. CT neck with contrast– evaluates size and extent of LAD and possible presence of extranodal extension in the neck. 6. MRI with gadolinium – best imaging modality for assessing extent of soft tissue involvement including suggestion of extranodal extension in the neck. 7. PET/CT – indicated for initial work-up for advanced stage HPV-negative HNCA, HPV-positive HNCA, unknown primary, and recurrence/metastasis or ~ 3 months after completion of treatment for surveillance.

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Table 1. Work up of suspicious neck mass cN+, known primary cN+, occult primary cN0 neck, known primary Salvage after definitive CRT

Physical exam, flexible fiberoptic laryngoscopy, DL + biopsy, FNA, p16 testing if oropharynx, CT + PET if advanced stage Physical exam, flexible fiberoptic laryngoscopy, FNA, p16, EBV, CT + PET, DLB, consider TORS BOT mucosectomy/tonsillectomy Driven by occult-metastasis risk, >15-20% = ND. SLNB or ND for oral cavity Post-treatment PET after 3 months

Primary Sites Mucosal cancers of the head and neck are divided into oral cavity (mucosal lip/vestibule, alveolar ridge, floor of mouth, oral tongue, buccal mucosa, hard palate, retromolar trigone), oropharynx (palatine tonsil, lingual tonsil, soft palate), larynx (supraglottis, glottis, subglottis), hypopharynx (piriform sinus, postcricoid/esophageal inlet, posterior pharyngeal wall), nasopharynx, and nasal cavity.

Figure 2. Mucosal sites and subsites of the head and neck (Illustration ©2022 Terese Winslow LLC).

Lymphatic Drainage and Likely Involvement of Neck Levels 1. Nasopharynx [3] a. Nasopharynx – II, V, retropharyngeal, often bilateral. 2. Oral cavity [4] a. Upper lip – IB, perifacial, periparotid, level II. b. Lower lip – IA, IB bilaterally, perifacial, level II. c. Upper alveolar ridge – IB, II, bilateral if midline.

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d. Lower alveolar ridge – IA, IB, II, bilateral if midline. e. Oral tongue – I, II, III, IV (skip metastases), bilateral if midline. f. Floor of mouth – IA, IB, II, bilateral if midline. g. Retromolar trigone – IIA, IIB, III. h. Hard palate – bilateral IB, II, retropharyngeal, perifacial. i. Buccal mucosa – IB, II. 3. Oropharynx [3] a. Base of tongue – II, III, deep drainage may cross contralaterally. b. Palatine tonsil – II, III, retropharyngeal nodes. c. Soft palate – II-IV, retropharyngeal nodes, bilateral if midline. 4. Larynx [3] a. Supraglottis – II, III, possibly bilateral. b. Glottis – sparse drainage, drainage is via extension to supra- or sub-glottis. c. Subglottis – II, III, IV, VI, possibly bilateral. 5. Hypopharynx [3] a. Pyriform sinus – II, III, bilateral if midline. IV, V if advanced disease.

Rates of Occult Regional Metastasis 1. Risk of occult metastasis ≥15% should undergo END or SNLB [5, 6]. 2. Elective or therapeutic neck dissection should be performed for all T3/T4 tumors and/or patients with clinically N+ neck. 3. Rates of occult regional metastases vary with tumor size, grade, anatomic subsite, midline involvement, and depth of invasion. 4. Oral cavity SCC: Increased risk for metastasis with DOI > 4mm for all oral mucosal subsites [7–9]. a. Lip: T1/T2 4%; T3/T4 23% [10]. b. Oral Tongue: 28.3%- 42%11–14; T1 21%, T2 45% [15]. i. DOI < 4mm 1.4%, ≥ 4mm 36% [9]. c. Hard palate/upper alveolar ridge: 15-25% [16, 17]. d. Lower alveolar ridge: 27.8% [18]. e. Floor of Mouth: T1 18.2% - 31.5% [13, 19], up to 62% in T2 SCC [20]. f. RMT: 8.3 - 20% [21–23]. g. Buccal mucosa: 22-26% [24, 25]. 5. Larynx SCC – ranges from 4% - 35% with risk of contralateral spread. There is higher risk with lateral spread beyond the true vocal cords and bilateral involvement. 6. Oropharyngeal SCC – ranges from 22% - 24% for ipsilateral neck, 21% - 28.6% contralateral [26, 27]. There is increased risk with high T stage and midline disease. HPV+ occult metastasis is rare. In the case of primary recurrence after an initially N0 neck is treated primarily with radiation, rates of occult metastases in the neck are 12.9% for oropharyngeal cancer, 16.2% for oral cavity, 23.7% for hypopharynx, and 27.3% for supra/transglottic cancers [28].

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Table 2. Levels of neck dissection by site and stage, HNSCC Primary

Extent of ND

OC T1-T4 N0

I-III/IV or SLNB [29]

OP T1-T2 N0-N2, HPV+

II-IV

OP T0-T2 N1, HPV+ OP T1-T2 N0-N1 HPVOP T3-T4 N0-N1 OP T1-4a, N2-3

II-IV II-IV II-IV BND II-IV

Larynx T2-T4

I-IV, ipsilateral VI

Hypopharynx

II-IV

Nasopharynx

Primarily treated with XRT; ND dictated by recurrent disease nodal station(s)

Variation Bilateral if FOM or involvement of midline Bilateral if BOT, post. pharyngeal wall, soft palate

May spare IIb if no level II disease. Consider bilateral if midline involvement or T3/T4 Highly consider level V/VI with more distal disease Retropharyngeal nodes; typically involves V

Types of Neck Dissection 1. Radical neck dissection – removes all lymphatic and adjacent structures (CN XI, IJV, SCM) 2. Modified radical neck dissection – spares at least one of CN XI, IJV, or SCM 3. Selective neck dissection – addresses highest risk levels by primary site; indicated for N0 or limited neck metastases. Classified by levels dissected (SND I-III, for example) and generally done as an elective neck dissection. a. Lateral neck dissection (II-IV): oropharynx, hypopharynx, larynx b. Posterolateral neck dissection (II-V): cutaneous malignancy posterior to ear c. Supraomohyoid neck dissection (I-III): oral cavity, anterior tongue, FOM d. Anterolateral neck dissection (I-IV): sometimes used if concern for skip metastases to IV 4. Superselective neck dissection – dissection of a very limited number of nodal levels with preservation of all adjacent structures; most commonly performed in salvage setting 5. Central neck dissection – dissection of level VI nodal basins 6. Retropharyngeal neck dissection – transcervical or transoral dissection of RPLNs

Technique 1. Strong knowledge of the landmarks in each level is essential to safe dissection and removal of fibrofatty contents.

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2. Informed consent should include bleeding, infection, pain, scar/cosmetic deformity, lower lip/arm/tongue/shoulder weakness or paralysis, failure of procedure, recurrence or persistence of disease, need for additional procedures.

Figure 3. Extent of neck dissection types (Illustration © 2022 Terese Winslow LLC).

Set Up 1. General anesthesia without long-acting paralysis to allow for nerve monitoring of marginal mandibular, CN XI, CN XII. 2. Clean case, only perioperative antibiotics indicated. If communication between the upper aerodigestive tract and neck during ablation of tumor, consider treating as a clean/contaminated wound. 3. Supine, neck extended with shoulder roll and turned contralaterally 4. Prep and drape to include lower lip, clavicle, trapezius, earlobe, midline neck.

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Incisions 1. Mark planned transverse incision roughly two fingerbreadths below the mandible / level of the cricoid, hidden in a skin crease. 2. Inject with lidocaine with epinephrine for analgesia and hemostasis. 3. Incise skin sharply with a #15 blade, carry the incision through the dermis until subcutaneous fat is encountered. Identify and preserve marginal mandibular nerve. 4. Raise superior and inferior flaps just deep to the platysma with care to avoid the external jugular vein and greater auricular nerve laterally. Dissect up to mandible superiorly and to clavicle inferiorly. If a tracheostomy is being performed, take care to avoid communication with surgical sites inferiorly. 5. Level I a. Dissect along submental mandible to identify contralateral anterior belly of the digastric muscle. b. Identify submandibular gland, incise fascia. Ligate, divide, and reflect facial vein and facial artery superiorly, protecting the marginal mandibular nerve. Ligate facial vein with sufficient length for microvascular reconstruction if a free flap is planned. c. Identity the lingual nerve and divide the submandibular gland ganglion if resecting the submandibular gland. d. Ligate, divide, and reflect facial artery along the posterior aspect of the digastric with sufficient length for microvascular reconstruction if a free flap is planned. e. Continue dissection of fibrofatty contents toward ipsilateral digastric and CN XII, reflecting down to include in level II content. 6. Levels II-IV a. Identify and skeletonize SCM, divide overlying fascia and reflect medially. b. Identify, skeletonize, and preserve CN XI. c. If IIB is to be included, contents may be dissected and passed below the nerve and included with IIA contents. d. Divide SCM fascia and fat to the floor of the neck (identify cervical rootlets), posterior to internal jugular vein to establish a posterior boundary to the dissection. e. Identify vagus nerve and carotid artery as specimen is retracted medial and divided from the jugular adventitia. f. Dissect specimen off strap muscles inferiorly, and level II structures superiorly (hypoglossal nerve, distal branches of IJ and external carotid). g. Inspect level IV for chyle leak as anesthesia holds Valsalva. 7. Level V a. After skeletonizing the SCM posterior border while taking care to identify and preserve CN XI, if uninvolved, to the trapezius. b. Divide fibrofatty tissue at level of transverse cervical vessels moving posteriorly toward the trapezius. c. Separate fibrofatty contents from anterior border of trapezius passing the contents beneath CN XI back toward the SCM and contents of levels II-IV.

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8. Level VI a. Often addressed simultaneously and in continuity with laryngectomy or thyroidectomy. b. Separate fibrofatty tissue from carotid sheath at level of hyoid superiorly to clavicle inferiorly taking care to identify and dissect from RLN when appropriate (thyroidectomy) moving toward the trachea. 9. Specimen a. Clearly label specimen labels with consistent nomenclature and technique. 10. Drains a. Place perforated drains which should be placed to continuous suction during closure to avoid clotting and transitioned to bulb suction post-op. 11. Closure a. Platysma and subcutaneous layer should be close with 3-0 vicryl, interrupted. b. Subdermal layer. c. Skin may be closed with running 5-0 fast, skin glue, or other closure techniques with consideration of prior radiation, nutritional status, and history of wound healing issues.

Complications 1. Chyle leak – highest risk when dissecting left level IV. Presents with milky and often high-volume drain output. Manage with very low or no fat diet, pressure dressing followed by re-exploration, IR intervention or VATs for refractory cases. 2. Marginal mandibular nerve weakness – from stretch, thermal, or accidental transection. 3. Accessory nerve weakness – from stretch injury, thermal injury, cicatrix formation, and/or accidental transection; all neck dissection patients should be evaluated by PT on POD#1 and as an outpatient, if indicated. 4. Hematoma/seroma – Good hemostasis is crucial. Rate of accumulation dictates management; observation, bedside evacuation, pressure dressing, and emergent return to OR to control bleeding.

Management of the N0 Neck and Other Controversies 1. Rates of occult metastasis vary with subsite. Elective neck dissection (END) allows for pathologic staging of the neck, prognosticating, and guiding adjuvant treatment decisions. 2. Consider sentinel lymph node biopsy for oral cavity cT1/T2N0. 3. A neck found to be N0 by traditional modalities (imaging, H&E stain) may later be shown to be positive by additional diagnostic modalities (immunohistochemistry or molecular testing, for example) [30]. 4. Oropharynx: rarely presents as N0, limited studies available. Generally, recommend ipsilateral END to achieve progression free survival [31].

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Early Oral Cavity, N0 Neck 1. Survival benefit with initial END compared to therapeutic ND at time of relapse with 80% and 67.5% 3-year survival, respectively [32]. 2. Previous recommendations set threshold for END at 15-20% rate of occult metastases [5, 6]. 3. More recent studies established that T2+ tumors warrant END with rates of occult metastasis nearing 25%. T1 (11.5%) is less clear cut and tumor subsite, DOI (oral tongue), and experience may inform the decision perform SLNB vs END [33]. 4. There is good evidence for SLNB or END in early oral cavity cancer with comparable outcomes [29, 34]. 5. DOI plays a critical role and warrants consideration when discussing treatment of neck. 6. High risk features including perineural invasion, lymphovascular invasion, poorly differentiated primary, and close or involved margins warrant more aggressive adjuvant treatment which may include END. 7. Recent retrospective cohort study recommended END for T1N0 SCC with DOI > = 3mm or < 3mm with high-risk features [35].

T1 Glottic Larynx, N0 Neck 1. Clear evidence for treatment of the neck for T2+ of supraglottis and T3+ of glottis and subglottis. 2. High rates of micro-metastases not detected on clinical and radiographic exam [30]. 3. Selective lateral neck dissection vs radiation vs intraoperative sentinel lymph node biopsy [36, 37] vs observation depending on treatment of primary cancer and patient/institution preference. 4. END provides useful staging and therapeutic information while initial radiation does not. 5. Surgery can be followed by radiation, if needed, while re-irradiation places patients at higher risk of complications. 6. Some authors advocate ipsilateral neck dissection with bilateral being performed if initial specimen is positive on frozen [38]. 7. T1 treatment of the neck remains controversial for the supraglottis and not indicated for the glottic larynx.

Inclusion of IIB and IV in Larynx SCC 1. Laryngeal lymphatics are very predictable with controversy regarding which levels to include in neck dissection. 2. Levels II-IV are at risk for lymphatic spread from T3-T4 glottic cancers. 3. Given low risk of spread (1.4-2.3%) to level IIB, some surgeons advocate excluding this from standard practice for laryngectomy patients if level IIA is not involved [39]. 4. Recent practice has trended toward selective neck dissection for the clinically negative neck.

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Questions: 1. For which oral cavity subsite is depth of invasion an important consideration for risk of occult metastatic disease and need to address the neck? a. Alveolar ridge b. Retromolar trigone c. Oral tongue d. Hard palate 2. The head and neck subsite that demonstrates the lowest propensity for occult metastatic disease for early T stage disease is which of the following: a. Glottis b. Oral tongue c. Pyriform sinus d. Tonsil 3. When performing neck dissection inclusive of level IV, which post-surgical complication is more likely to occur? a. Internal jugular vein laceration b. Chyle leak c. Vagus neuropathy d. Iatrogenic parathyroidectomy 4. Which structure anatomically demarcates the medial border of a lateral neck dissection? a. Trachea b. Internal jugular vein c. Sternohyoid muscle d. Ansa cervicalis 5. What extent of surgery is indicated for a midline cT1N0 oral tongue SCC a. SLNB b. END I-III c. Observation d. END II-IV

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Samuel Auger, Gina Jefferson and Nishant Agrawal Park J H, Nam W, Kim H J, Cha I H. Is elective neck dissection needed in squamous cell carcinoma of maxilla? J. Korean Assoc. Oral Maxillofac. Surg. 2017;43(3):166-170. doi:10.5125/jkaoms.2017.43. 3.166. Beltramini G A, Massarelli O, Demarchi M, Copelli C, Cassoni A, Valentini V, Tullio A, Giannì A B, Sesenna E, Baj A. Is neck dissection needed in squamous-cell carcinoma of the maxillary gingiva, alveolus, and hard palate? A multicentre Italian study of 65 cases and literature review. Oral Oncol. 2012;48(2):97-101. doi:10.1016/j.oraloncology.2011.08.012. Pimenta Amaral T M, Da Silva Freire A R, Carvalho A L, Pinto C A L, Kowalski L P. Predictive factors of occult metastasis and prognosis of clinical stages I and II squamous cell carcinoma of the tongue and floor of the mouth. Oral Oncol. 2004;40(8):780-786. doi:10.1016/j.oraloncology.2003.10.009. Hicks W L, Loree T R, Garcia R I, Maamoun S, Marshall D, Orner J B, Bakamjian V Y, Shedd D P. Squamous cell carcinoma of the floor of mouth: a 20-year review. Head Neck. 1997;19(5):400-405. doi:10.1002/(sici)1097-0347(199708)19:53.0.co;2-3. Demir U L, Öztürk Yanaşma H. Treatment Outcomes for Primary Retromolar Trigone Carcinoma: A Single Institution Experience. Turk. Arch. Otorhinolaryngol. 2020;58(2):87-92. doi:10.5152/tao. 2020.5153. Kowalski L P, Hashimoto I, Magrin J. End results of 114 extended “commando” operations for retromolar trigone carcinoma. Am. J. Surg. 1993;166(4):374-379. doi:10.1016/s0002-9610(05)803368. Hao S P, Tsang N M, Chang K P, Chen C K, Huang S S. Treatment of squamous cell carcinoma of the retromolar trigone. The Laryngoscope. 2006;116(6):916-920. doi:10.1097/01.mlg.0000214900. 07495.39. Hoda N, Bc R, Ghosh S, Ks S, B VD, Nathani J. Cervical lymph node metastasis in squamous cell carcinoma of the buccal mucosa: a retrospective study on pattern of involvement and clinical analysis. Med. Oral Patol. Oral Cirugia Bucal. 2021;26(1):e84-e89. doi:10.4317/medoral.24016. Diaz Jr. E M, Holsinger F C, Zuniga E R, Roberts D B, Sorensen D M. Squamous cell carcinoma of the buccal mucosa: One institution’s experience with 119 previously untreated patients. Head Neck. 2003;25(4):267-273. doi:10.1002/hed.10221. Lim Y C, Koo B S, Lee J S, Lim J Y, Choi E C. Distributions of cervical lymph node metastases in oropharyngeal carcinoma: therapeutic implications for the N0 neck. The Laryngoscope. 2006;116(7): 1148-1152. doi:10.1097/01.mlg.0000217543.40027.1d. Chung E J, Oh J I, Choi K Y, Lee D-J, Park I-S, Kim J-H, Rho Y-S. Pattern of cervical lymph node metastasis in tonsil cancer: predictive factor analysis of contralateral and retropharyngeal lymph node metastasis. Oral Oncol. 2011;47(8):758-762. doi:10.1016/j.oraloncology.2011.05.013. Finegersh A, Moss W J, Saddawi-Konefka R, Faraji F, Coffey C S, Califano J A, Brumund K T, Orosco R K. Meta-analysis of risk of occult lymph node metastasis in the irradiated, clinically N0 neck. Head Neck. 2020;42(9):2355-2363. doi:10.1002/hed.26248. Hasegawa Y, Tsukahara K, Yoshimoto S, Miura K, Yokoyama J, Hirano S, Uemura H, Sugasawa M, Yoshizaki T, Homma A, Chikamatsu K, Suzuki M, Shiotani A, Matsuzuka T, Kohno N, Miyazaki M, Oze I, Matsuo K, Kosuda S, Yatabe Y, HNCMM Research Group. Neck Dissections Based on Sentinel Lymph Node Navigation Versus Elective Neck Dissections in Early Oral Cancers: A Randomized, Multicenter, and Noninferiority Trial. J. Clin. Oncol. 2021;39(18):2025-2036. doi:10.1200/JCO.20.03637. Ferlito A, Rinaldo A. Controversies in the Treatment of N0; Neck in Laryngeal Cancer: Neck Dissection, No Surgery or Sentinel Lymph Node Biopsy? ORL. 2000;62(6):287-289. doi:10.1159/ 000027770. Jouhi L, Atula T, Mäkitie A, Keski-Säntti H. Management of clinically N0 neck in oropharyngeal carcinoma. Eur. Arch. Oto-Rhino-Laryngol. Off J. Eur. Fed. Oto-Rhino-Laryngol. Soc. EUFOS Affil. Ger. Soc. Oto-Rhino-Laryngol. - Head Neck Surg. 2019;276(4):1205-1210. doi:10.1007/s00405-01905314-x. D’Cruz A K, Vaish R, Kapre N, Dandekar M, Gupta S, Hawaldar R, Agarwal J P, Pantvaidya G, Chaukar D, Deshmukh A, Kane S, Arya S, Ghosh-Laskar S, Chaturvedi P, Pai P, Nair S, Nair D, Badwe

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R, Head and Neck Disease Management Group. Elective versus Therapeutic Neck Dissection in NodeNegative Oral Cancer. N. Engl. J. Med. 2015;373(6):521-529. doi:10.1056/NEJMoa1506007. Massey C, Dharmarajan A, Bannuru R R, Rebeiz E. Management of N0 neck in early oral squamous cell carcinoma: A systematic review and meta-analysis. The Laryngoscope. 2019;129(8):E284-E298. doi:10.1002/lary.27627. Lai S Y, Ferris R L. Evolving Evidence in Support of Sentinel Lymph Node Biopsy for Early-Stage Oral Cavity Cancer. J. Clin. Oncol. 2020;38(34):3983-3986. doi:10.1200/JCO.20.02716. Nguyen E, McKenzie J, Clarke R, Lou S, Singh T. The Indications for Elective Neck Dissection in T1N0M0 Oral Cavity Squamous Cell Carcinoma. J. Oral Maxillofac. Surg. Off J. Am. Assoc. Oral Maxillofac. Surg. 2021;79(8):1779-1793. doi:10.1016/j.joms.2021.01.042. Khadivi E, Daghighi M, Khazaeni K, Dabbagh Kakhki V R, Zarifmahmoudi L, Sadeghi R. IntraOperative Lymphatic Mapping and Sentinel Node Biopsy in Laryngeal Carcinoma: Preliminary Results. Iran. J. Otorhinolaryngol. 2015;27(81):285-291. Lawson G, Matar N, Nollevaux M C, Jamart J, Krug B, Delos M, Remacle M, Thierry Vander Borght. Reliability of sentinel node technique in the treatment of N0 supraglottic laryngeal cancer. The Laryngoscope. 2010;120(11):2213-2217. doi:10.1002/lary.21131. Desanto L W, Magrina C, O’Fallon W M. The “Second” Side of the Neck in Supraglottic Cancer. Otolaryngol. Neck Surg. 1990;102(4):351-361. doi:10.1177/019459989010200409. Riviere D, Mancini J, Santini L, et al. Nodal metastases distribution in laryngeal cancer requiring total laryngectomy: Therapeutic implications for the N0 Neck. Eur Ann Otorhinolaryngol Head Neck Dis. 2019;136(3S):S35-S38. doi:10.1016/j.anorl.2018.08.011

Chapter 19

Head and Neck Reconstructive Surgery Kristen A. Echanique, MD Joseph B. Meleca, MD Heather Edwards, MD Michael Fritz, MD, FACS and Rhorie P. R. Kerr, MD Introduction Defects of the head and neck can be challenging to repair. As the various components of the face, head, and neck are characterized by important forms and functions, the repair of each of these components is critical. Reconstructive surgery for these defects has advanced significantly in the last 40 years, first with the advent of microvascular free tissue transfer and most recently with the potential for full facial transplantation. This chapter serves to outline the various topics that should be reviewed when considering head and neck reconstructive surgery as well as to detail techniques for various defects of these regions.

Defect Analysis When considering a defect, all layers must be taken into account to successfully optimize reconstruction of the area. Analysis should include the following tissue layers: 1. 2. 3. 4. 5. 6.

Skin Mucosa Muscle Bone Cartilage Nerve(s)

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Skin 1. Layers a. Epidermis (Come, Let’s Get Sun Burned) i. Stratum corneum • Desquamating, dead layer ii. Stratum lucidum • May be absent in thin skin iii. Stratum granulosum iv. Stratum spinosum • Where desmosomes are located v. Stratum basale • Single layer of proliferating cells • Contains melanocytes b. Dermis i. Papillary dermis • Loose connective tissue, nerve endings, capillaries ii. Reticular dermis • Responsible for tensile strength • Blood vessels, hair follicles, lymphatics, nerves, sebaceous glands c. Subcutaneous layer/hypodermis i. Fat ii. Pacinian corpuscles that sense pressure changes 2. Methods of skin closure a. Primary/First intention i. Reapproximation of skin edges ii. Optimal for: clean wounds b. Secondary/Second intention i. Left to granulate, not closed primarily ii. Optimal for: dirty, contaminated wounds, areas that granulate well (See reconstructive ladder below) c. Tertiary/Third intention/delayed primary i. Delayed closure ii. May consider 2-3 days before closing wound that is potentially infected after thorough and adequate debridement

Wound Healing 1. 4 phases a. Phase 1: Tissue injury/Coagulation/Hemostasis i. Microvascular injury results in blood into wound ii. Reflex vasoconstriction → tissue environment becomes hypoxic and acidotic, triggering smooth muscle relaxation of vascular tissues

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iii. Coagulation cascade is activated, platelet plug and clot are formed through intrinsic and extrinsic pathways iv. Platelet plug contains growth factors that promote activation and chemotaxis of neutrophils, macrophages, endothelial cells, fibroblasts b. Phase 2: Inflammatory phase i. Early inflammatory phase: 24-36 hours • Complement cascade activated • Neutrophils migrate to site of injury and phagocytose bacteria, injured tissue, foreign particles ii. Late inflammatory phase: 48-72 hours • Macrophages appear and phagocytose bacteria and wound bed debris • At 72 hours, lymphocytes attracted to wound bed by IL-1, complement components and immunoglobulin G products c. Phase 3: Proliferative phase i. Day 3- 2 weeks • Fibroblasts proliferate, stimulate and provide lattice for collagen synthesis • Early granulation tissue made of approximately 40% type III collagen (compared to 80% type I and 20% type III in uninjured dermis tissue) • VEGF stimulates angiogenesis • Integrins mediate cellular migration d. Phase 4: Remodeling (maturation) phase i. 2 weeks to 1-2 years ii. Collagen fibers increase in diameter, collagen type I predominates iii. Hyaluronic acid and fibronectin degraded iv. Collagen fibers become cross linked, go on to regain 80-90% of tensile strength • At 3 weeks, wound has 20% of tensile strength • At 12 weeks, wound has 80% of tensile strength v. Wound contraction 2. Compromised wound healing should be considered: a. Tissue factors i. Hypoxia, edema, ischemia, necrosis • Temporary hypoxia after injury stimulates the wound healing process • Chronic hypoxia delays wound healing b. Infection i. leads to increased levels of matrix metalloproteinases (MMPs) Infection of wound bed results in prolonged inflammatory phase → that degrade the extracellular matrix and growth factors necessary for wound healing

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ii. Microorganisms may produce biofilms → prevent antibiotics from reaching infection sites Nutritional deficiencies • Table 1

Table 1. Vitamin and nutrient deficiencies and their impact on wound healing Vitamins Vitamin C Vitamin B12 (cobalamin) Vitamin B9 (folate) Vitamin A Vitamin D Vitamin E

Vitamin K

Impaired collagen synthesis, iron absorption, & fibroblast proliferation Plays a role in protein synthesis, requires intrinsic factor for production Important in synthesis of nitrogenous bases that make up DNA and RNA Decreased inflammatory response Increased bone mineralization and resorption Decrease antioxidant activity in wound bed, can result in excessive scar formation due to instability of cellular membrane integrity Results in impaired blood clotting

Nutrients Zinc

Impaired DNA, RNA, protein synthesis; decreased cellular proliferation Iron Responsible for hydroxylation of proline and lysine, when deficient leads to impaired collagen production Selenium Impaired wound healing Protein Increased susceptibility to wound infection; Can lead to impaired capillary formation, collagen synthesis, wound remodeling * This table is not all inclusive but summarizes the main vitamins and nutrients that when deficient can have detrimental impacts on wound healing

d. Current medications i. Immunomodulating medications ii. NSAIDS • Interfere with clot production, platelet function, inflammatory phase of wound healing iii. Supplements to consider • Ginseng − Impaired clot formation − Also known as Dong quai • Ginkgo biloba − Impairs clot formation e. Comorbidities i. Age • Patients >60 years old have alteration of all four phases of wound healing

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Estrogen: Males experience delayed wound healing when compared to age matched females − hypothesized as secondary to estrogen impact on regeneration and positive impact on wound healing Obesity • Higher rates of surgical site infections due to hypoperfusion and ischemia in adipose tissue • Increased wound tension on surgical wound edges → increases tissue pressure → reduces microcirculation and leads to hypoxia of wound Smoking • Higher rates of postoperative infections, anastomotic leak, wound dehiscence, wound and flap necrosis, decreased tensile strength of wounds • Alters neutrophil function → impairs migration and reduces bactericidal activity • Nicotine − Vasoconstrictive agent → induces tissue ischemia − Activates sympathetic nervous system → leads to release of epinephrine → decreases tissue blood perfusion − Increases blood viscosity Immunosuppression • Diabetes − Substantial increase in mortality and overall complications. − Wounds in diabetic patients are hypoxic → lead to increased free radicals within wound − Results in impaired bacterial clearance and angiogenesis, delayed wound healing globally − Surgery and anesthesia lead to production of stress hormones → worsening hyperglycemia − Basal intermediate or long acting insulin should be considered in these patients o Patients receiving enteric feeds should undergo point of care glucose testing every 4-6hrs and receive bolus insulin as needed Vascular disease • Peripheral arterial disease Connective tissue disorders • Ehlers Danlos • Osteogenesis imperfecta Prior radiation • Leads to endothelial cell injury and eventually endarteritis

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Causes delayed tissue repair, wound atrophy, fibrosis Can cause wounds in prior irradiated field to have deficient granulation tissue formation; epithelization may be compromised 3. Techniques to improve wound healing a. Hyperbaric oxygen (HBO) therapy i. Acts by increasing the blood-tissue oxygen gradient → enhances diffusion of oxygen into hypoxic tissue • Pearls: Increased oxygen leads to increased fibroblast and collagen proliferation, angiogenesis • Contraindicated if residual tumor left behind as this can expedite growth of cancer cells

Grafts and Implants 1. Types a. Autograft: utilizes patient’s own tissue i. i.e., calvarial bone graft for orbital floor reconstruction b. Allograft: from the same species, most often cadaveric i. i.e., cadaveric rib for complex rhinoplasty c. Xenograft: tissue from another species d. Alloplast: synthetic material 2. Materials a. Bone i. Advantages: limited resorption, resists infection, less chances of warping ii. Types • Cortical bone (outer layer) → provides strength • Cancellous bone (inner trabecular layer/diploic layer) → high #s osteocytes and osteoblasts i. Common donor sites: calvarium, rib, fibula, iliac crest ii. Pearls: • Cranial bone in adult is 6.8-7.7 mm thick, with the thickest region over the occipital region and thinnest over temporal region • Midline sagittal suture overlies superior sagittal dural sinus which can be 1.5 cm wide. • When harvesting calvarial bone graft, medial border should be > 2cm from midline to avoid injuring sagittal sinus b. Cartilage i. Advantages: harvested with ease, can be banked/stored in subcutaneous pocket, ease of shaping/carving ii. Common donor sites: auricular conchal bowl, nasal septum, rib

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c.

Skin i. See skin graft, below d. Fat i. ~50% of implanted fat graft will resorb ii. Must place precisely or can clump, most frequently when grafted to tear trough, infraorbital rim iii. Common donor sites: periumbilical, thigh, flank, submentum e. Synthetic i. Calcium hydroxyapatite • Allows ingrowth • Resists infection, little inflammation ii. Gore-tex • Expanded polytetrafluoroethylene • Low infection rate, some tissue ingrowth • Can extrude or become palpable iii. Medpor • Porous polyethylene; pores allow ingrowth of soft tissue • Can be autoclaved iv. Mersilene • Polyester fiber • Allows for soft tissue ingrowth v. Metals • Titanium: capable of osseointegration, low reactivity • Gold: soft/malleable, low reactivity • Stainless steel: does NOT osseointegrate, provides strength vi. Silicone rubber • Low reactivity, resists infection • Becomes encapsulated • Can be autoclaved

Reconstructive Ladder (Figure 1) 1. Secondary intention a. Involves leaving wound open so bed can granulate and contract b. Preferred in contaminated wounds c. Pearls i. Ideal for small wounds and those in concave areas, such as lateral forehead, glabella, medial canthal region, perinasal melolabial fold, ear in depressed regions ii. Require extended wound care

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Figure 1. The Reconstructive ladder.

2. Primary Closure (first intention) a. Wound edges reapproximated within hours b. Provides optimal cosmesis c. Best in clean wounds or those that have been adequately irrigated/debrided d. Pearls: i. Space sutures on the face 3-4 mm apart ii. Abrasions to reticular dermis are prone to scar, consider primary closure 3. Skin graft (see skin graft below) 4. Local flaps 5. Tissue Expansion (see tissue expansion below) 6. Regional flaps 7. Free tissue transfer 8. Tissue transplantation

Skin Grafts 1. Absolute requirements a. Vascularized recipient bed, contact between graft and recipient site 2. Factors to consider a. Contraindications i. Infected or irradiated sites ii. Sites with impaired vascularity→ greater take rate with STSG>FTFG

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iii. Exception: Small 50% diameter of facial nerve is violated iv. 9-0 or 10-0 monofilament suture for epineural repair b. Interposition grafts i. Required if tension-free anastomosis cannot be achieved ii. Serves as conduit for regrowth iii. Use when >1 cm between cut ends iv. Donor nerve options: • Sural − Best for gaps >10 cm − Can be harvested using variety of techniques, including stairstep incisions or endoscopic • Greater auricular nerve − Best for short nerve gaps with no history of head and neck malignancy • Medial cutaneous antebrachial cutaneous − Use for total facial nerve reconstruction from trunk to peripheral branches − Nerve coaptation techniques: suture, nerve wraps, tissue adhesive c. If only distal segment available: i. Hypoglossal nerve transfer (“12-7”) • Longitudinal splitting of muscle using only superior portion, ~30% • Provides new axons to innervate paralyzed muscle • Disadvantages: − May require coaptation graft − Can lead to functional deficit of tongue that interferes with speech and swallowing, less likely if preserving 70% ii. Masseteric nerve transfer • Nerve identified using sub zygomatic triangle, comprised of 1) zygomatic arch, 2) a vertical line through the anterior temporomandibular joint, and 3)the frontal branch of the facial nerve • Perform early if poor facial nerve recovery is anticipated • Pearls − 3 cm of masseteric nerve mobilization required for tension free anastomosis − Masseteric nerve has large number of motor fibers to donate

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iii. Cross-face nerve graft (CNFG) • May be used in conjunction with gracilis free flap or 5-7, 127 • Pearls − Provides volitional, coordinated, spontaneous movement − Improves tone − Carries risk of synkinesis or weakness of normal side iv. Babysitter procedure/dual innervation • Cross face nerve grafting AND ipsilateral masseteric or mini hypoglossal nerve transfer − Prevents muscle atrophy and fibrosis while cross face axons grow v. Gracilis • See gracilis free flap, above d. Pearls i. Nerve regenerates on average 1 mm/day ii. Expect return of muscle tone and movement to return 6-9 mo following surgery iii. Maximum improvement in House Brackmann score with primary neurorrhaphy or interposition is 3/6

Head and Neck Reconstruction 1. Eyelid reconstruction a. Reconstruction principles & goals i. Goals: preserve the function of the eyelid and surrounding periorbital structures, including corneal protection, while also reestablishing normal anatomic landmarks and structures b. Techniques based on region i. Defects: • 25% of eyelid width may require a local flap 2. Auricular reconstruction a. Reconstruction principles & goals i. Goals: to recreate complex structure of ear, reestablish anatomical landmarks, and conserve functions including directing sound waves into the external auditory canal and supporting glasses b. Techniques based on region i. Preserve helical rim, when possible to support glasses ii. Total auriculectomy may be managed with the use of a total auricle prosthetic that is held in place by osseointegrated bone anchors iii. Small helical rim defects may be replaced with a full thickness skin graft and bolster

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iv. Large, full thickness defects of antihelix/scapha may require staged postauricular flap or postauricular island pedicle Nasal reconstruction a. Reconstruction principles & goals i. Goals: reestablish native functions of nose (nasal airway, olfaction) as well as anatomical relationships to profile and surrounding facial structures b. Techniques based on region i. In cases in which >50% of a subunit is affected by the defect, replace entire subunit ii. Through and through defects require three layers of reconstructed tissue, including skin, cartilage, and inner mucosal lining iii. Large defects of the nasal tip may be reconstructed with paramedian forehead flap, dorsal nasal flap/Reiger flap iv. Defects of ala and columella may be reconstructed with melolabial flap • If defect is along alar rim, can reconstruct with helical rim graft with cartilage Lip reconstruction a. Reconstruction principles & goals i. Goals: to achieve oral competency, mobility, normal anatomical landmarks and proportions b. Techniques based on region i. Most early mucosal cutaneous malignancies managed with local mucosal advancement flaps if underlying muscle is not involved ii. When advanced or involving muscle, reconstruction options vary. See Figures 3 & 4 Cheek reconstruction a. Reconstruction principles & goals i. Goals: reestablish facial contour and support of globe b. Techniques based on region i. Most commonly repaired with rhomboid flaps and cervicofacial advancement flaps ii. Ensure incisions are placed along RSTL lines, when possible, to avoid tension on eyelid, oral commissure, and nasal ala Mandibular reconstruction a. Reconstruction principles & goals i. Goals: establish mandibular height, assist with oral competence, and provide bone for dental implants, if desired by patient b. Techniques based on region i. Segmental mandibular defects may be repaired with an osseous free flap • Fibula free flap most common, accepts implants well − See Fibula free flap above

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Figure 3. Upper lip reconstruction.

Figure 4. Lower lip reconstruction.

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Other options include iliac crest free flap, scapula free flap, or latissimus dorsi free flap with rib − These are poor candidates for dental implants; do not provide same amount of bone length as fibula

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7. Laryngeal reconstruction a. Goals: reestablish patent airway and neck contour, prevent fistulization from esophagus to trachea or surrounding neck skin b. Techniques i. Pectoralis flap commonly used in total laryngectomy to reduce the incidence of salivary fistula ii. Deltopectoral flap commonly used to repair tracheal-esophageal fistula, with flap interposed between trachea and esophagus 8. Tongue reconstruction a. Goals: reestablish tongue structure to aid in mastication, swallowing, and speech b. Techniques vary by degree of glossectomy surgery i. Total glossectomy: options to reestablish bulk include pectoralis major flap, pedicled latissimus dorsi flap, anterolateral thigh free flap, rectus abdominis free flap ii. Partial glossectomy: small T1 and T2 cancers may be left to granulate, closed primarily, or covered with a split thickness skin graft • Consider radial forearm free flap or other thin myocutaneous free tissue transfer for medium to large defects 9. Parotid reconstruction a. Goals: reestablish facial contour and prevent Frey syndrome from overly thin subcutaneous flap becoming reinnervated by parasympathetics from gland b. Techniques: i. Small contour defects: consider inferiorly based SCM flap to fill defect and cover parotid bed, alloderm for contour defects ii. Large contour defects/total parotidectomy: ALT for large defects after total parotidectomy, consider pectoralis major flap for large defects

Future Trends/Advances As we look to the future, the head and neck surgeon has much to look forward to by means of advances that are on the horizon. Today, tissue engineering and 3D printed facial implants have the potential to replace areas lacking bone height and offer restoration of bony contour and the potential for osseointegration. While already established, facial transplant will likely become more prevalent and a more available resource for patients with total facial reconstructive needs.

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Key Clinical Points 1. The reconstructive ladder is an important guideline to consider when faced with a defect in the head or neck. In addition to thorough defect analysis, patient comorbidities and functional status must be considered when choosing the optimal reconstructive strategy. 2. As much as possible, functional considerations should be paramount when reconstructing a defect. From a cosmetic standpoint, reconstructive efforts should aim to respect and recreate premorbid facial aesthetic units. 3. When possible, all deficient layers of a defect should be replaced, including skin, mucosa, muscle, bone, cartilage and nerve. As a general rule, missing tissue layers should be replaced “like for like” (e.g., missing mandibular bone replaced with fibular bone). 4. Microvascular free tissue transfer is the most robust and reliable reconstructive method, allowing for versatile neurovascular geometry, consistent blood supply, and tissue volume. Additionally, free tissue transfer allows defects of the head and neck to be replaced with customized tissue that can provide multiple layers in proportions that best match deficient tissue. 5. Determining the best approach to management of facial paralysis is based on an understanding of the cause, duration, and extent of paralysis, site of the lesion, and the expected outcomes. Several facial reanimation options exist with the above considerations in mind ranging from primary neurorrhaphy to static suspension and gracilis free tissue transfer.

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Questions 1. A biopsy of a wound that is 48-72 hours old would be most dense in which of the following? a. Neutrophils b. Fibroblasts c. Macrophages d. Matrix metalloproteinases 2. Which of the following is FALSE concerning split thickness skin grafts? a. Have higher rates of failure with large grafts b. Tend to have more secondary contraction during wound healing c. May be harvested from site of prior harvested STSG d. Have less immediate primary contraction following harvest than full thickness skin grafts 3. All of the following describe the changes seen in the first 6 months following placement of a tissue expander, except: a. Thinning of the dermis b. Increase in fibroblast number c. Decrease in muscle mass d. Thinning of the epidermis 4. All of the following are true of a pectoralis major flap, except: a. The pedicle of the flap can be found from a line drawn from the acromion to the xiphoid b. Primary blood supply is from the pectoral branch of the thoracoacromial artery c. Maximal reach of distal tip of flap is to the lateral canthus d. Inserts into the intertubercular sulcus of the humerus 5. Concerning ischemia time relating to free flaps, which of the following is/are true? a. Bone containing free flaps are the least sensitive to ischemia time b. Muscle can withstand up to 6 hours of ischemia time c. Placing the flap on iced saline during harvest may extend the time before irreversible damage may occur d. A and B are true

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References Asaria, J., Tan, S. L., and Adamson, P. A. (2016). Reconstructive head and neck surgery. In: Lee, KJ, ed. Essential Otolaryngology, Head and Neck Surgery. 11th ed. New York, NY: McGraw Hill; 940-959. Desai, S. C. (2017). Facial Plastic and Reconstructive Surgery. San Diego, CA: Plural Publishing. Hadlock, T. A. (2014). Facial Reanimation. In: Bailey’s Head and Neck Surgery- Otolaryngology. 5th ed. Baltimore, MD: Lippincott Williams and Wilkins; 2905-2918. Holt, G. R., and Stallworth, C. L. (2014). Grafts and Implants in Facial, Head, and Neck Surgery. In: Bailey’s Head and Neck Surgery- Otolaryngology. 5th ed. Baltimore, MD: Lippincott Williams and Wilkins; 27842796. Jefferson, G. D. (2014). Dynamic wound healing. In: Bailey’s Head and Neck Surgery- Otolaryngology. 5th ed. Baltimore, MD: Lippincott Williams and Wilkins; 75-85. Jewett, B. (2014). Local Cutaneous Flaps and Grafts. In: Bailey’s Head and Neck Surgery- Otolaryngology. 5th ed. Baltimore, MD: Lippincott Williams and Wilkins; 2797-2823. Joshi, R. R., Husain, Q., Park, R. C., Zoumalan, R., Goodman, J. F., Tanna, N., Arden, R. L., Golub, J. S., and Pasha, R. (2018). Reconstructive and Facial Plastic Surgery. In: Otolaryngology Head and Neck Surgery. 5th ed. San Diego, CA: Plural Publishing; 441-528. Wei, F. and Mardini, S. (2009). Flaps and Reconstructive Surgery. Philadelphia, PA: Elsevier, 2009.

Chapter 20

Chemotherapy, Targeted Therapy and Clinical Trials Kartik Sehgal, MD Deborah J. Wong, MD, PhD and Robert Haddad, MD Locally Advanced Squamous Cell Carcinoma of Head and Neck Introduction 1. Chemotherapy and/or targeted therapy is often part of a multi-modal plan of care for locally advanced squamous cell carcinoma of the head and neck arising from the oral cavity, oropharynx, hypopharynx and larynx. Three main roles of chemotherapy and/or targeted therapy in this curative intent setting include: a. Administration of chemotherapy or targeted therapy concurrently with radiation therapy (for radio-sensitization) as definitive treatment. b. Concurrent chemotherapy or targeted therapy with radiotherapy as adjuvant treatment after surgical resection. c. Induction chemotherapy before surgical resection or prior to a definitive radiation therapy-based approach (to decrease tumor volume and improve function). 2. Neoadjuvant chemotherapy has an evolving role in management of squamous cell carcinoma of larynx/hypopharynx, and unresectable oral cavity cancer, while neoadjuvant immunotherapy with or without chemotherapy has been evaluated in clinical trials with promising activity.

Radiosensitizing Chemotherapy and Targeted Therapy Agents 1. Cisplatin is the preferred and most utilized chemotherapy agent with two dosing schedule choices: a. Bolus regimen of 100 mg/m2 intravenously every 3 weeks b. Weekly regimen of 40 mg/m2 intravenously every week

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2. Weekly cisplatin regimen (at 40 mg/m2) is considered equivalent with respect to survival benefit and with improved toxicity profile compared to bolus cisplatin regimen, based upon data in adjuvant setting from JCOG 1008, meta-analyses and other cohort studies [1-3]. 3. The common adverse events associated with cisplatin include: nausea and vomiting, myelosuppression, nephrotoxicity, peripheral neuropathy, and ototoxicity. 4. Carboplatin (Area Under the Curve = AUC, 1.5 or 2 weekly) with paclitaxel (30 – 45 mg/m2 weekly) is an alternative chemotherapy regimen for radio-sensitization in those with contraindication for use of cisplatin, based upon data from a phase 2 study in stage III, IVa or IVb locally advanced disease [4]. 5. Carboplatin monotherapy is often utilized concurrently with radiation therapy after induction chemotherapy, based upon data from the TAX-324 clinical trial (see “Induction Chemotherapy“ section below) [5]. 6. The common adverse events associated with carboplatin include: myelosuppression, nausea and vomiting, peripheral neuropathy, and electrolyte changes. Side effects of paclitaxel include myelosuppression, hypersensitivity reaction, nausea and vomiting, alopecia, and neuropathy. 7. Cetuximab, a monoclonal antibody that inhibits epidermal growth factor receptor, is another alternative agent in those whom cisplatin is contra-indicated, extrapolated from a randomized phase 3 study in patients with stage III or IV cancer of oropharynx, larynx or hypopharynx [6]. 8. Cetuximab is administered as a 400 mg/m2 loading dose beginning one week prior to initiation of radiation, followed by 250 mg/m2 weekly. 9. The common adverse events associated with cetuximab include: acneiform rash, nail changes, infusion reactions, hypokalemia and hypomagnesemia. Table 1. Radiosensitizing agents for locally advanced head and neck cancer Drug(s) Cisplatin Carboplatin and Paclitaxel Carboplatin

Dosing (IV) 100 mg/m2 every 3 weeks or 40 mg/m2 weekly AUC 1.5 - 2 weekly and 30 - 45 mg/m2 weekly AUC 1.5 - 2 weekly

Cetuximab

400 mg/m2 loading dose Week 1 followed by 250 mg/m2 weekly AUC = Area under curve, IV = intravenously

Notes Preferred regimen Contra-indication to cisplatin Following induction TPF chemotherapy Least preferred option, Contraindication to cisplatin

Induction Chemotherapy Regimens 1. Two major regimens for locally advanced cancers of oral cavity, oropharynx, hypopharynx and larynx include:

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a.

427

TPF i.

Cisplatin (100 mg/m2 on Day 1), Docetaxel (75 mg/m2 on Day 1), and 5-Fluorouracil (1000 mg/m2/day by continuous infusion on Days 1 through 4) intravenously every 3 weeks. ii. 3 cycles before concurrent chemoradiation along with carboplatin (AUC 1.5 weekly). iii. Supported by data from TAX-324, a randomized phase 3 clinical trial which showed improved overall survival benefit with TPF compared to PF in patients with stage III or IV non-metastatic cancer of oral cavity, orophgarynx, larynx or hypopharynx [5]. b. PCC i. Carboplatin (AUC 2), Paclitaxel (135 mg/m2), and Cetuximab (400 mg/m2 loading dose week 1 followed by 250 mg/m2 weekly dose) intravenously weekly. ii. 6 weekly treatment cycles before radiation therapy-based approach which preferentially utilized cisplatin as the radio-sensitizing agent. iii. Supported by data from two phase II studies [7, 8] benefit appear to be more robust in patients with HPV related oropharyngeal cancer. iv. Can be used in those who are not candidates for TPF regimen due to functional status and comorbidities. Does not require central intravenous access. Table 2. Induction chemotherapy agents Regimen

Drugs

TPF

Cisplatin Docetaxel 5-Fluorouracil

Dosing (IV)

100 mg/m2 Day 1 75 mg/m2 Day 1 1000 mg/m2/day Days 1 to 4 PCC Carboplatin AUC 2 Day 1 Paclitaxel 135 mg/m2 Day 1 Cetuximab 400 mg/m2 Week 1 followed by 250 mg/m2 weekly AUC = Area under curve, IV = intravenously

Cycle Length/ No. of Cycles 3 weeks/ 3 cycles

1 week / 6 cycles

Followed by below radiosensitizing agent Carboplatin

Cisplatin

Indications for Chemotherapy in Adjuvant Setting 1. Chemotherapy with weekly or bolus cisplatin recommended concurrently with radiation therapy in adjuvant setting after upfront surgery in the following settings: a. Absolute indications: positive surgical margins and presence of extranodal extension (supported by comparative analysis of EORTC 22931 and RTOG 9501 trials) [9].

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b. Relative indications for a case by case basis decision: advanced nodal disease, lymphovascular invasion and/or perineural invasion.

Anatomic Subsite: Oral Cavity Cancers 1. Upfront surgical resection followed by adjuvant therapy with radiation therapy with or without chemotherapy is the mainstay of treatment for squamous cell carcinomas of oral cavity. The indication for addition of concurrent chemotherapy to adjuvant radiation therapy are listed in the section above on adjuvant setting. 2. Neoadjuvant chemotherapy before surgery for oral cavity cancers did not improve overall survival compared to upfront surgery in multiple randomized trials [10-12]. Anatomic Subsite: Human Papilloma Virus (HPV)-Positive Oropharyngeal Cancers 1. For patients with T1 / T2 disease with a single involved lymph node (measuring less than or equal to 3 cm) receiving definitive radiation therapy, decision regarding addition of concurrent chemotherapy is made on an individual patient level (based upon other risk factors: smoking history, ulcerative appearance of primary tumor and concern for extranodal extension). 2. For patients with T3 / T4 disease, single involved lymph node measuring greater than 3 cm or multiple involved lymph nodes receiving definitive radiation therapy, concurrent administration of chemotherapy is recommended. 3. Cetuximab is associated with inferior overall survival compared to cisplatin as a radiosensitizing agent for patients with HPV-positive oropharyngeal cancer, supported by data from De-ESCALate HPV, RTOG 1016 and ARTSCAN III trials [13-15]. 4. Please refer to the dedicated chapter on HPV+ oropharyngeal cancers for a detailed review. Anatomic Subsite: HPV-Negative Oropharyngeal Cancers 1. For Stage I or II disease (i.e., no nodal involvement), chemotherapy has a role in adjuvant setting only for indications described in the section above. 2. For Stage III, IVa or IVb disease, the addition of concurrent chemotherapy is recommended for primary definitive radiation therapy-based approach based upon improvement in overall survival seen in MACH-NC analysis [16]. Anatomic Subsite: Hypopharyngeal and Laryngeal Cancers 1. Non-surgical functional organ preservation approach with chemotherapy and radiation therapy-based approach is preferred when appropriate, supported by data from Department of VA Laryngeal Cancer Study Group larynx trial and EORTC 24891 [17, 18]. Those with at least partial response to induction chemotherapy proceeded with radiation therapy-based approach, while those without objective response proceeded with surgery-based approach. 2. Both primary concurrent chemoradiation therapy and induction chemotherapy followed by concurrent chemoradiation therapy are acceptable approaches for treatment of locoregionally advanced stage III or stage IV disease, supported by data from the GSTTC Italian Study Group [19].

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3. Induction chemotherapy approach is preferred in those with patients with large primary tumors and advanced nodal disease. Patients in need of immediate therapy due to disease burden and symptoms are best treated with induction chemotherapy first.

Future Directions 1. Neoadjuvant immunotherapy-based approach is currently being evaluated in clinical trials in both treatment naïve and previously treated settings, especially for oral cavity cancers. 2. In the setting of untreated oral cavity cancers, phase II clinical trials with immune checkpoint inhibitors have shown the safety and feasibility of this approach without any surgical delays [20, 21]. 3. Debio 1143, an inhibitor of apoptosis protein (IAP) antagonist, has received breakthrough designation by FDA for use in combination with standard of care cisplatin-based concurrent chemoradiation therapy, based upon data from Phase I/II study [22]. Phase III study is currently ongoing (NCT04459715).

Advanced Recurrent Incurable or Metastatic Squamous Cell Carcinoma of Head and Neck Introduction 1. The goals of treatment are palliative, i.e., prolongation of life with acceptable quality of life. 2. US FDA-approved treatment options can be broadly divided into three groups: a. Immunotherapy: immune-checkpoint inhibitors (examples include pembrolizumab, nivolumab). b. Chemotherapy (examples include platinum agents, 5-fluorouracil, taxanes, methotrexate). c. Targeted therapy (example includes cetuximab). 3. Participation in clinical trials, whenever available, is always encouraged (Figure 1).

First Line Palliative Intent Setting: Treatment Naïve 1. The current standard of care treatment regimen for patients with squamous cell carcinoma of oral cavity, oropharynx, hypopharynx and larynx is based upon KEYNOTE-048 clinical trial and includes pembrolizumab-based therapy in absence of contra-indication to immune checkpoint inhibitors. 2. KEYNOTE-048 was a phase III randomized study which compared pembrolizumab monotherapy, pembrolizumab along with chemotherapy (platinum + 5-fluorouracil) and chemotherapy (EXTREME regimen: platinum + 5-fluorouracil + cetuximab), and showed overall survival advantage with pembrolizumab-based approach. Of note, the

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3.

4. 5.

6.

7.

study excluded patients whose disease progressed within 6 months of curative intent treatment for locoregionally advanced disease [23]. Pembrolizumab monotherapy is FDA-approved first line palliative intent regimen for patients with tumors expressing programmed death ligand-1 (PD-L1), i.e., PD-L1 combined proportion score (CPS) ≥ 1%. Pembrolizumab + chemotherapy (platinum + 5-fluorouracil) is FDA-approved first line palliative intent regimen, irrespective of PD-L1 CPS. The current therapeutic paradigm is biomarker based according to tumor PD-L1 CPS. a. PD-L1 CPS ≥ 20%: Pembrolizumab monotherapy or participation in clinical trial b. PD-L1 CPS 1-19%: Options include Pembrolizumab monotherapy, Pembrolizumab + chemotherapy or participation in clinical trial c. PD-L1 CPS 0% (or unavailable): Pembrolizumab + chemotherapy or participation in clinical trial The decision regarding treatment with pembrolizumab monotherapy or pembrolizumab + chemotherapy is made on an individual patient-level, depending upon disease burden and performance status, and comorbidities. For patients with contra-indication to immune checkpoint inhibitors, standard treatment is chemotherapy-based and options include EXTREME regimen (platinum + 5-fluorouracil + cetuximab) and TPExtreme (platinum + docetaxel + cetuximab) [24, 25]. Participation in clinical trials is also recommended.

First Line Palliative Intent Setting: Platinum-Refractory 1. For those with recurrence of disease after 6 months from completion of curative intent treatment for locoregionally advanced disease, the therapeutic regimens are based upon KEYNOTE-048 trial and are discussed above. 2. For those with recurrence of disease within 6 months of curative intent platinum-based treatment for locoregionally advanced disease that included platinum chemotherapy, monotherapy with anti- PD-1 drugs (nivolumab or pembrolizumab) or participation in clinical trials is recommended. 3. Checkmate 141 (nivolumab) and KEYNOTE-040 (pembrolizumab) were the phase 3 trials that showed improvement in overall survival with anti-PD-1 monotherapy compared to single-agent systemic therapy (docetaxel, cetuximab or methotrexate) in patients with platinum-refractory recurrent squamous cell carcinoma of head and neck [26, 27].

Beyond First Line Setting 1. Molecular analysis of tumor with DNA sequencing is recommended, unless already obtained earlier. 2. Participation in available clinical trials, preferably biomarker-guided, is strongly recommended.

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3. Examples of non-clinical trial options include monotherapy with docetaxel, paclitaxel, cetuximab, 5-fluorouracil, capecitabine or methotrexate, or docetaxel along with cetuximab.

Future Directions 1. The combination of anti-PD-1 therapy with cetuximab has shown promising results in two phase I/II trials in patients with advanced squamous cell carcinomas of head and neck [28, 29]. 2. Inhibition of farnesyltransferase with tipifarnib showed high objective response rates in a phase II trial of patients with tumors harboring pathogenic HRAS mutations with variant allele frequency ≥ 20% [30].

Figure 1. Algorithm for management in recurrent/metastatic setting.

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Practice Guidelines 1. When patients are diagnosed with locoregionally advanced squamous cell carcinoma of head and neck, addition of concurrent chemotherapy (when indicated) to primary radiation therapy with curative intent for radio sensitization is a Qualified Option. 2. When patients who underwent surgical resection of locoregionally advanced disease have positive margins and/or extranodal extension of tumor on surgical pathology specimens, adjuvant therapy with concurrent chemoradiation therapy is a Qualified Option. 3. When patients with locoregionally advanced disease have bulky primary tumor, advanced nodal disease, and/or high risk of development of distant metastatic disease, induction chemotherapy followed by radiation therapy-based option is a Qualified Option. 4. When the patient presents with advanced incurable or metastatic squamous cell carcinoma of head and neck, first line palliative intent treatment regimen with pembrolizumab monotherapy OR pembrolizumab and chemotherapy based upon PDL1 CPS, disease burden and performance status is a Qualified Option. 5. When appropriate research studies are available at the time of patient presentation, informed discussion with patients is encouraged AND participation in clinical trials is a Qualified Option. Patient Characteristics Treatment with Radiation therapy-based approach for locoregionally advanced squamous cell carcinoma of head and neck • HPV positive oropharyngeal cancers: − T1/T2 + single involved node ≤ 3 cm) in presence of other adverse features (smoking, suspicion for extranodal extension, ulcerative primary) − T3/T4 or single lymph node > 3 cm or multiple lymph nodes • HPV negative oropharyngeal cancers/ hypopharynx/larynx: Stage III/ IV Treatment with Surgery-based approach for locoregionally advanced squamous cell carcinoma of head and neck, with following surgical pathology features • Absolute: positive margins, extra nodal extension • Relative: lymphovascular invasion, perineural invasion, advanced nodal involvement Locoregionally advanced squamous cell carcinoma of head and neck with • bulky primary tumor • advanced nodal disease • high risk of development of distant metastatic disease Advanced incurable or metastatic squamous cell carcinoma of head and neck, first line palliative intent setting Advanced incurable or metastatic squamous cell carcinoma of head and neck

Qualified Option

Addition of concurrent chemotherapy to primary radiation therapy for radio sensitization

Addition of concurrent chemotherapy to adjuvant radiation therapy for radio sensitization

Induction chemotherapy followed by radiation therapy-based approach Pembrolizumab monotherapy OR pembrolizumab and chemotherapy Clinical trials

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Chapter 21

Immunosurveillance and Immunotherapeutic Approaches in Head and Neck Cancer Vikash Kansal, PhD Robert L. Ferris, MD, PhD and Nicole C. Schmitt, MD Treatment Modalities for Head and Neck Squamous Cell Carcinoma (HNSCC) 1. Surgery 2. Radiation 3. Cytotoxic chemotherapy

Recent Developments HNSCC pathogenesis is strongly linked to immune escape, which can be partially overcome by using: 1. Immune checkpoint blockade 2. Other forms of immunotherapy

Tumor Immunology-Basic Principles 1. Cancer − a genetic disorder. a. Increased genomic instability over time due to chronic inflammation and cellular stress induced by carcinogens (e.g., tobacco). b. Key genetic mutations (such as TP53 mutation) hinder natural phenomenon of programmed cell death resulting in cancer formation. i. Inflammation and cellular stress are recognized by the innate immune system, while the adaptive immune system responds to specific tumor antigens. In: Essential Head and Neck Oncology and Surgery Editors: Maie A. St. John and Benjamin L. Judson

ISBN: 979-8-88697-438-6 © 2023 Nova Science Publishers, Inc.

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• • •

Tumor associated antigens: expressed by all cells; highly expressed by tumor cells (e.g., EGFR) Neoantigens: Mutated proteins (e.g., mutated p53) Viral antigens (e.g., HPV oncoproteins)

Innate Immunity as “The First Responders” 1. First line of defense in the immune response. 2. Promotes wound healing and attracts immune cells to the site of damage by activating damage-associated molecular pattern molecules (DAMPs). 3. As a result, tumor microenvironment becomes rich with macrophages, natural killer (NK) cells and other immune cells. 4. Cells exhibiting stress or aberrant signals (such as low expression of major histocompatibility complex molecules (MHC, also known as human leukocyte antigen or HLA in humans)), are recognized and killed by NK cells (Figure 1).

Figure 1. Anti-tumor immunity consists of antigen-dependent tumor cell killing (adaptive immunity) involving T cells and antigen-independent tumor cell killing (innate immunity) involving natural killer (NK) cells (Created with BioRender.com).

5. These “first responders” can also recognize and kill cells that are bound by antibodies, a process known as antibody-dependent cell-mediated cytotoxicity (ADCC; Figure 2).

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Figure 2. Antibody-dependent cell mediated cytotoxicity (ADCC) involves natural killer (NK) cells (Created with BioRender.com).

Adaptive Immunity and Tumor Antigens 1. Unlike innate immunity, adaptive immunity is long-lasting and much more effective in countering foreign antigens, leading to recruitment of antigen-specific T-cells. 2. T-cell receptors (TCRs) recognize neoantigens presented on tumor cells and adaptive immune response is generated. 3. High tumor mutational burden (TMB) directly correlates with tumor response to immunotherapy. 4. HNSCC has relatively high TMB; salivary cancers have relatively low TMB. 5. Antigen needs to be shuttled to cell surface via MHC class I molecule to generate adaptive immune response (Figure 3). a. Many HNSCCs are deficient in the machinery needed for this critical step. 6. MHC-antigen complex then presented to receptors on nearby T cells (TCRs). This is done by all cells, but particularly by cells called antigen presenting cells (APCs), such as dendritic cells (DCs). 7. APCs are activated by recognizing DAMPs secreted from stressed and dying cells. 8. To generate adaptive immune response, cascade of signaling (Figure 4) requires: a. the binding of an antigen-specific TCR to the antigen-MHC complex b. Activation of costimulatory receptors (CD27/CD28) c. Production of cytokines d. Immune-mediated tissue-specific destruction (ITD) to kill infected cells and reject tumor cells 9. Over time, tumor cells evade anti-tumor immunity via process known as immunoediting, thus expressing fewer neoantigens. 10. Chemotherapy, radiation, or oncolytic viruses can be used to selectively kill tumor cells, thus enhancing immune response. 11. “Immunologically cold” tumors are poorly infiltrated by immune cells may and be refractory to such treatments. 12. Expression of coinhibitory checkpoints, such as programmed cell death 1 (PD-1) and its ligand PD-L1 also inhibit the adaptive immune response.

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Figure 3. Antigen processing machinery (APM) required to process and load an antigenic peptide onto an MHC class I molecule for presentation to an antigen-specific T cell receptor (TCR). Many head and neck cancers are deficient in MHC I and/or TAP. MHC, major histocompatibility complex; TAP, transporter associated with antigen processing (Created with BioRender.com).

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Figure 4. Three signals must occur between the antigen presenting cell (APC) and CD8+ T cell, leading to activation and proliferation of antigen-specific T cells: 1) recognition of MHC/antigen complex by the TCR; 2) Activation of costimulatory CD27/CD28 signals; and 3) production of cytokines. These signals lead to activation of T cells into effectors, which then secrete cytolytic enzymes and cytokines upon recognition of cancer cells. MHC, major histocompatibility complex; TCR, T cell receptor (Created with BioRender.com).

Immune Escape in Head and Neck Cancer Despite high TMB and viral antigens in HNSCC, tumors develop mechanisms to escape the immune system (Table 1). Table 1. Mechanisms of immune escape in HNSCC Mechanisms Intrinsic to Tumor Cells Decreased expression/mutation of MHC class I and APM components

Aberrant Immune Responses

Secretion of immunosuppressive factors and cytokines by tumor cells (TGF-β, PGE2, IL-10) Increased expression of PD-L1

Dysfunction of effector T cells, NK cells and DCs

Decrease in circulating immune effector cells

Increased numbers of immunosuppressive cells (Tregs, M2 macrophages and MDSCs) in tumor microenvironment and circulation Dominance of Th2 cytokine response Decreased expression of T-cell receptor zeta chain Increased expression of coinhibitory checkpoint receptors and Decreased expression of co-stimulatory checkpoint receptors

HPV-Related Immune Escape Adaptive life cycle that minimizes exposure of immunogenic viral proteins to immune cells Decreased production and function of interferons and interferon-responsive genes Impaired host cell lysis by NK cells

Downregulation of Toll-like receptor 9 E6/E7- mediated inhibition of inflammatory response E5/E7-mediated decrease in expression of MHC class I and APM components Development of T cell tolerance to persistent HPV infection

APM, antigen processing machinery; IL-10, Interleukin 10; MDSC, myeloid-derived suppressor cell;MHC, major histocompatibility complex; NK, natural killer; PD-L1, programmed death ligand 1; PD-1, programmed cell death 1; PGE2, prostaglandin E2; TGF-β, transforming growth factor beta; Treg, regulatory T cell; HPV, human papillomavirus.

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Treatment of Head and Neck Cancer- Immunotherapeutic Approaches Several immunotherapeutic strategies are in use or under investigation for HNSCC and other tumors (Table 2). Table 2. Immunotherapeutic Strategies for Treatment of HNSCC Immunotherapeutic Strategy Tumor antigen-targeting monoclonal antibodies (cetuximab) Coinhibitory checkpoint inhibitors • Anti-PD-1/Anti-PD-L1 monoclonal antibodies • Anti-CTLA-4 monoclonal antibodies Costimulatory checkpoint agonists Vaccines • Peptide vaccines • Viral or bacterial (Listeria) vector (ADXS11-001) • Dendritic cell vaccines Adoptive T cell transfer • Pooled T cells responding to HPV oncoproteins • T cells with engineered T-cell receptors • Chimeric antigen receptor (CAR) T cells Inhibitors of immunosuppressive cells (trafficking/function of immunosuppressive MDSCs, Tregs, or macrophages) Enhancers of innate immunity • Toll-like receptor agonists • STING agonists

Study Phase FDA approved FDA approved Phase 3 Early Phase Early Phase Early Phase Early Phase Early Phase Early Phase Early Phase Early Phase

Early Phase Early Phase

MDSC, myeloid derived suppressor cell; Treg, regulatoy T cell; STING, stimulator of interferon genes.

Monoclonal Antibodies Targeting Tumor Antigens 1. Cetuximab, a chimeric mouse-human immunoglobulin G1 (IgG1) monoclonal antibody targeting epidermal growth factor receptor (EGFR), is FDA approved for HNSCC. 2. Anti-EGFR monoclonal antibodies appear to work in part by inducing antibodydependent cell-mediated cytotoxicity (ADCC; Figure 2). 3. The released antibody-coated tumor antigens can then be engulfed by antigen presenting cells or detected by Fcγ receptors, leading to antigen cross-presentation and activation of antigen-specific T cells. 4. Panitumumab (fully humanized IgG2 antibody) and EGFR tyrosine kinase inhibitors fail to induce these immune responses, suggesting that this process is antibody isotype specific.

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Immune Checkpoints Coinhibitory Checkpoints 1. Prevent exaggerated immune responses, such as autoimmunity 2. Coinhibitory checkpoints include programmed cell death 1 (PD-1) and cytotoxic Tlymphocyte-associated protein 4 (CTLA-4) pathways.

Programmed Cell Death 1 (PD-1) Pathway (Figure 5) 1. High PD-1 and PD-L1 expression in both HPV-positive and HPV-negative HNSCC. 2. PD-L2 appears to play a less critical role in the pathogenesis of HNSCC.

Figure 5. Blocking the interaction of PD-1 with PD-L1 allows immune attack of cancer cells. MHC, major histocompatibility complex; TCR, T cell receptor (Created with BioRender.com).

3. Multiple trials involving anti-PD-1 antibodies such as pembrolizumab, nivolumab or PD-L1 inhibitors durvalumab (MEDI4736) or avelumab. a. KEYNOTE-012: led to FDA approval of pembrolizumab for platinumrefractory, recurrent/metastatic HNSCC.

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b. Checkmate- 041: first randomized, phase 3 study of checkpoint blockade for HNSCC; one-year overall survival was double with nivolumab (anti-PD-1) versus investigator’s choice second-line chemotherapy. 4. Patients with higher tumor expression of PD-L1 respond better to anti-PD-1 therapy. a. Combined positive score (CPS): standard scoring system of PD-L1 expression in tumor cells and immune cells. 5. IFN-related gene expression profile (GEP) was developed using mRNA samples from patients with melanoma, HNSCC, and other solid tumors treated with pembrolizumab. a. A high GEP in pembrolizumab-treated patients correlated with responses and with stable disease in most patients. 6. Pembrolizumab alone is the first-line treatment for recurrent/metastatic HNSCC patients with PD-L1-positive tumors (CPS ≥1) and pembrolizumab plus chemotherapy is used for tumors that stain poorly for PD-L1 (CPS