Head and neck surgery [First edition.] 9789351524588, 9351524582

Table of contents :
Cover
Contributors
Foreword
Preface
Acknowledgments
Contents
Chapter-01 : The Molecular Biology of Head and Neck Cancer
Chapter-02_Principles of Radiation Oncology
Chapter-03_Principles of Medical Oncology
Chapter-04_Immunobiology and Immunotherapy in Head and Neck Cancer
Chapter-05_Head and Neck Imaging
Chapter-06_Sentinel Node Biopsy in Head and Neck Cancer
Chapter-07_Non-melanoma Skin Cancers of the Head and Neck
Chapter-08_Melanoma
Chapter-09_Pathology of Cutaneous Malignancies of the Head and Neck
Chapter-10_Merkel Cell Carcinoma and Other Rare Skin Cancers
Chapter-11_Surgical Anatomy and Embryology of the Thyroid and Parathyroid Glands
Chapter-12_Pathology of Thyroid and Parathyroid Neoplasms
Chapter-13_Diagnosis and Management of the Thyroid Nodule
Chapter-14_Management of Well-Differentiated Thyroid Cancer
Chapter-15_Medullary Thyroid Cancer
Chapter-16_Anaplastic Thyroid Cancer
Chapter-17_Principles and Technique of Thyroidectomy
Chapter-18_Management of Advanced Thyroid Cancer
Chapter-19_Management of Recurrent Thyroid Cancer
Chapter-20_Hyperthyroidism Graves Disease, Toxic Multinodular Goiter, and Solitary Toxic Nodule
Chapter-21_Surgical Management of Goiter
Chapter-22_Management of Primary and Secondary Hyperparathyroidism
Chapter-23_Management of Recurrent Hyperparathyroidism
Chapter-24_Paragangliomas of the Head and Neck
Chapter-25_Anatomy, Physiology, and Non-neoplastic Disorders of the Salivary Glands
Chapter-26_Pathology of Salivary Gland Neoplasms
Chapter-27_Salivary Gland Neoplasms
Chapter-28_Tumors of the Parapharyngeal Space
Chapter-29_Soft Tissue Sarcomas of the Head and Neck
Chapter-30_Bone Sarcomas of the Head and Neck
Chapter-31_Overview of Head and Neck Lymphomas
Chapter-32_Nasal Cavity and Paranasal Sinus Malignancies
Chapter-33_Benign and Premalignant Oral Lesions
Chapter-34_Lesions of the JawDental-Related Lesions
Chapter-35_Oral Cavity Cancer
Chapter-36_Nasopharyngeal Carcinoma
Chapter-37_Oropharyngeal Cancer
Chapter-38_Current Concepts in Transoral Approaches to Cancers of the Oropharynx and Oral Cavity
Chapter-39_Early Larynx Cancer
Chapter-40_Advanced Laryngeal Cancer
Chapter-41_Tracheal Stenosis and Tracheal Neoplasms
Chapter-42_Hypopharynx Cancer
Chapter-43_Cervical Esophageal Cancer
Chapter-44_Voice Rehabilitation after Laryngectomy
Chapter-45_Neck Dissection
Chapter-46_Unknown Primary Carcinoma
Chapter-47_Deep Neck Space Infections
Chapter-48_Complications of Head and Neck Surgery
Chapter-49_Salvage Surgery for Recurrent Head and Neck Cancer
Chapter-50_Perioperative Assessment in Elderly Patients Undergoing Head and Neck Surgery
Chapter-51_Overview of Regional Flaps in Head and Neck Cancer
Chapter-52_Overview of Free Flaps Used in Head and Neck Reconstruction
Chapter-53_Functional Oropharyngeal Reconstruction An Evidence-Based Approach
Chapter-54_Reconstruction of the Oral Cavity
Chapter-55_Reconstruction of the Hypopharynx and Larynx
Chapter-56_Reconstruction of Maxilla and Skull Base Defects
Chapter-57_Reconstruction of Parotidectomy Defects and Facial Nerve Paralysis
Chapter-58_Reconstruction of the Scalp
Chapter-59_Facial Transplantation
Index
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D
E
F
G
H
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M
N
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P
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Citation preview

Series Editor: Robert T Sataloff

 

SATALOFF'S COMPREHENSIVE TEXTBOOK OF OTOLARYNGOLOGY HEAD AND NECK SURGERY MD DMA FACS

HEAD AND NECK SURGERY

Series Editor: Robert T Sataloff

 

SATALOFF'S COMPREHENSIVE TEXTBOOK OF OTOLARYNGOLOGY HEAD AND NECK SURGERY MD DMA FACS

HEAD AND NECK SURGERY Vol. 5 Volume Editors

Patrick J Gullane MD FRCSC FACS Wharton Chair in Head and Neck Surgery Professor Department of Otolaryngology—Head and Neck Surgery Professor of Surgery University of Toronto Toronto, Ontario, Canada

David P Goldstein MD MSc FRCSC FACS Assistant Professor Princess Margaret Cancer Center Department of Otolaryngology—Head and Neck Surgery University of Toronto Toronto, Ontario, Canada

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Jaypee Brothers Medical Publishers (P) Ltd

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The views and opinions expressed in this book are solely those of the original contributor(s)/author(s) and do not necessarily represent those of editor(s) of the book. All rights reserved. No part of this publication may be reproduced, stored or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission in writing of the publishers. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. Medical knowledge and practice change constantly. This book is designed to provide accurate, authoritative information about the subject matter in question. However, readers are advised to check the most current information available on procedures included and check information from the manufacturer of each product to be administered, to verify the recommended dose, formula, method and duration of administration, adverse effects and contraindications. It is the responsibility of the practitioner to take all appropriate safety precautions. Neither the publisher nor the author(s)/editor(s) assume any liability for any injury and/or damage to persons or property arising from or related to use of material in this book. This book is sold on the understanding that the publisher is not engaged in providing professional medical services. If such advice or services are required, the services of a competent medical professional should be sought. Every effort has been made where necessary to contact holders of copyright to obtain permission to reproduce copyright material. If any have been inadvertently overlooked, the publisher will be pleased to make the necessary arrangements at the first opportunity. Inquiries for bulk sales may be solicited at: [email protected] Sataloff’s Comprehensive Textbook of Otolaryngology: Head and Neck Surgery: Head and Neck Surgery (Vol. 5) First Edition: 2016 ISBN: 978-93-5152-458-8 Printed at

Dedication I would like to dedicate this book to my loving wife, Dr Barbara Cruickshank; children Kira and John for their understanding and sacrifice of family time; to my sister Anna and brothers Eamon and Tomas for your friendship. In addition my thanks to Bob and Gerardina Wharton and family for the generous support they provided us in establishing the Wharton Head & Neck Center and the endowment of three Chairs within the Princess Margaret Hospital/University of Toronto. These contributions have helped enormously enhance patient care, education and research. Finally, to my colleagues for their support of my vision and to the courage and dignity of my patients for the confidence they have placed in me. Patrick J Gullane

I would like to dedicate my contribution to this book to my incredible wife, Simone, and our children Jack and Brooke for their support and encouragement. I would like to thank all the authors who put tremendous effort into providing outstanding chapters, as well as our residents and fellows who provide continued support and motivation. Special thanks to my co-editor and colleague Dr Patrick J Gullane for his mentorship, encouragement and support. David P Goldstein

Contributors David J Adelstein MD FACP Professor, Department of Medicine Cleveland Clinic Lerner College of Medicine of Case Western Reserve, University Staff Cleveland Clinic Taussig Cancer Institute Cleveland, Ohio, USA Sun M Ahn MD Resident Department of Otolaryngology— Head and Neck Surgery Johns Hopkins University Baltimore, Maryland, USA Daniel S Alam MD Professor Department of Surgery University of Hawaii John Burns School of Medicine Honolulu, Hawaii, USA Ashlin Alexander MD FRCSC Clinical Lecturer Division of Facial Plastic and Reconstructive Surgery Department of Otolaryngology— Head and Neck Surgery University of Toronto Mount Sinai Hospital and Rouge Valley Hospital Toronto, Ontario, Canada Nadya A Al-Faraidy MD Clinical Fellow Department of Pathology University of Toronto Toronto, Ontario, Canada

Doug Angel MD Fellow, Head and Neck Oncology & Reconstructive Surgery Department of Otolaryngology— Head and Neck Surgery Schulich School of Medicine and Dentistry Western University London, Ontario, Canada Kal Ansari MD Associate Professor Division of Otolaryngology University of Alberta Edmonton, Alberta, Canada Sylvia L Asa MD PhD Professor, Department of Pathology University Health Network University of Toronto Toronto, Ontario, Canada Eric Bissada MD DMD Professor Department of Otolaryngology— Head and Neck Surgery University of Montreal Montreal, Quebec, Canada James D Brierley MBBS FRCR FRCP FRCPC Professor Department of Radiation Oncology Princess Margaret Cancer Centre University of Toronto Toronto, Ontario, Canada

Ayman Al-Habeeb MBBS FRCPC Assistant Professor Department of Laboratory Medicine and Pathobiology University of Toronto Toronto, Ontario, Canada

J Kenneth Byrd MD Assistant Professor Department of Otolaryngology Georgia Regents University Augusta, Georgia, USA

Hussain A Alsaffar MBBS FRCSC Professor Department of Urology University of Virginia Charlottesville, Virginia, USA

Steven B Cannady MD Assistant Professor Department of Otorhinolaryngology University of Pennsylvania Philadelphia, Pennsylvania, USA

Trinitia Cannon MD Assistant Professor Department of Otorhinolaryngology University of Oklahoma Oklahoma City, Oklahoma, USA Jimmy Yu Wai Chan MD MS Clinical Assistant Professor Department of Surgery University of Hong Kong, Hong Kong Michael WK Chan MD Radiology Resident University of Toronto Toronto, Ontario, Canada Douglas Chepeha MD University of Michigan Medical Center Ann Arbor, Michigan, USA Sydney Ch’ng MBBS PhD FRACS Royal Prince Alfred Hospital New South Wales, Australia Jonathan R Clark MD Associate Professor Department of Head and Neck Surgery Sydney Head and Neck Cancer Institute University of Sydney Sydney, New South Wales, Australia Gary L Clayman DMD MD FACS Professor Department of Head and Neck Surgery The University of Texas MD Anderson Cancer Center Houston, Texas, USA Jonathan Cohen MD Department of Otolaryngology Sanford Health Sioux Falls, South Dakota, USA Marc A Cohen MD Assistant Professor Department of Otolaryngology— Head and Neck Surgery Weill Cornell Medical College/ New York Presbyterian Hospital New York, New York, USA

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Matthew D Cox MD Resident Department of Otolaryngology— Head and Neck Surgery University of Arkansas for Medical Sciences Little Rock, Arkansas, USA Gail E Darling MD Professor, Department of Surgery University of Toronto Toronto, Ontario, Canada Terry A Day MD Department of Otolaryngology— Head and Neck Surgery Medical University of South Carolina Charleston, South Carolina, USA John R de Almeida MD MSc Assistant Professor Department of Otolaryngology— Head and Neck Surgery University of Toronto Toronto, Ontario, Canada Karen Devon MD MSc FRCSC Assistant Professor Department of Surgery University of Toronto Toronto, Ontario, Canada M Dhiwakar MS (ENT) (AIIMS)

MRCS FRCS (ORL-HNS) CCST (UK)

Advanced Head and Neck Surgical Oncology Fellowship, SIU, USA Consultant ENT, Head and Neck Surgeon KMCH and KMCH Comprehensive Cancer Center Coimbatore, Tamil Nadu, India William S Duke MD Assistant Professor Department of Otolaryngology— Head and Neck Surgery Georgia Regents University Augusta, Georgia, USA David W Eisele MD FACS Andelot Professor and Director Department of Otolaryngology— Head and Neck Surgery Johns Hopkins University School of Medicine Baltimore, Maryland, USA

Danny J Enepekides MD FRCSC MPH Associate Professor Department of Otolaryngology— Head and Neck Surgery University of Toronto Toronto, Ontario, Canada

Adam S Garden MD Professor Department of Radiation Oncology The University of Texas MD Anderson Cancer Center Houston, Texas, USA

Douglas B Evans MD Professor and Chair Department of Surgery Medical College of Wisconsin Milwaukee, Wisconsin, USA

Eric M Genden MD Professor Department of Otolaryngology The Icahn School of Medicine at Mount Sinai New York, New York, USA

Robert L Ferris MD PhD Professor Department of Otolaryngology— Head and Neck Surgery University of Pittsburgh Medical Center Pittsburgh, Pennsylvania, USA Andrew Foreman MD BMBS(Hon) PhD FRACS Clinical Fellow Department of Otolaryngology— Head and Neck Surgery University of Toronto Toronto, Ontario, Canada Jeremy L Freeman Professor and Temmy Latner/ Dynacare Chair in Head and Neck Oncology Department of Otolaryngology— Head and Neck Surgery University of Toronto Toronto, Ontario, Canada Gerry F Funk MD Professor Department of Otolaryngology— Head and Neck Surgery University of Iowa Iowa City, Iowa, USA Shane A Gangatharan MD Department of Medical Oncology and Hematology Princess Margaret Cancer Center Toronto, Ontario, Canada Ian Ganly MD PhD Associate Professor Head and Neck Service Department of Surgery Memorial Sloan Kettering Cancer Center New York, New York, USA

Julien E Ghannoum DMD Attending—Oral and Maxillofacial Pathology Department of Stomatology Centre Hospitalier de Université de Montréal Montreal, Quebec, Canada Danny Ghazarian MD Associate Professor Department of Laboratory Medicine and Pathobiology University of Toronto Toronto, Ontario, Canada Ralph W Gilbert MD FRCSC Otolaryngologist-in-Chief University Health Network Gullane/O’Neil Chair Department of Otolaryngology— Head and Neck Surgery University Health Network Head Division of Head and Neck Oncology Professor Department of Otolaryngology— Head and Neck Surgery University of Toronto Toronto, Ontario, Canada Ann M Gillenwater MD Professor Department of Head and Neck Surgery The University of Texas MD Anderson Cancer Center Houston, Texas, USA Meredith E Giuliani MBBS Med FRCPC Assistant Professor Department of Radiation Oncology University of Toronto Toronto, Ontario, Canada

Contributors David P Goldstein MD MSc FRCSC FACS Assistant Professor Princess Margaret Cancer Center Department of Otolaryngology— Head and Neck Surgery University of Toronto Toronto, Ontario, Canada

Bruce H Haughey MBChB FACS FRACS Kimbrough Professor Department of Otolaryngology— Head and Neck Surgery Washington University School of Medicine St. Louis, Missouri, USA

Jennifer R Grandis Professor Otolaryngology and Pharmacology University of Pittsburgh Pittsburgh, Pennsylvania, USA

Chase M Heaton MD Assistant Professor Department of Otolaryngology— Head and Neck Surgery University of California San Francisco San Francisco, California, USA

Elizabeth G Grubbs MD Associate Professor Department of Surgical Oncology The University of Texas MD Anderson Cancer Center Houston, Texas, USA Patrick J Gullane MD FRCSC FACS Wharton Chair in Head and Neck Surgery Professor Department of Otolaryngology— Head and Neck Surgery Professor of Surgery University of Toronto Toronto, Ontario, Canada

Kevin M Higgins MD Associate Professor Department of Otolaryngology— Head and Neck Surgery University of Toronto Toronto, Ontario, Canada Christopher Holsinger MD FACS Professor and Chief Head and Neck Surgery Stanford University Palo Alto, California, USA

Patrick K Ha MD Associate Professor Department of Otolaryngology— Head and Neck Surgery Johns Hopkins University Baltimore, Maryland, USA

Jeffrey J Houlton MD Assistant Professor Department of Otolaryngology— Head and Neck Surgery University of Washington Seattle, Washington, USA

Stephan K Haerle MD Professor Department of Otolaryngology— Head and Neck Surgery University Hospital Basel Basel, Switzerland

Nicole M Hsu MD Ear, Nose, and Throat New York, New York, USA

Jeffrey R Harris MD MHA FRCS(C) Professor of Surgery Division of Otolaryngology— Head and Neck Surgery University of Alberta Hospital Edmonton, Alberta, Canada

Katherine A Hutcheson PhD Assistant Professor Department of Head and Neck Surgery The University of Texas MD Anderson Cancer Center Houston, Texas, USA

Robert D Hart MD Associate Professor Division of Otolaryngology— Head and Neck Surgery, Department of Surgery, Dalhousie University Halifax, Nova Scotia, Canada

Jonathan Irish MD FRCSC Professor Department of Otolaryngology— Head and Neck Surgery University of Toronto Toronto, Ontario, Canada

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Bradley T Johnson MD Staff Physician Department of Surgery Otolaryngology—Head and Neck Surgery Mercy Clinic Springfield, Missouri, USA Jonas T Johnson MD Professor and Chairman Department of Otolaryngology University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania, USA Dev P Kamdar MD Assistant Professor Department of Otolaryngology Assistant Professor, Department of Surgery Hofstra North Shore— LIJ School of Medicine Hempstead, New York, USA Jason I Kass MD Microvascular Head and Neck Fellow Department of Otolaryngology Icahn School of Medicine at Mount Sinai New York, New York, USA Emma King PhD FRCS-ORLHNS CRUK Senior Lecturer Head and Neck Surgery University of Southampton Consultant Head and Neck Surgeon Poole Hospital NHS Foundation Trust Poole, Dorset, UK Yekaterina A Koshkareva MD Head and Neck Fellow University of Pittsburgh Medical Center Pittsburgh, Pennsylvania, USA Vishal Kukreti MD FRCPC Assistant Professor Department of Medical Oncology and Hematology University of Toronto Toronto, Ontario, Canada Michael E Kupferman MD Associate Professor Department of Head and Neck Surgery University of Texas MD Anderson Cancer Center Houston, Texas, USA

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Laurent Létourneau-Guillon MD FRCPC Clinical Assistant Professor University of Montreal Neuroradiologist Notre-Dame Hospital University of Montreal Hospital Centers (CHUM) CHUM Research Center (CRCHUM) Montreal, Quebec, Canada

Brett A Miles DDS MD Assistant Professor Department of Otolaryngology— Head and Neck Surgery Division Oral and Maxillofacial Surgery Icahn School of Medicine at Mount Sinai New York, New York, USA

Jan S Lewin PhD Professor, Department of Head and Neck Surgery Section Chief Speech Pathology and Audiology The University of Texas MD Anderson Cancer Center Houston, Texas, USA

Pablo H Montero MD Fellow in Head and Neck Surgical Oncology Head and Neck Service Department of Surgery Memorial Sloan Kettering Cancer Center New York, New York, USA

Irene Low MBChB FRCPA Consultant Pathologist Department of Histology Middlemore Hospital Auckland, New Zealand

Mauricio A Moreno MD Assistant Professor Department of Otolaryngology— Head and Neck Surgery University of Arkansas for Medical Sciences Little Rock, Arkansas, USA

Matthew JR Magarey BMed FRACS Head and Neck Surgeon Division of Cancer Surgery Peter MacCallum Cancer Center Melbourne, Australia Becky L Massey MD Assistant Professor Medical College of Wisconsin Milwaukee, Wisconsin, USA Jesus E Medina MD Professsor Department of Otorhinolaryngology University of Oklahoma Oklahoma City, Oklahoma, USA Ozgur Mete MD Assistant Professor Department of Laboratory Medicine and Pathology University of Toronto Toronto, Ontario, Canada Zvonimir L Milas MD FACS Associate Professor Department of Surgery Carolinas Medical Center/ Levine Cancer Institute Charlotte, North Carolina, USA

Sami P Moubayed MD Resident Otolaryngology— Head and Neck Surgery University of Montreal Montreal, Quebec, Canada Nidal Muhanna MD Clinical Fellow Head and Neck Surgery Department of Otolaryngology— Head and Neck Surgery University of Toronto Toronto, Ontario Canada Wojciech K Mydlarz MD Assistant Professor Department of Otolaryngology— Head and Neck Surgery Johns Hopkins School of Medicine Baltimore, Maryland, USA Karen A Naert MD Assistant Clinical Professor Department of Pathology University of Calgary Calgary, Alberta, Canada

David Michael Neskey MD Assistant Professor Departments of Otolaryngology— Head and Neck Surgery and Cell and Molecular Pharmacology Medical University of South Carolina Charleston, South Carolina, USA Iain J Nixon PhD Consultant Surgeon Department of ENT— Head and Neck Surgery East Kent University Hospitals NHS Foundation Trust Ashford, Kent, UK Salem I Noureldine MD Postdoctoral Fellow Department of Otolaryngology— Head and Neck Surgery Johns Hopkins University School of Medicine Baltimore, Maryland, USA Brian Nussenbaum MD FACS FRACS Christy J and Richard S Hawkes Professor Department of Otolaryngology— Head and Neck Surgery Washington University School of Medicine St. Louis, Missouri, USA Daniel A O’Connell MD MSc Assistant Professor Division of Otolaryngology— Head and Neck Surgery University of Alberta Edmonton, Alberta, Canada Kerry D Olsen MD Professor Department of Otorhinolaryngology— Head and Neck Surgery Mayo Clinic Rochester, Minnesota, USA Lisa A Orloff MD Director of Endocrine Head and Neck Surgery Professor Otolaryngology— Head and Neck Surgery Stanford University Stanford, California, USA

Contributors Christian Ottensmeier MD PhD FRCP Director Experimental Cancer Medicine Centre Professor of Experimental Medicine University of Southampton Southampton, England, UK Nitin A Pagedar MD MPH Assistant Professor Department of Otolaryngology— Head and Neck Surgery University of Iowa Iowa City, Iowa, USA Aru Panwar MD House Officer VI University of Nebraska Medical Center Omaha, Nebraska, USA Snehal G Patel MD Associate Professor Department of Surgery Head and Neck Service Memorial Sloan Kettering Cancer Center New York, New York, USA Samip N Patel MD Assistant Professor Department of Otolaryngology— Head and Neck Surgery University of North California Chapel Hill, North Carolina, USA Phillip K Pellitteri DO FACS Chair Department of Otolaryngology— Head and Neck Surgery Guthrie Clinic Ltd Sayre, Pennsylvania, USA Bayardo Perez-Ordoñez MD Associate Professor Department of Pathology University Health Network University of Toronto Toronto, Ontario, Canada Jack Phan MD PhD Assistant Professor Department of Radiation Oncology, Head and Neck University of Texas MD Anderson Cancer Center Houston, Texas, USA

Daniel L Price MD Assistant Professor Department of Otorhinolaryngology— Head and Neck Surgery Mayo Clinic Rochester, Minnesota, USA Gregory W Randolph MD Director, Thyroid Surgical Division Massachusetts Eye and Ear Institute Harvard Medical School Boston, Massachusetts, USA Jana M Rieger MD Professor Faculty of Rehabilitation Medicine University of Alberta Edmonton, Alberta, Canada Jason T Rich MD Assistant Professor Department of Otolaryngology Washington University, School of Medicine St. Louis, Missouri, USA Matthew H Rigby MD MPH FRCSC Division of Otolaryngology— Head and Neck Surgery Dalhousie University Halifax, Nova Scotia, Canada K Thomas Robbins MD FRCSC FACS Professor Division of Otolaryngology— Head and Neck Surgery Southern Illinois School of Medicine Springfield, Illinois, USA Cristina P Rodriguez Assistant Professor Department of Medicine University of Washington Seattle, Washington, USA

Jatin P Shah MD Chief, Department of Surgery Head and Neck Service Memorial Sloan Kettering Cancer Center New York, New York, USA Ashok R Shaha MD Jatin P Shah Chair in Head and Neck Surgery and Oncology Memorial Sloan Kettering Cancer Center New York, New York, USA Richard V Smith MD FACS Professor and Vice Chair Department of Otolaryngology— Head and Neck Surgery Montefiore Medical Center/Albert Einstein College of Medicine Bronx, New York, USA Russell B Smith MD Professor University of Nebraska Medical Center Omaha, Nebraska, USA Matthew Spector MD Assistant Professor Otolaryngology University of Michigan Ann Arbor, Michigan, USA Sandro J Stoeckli MD Professor Department of Otorhinolaryngology— Head and Neck Surgery Kantonsspital St. Gallen St. Gallen, Switzerland

Lorne Rotstein MD FRCSC FACS Professor Department of Surgery University of Toronto Toronto, Ontario, Canada

S Mark Taylor MD FRCS(C) FACS Professor and Deputy Head Otolaryngology— Head and Neck Surgery Dalhousie University Halifax, Nova Scotia, Canada

Hadi Seikaly MD MAL FRSC Professor Departments of Surgery and Oncology Divisional Director Zone Clinical Department Section Chief University of Alberta and Alberta Health Services Edmonton, Alberta, Canada

David J Terris MD FACS Professor, Surgical Director GRU Thyroid Center Department of Otolaryngology— Head and Neck Surgery Georgia Regents University Augusta, Georgia, USA

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Gareth Thomas BDS MScD PhD Professor of Experimental Pathology University of Southampton Southampton, England, UK Kathleen M Tibbetts MD Resident Physician Department of Otorhinolaryngology— Head and Neck Surgery Albert Einstein College of Medicine Bronx, New York, USA Jonathan RB Trites MD Associate Professor Department of Surgery Division of Otolaryngology— Head and Neck Surgery Dalhousie University Halifax, Nova Scotia, Canada Richard W Tsang MD Professor Department of Radiation Oncology University of Toronto Toronto, Ontario, Canada Ralph P Tufano MD MBA FACS Charles W Cummings MD Professor Department of Otolaryngology— Head and Neck Surgery Johns Hopkins University School of Medicine Baltimore, Maryland, USA Hans Van Veer MD Thoracic Surgery at UZ Leuven Antwerp, Belgium

Allan D Vescan MD Assistant Professor Department of Otolaryngology— Head and Neck Surgery University of Toronto Toronto, Ontario, Canada Nadarajah Vigneswaran DMD Dr Med Dent Professor Department of Diagnostic and Biomedical Sciences The University of Texas School of Dentistry at Houston Houston, Texas, USA Paul C Walker MD Assistant Professor Department of Otolaryngology— Head and Neck Surgery Loma Linda University Medical Center Loma Linda, California, USA Tracy S Wang MD MPH Associate Professor Chief, Section of Endocrine Surgery Department of Surgery Medical College of Wisconsin Milwaukee, Wisconsin, USA Laura Y Wang MD Department of Surgery Head and Neck Service Memorial Sloan Kettering Cancer Center New York, New York, USA Mark K Wax MD FACS FR(SCC) Professor, Program Director Department of Otolaryngology— Head and Neck Surgery, Maxillofacial Surgery, Oregon Health Sciences University Portland, Oregon, USA

William I Wei FRCS FRCSE FACS (Hon) Head Li Shu Pui ENT Head and Neck Surgery Center Hong Kong Sanatorium and Hospital Hong Kong SAR Ilan Weinreb MD FRCPC Assistant Professor University of Toronto Department of Pathology University Health Network Toronto, Ontario, Canada Ian J Witterick MD MSc Professor and Chair Department of Otolaryngology— Head and Neck Surgery University of Toronto Toronto, Ontario, Canada Bin Xu PhD Pain Medicine Mineola, New York, USA John Yoo MD Professor Department of Otolaryngology— Head and Neck Surgery Schulich School of Medicine and Dentistry Western University London, Ontario, Canada Eugene Yu MD Associate Professor Medical Imaging University of Toronto Toronto, Ontario, Canada

Foreword Sataloff’s Comprehensive Textbook of Otolaryngology: Head and Neck Surgery is a component of the most extensive compilation of information in otolaryngology—head and neck surgery to date. The six volumes of the comprehensive textbook are part of a 12-volume, encyclopedic compendium that also includes a six-volume set of detailed, extensively illustrated atlases of otolaryngologic surgical techniques. The vision for the Comprehensive Textbook was realized with the invaluable, expert collaboration of eight world-class volume editors. Chapter authors include many of the most prominent otolaryngologists in the world, and coverage of each subspecialty is extensive, detailed and scholarly. Anil K Lalwani, MD edited the volume on otology/neurotology/skull base surgery. Like all six of the volumes in the Comprehensive Textbook, the otology/neurotology/skull base surgery volume is designed not only as part of the multivolume book, but also to stand alone or in combination with the atlas of otological surgery. Dr Lalwani’s volume covers anatomy and physiology of hearing and balance, temporal bone radiology, medical and surgical treatment of common and rare disorders of the ear and related structures, occupational hearing loss, aural rehabilitation, cochlear and brainstem implantation, disorders of the facial nerve, and other topics. Each chapter is not only replete with the latest scientific information, but also accessible and practical for clinicians. The rhinology/allergy and immunology volume by Marvin P Fried and Abtin Tabaee is the most elegant and inclusive book on the topic to date. Drs Fried and Tabaee start with a history of rhinology beginning in ancient times. The chapters on evolution of the nose and sinuses, embryology, sinonasal anatomy and physiology, and rhinological assessment are exceptional. The volume includes discussions of virtually all sinonasal disorders and allergy, including not only traditional medical and surgical therapy but also complementary and integrative medicine. The information is state-of-the-art. Anthony P Sclafani’s volume on facial plastic and reconstructive surgery is unique in its thoroughness and practicality. The volume covers skin anatomy and physiology, principles of wound healing, physiology of grafts and flaps, lasers in facial plastic surgery, aesthetic analysis of the face and other basic topics. There are extensive discussions on essentially all problems and procedures in facial plastic and reconstructive surgery contributed by many of the most respected experts in the field. The volume includes not only cosmetic and reconstructive surgery, but also information on diagnosis and treatment of facial trauma. The volume on laryngology edited by Dr Michael S Benninger incorporates the most current information on virtually every aspect of laryngology. The authors constitute a who’s who of world experts in voice and swallowing. After extensive and practical discussions of science and genetics, the volume reviews diagnosis and treatment (traditional and complementary) of laryngological disorders. Chapters on laser physics and use, voice therapy, laryngeal dystonia, cough, vocal aging and many other topics provide invaluable “pearls” for clinicians. The volume also includes extensive discussion of surgery for airway disorders, office-based laryngeal surgery, laryngeal transplantation and other topics. For the volume on head and neck surgery, Drs Patrick J Gullane and David P Goldstein have recruited an extra­ ordinary group of contributors who have compiled the latest information on molecular biology of head and neck cancer, principles of radiation, immunobiology, medical oncology, common and rare head and neck malignancies, endocrine neoplasms, lymphoma, deep neck space infections and other maladies. The surgical discussions are thorough and richly illustrated, and they include definitive discussions of free flap surgery, facial transplantation and other subjects. Dr Christopher J Hartnick’s vision for the volume on pediatric otolaryngology was expansive, elegantly scholarly and invaluable clinically. The volume begins with information on embryology, anatomy, genetics, syndromes and other complex topics. Dr Hartnick’s contributors include basic discussions of otolaryngologic examination in a pediatric patient, imaging, hearing screening and aural rehabilitation, and diagnosis and treatment of diseases of the ear, nose, larynx, oral cavity, neck and airway. Congenital, syndromic and acquired disorders are covered in detail, as are special, particularly vexing problems such as chronic cough in pediatric patients, breathing and obstructive sleep apnea in children, pediatric voice disorders, and many other subjects. This volume will be invaluable to any otolaryngologist who treats children.

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All of us who have been involved with the creation of the six-volume Sataloff’s Comprehensive Textbook of Otolaryngology: Head and Neck Surgery and its companion six-volume set of surgical atlases hope and believe that our colleagues will find this new offering to be not only the most extensive and convenient compilation of information in our field, but also the most clinically practical and up-to-date resource in otolaryngology. We are indebted to Mr Jitendar P Vij (Group Chairman) and Mr Ankit Vij (Group President) of M/s Jaypee Brothers Medical Publishers (P) Ltd., New Delhi, India, for their commitment to this project, and for their promise to keep this work available not only online but also in print. We are indebted also to the many otolaryngologists who have contributed to this work not only by editing volumes and writing chapters, but also by asking questions that inspired many of us to seek the answers found on these pages. We also thank especially the great academic otolaryngologists who trained us and inspired us to spend our nights, weekends and vacations writing chapters and books. We hope that our colleagues and their patients find this book useful. Robert T Sataloff MD DMA FACS Professor and Chairman Department of Otolaryngology—Head and Neck Surgery Senior Associate Dean for Clinical Academic Specialties Drexel University College of Medicine Philadelphia, Pennsylvania, USA

Preface Over the past 30–50 years we have witnessed a significant renaissance in the diagnostic techniques and management of neoplasms about the head and neck which includes the molecular genetics of tumor growth and spread, and in addition a much greater understanding of epidemiological and etiological factors. At the same time, cohort and populationbased studies have helped to identify more precisely the incidence and changing trends in oropharynx cancer with a reduction in tobacco and alcohol-induced cancers to the ever-increasing numbers of HPV-related malignancies. We are currently at a crossroads in understanding how best to de-intensify therapy and minimize the escalating complications associated with concurrent chemoradiotherapy. During the plan for the development of this six-volume textbook it was recognized that there would be some slight overlap between the volumes, especially those relating to reconstruction and endoscopic approaches. It was our goal that the head and neck volume be a comprehensive overview of neoplasms of the head and neck and as such we aimed to select authors with an experienced understanding of each of the subsites of the head and neck. The contributors have been carefully selected and represent different geographic regions so that a global perspective is obtained. The volume by nature of its content and contributors is multidisciplinary and comprehensive. The objective is to provide the reader with an overview of the diagnosis and up-to-date management approaches to benign and malignant tumors of the upper aerodigestive tract. This volume in its 59 chapters covers the breadth and depth of the fundamentals of head and neck cancer management to include surgery, radiation, medical oncology, reconstruction and rehabilitation. The chapters are therefore very comprehensive and are structured to introduce the novice to the challenges of head and neck oncology, and in addition, are of immense benefit as a reference to experienced practitioners. This volume is a most important and timely overview of our present knowledge of both the diagnosis and therapies available in present day practice. It therefore represents an important resource for trainees in the different surgical specialties and other healthcare professionals that overlap in the management of the head and neck tumors. We are indebted to the contributors for their unique contributions and hope that this text will stimulate younger readers and investigators to be innovative. Patrick J Gullane MD FRCSC FACS David P Goldstein MD MSc FRCSC FACS

Acknowledgments The editors would like to thank Joseph Rusko, Marco Ulloa, Carol Rogers Field, Bridget Meyer, Thomas Gibbons and the rest of the Jaypee Brothers team. Without their perseverance and hard work, this volume would not have been possible. Special thanks are offered to the authors, who have shared their expertise and experience in order to improve the care of the Head and Neck Surgery patients. We would also like to thank Mr Jitendar P Vij (Group Chairman), Mr Ankit Vij (Group President), Ms Chetna Malhotra Vohra (Associate Director), Mr Umar Rashid (Development Editor) and Production team of Jaypee Brothers Medical Publishers (P) Ltd., New Delhi, India.

Contents 1. The Molecular Biology of Head and Neck Cancer

1

Jason I Kass, Jennifer R Grandis

2. Principles of Radiation Oncology

13

Jack Phan, Adam S Garden

3. Principles of Medical Oncology

45

Cristina P Rodriguez, David J Adelstein

4. Immunobiology and Immunotherapy in Head and Neck Cancer

55

Emma King, Gareth Thomas, Christian Ottensmeier

5. Head and Neck Imaging

69

Laurent Létourneau-Guillon, Michael WK Chan, Eugene Yu

6. Sentinel Node Biopsy in Head and Neck Cancer

121

Stephan K Haerle, Sandro J Stoeckli

7. Non-melanoma Skin Cancers of the Head and Neck

129

Sydney Ch’ng, Irene Low, Ashlin Alexander, Jonathan R Clark

8. Melanoma

139

Trinitia Cannon, Jesus E Medina

9. Pathology of Cutaneous Malignancies of the Head and Neck

157

Ayman Al-Habeeb, Karen A Naert, Nadya A Al-Faraidy, Danny Ghazarian

10. Merkel Cell Carcinoma and Other Rare Skin Cancers

191

Sydney Ch’ng, Irene Low, Ashlin Alexander, Jonathan R Clark

11. Surgical Anatomy and Embryology of the Thyroid and Parathyroid Glands

201

Lorne Rotstein, Karen Devon

12. Pathology of Thyroid and Parathyroid Neoplasms

209

Sylvia L Asa, Ozgur Mete

13. Diagnosis and Management of the Thyroid Nodule

231

Chase M Heaton, Lisa A Orloff

14. Management of Well-Differentiated Thyroid Cancer

241

Iain J Nixon, Ashok R Shaha, Jatin P Shah

15. Medullary Thyroid Cancer

253

Elizabeth G Grubbs, Becky L Massey, Douglas B Evans, Tracy S Wang

16. Anaplastic Thyroid Cancer

265

Meredith E Giuliani, Richard W Tsang, James D Brierley

17. Principles and Technique of Thyroidectomy

273

William S Duke, David J Terris

18. Management of Advanced Thyroid Cancer

283

Zvonimir L Milas, Gary L Clayman

19. Management of Recurrent Thyroid Cancer Matthew JR Magarey, Jeremy L Freeman

297

xx

Head and Neck Surgery

20. Hyperthyroidism: Graves’ Disease, Toxic Multinodular Goiter, and Solitary Toxic Nodule

307

Aru Panwar, Russell B Smith

21. Surgical Management of Goiter

313

Laura Wang, Ian Ganly, Gregory W Randolph

22. Management of Primary and Secondary Hyperparathyroidism

327

Salem I Noureldine, Sun M Ahn, Ralph P Tufano

23. Management of Recurrent Hyperparathyroidism

345

Salem I Noureldine, Phillip K Pellitteri, Ralph P Tufano

24. Paragangliomas of the Head and Neck

361

Jason T Rich, Brian Nussenbaum

25. Anatomy, Physiology, and Non-neoplastic Disorders of the Salivary Glands

383

Wojciech K Mydlarz, Patrick K Ha, David W Eisele

26. Pathology of Salivary Gland Neoplasms

409

Bin Xu, Ilan Weinreb, Bayardo Perez-Ordoñez

27. Salivary Gland Neoplasms

451

Yekaterina A Koshkareva, Robert L Ferris

28. Tumors of the Parapharyngeal Space

471

Daniel L Price, Kerry D Olsen

29. Soft Tissue Sarcomas of the Head and Neck

481

Jonathan Irish, Nidal Muhanna

30. Bone Sarcomas of the Head and Neck

493

Jonathan Irish, Nidal Muhanna

31. Overview of Head and Neck Lymphomas

501

Shane A Gangatharan, Vishal Kukreti

32. Nasal Cavity and Paranasal Sinus Malignancies

519

John R de Almeida, Allan D Vescan, Ian J Witterick

33. Benign and Premalignant Oral Lesions

549

Ann M Gillenwater, Nadarajah Vigneswaran

34. Lesions of the Jaw/Dental-Related Lesions

569

Sami P Moubayed, Julien E Ghannoum, Eric Bissada

35. Oral Cavity Cancer

591

Pablo H Montero, Snehal G Patel, Ian Ganly

36. Nasopharyngeal Carcinoma

617

William I Wei, Jimmy Yu Wai Chan

37. Oropharyngeal Cancer

647

David Michael Neskey, Christopher Holsinger, Michael E Kupferman

38. Current Concepts in Transoral Approaches to Cancers of the Oropharynx and Oral Cavity

667

Jason T Rich, Bruce H Haughey

39. Early Larynx Cancer

679

J Kenneth Byrd, Jonas T Johnson

40. Advanced Laryngeal Cancer Hussain A Alsaffar, Dev P Kamdar, Andrew Foreman, Meredith F Giuliani, Patrick J Gullane, David P Goldstein

691

Contents 41. Tracheal Stenosis and Tracheal Neoplasms

xxi 711

Andrew Foreman, Bradley T Johnson, Patrick J Gullane

42. Hypopharynx Cancer

727

Samip N Patel, Patrick J Gullane, David P Goldstein

43. Cervical Esophageal Cancer

743

Hans Van Veer, Gail E Darling

44. Voice Rehabilitation after Laryngectomy

759

Katherine A Hutcheson, Jan S Lewin

45. Neck Dissection

771

M Dhiwakar, K Thomas Robbins

46. Unknown Primary Carcinoma

791

Jeffrey J Houlton, Terry A Day

47. Deep Neck Space Infections

805

Matthew D Cox, Mauricio A Moreno

48. Complications of Head and Neck Surgery

825

Kathleen M Tibbetts, Richard V Smith

49. Salvage Surgery for Recurrent Head and Neck Cancer

845

Nicole M Hsu, Marc A Cohen

50. Perioperative Assessment in Elderly Patients Undergoing Head and Neck Surgery

855

Hussain A Alsaffar, John R de Almeida, Patrick J Gullane, David P Goldstein

51. Overview of Regional Flaps in Head and Neck Cancer

861

Matthew H Rigby, Jonathan RB Trites, Robert D Hart, S Mark Taylor

52. Overview of Free Flaps Used in Head and Neck Reconstruction

881

Steven B Cannady, Jonathan Cohen, Mark K Wax

53. Functional Oropharyngeal Reconstruction: An Evidence-Based Approach

905

Hadi Seikaly, Daniel A O’Connell, Jana M Rieger, Kal Ansari, Jeffrey R Harris

54. Reconstruction of the Oral Cavity

927

Brett A Miles, Eric M Genden

55. Reconstruction of the Hypopharynx and Larynx

947

Paul Walker, Gerry F Funk, Nitin A Pagedar

56. Reconstruction of Maxilla and Skull Base Defects

957

Douglas Chepeha, Ralph W Gilbert, Matthew Spector

57. Reconstruction of Parotidectomy Defects and Facial Nerve Paralysis  

975

Doug Angel, John Yoo

58. Reconstruction of the Scalp

995

Danny Enepekides, Kevin M Higgins

59. Facial Transplantation

1009

Daniel S Alam

Index

1021

Chapter 1: The Molecular Biology of Head and Neck Cancer

1

CHAPTER

The Molecular Biology of Head and Neck Cancer

1

Jason I Kass, Jennifer R Grandis

INTRODUCTION Molecular biology has revolutionized our understanding of cancer biology. In the past 60 years, we have progressed from primarily using histopathology to now recognizing biomarkers, like p16, and assigning a molecular pheno­ type. Disease prognosis based on molecular information is now a reality, and clinical trials are underway to further personalize treatment based on molecular features. As an oncologic head and neck surgeon, it is essential to be familiar with the important molecules that are either in­activated or dysregulated in head and neck squamous cell carcinoma (HNSCC), particularly as our armamen­ tarium of targeted therapies grows. Here, we review the molecular pathways implicated in HNSCC and the targeted therapies that are available or emerging.

MOLECULAR CHANGES ASSOCIATED WITH HISTOLOGICAL CHANGES IN SQUAMOUS EPITHELIUM HNSCC is a heterogeneous entity initiated over time through repeated exposure to carcinogens, the major ones being tobacco and alcohol. In 1953, the term “field cancerization” was coined to recognize that there were separate populations of cells in close proximity that could give rise to second primaries despite having clear surgical margins.1 With advances in molecular biology a genetic model of progression from normal mucosa to invasive HNSCC was first proposed in 1996.2 In this series, 83 patients were followed with serial biopsies.

Specimens showing dysplasia, carcinoma in situ (CIS), and invasive cancer were analyzed by PCR, and a series of chromosomal regions containing key oncogenes/tumor suppressor genes were analyzed. A loss of heterozygosity (LOH) was seen in nearly all of the specimens with dysplasia or CIS. LOH of the tumor suppressor genes p53 and p16 was seen as early changes as the mucosa became dysplastic (Fig. 1.1). LOH of the tumor suppressor gene retinoblastoma (Rb) and cell cycle protein cyclin D1 were detected in CIS and loss of genes in chromosomes 6p, 8, and 4q was identified in invasive tumors.3 Cells accumulated these mutations over time, and there was heterogeneity within different specimens, although they appeared the same histologically. This work supported the molecular underpinning to the heterogeneity seen in field cancerization 40 years earlier. With advances in sequencing technology, the expres­ sion pat­terns of an entire genome could be assayed in individual tumors.4 Messenger RNA extracted from normal and pre­malignant mucosa as well as invasive cancer speci­ mens from 21 patients revealed several hundred genes that were either upregulated or downregulated in premalig­ nant tissues. Fewer genes had transcriptional changes as they progressed from premalignancy to invasive cancer. The genes identified were involved in nearly all of the cellular processes disrupted in cancer including the cell cycle, cell growth, cell adhesion, blood vessel ingrowth (angioge­nesis), and regulated cell death (apoptosis). Most recently, advances in high-throughput sequen­ cing technology have allowed for whole-exome sequencing (exons of all expressed genes) of nearly 125 squamous cell

2

Head and Neck Surgery

tumors.5,6 This data set, published by two separate groups in 2011, confirmed the importance of genes previously implicated in HNSCC, but also highlighted new genes not previously thought to be involved in disease progression (Table 1.1).

Terminology: Oncogenes, Tumor Suppressor Genes, and Mutations Genes that allow for uncontrolled cancer cell growth fall into two classes: proto-oncogenes and tumor suppressor

Fig. 1.1: Molecular alterations associated with histologic changes in squamous epithelium. Early events including mutations in p53 are seen in dysplastic mucosa, whereas late events such as PIK3CA activation and PTEN inactivation are seen in invasive cancers.

Table 1.1: Tumor suppressor genes and oncogenes in head and neck squamous cell carcinoma

Gene

Classification

DNA location

Frequency of genetic alteration5,22

Cell proliferation pathways TP53

Tumor-suppressor

17p13

Inactivating mutation/deletion (63%)

RB1

Tumor-suppressor

13q14

Inactivating mutation/deletion (3%)

CDKN2A

Tumor-suppressor

9p21

Inactivating mutation/deletion (25%)

CCND1

Proto-oncogene

11q13

Amplification (22%)

TGFBR2

Tumor-suppressor

3p22

Inactivating mutation/deletion (*)

SMAD4

Tumor-suppressor

18q21

Inactivating mutation/deletion (*)

Cell signaling pathways EGFR

Proto-oncogene

7p11

Amplification (90%)

HRAS

Proto-oncogene

11p15

Activating mutation (4%)

PI3KCA

Proto-oncogene

3q26

Activating mutation (8%)

PTEN

Tumor-suppressor

10q23

Inactivating mutation/deletion (8%)

Cell differentiation pathways NOTCH 1 (2,3 as well)

Tumor-suppressor

9q34

Inactivating mutation/deletion (22%)

TP63

Proto-oncogene

3q26

Activating mutation or amplification (8%)

CASP8

Tumor-suppressor

Cell death 2q33

Inactivating mutation (8%)

Virally-mediated pathways E6

Viral oncogene

Human papilloma virus (HPV)

N/A

E7

Viral oncogene

HPV

N/A

* Indicates that the two genes in the transforming growth factor beta pathway were not in the top 74 highly mutated genes identified in the study of Stransky et al.5 (N/A: Not applicable).

Chapter 1: The Molecular Biology of Head and Neck Cancer genes. Proto-oncogenes have the potential to become onco­genes, confer a survival advantage, and drive cancer progression. Only one copy of the gene requires an activating mutation for the proto-oncogene to become onco­genic. In HNSCC, the catalytic subunit of phosphatidyl-inositol3-kinase (PI3KCA) is a proto-oncogene. Mutations in this subunit can activate the kinase, driving cell division through downstream targets.7 In contrast, tumor suppres­ sor genes act to hamper uncontrolled cell growth. Tumors must overcome these genetic brakes by either mutating both copies or by losing a gene copy by LOH and then sustaining a second inactivating mutation. In HNSCC, p53 is a central tumor suppressor gene.8 It is mutated in nearly 65% of HNSCC and is a multifunctional protein that regulates entry into the cell cycle as well as directing cells toward apoptosis.9 Mutations of proto-oncogenes and tumor suppressor genes can occur through a wide variety of mechanisms, and the literature supports the entire spectrum of known mutation types in HNSCC. There are point mutations that can result in missense or nonsense mutations, duplica­ tions, translocations, insertions, and deletions. Interest­ ingly, in HNSCC, transversion mutations, where the purine guanine was substituted for the pyrimidine thymidine, were observed much more frequently in smokers.5,10

Cell Proliferation (p53, Rb, CDKN2A, CCND1) The cell cycle is one of the most conserved pathways in biology with gene homologs in the simplest eukaryotes including yeast.11 As such, it has evolved tightly regulated

3

checkpoints to prevent the disorganized and uncontrolled growth seen in cancer. Important cell cycle regulatory genes that are either mutated or downregulated in HNSCC include TP53 (p53), Rb (retinoblastoma), CDKN2A (cyclindependent kinase 2A), and CCND1 (cyclin D1). p53 is the most commonly mutated gene in HNSCC.12 It is one of the earliest mutations seen in dysplastic mucosa, and either inactivating mutations or downregulation of p53 expression was seen in 80% of the whole-exome sequen­cing data.5 p53 is a multifunctional protein that primarily acts as a master tumor suppressor gene.9 It con­tains a DNAbinding domain and acts as a transcription factor, turning on genes that suppress the cell cycle, induce apoptosis, and inhibit autophagy (intracellular protein turnover). In the cell cycle, p53 tetramers prevent progression into mitosis at the G2-M checkpoint by activating p21 and irreversibly leading to cell cycle arrest (Fig. 1.2).3 Although its effects as a transcription factor are well appreciated, p53 is multifunctional. In the absence of a DNA binding domain, p53 remains able to have both cytoplasmic and nuclear effects. In vitro experiments with mutated forms of p53 that lack the DNA binding domain induce apoptosis.9 Retinoblastoma, cyclin D1, and cyclin-dependent kinase inhibitor 2A are the proteins encoded by Rb, CCND1, and CDKN2A genes. These proteins are important for entry into the cell cycle and transition from G1 interphase to DNA synthesis by passing the G–S checkpoint. The critical step for DNA synthesis is the release of the transcription factor E2F.3 Normally, E2F is inactive and bound tightly to the retinoblastoma pocket proteins (Rb is the canonical member of a larger family). When the balance between cellular senescence and growth is tipped toward growth,

Fig. 1.2: Regulation of the cell cycle at the G1-S and G2-M checkpoints. Asterisks (*) indicate the respective checkpoints. Mutations in key regulatory proteins like p16 (CKDN2A), Rb, and p53 can abrogate checkpoint integrity and promote unregulated cell division.

4

Head and Neck Surgery

the growth inhibitor CDKN2A (also called p16Ink4A) is inactivated leading to cyclin D1 complexes with cyclindependent kinases CDK4 and CDK6. Cyclin D1-CDK4 or CDK6 complexes lead to partial inactivation of Rb. The pocket proteins are then further inactivated by cyclin-E activation of CDK2. Complete inactivation of Rb allows for release of E2F and DNA replication proceeds. Amplification of cyclin D1 is an early event in the prog­ ression from premalignant to invasive carcinoma.13 Overexpression of cyclin D1 is associated with poor prognosis in HNSCC with studies showing both worsening survival14 and higher recurrence rates.15 Whole-exome sequencing showed amplification in 22% of patients. Deletion of CDKN2A is also a poor prognostic indicator16 and was seen in 25% of HNSCC tumors analyzed by whole-exome sequencing to date.

Cell Signaling (EGFR, RAS, PI3KCA, TGFBR2, SMAD4) There are a number of signaling pathways dysregulated in HNSCC, and targeting these pathways represents some of the most exciting targets for selective drug therapies in HNSCC (see below). The most established signaling

pathway is the epidermal growth factor receptor (EGFR) (Fig. 1.3). EGFR is a receptor tyrosine kinase that dimeri­ zes to transduce its signal through several intracellular pathways, including the RAS–MAPK, PI3K–PTEN–AKT, JAK–STAT, and phospholipase C pathways.17 Interestingly, EGFR (also called ErbB-1; HER1 in humans) may have a dual role. EGFR can either act as a membrane bound receptor, forming dimers with itself and other members of the ErbB/HER family, or it can translocate to the nucleus and act directly as a transcription factor.18 Recent evidence with a tagged form of EGFR showed nuclear localization and association with the promoter region of cyclin D1. It suggests that the receptor itself can directly upregulate cyclin D1 to control the cell cycle. Although activating mutations in EGFR have been described in HNSCC, they are relatively uncommon.19-21 Instead, amplification of EGFR appears to be its mecha­ nism for driving cell growth in 90% of patients.22 One activating mutation, EGFRvIII, is a truncated form of the receptor that lacks the extracellular binding domain and is constitutively active.23 The PI3K–PTEN–AKT–mTOR signaling cascade is an­other important pathway in HNSCC, because it appears to contain one of the few proto-oncogenes in HNSCC and

Fig. 1.3: Key signaling pathways in head and neck squamous cell carcinoma (HNSCC). Epidermal growth factor receptor has wideranging intracellular effects in both modulating cytoplasmic enzymatic cascades (via MAPK–Ras pathway) but also at the level of gene transcription. PI3K–PTEN–AKT pathway inhibits apoptosis (via BAD–BIM) and drives cell growth and division through its effects on p53 and cyclin D1. TGF-β pathway inhibits cell growth and disruption of integral components (TFGBR2, Smad4) removes inhibitory signals in HNSCC.

Chapter 1: The Molecular Biology of Head and Neck Cancer may serve as a new target for selective drug therapy.24 As described above, most of the major genes identified in HNSCC are tumor suppressors. PIK3CA encodes the alpha catalytic subunit for the protein phosphatidyl-inositol-3kinase and is mutated in approximately 8% of HNSCC.5 This enzyme phosphorylates the cell membrane cons­ tituent phosphatidylinositol-1,4-bisphosphate (PIP2) to phosphatidylinositol-1,4,5-trisphosphate (PIP3). PIP3 then attracts another kinase, which selectively activates the proteins AKT and mammalian target of rapamycin (mTOR). AKT and mTOR are serine/threonine kinase with pleotrophic effects including inhibition of the apoptosis proteins (BAD and BIM), cell cycle inhibitors and inhi­bitors of p53. Thus, activation of this pathway strongly favors growth. To turn off this pathway, a phosphatase, PTEN, inactivates PIP3 to PIP2. Ten percent of HNSCC have inactivating mutations or deletions of PTEN. In cells where there is both inactivation of PTEN and activation of PIK3CA, there are no known regulatory controls of the AKT–mTOR pathway. In contradistinction to the PI3K–PTEN–AKT–mTOR pathway, which favors growth and cell division, the actions mediated by the cytokine transforming growth factor beta (TGF-β) inhibits growth, favors differentiation and apoptosis.25 In normal epithelium soluble, TGF-β forms a heterodimer with the membrane-bound TGF-β receptors 1 and 2. The TGF-β receptors have serine/threonine kinases in their intracellular domains and after binding with TGF-β phosphorylates transcription factors called Smads (so called because they are similar to the Sma and MAD genes in fruit flies and worms). In epithelial cells, Smad2 and Smad3 are phosphorylated, form a complex with Smad4, and then translocate to the nucleus. The nuclear Smad complex has wide ranging inhibitory cellular effects. It potently suppresses cell proliferation by activating genes, like p15, to prevent Rb phosphorylation, (inhibiting E2F release) and preventing entry into the cell cycle. It also stimulates production of cell adhesion proteins including collagen and integrin, inhibits enzymes like collagenase, and others that breakdown the extracellular matrix. Activated TGF-β receptors can also mediate intracellular changes independent of the Smad complex. TGF-β favors apoptosis through both Smad-dependent and Smadindependent interactions. Since the normal cellular effects of TGF-β are largely antioncogenic, TGFBR2 and SMAD4 act as tumor sup­ pressor genes. Loss of chromosome 18q, which contains SMAD4 is common in invasive HNSCC.26,27 A recent mouse

5

model has shown that loss of Smad4 in mouse oral mucosa causes HNSCC.28 Loss of Smad4 in patients with esophageal squamous cell carcinoma correlates with more invasive tumors,29 higher likelihood of local metastases and reduced survival.30

Cell Differentiation (NOTCH, TP63) The Notch pathway has gained recent attention in HNSCC because it is mutated or deleted in over 20% of patients. Notch is an evolutionarily well-conserved protein, first identified in a screen of the fruit fly Drosophila melano­ gaster because of its characteristic notched wing. It has previously been implicated in other cancers, particularly leukemia and lymphoma where it acts as an oncogene. In HNSCC, however, NOTCH mutations appear to be inactivating, implying that it acts as a tumor suppressor, although functional data are still lacking. NOTCH1 is a member of 4 Notch receptors in humans. It is a large transmembrane poplypeptide with an intra­ cellular domain that is cleaved following ligand binding and activation (Figs. 1.4A and B). The cleaved Notch intra­ cellular domain translocates to the nucleus where it regu­ lates genes involved in cell differentiation and cell survival.31 One important gene inhibited by Notch1 is TP63.32 TP63 encodes the protein p63, which is a homolog and member of the p53 family. p63 inhibits apoptosis and terminal differentiation and as such acts as a proto-oncogene. There is a direct reciprocal repression between Notch1 and p63. This interestingly is seen as a gradient of activity in epider­ mal layers. In basal layers where cell division is high and differentiation is low, there is elevated p63 expression and low Notch expression. In suprabasal layers where kerati­ nocytes mature the expression pattern is reversed. Both Notch1 and p63 were highlighted as common mutations in the whole-exome sequencing data.6 NOTCH1 and its family members NOTCH2 and 3 are putative tumor sup­ pressor genes that were mutated or deleted in 22% of the patients sequenced. TP63 is a putative oncogene that is mutated or amplified in 8% of patients.

Cell Death (CASP8) Apoptosis or programmed cell death is an established means for cells to detect injury or germline mutations and prevent propagation. For a cancer cell to survive it must not only drive replication, but also avoid triggering its own death. The apoptotic pathway is complex and involves caspases, which are proteases that cleave a host of

6

Head and Neck Surgery

A

B

Figs. 1.4A and B: Reciprocal role of Notch and p63 in driving cell differentiation and growth. (A) Basal epithelial layers are activity dividing and express low levels of Notch and high levels of p63. This reciprocal relationship is reversed as cells differentiate in more superficial cell layers. (B) The canonical Notch pathway with activation by adjacent cells and translocation of the cleaved Notch intracellular domain (NICD) to the nucleus.

proteins.33 They are translated as inactive zymogens until remain inactive until they form active caspase tetramers. There are a number of caspases that when stimulated initiate the apoptotic cascade. Caspase 8 is important in HNSCC and was found to be mutated in 8% of patients.

HPV-Associated Viral Molecular Mechanisms of HNSCC The emergence of human papilloma virus (HPV)-asso­ ciated HNSCC (HPV + HNSCC) has fundamentally chan­ ged the epidemiology of HNSCC. The patients are younger and do not necessarily have the typical tobacco and alcohol exposure as risk factors in HPV negative disease. In many ways HPV-associated disease is an entirely new disease entity. It has specific tissue-site proclivity, distinct clinical presentation, and unusual radiosensitivity. In addition, there is emerging evidence that classic indicators for poor prognosis, like extracapsular spread, may not apply to HPV + HNSCC.34,35 HPV has a particular tropism to epithelial tissue. In particular, it is the major driver for cervical cancer. In the head and neck, it has a proclivity for the lymphoid tissue of the oropharynx. There are over 120 different HPV genotypes, which have been categori­ zed into high-risk (15 members) and low-risk subtypes based on their risk of causing invasive cervical cancer.36 HPV-16 is the most common associated subtype found in HNSCC biopsies (85–95%) and is a high-risk subtype. Some low-risk subtypes including HPV-6 and 11 are asso­ ciated with benign oral cavity and oropharyngeal

papillomas; however, these lesions can undergo malignant transformation, for example, in verrucous carcinoma. The proposed viral mechanism of carcinogenicity for HPV highlights the molecular underpinnings of cancer as the virus hijacks the normal cellular machinery to drive sus­ tained replication. HPV is a small DNA virus (Figs. 1.5A to C). Its genome is approximately 8000 base pairs in length. The HPV-16 genome is composed of 9 genes, 7 “early” genes E1–E7, and 2 “late” genes that encode the capsid. Like many viruses, its genome does not encode for any enzymes and must use host machinery to replicate, assemble, and exit to infect other cells. In a typical acute HPV infection the virus enter through microscopic breaks in the skin, during sexual activity, and infects the basal cells of stratified squamous epithelia. These basal cells are the actively dividing progenitor cells of the suprabasal layers, which become differentiated, but do not normally continue to divide. Once infected the virus exists as a circular episome and drives continual replication of the suprabasal cells. Of the 7 “early” genes, HPV E7 binds to the Rb family of proteins (Rb, p107, p130) and targets them for degradation. As in the normal G1-S check point, Rb degradation results in the release and activation of E2F and DNA replication. In addition to driving replication HPV, E6 binds p53 and targets it for degradation. E6 and E7 therefore effectively prevent cells from entering apoptosis and allow cells to replicate unchecked by the cell cycle. All HPV subtypes express E6 and E7. What makes the high-risk subtypes more aggressive is their high affinity of E6 and E7 for p53 and Rb.

Chapter 1: The Molecular Biology of Head and Neck Cancer

A

7

B

C Figs. 1.5A to C: Oncogenic mechanisms associated with the human papilloma virus (HPV) and head and neck squamous cell carcinoma. (A) HPV-16 is a small DNA virus with a genome encoding for early and late proteins E1-E7, L1, and L2. (B) Direct inhibitory effects of E6 on the G1-S checkpoint and E7 on the G2-M checkpoint. (C) Additional effects of E6 and E7 on apoptosis, chromosome length, extracellular matrix proteins, and genetic instability. (TERT: Telomerase reverse transcriptase).

It is important to recognize that E6 and E7 interact with many cellular proteins to exert its oncogenicity (Fig. 1.3).36 In addition to binding p53, E6 inhibits apop­ tosis through interactions with caspase-8, and two pro­ apoptotic proteins BAX and BAK. E6 also promotes cell immortalizaton by interacting with telomerase and telomerase reverse transcriptase to prevent chromosomal shortening. E6 binds to cell adhesion proteins so that cells can divide without being attached to an extracellular matrix. E7 similarly has multiple intracellular interactions beyond Rb. E7 can drive cell proliferation by either inhibiting cyclin-dependent kinase inhibitors p21 and p27, or directly activating cyclins and cyclin-dependent kinases. E7 also inhibits apoptosis and avoids immune surveillance by interacting the interferon regulatory factor 1 (IRF1). Finally, E7 can itself cause genomic instability by damaging DNA and activating the DNA damage response pathways (ATM–ATR).

TARGETED DRUG THERAPY IN HNSCC Target: EGFR Pathway Cetuximab is a chimeric (mouse/human) monoclonal antibody that was developed with a high affinity for the

extracellular domain of EGFR.37 When bound it inhibits EGFR downstream pathways. It was first approved in 2006 and is currently the only Food and Drug Adminis­ tration-approved targeted therapy for HSNCC. There are four Phase III clinical trials that have evaluated the effec­ tiveness of cetuximab as combination therapy with either radiation or platinum-based treatments in locoregion­ ally advanced, recurrent, and/or metastatic disease (Table 1.2).38-41 In advanced disease cetuximab demon­ strated nearly 3 months of survival benefit when combined with conventional chemotherapy. Its major side effect is an acne-like rash that is not usually debilitating. Interest­ in­gly, the severity of the rash may indicate the extent of cetuximab effectiveness.42 Unfortunately, while amplifi­ cation of EGFR correlates with poor prognosis, it does not correspond to response to cetuximab. In addition resistance to cetuximab, either intrinsic or acquired, is common and limits its overall effectiveness. A number of mechanisms have been proposed to explain cetuximab resistance.43 A mutant variant of trun­ cated EGFR called EGFRvIII, estimated to be present in 40% of tumors, is constitutively active and lacks the extracellular domain where cetuximab binds.23 Small molecule tyrosine kinase inhibitors that can bind the intracellular

8

Head and Neck Surgery

Table 1.2: Phase III clinical trials evaluating the efficacy of cetuximab (Erbitux)

Study

Study population

Study design

Intervention

Results

Critique

Burtness, et al.

117 enrolled patients with metastatic or recurrent HNSCC (60 patients received cetuximab)

Randomized placebo controlled trial

Cisplatin ± cetuximab

Significant RR with the addition of cetuximab; however, no improvement in PFS or OS

Underpowered to detect less than a 50% difference in PFS or OS

Bonner, et al.39

424 enrolled patients with locoregionally advanced (stage III/ IV) nonmetastatic HNSCC

Randomized multinational study

Radiation ± cetuximab

Significant improvement in locoregional control, PFS and OS at 3 years

No placebo group

442 patients with recurrent or metastatic HNSCC

Randomized study

Platinum-5 FU ± cetuximab (extreme trial)

Significantly prolonged OS by 3 months. Two month PFS and 15% increase in RR

No placebo group

5-year survival update on 2006 Bonner trial

Randomized multinational study

Radiation ± cetuximab

Persistent at 5 years of significant improvement in overall survival

No placebo group

891 patients with locoregionally advanced (stage III/ IV) nonmetastatic HNSCC

Randomized

Radiation and cisplatin ± cetuximab

Triple therapy showed no improvement in PFS or OS; however, there was an increase in mucositis and skin reaction

25% of patients did not receive more than 5 weeks of cetuximab

38

Vermorken, et al.40

Bonner, et al.42

Ang, et al.41

Unknown HPV status

Unknown HPV status

Unknown HPV status

Possible overrepresentation of HPV+ patients (HNSCC: Head and neck squamous cell carcinoma; HPV: Human papilloma virus; OS: Overall survival; PFS: Progression free survival; RR: Response rate).

domain, including erlotinib, gefitinib, were initially posi­ ted as a method of overcoming this mechanism of cetuxi­ mab resistance; however, phase II and phase III trials of erlotinib and gefitinib have not been promising.44,45 A pilot study with a humanized monoclonal antibody (ABT-806) specifically targeting EGFRvIII, and activated EGFR has recently been reported (Table 1.3).46 In this study of solid tumors, at least two patients had HNSCC and exhibited stable disease for more than 2 months; one had stable disease for nearly six months. A second potential mechanism of cetuximab resistance relates to its ability to heterodimerize with other members of the HER family and cross-activation with other receptor tyrosine kinases (RTKs) like the hepatocyte growth factor receptor (gene is called MET). MET has been shown to be amplified or mutated in a small subset of HNSCC. There are several small molecule inhibitors of MET, including foretinib and crizotinib, that nonselectively inhibits MET as well as VEGF2 and may benefit patients harboring the mutation.43 A recent study demonstrated that single-agent foretinib

was well tolerated by 14 patients with recurrent/metastatic HNSCC, and 93% (13/14 patients) had stable disease or tumor shrinkage that was sustained for 13 months.47

Target: PI3CA–AKT–mTOR Pathways One of the challenges of treating HNSCC is that the majority of mutations associated with this disease are in­activating mutations or LOH of tumor suppressor genes. This makes targeted therapies of inactivated genes difficult since there are currently no drugs currently available that restore intrinsic function. Activating mutations seen in PIK3CA and mTOR are some of the few oncogenes and are therefore active areas for drug development. There are a number of multikinase inhibitors including the first PI3K/mTOR inhibitor, BEZ235 currently in early phase I/II clinical trials.24 Inhibitors of mTOR, including evero­ limus, rapamycin, and temsirolimus, are also under investi­ gation in both preclinical models and early clinical trials. Early results are encouraging. A phase I trial of 18 patients

Chapter 1: The Molecular Biology of Head and Neck Cancer

9

Table 1.3: Targeted therapies in development for head and neck squamous cell carcinoma

Target

Chemotherapeutic

Drug class/effect

EGFR (HER1)

Cetuximab (Erbitux)

Chimeric monoclonal antibody (MAb)

Matuzumab Nimotuzumab Panitumumab Pertuzumab

Specifically inhibits HER2 dimerization with other HER family members

Zalutumumab Erlotinib

Tyrosine kinase inhibitors (TKIs)

Gefitinib Afatinib Dacomitinib Lapatinib Vandetanib EGFRvIII

ABT-806

Specifically binds activated EGFR and EGFRvIII

Everolmus

Multikinase inhibitor (MKI)

PI3K–AKT–mTOR NVP-BEZ235 Rapamycin Temsirolimus (EGFR: Epidermal growth factor receptor; HNSCC: Head and neck squamous all carcinoma).

with locally and/or regionally advanced HNSCC treated with everolimus (in addition to cisplatin and docetaxel) as induction chemotherapy was just recently published.48 In addition to establishing a safe dose for phase II trials, progression-free survival of 87.5% and 77% was reported at 1 and 2 years, respectively. A note of caution: this is also an area of rapid change as evidenced by a phase II trial of temsirolimus and erlotinib that was closed early because of toxicity or death.49

CONCLUSION As head and neck oncologic surgeons, it is increasingly important to understand the molecular mechanisms underlying HNSCC. Here, we have reviewed the critical genes that affect cell replication, differentiation, growth, and death in this malignancy. These alterations lead to dysregulation of signaling pathways in both HPV-negative and HPV-positive HNSCC. Targeted therapies hold great promise in HNSCC by identifying the ideal agent(s) for the correct patient at the appropriate time.

ACKNOWLEDGMENT This work was supported in part by the following grants: NIH P50CA097190 and an American Cancer Society clinical research professorship (To JRG).

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Head and Neck Surgery

6. Agrawal N, Frederick MJ, Pickering CR, et al. Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science (New York, NY). 2011;333(6046):1154-7. 7. Estilo CL, O-Charoenrat P, Ngai I, et al. The role of novel oncogenes squamous cell carcinoma-related oncogene and phosphatidylinositol 3-kinase p110alpha in squamous cell carcinoma of the oral tongue. Clinical Cancer Res: an official journal of the American Association for Cancer Research. 2003;9(6):2300-6. 8. Field JK, Pavelic ZP, Spandidos DA, et al. The role of the p53 tumor suppressor gene in squamous cell carcinoma of the head and neck. Arch Otolaryngol–Head Neck Surg. 1993;119(10):1118-22. 9. Green DR, Kroemer G. Cytoplasmic functions of the tumour suppressor p53. Nature. 2009;458(7242):1127-30. 10. Somers KD, Merrick MA, Lopez ME, et al. Frequent p53 mutations in head and neck cancer. Cancer Res. 1992;52 (21):5997-6000. 11. Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nature Rev. Cancer. 2009;9(3):153-66. 12. Poeta ML, Manola J, Goldwasser MA, et al. TP53 mutations and survival in squamous-cell carcinoma of the head and neck. New Engl J Med. 2007;357(25):2552-61. 13. Izzo JG, Papadimitrakopoulou VA, Li XQ, et al. Dysregulated cyclin D1 expression early in head and neck tumorigenesis: in vivo evidence for an association with subsequent gene amplification. Oncogene. 1998;17(18):2313-22. 14. Michalides RJ, van Veelen NM, Kristel PM, et al. Overexpression of cyclin D1 indicates a poor prognosis in squamous cell carcinoma of the head and neck. Arch Otolaryngol – Head Neck Surg. 1997;123(5):497-502. 15. Michalides R, van Veelen N, Hart A, et al. Overexpression of cyclin D1 correlates with recurrence in a group of fortyseven operable squamous cell carcinomas of the head and neck. Cancer Res. 1995;55(5):975-8. 16. Akervall J, Bockmühl U, Petersen I, et al. The gene ratios c-MYC  : cyclin-dependent Kinase ( CDK ) N2A and CCND1  : CDKN2A correlate with poor prognosis in squamous cell carcinoma of the head and neck. Clin Cancer Res. 2003; 9:1750-5. 17. Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nature Rev Cancer. 2005;5(5):341-54. 18. Lin SY, Makino K, Xia W, et al. Nuclear localization of EGF receptor and its potential new role as a transcription factor. Nature Cell Biol. 2001;3(9):802-8. 19. Loeffler-Ragg J, Witsch-Baumgartner M, Tzankov A, et al. Low incidence of mutations in EGFR kinase domain in Caucasian patients with head and neck squamous cell carcinoma. Eur J Cancer (Oxford, England: 1990). 2006; 42(1):109-11. 20. Shintani S, Matsuo K, Crohin CC, et al. Intragenic mutation analysis of the human epidermal growth factor receptor (EGFR) gene in malignant human oral keratinocytes. Cancer Res. 1999;59(16):4142–7.

21. Lee JW, Soung YH, Kim SY, et al. Somatic mutations of EGFR gene in squamous cell carcinoma of the head and neck. Clin Cancer Res: an official journal of the American Association for Cancer Research. 2005;11(8):2879-82. 22. Grandis JR, Tweardy DJ. Elevated levels of transforming growth factor alpha and epidermal growth factor receptor messenger RNA are early markers of carcinogenesis in head and neck cancer. Cancer Res. 1993;53(15):3579-84. 23. Sok JC, Coppelli FM, Thomas SM, et al. Mutant epidermal growth factor receptor (EGFRvIII) contributes to head and neck cancer growth and resistance to EGFR targeting. Clinical Cancer Res: an official journal of the American Association for Cancer Research. 2006;12(17):5064-73. 24. Engelman JA. Targeting PI3K signalling in cancer: oppor­ tunities, challenges and limitations. Nat Rev Cancer. 2009;9 (8):550-62. 25. White RA, Malkoski SP, Wang X-J. TGFβ signaling in head and neck squamous cell carcinoma. Oncogene. 2010;29 (40):5437-46. 26. Perez-Ordoñez B, Beauchemin M, Jordan RCK. Molecular biology of squamous cell carcinoma of the head and neck. J Clin Pathol. 2006;59(5):445-53. 27. Pearlstein RP, Benninger MS, Carey TE, et al. Loss of 18q predicts poor survival of patients with squamous cell carcinoma of the head and neck. Genes Chromosomes Cancer. 1998;21(4):333-9. 28. Bornstein S, White R, Malkoski S, et al. Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation. J Clin Invest. 2009;119(11):3408-19. 29. Fukuchi M, Masuda N, Miyazaki T, et al. Decreased Smad4 expression in the transforming growth factor-beta signaling pathway during progression of esophageal squamous cell carcinoma. Cancer. 2002;95(4):737-43. 30. Natsugoe S, Xiangming C, Matsumoto M, et al. Smad4 and transforming growth factor beta1 expression in patients with squamous cell carcinoma of the esophagus. Clin Cancer Res: an official journal of the American Association for Cancer Research. 2002;8(6):1838-42. 31. Brakenhoff RH. Cancer. Another NOTCH for cancer. Science (New York, NY). 2011;333(6046):1102-3. 32. Dotto GP. Notch tumor suppressor function. Oncogene. 2008;27(38):5115-23. 33. Kurokawa M, Kornbluth S. Caspases and kinases in a death grip. Cell. 2009;138(5):838-54. 34. Haughey BH, Sinha P. Prognostic factors and survival unique to surgically treated p16+ oropharyngeal cancer. Laryngoscope. 2012;122 Suppl:S13-33. 35. Maxwell JH, Ferris RL, Gooding W, et al. Extracapsular spread in head and neck carcinoma: impact of site and human papillomavirus status. Cancer. 2013;119:3302-8. 36. Moody CA, Laimins LA. Human papillomavirus oncopro­ teins: pathways to transformation. Nat Rev Cancer. 2010; 10(8):550-60. 37. Goldstein NI, Prewett M, Zuklys K, et al. Biological effi­ cacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin Cancer

Chapter 1: The Molecular Biology of Head and Neck Cancer Res: an official journal of the American Association for Cancer Research. 1995;1(11):1311-8. 38. Burtness B, Goldwasser MA, Flood W, et al. Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol: official journal of the American Society of Clinical Oncology. 2005;23(34):8646-54. 39. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. New Engl J Med. 2006;354(6):567-78. 40. Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. New Engl J Med. 2008;359(11):1116-27. 41. Ang KK, Zhang QE, Rosenthal DI, et al. A Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III to IV head and neck carcinoma: RTOG 0522. J Clin Oncol. 2014;32(27). 42. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol. 2010;11(1):21-8. 43. Bauman JE, Michel LS, Chung CH. New promising molecular targets in head and neck squamous cell carcinoma. Curr Opin Oncol. 2012;24(3):235-42.

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44. Martins RG, Parvathaneni U, Bauman JE, et al. Cisplatin and radiotherapy with or without erlotinib in locally advanced squamous cell carcinoma of the head and neck: a ran­ domized phase II trial. J Clin Oncol: official journal of the American Society of Clinical Oncology. 2013;31:1415-21. 45. Argiris A, Ghebremichael M, Gilbert J, et al. Phase III ran­ domized, placebo-controlled trial of docetaxel with or with­ out gefitinib in recurrent or metastatic head and neck cancer: an eastern cooperative oncology group trial. J Clin Oncol: official journal of the American Society of Clinical Oncology. 2013;31(11):1405-14. 46. Cleary JM, Yee LK-C, Azad N, et al. Abstract 2506: a phase 1 study of ABT-806, a humanized recombinant anti-EGFR monoclonal antibody, in patients with advanced solid tumors. Cancer Res. 2012;72(8 Suppl):2506-6. 47. Seiwert T, Sarantopoulos J, Kallender H, et al. Phase II trial of single-agent foretinib (GSK1363089) in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. Invest New Drugs. 2013;31(2):417-24. 48. Fury MG, Sherman E, Ho AL, et al. A phase 1 study of evero­ limus plus docetaxel plus cisplatin as induction chemother­ apy for patients with locally and/or regionally advanced head and neck cancer. Cancer. 2013;119(10):1823-31. 49. Bauman JE, Arias-Pulido H, Lee S-J, et al. A phase II study of temsirolimus and erlotinib in patients with recurrent and/or metastatic, platinum-refractory head and neck squamous cell carcinoma. Oral Oncol. 2013;49(5):461-7.

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Head and Neck Surgery

CHAPTER

2

Principles of Radiation Oncology Jack Phan, Adam S Garden

Radiation oncology is a medical specialty predominantly focused on the treatment of neoplastic diseases with the use of ionization radiation. The roots of radiation therapy can be traced back to German physicist Wilhelm Conrad Roentgen, who first discovered X-rays in 1895. The X-ray tube was developed within a year, leading to one of the first documented use of radiation for therapeutic purpose by Professor Leopold Freund in 1897. Freund demonstrated before the Vienna Medical Society the resolution of a hairy mole after exposure to low dose X-ray. However, this was considered a tragic failure as a deep ulceration resulted, prompting resistance by the medical community

to the therapeutic use of radiation. The first successful use of radiation was by Eduard Schiff, who treated a case of lupus vulgaris. The discovery of radium in 1898 by Marie Curie, and later its physiological effect confirmed by Henry Becquerel in what is referred famously as the “Becquerel burn” when he left a tube of radium in his coat pocket where it remained for a few hours, resulting in skin inflammation a week later, led to wider application of radiation as radium could be applied in more ways in which X-rays could not, such as in the form of radium emanation (radon) and radium salts (Figs. 2.1A and B). By the turn of the century, surgeons and dermatologists in Europe and North America primarily used X-rays for hair removal and treatment of skin inflammatory condi­ tions such as lupus and epithelioma. Prior to the 1920s,

A

B

INTRODUCTION

Figs. 2.1A and B: (A) Radium salt tube. (B) Standard radium emanatory, office style for treatment of one person.

14

Head and Neck Surgery

radiation was given as a single-high-dose treatment, resulting in significant treat­ment morbidity and skepticism about its usefulness as a therapeutic modality, ushering in a period of pessimism in the medical profession lasting from about 1905 to 1912. After 1920, there was a shift toward fractionated radiation treatment led by pioneering work from biologists in Paris, France, based on sterilization of animal testes by radiation. This work showed that sterilization in a single dose resulted in large amounts of sloughing off of skin from the scrotum, but if the same dose was fractionated over several weeks, steri­ lization could be achieved with minimal skin damage. Further understanding of the biological effects of radiation occurred in the wake of atomic weaponry use on Hiroshima and Nagasaki in World War II. These collective works have led to milestone developments in the field of radiobiology, including biological effects of radiation exposure, deter­ mining the cell survival curve after radiation exposure and the foundations of radiation-induced carcinogenesis and mutagenesis. Radiation onco­logy has continued to evolve, first as a subspecialty within the field of diagnostic radiology, and subsequently as a separate specialty. Currently, radiation therapy carries an important role in the treatment of head and neck (H&N) cancers. Radia­ tion can be given as a curative treatment or to palliate tumor-related symptoms in patients with incurable cancers. Curative treatment with radiation can be either definitive, where radiation is the principle modality, or adjuvant, to reduce the incidence of recurrence from surgery. In the majority of early stage head and neck squamous cell carcinomas (HNSCC), radiation therapy is the primary definitive treatment modality, providing similar local tumor control as surgery with the added benefit of organ sparing. For intermediate-stage disease, radiation can be given using altered fractionation sched­ ules and/or combined with chemotherapy to improve its efficacy. In this setting, radiation is often preferred over surgery since many surgically treated patients still require postoperative radiotherapy as a result of adverse surgi­ cal-pathologic features. For larger and more extensive tumors, radiation when compared with more radical surgery also offers the potential for better anticipated functional and aesthetic outcomes. For HNSCCs located in areas that are preferentially amenable to surgical resec­ tion, radiotherapy is given as adjuvant treatment where both modalities are mutually complementary. Surgery removes the gross clinical disease, a common source of radiation failure, and radiation serves to sterilize the

potential microscopic tumor (subclinical) spread beyond the surgical margin, a common source of recurrence after surgery. In the palliative setting, radiation is used for symptomatic relief of tumor burden in patients with incur­ able cancers. Considerable inroads in radiation treatment planning and delivery techniques have been made in the last decade toward improving the practice and changing the philosophy of H&N radiation oncology. Increasingly advanced computerized radiotherapy treatment plan­ ning and delivery techniques such as intensity-modulated radiation therapy (IMRT) have allowed for more precise delivery of higher doses to target structures of irregular shapes while minimizing radiation exposure to nearby normal organs. Altered fractionation schedules have sought to exploit inherent biological differences between tumor and nontumor cells to improve the therapeutic ratio. Further refinement in systemic cytotoxic chemo­ therapy and introduction of molecular targeted agents seek to enhance the effects of radiotherapy and reduce treatment burden and toxicity. Finally, advances in func­ tional and metabolic imaging have led to improved disease evaluation and facilitate treatment planning. These major transformations in radiation oncology have opened up exciting possibilities in the field with greater prospect for improved locoregional tumor control without the added morbidity, thereby improving upon the thera­ peutic ratio for the treatment of H&N cancers.

PRINCIPLES OF RADIATION PHYSICS Types of Radiation The types of radiation used in radiation therapy are those with the capacity to produce excitation and ionization when interacting with biologic tissue. Excitation involves the raising of an electron in an atom, or molecule, to a higher energy level without ejection from its atomic orbit, whereas ionization occurs if sufficient energy is raised to elicit ejection of one or more electrons from its atomic orbit. Ionizing radiation when absorbed by an atom can liberate an atomic particle from an atom, producing ions and altering chemical bonds. A key characteristic of ionizing radiation is its ability to release large amounts of energy locally, resulting in the breaking of chemical bonds, consequentially producing a large biologic effect for a relatively small total amount of energy consumed. Ionizing radiation can be categorized based on the nature of the particles making up the radiation. These various

Chapter 2: Principles of Radiation Oncology particles have different ionization mechanisms and can be grouped as directly or indirectly ionizing. Directly ionizing radiation, such as charged particles, can ionize atoms directly through Coulomb forces if it carries sufficient kinetic energy. In contrast, neutral particles have less direct interaction with their target matter, and most of their ioni­ zation effects results from the production of secondary charged atomic particles, which themselves are directly ionizing when interacting with material.

Electromagnetic Radiation High-energy X-rays or γ-rays represent the most com­ monly utilized form of electromagnetic radiation in clinical radiotherapy (Fig. 2.2). Electromagnetic radiation is indirectly ionizing, and thus does not produce bio­ chemical changes itself when interacting with biologic material, but when it is absorbed in the medium through which it passes, it will give up its energy to produce fast

15

moving electrons by either the Compton, photoelectric, or pair-production effects (Fig. 2.3). Both X-rays and γ-rays have similar physiologic and biologic properties. They primarily differ in their origin and in their ability to penetrate biologic tissue. X-rays are generated outside the nucleus (extranuclearly) by electric devices such as linear accelerators (linacs). Linacs accelerate electrons to a high energy and then direct them to hit a metal target (usually made of tungsten), causing the moving electron to lose kinetic energy, which is converted into a photon of X-rays because energy is conserved. In contrast, γ-rays are emitted by the nucleus of radioactive isotopes (i.e. they are produced intranuclearly). Most modern radio­ therapy centers primarily use linac-produced high energy X-rays due to the higher dose rate and radiation safety advantages. The energy of X-rays is composed of a spec­ trum of energies and expressed in megavolts (MV), where the number (e.g. 6 MV) refers to the maximum energy of the spectrum. Thus, a 6-MV photon beam will produce

Fig. 2.2: The electromagnetic spectrum from highest wavelength (lowest energy) to lowest wavelength (highest energy).

Fig. 2.3: Illustrative summary of X-ray and γ-ray interaction with matter. (a) Primary photon beam does not interact with material. (b) Photoelectric effect results in the ejection of a bound electron from an incoming photon that has energy greater than the binding energy of the electron in its shell, with excess energy distributed to the kinetic energy of the electron. (c) Rayleigh scattering is interaction with electron in which no energy is exchanged and incoming photon energy equals the scattered X-ray energy. (d) Compton scattering occurs when the incoming photon collides with an essentially unbound electron and scattered at one angle. It also transfers a portion of its energy to the recoil electron that is scattered in another direction.

16

Head and Neck Surgery

a spectrum of energies of no more than 6 MV, where the mean X-ray energy is about one third of the maximum energy.

Particle Radiation Particle radiation includes electrons, protons, neutrons, alpha-particles, and other high-energy heavy-charged particles and has broad clinical use in the treatment of HNSCC due to their favorable depth–dose distribution characteristics (Fig. 2.4). Electrons and protons are the most relevant to clinical radiotherapy. Neutron irradia­ tion was studied in the past due to its theoretical advan­ tage over photons in hypoxic (low oxygen) conditions, but neutrons have largely been abandoned owing to their limited clinical usefulness and outcomes compared with other types of particles. Neutrons remain of interest in the treatment of unresectable salivary gland cancers. Electrons, on the other hand, have attractive depth–dose charac­teristics and are widely employed in external beam radiotherapy. Electrons are light, negatively charged par­ti­ cles that can be accelerated to high energy (up to 50 MeV) by devices such as linacs. Conventionally, the electron beam of a linac in electron mode is directed to strike an electron-scattering foil instead of a tungsten target so that the beam is spread and a uniform electron fluence is yielded across the treatment field. The higher the energy of the electron beam, the more deeply it pene­trates tissue (Fig. 2.5).

Fig. 2.4: Relative dose as a function of depth in tissue shown for 60 Cobalt γ-rays, 22 MV X-rays, 200 kV X-rays, 22 MeV electrons, a proton Bragg peak and a Spread Out Bragg Peak. Source: Levy RP, Reinhard WM. Charged particle beams: technique and clinical experience. Transl Cancer Res. 2012;1:22-33.

Protons are positively charged particles with a mass ~1835 times greater than that of electrons and have similar radiobiologic properties as conventional electrons or photon beams. Due to their relatively large mass, protons have little lateral side scatter in tissue. This prevents broad­ ening of the beam in tissue; instead, it stays focused on the tumor shape and delivers less unintended dose to surrounding normal tissue. The most attractive characteristic of proton beam therapy from a clinician’s perspective is the Bragg Peak (Figs. 2.6A to C), the maximum range of the proton beam such that very few protons penetrate beyond that distance, even by a few millimeters. Thus high dose can be delivered to the tumor, whereas the normal tissue distal to the tumor gets essentially no radiation. In clinical use, several energies are used to produce multiple Bragg Peaks to produce one broader peak called the Spread Out Bragg Peak (SOBP), which then can be applied to treat the entire tumor. Figure 2.6 shows that while tissues behind the tumor (distal to beam path) receive no radiation, the tissues in front of the tumor (proximal to beam path) receive radia­ tion dose based on the SOBP. The chief advantage of proton therapy is the ability to more precisely modulate the beam in both its width and its depth to generate a more conformal radiation dose to tumors that are located in regions with multiple nearby critical organs such as in the oral cavity anteriorly and critical neurologic structures posteriorly (Fig. 2.7). Disadvantages of proton therapy are

Fig. 2.5: Measured and simulated depth–dose characteristics for electron beams of various energies. Source: Werner et al. Kilovoltage electron energy loss distribution in Si. J Phys D. Appl Phys. 1998;21:116.

Chapter 2: Principles of Radiation Oncology

17

B

A

Figs. 2.6A to C: The Spread Out Bragg Peak (SOBP). Compared to X rays where the dose falls off gradually after an initial buildup, the dose for the proton beam rises slowly and peaks at the Bragg peak (BP), where the proton stops. The SOBP is the sum of several individual BPs when the proton is modulated. The advantage of proton therapy is the sharp fall off and absence of dose beyond the BP and lower surface dose.

C the size, complexity, and cost of equipment (e.g. cyclotron or synchrotron) needed to accelerate protons (due to their heavier mass) to clinically useful energies. Clinical evidence is emerging that proton beam therapy may benefit patients with HNSCC by reducing unwanted dose to the salivary glands, mandible and maxillary to lower the risk of xerostomia, dental caries, dental extractions, and osteoradionecrosis.1-4

PRINCIPLES OF RADIOBIOLOGY Fate of Irradiated Cells Exposure of cells to ionizing radiation produces a variety of biological and molecular changes that may manifest clinically as tumor killing or normal tissue toxicity. The type and severity of these effects depend on variables such as the energy and type of radiation, the composition of

target biologic tissue, the cellular and molecular response, duration of exposure, and cellular microenvironment. From a molecular and cellular perspective, irradiated cells undergo one or more of several processes, including division delay, apoptosis, reproductive failure, genomic instability, mutation, transformation, bystander effects, and adaptive responses.

Primary Target Is DNA It is widely regarded that the critical molecular targets of radiation damage in the mammalian cell that produces the observed biologic changes are the DNA and nuclear membrane. DNA and phospholipid membrane damage from ionizing radiation can be due to direct damage by charged particles or by indirect damage mediated by highly reactive free radicals (Fig. 2.8). Damage to the DNA itself can produce either single-strand or double-strand

18

Head and Neck Surgery

Fig. 2.7: Proton beam therapy plan using active spot scanning allows for increased sparing of critical head and neck structures such as oral cavity and brainstem. Courtesy: Steven F. Frank, MD Anderson Cancer Center, Houston, TX, USA.

breaks, and the ability to repair the damage ultimately determines cell viability. Single-strand breaks are the most frequent lesions observed and often readily repaired due to the existence of the opposite strand that is utilized as a template. Because of this, they are of lesser significance in regard to cell killing by therapeutic doses of ionizing radiation. If, however, the DNA is erroneously repaired, a mutation develops, which potentially can lead to altered gene function and, in turn, give rise to cancer development. By contrast, double-stranded DNA breaks, when they occur in close proximity to each other, often have lasting biological consequence since they are not as readily repaired and are considered the major cause of mitotic cell death. One Gy of ionizing radiation can produce approximately 1000 single-strand breaks and 35 double-strand breaks per cell.5,6

Interaction with Ionizing Radiation The mechanism of biologic damage when cells absorb ionizing radiation can occur directly or indirectly. In general, sparsely ionizing radiation such as X-rays and γ-rays tend to produce damage through indirect mecha­ nisms, whereas densely ionizing radiation such as neutrons and alpha-particles produce cellular damage primarily through direct effects. In direct interactions, the radiation interacts directly with the target in the cell and leads to direct ionization or excitation through Coulomb interactions. This leads to a chain of physical and chemical events that eventually produce biological damage. Direct

Fig. 2.8: Diagram of the direct and indirect effects of ionizing radiation on the cell. Ionizing radiation can directly disrupt the chemical bonds of subcellular structures such as DNA. Ionizing radiation can also cause indirect damage by generation of reactive oxygen free radicals produced by radiolysis of water. Ionizing radiation can also disrupt mitochondrial function. Source: Azzam et al. Ionizing radiation-induced metabolic oxidative stress and prolonged cell injury. Cancer Lett. 2012;327:48-60.

action is the dominant process when radiation with high linear energy transfer (LET) interacts with biological material (discussed in more detail below). In indirect action, the radiation interacts with other atoms and molecules within the cell (mainly water) to produce short lived yet extremely reactive free radicals (e.g. hydroxyl radicals), which can damage critical cellular targets through diffusion in the cell (Fig. 2.8). Although ionizing radiation can produce several biological effects on the cell, the major effect in the therapeutic dose range is cell killing.

Radiation Effects on Normal Tissues Most normal tissues can tolerate varying amounts of moderate radiation doses without losing structural or functional integrity. However, distinct radiation-induced tissue injuries occur when critical numbers of clonogenic cells are killed, leading to an inadequate replenishment of mature cells that are lost through normal physiologic wear-and-tear processes. The timing of when the damage is manifested is often classified as acute, subacute, or late (chronic) and varies greatly among different tissue types

Chapter 2: Principles of Radiation Oncology and depends on several factors, including the organ­ izational structure, and cell kinetics and turnover. The timescale involved between the breakage of chemical bonds and the biologic effect may occur in hours or even years, depending on the type of damage. If cell killing is the result, it usually happens in hours to days, often when damaged cells attempt to divide (i.e. early effects of radiation). If enough cells are killed, this can result in an early tissue reaction (deterministic effect). On the other hand, if the damage is sublethal and not repaired, the accumulation of genetic changes can lead to late effects of radiation where its expression may be delayed for years (late effects of radiation). Late radiation effects tend to be oncogenic. For example, ionizing radiation has been demonstrated to cause various types of malignancies, including leukemia and sarcomas in soft tissues and bones.7,8 In addition to carcinogenesis, other late effects of radiation include delayed tissue reactions (deterministic effects) such as tissue fibrosis and other reactions as a result of vascular deficiencies. Nonlethal genetic damage can also lead to expression in subsequent generations. Acute effects tend to manifest themselves soon after exposure to radiation and are characterized by edema, inflammation, denuding of epithelia, and in more severe cases, hemorrhage. Classically, “Type H” tissues have a tendency to manifest radiation injury acutely. These tissues tend to have a small number of slowly proliferating stem cells but with a very rapidly proliferating pool of proge­ nitor cells that subsequently differentiates into mature, nonproliferating functional cells. An example in the H&N region include the mucosa and skin. These tissues have both their stem cell and progenitor cell compartments depleted in response to irradiation, whereas the mature differentiated cells continue to maintain their tissue function until they are depleted through normal turnover and deterioration. As a consequence, radiation injury appears at a predictable time period that is determined by the lifespan of the mature cells. Patchy oral mucositis, for example, begins to manifest itself by the third week of conventionally fractionated radiotherapy. After comp­ letion of radiotherapy, when the stem cell numbers are replenished and the depleted mature cell population is reconstituted, the mucosal epithelial cells essentially recover all their function. Subacute effects often manifests several months after radiation exposure and occur in tissues that have a longer cell turnover time. These effects are generally reversible. Examples of subacute injury in the H&N region include Lhermitte’s syndrome (an electric shock sensation that

19

is often triggered by neck flexion), somnolence, and sub­ acute pneumonitis. These can occur after radiation of the spinal cord, brain, and lung, respectively. Chronic effects are delayed radiation injury reactions that can occur months-to-years after irradiation. They are characterized by fibrosis, atrophy, ulceration, or stenosis. Chronic effects are typically observed in “Type F” tissues. These tissues are composed of functional parenchymal cells with very low cell turnover rates yet have high rates of regaining reproductive function after tissue loss. The time of onset partially depends on the radiation dose given. Their effects tend to increase in severity over time as a consequence of an “avalanche” phenomenon, such that the first wave of cell death triggers subsequent prolife­ ration of other injured cells, resulting in cell death while attempting to divide. Progressive and massive cell deple­ tion as well as functional tissue failure occurs as a result. Examples in the H&N include bone, endocrine tissues, and nervous system. Late complications after irradiation to the H&N include hypothyroidism, fibrosis, trismus, soft tissue bone necrosis, and myelopathy. The majority of radiation treat­ment regimens have been designed to minimize these types of irreversible late complications.

Radiation Cell Killing Radiation damage to cells can also be operationally defi­ ned in terms of the proportion of cells surviving: (1) Lethal damage is irreversible and irreparable, leading to cell death. (2) Sublethal damage, as the name indicates, is not lethal to cells but can be repaired, often in hours, unless additional injury is inflicted such as with further radiation treatment to produce lethal damage. (3) Potentially lethal damage is injury that in one set of conditions is lethal but under another is not. For example, if slowly or nondivid­ ing cells are stimulated to proliferate shortly after radiation exposure, the damage will be lethal as opposed to allow­ing some time to elapse before stimulation. Cells that are lethally damaged by ionization radiation die by two processes: reproductive failure (mitotic cell death) or apoptosis. In reproductive failure, cells die when they attempt to divide, either at the first or subsequent mitosis. This is considered the dominant method of cell killing by therapeutic dose radiation. Also depending on the dose given, the injured cell may die either at the first postradiation proliferative event or after they have undergone a limited number of cell divisions. For example, at the clinical relevant dose of 2 Gy, irradiated cells appear

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Head and Neck Surgery

Fig. 2.9: DNA damage in response to genotoxic damage such as ionizing radiation leads to a signaling cascade that activates p53. Several checkpoint kinase complexes such as DNA dependent protein kinase, ataxia telangiectasia mutated kinase, and ataxia telangiectasia and Rad3 related mediate DNA damaging signaling upstream of p53. Once activated, p53 transcriptionally induces a host of target genes to promote cell-cycle arrest to allow time for DNA to repair, apoptosis leading to cell death, and senescence, which ultimately contributes to tissue degeneration. Source: Ljungman et al. Guarding the genome by sensing DNA damage. Nat Rev Cancer. 2004;4:727-37.

morphologically and metabolically functional. They typi­ cally complete two to three apparently successful cell divisions before undergoing necrosis, characterized by cell swelling, dissolution of cellular structures, and rupture of cellular membrane. As shown in Figure 2.6, ionizing radia­ tion gives rise to a variety of cellular lesions, includ­ing damage to both DNA and phospholipid membrane. The cellular responses to DNA damage are mediated through highly conserved DNA checkpoint mechanisms and are important for cell-cycle arrest, apoptosis, stress res­ponse, and activation of DNA repair processes.9 Failure of these checkpoints leads to cell death. The tumor suppressor protein p53 plays a key regulatory role in the DNA damage repair mechanism and is often referred to as the “guardian of the genome”. In response to ionizing radiation-induced DNA-strand breaks, multiple proteins initiate a cascade of signaling events that activate p53

(Fig. 2.9). Important DNA damage sensors are the DNAdamage inducible kinase family members: ataxia telangiec­ tasia mutated (ATM) kinase and ataxia telangiectasia and Rad3 related (ATR), as well as poly (ADP ribose) poly­ merase (PARP), which bind to DNA strand breaks. ATM is primarily activated by double-strand breaks formed directly by ionizing radiation. ATR is activated in respo­ nse to stalled DNA replication fork, which can be induced by ionizing radiation. Both ATM and ATR are implicated in regulation and stimulation of double-stranded DNA repair, activation of cell cycle checkpoints, and cell death signaling.10-12 Studies of PARP knockout mice demons­ trate that the lack of PARP causes extreme sensitivity to ionizing radiation, implicating its importance in post irradiation survival response.13 Cell death by radiation-induced apoptosis occurs less frequently than reproductive death, varies considerably

Chapter 2: Principles of Radiation Oncology

21

Fig. 2.10: The mitochondrial apoptosis (intrinsic) pathway depends on the regulation of cytochrome c release from the mitochondria into the cytoplasm. Upon release, cytochrome c together with caspase-9 and Apaf-1 form the apoptosome. The apoptosome initiates the caspase cascade leading to protein and DNA lysis by proteases and nucleases, respectively. From Kiang JG, Fukumoto R, Gorbunov NV. Lipid peroxidation after ionizing irradiation leads to apoptosis and autophagy. In: Catala A (ed), Lipid peroxidation. Rijeka, Croatia: InTech Open Access Publisher; 2012. http://www.intechopen.com/books/lipid-peroxidation/lipid-peroxidation-after-ionizing-irradiationleads-to-apoptosis-and-autophagy.

among different tissue types, and is not usually linked to cell division. Apoptosis was a phenomenon recognized by radiation biologists for decades under the term inter­ phase death. Unlike mitotic death, interphase death usually occurs within hours of radiation exposure and is typically observable even after exposure to lower doses of radia­ tion. It is an active process of cell death characterized by distinc­tive biochemical and morphologic changes, inclu­ ding endo­nuclease activation, chromatin condensation, and cellular shrinkage and fragmentation. The apoptotic cells shrink in volume and detach from neighboring cells, then frag­ment into a cluster of membrane-bound apoptotic bodies that in tissues are phagocytosed by adjacent cells or macrophages. At the biochemical level, endonucleases are activated and cleave DNA into multi­ ple pieces of 180–200 base pairs, producing a character­ istic “ladder” pattern on gel electrophoresis. Apoptosis plays an important role in determining the responses of some tumors and normal tissues to radiotherapy, chemo­ therapy, and their combi­nation. Some tumor types such

as lymphomas and semi­nomas are very susceptible to this form of radiation-induced cell death. Experiments with rodent tumors have shown that about one third of solid tumors respond to radiation by apoptosis. Unrepaired DNA damage can often active the extrin­ sic death receptor apoptosis pathway, which is mediated by Fas, CD95, and Apo-1. Activation of Fas pathway, for example, depends on receptor activation and procaspase-8 and -10, which lead to activation of the caspase cascade that culminates with the proteolytic inactivation of cellular proteins by executing caspases-3 and -7, and digestion of DNA by nucleases called CAD (caspase activated DNAse).10 Some apoptotic signaling pathways are not initiated at the site of DNA damage, but at the mitochon­ dria plasma membrane (i.e. intrinsic pathway), where the initiation of apoptosis is the result of a process by which mitochondria and caspases engage in a self-amplifying pathway of mutual activation14 (Fig. 2.10). Recent studies have highlighted the importance of mitochondria to the death process.14,15 Radiation-induced activation of apop­

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Head and Neck Surgery

A

B

Figs. 2.11A and B: Cell cycle and CDKs. Briefly, cyclin D interacts with CDK4 and CDK6 to regulate transition through G1 phase by phosphorylating retinoblastoma protein (pRb), relieving the sup­pression of the activity of the E2F family of transcription factors. This occurs before cyclin E binds to CDK2 during the late G1-phase to regulate entry of cells into S-phase. During S-phase, cyclin A binds to CDK2 to suppress E2F activity to prevent triggering of apoptosis. Finally, cyclin B binds to CDK2 to regulate the G2–M transition and control entry into mitosis.

totic signaling initiated at the level of the plasma mem­ brane of the mitochrondria is mediated by the Bcl-2 family proteins.16 This culminates in the release of pro­ teins (most notably cytochrome c) from mitochondria that similarly activates the caspases (a class of proteases) and nucleases to bring about the systemic cellular death pro­ cess (Fig. 2.8). Some caspases are initiator or signaling caspases (e.g. caspase-8 and caspase-9), whereas others act as effector caspases (e.g. caspase-3 and caspase-7). Both reproductive death and apoptosis are dependent on radiation dose but express different dose–response profiles. Reproductive failure is an exponential function of radiation dose, whereas apoptotic cell death is most evident between 1.5 and 5 Gy. Notably, serous cells of salivary and lacrimal glands are particularly sensitive to radiation-induced apoptosis, which may explain the rapid onset of xerostomia and xerophthalmia after administra­ tion of even modest radiation doses. The exact mecha­ nism of radiation-induced cell death varies depen­ding on tissue type and cellular status and remains an active area of investigation.

Radiation Effects on Cell Kinetics In addition to inducing lethal injury to cells by mitotic or apoptotic cell death, radiation can also affect the pro­ cesses of the cell cycle in surviving cell fractions necessary

for normal cellular function. The molecular mechanisms governing the mammalian cell cycle were first elucidated in the 1970s and 1980s by Hartwell, Hunt, and Nurse.17,18 These and other works have established cyclin-dependent kinases (CDKs) as master regulators of cell-cycle check­ points. Figures 2.11A and B illustrates some of the CDKs and major cyclins as well as regulatory proteins that regu­ late the typical mammalian cell cycle. The activation of kinases by cyclins is regulated by a number of proteins. For example, p21 or p27 can inhibit CDK2 activation by cyclin E and, therefore, influence the G1/S transition. Many of these processes are under active investigation to further elucidate their mechanism and identify pathways that may potentially improve radiotherapy effec­tiveness.

Cell Survival and Radiation Dose–Response Curves Cell survival after exposure to ionizing radiation can be graphically expressed by plotting the fraction of surviv­ ing cells on a logarithmic scale on the ordinate against irra­diated dose on a linear scale on the abscissa (Fig. 2.12A). The surviving fraction of cells, determined using in vitro and in vivo techniques, represent irradia­ted cells that maintain their reproductive integrity (clo­ nogenic cells). Because deposition of radiation energy and

Chapter 2: Principles of Radiation Oncology

A

23

B

Figs. 2.12A and B: (A) The cell survival curve after exposure to ionizing radiation can be expressed on a logarithmic curve of survival versus dose. The curve forms an initial shoulder followed by a logarithmic decline in survival, which varies with dose. Sublethal damage (which must be overcome with each fraction of radiation therapy) is thought to cause the shoulder region. (B) The effect of fractionation. Repeated small doses of radiation (200 cGy x 4) are less damaging to a sensitive cell than a single fraction (800 cGy x 1) containing equivalent total dose.

radi­ation-induced biochemical injury are random pro­ cesses, radi­ation cell killing is exponential as a function of dose. That is doubling a dose that results in a survival rate of 50% will further diminish the survival rate to 25%, and tripling the dose will decrease it to 12.5%, and so forth. The curve forms an initial shoulder followed by an exponential decline in survival as dose increases (see Figs. 2.12A and B). Sublethal damage is thought to be the cause of the initial shoulder, and it must be overcome with each fraction of radiation therapy. Figure 2.12B shows that repeated small doses of radiation are less damaging to a sensitive cell than a single fraction of an equivalent dose.

Linear-Quadratic Model Fig. 2.13: Linear-quadratic model. Several models have been used to explain the cell survival curve and conceptualize radiationinduced cell death. The linear-quadratic model can be used to interpret the cell survival curve after irradiation. According to this model, the survival fraction is equivalent to e(αD – βD^2), where α and β represent the alpha and beta components, respectively. In the linear quadratic model, two components of cell injury are present. The linear alpha component is responsible for the initial shoulder on the cell survival curve and is caused by repairable damage to the cell. The quadratic beta component represents irreparable damage. The linear component is proportional to the dose, whereas the quadratic component is proportional to the dose squared. Earlyresponding tissues and tumors have a relatively large a:b ratio, whereas late-responding tissues have a smaller a:b ratio. The difference between tumor and late-responding tissues is useful in designing therapeutic strategies such has hyperfractionation to exploit their differences and increase the therapeutic ratio.

Several mathematical models have been used to explain the cell survival curve and conceptualize radiation-indu­ ced cell killing, each with varying degrees of complexity and based on the random nature of energy deposition and injury by radiation. The linear-quadratic model (Fig. 2.13) is the preferred tool used by radiation oncologists and radiobiologists to interpret the cell survival curve and calculate isoeffect doses when alternate fractionation schemes are considered. This is largely because it has a biological basis and describes cell killing for both tumor control and normal tissue complications. This model assu­ mes there are two components to cell killing by radia­ tion. The linear (α) component is responsible for the initial shoulder on the cell survival curve and represents the

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Head and Neck Surgery

portion of cell killing that is proportional to the dose (αD). The quadratic (β) component represents the exponential portion of the curve and is proportional to the dose squared (βD2). The survival fraction (S) to a given dose (D) can be expressed with the equation S(D) = e–αD– βD2, where S(D) is the fraction of cells surviving a dose D. The α:β ratio describes the shape of the shoulder region of the cell survival curve and represents the dose at which the linear (single hit killing) and quadratic (multiple hit

Fig. 2.14: The linear-quadratic model is used to determine the α:β ratio on the cell survival curve. The α:β ratio is the dose at which the linear and quadratic components of cell killing are equal (10 Gy in the example shown).

killing) components of cell killing are equal (Fig. 2.14). A high α:β ratio illustrates a curve with a steep initial slope and small curvature, whereas a low α:β ratio is rep­ resented by a curve in the shoulder region with a shallow initial slope and larger curvature (Fig. 2.15). The size of the shoulder is characterized by the absolute values of α and β, which varies considerably among all tissue types. The α:β ratio model offers a radiobiologic explanation for the differences in early (skin, mucosa) versus lateresponding tissues (spinal cord) (Fig. 2.15). For earlyresponding tissues, the α:β ratio is large and α dominates at low doses. For late-responding tissues, α:β ratio is small and β has an influence even at low doses. The lists of α:β values for several tissue and tumor types are presented on Table 2.1. The values for late responding tissues approximate an α:β ratio of 2–4 Gy. Early-responding tissues (e.g skin, oral mucosa) have an α:β ratio of appro­ ximately 9–12 Gy, whereas most H&N tumors have large α:β ratios, resembling that of acutely reacting tissues. There is a clear relationship between timing of tissue response and the α:β ratio of the corresponding tissue such that the radiation response for early- and late-responding tissues mirrors the radiation response for low versus high α:β ratio, respectively.

Fractionation Fractionation represents an effort to exploit the differences in sensitivities between tumor and normal late-reacting tissues (Fig. 2.12B). When radiation dose is fractionated, Table 2.1: Values for α:β

Values for α:β in early-responding normal tissue Skin

Erythema - 10.6

Oral mucosa

Mucositis - 10.8

Desquamation - 11.2

Values for α:β in early-responding tumor Nasopharynx - 16 Oropharynx - 16 Vocal cord - 13 Tonsil - 7 Skin (squamous carcinoma) - 8.5 Fig. 2.15: Hypothetical cell survival curves for early-responding tissues (curve A) and late responding tissues (curve B). The cell survival curves for late-responding tissues are more curved than for early-responding tissues. Early-responding tissues are characterized by a high α:β ratio, whereas late-responding tissues are characterized by a low α:β ratio.

Values for α:β in late-responding normal tissue Skin

Telangiectasia – 2.7

Spinal cord

Myelitis – 3.3

Cartilage

Fibrosis – 4.5

Fibrosis – 1.7

Chapter 2: Principles of Radiation Oncology allowing several hours to elapse between individual doses, the shoulder region reappears after each incremental dose. This is due to repairing of sublethal damage during the elapsed interval between treatments. This has clinical importance in radiotherapy because dividing dose into fractions spares normal tissues as a function of repair of sublethal injuries between dose fractions. With fractio­ nation, there is an increase in survival of cells, which is more pronounced in cells with a more shallow shoulder. When a dose is fractionated, with each fraction separated by a time interval to allow for adequate repair of sublethal damage, the shoulder must be expressed each time, and the cumulative dose survival curve appears as a simple exponential straight line on the survival curve (Fig. 2.12B). This slope is shallower than that of a single-dose treatment and is dependent on the dose per fraction as well as the cell type. Cells with higher α:β ratio in theory have a shallower slope than cells with a smaller ratio. The result is a better therapeutic ratio. However, to achieve a desired level of biological damage to tumor cells, the total dose in a fractionated treatment must be much larger than that in a single treatment. Densely ionizing radiation shows a curve that is nearly an exponential function of dose, represented by a straight line on the log–linear plot. Sparsely ionizing radiation, in contrast, exhibit a curve with an initial slope followed by a shoulder region that then becomes strai­ ghter at higher doses.

Factors Affecting Radiation Sensitivity In addition to repair of sublethal damage and reappea­ rance of the shoulder in dose–response curves, multiple factors affect radiosensitivity of normal and tumor cells. Factors that lessen radiosensitivity include a hypoxic state (such as a postoperative tissue bed), addition of chemical radical scavengers, and use of low dose rates or multifractionated radiation. The obvious and most impor­ tant determinant of radiosensitivity is the radiation dose (energy deposited per unit mass; in Gy). Other factors include physical factors such as LET, relative biological effectiveness (RBE), and fraction and protraction, and biological factors such as oxygen effect, cell-cycle age, and chemical and hormonal agents. Here, we describe a few major factors that affect cell radiosensitivity: type of radiation, oxygenation status, and cell-cycle age.

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Type of Radiation and Linear Energy Transfer The LET is a physical parameter that describes the average rate of energy per unit length along the track that is transferred from ionizing radiation to tissue. X-rays and γ-rays, electrons, and protons are called low-LET radiation, because they produce a sparse density of ionization (or energy deposition) along their track. In contrast, neutrons and heavy nuclei produce dense ionization along their track and are called high-LET radiation. Radiation dose is the amount of energy per unit of biological material (e.g. number ionizations per cell). Thus, high-LET radiation, Gy for gray, produces a more destructive biologic effect than low-LET radiation. This is because it produces mostly lethal and irreparable single-hit injuries as the localized DNA damage cause by dense ionization from high-LET radiation is more difficult to repair than diffuse DNA damage caused by low-LET radiation. The shape of highLET radiation on a dose–survival curve shows a smaller or no shoulder and a steeper terminal slope when compared with low-LET radiation. Thus, there is much less sparing effect of dose fractionation with high-LET radiation. As the LET of radiation increases, the ability of the radiation to produce biological damage also increases. The RBE compares the dose of test radiation to the dose of standard radiation (for historic reasons 250 kVp X-rays are commonly used) to produce the same biologic effect. The RBE varies not only with the type of radiation but also with the type of tissue or cell, dose rate, and fractionation. In general, RBE increases with LET to reach a maximum value of 3–8 (depending on the level of cell kill at LET of approximately 200 KeV/µm). The RBE of high-LET radiation increases with decreasing dose per fraction. Thus, higher LET has a higher ability to produce biologic damage. Note that an increase in RBE in itself offers no therapeutic advantage unless there is a differential effect making the RBE for normal tissue smaller than that for the tumor, and thus increasing the therapeutic ratio.

Oxygen Status Oxygen is a potent modulator of cellular radiosensitivity, giving rise to a large difference in biologic effect in res­ ponse to ionizing radiation. Oxygenated tissue or tumors are much more radiosensitive when compared with tissues in a hypoxic, or anoxic, state. This is known as the oxygen effect, which is particularly important for photons and electrons since they cause biological damage through indirect action. The effect of oxygen was observed about

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Head and Neck Surgery

a century ago when it was observed that interrupted blood supply to the irradiated area reduced the intensity of erythema. Oxygen affects radiosensitivity by altering how cells process radiation-induced free radicals, produc­ ing irreparable damages leading to cell lethality. This is because oxygen is required to make permanent (“fix”) the damage caused by free radicals. Without oxygen (hypoxia or anoxia), the radiation-induced DNA radical lesion created after reacting with the hydroxyl radical is simply repaired. The oxygen effect is enhanced by increasing oxygen concentration, with a maximal effect occurring in the range of 0–20 mm Hg. Further increase in oxygen con­ cen­tration beyond this point has minimal effect on inc­ reasing radiosensitivity. The magnitude of the oxygen effect is called the oxygen enhancement ratio (OER). This is the ratio of effect caused by oxic versus anoxic condi­tions, given by the formula OER = Dose to produce a given effect without oxygen/Dose to produce a given effect with oxygen. The maximal OER value in most mammalian cells is between 2.5 and 3.0 for about 2 Gy, and falls to about 2 for doses between 1 and 2 Gy. For low-LET radia­ tions, such as photons and electrons, the OER approa­ ches 3 for most cell types (i.e. cell killing is three times more effective in oxic conditions versus anoxic condi­ tions). In contrast, for high-LET radiations that rely more on direct action, the radiosensitizing effect of oxygen is much less pronounced. This is because oxygen is not required to “fix” the damage cause by these radiation types, as they directly damage the DNA molecule. Many solid tumors contain radioresistant hypoxic cells because of deficient or impaired angiogenesis. Since oxygen diffusion distance is limited to 50–75 µm, cells located > 100–150 µm away from vascular sources remain in a chronic hypoxic state. This is in contrast to acute hypoxia, which results from temporary closure of tumor blood vessels.

Cell Cycle Age As mammalian cells move through the various divisions of the cell cycle, they exhibit significant variation in radiosensitivity, which has been extensively demonstrated with the use of synchronized cell populations. Generally, cells in the late G2 or mitosis are most radiosensitive, whereas those in the late S-phase are least radiosensitive. Cells in the late G1 and early S-phase exhibit moderate radiosensitivity. Cells having a long G1-phase tend to show a peak of resistance in early G1-phase. The relative

magnitude of this variability, for example, was demon­ strated by an in vitro study on V-70 cells exposed to 2 Gy and showed that the most resistant late S-phase cells even under well-oxygenated conditions had higher radio­ resistance than did the most sensitive G2–M phase cells under hypoxic conditions.19

Biologic Basis of Dose Fractionation (Fractionation and the 4 Rs) Since the early 20th century, fractionated radiotherapy has replaced single-dose radiation as the major form of therapeutic radiation. An important conceptual deve­ lopment occurred in the early 1900s from studies of sper­ matogenesis in the ram, reported by Regaud.20 Regaud demonstrated that a ram could not be sterilized by exposing its testes to single dose of radiation without extensive skin damage. However, if radiation was given in a series of smaller daily doses, sterilization was achieved with acceptable skin damage. This subsequently gave rise to the strategy of fractionated radiotherapy. The four well-established radiobiologic principles underlying dose frac­tionation are repair of sublethal damage, reas­ sortment, repopulation, and reoxygenation (the 4 Rs of radiobiology).

Repair of Sublethal Damage As mentioned earlier, sublethal damage is an operational term defined as the increase in survival observed when a dose of radiation is split into two or more fractions with a time interval in between to allow for adequate repair of the damage. The molecular basis of this phenomenon, however, is not fully understood. When radiation dose is fractionated, there is a reappearance of the shoulder on the cell survival curve, which reflects the ability of cells to recover from nonlethal damage. The capacity to repair sublethal damage varies among different cell types and tissues and correlates with the size of the shoulder of cell survival curves. The extent of repair is greater in mature, late-responding tissues than in rapidly proliferating tissues. The cell survival curves of late-responding tissues are characterized by a small α:β ratios, whereas rapidly divid­ing cells have a large α:β ratio. The clinical implication is that decreasing dose per fraction will result in increased sparing of late responding tissues, which is often the dose limiting in radiotherapy. This concept underlies the principles of hyperfractionated radiotherapy (see below under Clinical Biology—Altered Fractionation).

Chapter 2: Principles of Radiation Oncology

Reassortment As previously mentioned, cells in the G2–M transition exhibit the highest radiosensitivity. In reality, most cells in tissue are asynchronous that is they can be found at various stages of the cell cycle. In asynchronous popu­ lations, ionizing radiation will preferentially kill cells that are in the most sensitive phases of the cell cycle (i.e. G2–M). Cells that survive the first dose will continue their progression through the cell cycle into more radiosensitive phases, consequently becoming more radiosen­ sitized to the next dose fraction. The magnitude of this phenomenon is proportional to the cell proliferation kinetics. It occurs mainly in tissues with moderate to rapid cell turnover rate, such as acutely reacting tissues and tumors, whereas it is negligible in late-responding normal tissues. Thus, fractionation is a commonly used strategy to exploit the phenomenon of cell cycle reassortment to increase the therapeutic ratio between tumor control and late normal tissue toxicity.

Repopulation When normal and tumor cells are depleted by either radiation, cytotoxic agents, or subtotal surgical resection, a regenerative response is triggered prompting an acce­ leration of the clonogenic proliferation rate (a phenome­ non called accelerated repopulation). The time of onset and kinetics of regeneration vary greatly among different tissue types and the magnitude depends on the number of remaining cells retaining their proliferative capacity. Tumor repopulation during treatment breaks or delays likely accounts for local treatment failures and recurre­ nces during and after radiotherapy.21,22 For example, Rosenthal et al. demonstrated that a total treatment package time (defined as the total time from surgery to comple­tion of radiotherapy) >100 days is associated with decrea­sed local tumor control and survival in patients trea­ ted for HNSCC.21 The authors attribute the worse outcome to the phenomenon of accelerated repopulation in res­ ponse to surgical resection and radiotherapy. When the regene­rative capacity of tumor exceeds that of critical acute-reacting normal tissue, such as occurs in a subset of HNSCC, therapeutic gains can result from shortening the course of radiotherapy, called accelerated fractiona­ tion (see also section Altered Fractionation).

Reoxygenation As previously discussed, the lack of oxygen in the tumor microenvironment is a major cause of tumor radiation

27

resistance. Reoxygenation is the event in which cells in a tumor that are hypoxic after a dose of radiation become oxygenated again, often as the tumor shrinks or as the demand for oxygen is reduced. Multiple studies in mice have demonstrated that during a course of fractionated radiotherapy, the oxygen status of originally hypoxic cells may gradually improve before subsequent doses are given. This process of reoxygenation may result from a number of mechanisms. For example, the preferential elimination of more radiosensitive oxygenated cells increases oxygen availability to the remaining surviving cells and also lowers the interstitial pressure on microvessels within the tumor, resulting in improved tumor microcirculation and oxygen supply. Tumor shrinkage also brings the surviving cells closer to the blood supply. Animal tumor studies have demonstrated a significant effect of reoxygenation, although with considerable variation among different animal tumors. Whether reoxygenation occurs in human tumors at a magnitude that is clinically measurable is less clear.

ADVANCES IN RADIATION ONCOLOGY Altered Fractionation The fractionation (or distribution) of radiation dose over time is an important factor in modulating radiotherapy efficacy. A variety of fractionation schemes have been developed over the past several decades for use in treating HNSCCs, including standard fractionation (i.e. 1.8–2 Gy/ day), hyperfractionation, and accelerated fractionation.23 As shown previously, most late-responding tissues are more sensitive to changes in dose per fraction when com­ pared with early-responding normal tissues and tumors. This is particularly true for dose rates below 2 Gy per fraction. Hyperfractionation exploits this difference in fractionation sensitivity to increase sparing of late tissue toxicity. Hyperfractionation schedules are characterized by the administration of higher numbers of smaller fractions, thus increasing the total number of treatments, without a significant change in overall treatment time. By using smaller doses per fractions, the tolerance of latereacting tissue is increased. A commonly administered schedule is to give two smaller dose fractions on each treatment day, with each fraction separated by a 6-hour interval to allow repair of sublethal damage. By doing so, a theoretical increase in total radiation dose of 10–15% can be achieved without increasing late tissue toxicity risk. Accelerated fractionation is the shortening of overall

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Head and Neck Surgery

treatment time to minimize tumor repopulation during radiation therapy. This is achieved without altering total dose or dose per fraction. Both hyperfractionation and accelerated fractionation are often combined to shorten overall treatment time and improve locoregional control rate. The overall goal of altered fractionation is to improve the therapeutic ratio, either through exploiting the diffe­ rential response between tumors and normal tissues (i.e. via hyperfractionation) or minimizing accelerated tumor repopulation (e.g. via accelerated fractionation). Multiple phase III trials investigating the merits of altered fractionation have been conducted in HNSCC patients. Table 2.2 briefly summarizes the results of these randomized studies that examined the role of altered fractionation in HNSCC. The primary tumor sites were oropharynx and larynx, with the majority of patients having intermediate to locally advanced H&N cancers. It should be emphasized that while the lack of uniform reporting criteria make it difficult to directly compare outcomes, the collective finding of these trials demons­ trate a moderate (10–15%) but consistent improvement

in local control, which may translate into survival benefit. The survival benefit appeared mainly attributed to the group with increased total dose (i.e. hyperfractionation), with a corresponding absolute benefit of 8% in 5 years. However, the incidence of associated late toxicity did increase by approximately 12% when comparing twicedaily fractionation versus standard fractionation. A metaanalysis of individual patient data from these trials was reported by Bourhis et al., which included a total of 6515 patients enrolled in 15 phase III trials.24 This analysis demonstrated a 3% survival advantage with altered fractionation, although the main benefit was seen in the hyperfractionation studies. These studies illustrate an example of successfully applying radiobiology principles toward improving clinical outcomes. On the basis of data generated from these multiple randomized trials, many centers have adopted altered fractionation as the standard of care for the treatment of patients with intermediate stage HNSCC (i.e. T2N0-1 or favorable T3N0-1), or those with locally advanced HNSCC but are not candidates for chemotherapy. The six frac­tions per week (in weeks 2–6) are supported by the

Table 2.2: Hazard ratio (HR) (95% confidence interval) and 5-year survival and locoregional control benefit with altered fractionation versus standard fractionation radiotherapy

5-year overall 5-year locoresurvival gional control

HR total death

HR locoregional HR cancer death relapse

HR metastatic relapse

Hyperfractionation (EORTC 22791, RIO, PMH Toronto, RTOG 9003) Standard RT

36.7%*

57.9%*

0.78 (0.69–0.89)

0.78 (0.68–0.90)

0.76 (0.66–0.89)

1.09 (0.76–1.58)

28.5%

48.5%

Accelerated RT without total dose reduction (EORTC 22851, RTOG 9003, BCCA 9113, DAHANCA, Oro 9113, CAIR KBN PO 79) Standard RT

44.4%

47.5%

0.97 (0.89–1.05)

0.91 (0.83–1.00)

0.79 (0.72–0.87)

0.93 (0.74–1.19)

42.4%

40.2%

Accelerated RT with total dose reduction (RTOG 7913, CHART, Vienna, RTOG 9101, GORTEC 9402) Standard RT

31.9%

59.8%

0.94 (0.84–1.05)

0.93 (0.83–1.05)

0.90 (0.80–1.02)

0.95 (0.68–1.32)

30.2%

57.5%

3.4%*

6.4%*

0.92* (0.86–0.97)

0.88* (0.83–0.94) 0.82* (0.77–0.88) 0.97 (0.82–1.15)

Overall benefit

*p < 0.001. (RT: Radiotherapy; RTOG: Radiation Therapy Oncology Group). Source: Modified with permission from Bourhis et al.24

Chapter 2: Principles of Radiation Oncology DAHANCA trial25 and has become a standard practice per NCCN H&N Guidelines 2010. The use of altered frac­ tionation regimens has declined in use in recent years due to increase use of combining potentially less-toxic molecular targeted agents with radiotherapy as well as advances in high-precision radiotherapy such as IMRT (discussed further below), which combines the principles of both hyperfractionation and accelerated fractionation.

HIGH-PRECISION RADIATION THERAPY Conformal Radiotherapy Technological advances in computerized radiotherapy planning and delivery have allowed the possibility of conforming radiation doses to irregular tumor volumes. This approach of treatment planning, and delivery is commonly referred to as conformal radiotherapy (CRT).26 Through CRT approaches, it is now feasible to reduce radiation dose to critical normal structures nearby the tumor without compromising dose delivery to the inten­ ded target, thereby reducing treatment toxicity. Conse­ quently, this also allows for dose escalation for more advanced HNSCC to improve tumor control without sig­ nificantly increasing the associated toxicity. The goal of improving tumor control with higher doses using high precision radiotherapy must be balanced against the cor­ responding increased risk of complications since H&N cancer treatment is considered among the most difficult to plan because of patient’s anatomy, multiple targets with different dose rates and prescriptions, extended cove­ rage areas of potential tumor spread, and simultaneously sparing multiple normal organs at risk.

29

described 25 years ago28 and has seen increased utiliza­tion in clinics and academic centers over the past decade. An important initial step to proper radiotherapy treat­ ment planning is the selection and delineation of the target volume(s) and the organs at risk. In HNSCC, this has typically been done using anatomic-based [computed tomography (CT) and magnetic resonance imaging (MR)] and molecular-based imaging (positron emission tomo­ graphy). Target volumes can be “dose painted” in IMRT such that all target volumes can be irradiated at every radiation session but at varying dose rates, thereby allow­ ing the gross disease to receive a higher dose per fraction, while simultaneously treating subclinical disease to a lower standard dose per fraction. The cumulative effect of this is the capability to dose escalate to improved tumor control while simultaneously mitigating adverse effects

A

B

Intensity-Modulated Radiotherapy The IMRT is a highly sophisticated application of CRT that modifies the intensity of photon beams to provide greater flexibility and precision in treating irregular tumor targets resulting in a sharper dose-fall off gradient, con­cave dose distribution, and narrower treatment margins (Figs. 2.16A to C). When applied correctly by proficient clinicians with detailed knowledge of the complex H&N anatomy, normal tissue tolerance, and pathways of tumor spread, IMRT affords the opportunity to increase sparing of criti­ cal normal structures in close proximity to tumor when com­pared with traditional three dimensional-CRT (Figs. 2.17A to C) and thus alter the severity of treatment com­p­ lications experienced by H&N patients.27 IMRT was initi­ally

C Figs. 2.16A to C: Beam arrangements for (A) conventional opposed lateral fields and (B) static 9-field intensity-modulated radiation therapy. (C) Intensity-modulated beams delivered using a beam shaping device called a multileaf collimator (or MLC). The linear accelerates rotates around the patient to send beams from multiple angles in and out of plane to tumor while sparing nearby normal tissue. Sophisticated computer software guide the movement of the linac and MLC to precisely match the treatment plan, delivering the intended dose to the target.

30

A

Head and Neck Surgery

C

B

Figs. 2.17A to C: Comparison of (A) opposed lateral field plan from 1990, (B) conformal 3D radiotherapy plan from 2000, and (C) intensity-modulated radiation therapy (IMRT) plan from 2010 for a nasopharyngeal carcinoma. IMRT demonstrates a degree of dose-target conformality not possible with conventional radiotherapy, allowing for improved parotid gland sparing.

through improved sparing of at-risk organs. In clinical practice, this results in a well-demonstrated sparing of nearby critical organs, reducing both acute and late toxi­ cities without compromising tumor coverage.29-32 Several clinical studies have demonstrated that tumor control rates with IMRT are at least comparable with those achieved with conventional radiotherapy.33-36 Clinical data is emer­ging that validates its utility in normal tissue sparing, particularly the sparing of parotid gland toxicity to imp­rove xerostomia.27,32,37 Although IMRT for HNSCC was initially developed to spare the parotid gland, attention has recently focused on its utility to selectively decrease radiation dose to specified anatomic structures involved in functional swallow. The rationale for use of IMRT in this setting is that reducing dose to structures responsi­ble for swallowing would lead to less dysphagia and a corresponding improvement in quality of life. While it is clear clinical factors such as primary tumor size and location influence the severity of dysphagia, studies have shown that improving dosimetric parameters of struc­tures involved in anatomic swallowing may translate to clinical benefits.38,39 Despite a high-utilization rate, there remains consi­ derable heterogeneity in IMRT practice across institutions, owing mainly to the complexity of H&N target delineation and high dependence on physics support and rigorous quality assurance. In a study by Hong et al., the authors assessed patterns of IMRT practice from 20 institutions with established H&N IMRT expertise.40 They found sig­ nificant heterogeneity in target delineation and choice

of dose and fractionation schedules (Fig. 2.18). Senior radiation oncologists from these centers were invited to contour an identical challenging case of a stage III (T2 N1 M0) squamous cell carcinoma of the left tonsil. Major differences included ipsilateral versus bilateral neck treat­ ment, use of concurrent chemotherapy and target and dose and fraction delineation (Fig. 2.18). The differen­ ces in neck management in tonsil cancer highlight the complexity of the treatment and management of HNSCC patients. The historical approach, pre-IMRT era, has been treatment of the bilateral neck. However, there are established data demonstrating excellent locoregional and survival rates for ipsilateral neck treatment in patients with well-lateralized, T1-T2 tonsil cancer with no base of tongue or soft palate extension.41,42 There was consi­ derable concordance in the coverage of ipsilateral neck levels II and III and use of the equivalent 2 Gy dose frac­ tions (this accounts for overall treatment time and tumor repopulation), reflecting the expertise of participating centers with regard to understanding spread patterns and dose and fractionation of H&N cancers. These find­ings highlight the potential benefit of a published stan­dardized H&N IMRT guideline but also speak to the complexity of H&N cancer treatment in the IMRT era.

IMRT Delivery The technology to deliver IMRT has evolved since first implemented in the clinic in the 1990s. This evolution has been due to major advances in both the software and

Chapter 2: Principles of Radiation Oncology

31

Fig. 2.18: Representative clinical target volume contours and dose prescriptions from nine different centers. The marked variation in target delineation strategies among senior practitioners from centers with established head and neck (H&N) expertise highlight the complexity of H&N cancer treatment in the intensity-modulated radiation therapy-era. Source: Adapted from Hong et al.40

hardware of treatment delivery systems. The first systems used attachments to linacs that could deliver IMRT to a 2 × 20 cm field, and the table would be shifted 2 cm after

completion of each field until the entire targets were treated. The development of multileaf collimation sys­ tems that were built into linacs allowed for more routine

32

Head and Neck Surgery

deli­very of IMRT, using either dynamic rotational techni­ ques, or step-and-shoot techniques, in which a radiation field would have multiple minifields to allow for the beam modulation. Further developments included the use of tomo­ therapy, still popular today. Tomotherapy is a system that combines a linac and a CT scanner. The patient is treated after the setup is verified at each treatment with the CT scanner (thus incorporating image-guided therapy) and then treated with a dynamic rotational technique. The ability to improve conformality of the treatment plan is an advantage of tomotherapy. Its expense, need for daily CT for less complex treatments, and potential need for redundant systems in case of system breakdown are noted as disadvantages. One of latest IMRT systems is volumetric-modulated arc therapy (VMAT). VMAT is a novel application of IMRT that incorporates an arc-based radiotherapy to deliver radiation from a continuous rotation of the radiation sources, allowing the patient to be treated from a conti­ guous full 360° beam angle similar to tomotherapy. VMAT is available in modern linacs and offers the added advantage of reduced treatment delivery time compared with IMRT that uses a static beam arrangement as previously shown. This allows conformal treatment with improved efficiency in treatment delivery, which reduces overall treatment time and exposure of patient to unintended low-dose scatter radiation. Several studies have compared results of VMAT plans to conventional fixed field IMRT plans in patients with locally advanced cancers of the oropharynx, nasopharynx, and hypopha­ rynx.43-45 The data showed similar target coverage and normal organ sparing between the two plans, with imp­ roved dose homogeneity (i.e. fewer hot or cold spots in region of prescribed dose) when using VMAT. Additional benefits of VMAT include reduced treatment delivery time, and exposure to scatter radiation. Most of the available published data are dosimetric plan­ning studies, and clinical data are still limited. Thus, whether the benefits can be generalized to improved patient outcome remain uncer­ tain. As VMAT is still a novel technology with an increas­ ing number patients treated with this technique, more clinical data should emerge, which will help answer this question.

Adaptive Radiotherapy Adaptive radiotherapy (ART) involves the changing of radiotherapy plans during treatment course to reoptimize

treatment based on changes that have occurred since, or not taken into account during, the initial planning pro­ cess (e.g. tumor shrinkage, weight loss, internal target motion, or changes in tumor biology or function such as hypoxia). During fractionated radiotherapy, interfractio­ nal uncertainties such as repositioning accuracy or daily organ motion are the center of attention. Discrepancies such as setup variations can be kept to a minimum through the use of immobilization devices and daily onboard imaging to verify patient positioning.46 In addition, adding 3–5 mm planning target volume (PTV) margin to the clinical target volume is routinely done to account for daily setup variations and variations in patient posi­ tioning.47 Other adaptive type strategies such as imageguided radiation therapy (IGRT) involve the use of two-dimensional and three-dimensional imaging during the course of treatment to account for setup uncertain­ ties and patient positioning on the treatment table and ensure accurate placement of the radiation field accor­ ding to the initial radiation treatment plan. Typically, the correction parameter involves repositioning the patient or treatment table to shift the target to the isocenter of the treatment devices. In modern day, this is often aided by the use of IGRT. Prior to the advent of IGRT, PTV margins were the most widely used method to account for these types of geometric uncertainties. With improved treat­ ment delivery accuracy offered with IGRT, the radiation (PTV) margin can be decreased to surrounding normal tissues, allowing better normal tissue sparing and dose escalation to the tumor. The term ART often refers to procedures different than the abovementioned techniques used to account for anatomic and functional changes during the course of treatment to maintain accuracy. Commonly, ART refers to the making of a new radiation plan for the patient by modifying original IMRT targets to improve dose dis­ tribution, which can occur between treatment fractions (offline), immediately prior to a fraction (online), or in real time during a treatment fraction. The concept of ART is not new, but technical limitations have held back its implementation in routine clinical care. IMRT planning requires obtaining anatomic imaging (CT or MRI) days to week prior to radiotherapy. However, tumor and normal tissue anatomy can change significantly during the time leading up to treatment and during the course of treatment (often 6–7 weeks in duration) due to treat­ ment response, weight loss, or postoperative healing.48 In H&N cancers, the majority of studies on in-treatment

Chapter 2: Principles of Radiation Oncology fluctua­tions have focused largely on the positional and volu­metric variations of the parotid gland with respect to the target volumes. For example, it has been reported that the parotid gland progressively shrinks by approxi­ mately 1% per daily treatment, with a resulting displace­ ment of the ipsilateral parotid by the end of treatment by as much as 3–4 mm.49 Other studies have demonstrated that primary and nodal tumor gross target volumes can shrink by 2–3% per treatment day.50 These positional and volumetric changes in tumor target volumes and organ at risk volumes can result in significant variations in the delivered dose compared with the planned dose.51 This can be due to tumor shrinkage during treatment (Fig. 2.19) or changes in patient anatomy, which frequently occurs from weight loss and/or from tumor shrinkage. When it comes to parotid gland sparing, these changes in patient anatomy and positioning can lead to increased mean doses to the ipsilateral and contralateral parotid glands by as much as 15% and 10%, respectively.52 The adaptive replanning process involves (1) recog­ nizing changes that would significantly alter dose distri­ bution when compared with the initial plan and (2) treatment replanning itself. Observations that may trigger an adaptive replan include clinical observation of weight loss, tumor shrinkage or growth, or dosimetric or volume­ tric changes made based on repeat imaging, or changes

Fig. 2.19: Comparison of the initial radiation plan during initial planning computed tomography (CT) and the actual dose delivered during treatment on the 15th fraction. Image on the left shows the clinical target volume (CTV) contours based on the initial planning CT scan. Image on the right represents CT scan during the 15th fraction with the initial CTV contours overlaid. This shows significant anatomic changes, including significant decrease in tumor size resul­ ting in poor matching of initial CTV contours with intended targets.

33

observed that are facilitated by deformable image regis­ tration, which involves the transformation of a fixed image to a moving image to account for nonrigid changes in patient anatomy and tumor during treatment (Figs. 2.20A to C). This offers an advantage over positional shift based on IGRT since IGRT cannot fully account for nonrigid changes, yet it is also technically challenging and requires algorithms that can identify nonrigid deformations. In practice, IGRT and ART are commonly used together. While ART holds promising value, there is currently little published data available about the uncertainties as well as clinical significance of ART, and the concept of adaptive planning still requires validation. Implementation of IMRT adaptive planning relies on sophisticated hardware/ software tools and image registration techniques and is currently widely investigated.

Combination Chemotherapy with Radiotherapy The combination of systemic therapy agents (e.g. chemo­ therapy) with radiotherapy has been extensively studied in treatment of patients with HNSCC to improve local tumor control, increase survival, and organ preservation. The biologic rationale for combining these two modalities includes increased tumor cytotoxicity, enhanced tumor radiosensitivity and eradicating disease outside the radia­ tion field. From a sequencing perspective, chemotherapy drugs can be given before (induction or neoadjuvant), after (adjuvant) or concurrently with radiation. Up through the 1980s, surgery and postoperative radiotherapy repre­ sented the mainstay local therapy for localized H&N cancers. The concept of organ preservation through the use of radiation and chemotherapy was validated by the Department of Veteran Affair (VA) larynx preservation trial in 1991.53 Since then multiple phase III trials have been conducted to examine combined effects of chemo­ therapy and radiation. A very extensive meta-analysis of phase III trials was conducted by the Meta-Analysis of Chemotherapy on Head and Neck Cancer (MACHNC) Collaborative Group between 1965 and 1993 to compare the effects of radiation with and without che­ motherapy.54 A recent update of that analysis added an additional 24 randomized trials enrolling over 5000 patients treated between 1994 and 2000 to bring the series to a total of 87 trials with over 16,000 patients.55 Although interpretation of the data is complicated by the marked heterogeneity particularly among the earlier trials with

34

Head and Neck Surgery

A

B

C

Figs. 2.20A to C: (A) Sagittal image of daily image-guided radiation therapy using cone-beam computed tomography (CT) with planning contour overlay shows difficulty in alignment of the spine. (B) Axial image of planning CT and CT performed 2 weeks into treatment showing change in tumor size and shape. (C) Changes in tumor size and shape after 1st treatment fraction. Source: Dong et al. AAMD Meeting Abstract, Houston, TX, USA, September 13–14, 2012).

regard to tumor and patient characteristics, treatment regimen, and follow-up, several important findings were noted. The investigators found that the addition of concurrent chemotherapy to radiation yielded an overall hazard ratio (HR) of 0.81 [95% confidence interval (CI) 0.78–0.86, p < 0.0001], which corresponded to an abso­ lute benefit of 6.5% at 5 years. The chemotherapy benefit was due to reduced cancer-related deaths (HR 0.78, 95% CI 0.73–0.84, p < 0.0001) with no effect on intercurrent deaths (HR 0.96, 95% CI 0.82–1.12, p = 0.62). By contrast, sequential chemotherapy and radiotherapy, given either in an adjuvant or neoadjuvant setting, failed to show a survival or local control benefit. The HR for induction chemotherapy was 0.96 (p = 0.18) with an absolute dif­ ference of 2.4% at 5 years. With regard to local control effects, concurrent chemoradiation showed a signifi­ cant local control benefit (HR 0.74, 95% CI 0.70–0.79, p  90%) in HNSCC and its key regulatory role in cellular differentiation, proliferation, metastasis, angiogenesis, and apoptosis.66 Studies have demonstrated inhibition of EGFR may lead to G1 cycle arrest due to accumulation of certain CDK inhibitors that can prevent cellular proliferation. Inhibition of EGFR can be achieved extracellularly by monoclonal antibodies and intracellularly through tyrosine kinase inhibitors. Cur­ rently, EGFR inhibitors have been tested as a single agent and in combination with other therapies. Cetuximab is a human-murine chimeric high-affinity monoclonal antibody against EGFR that has been vastly studied.67,68 Preclinical and clinical trials on EGFR targeting opened the way for launching and com­pleting the multinational phase III study investigating the effi­ cacy of radiation with and without cetuximab for the treatment of locally advanced HNSCC.69 A total of 424 patients from 87 centers from multiple countries were randomly assigned to either high-dose radiotherapy alone or the same radiotherapy regimens plus eight doses of cetuximab, given 1 week prior to radiotherapy start and weekly during the course of radiotherapy treatment. The initial results and recent update of this trial demonstrated both an improvement in locoregional control (3-year locoregional control 47% vs 34%, p = 0.005) and survival (5-year overall survival 45.6% vs 36.4%, p < 0.05).70 There was no significant difference in radiation-induced toxi­ city. Patients in the cetuximab arm did have a very high rate of an acneiform rash that is common to EGFR inhibi­ tors, and some patients experienced infusion reactions precluding them from receiving further cetuximab treat­ ment. The update also showed that survival was improved in patients who experienced the rash of at least grade 2 toxicity. In addition to the monoclonal antibody cetuximab, several tyrosine kinase inhibitors of EGFR are being studied. Currently, there are sparse clinical data available on the use of tyrosine kinase inhibitors in H&N cancers. Gefitinib and erlotinib are the two most advanced drugs available, but their use for treatment of HNSCC is still experimental.71,72

RECENT ADVANCES IN HEAD AND NECK CANCER Biomarkers At present time, several prognostic biomarkers after treat­ ment with current standard therapies have emerged for

several HNSCC sites. These include the absence of Epstein–Barr Virus (EBV) DNA titer in patients with naso­ pharyngeal carcinoma (NPC), the presence of HPV in oropharyngeal HNSCC, and H&N tumors with low EGFR expression. These have implications for further tailoring of treatment regimens to improve the thera­peutic ratio. Whether these biomarkers may have predi­ctive value with newer therapies is an area of active investigation.

Circulating EBV DNA Titers in Nasopharyngeal Carcinoma It has been established that NPC patients with persis­ tent titers of circulating EBV DNA after completion of concurrent chemoradiation with cisplatin have higher rates of distant relapse.73-75 Multiple epidemiological studies have demonstrated that EBV plays a major role in the pathogenesis of nonkeratinizing subtype of NPC, as they are endemic in areas where EBV infection is also endemic.76,77 More recently, it has been reported that a vast majority of NPC tumors, regardless of histologic subtype, have comorbid EBV infections, providing a strong case for EBV as the etiology of NPC.78 Investigations of the mole­ cular mechanism underlying the pathogenesis of EBVassociated NPC have identified and characterized several oncogenes with key regulatory roles in EBV-induced car­ cinogenesis. In particular, EBV tumorigenic potential is due to a set of latent genes predominantly expressed in NPC, with latent membrane protein 1 (LMP1) as the principal oncogene of NPC.79 It is required for cell immor­ talization and present in 80–90% of NPC tumors.80 LMP prevents apoptosis and directly activates a number of signaling pathways including nuclear factor κ-B (NF-κB), mitogen-activated protein (MAP) kinases, and phos­ phoinositol-3-kinase (PI3K).79,81 It also has intrinsic T-cell inhibitory properties82 and mediates downregulation of CD99,83 an important component of the anti-NPC immune response. The result is suppression of host immunogenic response and development of cells with greater mobility, which together enhances the metastatic potential. More recently, the advent of real-time polymerase chain reaction (PCR) has allowed for easier detection of EBV DNA in the serum of NPC patients.84,85 Using this detection method, it was found that pretreatment serum EBV DNA levels are quite variable among NPC patients, with the highest titers found in those from endemic areas. In addition, the higher the circulating EBV DNA levels, the greater the risk of disease recurrence and that an increase in serum titers during post-treatment follow-up

Chapter 2: Principles of Radiation Oncology often signifies recurrent or metastatic disease86,87 and therefore may be a useful biomarker for monitoring NPC patients.88 Patients receiving chemoradiation for treatment of NPC can be stratified into subgroups based on their pre- and post-treatment EBV DNA levels. Lin et al. demon­ strated significantly better 5-year overall survival and relapse-free survival in groups with low or high pretreat­ ment and undetectable post-treatment levels compared with those with detectable levels after chemoradiation.89 This appears to apply to patients from Western regions as well, as a study by Ferarri et al. on a cohort of patients of European origin demonstrated that elevated pretreatment EBV DNA levels correlated with tumor stage and pro­ba­ bility of relapse, whereas elevated post-treatment levels correlated with locoregional and distant disease recur­ rence.75 The combination of IMRT and concurrent cisplatin chemotherapy has resulted in excellent locoregional con­ t­rol rates among patients with NPC, even among those with locally advanced presentation. With impro­ved local control, distant metastasis has become the primary pat­ tern of relapse. Thus, identifying high-risk patients with persi­stent circulating EBV DNA after treat­ment can be preselected for treatment intensi­fication, using a combi­ nation of novel agents with conven­tional chemotherapy and radiation, to eliminate occult metas­ tatic disease. New immunotherapy strategies utiliz­ ing EBV-specific cyto­ toxic T lymphocytes for treatment of high-risk patients have shown promising response rates in heavily pretreated patients in preliminary studies.90,91

HPV and Oropharyngeal Carcinoma It is becoming clearer that HPV-positive oropharyngeal carcinomas (OPCs) represent a distinct entity separate from their HPV-negative counterparts in terms of their clinical presentation, etiology, prognosis, and pattern of spread.92 The incidence of HPV-associated OPC is quickly rising, particularly in Western countries. Current estimates indicate that HPV-positive cancers represent up to 20% of all HNSCCs and 80–90% of those arising from the oropharynx. There are more than 100 HPV genotypes, categorized as low and high risk according to their malignancy transformation potential.93 The highrisk HPV-16 subtype is by far the most common HPV subtype detected in OPC, and also considered the defi­ nitive carcinogenic subtype for the H&N region,94 in addition to its already established linkage to human

37

cervical cancers. Patients with HPV-associated OPC when compared with non-HPV-associated patients tend to be middle aged white men, of working and reproductive age, have limited tobacco exposure, consume less alcohol, and have higher socioeconomic status and performance status.95,96 HPV-positive tumors are often characterized as poorly differentiated, nonkeratinizing carcinomas arising from the palatine tonsils and tongue base, and diagnosed at an earlier T-stage with a trend for more advanced N-staging, with primary lesions having well-defined bor­ ders and metastatic neck nodes with cystic appearance on imaging when compared with HPV-negative carcinomas.92 The HPV-positive OPC is associated with improved treatment response and survival that is independent of treatment modality.64 Several meta-analysis of retros­ pective studies have demonstrated that patients with HPV-positive OPC had a 50% reduction in risk of death compared with those with HPV-negative tumors and suggested a distinct etiology of HPV-positive tumors ari­ sing from the oropharynx.97,98 A prospective study by ECOG investigators reported a higher response rate after an induction regimen of paclitaxel and carboplatin for HPV-positive cancers compared with HPV-negative patients.99 Ang et al. were among the first to establish HPVstatus as an independent prognostic factor for overall survival among patients with OPC. In an analysis restricted to oropharyngeal patients, Ang et al. found that HPVstatus emerged as the strongest determinant of survival for patients with locally advanced stage oropharyngeal cancer with at least a 50% improvement in survival at 5 years, even when accounting for multiple factors, including age, race, T-stage, N-stage, smoking status, and treatment assignment.64,97 More and more data continue to show that patients with HPV-related OPC fare much better than their HPV-negative counterparts after definitive treatment with surgery,100 radiotherapy,101,102 concurrent chemo­radiation with cisplatin,64 and induction chemo­ therapy followed by chemoradiation.99 Together, these studies establish HPV-status as a strong and independent prog­nostic factor for survival among patients with OPC. In fact, determining HPV-status is now a routine part of diagnostic evaluation to assess prognosis in most centers and clinics.94,103 The HPV owes its oncogenic potential to its ability to insert early genes (E5, E6, and E7) into the host cellular genome.33 The onset of HPV-mediated carcinogenesis is thought to occur through the expression of E6 and E7, which inactivates the tumor suppressor protein p53

38

Head and Neck Surgery

(encoded by TP53 gene) and retinoblastoma protein (pRb), which acts to inhibit cell-cycle progression.104,105 Together, inhibition of these two proteins results in supp­ ression of tumor suppression factors leading to loss of apoptosis, DNA damage repair, and cell-cycle regulation, with simultaneous promotion of proliferation and cel­ lu­ lar dedifferentiation. The end result is that HPVaffected cells do not need as many mutations to undergo malignant transformation. Interestingly, in vivo and in vitro studies demonstrate that when HPV-positive cancer cell lines are exposed to genotoxic agents, they repress E6 and E7 expression and thereby increase p53 pro­ duction.106,107 Thus, the ability of HPV-positive cancer cells to induce apoptotic cell death in response to DNA damage from genotoxic chemotherapy or ionizing radia­tion may offer a potential explanation as to why HPV-associated tumors have improved survival outcomes and treatment responses.107,108

EGFR Expression in Head and Neck Tumors There is a developing consensus in the HNSCC commu­ nity that alteration in EGFR signaling is a major cause of malignant transformation and progression.109,110 EGFR (also known as ErbB1 and HER 1) is the first type 1 receptor tyrosine kinase identified. EGFR is a promi­ sing candidate for therapeutic targeting with a high exp­ ression rate of over 90% and possesses a key regulatory role in cellular differentiation, proliferation, metastasis, angio­genesis, and apoptosis.66 Of major significance in this context, is that ionizing radiation can activate EGFR and other receptor tyrosine kinases,111-113 inducing a range of cytoprotective responses such as increased cell proli­ feration, reduced apoptosis, and enhanced DNA repair. EGFR overexpression is not correlated with T or N staging, American Joint Committee on Cancer stage grouping, or recursive partitioning analysis classes. EGFR overexpression was found to be a strong independent marker for higher local regional relapse rate and lower survival rate but not for incidence of metastasis.114,115 Several studies have looked at the prognostic sig­ nificance of EGFR in HNSCC patients treated with fractionated radiotherapy. Ang et al. performed an immu­ nohistochemical analysis of pretreatment biopsy speci­ mens derived from cohort of patients randomly assigned to the conventional fractionation arm of the RTOG 90-03 trial, and a demonstrated high concordance between EGFR expression and risk of death and local–regional

relapse.114 The opportunity to examine the potential pre­dictive value of EGFR in selecting candidates for acce­ le­rated radiotherapy was provided by data taken from two large European accelerated fractionation trials (DAHANCA and CHART trials) in which biopsy material from both the conventional and accelerated radiotherapy arms were sampled. In the DAHANCA trial, the authors showed that high EGFR expression was associated with significantly worse local control in the conventional arm but not accelerated arms.116 In the CHART trial, the authors showed that while in the conventional arm of the study, patients with high EGFR expression tended to have worse locoregional outcome than patients with low EGFR expression, that after the CHART, the high EGFR expressing patients did better than the low EGFR group, indicating that high EGFR expression predicted for better treatment res­ponse in those treated with accelerated fractination.111 Taken together, these findings reveal a key functional role for EGFR in determining accelerated tumor repopu­lation during fractionated radiation and that the negative impact of high EGFR expression may be partially counteracted by shortening overall treatment time.111,116

PALLIATIVE RADIOTHERAPY Radiation is increasingly used in the palliative setting for symptomatic relief of tumor burden in patients with incurable cancers. Up to 40% of HNSCC patients in some areas of the world are treated with palliative intent.117,118 There is no consensus regarding the preferred fractiona­ tion schedule for palliative radiotherapy; however, many would agree that an effective palliative regimen ideally would be simple to administer yet provide worthwhile symptom control and tumor regression with minimal treatment toxicity. Conventional palliative radiotherapy consists of a prescribed dose of 30 Gy given in 10 fractions over 2 weeks. This provides a decent rate of symptom response of approximately 65%, with about three quarters of patients completing planned radiotherapy. The grade 3+ toxicity rates however were higher than anticipated at approximately 48%.119 Several studies have investigated the role of alternative hypofractionation schedules to further reduce overall treatment duration.119-121 In a large Indian study evaluating symptom relief and tumor res­ ponse in 505 patients with incurable HNSCC using a regimen of 20 Gy in five fractions over 1 week showed 37% partial response rate with one-half of patients reporting symptomatic relief. The main toxicity was mucositis, with all patients having patchy mucositis at 1-month posttreatment follow-up.

Chapter 2: Principles of Radiation Oncology A regimen initially piloted and currently utilized at MD Anderson Cancer Center (Houston, TX, USA) is the Quad Shot palliative regimen, consisting of 14 Gy in four fractions given twice daily over 2 days. The concept is to deliver short cyclical courses of radiotherapy, with each cycle designed to give a biologically equivalent dose just below the threshold for producing mucositis. The number of dose fractions in each cycle was set at four to allow for tumor reoxygenation without protracting the duration of each cycle of treatment. In addition, sufficient time was allotted between treatment cycles to allow for repopulation of depleted mucosal stem cells; although tumor repopulation was anticipated to occur, the longer lag time for onset of tumor cell repopulation would favor the normal epithelium. In a phase II trial examining symptom relief and quality of life benefit of the Quad Shot regimen, Corry et al. observed a 53% response rate, with disease stabilization in one third of patients, translating to improved quality of life with negligible treatment toxicity.120 Although the technical component of palliative radio­ therapy may be relatively simpler when compared with that of definitive radiotherapy, the decision-making pro­ cess involved often times can be challenging. This inc­ ludes diagnostic challenges related to patients referred for palliation and deciding which patients are not suitable for more radical curative treatment. Those unsuitable for curative treatment can be because of advance disease and/or too fragile of physical or medical condition for radical treatment. Equally important is effective commu­ nication of therapy goals, as patient’s hopes and expecta­ tions may not coincide with treatment intent. The use of radiotherapy in these settings requires careful consi­ deration as the possibility of causing further distress with minimal or modest therapeutic gains in patients with already limited life expectancies must be considered before initiating locoregional treatment. A new paradigm has emerged in setting of oncology practice: The oligometastatic state. Traditional oncologic treatments distinguish between two separates and incom­ mensurable states in the evolution of solid tumors: the curable, localized disease, and disseminate incurable disease, which is palliative. Traditionally, patients are generally assigned to either one or the other treat­ment class. The general understanding of metastasis of tumor beyond the primary lesion and particularly the mecha­ nism of the “invasion metastasis cascade”, describing how cancer cells from a primary lesion develop invasive and metastatic properties through a sequence of steps,

39

is likely experiencing a fundamental revision. Recently, a sizeable body of data suggests an interme­diate state in the trajectory of solid tumors called oligo­metastatic state, generally defined as 1–5 lesions besides the primary tumor.122 Emerging evidence also suggests that active intervention in the oligometastatic state might be of measureable clinical benefit for the patient.123,124 In this context, the concept of metastatic cancer is seen in a more dynamic spectrum than as a dichotomous static state of disease manifestation with regard to the number and site of lesions. Radiotherapy could play a determin­ ing role in the local control of oligometastatic cancer.125 CRT, in particular stereotactic ablative and bra­chythe­ rapy, may well provide a higher level of therapeutic effi­cie­ncy and safety compared with minimal or non­ invasive methods with lower morbidity, lower costs, and potential for delivering ablative treatments on an out­ patient basis.

SUMMARY The field of H&N radiation oncology has been exciting and rewarding in the past few decades. From the enthu­ siasm associated with enrolling patients into large-scale, cooperative group clinical trials to recent advances in treatment planning and delivery techniques, including higher quality imaging, better understanding of the complexities of IMRT H&N treatment, and more meti­ culous management approaches, the primary goal has been to improve patient outcome and enhance the thera­ peutic ratio. This is partly reflected in the observation that although the overall incidence of H&N cancer has been relatively stable over the past three decades, there has been a significant improvement in overall survival (4.6% as of 2009) irrespective of age, particularly in the past decade, and in those patients with tongue and tonsil cancers.126 Unfortunately, with longer survival and followup, there is a developing consensus that this reduction in mortality rate is achieved too often at the cost of in­cre­ ased toxicity, particularly when cytotoxic agents are given concurrently with radiation therapy. However, recent advances in radiation oncology have generated a great deal of optimism as novel strategies for improving quality of life and survival rates are being developed for clinical testing. Technical innovations in radiation planning and deli­ very techniques have greatly improved the precision of radiotherapy. Advancements such as IMRT, IGRT, and ART have ushered in greater opportunities to reduce treat­ment

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Head and Neck Surgery

toxicity and perhaps also improve tumor control through dose intensification. However, to safely implement these technologies and extract their maximum benefit requires expertise in defining tumor and normal tissue target volu­ mes, comprehension of the complex clinical and imagebased anatomy of and pathophysiology of tumors arising from the H&N, rigorous approach to treatment planning, and quality assurance. The use of cetuximab highlights new alternative stra­ tegies as compared with traditional attempts to over­come treatment resistance from accelerated tumor repopula­ tion by altering the dose–time fractionation pattern. The concern stems from some who believe the therapeutic gain from altered fractionation regimens observed in recent HNSCC trials may be close to the limit of what can achi­ eved by this strategy alone in unselected patients.127 Other strategies include development of predictive assays such as gene expression and genomic profiling, or a panel of immunohistochemical markers involved in various aspects of cellular response to radiotherapy (represen­ ting a more hypothesis-driven and tailored approach), to select patients who would be at greater-than-average to benefit from intensified therapy. There is little doubt the pace of progress will increase in the coming years. The use of biologic agents represents a strategy guided by bench and translational work to improve outcome based on a better understanding of the molecular mechanisms behind treatment resistance and repopulation of tumors. Better radiobiologic insight to help identify new molecular targets for selectively sensi­ tizing tumor to radiation and thus improve upon the therapeutic ratio. And finally, maturating of randomized trials with combination radiation and systemic therapy, including molecular pathway targeted agents, to help pair individuals at different risks of relapse with the appro­ priate treatment regimen.

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110. Grandis JR, Zeng Q, Drenning SD, et al. Norma­lization of EGFR mRNA levels following restoration of wild-type p53 in a head and neck squamous cell carcinoma cell line. Int J Oncol. 1998;13(2):375-8. 111. Bentzen SM, Atasoy BM, Daley FM, et al. Epidermal growth factor receptor expression in pretreatment biopsies from head and neck squamous cell carcinoma as a predictive factor for a benefit from accelerated radiation therapy in a randomized controlled trial. J Clin Oncol. 2005;23(24): 5560-7. 112. Harari PM, Huang SM. Head and neck cancer as a clinical model for molecular targeting of therapy: combining EGFR blockade with radiation. Int J Radiat Oncol Biol Phys. 2001; 49(2):427-33. 113. Huang SM, Li J, Armstrong EA, Harari PM. Modulation of radiation response and tumor-induced angiogenesis after epidermal growth factor receptor inhibition by ZD1839. Cancer Res. 2002;62(15):4300-6. 114. Ang KK, Berkey BA, Tu X, et al. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res. 2002;62(24):7350-6. 115. Chung JH, Rho JK, Xu X, et al. Clinical and molecular evidences of epithelial to mesenchymal transition in acquired resistance to EGFR-TKIs. Lung cancer. 2011;73(2): 176-82. 116. Eriksen JG, Steiniche T, Askaa J, et al. The prognostic value of epidermal growth factor receptor is related to tumor differentiation and the overall treatment time of radiotherapy in squamous cell carcinomas of the head and neck. Int J Radiat Oncol Biol Phys. 2004;58(2):561-6. 117. Ghoshal S, Chakraborty S, Moudgil N, et al. Quad shot: a short but effective schedule for palliative radiation for head and neck carcinoma. Indian J Palliat Care. 2009; 15(2):137-40.

118. Senn HJ, Glaus A. Supportive Care in Cancer--15 years thereafter. Support Care Cancer. 2002;10(1):8-12. 119. Chen AM, Vaughan A, Narayan S, et al. Palliative radiation therapy for head and neck cancer: toward an optimal fractionation scheme. Head Neck. 2008;30 (12):1586-91. 120. Corry J, Peters LJ, Costa ID, et al. The 'QUAD SHOT'--a phase II study of palliative radiotherapy for incurable head and neck cancer. Radiother Oncol. 2005;77(2):137-42. 121. Mohanti BK, Umapathy H, Bahadur S, et al. Short course palliative radiotherapy of 20 Gy in 5 fractions for advanced and incurable head and neck cancer: AIIMS study. Radiother Oncol. 2004;71(3):275-80. 122. D'Agostino GR, Autorino R, Pompucci A, et al. Wholebrain radiotherapy combined with surgery or stereotactic radiotherapy in patients with brain oligometastases: longterm analysis. Strahlentherapie und Onkologie: Organ der Deutschen Rontgengesellschaft [et al.]. 2011;187(7):421-5. 123. Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol. [Editorial]. 1995;13(1):8-10. 124. Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis. Science. 2011;331(6024):1559-64. 125. Gibbs IC, Kamnerdsupaphon P, Ryu MR, et al. Image guided robotic radiosurgery for spinal metastases. Radiother Oncol: journal of the European Society for Therapeutic Radiology and Oncology. 2007;82(2):185-90. 126. Rodriguez CP, Adelstein DJ. Survival trends in head and neck cancer: opportunities for improving outcomes. Oncologist. [Comment]. 2010;15(9):921-3. 127. Bentzen SM. Repopulation in radiation oncology: perspectives of clinical research. Int J Radiat Biology. 2003;79(7): 581-5.

Chapter 3: Principles of Medical Oncology

45

CHAPTER

Principles of Medical Oncology

3

Cristina P Rodriguez, David J Adelstein

INTRODUCTION Malignant tumors of the head and neck are remarkable in the diversity of their anatomic sites of origin, histology, disease behavior, and in the range of available thera­peu­ tic options. Contemporary management now routinely involves multiple disciplines, including the medical onco­ logist, whose role in treating these malig­nancies continues to expand. Squamous cell carcinoma is the most common malig­ nancy in the head and neck, and the use of systemic therapy has been most extensively investigated in this disease. In the 1960s, with the introduction of the earliest generation chemotherapy agents, a surprising sensitivity to chemotherapy was demonstrated.1 Today, the role of systemic therapy is no longer limited to the management of squamous cell carcinoma, but extends to the less frequently occurring histologic subtypes, including the sinus and salivary gland cancers, and advanced cancers of the thyroid. This primarily reflects an increasing understanding of the underlying molecular mechanisms influencing tumor biology, and the subsequent identi­ fication of active systemically administered agents that modify these mechanisms. Unlike locoregional treatments like surgery and radiation, the use of systemic therapy is influenced more by histology and biologic behavior than by anatomic subsite. Scientific investigation has led to defined roles for conventional chemotherapeutic agents in curative and palliative management strategies as well as to the identification of newer, targetable mole­ cular markers, resulting in the development, approval, and clinical availa­bility of several novel agents for the treatment of these malignancies.

This chapter will provide the reader with a foundation for understanding the basic tenets behind the use and selection of systemic therapeutic agents in the treatment of head and neck carcinomas, with a major emphasis on squamous cell carcinomas. The specifics of the regimens used and approved for curative and palliative treatment approaches will be discussed elsewhere in this book.

THE MOLECULAR BASIS FOR SYSTEMIC THERAPY It is well documented that many epithelial malignancies represent the sequela of accumulated molecular changes that begin during the gradual progression from normal mucosa to dysplasia and to invasive carcinoma. In head and neck malignancies, this is best illustrated by the tobacco-related squamous cell carcinomas of the oral cavity, oropharynx, larynx, and hypopharynx. Alterations at the molecular level initiated by continued carcinogen exposure involve oncogenes and proto-oncogene, and result in genomic instability, impairment of DNA repair mechanisms, and loss of apoptosis.2 For example, chro­ mo­some 9p and 3p deletions and p53 mutations have been reproducibly demonstrated in dysplastic epithelia and are felt to be mutations that occur early in the process of carcinogenesis. On the other hand, 18q deletions are more commonly found in severely dysplastic epithelium and/or frankly invasive carcinoma. These genetic changes can also be detected in the surrounding nonmalignant mucosa, supporting the theory of a “field defect” shared by carcinogen-exposed epithelia, and the frequent obser­ vation of second primary upper aerodigestive malignancies

46

Head and Neck Surgery

in this population.3 The resulting dysregulated cellular growth and inability to repair genetic damage are proces­ ses that are commonly exploited by systemic chemo­ therapeutic agents. This model by no means fully encompasses the tre­ mendous complexity underlying carcinogenesis and tumor behavior among head and neck malignancies. Viral infec­ tions and immune factors also appear to be invol­ved in specific subsets of head and neck squamous cell carci­ nomas. Epstei–Barr viral DNA is a marker of endemic nasopharyngeal carcinoma, which has a unique geogra­ phic and demographic distribution, as well as a distinct biology compared with squamous cell carcinomas of the oral cavity, oropharynx, larynx, and hypopharynx.4 Loss of serologic evidence of Epstein–Barr viral infection after completion of therapy appears to predict treatment outcome.5 Among oropharynx squamous cell carcinomas, the human papillomavirus (HPV) has been established as an important etiologic agent6-8 The incidence of HPVinitiated squamous cell carcinomas of the oropharynx continues to increase, and this disease appears to be bio­ logically, demographically, and prognostically distinct from its HPV negative counterpart.9,10 Further insight into the drivers of malignant trans­ formation and behavior has led to the identification of tumor-specific targets for therapy. Certain malignancies appear to rely heavily on cellular pathways that are abnor­ mally activated by mutated, amplified, or over-expressed receptors or protein kinases. Relatively new to the systemic therapy armamentarium are agents with the ability to inhibit specific proteins involved in these pathways. One example is the epidermal growth factor receptor (EGFR), which is frequently overexpressed in the mucosal head and neck squamous cell carcinomas.11 EGFR belongs to a family of transmembrane cellular receptors Ligand binding and activation of these receptors result in downstream intracellular events, which lead to invasion, dediffe­ rentiation, and loss of apoptosis. Several EGFR inhibitors have been developed and studied in squamous cell carcinomas of the head and neck, including the mono­ clonal antibody EGFR inhibitor, cetuximab, which has demonstrated efficacy, and Food and Drug Administra­ tion approval when used in combination with radiation therapy in locoregionally advanced head and neck squa­ mous cell carcinoma, and in combination with conven­­ tional chemotherapy in patients with metastatic disease.12,13 Prognostic and predictive molecular markers are actively being studied in other head and neck cancer malignancies.

For example, Her2neu, C-kit, and vascular endothelial growth factor (VEGF) are targets of interest among the salivary gland cancers; RET appears important in medu­l­ lary thyroid cancer, as does BRAF in differentiated thyroid malignancies.14,15 Overall, this underscores the inherent molecular heterogeneity among the head and neck malignancies Identification of these molecular markers makes targeted therapy the intuitive direction for future scientific inquiry and for improving treatment outcomes.

GENERAL PRINCIPLES IN SYSTEMIC THERAPY ADMINISTRATION Defining Treatment Goals The therapeutic goals of treatment for any malignancy can be considered either curative or palliative in intent. Patients with head and neck malignancies who have locally or locoregionally confined disease can usually be approached with curative intent. The cornerstone of their treatment will be locoregional therapies, including surgical resection and/or radiation therapy. It must be emphasized that to date, systemic therapy as a single modality is not a curative intent approach for malignancies of the head and neck and is largely utilized to augment local tumor control and/or modify the risk of distant metastatic recurrence. In situations where a cure is attainable, the administration of planned local and systemic therapy with minimal or no interruptions and maximal dose intensity is a treatment priority. Acute toxicities of treatment are often more acceptable to these patients and their physicians when the curative potential of therapy outweighs the morbidity and potentially mortality associated with the treatment approach. Consequently, aggressive supportive care is fundamental to successful completion of treatment. These curative intent regimens involve significant pretreatment planning and are often logistically challenging for patients. Appropriate patient selection is essential, with specific attention to those somewhat unique factors relevant to the head and neck cancer population, including comorbidity, compliance, and social support. When long-term survival is anticipated, late toxicities and long-term side effects of therapy must also be taken into consideration during treatment planning. Patients considered medically unfit for curative intent therapy, and those with systemic metastases at presen­ tation, or recurrent disease not amenable to local therapy,

Chapter 3: Principles of Medical Oncology have incurable disease and are treated with palliative intent. Therapeutic intervention in these circumstances is directed towars improving quality of life, amelioration of symptoms related to tumor burden, and survival pro­ longation, and chemotherapy can often be of signifi­cant, albeit temporary benefit. When systemic therapy is used in these settings, however, regimens with high rates of acute toxicity and cumbersome administration schedules fall out of favor. Because of the importance of quality of life and minimizing toxicities, the use of novel targeted agents in this group is particularly attractive.

Chemotherapy Administration Systemically administered chemotherapeutic agents achieve cell death by targeting cellular processes that, although present in normal tissues, may be amplified in the malignant cell. This is responsible for the narrow therapeutic window of these drugs. Remaining within this therapeutic window, and avoiding severe morbidity and patient mortality, is therefore key to the successful administration of chemotherapy. Most chemotherapeutic agents are cleared through either a renal or hepatobiliary route. Patients with com­ promised renal or hepatic function will have prolonged drug half lives, extended drug exposure, and therefore magnified drug-related toxicity. Patient selection with these factors in mind is routine. Myelosuppression is often a dose-limiting toxicity of chemotherapeutic agents, due to the potentially fatal complication of enteric bacteremia that can develop during neutropenia. The necessity for bone marrow recovery after chemotherapy treatment in avoiding this risk dictates the intermittent administration of chemotherapy. The typical chemotherapy admini­ stration “cycle” includes the drug administration, followed by a period of no drug exposure, to allow for normal tissue recovery. Supportive care is an equally critical component to the successful administration of chemotherapy. Very effective antiemetics have entered routine practice and have been instrumental in mitigating the toxicities of highly emetogenic agents such as cisplatin. Growth factors that stimulate bone marrow stem cells have also been approved for use after chemotherapy, to shorten the duration of myelosuppression and prevent the infectious compli­ cations of chemotherapy-induced neutropenia. An cillary supportive services including nutritional support, physical and occupational rehabilitation, speech pathology, and dentistry all play important roles in patient care.

47

Efficacy Measurement Approving a new drug with promising preclinical activity in the laboratory for use in the clinic typically requires a rigid stepwise process, which begins with phase I clinical trials. These human studies aim to define the safety and toxicity profile of the agent under study and provide additional insight into its pharmacokinetic and pharma­ codynamic properties. Once the maximum tolerated dose of drug is determined, testing its activity in specific tumor types is usually done through phase II clinical trials. Promising activity in phase II studies often leads to phase III studies, which are comparisons of the promis­ ing drug or drug regimen with the current treatment standard of care. The gold standard measure of benefit from a cancer therapy is an improvement in overall survival.16 Survival is an unequivocal endpoint in reporting clinical trial results. Among certain patient populations, however, such as those tobacco-related head and neck malignancies, overall survival may not entirely reflect the success of a treatment regimen, due to competing causes of mortality including comorbidity and second primary malignancies.17 Objective response or tumor shrinkage after exposure to systemic therapy is another endpoint used in measuring treatment efficacy and has been repeatedly demonstrated to be a predictor of superior outcome in patients with squamous cell carcinomas of the head and neck.18-20 Whether this correlation between objective tumor re­s­ponse and survival relates to drug efficacy or to patient and tumor biology is often challenging to distinguish. The subjectivity and inherent inter observer variability in physical exami­nation findings and imaging study inter­ pretation have necessitated the standardization of re­s­ po­nse criteria for reporting in clinical trial results. For the majority of solid tumors including head and neck cancers, the Response Evaluation Criteria in Solid Tumors definitions for complete, partial, stable, and progressive disease are employed in describing responses to systemic therapy.21 A relatively new endpoint in determining drug activity is the concept of “clinical benefit”, the sum of the rates of objective responses and stable (nonprogressive) disease. This endpoint holds particular relevance in the era of targeted agents, which, when used as single agents, often halt disease growth but generally produce low rates of objective tumor shrinkage. Contemporary clinical trials describing the activity of targeted agents often report the “clinical benefit” as the outcome of interest. This

48

Head and Neck Surgery

Table 3.1: Commonly used chemotherapy agents in head and neck malignancies

Agents

Class

Mechanism of action

Common adverse effects

Cisplatin Carboplatin Oxaliplatin

Platinum compounds

DNA adduct formation

Nausea Nephro- and neurotoxicity Myelosuppression

Methotrexate

Antifolates

Depletion of intracellular reduced folate required for purine and pyrimidine synthesis

Myelosuppression Gastrointestinal toxicity Renal insufficiency

5-Fluorouracil Capecitabine

Antimetabolites

Depletion of thymidine precursors

Gastrointestinal toxicity Myelosuppression

Paclitaxel Docetaxel

Taxanes

Microtubule stabilization

Hypersensitivity Peripheral neuropathy Myelosuppression

can be misleading, however. Among the more in­dolent malignancies of the head and neck such as differentia­ ted thyroid cancer, or adenoid cystic salivary gland carcinomas, disease progression may take place very slowly over a period of many months. When clinical trials in these diseases report clinical benefit rates, this may only reflect the natural history of the disease. Somewhat unique to the management of head and neck malignancies is the importance of preserving local anatomic structures involved in speech, eating, swallow­ ing, sight, and airway patency. Locoregional disease control and its impact on function and cosmesis are of particular concern to the patient and physician. Provo­ cative data havs been published suggesting that patients may be willing to accept some decrement in the success of curative intent therapy in exchange for preserving functional anatomy in the head and neck.22 Prior to the use of concurrent chemoradiotherapy approaches in squamous cell carcinomas, the standard of care was often surgical ablation. The development of surgical and nonsurgical interventions that successfully avoid radical resection of critical structures (most studied in laryngeal squamous cell carcinomas) hae made organ preservation an important endpoint in the head and neck cancer management.23,24 Some of the more challenging endpoints to measure in this disease group, and arguably some of the most important to patients, are those involving functional outcomes and long-term quality of life. Although feeding tube dependence and the presence of a tracheostomy are easily recorded, these are often gross and imperfect indicators of intact organ function. The repercussions of head and neck cancer treatment encompass a wide spectrum of measures of well-being, which also include

mood, diet, taste, and social integration. An increasing number of validated instruments to measure patientreported quality of life are now available and are being routinely incorporated into clinical trial design.25,26

CHEMOTHERAPY AGENTS There are numerous drugs with demonstrated cytotoxic activity in head and neck malignancies. Some of the earli­ est and most frequently used agents in systemic therapy of head and neck malignancies are the platinum com­ pounds, the antifolate methotrexate, the antimetabolite 5-fluorouracil, and the taxanes (Table 3.1).

Platinum Compounds The most extensively used platinum agent is cisplatin. It is a compound that appears to exert its cytotoxic effects by forming adducts with DNA resulting in disruption of its helical structure and subsequent cell death.27 The major acute toxicities of cisplatin administration are its emeto­ genicity and the potential for renal toxicity. These toxicities are often prevented and managed by aggressive antie­ metic administration and intravenous hydration. Neuro­ toxicity, including ototoxicity, can be a consequence of cumulative exposure to the drug. Carboplatin is an analoe of cisplatin with a more stable chemical structure.28 Eme­ togenicity, nephro- and neurotoxicity are less pronou­ nced than with cisplati ; however, the drug produces more myelosuppression. Oxaliplatin is a newer platinum analog, which has neurotoxicity as its predominant dose-limiting side effect.29 Compared to carboplatin and cisplatin, drug-related ototoxicity and myelosuppression are less common.

Chapter 3: Principles of Medical Oncology

Methotrexate Methotrexate is an antifolate chemotherapy agent first introduced in the 1950s. This drug can be given both orally and parenterally. Its mechanism of action lies in its competitive inhibition of dihydrofolate reductase, an enzyme critical for folate synthesis.30 This ultimately results in the malignant cells’ inability to produce purine and pyrimidine precursors. Methotrexate is renally excreted. The adverse effects of methotrexate range widely and can include a variety of organ system toxicities, depending on the dose and the treatment schedule used. Oral mucositis, diarrhea, myelosuppression, and renal insufficiency from tubular damag, are some of the more common side effects of drug administration.

5-Fluorouracil 5-Fluorouracil is an antimetabolite that acts primarily through inhibition of the enzyme thymidilate synthetase, which catalyzes the conversion of deoxyuridine monopho­ stphate (dUMP) into thymidine monophosphate (dTMP) a critical step in intracellular thymidine production.31 The thymidine deficient cellular environment produced in the presence of the drug results in cell cycle arrest and eventual apoptosis. This drug is deactivated in the liver, and its inactive form is renally excreted. The toxicities observed are typically mucosal (stomatitis, mucositis, diar­rhea) and myelosuppression. 5-Fluorouracil is admi­n­ is­tered intrave­nously, whereae its prodrug capeci­tabine is an orally admi­nistered drug.

Taxanes The taxanes are a group of systemic agents whose mechanism of action is related to the stabilization of the cellular microtubule structure, resulting in mitotic arrest and cell death.32 The earliest taxane introduced in the management of head and neck malignancies was pacli­ taxel, a derivative of the pacific yew tree. Docetaxe is a synthetic counterpart that is also approved for use in head and neck malignancies. Both of these drugs are hepatically metabolized and excreted through the biliary system. The toxicities of this class of agents are predomi­ nantly neurologic (peripheral neuropathy) and myelosuppression.

MOLECULAR TARGETING Spurred by the paradigm shifting success of the drug imatinib, an oral tyrosine kinase inhibitor of the mutant

49

BCR/ABL protein in chronic myelogenous leukemia,33 and trastuzumab, a monoclonal antibody targeting the Her2 receptor in breast cancer,34 there has been tremen­ dous interest in identifying molecular markers and deve­ loping novel therapeutics targeted toward these markers in epithelial malignancies. Targeted agents or biological therapies differ from traditional chemotherapy drugs due to their specificity for one or more molecular markers that are overexpressed, amplified, or mutated in the malignant cell.35 This in theory will result in relative sparing of normal tissues from drug-related toxicities and is consistent with the more favorable side effect profiles of these drugs when compared with traditional chemotherapy. These targeted agents, when used alone in solid tumors, also tend to pro­duce lower rates of objective response than conven­ tional chemotherapeutics and appear to have a cytostatic rather than cytotoxic antitumor effect. Currently avail­ able targeted agents fall into two broad categories, intra­ venously administered monoclonal antibodies and oral tyrosine kinase inhibitors.35 The monoclonal antibodies in clinical use today are typically chimeric, humanized, or fully humanized with their variable regions specific to an epitope directed toward extracellular targets on the malignant cell. The specificity of these antibodies to the target of choice and their clear­ ance by nonrenal or hepatic means, allows them to be better tolerated even when administered in the setting of organ dysfunction. The mechanisms of action of mono­ clonal antibodies are incompletely understood, but they are not believed to be solely related to binding and inhi­ bition of a cellular receptor expressed on the malignant cell surface. Specific host immune factors are also likely involved by either recruitment of cytotoxic cellular immune responses to the target or complement activation. In contrast, the tyrosine kinase inhibitors are a class of small molecule orally bioavailable targeted agents. These drugs modulate enzymes catalyzing the transfer of the terminal phosphate to adenosine triphosphate in tyrosine residues of cellular proteins involved in signal transduction-mediating cellular proliferation, invasion, and immortalization. These drugs can act on extracellular, transmembrane, or intracellular targets and generally exert their inhibitory action on protein kinases by compe­ titive inhibition or by producing a conformational change at the kinase ATP binding site. In squamous cell carcinomas of the head and neck, the EGFR is frequently overexpressed and makes intui­ tive sense to target. Cetuximab, a chimeric monoclonal

50

Head and Neck Surgery

anti­body, which binds to the EGFR and competitively inhi­bits ligand binding, has been the most extensively studied targeted agent in this disease.36 In clinical trials, it produces modest response rates when used as a single agent. How­ever, phase III clinical trials that have investi­ gated cetu­ximab given concurrent with radiation therapy for locally advanced disease, or in combination with chemo­therapy for recurrent/metastatic disease, have demon­ strated survival benefit, and have led to approval of cetuximab for both indications.37 Oral tyrosine kinase inhibitors directed against the EGFR have, to date, not proven as effective.38,39 The identification of molecular targets has also proven successful in the management of advanced thyroid malig­ nancies. The oral drugs vandetanib and cabozantinib, both inhibitors of RET (as well as other targets) have rece­ntly been approved for use in metastatic medullary thyroid carcinoma.40,41 Iodine-refractory-differentiated thyroid cancers have been successfully targeted by sorafenib, a multikinase inhibitor of VEGF and BRAF, and a recently completed large phase III clinical trial demonstrated a progression-free survival benefit from this agent.42 Sali­ vary gland cancer subtypes can overexpress markers such as Her2, c-kit, EGFR, and VEGF. However, clinical trials of targeted agents in this disease have not yet yielded promising results.43-45 Table 3.2 summarizes selec­ ted mole­cular targets of interest in head and neck malig­ na­ncies. Table 3.2: Molecular targets of possible interest in head and neck malignancies

Disease

Molecular marker

Squamous cell carcinoma

EGFR VEGF

Salivary gland carcinoma

Her2 EGFR VEGF C-kit Androgen receptors

Papillary thyroid cancer

RET/PTC BRAF RAS

Follicular thyroid cancer

RAS PAX8/PPAR gamma

Medullary thyroid cancer

RET

(EGFR: Epidermal growth factor receptor; VEGF: Vascular endothelial growth factor).

INTEGRATION OF SYSTEMIC THERAPY INTO CURATIVE INTENT TREATMENT The integration of systemic therapy into curative intent treatment approaches has been extensively studied in locoregionally advanced squamous cell carcinomas of the larynx, hypopharynx, oral cavity, and oropharynx. Table 3.3 provides a summary of the standard nomencla­ ture for multimodality treatment approaches incorpora­ ting systemic therapy. The rationale is to both decrease the risk of systemic metastases, and, based on its known synergism with radiation therapy, improve locoregional control. Numerous clinical trials completed over the past 3 decades have studied the use of chemotherapy prior to, during, or after locoregional therapy. A meta-analysis of these studies revealed that only the concurrent adminis­ tration of chemotherapy with radiation therapy conferred a survival benefit.46,47 The use of chemotherapy prior to locoregional treatment (also referred to as induction or neoadjuvant chemotherapy) decreased the risk of distant metastases without an appre­ciable improvement in loco­ regional control or overall survival. It did, however, appear to have a benefit in organ preservation strategies. Adjuvant single modality postoperative chemotherapy was of no benefit, although postoperative adjuvant concurrent che­ moradiotherapy with single-agent cisplatin conferred a survival advantage in high-risk patients with positive margins of resection or extracapsular nodal extension.48 The use of induction chemotherapy prior to defini­ tive concurrent chemoradiotherapy (termed “sequential therapy or sequential chemoradiotherapy”) has generated some enthusiasm in recent years. The rationale is based on an anticipated improvement in distant metastatic disease control from induction, when it is added to the effective locoregional control achieved by the concurrent treatment. Randomized trials to date, however, have not demons­ trated a benefit from this approach.49,50 Table 3.4 outlines the results of a meta-analysis of clinical trials examining systemic therapy in the induction, concurrent, and adjuvant settings. The applicability of these multimodality treatment approaches to the other less common head and neck cancer malignancies has not yet been established, pri­ marily due to the rarity of these diseases, although multiinstitutional clinical trials are currently ongoing.

Chapter 3: Principles of Medical Oncology

51

Table 3.3: Multimodality treatment approaches incorporating chemotherapy

Nomenclature

Definition

Rationale

Induction chemotherapy

Administration of chemotherapy prior to surgery and/or radiation

Decrease risk of distant metastases Organ preservation

Adjuvant chemotherapy

Administration of chemotherapy after surgery and/or radiation

Decrease risk of distant metastases

Definitive concurrent chemoradiotherapy Simultaneous administration of chemo­ therapy with radiation therapy

Improve locoregional control through radiation sensitization Decrease risk of distant metastases Organ preservation

Adjuvant chemoradiotherapy

Simultaneous administration of chemo­ therapy with radiation therapy after resection

Improve locoregional control through radiation sensitization Decrease risk of distant metastases

Sequential therapy/sequential chemora­ diotherapy

Induction chemotherapy administration prior to definitive concurrent chemora­ diotherapy

Decrease risk of distant metastases Improve locoregional control through radiation sensitization Organ preservation

Table 3.4: Meta-analysis of the effect of chemotherapy timing on overall survival in head and neck squamous cell cancer47

Timing

No. of trials

No. of patients

Hazard ratio (95% confidence interval)

p value

5-year survival benefit

Induction

31

5311

0.96 (0.90–1.02)

NS

2.4 %

Adjuvant

12

2567

1.06 (0.95–1.18)

NS

–1.0%

Concurrent

50

9615

0.81 (0.78–0.86)

 50% of oral squamous cell carcinoma tissues, and the expres­ sion of MAGED4B is associated with both lymph node

64

Head and Neck Surgery

metastasis and poor disease-specific survival.38 Head and neck cell lines that overexpress MAGED4B promote mig­ration in vitro and appear more resistant to apoptosis compared with control cells, sugge­ sting this protein represents a potential therapeutic target in head and neck cancer patients. Where the TAA is known, short specific peptides of that antigen can be introduced as a vaccine. These vaccines have the ability to induce “epitope spreading” whereby killed target cells release new anti­ genic peptides, which are subsequently taken up and processed in antigen-presenting cells, before inducing further cell lysis. A very attractive target in HNSCC is HPV.39 The viral proteins are “foreign” and therefore can be “seen” by the host immune system without the limiting effects of central immunological tolerance that dampens immune response against self-antigens. The viral genes that drive the malignant transformation are mandatory for the cancer cells, meaning that elimination by selective pressure is not possible, and finally, a large body of data is available on the immunological consequences of HPV infection. This has in turn made many tools available for the study of adaptive immune responses to HPV infection and tumorigenesis, offering the opportunity to both study and manipulate human immune outcomes for clinical benefit. Vaccination for the prevention on HPV-driven cancers: Prophylactic HPV-vaccination programs are now in place in North America, Europe, Australia, and most industrial countries. Prophylactic HPV vaccines are based on hollow virus-like particles assembled from recombinant HPV coat proteins. Every subunit of the virus is composed of two proteins molecules, L1 and L2. The vaccination program was developed to reduce cervical cancer and anogenital warts, but in the long term should also reduce HPVdriven head and neck cancer as both the bivalent (Cervarix, marketed by GlaxoSmithKline, Brentford, United Kingdom) and tetravalent vaccines (Gardasil, marketed by Merck, Whitehouse Station, NJ, USA) protect against HPV-16 infection. The prophylactic vaccines are only beneficial if they are administered prior to HPV exposure and are not efficacious at treatment of established infection or malignancy. Vaccination to treat established viral disease, including HPV-driven malignancy: Therapeutic HPV-vaccination programs are now in development and are based on the E6 and E7 oncoprotiens. Different strategies of vaccina­ tion are in development and include both protein and nucleic acid vaccines.40

Interestingly, it has been reported that approximately 30% of HPV-driven head and neck tumors do not express MHC Class I molecules, perhaps as a result of the exp­ ression of E5 and E7 oncoproteins.41 E5 has been shown to retain the heavy chain of MHC Class I molecules in the endoplasmic reticulum, whereas E7 is known for its capacity to repress transcription from the MHC Class I genetic locus. Nonetheless, class I loss appears to be at least in part compensated by re-expression of the mole­ cule through interferon production in the tumor by ada­p­ tive immune cells. In cancers not transformed by an oncogenic virus (i.e. HPV, EBV), the identification of suitable TAA is impor­ tant. Traditionally, this has been achieved by screening recom­binant DNA libraries with cytotoxic T-lymphocytes or analyzing peptides eluted from MHC molecules expressed on tumor cells. More recent strategies to identify antigens use the antibody repertoire in the peripheral blood of cancer patients by recombinant cDNA expres­ sion cloning (SEREX). From head and neck cancer patients, 17 immu­ nogenic antigens were isolated, and further analysis regarding their feasibility as target structures for an immu­notherapy approach is currently underway.42 A novel peptide has recently been identified from a TAA (kinesin family member 20A), which is able to induce tumor-specific T-helper 1(TH1) cells and CD8 T cells.43 Computer algorithms to predict TH1 epitopes containing CD8 T cell epitopes were generated and peripheral blood from head and neck cancer patients was used to study the immunogenicity of identified peptides. KIF20A long pep­ tide was identified containing naturally processed epi­ topes recognized by both CD4 and CD8 T cells. This group demonstrated the presence of KIF20A-specific Th1 cell responses in head and neck cancer patients and suggested the possible utility of KIF20A long peptides for propaga­ tion of both Th1 cells and CD8 T cells in this patient cohort.

Dendritic Cell Vaccine A DC vaccine was the first licensed cancer vaccine. Con­ ceptually, these vaccines are attractive, as DCs are the key and professional antigen-presenting cells for initiating and maintaining immune responses. However, compared with other vaccines, DC vaccines are expensive to produce as they are made new for each patient and use autologous DC as a source of vaccine production. Peripheral circu­ lating monocytes are removed and matured into DCs. They are pulsed with either autologous tumor cells, proteins or specific peptides before being injected back

Chapter 4: Immunobiology and Immunotherapy in Head and Neck Cancer into the patient. Alternatively, the DCs can be fused with irradiated tumor cells by electroporation. In addition, they can have DNA or RNA introduced by recombinant viruses, inactive plasmids or by simple electroporation. With the exception of Sipeuleucel T, DC vaccination has been clinically disappointing and particularly in mela­ noma, randomized data failed to show a benefit over standard of care with chemotherapy (dacarbazine). To date, no standard has emerged to characterize the best strategy for DC vaccination.44 Recently, the presence and persistence of survivinspecific T cells after repeated in vitro stimulation with autologous DCs has been reported in head and neck cancer patients. Survivin is important for the survival and prolife­ration of tumor cells and was therefore thought to be an important target in this patient cohort. However, despite being able to induce survivin-specific T cells in vitro, it was not possible to maintain enriched or cloned survivin-specific T cells for prolonged periods of time in vivo.45

Vectored Vaccines Vectors may be either viral, bacterial or fungal and are used to produce antigenic proteins from the DNA they are carry­ing. The vectors are usually genetically modified so they can no longer cause disease. There are a number of advan­tages of using vectors, including the fact that the vector itself will have an immune response mounted against it, creating an enhanced overall immune response. In addi­tion, they are cheap to produce. However, prior sys­temic immunity can cause resistance, which can be overcome by mucosal immunization. Mucosal vaccina­ tion has been found to induce both mucosal and syste­mic immunity, but systemic vaccination may not induce mucosal immunity. Geneti­ cally recombinant viruses including adenovirus, vaccinia, and avipox have all been used to deliver tumor antigens and cytokines. Reovirus (respiratory enteric orphan virus) is a member of the Reoviridae family, which includes the major human pathogen rotavirus, and is currently being investigated as “Reolysin” in a phase III study as secondline therapy in relapsed/metastatic platinum-refractory head and neck cancer (NCT01166542).46 Reovirus enters all cells, but it can only replicate in those cells with an activated/mutated Ras pathway, thus selectively affecting mutated cells. This oncolytic virus has also been combined with chemotherapy agents (including a platin/taxane doublet) and tested in phase I and II trials.

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Adoptive T-Cell Transfer Adoptive T-cell transfer is immunotherapy based on the adoptive transfer of naturally occurring or genetically engi­neered T cells. Naturally occurring TILs can be iso­ lated after tumor resection and fragmentation, and tumor-specific T cells can be expanded using specific growth factors (i.e. IL-2). T cells with the appropriate T-cell receptor speci­ficity can be selected and expanded, and then adoptively transferred back into the patient. Before the transfer, patients can be prepared by immunodeple­ tion, using either chemotherapy with or without total-body irradiation. EPV-specific TIL cells have been expanded from naso­ pharyngeal cancer biopsies and expanded ex vivo. These expanded cells secreted high levels of TH1 cytokines, but low TH2 cytokines and could recognize autologous EBVtransformed B lymphoblast cell lines, suggesting a poten­ tial method to establish T-cell-based immunothe­rapy in these patients.47 T cells for adoptive transfer can also be genetically engineered in a number of ways: If a patient expresses a TAA that is recognized by an available receptor structure, autologous T cells can be genetically engineered to express the desired receptor. These new receptors can be generated in a variety of ways: (1) if patients have a good antitumor response, T cells can be isolated, and their T-cell receptor cloned and inserted into retroviruses or lentiviruses. These viruses are then used to infect autologous T cells from the patient, which are then transferred back into the patient. (2) Chimeric antigen receptors can be generated using sequences encoding the variable regions of antibodies to encode a single chain, which is genetically engrafted onto the T-cell receptor intracellular domains, which is capable of activating T cells. (3) T-cell receptors can also be iso­ lated from humanized mice, primed to recognize tumor antigens. These mice express human MHC class I or MHC class II molecules and can be immunized with the tumor antigen of interest. Mouse T cells specific for the MHCrestricted epitope of interest can then be isolated, and their T-cell receptor genes can be cloned into recombinant vectors that can be used to genetically engineer autologous T cells from the patient.

Small Molecule Modulators and Adjuvants As discussed above, vaccination with TAAs alone is insuf­ ficient to elicit a potent immune response. Nonspecific

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immunotherapies and adjuvants are agents that stimulate the immune system to improve immune efficacy and ideally skew the immune response to a type 1 response.48 They are either given in conjunction with other immuno­ therapies or as stand-alone treatments. A wide range of mechanisms have been exploited, including depot action resulting in a slow release of antigen and stimulation of local inflammation to enhanced recruitment of DCs to the injection site. Other adjuvants enable antigens to be delivered into the cytosol, promoting cross-priming (pre­ sentation via MHC class I and II simultaneously) and mimicking a danger signal.7 Examples include cytokines (IL-2, IFN-α, granulocyte-macrophage colony-stimulat­ ing factor, Bacille Calmette-Guérin) and thalidomide and blo­ ckade of signaling molecules including p110δ PI 3-kinase. Lapatinib, a dual tyrosine kinase inhibitor (TKI) tar­ geting EGFR and ErbB2/HER2, has been tested in a phase II setting in patients with locally advanced HNSCC treated with primary chemoradiotherapy (NCT00387127; Fig. 4.8). TKIs have the advantage over mAbs of oral bioavailability and the potential to inhibit more than one member of the ErbB family, therefore potentially addressing a mechanism of resistance to EGFR inhibition. The addition of lapatinib was shown to improve both complete remission rate and progression-free survival in p16-negative patients, although neither were statistically significant. Lapatinib is currently in phase III trials with chemoradiotherapy in patients with high-risk features after surgical treatment of stage III/IV head and neck cancer (NCT00424255).49

Improving Immunotherapy Outcomes Patient selection will be central to good immunotherapy outcomes. Patients without a fully competent immune system are likely to benefit from immune modulation, prior to immunotherapy, to maximize the immunotherapy effect. This may take the form of intense dietary supple­ mentation, as the link between nutritional status and immune competence is well established.50 In addition, choosing the “right” patient for immuno­ therapy will be crucial to maximize the potential benefit that this therapy offers. Accurate molecular and immuno­ logical “staging” will be central to provide appropriate “personalized” therapy.

REFERENCES 1. D'Souza G, Kreimer AR, Viscidi R, et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med. 2007;356:1944-56. 2. Burnet FM. Immunological factors in the process of carcinogenesis. Br Med Bull. 1964;20:154-8. 3. Ward MJ, Thirdborough SM, Mellows T, et al. Tumourinfiltrating lymphocytes predict for outcome in HPV-positive oropharyngeal cancer. Br J Cancer. 2014; 110(2):489-500. 4. Boshoff C, Weiss R. AIDS related malignancies. Nat Rev Cancer. 2002;2:373-82. 5. Sheil AG. Cancer after transplantation. World J Surg. 1986; 10:389-96. 6. Vesely MD, Schreiber RD. Cancer immunoediting: antigens, mechanisms, and implications to cancer immunotherapy. Ann N Y Acad Sci. 2013;1284:1-5. 7. Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol. 1994; 12:991-1045. 8. Smyth MJ, Godfrey DI, Trapani JA. A fresh look at tumor immunosurveillance and immunotherapy. Nature Immu­ nol. 2001;2:293-9. 9. Ikeda H, Old LJ, Schreiber RD. The roles of IFN- in protection against tumor development and cancer immunoediting. Cytokine Growth Factor Rev. 2002;13:95-109. 10. Belardelli F, Ferrantini M. Cytokines as a link between innate and adaptive antitumor immunity. Trends Immunol. 2002;23(4):201-8. 11. Banerjee A, Vasanthakumar A, Grigoriadis G. Modulating T regulatory cells in cancer: how close are we? Immunol Cell Biol. 2013;91(5):340-9. 12. Kreimer AR, Johansson M, Waterboer T, et al. Evaluation of human papillomavirus antibodies and risk of subse­ quent head and neck cancer. J Clin Oncol. 2013;31(21): 2708-15. 13. Liang C, Marsit CJ, McClean MD, et al. Biomarkers of HPV in head and neck squamous cell carcinoma. Cancer Res. 2012;72(19):5004-13. 14. Wherry EJ. T cell exhaustion. Nat Immunol. 2011;12(6):492-9. 15. Jonuleit H, Schmitt E. The regulatory T-cell family: distinct subsets and their interrelations. J Immunol. 2003;171 (12): 6323-7. 16. Wing K, Yamaguchi T, Sakaguchi S. Cell-autonomous and -non-autonomous roles of CTLA-4 in immune regulation. Trends Immunol. 2011;32(9):428-33. 17. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009;9(3):162-74. 18. Beachler DC, D’souza G. Oral human papillomavirus infection and head and neck cancers in HIV-infected individuals. Curr Opin Oncol. 2013;25(5):503-10. 19. Deeb R, Sharma S, Mahan M, et al. Head and neck cancer in transplant recipients. Laryngoscope. 2012;122(7):1566-9. 20. Schaefer C, Kim GG, Albers A, et al. Characteristics of CD4+CD25+ regulatory T cells in the peripheral circulation of patients with head and neck cancer.Br J Cancer. 2005;92 (5):913-20.

Chapter 4: Immunobiology and Immunotherapy in Head and Neck Cancer 21. Okita R, Saeki T, Takashima S, et al. CD4+ CD25+ regu­ latory T cells in the peripheral blood of patients with breast cancer and non-small cell lung cancer. Oncol Rep. 2005;14(5):1269-73. 22. Bron L, Jandus C, Andrejevic-Blant S, et al. Prognostic value of arginase-II expression and regulatory T-cell infiltration in head and neck squamous cell carcinoma. Int J Cancer. 2013;132(3):E85-93. 23. Chikamatsu K, Sakakura K, Toyoda M, et al. Immuno­ suppressive activity of CD14+ HLA-DR- cells in squamous cell carcinoma of the head and neck. Cancer Sci. 2012;103 (6):976-83. 24. Young MR, Wright MA, Pandit R. Myeloid differentiation treatment to diminish the presence of immune-suppressive CD34+ cells within human head and neck squamous cell carcinomas. J Immunol. 1997;159(2):990-6. 25. Marsh D, Suchak K, Moutasim KA, et al. Stromal features are predictive of disease mortality in oral cancer patients. J Pathol. 2011;223 (4):470-81. 26. Doorbar J, Quint W, Banks L, et al. The biology and lifecycle of human papillomaviruses. Vaccine. 2012;30(Suppl 5): F55-70. 27. Takeda K, Okumura K, Smyth MJ. Combination antibodybased cancer immunotherapy. Cancer Sci. 2007;98:1297-302. 28. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517-26. 29. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443-54. 30. Drew M. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12, 252-64. 31. Hodi F, O’Day S, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. New Engl J Med. 2010;363(8):711-23. 32. Rech AJ, Mick R, Martin S, et al. CD25 blockade depletes and selectively reprograms regulatory T cells in concert with immunotherapy in cancer patients. Sci Transl Med. 2012;4(134):134ra62. 33. Langer CJ. Targeted therapy in head and neck cancer: state of the art 2007 and review of clinical applications. Cancer. 2008;112:2635-45. 34. Marur S, Forastiere AA. Head and neck cancer: changing epidemiology, diagnosis, and treatment. Mayo Clin Proc. 2008;83:489-501. 35. Dreier A, Barth S, Goswami A, et al. Cetuximab induces mitochondrial translocalization of EGFRvIII, but not EGFR: involvement of mitochondria in tumor drug resistance? Tumour Biol. 2011;11:11. 36. Harris M, Wang XG, Jiang Z, et al. Combined treatment of the experimental human papilloma virus-16-positive cervical and head and neck cancers with cisplatin and radioimmunotherapy targeting viral E6 oncoprotein. Br J Cancer. 2013;108(4):859-65. 37. Aly HA. Cancer therapy and vaccination. J Immunol Methods. 2012;382(1-2):1-23.

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38. Chong CE, Lim KP, Gan CP, et al. Over-expression of MAGED4B increases cell migration and growth in oral squamous cell carcinoma and is associated with poor disease outcome. Cancer Lett. 2012;321(1):18-26. 39. Morrow MP, Yan J, Sardesai NY. Human papillomavirus therapeutic vaccines: targeting viral antigens as immuno­ therapy for precancerous disease and cancer. Expert Rev Vaccines. 2013;12(3):271-83. 40. Bagarazzi ML, Yan J, Morrow MP, et al. Immunotherapy against HPV16/18 generates potent TH1 and cytotoxic cellular immune responses. Sci Transl Med. 2012;4(155): 155ra138. 41. Näsman A, Andersson E, Nordfors C, et al. MHC class I expression in HPV positive and negative tonsillar squamous cell carcinoma in correlation to clinical outcome. Int J Cancer. 2013;132:72-81. 42. Heubeck B, Wendler O, Bumm K, et al. Tumor-associa­ ted antigenic pattern in squamous cell carcinomas of the head and neck–analysed by SEREX. Eur J Cancer. 2013; 49(4):e1-7. 43. Tomita Y, Yuno A, Tsukamoto H, et al. Identification of promiscuous KIF20A long peptides bearing both CD4+ and CD8+ T-cell epitopes: KIF20A-specific CD4+ T-cell immunity in patients with malignant tumor. Clin Cancer Res. 2013;19(16):4508-20. 44. Schadendorf D, Ugurel S, Schuler-Thurner B, et al. Dacarbazine (DTIC) versus vaccination with autologous peptide-pulsed dendritic cells (DC) in first-line treatment of patients with metastatic melanoma: a randomized phase III trial of the DC study group of the DeCOG. Ann Oncol. 2006;17(4):563-70. 45. Turksma AW, Bontkes HJ, Ruizendaal JJ, et al. Exploring dendritic cell based vaccines targeting survivin for the treatment of head and neck cancer patients. J Transl Med. 2013;11:152. doi: 10.1186/1479-5876-11-152. 46. Kyula JN, Roulstone V, Karapanagiotou EM, el al. Oncolytic reovirus type 3 (Dearing) as a novel therapy in head and neck cancer. Expert Opin Biol Ther. 2012;12(12):1669-78. doi: 10.1517/14712598.2012.745507. 47. He J, Tang XF, Chen QY, et al. Ex vivo expansion of tumorinfiltrating lymphocytes from nasopharyngeal carcinoma patients for adoptive immunotherapy. Chin J Cancer. 2012;31(6):287-94. 48. Dredge K, Marriott JB, Todryk SM, et al. Adjuvants and the promotion of Th1-type cytokines in tumour immunotherapy. Cancer Immunol Immunother. 2002;51 (10): 521-31. 49. Harrington K, Berrier A, Robinson M, et al. Randomised phase II study of oral lapatinib combined with chemo­ radiotherapy in patients with advanced squamous cell carcinoma of the head and neck: rationale for future randomised trials in human papilloma virus-negative disease. Eur J Cancer. 2013;49(7):1609-18. 50. Calder PC, Jackson AA. Undernutrition, infection and immune function. Nutr Res Rev. 2000;13(1):3-29.

CHAPTER Head and Neck Imaging

5

Laurent Létourneau-Guillon, Michael WK Chan, Eugene Yu

INTRODUCTION Contemporary treatment of the head and neck cancer patient requires a multidisciplinary team approach that involves surgeons, radiation and medical oncologists, pathologists, and radiologists. The role of medical imaging is to provide information that is difficult to assess via history and physical examination. The clinician is able to assess the superficial components of a tumor mass while imaging provides information relating to submucosal spread— particularly into adjacent critical bony and neurovascular structures – as well as identifying the presence of perineural tumor spread (PTS). These factors can significantly influ­ ence the staging, prognosis, and treatment options for the patient. This chapter provides an introductory overview of the main subsites of the extracranial head and neck with emphasis on the radiologic anatomy as well as highlighting key upstaging features of cancer involving each region.

IMAGING MODALITIES Head and neck pathologies can be evaluated using the whole spectrum of current imaging modalities from ultra­ sound (US) to magnetic resonance imaging (MRI). Since each modality has specific strengths and weaknesses, a thorough evaluation requires the complementary use of different imaging modalities (Figs. 5.1A to G). In many instances, tumor evaluation has already been performed clinically, often by endoscopy, before the patient is first imaged. Imaging is used to determine the lesion’s relation­ ship to the surrounding structures, the status of sub­ mucosal, deep, orbital or intracranial extension, as well the presence of nodal or distant metastasis.

Radiography The current use of plain films is generally restricted to the evaluation of acute airway processes such as epiglottis or croup (generally in the pediatric population), gross trauma, or foreign body detection [although computed tomography (CT) has much higher sensitivity for laryngeal fracture or foreign body detection]. Only barium swallow still has a role in oncology by allowing the detection of postoperative fistula or functional swallowing problems secondary to surgery or radiation therapy.

Ultrasound Ultrasound is a relatively inexpensive, widely available modality that provides exquisite detail of superficial lesions due to the high spatial resolution provided by high-frequency probes. It can also provide information regarding blood flow and allows fast and safe guidance for percutaneous biopsies. The main drawbacks are the high interobserver variability, which necessitates experienced imagers, lack of penetrability for deep, calcified or aircontaining structures, and the time-consuming nature of its use. US is especially useful in the evaluation of the thyroid, parotid, and submandibular glands, as well as neck adenopathy. US-guided fine-needle aspiration (FNA) can prove very useful in determining the nature of indeter­ minate nodes in the oncologic setting. FNA-guided biopsy in the head and neck is fast, extremely safe, and very well tolerated, but it yields nondiagnostic material in up to 10–15%. Core-needle biopsy involves a slightly higher risk of complications such as hematoma formation, but

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A

B

C

D

E

F

Figs. 5.1A to F: This 53-year-old woman was assessed for a slowly growing right neck mass. Axial and coronal images from a contrastenhanced computed tomography revealed a well-defined, fat containing, mass in right level IIB (arrows 5.1A). The initial differential diagnosis included a venous vascular malformation or a liposarcoma given the mixed solid and fat content. Further assessment with magnetic resonance imaging (MRI) was performed including axial T1-weighted (C), axial T2-weighted (D), and postgadolinium axial T1-weighted with fat saturation (E). In this particular case, MRI was not able to refine the differential diagnosis. (F) Finally, ultrasound with color Doppler interrogation revealed a heterogeneous mass (arrows). The lack of compressibility and lack of venous flow on pulsed Doppler (not shown) were against a venous vascular malformation.

Chapter 5: Head and Neck Imaging

G it is generally well tolerated and offers a less invasive alterna­tive to open biopsy or excision. Core needle biopsy delivers tissue samples with preserved archi­tecture, which increases the overall diagnostic yield of the procedure. In the largest series, no major hemorrhage, death, nerve injury, or infections have been reported.1 Seeding of the needle tract is exceedingly rare, with an incidence below 1%. Seeding risk depends on the nature of the primary tumor (higher for sarcomas), caliber of the biopsy needle, and number of biopsy passes.

Computed Tomography Computed tomography is by far the most commonly used technique to image the head and neck. Compared with the MRI, it is relatively inexpensive, widely available, time efficient, less prone to motion artifacts, and reproducible. It is also more sensitive to bony detail and better at asses­ sing the cervical lymph nodes. CT is generally the sole imaging modality used to assess laryngeal and hypo­ pharyngeal cancer, as well as oral cavity and oropharyngeal cancer, although some centers may also use MRI in some situations. Current multidetector CT scanners allow high-quality multiplanar reformations in sagittal, coronal or oblique planes. The addition of angled acquisitions or puffed cheek acquisitions can help overcome dental artifacts, which may impair the visualization of the oral cavity and oropharynx in some patients. Protocols differ from one institution to another, but generally approximately 100 mL of iodinated contrast is given intravenously and acquisition is performed following a variable delay (most often at least 80 seconds, although delayed scanning of

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Fig. 5.1G: After discussion with the referring physician, an 18-gauge core needle biopsy (arrowheads) was performed. Since there was a possibility of sarcoma, the skin entry site was marked and the sternocleidomastoid muscle (asterisks) carefully avoided given the theoretical higher risk of tumor seeding along the biopsy tract in sarcomas. The pathologist could not make a definite diagnosis after core biopsy. The final pathology after tumor excision revealed a fat-forming solitary fibrous tumor, an exceedingly rare entity.

up to 3–5 minutes is performed in some institutions). Delayed imaging after contrast injection is thought to provide better tumor enhancement and delineation from surrounding normal soft tissue structures. Dynamic maneuvers may allow better visualization of certain structures. A prolonged phonation (e.g. “iii”) results in better distension of the laryngeal ventricles, slight disten­ sion of the pyriform sinuses, and better delineation of the aryepiglottic folds while allowing assessment of ary­ tenoid mobility. A modified Valsalva maneuver (blowing air against closed lips while using a puffed cheek techni­ que) produces dilation of the hypopharynx and allows optimal visualization of the pyriform sinuses and post­ cricoid region. A puffed cheek technique also renders better visualization of the buccal and gingivobuccal sulci mucosa.

Magnetic Resonance Imaging The MRI has better soft tissue contrast resolution than CT, does not involve the use of radiation, and is well suited for local extent of disease. It is also the modality of choice in the evaluation of perineural spread and intracranial extension of neoplastic processes. Some of the drawbacks related to MRI include the potential for claustrophobia, susceptibility to motion and metal artifacts, long imaging time, cost, and availability. Often, CT is used in conjun­ ction with MRI for locoregional staging since both modalities are often complementary. In general, MRI is most often used to resolve indeterminate findings on CT (e.g. laryngeal cartilage invasion or intracranial extension) and to evaluate nasopharyngeal, sinonasal, parotid, or submandibular gland lesions.

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Imaging sequences usually include a combination of T1 and T2-weighted sequences and postgadolinium T1 imaging. Generally, T1 sequences provide high-resolution detail of soft tissue anatomy. It also allows assessment of the normal hyperintense fatty bone marrow, and depicts hyperintense subacute blood degradation products or proteinaceous secretions as well as occasional melanin content of melanocytic tumors. T1 series also provide good contrast with the normal fatty background of the head and neck region, which is useful in assessing tumor margins and disruption of normal structure such as the pterygopalatine fossa (PPF). The T2 sequences will depict inflammatory changes (edema, fluid collections, sinonasal secretions, and some tumors) as having hyperintense signal. As routine T2 sequences will also render fat hyperintense, the addition of a fat saturation or inversion recovery technique (e.g. short tau inversion recovery [STIR], spectral pre-saturation with inversion recovery [SPIR], spectral adiabatic inversion recovery [SPAIR]) may be used to render fatty tissues hypointense and thus increase the conspicuity of pathologic processes. Post-gadolinium T1 sequences provide further infor­ mation on the nature of mass lesions (e.g. distinction of solid vs cystic lesions). Again, the use of fat saturation allows distinction of enhancement from a background of normal fat hyperintensity. Advanced imaging techniques include diffusionweighted imaging (DWI), perfusion and spectroscopy. DWI renders information about the movement of water molecules in tissue. Generally, malignant tumors have a higher cellular density and lower cytoplasm to nucleus ratio, which, in turn, decreases the volume of the extra and intracellular compartments. This results in restriction of the motion of the water molecules and is depicted as hyperintensity on DWI sequences and hypointense on apparent diffusion coefficient (ADC) maps. Entities generally associated with restricted diffusion include lymphoma, high-grade tumors, and abscesses (due to increased viscosity of the purulent exudate). Perfusion MRI usually is performed using a T1 techni­ que [so called dynamic contrast enhanced perfusion (DCE)]. Semiquantitative assessment of the perfusion curves can provide additional tissue characterization but is currently in its infancy.

Positron Emission Tomography Positron emission tomography (PET) evaluates the biodistribution of positronemitting radiopharmaceuticals.

PET can use a variety of biomarkers, but the most fre­­ quently used in clinical practice is fluorine-18-labeled 2-fluoro-2-deoxy-D-glucose (18F-FDG). Compared with CT and MRI, PET suffers from lower spatial resolution (approximately 7 mm), but it will probably decrease in the future with further technical developments. However, physical limits imposed by the motion of positron until annihilation and residual momentum of the positron– electron pair limit to a certain extent the potential increase in spatial resolution. Nowadays, most PET examinations are performed in conjunction with CT (PET-CT), which allows better anatomical mapping of tracer uptake. The physiological basis of PET imaging is based upon the higher rate of glucose metabolism in cancer cells compared with nonmalignant tissue. Fluorodeoxyglucose (FDG) uptake by malignant cells is mainly related to the number of viable malignant cells, which can lead to falsenegative results in necrotic tumors. Some benign tumors can also show significant FDG uptake (e.g. Warthin’s tumors of the parotid gland). In addition, inflammatory processes may exhibit an increased FDG uptake, which can result in false-positive studies. This is of particular relevance in post-treatment surveillance in which signi­ ficant FDG uptake can be seen up to 8–12 weeks after radiation therapy. Normal tissues can show physiological uptake in the head and neck region such as salivary glands, lymphoid tissues, muscles, and brown fat. In laryngeal carcinoma staging, muscular activity related to a patient speaking can cause FDG uptake within the true cord and mimic tumor. PET is particularly useful for the detection of adenopathy unless metastatic nodes are purely necrotic or below the limited spatial resolution of PET scanners.

PARANASAL SINUSES AND NASAL CAVITY Anatomy The paranasal sinuses are air filled spaces formed by the invagination of nasal mucosa into the lateral nasal wall, as well as the frontal, ethmoid, maxilla, and sphenoid bones during fetal development. They include four-paired sinuses: frontal, ethmoidal, sphenoidal, and maxillary. The anterior ostiomeatal unit (OMU) drains the anterior sinuses—including the frontal, maxillary, and anterior ethmoidal sinuses—whereas the sphenoethmoidal recess, also known as the posterior OMU, drains the posterior sinuses – posterior ethmoidal and sphenoid sinuses. The anterior OMU consists of the frontal recess, maxillary

Chapter 5: Head and Neck Imaging

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Fig. 5.2: Coronal computed tomography image showing the components of the ostiomeatal unit. Maxillary sinus osium (asterisk). Infundibulum (elongated shaded green), anterior ethmoid air cells (shaded blue), frontal recess (double arrows), hiatus semilunaris (blue triangle).

Fig. 5.3: Coronal magnetic resonance imaging showing the anatomy in the region of the sphenoid sinus (Sph). Pituitary gland (asterisk).

sinus ostium, ethmoid infundibulum, hiatus semilunaris, middle meatus, and anterior ethmoidal air cells (Fig. 5.2). The frontal sinus, located anterior to the ethmoidal sinuses, is a funnel-shaped sinus that shows marked variation between individuals. A central septum usually divides the sinus into two parts. The frontal recess drains the frontal sinus inferiorly into either the middle meatus or ethmoid infundibulum, depending on the superior attachment of the uncinate process. This recess is bound by the agger nasi air cells (ANC) anteriorly and inferiorly, the ethmoidal bulla posteriorly, the lamina papyracea laterally, and the lateral wall of the olfactory fossa and the middle turbinate medially. There are also a number of accessory air cells in the frontal sinus region exhibiting varying degrees of pneumatization between individuals. These include the ANC (located anterior to the vertical attachment of the middle turbinate to the skull base) and frontoethmoidal (Kuhn) cells (generally located superior to the ANC and may extend into the frontal sinus). The ethmoid sinus is composed of numerous small air cells and has the greatest anatomic variation among the paranasal sinuses. The roof of the ethmoid sinuses is formed by the fovea ethmoidalis and cribriform plate. The lateral wall is formed by the lamina papyracea. The sinus is divided into two groups by the basal lamellae of the middle turbinate: the anterior ethmoid air cells (which drain into the infundibulum of the middle meatus) and the posterior ethmoid air cells (which drain into the superior meatus). The anterior ethmoid air cells include

the ANC, ethmoid bulla, concha bullosa, and infraorbital (Haller) air cells. The posterior ethmoid air cells include the sphenoethmoidal air cells (Onodi cell). The sphenoid sinus is located in the body of the sphenoid bone posterior to the ethmoid sinus. A septum usually divides the sinus into two parts, but the sinus has a variable anatomy. It drains through the sphenoid sinus ostium in the anterior wall, which communicates with the sphenoethmoidal recess and the posterior portion of the superior meatus. The sphenoethmoid recess is located lateral to the nasal septum. A number of important structures are located around the sphenoid sinus, includ­ ing the carotid artery laterally, the pituitary gland and optic nerves superiorly, the cavernous sinus laterally, and the vidian canal inferolaterally (Fig. 5.3). The carotid artery may bulge into the sinus with or without bony dehiscence. The maxillary sinuses are a pair of pyramidal-shaped cavities representing the largest of the paranasal sinuses. Located in the maxilla, its medial wall is formed by the lateral wall of the nasal cavity, its floor by the maxillary alveolar process, and its roof by the orbital floor. The anterior wall, which corresponds to the facial surface of the superior maxilla, houses the anterior superior alveolar nerve canal. This canal contains neurovascular structures that emerge from the infraorbital foramen superiorly to supply the anterior teeth inferiorly. The posterior wall is formed by the infratemporal surface of the maxilla and separates the sinus from the pterygoid plates, ptery­ gomaxillary fissure, and infratemporal fossa. The sinus

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Fig. 5.4: Coronal T2-weighted image shows a low signal tumor mass within the right and left nasoethmoid region. The very high T2 signal contents in the right maxillary and right frontal sinuses represent retained secretions.

Fig. 5.5: Axial T1-weighted-enhanced magnetic resonance imaging shows a large enhancing mass in the ethmoid region. There is lateral extension into the left orbital apex (arrow). There is mass effect upon the left medial rectus muscle and proptosis. There is also contiguous extension posteriorly into the sphenoid sinus.

drains through the maxillary sinus ostium into the infun­ dibulum and drains through the hiatus semilunaris into the middle meatus (Fig. 5.2).

scans are typically the initial imaging modality of choice to evaluate the paranasal sinuses. Although CT scans provide superior osseous detail for examining bony erosion, MRI has superior soft tissue resolution and ability to evaluate for the extent of tumor infiltration, including bone marrow involvement, orbital and intracranial exten­ sion, and perineural spread. The highest diagnostic accu­ racy is achieved when both modalities are used. Imaging features suggestive of malignancy include unilateral sinus disease, bone destruction, the presence of an extensive soft tissue mass, tumor necrosis, and lymphadenopathy. On CT, paranasal sinus SCC appears as a hyperdense, inhomogeneous soft tissue mass that often erodes through the sinus wall and infiltrates adjacent structures. On MRI, paranasal sinus SCC has intermediate to low signal intensity on both T1-weigthed and T2-weighted images, unlike normal sinus mucosa and secretions, which tend to have higher T2-weighted signal intensities (Fig. 5.4). Heterogeneity is seen secondary to hemorrhage and necrosis, which is more common in larger tumors. With contrast administration, solid components of the tumor will show mild enhancement on CT and MRI (Fig. 5.5). Osseous erosion is seen in up to 80% of cases, and may be visualized on CT as a breach of the continuity of the cortical bone.7 On MRI, replacement of the normally hyperintense signal of the bone marrow with the inter­ mediate signal intensity suggests the presence of tumor infiltration.

Malignancy Malignancies arising in the paranasal sinuses are uncom­ mon compared with other head and neck sites, accounting for  180° to 270°. It has impor­tant implications for treatment as it often precludes surgical resection (Fig. 5.65).

Chapter 5: Head and Neck Imaging

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The goals of post therapy and surveillance imaging of a patient with head and neck cancer are many fold and include: evaluation of treatment response after surgery, radiation therapy and/or chemotherapy; the early dete­ ction of recurrence tumor; detection of new primary aero­ digestive tract malignancy and distant metastases; and the assessment of post therapy related complications. Routine scheduled history and physical examination, as well as patient initiated follow up due to the develop­ ment of new symptoms or complaints are the foundation for patient care in the post therapy setting. Imaging also has an important role in this setting, although there is no absolute, universally accepted consensus regarding the appropriate use of imaging.75 The National Comprehensive Cancer Network guidelines76 recommend post treatment baseline imaging of the primary (and neck if treated) within 6 months of treatment. It also states that imaging is recommended for T3–4 or N2–3 disease only for cancer of the oropharynx, hypopharynx, glottic larynx, supraglottic larynx, and nasopharynx. It also recommends further reimaging as indicated based on signs/symptoms and is not routinely recommended for asymptomatic patients.





POST-THERAPY AND SURVEILLANCE IMAGING

In most centers, and from the authors’ own experience, the clinician’s own personal preference, experience, and intuition will more commonly guide the timing and imag­ ing modality used in the post therapy setting. Regardless of the variability in post therapy imaging follow up routines, one key important concept is the need to perform a baseline imaging scan at approximately 6–12 weeks after the completion of therapy. The actual imaging modality used will depend on factors such as the clinician’s and radiologists’ preference, the initial stage and extent of disease, the patient’s clinical status, as well as the imaging modalities available. Most cancer centers rely on one or a combination of CT, MRI, and PET CT. At this time (6–10 weeks post therapy), most treatment related inflamma­ tory changes, edema, and tissue distortion will have significantly settled. Also, if a gross total tumor resection has been performed, any localized soft tissue density in the treatment area can more confidently be interpreted as post therapy related distortion and scarring. Imaging beyond the initial baseline study is also im­ portant as post therapy changes related to surgery, and radiation will act to alter and distort the normal anatomy. Tissue edema and fibrosis will hamper the sensitivity of the physical examination. Edema and soft tissue inflammatory changes after radiation therapy will manifest radiologically as haziness and reticular change in the subcutaneous fat and thicken­ ing of the platysma and skin. Swelling of the oropharynx, larynx, and hypopharynx as well as retropharyngeal fluid are also common after radiation (Figs. 5.66A and B). Imaging after neck dissection will vary depending upon the degree of resection (radical vs modified) but typically involves a paucity of posterior cervical region fat as well as an absence of structures such as the sternomas­ toid muscle, internal jugular vein, and submandibular gland (Fig. 5.67). Successfully treated regions of adenopathy will show a decrease in size on CT and MRI. Successfully treated nodes will tend to show a loss of T2 signal, reflecting the presence of fibrosis. A node that has decreased in volume by > 90% is likely to have been sterilized. Successfully radiated mucosal lesions will show a dramatic decrease in volume and often will completely resolve. Large tumors in the tongue base may often drama­ tically decrease in size leaving a focal region of volume loss and in drawing along the tongue surface. Another feature of a successfully treated pharyngeal primary is the

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The presence of nodal enhancement implies increa­ sed vascularity. This can be seen secondary to a variety of infectious or inflammatory processes that can affect the head and neck. Certain neoplasms however can give rise to enhancement within nodal metastases; these include thyroid carcinoma, melanoma, and renal cell carcinoma (Fig. 5.63). In addition, the presence of an increased number of clustered nodes (three or more) located along the drain­ age pathway of a primary tumor may also be a sign of nodal metastases. The PET scans play a role in the evaluation of cervical lymphadenoapthy. Compared with CT, MRI, or US, PET increases the sensitivity and specificity of disease detec­ tion.74 Pretreatment PET scans are particularly useful for upstaging in cases of advanced primary tumors with less nodal disease than expected, for baseline imaging in patients undergoing primary radiotherapy to compare with post treatment imaging, and for patients with inde­ terminate nodes seen on CT or MRI. PET scans also have a role in the detection of the unknown primary tumors and for detecting recurrent disease.

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Figs. 5.66A and B: Axial computed tomography contrast-enhanced images after neck radiation demonstrates marked haziness and stranding within the subcutaneous fat and thickening of the platysma (A). There is also marked swelling throughout the larynx and hypopharynx (B). These features are reflective of edema and inflammatory change.

Fig. 5.67: Axial computed tomography showing typical features after a right neck dissection. There is absence of the right sternomastoid muscle and posterior cervical fat. The right internal jugular vein has been preserved.

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Figs. 5.68A and B: Axial T2-weighted magnetic resonance imaging showing a pretreatment right tonsillar mass as well as ipsilateral level II adenopathy (A). After radiation therapy, the right tonsillar mass has resolved and has been replaced by a linear, band-like region of very low T2 signal corresponding to fibrosis (B).

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Figs. 5.69A and B: Axial computed tomography (CT) image after left parotidectomy (A). A large fasciocutaneous flap has been used to reconstruct the defect. A sagittal CT (B) in a patient after total laryngectomy shows a vertically oriented flap reconstructing a neopharynx. Matured soft tissue flaps demonstrate fatty attenuation or signal on CT and magnetic resonance imaging, respectively.

Fig. 5.70: Axial computed tomography in a patient with flap reconstruction after resection of a right retromolar carcinoma. There is a focal of necrotic tumor along the deep margin of the flap.

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1. Novoa E, Gurtler N, Arnoux A, et al. Role of ultrasound gui­ ded coreneedle biopsy in the assessment of head and neck lesions: a meta analysis and systematic review of the litera­ ture. Head Neck. 2012;34(10):1497 503. Epub Dec 1, 2011. 2. Myers LL, Nussenbaum B, Bradford CR, et al. Paranasal sinus malignancies: an 18 year single institution experience. Laryngoscope. 2002;112(11):1964 9.



REFERENCES



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be considered disease recurrence until proven otherwise (Fig. 5.70). Recurrent tumor typically demonstrates soft tissue attenuation on CT, intermediate signal on T1, and intermediate to mild high signal on T2 sequences with mild enhancement.





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development of a linear or band like region of very low T2 signal in keeping with fibrosis (Figs. 5.68A and B). The appearance of flap reconstructions will vary depending upon the nature and composition of the flap – namely fasciocutaneous, myogenous, osteomyocutaneous, etc. Imaging of such reconstruction in the immediate postoperative phase is rare unless there is a complication. The soft tissue component of matured flaps is that of fat attenuation or signal (Figs. 5.69A and B). Radiographic features of disease recurrence include the redevelopment of a soft tissue mass in the region of the treated primary. The development of a focal ulceration, particularly with focal nodularity or enhancement is also a suspicious finding. The presence of focal nodularity along the margins or within the substance of a flap is to

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3. Mossa-Basha M, Blitz AM. Imaging of the paranasal sinuses. Semin Roentgenol. 2013;48(1):14-3. 4. Turner JH, Reh DD. Incidence and survival in patients with sinonasal cancer: a historical analysis of population-based data. Head Neck. 2012;34(6):877-85. 5. Madani G, Beale TJ, Lund VJ. Imaging of sinonasal tumors. Semin Ultrasound CT MR. 2009;30(1):25-38. 6. Maghami E, Kraus DH. Cancer of the nasal cavity and paranasal sinuses. Expert Rev Anticancer Ther. 2004;4(3): 411-24. 7. Loevner LA, Sonners AI. Imaging of neoplasms of the paranasal sinuses. Magn Reson Imaging Clin N Am. 2002; 10(3):467-93. 8. Raghavan P, Phillips CD. Magnetic resonance imaging of sinonasal malignancies. Top Magn Reson Imaging. 2007; 18(4):259-67. 9. Sklar EM, Pizarro JA. Sinonasal intestinal-type adeno­ carcinoma involvement of the paranasal sinuses. AJNR Am J Neuroradiol. 2003;24(6):1152-5. 10. Bernardo T, Ferreira E, Silva J, et al. Sinonasal adeno-carci­ noma – experience of an oncology center. Int J Otolaryngol Head Neck Surg. 2013;2(1):13-16. 11. Sanghvi S, Patel NR, Patel CR, et al. Sinonasal adenoid cystic carcinoma: Comprehensive analysis of incidence and survival from 1973 to 2009. Laryngoscope. 2013;123(7):1592-7. 12. Michel J, Fakhry N, Santini L, et al. Sinonasal adenoid cystic carcinomas: clinical outcomes and predictive factors. Int J Oral Maxillofac Surg. 2013;42(2):153-7. 13. Yousem DM, Gad K, Tufano RP. Resectability issues with head and neck cancer. AJNR Am J Neuroradiol. 2006;27 (10):2024-36. 14. Gal TJ, Silver N, Huang B. Demographics and treatment trends in sinonasal mucosal melanoma. Laryngoscope. 2011;121(9):2026-33. 15. Chang ET, Adami HO. The enigmatic epidemiology of nasopharyngeal carcinoma. Cancer Epidemiol Biomarkers Prev. 2006;15(10):1765-77. 16. Comoretto M, Balestreri L, Borsatti E, et al. Detection and restaging of residual and/or recurrent nasopharyngeal carci­ noma after chemotherapy and radiation therapy: comparison of MR imaging and FDG PET/CT. Radiology. 2008; 249(1):203-11. 17. Liu T, Xu W, Yan WL, et al. FDG-PET, CT, MRI for diagnosis of local residual or recurrent nasopharyngeal carcinoma, which one is the best? A systematic review. Radiother Oncol. 2007;85(3):327-35. 18. Tabuchi K, Nakayama M, Nishimura B, et al. Early dete­ ction of nasopharyngeal carcinoma. Int J Otolaryngol. 2011; 2011:638058. 19. Kao CH, Shiau YC, Shen YY, et al. Detection of recurrent or persistent nasopharyngeal carcinomas after radiother­ apy with technetium-99m methoxyisobutylisonitrile single photon emission computed tomography and computed tomography: comparison with 18-fluoro-2-deoxyglucose positron emission tomography. Cancer. 2002;94(7):1981-6. 20. Yen RF, Hung RL, Pan MH, et al. 18-Fluoro-2-deoxyglucose positron emission tomography in detecting residual/

recurrent nasopharyngeal carcinomas and comparison with magnetic resonance imaging. Cancer. 2003;98(2):283-7. 21. Yen RF, Hong RL, Tzen KY, et al. Whole-body 18F-FDG PET in recurrent or metastatic nasopharyngeal carcinoma. J Nucl Med. 2005;46(5):770-4. 22. Ng SH, Joseph CT, Chan SC, et al. Clinical usefulness of 18F-FDG PET in nasopharyngeal carcinoma patients with questionable MRI findings for recurrence. J Nucl Med. 2004;45(10):1669-76. 23. Urquhart A, Berg R. Hodgkin’s and non-Hodgkin’s lym­ phoma of the head and neck. Laryngoscope. 2001;111(9): 1565-9. 24. Liu XW, Xie CM, Mo YX, et al. Magnetic resonance imaging features of nasopharyngeal carcinoma and nasopharyngeal non-Hodgkin’s lymphoma: are there differences? Eur J Radiol. 2012;81(6):1146-54. 25. Cho KS, Kang DW, Kim HJ, et al. Differential diagnosis of primary nasopharyngeal lymphoma and nasopharyngeal carcinoma focusing on CT, MRI, and PET/CT. Otolaryngol Head Neck Surg. 2012;146(4):574-8. 26. Pineda-Daboin K, Neto A, Ochoa-Perez V, et al. Nasopha­ ryngeal adenocarcinomas: a clinicopathologic study of 44 cases including immunohistochemical features of 18 papillary phenotypes. Ann Diagn Pathol. 2006;10(4):215-21. 27. Xu T, Li ZM, Gu MF, et al. Primary nasopharyngeal adenoca rcinoma: a review. Asia Pac J Clin Oncol. 2012;8(2):123-31. 28. de Camargo Cancela M, de Souza DL, Curado MP. Inter national incidence of oropharyngeal cancer: a populationbased study. Oral Oncol. 2012;48(6):484-90. 29. Chaturvedi AK, Engels EA, Pfeiffer RM, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol. 2011;29(32):4294-301. 30. Ihloff AS, Petersen C, Hoffmann M, et al. Human papilloma virus in locally advanced stage III/IV squamous cell cancer of the oropharynx and impact on choice of therapy. Oral Oncol. 2010;46(10):705-11. 31. Trotta BM, Pease CS, Rasamny JJ, et al. Oral cavity and oro­pharyngeal squamous cell cancer: key imaging findings for staging and treatment planning. Radiographics. 2011; 31(2):339-54. 32. Fakhry C, Westra WH, Li S, et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst. 2008;100(4):261-9. 33. Ragin CC, Taioli E. Survival of squamous cell carcinoma of the head and neck in relation to human papillomavirus infection: review and meta-analysis. Int J Cancer. 2007; 121(8):1813-20. 34. Wong WL, Sonoda LI, Gharpurhy A, et al. 18F-fluorodeoxyglucose positron emission tomography/computed tomography in the assessment of occult primary head and neck cancers–an audit and review of published studies. Clin Oncol (R Coll Radiol). 2012;24(3):190-5. 35. Lin DT, Cohen SM, Coppit GL, et al. Squamous cell carcinoma of the oropharynx and hypopharynx. Otolaryngol Clin North Am. 2005;38(1):59,74, viii.

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54. Guevara Canales JO, Morales Vadillo R, de Faria PE, et al. Systematic review of lymphoma in oral cavity and maxillofacial region. Acta Odontol Latinoam. 2011;24(3): 245 50. 55. Baugnon KL, Beitler JJ. Pitfalls in the staging of cancer of the laryngeal squamous cell carcinoma. Neuroimaging Clin N Am. 2013;23(1):81 105. Epub Dec 4, 2012. 56. Beitler JJ, Muller S, Grist WJ, et al. Prognostic accuracy of computed tomography findings for patients with laryngeal cancer undergoing laryngectomy. J Clin Oncol. 2010; 28(14):2318 22. Epub Apr 7, 2010. 57. Moubayed SP, Belair M, Saliba J, et al. Prognostic value of cartilage sclerosis in laryngeal cancer treated with primary radiation therapy. Otolaryngol Head Neck Surg. 2012; 147(1):57 62. Epub Feb 24, 2012. 58. Li B, Bobinski M, Gandour Edwards R, Farwell DG, Chen AM. Overstaging of cartilage invasion by multidetector CT scan for laryngeal cancer and its potential effect on the use of organ preservation with chemoradiation. Br J Radiol. 2011;84(997):64 9. Epub Sept 23, 2010. 59. Becker M, Zbaren P, Casselman JW, et al. Neoplastic invasion of laryngeal cartilage: reassessment of criteria for diagnosis at MR imaging. Radiology. 2008;249(2): 551 9. Epub Oct 22, 2008. 60. Hsu WC, Loevner LA, Karpati R, et al. Accuracy of magnetic resonance imaging in predicting absence of fixation of head and neck cancer to the prevertebral space. Head Neck. 2005;27(2):95 100. Epub Jan 1, 2005. 61. Yousem DM, Hatabu H, Hurst RW, et al. Carotid artery invasion by head and neck masses: prediction with MR imaging. Radiology. 1995;195(3):715 20. Epub June 1, 1995. 62. Schmalfuss IM, Mancuso AA, Tart RP. Postcricoid region and cervical esophagus: normal appearance at CT and MR imaging. Radiology. 2000;214(1):237 46. Epub Jan 22, 2000. 63. Weissman JL, Carrau RL. Anterior facial vein and sub mandibular gland together: predicting the histology of submandibular masses with CT or MR imaging. Radiology. 1998;208(2):441 6. Epub July 29, 1998. 64. Patel ND, van Zante A, Eisele DW, et al. Glas tonbury CM. Oncocytoma: the vanishing parotid mass. AJNR Am J Neuroradiol. 2011;32(9):1703 6. Epub July 16, 2011. 65. Raz E, Saba L, Hagiwara M, et al. Parotid gland atrophy in patients with chronic trigeminal nerve denervation. AJNR Am J Neuroradiol. 2013;34(4):860 3. Epub Oct 9, 2012. 66. Som PM, Curtin HD, Mancuso AA. An imaging based classification for the cervical nodes designed as an adjunct to recent clinically based nodal classifications. Arch Otolaryngol Head Neck Surg. 1999;125(4):388 96. 67. Kao J, Lavaf A, Teng MS, et al. Adjuvant radiotherapy and survival for patients with node positive head and neck cancer: an analysis by primary site and nodal stage. Int J Radiat Oncol Biol Phys. 2008;71(2):362 70. 68. Hoang JK, Vanka J, Ludwig BJ, et al. Evaluation of cervical lymph nodes in head and neck cancer with CT and MRI: tips, traps, and a systematic approach. AJR Am J Roentgenol. 2013;200(1):W17 25.



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36. Cohan DM, Popat S, Kaplan SE, et al. Oropharyngeal cancer: current understanding and management. Curr Opin Otolaryngol Head Neck Surg. 2009;17(2):88 94. 37. Stambuk HE, Karimi S, Lee N, et al. Oral cavity and oropha­ rynx tumors. Radiol Clin North Am. 2007;45(1):1 20. 38. Aiken AH, Glastonbury C. Imaging Hodgkin and non Hodgkin lymphoma in the head and neck. Radiol Clin North Am. 2008;46(2):363,78, ix x. 39. Kato H, Kanematsu M, Kawaguchi S, et al. Evaluation of imaging findings differentiating extranodal non Hodgkin’s lymphoma from squamous cell carcinoma in naso and oropharynx. Clin Imag. 2013;37(4):657 63. 40. Johnson NW, Jayasekara P, Amarasinghe AA. Squamous cell carcinoma and precursor lesions of the oral cavity: epidemio­ logy and aetiology. Periodontol 2000. 2011;57(1): 19 37. 41. Petti S. Lifestyle risk factors for oral cancer. Oral Oncol. 2009;45(4 5):340 5. 42. Rohren EM, Turkington TG, Coleman RE. Clinical appli­ cations of PET in oncology. Radiology. 2004;231(2):305 32. 43. Adams S, Baum RP, Stuckensen T, et al. Prospective comparison of 18F FDG PET with conventional imaging modalities (CT, MRI, US) in lymph node staging of head and neck cancer. Eur J Nucl Med. 1998;25(9):1255 60. 44. AAssar OS, Fischbein NJ, Caputo GR, et al. Metastatic head and neck cancer: role and usefulness of FDG PET in locating occult primary tumors. Radiology. 1999;210(1):177 81. 45. Yamamoto Y, Wong TZ, Turkington TG, et al. Head and neck cancer: dedicated FDG PET/CT protocol for detection–phantom and initial clinical studies. Radiology. 2007;244(1):263 72. 46. Aiken AH. Pitfalls in the staging of cancer of oral cavity cancer. Neuroimaging Clin N Am. 2013;23(1):27 45. 47. Eveson JW, Cawson RA. Tumours of the minor (oropha­ ryngeal) salivary glands: a demographic study of 336 cases. J Oral Pathol. 1985;14(6):500 9. 48. Ellis G, Auclair P, Gnepp D. Surgical pathology of the salivary glands. Philadelphia, PA: Saunders; 1991. 49. Seifert G, Miehlke A, Haubrich J, et al. Diseases of the sali­ vary glands: pathology diagnosis treatment facial nerve surgery. Stuttgart: Thieme Publishing; 1986. 50. Beckhardt RN, Weber RS, Zane R, et al. Minor salivary gland tumors of the palate: clinical and pathologic correlates of outcome. Laryngoscope. 1995;105(11):1155 60. 51. Waldron CA, el Mofty SK, Gnepp DR. Tumors of the intraoral minor salivary glands: a demographic and histologic study of 426 cases. Oral Surg Oral Med Oral Pathol. 1988;66(3):323 3. 52. Buchner A, Merrell PW, Carpenter WM. Relative frequency of intraoral minor salivary gland tumors: a study of 380 cases from northern California and comparison to reports from other parts of the world. J Oral Pathol Med. 2007;36(4): 207 14. 53. Epstein JB, Epstein JD, Le ND, et al. Characteristics of oral and paraoral malignant lymphoma: a population based review of 361 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2001;92(5):519 25.

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69. Kaji AV, Mohuchy T, Swartz JD. Imaging of cervical lympha­ denopathy. Semin Ultrasound CT MR. 1997;18(3):220-49. 70. van den Brekel MW, Stel HV, Castelijns JA, et al. Cervical lymph node metastasis: assessment of radiologic criteria. Radiology. 1990;177(2):379-84. 71. Steinkamp HJ, Hosten N, Richter C, et al. Enlarged cervical lymph nodes at helical CT. Radiology. 1994;191(3):795-8. 72. Connor SE, Olliff JF. Imaging of malignant cervical lympha­ denopathy. Dentomaxillofac Radiol. 2000;29(3):133-4. 73. Eisenkraft BL, Som PM. The spectrum of benign and mali­ gnant etiologies of cervical node calcification. AJR Am J Roentgenol. 1999;172(5):1433-7.

74. Kyzas PA, Evangelou E, Denaxa-Kyza D, et al. 18F-fluorodeo­ xyglucose positron emission tomography to evaluate cer­ vical node metastases in patients with head and neck squamous cell carcinoma: a meta-analysis. J Natl Cancer Inst. 2008;100(10):712-20. 75. Liu G, Dierks EJ, Bell RB, et al. Post-therapeutic surveillance schedule for oral cancer: is there agreement? Oral Maxillofac Surg. 2012;16:327-40. 76. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology, head and neck cancers, version 2. Fort Washington, PA, USA: NCCN; 2013: 1-175.

Chapter 6: Sentinel Node Biopsy in Head and Neck Cancer

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CHAPTER

6

Sentinel Node Biopsy in Head and Neck Cancer Stephan K Haerle, Sandro J Stoeckli

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Head and neck cancer represents the fifth most common cancer worldwide. Within the upper aerodigestive tract (UADT), the oral cavity and oropharynx are the most affected subsites.1 Ninety percent of all head and neck malignancies are of squamous cell origin and arise from the surface epithelium of the UADT.2 The estimated annual incidence for oral and oropharyngeal squamous cell carcinoma (OOSCC) is 10.4/100,000, with an annual mortality rate of 2.5/100,000 and an overall 5-year survival of approximately 60%.3 As in other subsites of the head and neck, OOSCC tends to metastasize primarily via the lymphatic vessels to the regional lymph basin and nodes. In this patient group, the presence of cervical lymph node involvement is the single most important factor associated with survival.4 The National Cancer Institute reports that the overall 5-year survival drops from 82% to 53% as a result of regional lymphatic involvement.3 Only 1 out of 10 patients is found to have distant metastases at presentation, with the remainder of patients having stage I/II (33%) or stage III (50%) disease. The marked difference in outcome between the latter two patient groups serves to highlight the significance of detec ting cervical lymph node involvement, both for prognostic and treatment purposes.5 Determining the extent of the disease begins with clinical examination including palpation of the neck. Since the sensitivity of neck palpation as a sole staging modality

is approximately 70%, adjuvant staging techniques are warranted.6,7 Different imaging devices such as ultra sound (US), ultrasound-guided fine needle aspiration cytology (USgFNAC), computed tomography (CT), mag netic resonance imaging (MRI), and recently positron emission tomography with CT (PET/CT) have been studied for accurate neck assessment.8-10 Still, there are ongoing concerns regarding the true sensitivities of these currently available modalities. None is generally considered to be reliable enough to accurately stage the neck as a sole staging tool11,12 and may be related to the lack of consen sus regarding the imaging criteria for nodal involvement. The context of central nodal necrosis and nodal size may be an important consideration for malignancy with still a low specificity and negative predictive value.13-15 Overall, 20–30% of patients with clinically negative (cN0) neck involvement, determined using currently available clinical staging tools, will subsequently be diagnosed with occult neck disease within the cervical lymphatic drainage.16,17 To overcome the problem of false-negative staging, routine neck surgery has been recommended according to the primary tumor characteristics and location. The strongest predictive factor in oral cavity cancer is related to the depth of tumor infiltration.18,19 Yuen et al. proposed that all patients whose tumor harbors a greater risk of 20% sub clinical lymph node involvement should undergo elective neck dissection (END) for staging and treatment.11 The reduction of potential subsequent nodal involvement has been shown to increase the disease-free survival (DFS).20 The downside of this treatment approach is a considerable surgery-related morbidity and the representation of over treatment in approximately 75% of all cN0 patients with ­

OVERVIEW OF ROLE AND INDICATIONS FOR SENTINEL NODE BIOPSY

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early stage OOSCC. Avoiding surgical morbidity is the primary goal of a wait and scan strategy. The disadvan­ tage of this strategy includes the lack of proper his­ topathologic staging and the delayed presentation of lymph node metastases lea­ding to more extensive surgery and an increased need for postoperative adjuvant radio­­ therapy.21 Furthermore, observational trials showed a neck recurrence rate of 4% in patients with stage I/II OOSCC treated with END compared with up to 47% in patients managed by the wait-and-scan concept.22-24 Novel imaging technology such as 18F- Fluorodeoxyglu­ cose (18F-FDG) PET/CT does not improve the neck failure rate using a watchful strategy, and USgFNAC still seems to be the most accurate neck stag­ing tool with a maximum sensitivity of 80–85% in experie­nced hands.8,9,25

THEORY AND BACKGROUND With regard to minimal invasive staging procedures of the cN0 neck and the neck dissection controversies, sentinel node biopsy (SNB) has been introduced in the management of mucosal OOSCC. The concept of using SNB as a staging procedure is not new, with the first appearance in the literature dating back to 1960. It was Gould et al. who first reported on a total parotidectomy with intraoperative frozen section evaluation of a single lymph node used to guide the potential need of an adju­ vant radical neck dissection.26 A few years later, Cabanas described “sentinel node biopsy” in 46 patients suffering from penile squamous cell carcinoma (SCC) with the erroneous belief that the sentinel lymph node (SLN) is in a fixed location in all patients.27 In the same year, Holmes et al. reported on the use of radioactive colloidal gold injections to determine the lymph node drainage basin for skin melanoma.28 The use of vital dye as an injection agent for the visual identification of the SLN was intro­ duced for melanoma and breast cancer a few years later.29,30 In 1993, the handheld gamma probe was proposed by Alex and Krag to improve intraoperative acoustic SLN identification.31 The same authors described the first successful use of SNB in head and neck squamous cell carcinoma 3 years later.32 The combination of blue dye and a radiocolloid mimicking the lymphatic drainage pattern was suggested by Shoaib et al. in 1999.33 It was during the first decade of this century when the concept of SNB was successfully implemented in the staging procedure of cN0 neck for patients with OOSCC. A number of European validation studies performed SNB followed by END as standard of reference and showed

the safety of the procedure establishing high sensitivities for the identification of the true sentinel node and low false negative rates for negative SNB.34-36 This has also been confirmed in a large multi-institutional validation trial from the United States.37 These initial findings were accomplished by the initiation of observational trials with elective neck dissection performed only in cases of a positive SLN. Two European institutional trials were able to show a very low false negative rate for a negative SNB during short-term follow-up,38,39 which was confirmed in long-term follow-up.40,41 A number of subsequent trials and international conference consensus documents have followed with the consequence of meta-analyses and the establishment of joint practice guidelines.42-44 A limitation for SNB has been recognized in primary tumor size. Large tumors are technically demanding and difficult for a throughout surrounding tracer injection. Furthermore, they show a tendency to spread out via multiple lymphatic basins. The current consensus recom­ men­ dations therefore include only early stage tumors clas­sified as T1 or T2.45 Most initial trials were restricted to primary tumors arising from the oral cavity and oro­ pharynx with oral cavity being the most commonly used head and neck subsite. SNB is therefore only considered validated for tumors arising in these two subsites. For the oropharynx, only accessible subsites such as the soft palate and the lateral pharyngeal wall are eligible. There are reports of SNB applied to different head and neck subsites such as the supraglottis or the thyroid; however, the data are still not as profound and validated as in OOSCC. Therefore, more trials need to be completed be­fore considering other subsites as validated for the con­ cept of SNB.46,47 Reviewing the different staging possibilities, SNB is predominantly advocated in T1/2 OOSCC to accurately stage the ipsilateral cN0 neck in the presence of a unila­ teral primary tumor. However, SNB is also indicated to stage both sides of the cN0 neck in cases where the primary tumor is close or crossing the midline or to stage the contralateral cN0 neck in primaries close or crossing the midline presenting with an ipsilateral N-positive neck. With the latter two techniques, a bilateral END can be avoided and potential bilateral morbidity can be dec­ reased. Treatment of the neck by either surgery or radiothe­ rapy is thought to alter the lymphatic drainage pattern, and therefore rendering SNB unreliable; however, a recent study demonstrated encouraging results using SNB in

Chapter 6: Sentinel Node Biopsy in Head and Neck Cancer

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The hypothesis behind SNB is the SLN being the first drain ing lymph node for a tumor of a specific site and all other lymph nodes are only reached subsequently. Therefore, if metastases occur they always first occur in the SLN. The goal is to localize the SLN and to selectively excise it. The principle is to inject a radiolabeled agent, which mimics the lymphatic drainage of tumor cells. The anatomical identification of the SLN is achieved by radiolocalization. The high density of lymph nodes and the unique comple xity of lymphatic pathways in the head and neck area in addition to the close proximity of the SLNs to the primary tumor require sophisticated mapping techniques. For these reasons, radiolocalization is achieved by preoperative lymphoscintigraphy (LS) and the use of an intraoperative handheld gamma probe. The success of this technique with sentinel node detection rates approaching 99% has been abundantly reported in the past. Patients undergo LS up to 24 hours prior to the pro cedure depending on the institutional guidelines and the radiolabeled agent used. Usually, a radiolabeled colloid solution is injected mucosally and submucosally around the tumor either by the nuclear specialist or by the surgeon and expected to drain along the afferent lymphatics to first echelon lymph node(s), where it accumulates. A variety of Technetium (Tc)99m-labeled colloids are commercially available. However, licensing varies between regions, and this frequently restricts the available choices. In some centers, localization of the SN is complemented by preoperative injection of blue dye around the pri mary tumor. The dye enters the lymphatic channels, aiding visualization of both the draining channels and the sentinel nodes. However, this technique is not univer sally accepted in OOSCC. There is a concern that the injection of blue dye might obscure the surgical margins. In addition, it has been abundantly reported that blue dye is unnecessary to ensure excellent sentinel node iden tification rates.



­

­

Imaging and Radiolocalization

Lymphatic mapping is monitored according to institu tional preferences dynamically with a gamma camera in the anteroposterior projection starting immediately after radiocolloid injection. The lymphatic drainage can be observed by the head and neck surgeon at the monitor. When accumulation of the radiotracer in the first echelon node(s) occurs, the dynamic imaging is interrupted and static imaging in the anteroposterior, lateral, and, if needed, anterior oblique view is performed. The location of the SLNs is marked on the patient's skin under radio logic guidance during planar LS. Other more recent technologies for SLN localization include single photon emission CT/CT (SPECT/CT). Pre vious reports using SPECT/CT for SLN in breast cancer found a superiority of SPECT/CT over planar LS.49 The application of SPECT/CT in OOSCC has been reported by several authors allowing the surgeon better topographical orientation and delineation of the SLNs around surroun ding structures; however, with the excellent results by using LS and the intraoperative use of the gamma probe, SPECT/CT is not indispensable for successful SNB (Figs. 6.1A to D).50,51 After imaging, the patient is transferred to the ope rating room, and the images are available to the surgeon in the operating room. Surgical dissection of the SLN is then guided by the preoperative LS and SPECT/CT images, with confirmation by the intraoperative use of a handheld gamma probe. One of the controversies in SNB is the number of SLNs to be dissected. By removing too many lymph nodes, the meaningfulness of the procedure as a minimally invasive procedure becomes questionable. According to the present guidelines, SLNs have to be sepa rately ranked for each level according to their respective tracer uptake ex situ.44 On average, two to three SNs per patient will be found. The radioactivity count should be noted. LNs with a radioactive count greater than five times of the background noise are considered SLNs. At the end of the procedure, the handheld gamma camera should exclude any residual radioactivity in the surgical bed (Fig. 6.2). The overall detection rate of the SLNs by LS or SPECT/CT is between 93–97%, with the addition of the handheld gamma probe the rates are increased up to 95–100%.37-39,51 The next important step for successful application of SNB includes the histopathological workup of the excised SLNs.

the previously treated neck.48 Using SNB in this context, it is potentially possible to assess the individual lympha tic drainage pattern, which may be disturbed and give rise to unexpected localizations of occult metastases. Further validation studies are needed to investigate this principle.

123

Histopathological Workup According to the histopathologic criteria set by Hermanek et al occult lymph node metastases are subdivided in

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Head and Neck Surgery

A

B

C

D

Figs. 6.1A to D: Lymphatic mapping of the sentinel lymph node. A 60-year-old female patient suffering from a right-sided floor of mouth squamous cell carcinoma, (A) shows the coronal lymphoscintigraphy (LS) image with a large uptake at the injection site with two small ipsilateral focal uptakes in level I, and one large focal uptake in the contralateral neck region level III, (B) shows the LS acquisition in the anteroposterior view with the corresponding cross hair in the ipsilateral sentinel nodes, (C) shows the corresponding low-dose computed tomography (CT) scan localizing the uptakes by linked cross hair into the ipsilateral neck level I, (D) shows a fused coronal single photon emission CT/CT image that localizes the small focal uptakes in level I ipsilateral.

isolated tumor cells (4 mm) primary melanoma. Ann Surg Oncol. 1998;5(4):322-8. 74. Zitelli JA, Brown CD, Hanusa BH. Surgical margins for excision of primary cutaneous melanoma. J Am Acad Dermatol. 1997;37(3:Pt 1):t-9.

Chapter 8: Melanoma











95.

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100.







99.





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104.



103.



105.



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106.





Breslow range between 0.76 and 1 mm: a follow-up study of 148 patients. Int J Cancer. 2007;121(3):689-93. Han D, Zager JS, Shyr Y, et al. Clinicopathologic predictors of sentinel lymph node metastasis in thin melanoma. J Clin Oncol. 2013;31(35):4387-93. Balch CM, Buzaid AC, Soong SJ, et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. [Review] [83 refs]. J Clin Oncol. 2001; 19(16):3635-48. Agnese DM, Abdessalam SF, Burak WE Jr, et al. Costeffectiveness of sentinel lymph node biopsy in thin melanomas. Surgery. 2003;134(4):542-7. Morton DL, Thompson JF, Cochran AJ, et al. Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med. 2006;355(13):1307-17. Retsas S. Sentinel node biopsy confers no added protection to patients with melanoma. J R Soc Med. 2007;100(8):391-2. Retsas S. Sentinel-node biopsy in melanoma. N Engl J Med. 2007;356(4):419-21. Gutzmer R, Satzger I, Thoms KM, et al. Sentinel lymph node status is the most important prognostic factor for thick (> or = 4 mm) melanomas. J Dtsch Dermatologischen Ges. 2008;6(3):198-203. Mozzillo N, Pennacchioli E, Gandini S, et al. Sentinel node biopsy in thin and thick melanoma. Ann Surg Oncol. 2013;20(8):2780-6. Oliveira Filho RSd, Silva AMd, Oliveira DAd, et al. Sentinel node biopsy should not be recommended for patients with thick melanoma. Rev Col Bras Cir. 2013;40(2):127-9. Bonnen MD, Ballo MT, Myers JN, et al. Elective radiothe rapy provides regional control for patients with cuta neous melanoma of the head and neck. Cancer. 2004; 100(2):383-9. Shah JP, Kraus DH, Dubner S, et al. Patterns of regional lymph node metastases from cutaneous melanomas of the head and neck. Am J Surg. 1991;162:320-3. Pathak I, O'Brien CJ, Petersen-Schaeffer K, et al. Do nodal metastases from cutaneous melanoma of the head and neck follow a clinically predictable pattern? Head Neck. 2001;23(9):785-90. Grunhagen DJ, Eggermont AM, van Geel AN, Graveland WJ, deWilt JH. Prognostic factors after cervical lymph node dissection for cutaneous melanoma metastases. Mela noma Res. 2005;15(3):179-84. O'Brien CJ, Petersen-Schaefer K, Ruark D, et al. Radical, modified, and selective neck dissection for cutaneous malignant melanoma. Head Neck. 1995;17:232-41. Hamming-Vrieze O, Balm AJ, Heemsbergen WD, et at. Rasch CR. Regional control of melanoma neck node metastasis after selective neck dissection with or without adjuvant radiotherapy. Arch Otolaryngol Head Neck Surg. 2009;135(8):795-800. O'Brien CJ, McNeil EB, McMahon JD, et al. Incidence of cervical node involvement in metastatic cutaneous malignancy involving the parotid gland. Head Neck. 2001;23 (9):744-8. ­





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75. Mohs FE. Microscopically controlled surgery for periorbi tal melanoma: fixed-tissue and fresh-tissue techniques. J Dermatol Surg Oncol. 1985;11(3):284-91. 76. Mohs FE. Fixed-tissue micrographic surgery for melanoma of the ear. Arch Otolaryngol Head Neck Surg. 1988; 114(6):625-31. 77. Bricca GM, Brodland DG, Ren D, et al. Cutaneous head and neck melanoma treated with Mohs micrographic surgery. J Am Acad Dermatol. 2005;52(1):92-100. 78. Zitelli JA, Moy RL, Abell E. The reliability of frozen sections in the evaluation of surgical margins for melanoma. J Am Acad Dermatol. 1991;24(1):102-6. 79. Cascinelli N, Morabito A, Santinami M, et al. Immediate or delayed dissection of regional nodes in patients with melanoma of the trunk: a randomised trial. WHO melanoma programme. Lancet. 1998;351(9105):793-6. 80. Sim FH, Taylor WF, Ivins JC, et al. A prospective randomized study of the efficacy of routine elective lymphadenectomy in management of malignant melanoma. Preliminary results. Cancer. 1978;41(3):948-56. 81. Veronesi U, Adamus J, Bandiera DC, et al. Delayed regional lymph node dissection in stage I melanoma of the skin of the lower extremities. Cancer. 1982;49(11):2420-30. 82. Morton DL, Wen DR, Wong JH, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg. 1992;127(4):392-9. 83. Morton DL, Thompson JF, Essner R, et al. Validation of the accuracy of intraoperative lymphatic mapping and sentinel lymphadenectomy for early-stage melanoma: a multicenter trial. Multicenter Selective Lymphadenectomy Trial Group. Ann Surg. 463;230(4):453-63. 84. Trifiro G, Verrecchia F, Soteldo J, et al. Modification of lymphoscintigraphic sentinel node identification before and after excisional biopsy of primary cutaneous melanoma. Melanoma Res. 2008;18(6):373-7. 85. de Rosa N, Lyman GH, Silbermins D, et al. Sentinel node biopsy for head and neck melanoma a systematic review. Otolaryngol Head Neck Surg. 2011;145(3):375-82. 86. McMasters KM, Reintgen DS, Ross MI, et al. Sentinel lymph node biopsy for melanoma: how many radioactive nodes should be removed? Ann Surg Oncol. 2001;8(3):192-7. 87. Abou-Nukta F, Ariyan S. Sentinel lymph node biopsies in melanoma: how many nodes do we really need? Ann Plast Surg. 2008;60(4):416-9. 88. Warycha MA, Zakrzewski J, Ni Q, et al. Meta-analysis of sentinel lymph node positivity in thin melanoma (1 mm or less). Cancer. 2009;115(4):869-79. 89. Andtbacka RH, Gershenwald JE. Role of sentinel lymph node biopsy in patients with thin melanoma. J Natl Compr Cancer Netw. 2009;7(3):308-17. 90. Thompson JF, Shaw HM. Is sentinel lymph node biopsy appropriate in patients with thin melanomas: too early to tell? Ann Surg Oncol. 2006;13(3):279-81. 91. Starz H, Balda B. Benefit of sentinel lymphadenectomy for patients with nonulcerated cutaneous melanomas in the

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108. Caldwell CB, Spiro RH. The role of parotidectomy in the treatment of cutaneous head and neck melanoma. Am J Surg. 1988;156:318-22. 109. Ang KK, Byers RM, Peters LJ, et al. Regional radiotherapy as adjuvant treatment for head and neck malignant melanoma. Preliminary results. Arch Otolaryngol Head Neck Surg. 1990;116:169-72. 110. Moncrieff MD, Martin R, O'Brien CJ, et al. Adjuvant postoperative radiotherapy to the cervical lymph nodes in cutaneous melanoma: is there any benefit for high-risk patients? Ann Surg Oncol. 2008;15(11):3022-7.

111. Burmeister BH, Henderson MA, Ainslie J, et al. Adjuvant radiotherapy versus observation alone for patients at risk of lymph-node field relapse after therapeutic lymphadenectomy for melanoma: a randomised trial. Lancet Oncol. 2012;13(6):589-97. 112. Verma S, Quirt I, McCready D, et al. Systematic review of systemic adjuvant therapy for patients at high risk for recurrent melanoma. Am Cancer Soc. 2006;106(7): 1431-42. 113. Johnson D, Sosman J. Update on the targeted therapy of melanoma. Curr Treat Options Oncol. 2013;14(2):280-92.

CHAPTER

9

Pathology of Cutaneous Malignancies of the Head and Neck Ayman Al-Habeeb, Karen A Naert, Nadya A Al-Faraidy, Danny Ghazarian

INTRODUCTION Optimal management of cutaneous neoplasms of the head and neck requires accurate diagnoses, for which histopathologic evaluation is essential. These neoplasms may arise from any component of the normal structures of the skin, including the more common epithelial tumors

such as basal and squamous cell carcinoma (SCC), and the potentially lethal melanoma. Rare mesenchymal tumors may also occur at this site. This chapter discus­ ses the basic histologic features of cutaneous malignant tumors of the head and neck, along with ancillary studies that may be used to facilitate the diagnostic process.

PART A: MELANOMA INTRODUCTION

Table 9.1: Risk factors for melanoma

Sun exposure particularly intermittent exposure and sunburn history

The incidence of cutaneous melanoma has been steadily increasing since the mid 1960s in the white population ranging from 3% to 7% annually. Melanoma is the fifth leading cancer in males and the seventh in females in the United States. Despite increasing incidence in the 1970s and 1980s, mortality rates of melanoma have stabilized since the early 1990s in many countries including Australia, United States, and certain European countries, possibly reflecting the effects of early recognition and the diagnosis of the more favorable thin melanomas.1 -

Indoor tanning  

Number of common nevi (> 100) (RR = 6.89) Number of atypical nevi (RR = 6.36 with 5 dysplastic nevi) Family history of melanoma (RR = 1.74) Skin type (I vs IV RR = 2.09) High density of freckles (RR = 2.10) Skin color (fair vs dark; RR = 2.06) Eye color (blue vs dark; RR = 1.47) Hair color (red vs dark; RR = 3.64)

Risk Factors

Biopsy Diagnosis of melanoma starts with clinical suspicion that is confirmed by a biopsy for pathological evaluation.

Immunosuppression/immunodeficiency states Source: References 3–5.

Excisional biopsies with 1–2 mm margins are the most ideal biopsies for suspected melanomas. The excisional biopsy serves both diagnostic and prognostic purposes with evaluation of full melanoma attributes.

There are many risk factors for the development of melanoma. Table 9.1 lists the most common risk factors.

Premalignant and skin cancer lesions (RR = 4.28)

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Head and Neck Surgery

Incisional biopsies are acceptable alternatives for larger lesions. The most important thing to remember is to biopsy the thickest and/or most pigmented part of the lesion to maximize the value of the biopsy and avoid­ ing sampling adjacent normal skin. Shave biopsies are dicouraged as they usually provide little value for either diagnosis or prognostication. The only exception is deep saucerization which is acceptable for superficial lesions. Punch biopsies are useful in small lesions where the whole lesion can be included in the punch in which case they serve as an excisional biopsy. Also they can be valu­ able in large lesions where multiple areas can be biopsied prior to definitive excision of the lesion (mapping).

Lentigo Maligna Clinical Presentation Lentigo maligna (LM) is melanoma in situ of the solar type that occurs most commonly on the sun exposed skin of the middle aged and elderly. It presents as a large patch of variable shades of tan, brown, and black discoloration that expands centrifugally.6

Histology LM is characterized by proliferation of atypical melano­ cy­tes at the dermoepidermal junction mostly as crowded single cells admixed with nests. There is usually extension of these atypical melanocytes along the hair follicles. The epidermis is usually atrophic and the dermis shows significant solar elastosis. In contrast to superficial sprea­ ding melanoma (SSM) where there is prominent pagetoid spread, the melanocytic proliferation in LM is mainly

along the basal layer with minimal upward migration seen. The dermis may also show chronic inflammatory cell infiltrate and scattered melanophages. The main challenges histologically in LM are the assessment of the margins and exclusion of invasion. It is fairly common in solar damaged skin to observe a degree of melanocytic atypia and an overall increase in melanocytic density at the dermoepidermal junction. Unless there is crowding of melanocytes, we usually con­ sider the changes as part of the solar damage and hence not LM. Invasion can be masked, particularly in areas of chronic inflammation, and detailed examination of such areas is necessary with the utilization of multiple sections and immunostains. Careful examination of the sections is necessary to differentiate between pigmented actinic keratosis (AK), solar lentigos, and LM (Table 9.2).

Lentigo Maligna Melanoma Lentigo maligna melanoma (LMM) is an invasive mela­ noma that arises from LM (in situ). It shares the same clinical characteristics as LM. It typically takes many years before LM develops an invasive component. Histologically there is background LM (in situ). The dermal component is variable in LMM according to the progression of the disease. There may be only small foci of either single cells or small nests in the papillary dermis that sometime require careful examination of the hema­ toxylin and eosin (H&E) slides with multiple levels and immunostains. The other extreme is atypical melanocytic growth spanning the full dermis and even extending to the subcutis. Severe solar elastosis is present.

Table 9.2: Differential diagnosis for lentigo maligna

Epidermis

Keratinocytes

Melanocytes

Solar lentigos

Normal or hyperplastic (nonatrophic)

No atypia

•  I ncrease in the number of plump melanocytes •  No melanocytic atypia, crowding or nesting •  No extension of melanocytes into the hair follicles

Pigmented AK

Normal, hypertrophic, or atrophic

Basal keratinocyte atypia

•  I ncrease in the number of plump melanocytes •  No melanocytic atypia, crowding, or nesting •  No extension of melanocytes into the hair follicles

Lentigo maligna

Usually atrophic but occasionally elongated rete ridges may be seen

•  E  ither no atypia or associated with pigmented •  AK with basal keratinocytic atypia

•  I ncrease in the number of atypical epithelioid or spin­ dled melanocytes at the dermoepidermal junction •  Extension of the melanocytic proliferation into the hair follicles •  Upward migration of melanocytes in the epidermis may be seen but is not prominent

Chapter 9: Pathology of Cutaneous Malignancies of the Head and Neck

DMM have been considered a subtype with a better prognosis when compared to other types of melanoma of equivalent depth; however, several studies contradic­ ted this finding and DMM has a very similar survival rate when compared to other melanomas matched for tumor thickness.8 Differential diagnostic considerations for DMM and their immunoprofiles are summarized in Table 9.3.

Desmoplastic Melanoma

159

Table 9.3: Immunohistochemical differential for desmoplastic melanoma

Immunohistochemistry

Desmoplastic melanoma

•  Positive for S100, Sox10 •  Negative for other mel­ anocytic markers such as HMB45, MelanA

Blue nevus, spindle cell predominant

•  Positive for HMB45, S100 and MelanA

Congenital nevus with spindle cells

•  Positive for MelanA, S100 •  Negative for HMB45

Invasive melanoma with spindle cell morphology arising in nodular or superfi­ cial spreading melanoma

•  Positive for MelanA, S100 and HMB45

Scar*

•  May be positive for S100 •  Negative for MelanA and HMB45





Diagnosis

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Fig. 9.1: Plaque or scar-like architecture on low power seen in desmoplastic melanoma.

     





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Desmoplastic melanoma (DMM) is a rare type of mela­ noma that represents < 1% of all melanoma variants and is a locally aggressive form of melanoma that typically occurs in sun exposed sites in older individuals particu­ larly the head and neck.7 Regional lymph node metastasis is very rare. However, distant metastasis may occur in longstanding cases. Clinically they may be confused with nonmelanocytic skin tumors.8 The diagnosis of desmoplastic melanoma should be questioned in the absence of significant sun exposure either clinically (older patient in sun exposed sites) or pathologically (background evidence of solar damage usually in the form of severe solar elastosis, AK, and LM). However, DMM have been reported, though rarely, in nonsun exposed areas in younger individuals.7 Desmoplastic melanoma may arise de novo in a pure form or in association with other forms of melanoma particularly LM melanoma.7 Histologically DMM appear as an infiltrative spindle cell lesion embedded in a desmoplastic stroma with or without an in situ component (Fig. 9.1). The cells may have a dendritic morphology and often show subtle atypia (Fig. 9.2). They typically extend to the deep dermis (Clark’s level 4) or the subcutis (Clark’s level 5) and are commonly associated with perineural invasion. By immu­ nohistochemistry they are different than other types of melanomas as DMM usually stain for S 100, Sox 10, and WT 1 and are usually negative for HMB 45, Melan A, tyro­ sinase, and microphthalmia transcription factor (MiTF).

*Because the immunoprofile of a scar overlaps with that of desmoplastic melanoma, the diagnosis rests on morphology and clinical history.

Fig. 9.2: On intermediate power, a spindle cell proliferation is seen intersecting collagen bundles in the deep dermis in desmoplastic melanoma.

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Head and Neck Surgery

Superficial Spreading Melanoma Clinical Presentation Superficial spreading melanoma usually occurs in youn­ger patients than nodular melanoma (NM) or LM melanoma. They typically involve intermittently sun-exposed antomical sites such as trunk and extremities and usu­ ally present as a flat slowly growing irregular lesion with varie­gated pigmentation that enlarges in a radial man­ ner. The development of a raised area suggests dermal invasion.9

Histological Findings The junctional component shows nests and single atypical melanocytes associated with prominent pagetoid spread (Fig. 9.3). There is confluence of single melanocytes and nests within the epidermis associated with variable epi­ dermal thickening and elongation of the rete ridges. The dermal component shows atypical melanocytes arran­ ged in nests and single cells with variable mitotic activity. A background bland nevus is frequently encountered in SSM.

Nodular Melanoma Clinical Presentation Nodular melanoma tends to occur more often in older patients. It presents as a rapidly expanding nodule that may ulcerate and bleed. They can be amelanotic and may look like basal cell carcinoma (BCC) clinically.9,10

melanoma without regional or distant metastasis is vari­ able according to the stage. Based on TNM classification the 5-year and 10-year survival rates ranges from 97% and 93% for patients with T1aN0M0 to 53% and 39%, res­ pec­tively, for patients with T4bN0M0. The use of synop­tic reporting as part of the pathology report for melanoma is considered the standard of care, and inclu­des all rele­ vant prognostic details. A standard synoptic report for melanoma released by the College of American Patho­logists can be found at www.cap.org/cancerprotocols. The following are the main prognostic factors accord­ ing to the 2009 AJCC melanoma staging and classifica­tion (refer to Ref. 11 for further details).

Primary Tumor Thickness There is an inverse relationship between tumor thickness and survival rate11 (see Table 9.5). In T1 melanoma (i.e. 1 mm or less), the 10-year survi­val rate is variable and ranges from 85% to 99% depending on the presence of secondary characteristics of mitotic rate and ulceration.11 In this group tumor thickness, ulceration and mitotic rates are the most powerful pre­dictors of survival, and the level of invasion is not stati­ stically significant when mitotic and ulceration rates are included in the analysis.

Primary Tumor Ulceration Survival rates of patients with an ulcerated melanoma are lower than those of patients with a nonulcerated mela­ noma of equivalent T category and almost mirror the

Histological Findings Nodular melanoma is a neoplastic proliferation of mali­ gnant melanocytes exhibiting a vertical growth phase in the absence of a horizontal growth phase.10 Usually, the junctional component does not extend more than three rete ridges beyond the most lateral dermal component. Architecturally they are fairly demarcated and commonly ulcerated obliterating the junctional component. Nodular melanomas tend to be thicker at presentation and they frequently show high mitotic rate.10 Other less common types of melanoma are listed in Table 9.4.

Melanoma Prognostic Factors There are many prognostic factors used to stratify pa­ tients. The overall prognosis for patients with localized

Fig. 9.3: Superficial spreading melanoma is characterized by pagetoid scatter of individual melanocytes above the dermoepidermal junction.

161

Chapter 9: Pathology of Cutaneous Malignancies of the Head and Neck Table 9.4: Less common variants of melanoma

Table 9.5: Correlation between melanoma thickness and survival

Thickness

Blue nevus like melanoma or malignant blue nevus

T1 (≤ 1)

92%

Primary dermal melanoma

T2 (1.01–2.0)

80%

Animal type (equine) or histiocytoid melanoma

T3 (2.01–4)

63%

T4 (> 4)

50%

10-year survival

 

 

-

Spitzoid melanoma

Table 9.6: Common mutations in melanoma

%

BRAF

40–60%

NRAS

15–20%

KIT

5% (1/3 of mucosal and acral lentiginous)

In benign nevi, HMB 45 is typically lost in the dermal component as it is a marker of melanocytic immaturity and typically highlights malignant melanoma rather than benign nevi. In some cases, CyclinD1 shows a gradient pattern similar to that observed with HMB45 when stain­ ing benign lesions, such that full thickness CyclinD1 may be taken as another marker suggestive that a lesion is melanoma rather than a benign nevus. Likewise, some melanomas show loss of nuclear p16 staining, which is typically positive in benign nevi. In our experience Cyclin­ D1 and p16 show variable staining within melanocy­ tic tumors and they should not be relied upon to reach a definitive diagnosis in the absence of morphologic support. Other useful markers include proliferative markers (MiB 1/Ki 67). These markers are helpful in difficult melanocytic lesions and when > 10% of the lesional mela­ nocytes are labeled then it is most likely associated with a melanoma rather than a benign nevus. The practice of pathology evolves to encompass mole­ cular profiling, tumor cytogenetics, and targeted therapies. Fluorescence in situ hybridization (FISH) testing is currently used for ambiguous melanocytic lesions. This technique targets individual chromosomes or specific regions within a chromosome. The main targets are CC­ DN1(11q13), RREB1(6p25), MYB(6q23), and centromeric probe 6. Comparative genomic hybridization (CGH) is a method to detect copy number changes throughout the genome. The vast majority of melanomas show chromosomal aber rations such as losses of chromosomes 6q, 8p, 9p, and 10q along with copy number gains of 1q, 6p, 7, 8q, 17q, and 20q.12 Techniques such as FISH and CGH are parti­ cularly helpful in borderline lesions, including atypical Spitzoid neoplasms. Molecular tests for mutational ana­ lysis is currently utilized for therapeutic purposes with the advent of targeted therapies as part of the imple­ mentation of personalized medicine. See Table 9.6 for most commonly tested mutations. -

Mutation

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According to a multifactorial analysis of 10,233 patients with clinically localized melanoma by the AJCC, mitotic rate was the second most powerful predictor of survival after tumor thickness. Mitotic rate is applied as a progno­ stic factor specifically in thin melanomas (< 1.0 mm), wherein a single mitotic figure within the invasive com­ ponent will alter the management of the patient, being an indication for sentinel lymph node biopsy.

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Primary Mitotic Rate



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survival rate of patients with nonulcerated melanoma of the next T category. For example, 5 year survival rate for a T3a nonulcerated melanoma is 79% and is 82% for a T2b ulcerated melanoma.11

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GNAQ/GNA11 83% of uveal melanoma

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Ancillary studies are used to confirm the melanocytic nature of the lesions or help in assessing the malignant potential for borderline melanocytic lesions. Immunohi­ stochemical stains are routinely used. The most common stains that help identify the melanocytic nature of suspec­ ted lesions are S 100, Melan A, HMB 45, MiTF, and Sox 10. WT 1 (cytoplasmic) may also be positive in melano cytic lesions, and may be particularly helpful in DMM.

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Ancillary Studies



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Clark level of invasion is no longer a part of AJCC staging; however, it may be relevant in melanomas arising on sites where the skin is thin, such as the ear, where the Breslow thickness may be relatively low, but invasion extends to Clark levels IV or V.

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Clark/Anatomic Level of Invasion

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PART A REFERENCES 1. Nikolaou V, Stratigos AJ. Emerging trends in the epidemiol­ ogy of melanoma. Br J Dermatol. 2014;170(1):11-9. 2. Colantonio S, Bracken MB, Beecker J. The association of indoor tanning and melanoma in adults: systematic review and meta-analysis. J Am Acad Dermatol. 2014;70 (5):847-57.e18. 3. Gandini S, Sera F, Cattaruzza MS, et al. Meta-analysis of risk factors for cutaneous melanoma: I. Common and atypical naevi. Eur J Cancer. 2005;41(1):28-44. 4. Gandini S, Sera F, Cattaruzza MS, et al. Meta-analysis of risk factors for cutaneous melanoma: II. Sun exposure. Eur J Cancer. 2005;41(1):45-60. 5. Gandini S, Sera F, Cattaruzza MS, et al. Meta-analysis of risk factors for cutaneous melanoma: III. Family history, actinic damage and phenotypic factors. Eur J Cancer. 2005;41(14):2040-59. 6. McKenna JK, Florell SR, Goldman GD, et al. Lentigo maligna/lentigo maligna melanoma: current state of diag­ nosis and treatment. Dermatol Surg. 2006;32(4):493-504.

7. Sade S, Al Habeeb A, Ghazarian D. Spindle cell melano­ cytic lesions: part ii--an approach to intradermal prolif­ erations and horizontally oriented lesions. J Clin Pathol. 2010;63(5):391-409. 8. Rigel DS. (2011). Cancer of the skin. Available from http:// www.clinicalkey.com/dura/browse/bookChapter/3s2.0-C20090310430 [Accessed August 9, 2014]. 9. Scolyer RA, Long GV, Thompson JF, et al. Evolving con­ cepts in melanoma classification and their relevance to multidisciplinary melanoma patient care. Mol Oncol. 2011; 5(2):124-36. 10. Sade S, Al Habeeb A, Ghazarian D. Spindle cell melano­ cytic lesions – part I: an approach to compound naevoidal pattern lesions with spindle cell morphology and spitzoid pattern lesions. J Clin Pathol. 2010;63(4):296-321. 11. Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009;27(36):6199-206. 12. Busam KJ. Molecular pathology of melanocytic tumors. Semin Diagn Pathol. 2013;30(4):362-74.

Chapter 9: Pathology of Cutaneous Malignancies of the Head and Neck

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PART B: NONMELANOMA SKIN CANCER In Australia, NMSC incidence is as high as 1.17/100. This rate is five times higher than all other cancers com­ bined. Extensive sun exposure in fair skinned individuals along with ozone depletion is reported culprit.13



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Human papilloma virus (HPV) is associated with 90% of NMSC; especially SCC in immunodeficient patients and 50% of immunocompetent individuals. Viral protein E6 and E7 have been shown to inhibit p53. Human papilloma virus may act as a cofactor for tumor initiation along with UV radiation.18 Other risk factors are listed in Table 9.7.

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Human Papilloma Virus and NMSC

Sampling Technique and Pitfalls for NMSC



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Ultraviolet radiation does not only prolong the keratino­ cyte cellular proliferation cycle, leading to more transcri­ ption errors, but also causes direct signature mutations in keratinocyte DNA leading to cellular mutation and deactivation of tumor suppressor genes. Furthermore, UVR disrupts immunosurveillance by decreasing Lange­ rhans cells in the superficial dermis.8 Signature mutations CC to TT and C to T transitions are seen in 50% of SCC and 50% of BCCs. Skin cancers are also reported at a much earlier age in genetic disor­ ders that have deficient DNA repair mechanisms such as Xeroderma pigmentosum.9–11 Melanin pigment is the skin’s natural protector against UVR, absorbing carcinogenic wavelengths of UVB (290– 320 nm) as well as UVA. Fair skinned individuals, there­ fore, are at high risk for development of NMSC.12 Nonmelanoma skin cancers have a higher incidence in males compared to females. Gender differences may be related to less protective clothing and more solar expo­ sed recreational and occupational choices. However, in the past decades, an increase in NMSC in females has been seen at a younger age, which may be related to tanning and solar beds. Current M:F is 2:1, but this ratio is gradually decreasing.65

The introduction of various immune modulating medi­ cations, radiation therapy, as well as disease states such as lymphoma and autoimmune illnesses decreases the immunosurveillance for cancer cells. For organ transplant patients, skin cancers account for 90% of malignancies. The increased incidence is proportionate to the dose and duration of the immuno­ suppressive medications.14,15 Squamous cell carcinoma is not only more frequent in transplant patients compared to immunocompetent individuals, but also assumes a more aggressive course with poor differentiation and higher tendency to meta­ stasize. Moreover, transplant patients diagnosed with SCC pose a 66% risk to developing SCC in 5 years.16 Patients with HIV associated immunosuppression, on the other hand, have a less striking elevated risk of deve­ loping an NMSC (3–5 times that of the general popula tion) and do not have the altered SCC to BCC ratio typical of transplant recipients.17



Ultraviolet Radiation

Immune Status





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Nonmelanoma skin cancer (NMSC) comprises approxi­ mately one third of all cancers in the United States1 and have an incidence that is 20 fold that of melanoma.2 Basal cell carcinoma and SCC together account for over 95%3 of skin cancers. With this, it is no surprise that the term NMSC is often used for these two epithelial tumors of the skin. Other NMSC arising from the epidermis in­ cludes adnexal tumors and Merkel cell carcinoma. Despite the increased awareness of solar irradiation and its deleterious effects on skin cell maturation and rejuvenation, the incidence of NMSC and its precursor lesions continues to rise. This rise may be attributed to early detection, an aging population, personal habits, and behaviors that lead to increased exposure and de­ creased tolerance to ultraviolet radiation (UVR) as well as environmental factors as ozone layer depletion, higher latitude and living close to the equator.3–7

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OVERVIEW



With the considerable clinical overlap between NMSC, its precursor lesions, as well as other benign adnexal tumors, the importance of sufficient sampling to reach a proper diagnosis cannot be emphasized enough. Superficial biopsies may reveal only ulceration and underlying basaloid cords, which pose a problem differen­ tiating BCC from SCC.

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Head and Neck Surgery

Table 9.7: Risk factors for nonmelanoma skin cancer

Age Male Chronic sun exposure PUVA (SCC) Previous history of NMSC Albinism (SCC) Vitiligo (SCC) Genetic conditions such as XP and BCC nevus syndrome Ionizing radiation Tar asphalt Arsenic Smoking (especially sclerosing BCC) Hydroxyurea Transplant recipients (SCC) Lymphoma Leukemia Acquired immune deficiency syndrome Human papilloma virus Burns (SCC) Scars, chronic wounds (SCC) Immune-modulating therapies (anti-BRAF and anti-TNF) (BCC: Basal cell carcinoma; NMSC: Nonmelanoma skin cancer; SCC: Squamous cell carcinoma).

Superficial or insufficient sampling may recognize only AK, a finding commonly seen in the background of NMSC, with no measure to ascertain a deeper pathology that may require more serious intervention. A superficial shave on a clinically suspected keratoa­ canthoma will fail to represent its well-circumscribed base, as opposed to the infiltrating cords and cells of a SCC. Biopsy of a suspected NMSC should contain fullthickness skin, in order to evaluate the depth of the lesion. Shave biopsies are not recommended. Excisional biopsies of small, nonscarring, well-circum­ scribed lesions are both diagnostic and therapeutic, pro­ vided the entire area is removed. For larger lesions or those located in functionally cristi­cal areas, a diagnostic incisional biopsy may be the pro­per ini­ tial approach to plan proper interventional management.19 It is often a misconception that the pathologist should be provided with a biopsy from the edge of the lesion, at the transition point from normal skin, for comparison pur­poses. However, this is not as preferable to pathologists,

as it frequently provides only a small sample of tumor to evaluate. The most suspicious area of a lesion may be sampled. A biopsy that contains sufficient dermis may be all that is required for diagnosis of BCC.

Synoptic Report in NMSC Synoptic reporting is a structured method for entering diagnostic and prognostic information in precise and reliable fashion for pathology specimens. This has been found to reduce transcription services, specimen turn­ around time, and typographical and transcription errors. The structured data can be imported into a database, which facilitates access and improved interdisciplinary communication for management of cancer patients. Synop­ tic templates can be shared research projects to enhance basic and translational research. The College of American Pathologists provides standardized synoptic reporting worksheets along with explanatory notes on filling these in on their website (www.cap.org/cancerprotocols).20 This website includes templates for SCC of the skin, along with melanoma and Merkel cell carcinoma.

BASAL CELL CARCINOMA Introduction Basal cell carcinoma is the most frequent form of skin cancer in immune competent individuals, especially those of Fitzpatrick skin types I and II. It accounts for 70–80% of primary cutaneous malignancies. Its incidence increases with age and is higher in men than in women.21 Basal cell carcinoma usually assumes a slow, indolent, locally invasive growth pattern with a low tendency to metastasize. The rate of metastasis varies between 0.028% and 0.55%.22–24

Clinical Presentation Ninety percent of BCC present on sun exposed skin, ref­lecting the vital role of UV exposure in its pathogenesis (Table 9.8). Several clinical variants have been reported: Macular, papulonodular, rodent ulcer, erythematous plaque with telangiectasia, pearly papule, giant, linear, polypoid, keloid, or dermatitis. Two to five percent of BCCs present are pig­ mented BCC. Those are seen more in Asian and African populations and may be mistaken for a melano­ cytic lesion.

Chapter 9: Pathology of Cutaneous Malignancies of the Head and Neck

Pathophysiology



Table 9.8: Distribution of BCC

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Although the exact etiology of BCC is unknown, its relationship with the pilosebaceous unit is well establi­ shed, as tumors are often discovered on hair bearing areas. Basal cell carcinomas are believed to arise from pluri­ potent stem cells in basal layer of the epidermis and the bulge region of outer root sheath of a hair follicle.26 The patched/hedgehog intracellular signaling path­ way plays a major role in BCC tumorigenesis. This pathway is significant for regulation of cell growth and di erentiation.27,28 UV induced mutations in the TP53 tumor suppressor gene as well as frameshift mutations of the BAX gene (BCL2 associated X protein) have been reported in BCC. Recent studies speculate about a possible role for dysregu­ lation of COX 2 expression in carcinogenesis.29

Occasional amyloid may be detected that has been reported to give resistance to radiation treatment.26 Several histological variants of BCC have been des­ cribed, which may vary in clinical appearance (Table 9.9). Patterns that pose high risk of recurrence are those with superficial multifocal and infiltrative patterns.



Perineural invasion occurs most commonly in malar and preauricular areas. This may clinically present with pain, paresthesias, or paralysis.25

165



Solar damaged skin 80% on head and neck, especially nose tip and nasal ala, lower eye lid in periocular Organoid nevi 20% risk of developing BCC

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Epidermal nevi: Rare Children and young adults Consider syndromes such as BCC nevus (Gorlin), Bazex, Rombo, McKusick, XP

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f­f



20% shoulder and upper trunk

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(BCC: Basal cell carcinoma). Table 9.9: Clinical appearance of BCC histologic variants

Histology

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Nodular: Pearly, flesh colored papule with telangiectases

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Fig. 9.4: Superficial multifocal basal cell carcinoma. Notice the extension of basaloid nests from the epidermis, along with peripheral palisading.

Pigmented nodular: May mimic melanocytic lesions Infiltrative: Atrophic mass extending beyond clinical margins Micronodular: Yellow white firm nodule Morpheaform (sclerosing): White or yellow, waxy, sclerotic plaque, rarely ulcerates Superficial: Well circumscribed patch or plaque, often with a whitish scale on upper trunk or shoulders -

Basal cell carcinoma presents with an epidermal attach­ ment of nests of basaloid cells with palisading peripheries (Fig. 9.4). The cells within the nests are haphazardly arranged, hyperchromatic and uniform, showing multiple apoptotic and mitotic figures. The islands are surrounded by loose mucopolysaccharide rich stroma. Often a sepa­ ration artifact is appreciated between the nests and the dermis (Fig. 9.5).

(BCC: Basal cell carcinoma).

Fig. 9.5: Separation or “clefting” of nests of basal cell carcinoma from the adjacent stroma.

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Head and Neck Surgery

Fig. 9.6: Infiltrative pattern basal cell carcinoma shows deep extension and behaves more aggressively.

Features of aggressive BCC include basosquamous differentiation, deep nested infiltrative cords (Fig. 9.6), loss of peripheral palisading, and sclerotic stroma.30–32 The overlying epidermis may be acanthotic, atrophic, or ulcerated, and may have AK. It should be noted that a BCC with previous intervention or that which re-epithe­ lized after ulceration may present with no connection to the overlying epidermis, and may assume a more squa­ moid and infiltrative form. Basal cell carcinoma may be associated with other lesions such as nevus sebaceous of Jadassohn and SCC. It may also be overly dermatofibroma (DF), myxoma, and other hamartomas. It may be associated with ossifica­tion and calcification as well as signs of regression.26

Ancillary Studies Basal cell carcinoma is positive for high molecular keratin markers such as CK5/6 and pan keratin AE1/AE3, as well as p63 stain. BER-EP4 shows positive staining for BCC.33 Basal cell carcinoma has been demonstrated to be con­ sistently positive for EMA, making it a useful mar­ker to distinguish BCC from SCC and eccrine tumors. Basal cell carcinoma is positive for antiapoptotic mar­ kers bcl-2, a marker of the basal layer. Morpheic variant of BCC has been recently found to have reduced bcl-2 staining.34 Mimickers of BCC may be tumors of follicular, eccrine, sebaceous origin, or Merkel cell carcinoma. Table 9.10 summarizes their distinguishing features.

Metastasis and Recurrence Although BCC is known to be locally invasive with a fairly slow progressing course, it has been reported to metastasize

in 2 cm) Recurrence despite intervention (BCC: Basal cell carcinoma; NMSC: Nonmelanoma skin cancer).

Fig. 9.7: Well-differentiated squamous cell carcinoma.

Table 9.12: Histopathological variants of AK

1. Hypertrophic: Most common variant, with parakeratosis, and acanthosis with thinning granular cell layer 2. Atrophic: Thinned epidermis in comparison to surround­ ing tissue 3. Acantholytic: Dyscohesion between keratinocytes in the downward epidermal buds 4. Pigmented: Increased melanin in the basal layer 5. Lichenoid: Dense band like lymphocytic infiltrate under the lesion 6. Bowenoid: Keratinocyte atypia with larger size nuclei and focal full-thickness involvement

Fig. 9.8: High-power image of well-differentiated squamous cell carcinoma showing irregular infiltrative nests of atypical squamous cells.

Chapter 9: Pathology of Cutaneous Malignancies of the Head and Neck

169

Table 9.13: Differential diagnosis of SCC subtypes

Differential diagnosis

Distinguishing features

Poorly differentiated SCC (epithelioid type)

Melanoma

•  Usually no overlying keratinocytic dysplasia in melanoma; may show melanoma in situ and pigment •  Melanoma is positive for S100, MelanA, HMB45

Lymphoma

•  Usually no overlying keratinocytic dysplasia in lymphoma •  Lymphoma is positive for various lymphoid markers such as CD3 or CD20

Merkel cell carcinoma

•  Usually no overlying keratinocytic dysplasia in MCC •  MCC shows neuroendocrine features including salt and pepper chro­ matin and synaptophysin/chromogranin positivity

Metastatic carcinoma

•  Usually no overlying keratinocytic dysplasia in MCC •  Distinction based on clinical history and immunoprofile in keeping with a distant primary

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Variant

Poorly differentiated SCC (spindle cell type)

Refer to Table 9.16 for details

Pseudoglandular SCC

Adnexal (eccrine) carcinoma

Positive for low molecular weight keratin

Metastatic adenocarci­ noma

Distinction based on clinical history and immunoprofile in keeping with a distant primary

(BCC: Basal cell carcinoma; SCC: Squamous cell carcinoma).

Table 9.14: Tumor-related factors for high-risk SCC

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Squamous cell carcinoma stains positive for high mole­ cular weight keratin, EMA, involucrin, p63 (50%), while having variable staining for carcinoembryonic antigen (CEA). Squamous cell carcinoma cells will not stain for melanoma markers as HMB45, Melan A, Sox10, and S100. Lymphoma cells will stain negative for keratin markers and positive for CD. Negative stains that are helpful in distinguishing SCC from other spindle cell and epithelioid tumor of the head and neck are CK7, CK20, smooth muscle actin (SMA), and CD10 (refer to Table 9.16 for spindle cell dif­ ferentiation).

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Tumor location (i.e. lips, ears, anogenital region, within a scar or chronic wound) Tumor size > 2 cm (or 1.5 cm on ear or lip) Invasion to subcutaneous fat (or deeper) Poorly differentiated tumor cells Recurrent tumor Perineural involvement to large caliber nerves61

lymphvascular invasion, poor differentiation, histologic subtypes: adenosquamous, desmoplastic, invasive Bowen’s disease, area of chronic inflammation, immunosuppres­ sion, HPV related, anatomic locations as ear and lip and inadequate resection (Table 9.14).59,60 Immunosuppressed patients, those with metastasis to multiple lymph nodes, and those with cervical lymph nodes > 3 cm in diameter have an exceptionally poor prognosis.43 Location is one of the most significant indicators for metastasis. Eyelid or ear lesions with rapid growth meta­ stasize in up to one third of cases.61 Five year survival rate after metastasis from these primary sites ranges from 25% to 40%. Scalp, forehead, and temple have also high risk for metastasis.43,62  



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Usually, complete excision of early stage SCC will result in complete cure with a 90% five year survival. For patients with lymph node metastases, the five year survival lowers to 25–45%. Metastasis to distant organs such as the lung remains incurable. Therefore, early disease control is of paramount importance. High risk SCC is a subset of SCCs that carries an increased risk of local recurrence, nodal or distant meta­ stasis, and death. High risk factors include tumor size over 2 cm, depth over 2 mm,53 Clark’s level of IV or more, perineural invasion,



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High-Risk SCC

(SCC: Squamous cell carcinoma).

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Head and Neck Surgery

A 2008 prospective study found a rate of metastasis of 4% for tumors with a thickness of 2–6 mm. The risk increased to 16% in tumors thicker than 6 mm.53 More poorly differentiated tumors have a worse pro­ gnosis in SCC, with reported recurrence rates of 33–54% and behave more aggressively.62 Perineural invasion has been estimated to occur in up to 7% of persons with cutaneous SCC. This feature increases the risk for metastasis in up to 47% on cases. The degree of nerve involvement and the diameter of the involved nerves, and involvement of major nerve branches especially V3,63 impacts on the prognosis.64

MERKEL CELL CARCINOMA Background Merkel cell carcinoma (MCC) is a rare cutaneous mali­ gnancy seen most commonly on the sun-exposed skin of elderly individuals. Originally described as “trabecular carcinoma” by Toker in 1972,1 it has subsequently been suspected to be derived from the Merkel cell, a neuroe­ ndocrine cell with mechanoreceptor function first iden­ tified in 1875 by Friedrich Merkel.2 The exact origin of the tumor is, however, disputed, and further study is required to clarify the exact nature of both the Merkel cell itself and the cell of origin of MCC. Although long thought to be related to UV exposure and immunosuppression, a breakthrough occurred in 2008 when a novel polyoma­ virus named Merkel cell polyomavirus (MCV) was iden­ tified3 and determined to have an etiologic role in many (but not all) cases.

Clinical Presentation Merkel cell carcinoma typically presents on the sunexposed skin of elderly individuals, with the head and neck being the most common site,4,5 followed by the extremities, although any site can be involved. It typically presents as a rapidly growing cutaneous nodule with relatively nonspecific features, with the clinical differen­ tial diagnosis including BCC and amelanotic melanoma. Some patients present with multiple satellite lesions or with metastases most often to the regional lymph nodes. The risk is increased in immunosuppressed patients, in­ cluding organ transplant patients,6,7 HIV/AIDS patients8 and those with B-cell neoplasms, particularly chronic lymphocytic leukemia.9 Many patients have a history of other UV-related skin cancers.

Pathogenesis Merkel cell carcinoma is now known to be etiologically linked to MCV, a double-stranded DNA virus that contains a large T antigen domain (LT) in which mutations have been identified that result in modification of its binding to important cell cycle regulators such as Rb and p53.10 MCV has been implicated in > 80% of MCC cases in some studies10,11 and seems to be more common in tumors from female patients.12,13 Further study is required, but it may be implicated in UV-exposed tumors10 and may have prognostic significance, with some evidence that virusnegative tumors are more likely to present with nodal metastasis at the time of diagnosis.14 As mentioned, both UV exposure and immune compromise increase the risk of developing MCC.

Histology Merkel cell carcinoma is a high-grade neuroendocrine tumor, the histologic prototype of which is small cell car­ cinoma of the lung. It is characterized by sheets, nodules, or trabeculae of small-to-medium sized cells with high nuclear-to-cytoplasmic ratios, a thin rim of cytoplasm, and nuclei with fine powdery or granular chromatin (“salt-and-pepper”) with indistinct nucleoli. The cells may show crush artifact and are relatively dyscohesive. Mitoses, apoptoses, and necrosis are common. The tumor is dermally based in most cases, but may extend into the subcutis. Although uncommon, epidermotropism is a wellrecognized occurrence in some cases.15,16 Figures 9.9 and 9.10 highlight low- and high-power features of MCC. The tumor has been reported to occur coincidentally or admixed with other tumors, including squamous neo­ plasms10 and others; therefore, the presence of a compo­ nent of MCC does not preclude the existence of another lesion in the same specimen. Occasionally divergent dif­ ferentiation may be seen within the tumor, including squamous or adnexal-type epithelial changes.17,18 Further­ more, we have seen three cases of primary neuroendo­ crine carcinoma of skin that appears to arise directly from cutaneous glands, with both an in situ glandular compo­ nent and an invasive component that is morphologically identical to classic Merkel cell carcinoma.

Ancillary Studies Because of the nonspecific histologic appearance of the tumor, immunohistochemistry is essential both in primary diagnosis as well as to exclude the possibility of

Chapter 9: Pathology of Cutaneous Malignancies of the Head and Neck

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Differential Diagnosis The most important differential is metastatic neuroen­ docrine carcinoma. Small cell carcinoma of the lung bears striking histologic similarity, and cutaneous metastases

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Prognosis Merkel cell carcinoma is an aggressive neoplasm with overall five year survival ranging from 33–41% for patients presenting at stage I.19,20 It is characterized by local recurrence as well as the development of both regional lymph node and distant metastases. The approach to treatment is multidisciplinary, particularly in advanced -

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a metastatic lesion. Merkel cell carcinoma is typically positive for CK20 and/or CAM5.2 with a paranuclear dot like pattern. It is also positive for one or more neu­ roendocrine markers, such as synaptophysin and chro­ mogranin. The tumor is usually negative for CK7 and TTF 1, as well as for markers of hematolymphoid and melanocytic differentiation. Rare examples of CK7 posi­ tive, CK20 negative tumors, as well as tumors either nega­ tive or positive for both markers, have been reported; therefore, a small panel is sometimes required to confirm the diagnosis. See Table 9.15 for the typical immunoprofile of Merkel cell carcinoma.

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(MCC: Merkel cell carcinoma; MCV: Merkel cell polyomavirus).





Variable or limited data CD99 Fli1 Pankeratin P63 Villin EMA Neurofilament



Negative CK7 CK5/6 CEA LCA Vimentin TTF 1 HHV 8 -

Positive CK20 Cam 5.2 (or CK18) Synaptophysin Chromogranin Neuron specific enolase PAX5 CD117 CD56 MCV

may be the first presentation of the tumor. Immunohis­ tochemistry is helpful in most cases, with MCC being CK20 positive, CK7 and TTF 1 negative, with small cell lung carcinoma having the opposite profile. As mentioned above, exceptions exist. Neuroendocrine carcinomas of other primary sites are difficult to exclude. Some may be CK7 positive and CK20 negative. Neuroendocrine carcinomas of gastrointestinal origin may express cdx2, which is negative in MCC. Clinical history is the most valuable tool in making the final diagnosis. The small cell variant of melanoma is an important consideration, particularly in tumors with an epidermal component. Histologic features of use include a promi­ nent epidermal component, particularly if junctional nests are present, the presence of melanin pigment, and prominent nucleoli. Other “small round blue cell” tumors such as neuro­ blastoma, rhabdomyosarcoma, and others are usually easily distinguished from MCC based on clinical history and patient age alone. However, most of these tumors show little or no cytokeratin staining, compared to the typical more prominent CK20 staining seen in MCC. ­

Table 9.15: Typical immunoprofile of MCC

Fig. 9.10: Merkel cell carcinoma with atypical small round blue cells showing salt-and-pepper chromatin and numerous mitotic figures.

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Fig. 9.9: Merkel cell carcinoma on lower power appears as a large nodular proliferation in the dermis, sometimes extending to the subcutis.

171

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Head and Neck Surgery

cases, and includes wide local excision, often with loco­ regional radiation and sometimes chemotherapy. Sentinel lymph node biopsy is recommended for all patients who can tolerate the procedure. The most important prognostic factor is stage at diagnosis. Other factors with possible prognostic signifi­ cance include tumor size and thickness, the presence of lymphvascular invasion, and extent into subcutis. Women appear to have better outcomes than men.21 The role of histological factors in predicting outcomes is still not well defined, but some factors that may be of import include growth pattern (e.g. nodular versus diffuse) and the presence of tumor infiltrating lymphocytes.21

MALIGNANT ADNEXAL TUMORS OF THE HEAD AND NECK Introduction Although malignant adnexal neoplasms are uncommon in the head and neck area and other parts of the body, when they occur, they usually behave in an aggressive way. Thus, recognition and treatment of these neoplasms is critical to the patient’s outcome. The most common of these neoplasms will be briefly discussed. See Flowchart 9.1 for a brief review.

Tumors of the Follicular Epithelium

by clear­ing of the cytoplasm of the malignant cells, peri­ pheral palisad­ ing of the nuclei, lobulation, trichilemmal kerati­ nization, prominent basement membrane, and fol­ liculocentricity. It is not unusual for these tumors to be diagnosed as BCC in a superficial shave biopsy, similar to other basaloid adnexal tumors, and complete excision is necessary for the final correct diagnosis. Prognosis is favorable after complete exci­sion; however, we have seen rare cases that recurred in transit and also metastasized to regional lymph nodes.1

Trichoblastic Carcinoma Trichoblastic carcinoma is a rare tumor, usually the result of malignant transformation of trichoblastoma. The tumor is usually biphasic (stromal-epithelial); however, one com­ ponent may be predominant. Such lesions may demon­strate the presence of dendritic cells (CD1a and S100) within the epithelium in addition to T-lympho­ cytes, which may produce a resemblance to lymphoepi­ thelio­ma-like carcinoma. The epithelium usually exhibits basaloid morphology that may be admixed with more poorly differentiated large cells, depending on tumor differentiation. Primitive hair bulb-like structures can be seen with organoid structures noted. Clearing of the cyto­ plasm can be seen. The stromal element might undergo malignant transformation, in which case the term tricho­ blastic carcinosarcoma is applied.2,3

Trichilemmal Carcinoma

Malignant Proliferating Pilar (Trichilemmal) Tumor

Trichilemmal carcinoma is considered to be a malig­ nant counterpart of trichilemmoma that is characterized

Malignant proliferating pilar (trichilemmal) tumor usu­ ally arises in a pre-existing pilar cyst/tumor that may be

Flowchart 9.1: Overview of malignant adnexal tumors of the head and neck.

Chapter 9: Pathology of Cutaneous Malignancies of the Head and Neck

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Sebaceous Carcinoma

Tumors of the Cutaneous Sweat Glands Microcystic Adnexal Carcinoma



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Sebaceous carcinoma is a malignant adnexal tumor of the sebaceous unit. Although the etiology is uncertain, some cases may be related to actinic damage and there is a significant association with Muir Torre syndrome. Patients with Muir Torre syndrome have a predisposition to sebaceous skin tumors as well as keratoacanthomas and visceral malignancies. Sebaceous carcinoma typically presents in the elderly, with a higher incidence in females. The eyelid is the most common site, followed in frequency by other head and neck sites, trunk, and extremities. The tumor may present

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Histology: The pre existing pilar tumor can be seen with a multilobulated and cystic dermal based proliferation with areas of squamous differentiation and squamous eddies. Trichilemmal type keratinization is seen, and there may be some peripheral palisading. The lesional cells in the malignant forms are atypical with numerous mitotic figures and pleomorphism. As noted above, the malignant cells may be in situ or may invade the surrounding stroma.

with nodules, firm, yellow tan in color, with or without ulceration and ranging from 1.0 cm to 4.0 cm in size. Sebaceous carcinoma is an aggressive tumor with > 30% incidence of metastasis if not discovered early.7–9 Histologically, the tumor consists of lobules and sheets of atypical cuboidal cells with increased mitotic figures (Figs. 9.11 and 9.12). The cells may show sebaceous differentiation including clear cytoplasm, or the cells may be basaloid and poorly differentiated. Pagetoid spread and comedo necrosis may be seen, and rarely squamous differentiation is observed. Sebaceous carcinoma is divided into well, moderately, and poorly differentiated carcinoma depending on the degree of the cytologic atypia. Also, they may be graded as grade I, II, or III, depending on the level of invasion: grade I being mainly in situ with minimal invasion; grade II where invasion is seen but not extensive; and grade III where the tumor is deeply invasive into the subcutaneous tissue. The tumor cells are immunopositive for EMA, cyto­ keratin, AR, p63, D2 40, CK5/6, GATA3, CK18 and BerEP4. The immunostains may vary depending on the cellular differentiation of the tumor, with less expression in the poorly differentiated lesions.

related to chronic inflammation or trauma. It is much more common in females and typically occurs in the scalp (postauricular). It may also occur on the face, trunk, and extremities.4–6 Malignancy within a pilar tumor can be either in situ (malignant pilar cyst) or show invasion into the surrounding stroma (invasive malignant pilar tumor). When invasive, the lesion is aggressive and can metastasize to regional lymph nodes and distant organs such as the lung.

173

Fig. 9.11: Sebaceous carcinoma.

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Microcystic adnexal carcinoma (MAC) is a low grade malignant adnexal tumor with follicular and ductal dif­ ferentiation. It may be pathogenetically related to sun

Fig. 9.12: On high power, the vacuolated cytoplasm of sebaceous carcinoma can be appreciated.

174

Head and Neck Surgery

damage, with higher incidence reported on the left side (driver’s side) of the face. Usually seen in the middle-aged to older adults, MAC is more common in females, with the most common site being the face. The tumor may also occur on the scalp. Microcystic adnexal carcinoma can arise in previously irradiated skin. It can present as an indurated, plaque-like, or nodular lesion that is deeply infiltrative. Recurrence is not uncom­ mon and metastasis is very rare, mainly to local lymph nodes.10,11 By morphology, MAC is a bland-appearing dermalbased basaloid tumor with deep infiltration (Fig. 9.13). The superficial portion consists of nests and islands of infundibulocystic structures with follicular keratinous mate­ rial noted simulating a trichoepithelioma. Small du­ctal and tubular structures are noted that may suggest that this lesion may represent a hybrid tumor of follicular and sweat ductular elements (Fig. 9.14). Clear cell change may be seen in some of the tumors. Sclerosing stroma is appreciated and perineural invasion may be seen. Microcystic adnexal carcinoma should be differentiated from mainly sclerosing BCC and syringoid eccrine carci­ noma (SEC). Immunohistochemistry is not helpful in most cases, although EMA and monoclonal CEA are typi­ cally positive and are negative in sclerosing BCC.

skin-colored dermal mass. Perineural invasion is common and is the usual source of recurrences. Metastases are rare and when they occur are typically to the lymph nodes and lungs. Adenoid cystic carcinoma of the lacrimal glands has the worst prognosis compared to the other head and neck cutaneous sites.12,13 Adenoid cystic carcinoma of the skin resembles its more common salivary gland counterpart, and is a poorly circumscribed dermal-based proliferation of lobules, islands and strands of basaloid cuboidal cells forming tubular, solid and cribriform patterns (Figs. 9.15A and B). It is advisable to examine multiple level sections to iden­ tify perineural invasion, which is common in this tumor. Perio­ dic acid Schiff (PAS)-positive eosinophilic hyaline membrane-like material is seen both between tumor cells and also around the lobules. The luminal material is positive for acid mucin (Alcian blue, pH 2.5, colloidal iron stains are positive) and the lesional cells are positive for EMA, monoclonal CEA, p63, S100, SMA, and cyto­keratins.

Syringoid Eccrine Carcinoma

Adenoid cystic carcinoma is a rare tumor occurring on the skin that typically occurs in adults and may be related to sun damage. It usually presents as a slow-growing,

Syringoid eccrine carcinoma is probably the most com­ mon malignant cutaneous sweat ductal/glandular tumor encountered in the head and neck area. The tumor may present as a slow-growing plaque or nodule, typically without ulceration. It can occur anywhere on the head and neck skin and might be related to UV light expo­ sure.14–17 Syringoid eccrine carcinoma is an infiltrative tumor composed of cohesive epithelial cells with ductal/tubular

Fig. 9.13: Microcystic adnexal carcinoma is recognized at low power by its deep infiltration.

Fig. 9.14: Microcystic adnexal carcinoma shows the formation of small duct-like structures.

Adenoid Cystic Carcinoma

Chapter 9: Pathology of Cutaneous Malignancies of the Head and Neck

A

175

B

Figs. 9.15A and B: Adenoid cystic carcinoma of the skin.

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Malignancy can arise in pre existing benign adnexal tumors of the head and neck such as hidradenoma (hidradenocarcinoma), spiradenoma (spiradenocarcinma), cylindroma (malignant cylindroma), and chondroid syrin­ goma (malignant mixed tumor of the skin). These have the morphology of the original benign tumor with areas evolving that exhibit definite malignant features such as nuclear pleomorphism, increased mitoses, necrosis and invasion into the surrounding stroma. Perineural and lymphovascular invasion can be seen. The malignant por tion has a tendency to metastasize to regional lymph nodes. It is advised that benign adnexal tumors be com­ pletely excised to prevent the rare but dismal occurrence of malignant transformation. -



Apocrine carcinoma occurs most often in the axilla, but can rarely be seen in head and neck sites, specifically the scalp. It can arise de novo or occur secondarily in a benign apocrine tumor such as tubular apocrine adenoma or within the apocrine portion of nevus sebaceous.18 The tumor presents as a nodule or plaque with or without ulceration. The prognosis is variable, with some cases presenting as slow growing indolent lesions and others behaving aggressively with rapid growth and lymph node metastasis. ­

Other Malignant Adnexal Tumors

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Apocrine Carcinoma

Apocrine carcinoma presents as nests, islands, sheets, and complex glands composed of pleomorphic apocrine cells with prominent nucleoli. Tumor necrosis and vas­ cular invasion may be present and deep infiltration into the subcutaneous tissue can be seen. Mitotic figures are frequent. Pagetoid spread into the overlying epidermis may be present. Immunohistochemical stains for GCDFP 15, CK7, CK18, p63, androgen receptors are positive.

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lumina identified. Desmoplastic stroma is appreciated with perineural invasion seen. Squamous differentiation can be present (squamoid variant). Tadpole structures resembling syringoma and cribriform patterns can be seen. Syringoid eccrine carcinoma can metastasize to regional lymph nodes. Although immunohistochemi­ stry is of limited value in the diagnosis, SEC is positive for CK14, CK 5/6, and p63. EMA and monoclonal CEA usually stain the lumina. CK18 and CK7 may be focally positive. A few cases can be positive for estro­ gen and progesterone receptors but not for androgen receptors.





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3. Yanofsky VR, Mercer SE, Phelps RG. Histopathological variants of cutaneous squamous cell carcinoma: a review. J Skin Cancer. 2011;2011:210813. 4. Ghissassi F, Baan R, Straif K, et al. A review of human car­ cinogens. Part D: radiation. Lancet Oncol. 2009;10:751 2.

1. Diepgen TL, Mahler V. The epidemiology of skin cancer. Brit J Dermatol. 2002;146(Suppl 61):1 6. 2. Weinstock MA. Epidemiologic investigation of non mela­ noma skin cancer mortality: the Rhode Island follow back study. J Invest Dermatol. 1994;102:6S 9S.



PART B REFERENCES

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5. Fahey DW. Twenty Questions and Answers about the Ozone Layer. 2006 Update. Geneva:: World Meteorological Organization; 2007. 6. Leiter U, Garbe C. Epidemiology of melanoma and non­ melanoma skin cancer—the role of sunlight. Adv Exp Med Biol. 2008;624:89-103. 7. Madan V, Lear JT, Szeimeis RM. Non-melanoma skin can­ cer. Lancet. 2010;375(9715):673-85. 8. Katiyar SK. UV-induced immune suppression and pho­ tocarcinogenesis: chemoprevention by dietary botanical agents. Cancer Lett. 2007;255:1-11. 9. Dumaz N, van Kranen HJ, de Vries A, et al. The role of UV-B light in skin carcinogenesis through the analysis of p53 mutations in squamous cell carcinomas of hairless mice. Carcinogenesis. 1997;18(5):897-904. 10. Mouret S, Baudouin C, Chevron M, et al. Cyclobutane pyrimidine dimers are predominant DNA lesions in whole human skin exposed to UVA. Radiat Proc Natl Acad Sci USA. 2006;103(37):13765-70 11. Zhang H, Ping X, Lee KL, et al. Role of PTCH and p53 genes in early-onset basal cell carcinoma. Am J Pathol. 2001;158(2):381-5. 12. Brenner M, Hearing V. The protective role of melanin against UV damage in human skin. Photochem Photobiol. 2008;84(3):539-49. 13. Staples MP, Elwood M, Burton RC, et al. Non-melanoma skin cancer in Australia: the 2002 national survey and trends since 1985. Med J Aust. 2006;184(1):6-10. 14. Herman S, Rogers HD, Ratner D. Immunosuppression and squamous cell carcinoma: a focus on solid organ transplant recipients. Skinmed. 2007;6(5):234-8. 15. Mehrany K, Weenig RH, Pittelkow MR, et al. High recur­ rence rates of squamous cell carcinoma after Mohs’ surgery in patients with chronic lymphocytic leukemia. Dermatol Surg. 2005;31(1):38-42; discussion 42. 16. Euvrard S, Kanitakis J, Decullier E, et al. Subsequent skin cancers in kidney and heart transplant recipients after the first squamous cell carcinoma. Transplantation. 2006;81(8):1093-100. 17. Silverberg MJ, Leyden W, Warton AM, et al. HIV infection status, immunodeficiency, and the incidence of non-mel­ anoma skin cancer. J Natl Cancer Inst. 2013;105(5):350-60. 18. Masini C, Fuchs PG, Gabrielli F, et al. Evidence for the asso­ ciation of human papillomavirus infection and cutaneous squamous cell carcinoma in immunocompetent individu­ als. Arch Dermatol. 2003;139(7):890-4. 19. Tan KB, Tan SH, Aw DC, et al. Simulators of squamous cell carcinoma of the skin: diagnostic challenges on small biopsies and clinicopathological correlation. J Skin Cancer. 2013;2013:752864 20. College of American Pathologists (2012–2013). Cancer Pro­ tocols and Checklists. College of American Pathologists. Available from www.cap.org/cancerprotocols [Accessed May 16, 2014]. 21. Crowson N. Basal cell carcinoma: biology, morphology and clinical implications. Mod Pathol. 2006;19:S127-47.

22. Mikhail GR, Nims LP, Kelly AP, et al. Metastatic basal cell carcinoma: review, pathogenesis, and report of two cases MD. Arch Dermatol. 1977;113(9):1261-9. 23. Safai B, Good RA. Basal cell carcinoma with metastasis. Rev Lit Arch Pathol Lab Med. 1977;101(6):327-31. 24. Ting PT, Kasper R, Arlette JP, et al. Metastatic basal cell carcinoma: report of two cases and literature review. J Cutan Med Surg. 2005;9(1):10-15. 25. Casson PR, Robins P. Malignant tumors of the skin. In: McCarthy JG (Ed). Plastic Surgery. Philadelphia, PA: WB Saunders Co.; 1990. pp. 3619–23. 26. Weedon D. Weedon’s Skin Pathology. London: Churchill Livingstone Elsevier; 2010. 27. Robert J. Gorlin RJ, Goltz RW. Multiple nevoid basal-cell epithelioma, jaw cysts and bifid rib a syndrome. N Engl J Med. 1960;262:908-12. 28. Johnson RL, Rothman AL, Xie J, et al. Human homolog of patched, a candidate gene for the basal cell nevus syn­ drome. Science. 1996;272(5268):1668-71. 29. Abujuba B, Şovrea A, Crisan D, et al. Apoptotic markers in photoinduced cutaneous carcinoma Rom J Morphol Embryol. 2013;54(3):741-7. 30. Freeman RG, Duncan WC. Recurrent skin cancer. Arch Dermatol. 1973;107:395. 31. Sloan JP. The value of typing basal cell carcinomas in pre­ dicting recurrence after surgical excision. Brit J Dermatol. 1977;96(2):127-32. 32. Jacobs GH, Rippey JJ. Prediction of aggressive behavior in basal cell carcinoma. Cancer. 1982;49(3):533-7. 33. Ansai S, Takayama R, Kimura T, et al. Ber-EP4 is a useful marker for follicular germinative cell differentiation of cuta­ neous epithelial neoplasms. J Dermatol. 2012;39(8):688–92. 34. Puizina-Ivi N, Sapunar D. An overview of Bcl-2 expression in histopathological variants of basal cell carcinoma, squamous cell carcinoma, actinic keratosis and seborrheic keratosis. Coll Antropol. 2008;32(Suppl 2):61-5. 35. Lyubomir AD, Darena R, Ivan B. Clinical variants, stages, and management of basal cell carcinoma. Indian Dermatol Online J. 2013;4(1):12-17. 36. Margaret M, Basset-Seguin N, Dummer R, et al. Metastatic basal cell carcinoma: prognosis dependent on anatomic site and spread of disease. Eur J Cancer. 2014;50(4)774-83. 37. Pieh S, Kuchar A. Long term results after surgical basal cell carcinoma excision in the eyelid region. Br J Ophthalmol. 1999;83:85-8. 38. Lewis KG, Weinstock MA. Trends in nonmelanoma skin cancer mortality rates in the United States, 1969 through 2000. J Invest Dermatol. 2007;127:2323-7. 39. Berg D, Otley C. Skin cancer in organ transplant recipients: epidemiology, pathogenesis, and management. J Am Acad Dermatol. 2002;47:1-20. 40. Yakubu A, Mabogunje OA. Skin cancer in African Albinos. Acta Ongologica. 1993;32(6):621-2. 41. Chuang T, Heinrich L, et al. PUVA and skin cancer: a his­ torical cohort study on 492 patients. J Am Acad Dermatol. 1992;26(2, Part 1):173-7.

Chapter 9: Pathology of Cutaneous Malignancies of the Head and Neck

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1. Toker C. Trabecular carcinoma of the skin. Arch Dermatol. 1972;105:107 10. 2. Merkel F. Tastzellen und Taskoerperchen bei den Haustieren und beim Menschen. Arch Mikr Anat. 1875;2:636 52. 3. Feng H, Shuda M, Change Y, et al. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science. 2008;319:1096 199. 4. Albores Saavedra J, Batich K, Chable Montero F, et al. Merkel cell carcinoma demographics, morphology, and survival based on 3870 cases: a population based study. J Cutan Pathol. 2010;37:20 27. 5. Mott RT, Smoller BR, Morgan MB. Merkel cell carcinoma: a clinicopathologic study with prognostic implications. J Cutan Pathol. 2004;31:217 23. 6. Koljonen V, Kukko H, Tukiainen E, et al. Incidence of Merkel cell carcinoma in renal transplant recipients. Nephrol Dial Transplant. 2009;24:3231 5. 7. Buell JF, Trofe J, Hanaway MJ, et al. Immunosuppression and Merkel cell cancer. Transplantation Proc. 2002;34:1780 1. 8. Engels EA, et al. Merkel cell carcinoma and HIV infection. Lancet. 2002;359:497 8. 9. Koljonen V, Kukko H, Pukkala E, et al. Chronic lymphocytic leukaemia patients have a high risk of Merkel cell polyomavirus DNA positive Merkel cell carcinoma. Br J Cancer. 2009;101:1444 7.



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Merkel Cell Carcinoma















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58. McLean T, Brunner M, Ebrahimi A, et al. Concurrent primary and metastatic cutaneous head and neck squa mous cell carcinoma: analysis of prognostic factors. Head Neck. 2013;35(8):1144 8. doi: 10.1002/hed.23102. Epub 2012 Aug 21. 59. Nuño González A, Vicente Martín FJ, et al. High risk cuta­ neous squamous cell carcinoma. Actas Dermosifiliogr. 2012;103(7):567 78. Epub 2012 Jan 17. 60. Schmults CD, Karia PS, Carter JB, et al. Factors predictive of recurrence and death from cutaneous squamous cell carcinoma: a 10 year, single institution cohort study. JAMA Dermatol. 2013;149(5):541 7. 61. Clayman GL, Lee JJ, et al. Mortality risk from squamous cell skin cancer. J Clin Oncol. 2005;23(4):759 6. 62. Rowe DE, Carroll RJ, Day CL Jr. Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection. J Am Acad Dermatol. 1992; 26(6):976 90. 63. Solares CA, Lee K, Parmar P, et al. Epidemiology of clinical perineural invasion in cutaneous squamous cell carcinoma of the head and neck. Otolaryngol Head Neck Surg. 2012;146(5):746 51. 64. Carter JB, Johnson MM, Chua TL, et al. Outcomes of pri­ mary cutaneous squamous cell carcinoma with perineu­ ral invasion: an 11 year cohort study. JAMA Dermatol. 2013;149(1):35 41. 65. Christenson LJ, Borrowman TA, Vachon CM, et al. Incidence of basal cell and squamous cell carcinomas in a population younger than 40 years. JAMA. 2005;294(6):681 90.



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42. Stern R, Laird N, Melski J, et al. Cutaneous squamous cell carcinoma in patients treated with PUVA. N Engl J Med. 1984;310:1156 61. 43. Veness MJ, Palme CE, Morgan GJ. High risk cutaneous squamous cell carcinoma of the head and neck: results from 266 treated patients with metastatic lymph node disease. Cancer. 2006;106(11):2389 96. 44. Yantsos VA, Conrad N, Zabawski E, et al. Incipient intraepi­ dermal cutaneous squamous cell carcinoma: a proposal for reclassifying and grading solar (actinic) keratoses. Semin Cutan Med Surg. 1999;18(1):3 14. 45. Schwartz RA, Bridges TM, Butani AK, et al. Actinic kera­ tosis: an occupational and environmental disorder. J Eur Acad Dermatol Venereol. 2008;22(5):606 15. 46. Moon TE, Levine N, Cartmel B, et al. Effect of retinol in preventing squamous cell skin cancer in moderate risk subjects: a randomized, double blind, controlled trial. Southwest Skin Cancer Prevention Study Group. Cancer Epidemiol Biomarkers Prev. 1997;6:949 56. 47. Mandrell JC, Santa Cruz D. Keratoacanthoma: hyperplasia, benign neoplasm, or a type of squamous cell carcinoma? Semin Diagn Pathol. 2009;26(3):150 63. 48. Kossard S, Tan KB, Choy C. Keratoacanthoma and infundib­ ulocystic squamous cell carcinoma. Am J Dermatopathol. 2008;30(2):127 34. 49. Tan KB, Lee YS. Immunoexpression of Bcl x in squamous cell carcinoma and keratoacanthoma: differences in pattern and correlation with pathobiology. Histopathology. 2009;55(3):338 45. 50. Melendez ND, Smoller BR, Morgan M. VCAM (CD 106) and ICAM (CD 54) adhesion molecules distinguish kera­ toacanthomas from cutaneous squamous cell carcinomas. Mod Pathol. 2003;16(1):8 13. 51. Petter G, Haustein UF. Squamous cell carcinoma of the skin—histopathological features and their significance for the clinical outcome. J Eur Acad Dermatol Venereol. 1998; 11(1):37 44. 52. Joseph MG, Zulueta WP, Kennedy PJ. Squamous cell carcinoma of the skin of the trunk and limbs: the incidence of metastases and their outcome. Aust N Z J Surg. 1992; 62:697. 53. Brantsch KD, Meisner C, Schönfisch B, et al. Analysis of risk factors determining prognosis of cutaneous squamous cell carcinoma: a prospective study. Lancet Oncol. 2008;9:713. 54. Brougham ND, Dennett ER, Cameron R, et al. The inci­ dence of metastasis from cutaneous squamous cell car­ cinoma and the impact of its risk factors. J Surg Oncol. 2012;106:811. 55. Cutaneous squamous cell carcinoma. N Engl J Med. 2001; 344:975 83. 56. Cockerell CJ. Histopathology of incipient intraepidermal squamous cell carcinoma (‘actinic keratosis’). J Am Acad Dermatol. 2000;42(1, Part 2):11 7. 57. Anwar J, Wrone DA, Kimyai Asadi A, et al. The development of actinic keratosis into invasive squamous cell carcinoma: evidence and evolving classification schemes. Clin Dermatol. 2004;22(3):189 96.

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10. Milman T, McCormick SA. The molecular genetics of eyelid tumors: recent advances and future directions. Graefes Arch Clin Exp Ophthalmol. 2013;251:419-33. 11. Becker JC, Houben R, Ugurel S, et al. MC Polyomavirus is frequently present in Merkel cell carcinoma of European patients. J Invest Dermatol. 2009;129:248-50. 12. Schrama D, Peitsch WK, Zapatka M, et al. Merkel cell polyomavirus status is not associated with clinical course of Merkel cell carcinoma. J Invest Dermatol. 2011;131:1631-8. 13. Andres C, Belloni B, Puchta U, et al. Prevalence of MCPyV in Merkel cell carcinoma and non-Merkel cell carcinoma tumors. J Cutan Pathol. 2010;37:28-34. 14. Sihto H, Kukko H, Koljonen V, et al. Clinical factors associated with Merkel cell polyomavirus infection in Merkel cell carcinoma. J Natl Cancer Inst. 2009;101:938-45. 15. Traest K, De Vos R, van den Oord JJ. Pagetoid Merkel cell carcinoma: speculations on its origin and the mechanism of epidermal spread. J Cutan Pathol. 1999;26:362-5. 16. Smith KJ, Skelton HG 3rd, Holland TT, et al. Neuroendocrine (Merkel cell) carcinoma with an intraepidermal component. Am J Dermatopathol. 1993;15(6):528-33. 17. Acebo E, Vidaurrazaga N, Varas C, et al. Merkel cell car­ cinoma: a clinicopathologic study of 11 cases. JEADV. 2005; 19:546-51. 18. Hattori H. Merkel cell carcinoma composed of small, intermediate and squamous cell foci showing mutually exclusive expression of neuroendocrine markers and cytokeratin 20. Br J Dermatol. 2003;148:183-5. 19. Assouline A, Levy A, Chargari C, et al. Clinical and therapeu­ tic aspects in elderly patients with Merkel cell carcinoma: special focus on radiotherapy. JAGS. 2009;57(10):1946. 20. Goldberg SR, Neifeld JP, Frable WJ. Prognostic value of tumor thickness in patients with Merkel cell carcinoma. J Surg Oncol. 2007;95:618-22. 21. Schrama D, Ugurel S, Becker JC. Merkel cell carcinoma: recent insights and new treatment options. Curr Opin Oncol. 2012;24:141-9.

Malignant Adnexal Tumors of the Head and Neck 1. Chai LL, Bi S, Dai X, et al. Huge trichilemmal carcinoma of the scalp. Chin Med J (Engl). 2013;126(23):4599. 2. Kirby JS, Siebert Lucking SM, Billingsley EM. Trichoblastic carcinoma associated with multiple familial trichoepithe­ lioma. Dermatol Surg. 2012;38(12):2018-21. 3. Kazakov DV, Vittay G, Michal M, et al. High-grade tri­ cho­blastic carcinosarcoma. Am J Dermatopathol. 2008; 30(1):62-4.

4. Eskander A, Ghazarian D, Bray P,et al. Squamous cell carcinoma arising in a proliferating pilar (trichilemmal) cyst with nodal and distant metastases. J Otolaryngol Head Neck Surg. 2010;39(5):E63-7. 5. Khaled A, Kourda M, Fazaa B, et al. Malignant proliferat­ ing trichilemmal cyst of the scalp: histological aspects and nosology. Pathologica. 2011;103(3):73-6. 6. Lopez-Rios F, Rodriguez-Peralto JL, Aguilar A, et al. Pro­ liferating trichilemmal cyst with focal invasion: report of a case and a review of the literature. Am J Dermatopathol. 2000;22(2):183-7. 7. Troiano G, Staibano S, Licata ME, et al. Sebaceous carci­ noma of the lip. Ann Stomatol (Roma). 2013;4(Suppl 2): 46-7. 8. Alawi F, Siddiqui A. Sebaceous carcinoma of the oral mucosa: a case report and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2005;99(1):79-84. 9. Jakobiec FA, Mendoza PR. Eyelid sebaceous carcinoma: clinicopathologic and multiparametric immunohistochem­ ical analysis that includes adipophilin. Am J Ophthalmol. 2014;157(1):186-208. 10. Hoang MP, Dresser KA, Kapur P, et al. Microcystic adnexal carcinoma: an immunohistochemical reappraisal. Mod Pathol. 2008;21(2):178-85. 11. Antley CA, Carney M, Smoller BR. Microcystic adnexal carcinoma arising in the setting of previous radiation therapy. J Cutan Pathol. 1999;26(1):48-50. 12. Ramakrishnan R, Chaudhry IH, Ramdial P, et al. Primary cutaneous adenoid cystic carcinoma: a clinicopathologic and immunohistochemical study of 27 cases. Am J Surg Pathol. 2013;37(10):1603-11. 13. Barnes J, Garcia C. Primary cutaneous adenoid cystic car­ cinoma: a case report and review of the literature. Cutis. 2008;81(3):243-6. 14. Sidiropoulos M, Sade S, Al Habeeb A, et al. Syringoid eccrine carcinoma: a clinicopathological and immuno­ histochemical study of four cases. J Clin Pathol. 2011; 64(9):788-92. 15. Jung YH, Jo HJ, Kang MS. Squamoid eccrine ductal carci­ noma of the scalp. Korean J Pathol. 2012;46(3):278-81. 16. Ahmed MK, Ishino T, Hirakawa K, et al. Syringoid eccrine carcinoma of external auditory canal. A case report. Auris Nasus Larynx. 2010;37(4):519-21. 17. Ohnishi T, Kaneko S, Egi M, et al. Syringoid eccrine carci­ noma: report of a case with immunohistochemical analy­ sis of cytokeratin expression. Am J Dermatopathol. 2002; 24(5):409-13. 18. Weinreb I, Bergfeld WF, Patel RM, et al. Apocrine carci­ noma in situ of sweat duct origin. Am J Surg Pathol. 2009; 33(1):155-7.

Chapter 9: Pathology of Cutaneous Malignancies of the Head and Neck

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PART C: CUTANEOUS MESENCHYMAL TUMORS OF THE HEAD AND NECK

DERMATOFIBROSARCOMA PROTUBERANS Clinical Background Dermatofibrosarcoma protuberan (DFSP) is a sarcoma of the skin and subcutaneous tissue that is seen in a wide age range and at a variety of sites. The most common location, representing about half of cases, is the trunk,1–3 with fewer than 20% of cases occurring on the head and

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Histologic Features

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The classic DFSP is a relatively cellular tumor composed of bland spindle cells arranged in a storiform or pinwheel pattern (Fig. 9.16). The cytology is typically low grade with mitoses being rare. A distinctive morphologic clue to the diagnosis is the pattern of fat infiltration that pro­ duces a honeycomb pattern around adipocytes.8 Nume­ rous histologic variants have been reported, including myxoid change,8 focal pigmentation (so called Bednar tumor),5,7 and the presence of multinucleated giant cells in some cases.5 Sarcomatous transformation may be seen in DFSP, most often referred to as fibrosarcomatous transforma tion and occurring in approximately 10–20% of cases.5,8 This change is defined as a distinct morphologic change in the tumor characterized by a herringbone pattern reminiscent of fibrosarcoma, increased cellularity, atypia and mitotic rate.5,8 Although the majority show these changes and resemble fibrosarcoma, a small number of transformed DFSP instead show more bizarre cytology morphologically in keeping with so called malignant fibrous histiocytoma. Of transformed DFSP, the majority are of fibrosarcomatous morphology.3,9 This change occurs most often de novo in DFSP but can be seen as a recurrence in some cases.2,3 Fibrosarcomatous areas make up a variable percentage of the tumor as a whole, ranging from 5% to 95% of the total tumor.2,3 -

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As in other cutaneous sites, in addition to epithelial tumors and melanocytic tumors, the mesenchymal ele­ ments of the skin of the head and neck can give rise to numerous neoplasms. Most mesenchymal neoplasms of the skin are uncommon; those that are most common on the head and neck will be discussed in more detail here. Mesenchymal neoplasms may differentiate toward any of the elements normally found in the skin such as neural, smooth muscle, vascular, etcetera, and these neoplasms show varying degrees of differentiation, with some closely resembling their normal counterparts, and others being simply pleomorphic or anaplastic neop­ lasms. Essentially, mesenchymal neoplasms of the skin fall under the category of “spindle cell lesions of the skin.” It is important from a pathologic standpoint to have a standard approach to diagnosing spindle cell lesions of the skin, which includes attention to morphologic clues, as well as a basic immunohistochemical panel to diffe­ rentiate these neoplasms. The differential diagnosis of spindle cell lesions of the skin includes mesenchymal tumors such as atypical fibro­ xanthoma (AFX), atypical intradermal smooth muscle neoplasms (AISMNs; formerly called leiomyosarcoma of the skin), angiosarcoma (AS), dermatofibrosarcoma pro­ tuberans, and Kaposi sarcoma (KS), as well as other less common tumors. Also critical when evaluating spindle cell lesions of the skin is to remember that both melanoma and SCC may present as spindle cell lesions; therefore, it is essential to include markers of melanocytic and epithe­ lial differentiation in any immunopanel targeted at spin­ dle cell skin tumors. Clues for the differential diagnosis of atypical spindle cell lesions of the skin are summarized in Table 9.16.

neck.2,3 On the head and neck, the scalp and supraclavi­ cular fossa are the most common sites of involvement.3,4 The site of involvement does not differ based on age or histologic pattern.1,5 In all sites, the tumor may be locally infiltrative; in the scalp, this pattern may lead to bone erosion or even brain invasion.6 Men are affected slightly more often than women4 and tumors arise most often in middle age,4 with a higher median age reported in cases showing fibrosarcomatous transformation (FS DFSP) compared to conventional DFSP.5 Dermatofibrosarcoma protuberan is rare in chil­ dren, with fewer than 200 cases reported.1 The clinical presentation has been reported to be variable in children, in whom the tumor may be congenital or acquired.1 Clinically, the lesions present as a slow growing macule, nodule, or plaque that may be exophytic.1,4,7 Coloration of the lesion is variable, and pigmentation occurs in some cases.1,7 The size ranges from 2 cm to 5 cm.4



INTRODUCTION

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Head and Neck Surgery

Table 9.16: Differential diagnosis of primary atypical spindle cell lesions of the skin

Morphologic clues

Immunohistochemistry

Atypical fibroxanthoma •  B  izarre pleomorphic cytomorphology with •  CD10, procollagen, CD68, vimentin positive multinucleated giant cells or fascicular spindle •  F  actor XIIIA variable cell tumor with high-grade nuclear features and •  Negative for markers of epithelial, mesenchy­ brisk mitotic rate with atypical mitoses mal, vascular and smooth muscle differentia­ •  No epidermal involvement tion* Spindle cell melanoma

•  E  pidermal in situ component may be present with nests •  Cytoplasmic pigmentation, sometimes

•  P  ositive for some or all melanocytic markers (S100, HMB45, MelanA, Sox10, MiTF), WT-1 (cytoplasmic) •  May be CD10 positive in some cases •  May show focal positivity for other markers such as CK18, Cam5.2

Spindle cell SCC

•  M  ay see in situ carcinoma or AK overlying the invasive lesion or focal attachment to the epidermis •  Look for evidence of squamous differentiation (keratinization, intercellular bridges)

•  P  ositive for epithelial markers such as CK5, p63, high molecular weight keratin •  If positivity for low molecular weight keratins is seen, consider metastatic carcinoma or primary skin carcinoma of adnexal origin

Angiosarcoma

•  C  an be epithelioid or spindled •  Look for vasoformative areas and cytoplasmic lumina

•  P  ositive for some or all vascular markers (ERG, CD31, Fli-1, CD34, D2-40, FVIII, WT-1 and SMA)

Atypical intradermal smooth muscle neo­ plasm

•  L  ower grade tumors show a more uniform fascicular spindle cell population with less pleomorphism than typical AFX

•  P  ositive for muscle markers (smooth muscle actin†, desmin, caldesmon)

Kaposi sarcoma

•  D  issecting spindle cells forming vascular chan­ •  Positive for D2-40, CD34 nels in early stages •  V  irtually all cases positive for HHV-8 •  In later stages, nodular proliferations of spindle cells with or without vascular channels

Malignant peripheral nerve sheath tumor‡

•  V  ariable morphology including spindled and epithelioid variants, possibly arising in the set­ ting of neurofibromatosis

Rhabdomyosarcoma‡

•  V  ariable forms including spindle cell, rhabdoid, •  Positive for markers of muscle differentiation and pleomorphic (desmin, myogenin, MyoD1)

Interdigitating den­ dritic cell sarcoma‡

•  S  pindle cell tumor with cytologic atypia and •  Positive for WT-1 and melanocytic markers mitoses, often with brisk lymphoplasmacytic •  C  haracteristic electron microscopic findings infiltrates help in the distinction with melanoma •  May be indistinguishable morphologically from metastatic melanoma •  No epidermal connection

•  S  100 may be only focal or weak when com­ pared to benign nerve sheath tumors

(AFX: Atypical fibroxanthoma; MiTF: Microphthalmia transcription factor). *Occasional cases of AFX are positive for some markers of other differentiation, such as SMA and CD31. †Occasional cases of AFX are positive for smooth muscle actin. ‡Readers are referred to other specialized texts for further consideration of these uncommon entities.

When metastases occur, they are usually of similar morphology to the primary tumor.8

Ancillary Studies Immunohistochemistry is frequently used to confirm a diagnosis of DFSP. Dermatofibrosarcoma protuberan is a CD34-positive tumor, with positivity for this marker in

> 90% of cases.3,10 CD34 has been used in some centers in a frozen section setting for assessment of margins.6 Although CD34 is a reliable marker for DFSP, one must be aware that the transformed areas of DFSP are less often and less strongly positive for CD34.2,3 Other markers distinguishing conventional DFSP from FS-DFSP are MIB1 and p53, both of which show greater expres­sion in FS-DFSP.2,8

Chapter 9: Pathology of Cutaneous Malignancies of the Head and Neck

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Table 9.17: Differentiating dermatofibroma and dermatofibrosarcoma protuberans

DFSP

DF

Architecture

Plaque-like, deep extension “Honeycombing” around adipocytes in the fat

•  C  ircumscribed edge •  Wrapping of collagen bundles at the periphery of the lesion •  No deep extension into subcutis, no “honeycombing”

Immunohis­ tochemistry

•  C  D34 positive •  D2-40, Factor XIIIA negative or patchy •  CD68 usually negative or focal/ patchy

•  C  D34 negative •  D2-40, Factor XIIIA, CD68 positive

Cytogenetics

t(17;22) fusion in majority of cases

No t(17;22) fusion

Fig. 9.16: Dermatofibrosarcoma protuberans shows a storiform pattern of spindle cells with only mild cytologic atypia.

Unlike DF, DFSP is typically negative for Factor XIIIA and for D2-4011 but is positive for vimentin. CD68 is variable but also frequently negative in DFSP. Dermatofibrosarcoma protuberan is now known to be a translocation sarcoma, with the majority of cases (> 85% in most series) showing t(17;22) COL1A1-PDGFB.10,12–14 Microsatellite instability has been detected, most com­ monly in FS-DFSP.15

Differential Diagnosis The diagnosis of DFSP is not difficult on morphologic grounds alone when a generous biopsy, including sub­ cutis, is available. However, in practice, several other entities enter into the differential, particularly when only a partial biopsy has been performed. The main differential diagnosis includes cellular DF and deep cellular DF, solitary fibrous tumor, and spindle cell lipoma. Other malignancies, including spindle cell melanoma and carcinoma as well as smooth muscle and neural tumors, also enter the differential diagnosis. The finding of a t(17;22) fusion is characteristic of DFSP and is not seen in any of the other entities on the differential.12 However, rare cases of DFSP are negative by FISH for this translocation. The differentiating features between DF and DFSP are summarized in Table 9.17. The cytomorphology of DF is similar to DFSP, with bland spindle cells infiltrating the dermis. The periphery of DF tends to show enwrap­ ping of collagen bundles, which is not seen in DFSP.

(DF: Dermatofibroma; DFSP: Dermatofibrosarcoma protuberans).

Furthermore, DF may show focal infiltration of the subcu­ taneous fat, but does not show honeycombing around adipocytes as in DFSP. By immunohistochemistry, DF is diffusely positive for factor XIIIA and negative or shows very minimal reactivity for CD34.11 D2-40 has also been used, reported to be strongly positive in DF and negative or weak and patchy in DFSP.11 Solitary fibrous tumor (SFT) also may show similar cytomorphology to DFSP but may have more distinct dilated vascular channels intermixed with the tumor. Solitary fibrous tumor also shows immunohistochemi­ cal overlap with DFSP, including CD34 positivity. In one study, the presence of tumor proliferating around adnexal units resulting in adnexal entrapment was found in nearly all cases of DFSP but not in SFT.16 FISH for the t(17;22) translocation will be negative in SFT. Spindle cell lipoma shares an immunoprofile with DFSP but lacks the fusion transcript and shows distinct morphologic features, including adipose tissue as an intrinsic part of the lesion rather than being entrapped by the spindle cell component, as well as frequent myxoid changes in the stroma, which is less often seen in DFSP. Spindle cell melanoma and carcinoma can usually be easily ruled out as both typically show a greater degree of cytologic atypia and more mitotic figures than DFSP. Both are negative for CD34 in the majority of cases. Spindle cell melanoma is positive for S100, and some­times

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for HMB45 and MelanA, and spindle cell carci­ noma is positive for markers of epithelial differentiation such as p63 and cytokeratin; these immunohistochemical mar­kers are negative in DFSP. S100, neuron-specific enolase and neurofilament im­ mu­nohistochemistry help to differentiate neural tumors (positive for these markers) from DFSP (typically negative). Furthermore, DFSP is negative for markers of smooth muscle differentiation, distinguishing it from neoplasms of muscle derivation.

Prognosis The prognosis of DFSP is relatively good but local recur­ rences are not uncommon, occurring in 20–75% of cases2,4,8 with higher rates of recurrence reported in head and neck tumors.4 Local recurrence may be more fre­quent in FS-DFSP but the rates are variable across different studies.2,3,17 Recurrences occur within the first 3–5 years of the diagnosis in most cases. Frozen section is sometimes used to ensure clear margins when re-excising DFSP. This approach is useful but must be employed with the caveat that the frozen sections should be interpreted by a pathologist with expe­ rience evaluating these specimens. It can be extremely challenging on frozen section to distinguish DF from scar tissue. Distant metastases most often involve the lung or bone4 and occur in 3–6% of conventional cases.4,9 In most studies, metastases are more common in FS-DFSP, occurring in between 10% and 15% of cases,2,17 although one series showed no metastases in 18 cases of FS-DFSP.3 The overall five-year survival is > 90%,8,18 with the presence of metastases the only factor significantly correlated with overall survival in one study.8 The most consistently agreed-upon risk factor for local recurrence is inadequate surgical margins.8 Factors correlating with decreased recurrence free survival also include acral location of tumor8 and presence of fibro­ sa­rcomatous change in some studies8 but not others.3 Vari­ables thus far not associated with outcome include pro­portion of fibrosarcomatous change within a tumor, mitotic count, or the presence or absence of the t(17;22) translocation.2,10 In order to diminish the risk of local recurrence, wide local excision with 2.0 or 2.5 cm margins is advocated.6,17 Periosteum should be stripped in scalp cases.6 Adjuvant radiation therapy may be used for tumors with invol­ ved margins17 or as a primary mode of treatment in

unresect­able cases.18 Treatment with targeted therapy such as imatinib is also useful in those with unresectable or metastatic disease.17

ANGIOSARCOMA Clinical Background Angiosarcoma is a tumor that can arise from a range of body sites from skin to visceral organs. In the skin, AS tends to arise in three different clinical settings: in the setting of chronic lymphedema, in areas of previous radiation, and in the sun-exposed head and neck of the elderly. Only the latter clinical setting will be further considered here, with this group accounting for > 50% of all cutaneous ASs.1 Angiosarcoma of the head and neck is typically a disease of the elderly, with the median age in the eighth decade,2,3 but a wide age range has been reported. Most studies show males affected more often than females,1,2 although this has not been invariably true.3 Of head and neck tumors, the scalp is the most frequent subsite of involvement.4,5 The lesion presents most often as a plaque or bruiselike area on the sun-exposed skin with an average size of 3–4 cm.1,4 Erythematous or purple color may be observed, and larger nodular tumors may develop. The clinical features may be nonspecific and the diagnosis may not be suspected by the clinician, with systemic lupus erythematosus being suggested on the clinical differential in a number of cases.2 In one study, about a third of patients with AS of the head and neck presented with multifocal disease.5

Histologic Findings A range of morphologic differentiation can be seen in AS, with well-differentiated tumors being obviously vaso­ formative and composed of vascular spaces lined by plump endothelial cells showing hyperchromasia and varying cytologic atypia. Mitoses may be seen but are rare in low-grade lesions. With increasing grade, a solid com­ ponent may become predominant with vascular spaces being difficult to find. Severe pleomorphism and nume­ rous mitoses may be found in high-grade examples. Epithelioid morphology is not uncommon at least focally within AS and is reported in between 12% and 17% of cases.1,3 Divergent morphologies including Masson body-like morphology, plasmacytoid features, cytoplas­ mic clearing, and pseudoglandular formations have been reported.3 Caution should be exercised in superficial

Chapter 9: Pathology of Cutaneous Malignancies of the Head and Neck biopsies that may show these divergent morphologies. Necrosis is seen in some cases,1 and in one study, the presence of epithelioid features and/or necrosis was proposed to be useful in distinguishing high-risk tumors from low-risk tumors.1 These features should be recorded in the pathology report if they are identified within a specimen. Angiosarcoma may involve any part of the skin with the majority involving the deep dermis and/or subcutis, but some can be confined to either the papillary or reticular dermis.1

Ancillary Studies In cases that are obviously vasoformative, ancillary studies may not be required. However, in predominantly solid or epithelioid cases, immunohistochemistry is useful in ruling out other entities on the differential. Vascular markers are generally positive. Most reliable is CD31, positive in 90–100% of cases.2,3,6,7 Factor VIII is variable, with some reports showing all cases positive and others showing only a subset of positive cases.2,6,7 CD34 is variable, positive in 20–75% of cases.2,3,6,7 A recent study has shown ERG and FLI1 positivity to be useful in the diagnosis of cutaneous AS, with all cases positive for both markers in the series.8 At least some ASs are thought to be of lymphatic origin, which is reflected in D2-40 positivity in most cases.2 Vimentin is nonspecific but is usually positive.2 Nega­ tive immunohistochemical stains include S100, CD45, MelanA, desmin, CD30, and EMA,3 although aberrant S100 staining has been reported in one case.7 Although cytokeratin positivity has been reported in some epithelioid AS at various sites, the majority of studies have found cytokeratin to be negative in all AS cases,2,3,6,7 including epithelioid AS.

Differential Diagnosis As mentioned, the diagnosis of AS in cases with wellformed vascular differentiation is not challenging. In those epithelioid or solid cases, the differential diagnosis is broad and includes carcinoma, melanoma, and other sarcomas. Immunohistochemistry is usually able to distinguish these entities reliably using a basic panel of markers. In most cases, the use of CD31, pancytokeratin, S100, and smooth muscle actin will be useful, with these markers typically positive for AS, carcinoma, melanoma, and leiomyosarcoma, respectively, and negative for the

183

Table 9.18: High-risk features in angiosarcoma

Tumor necrosis Epithelioid morphology Increasing tumor depth Tumor size > 5 cm Satellitosis

other markers. Atypical fibroxanthoma, also on the differ­ ential, is typically negative for all of the above markers but may be positive for CD10 and procollagen. In some cases, AS may have a prominent lymphoid background that may mask the vascular proliferation and instead give the impression of a lymphomatous lesion.9 It is important to be aware of this variant by recognizing the presence of larger, nonlymphoid cells admixed with the background population. New evidence suggests that ERG may be a reliable marker for AS, being reported as positive in all cases of AS and negative in all cases of SCC, atypical fibroxanthoma, melanoma, and leiomyosarcoma in one study.8

Prognosis The prognosis of AS is poor, with the 5-year disease free survival reported between 26% and 48%.1,5 Local recur­ rence and metastases to lung, liver, lymph node, and other sites are common.1,5 Histologically, it has been proposed that dividing AS into high- and low-risk groups based on the presence of necrosis and/or epithelioid morphology can stratify tumors prognostically.1 Other features associated with higher risk of recurrence and/or mortality include tumor depth, tumor size > 5 cm, satellitosis, and high histologic grade.1,4,10 Older age and primary site of extremities or trunk versus head and neck1 as well as predominantly vasoformative as opposed to solid tumors11 have also been reported as indicative of poor outcomes. High-risk features in AS are summarized in Table 9.18. While surgery is the mainstay of treatment, combi­ ned treatment modalities including radiation therapy have been associated with better overall and diseasespecific survival in some studies;5,10 however, treatment moda­lity was not correlated with outcome in other stu­ dies.1 Pro­phylactic regional lymph node dissection may result in prolonged time to local recurrence or distant metastasis.12

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Head and Neck Surgery

ATYPICAL FIBROXANTHOMA Clinical Background Atypical fibroxanthoma is a sarcomatoid neoplasm of the skin that most commonly presents on the sun-exposed head and neck of elderly patients. Men are affected more often than women,1,2 and many patients have a history of other skin lesions such as keratosis and epithe­ lial skin carcinomas.1 In younger patients, the tumor may arise on other sites such as trunk or limbs.1 In addition to UV exposure,3 there is an increased risk of developing AFX in patients who are immunocompromised, such as organ transplant patients, in whom the tumor tends to arise at a younger age and behave more aggressively.4 The tumors are usually rapidly growing, of short duration, and often show surface ulceration.1 The median size at presentation in one study was 25 mm.2 There are no specific clinical features to allow definitive diagnosis.

Histologic Findings The morphologic features of AFX are variable. The clas­ sic appearance is that of a dermal tumor composed of bizarre and pleomorphic cells with numerous mitoses, arranged in haphazard sheets1 (Figs. 9.17 and 9.18). Multi­ nucleated giant cells are frequent. However, some cases show predominant spindle-cell morphology, with more uniform atypical spindle cell morphology and a fascicular arrangement of tumor cells.1 The epidermis is not involved but is often thinned over the lesion and may be ulcerated.1

Fig. 9.17: Atypical fibroxanthoma.

Architecturally, the tumor is often circumscribed and shows expansile rather than infiltrative growth at the periphery.1 Dilated capillaries and a lymphoplasmacytic infiltrate may be seen within the tumor or at the peri­ phery.1 In the tumor background, there may be actinic damage,1 and other lesions such as DF, SCC, or AK may also be associated with AFX.1 Occasionally, extensive fibrosis within a lesion may inhibit recognition of the neoplastic cells.5 In recent years, distinction has been made between AFX and a morphologically similar tumor termed pleo­ morphic dermal sarcoma (undifferentiated pleomorphic sarcoma of the skin). The differentiating feature between these tumors is infiltration of the subcutaneous or deeper tissues in the latter, sometimes with necrosis, lympho­ vascular or perineural invasion, and a more infiltrative rather than expansile growth pattern.2 Recognition of these features microscopically is important because tumors with these features tend to behave more aggressively.

Ancillary Studies Atypical fibroxanthoma has a nonspecific morphology and immunoprofile and is therefore a diagnosis of exclu­ sion. Therefore, the primary role for ancillary studies is to exclude other entities in the differential diagnosis. Positive immunomarkers in AFX include vimentin, CD10, and procollagen; however, none of these are specific. Atypical fibroxanthoma is typically negative for markers of melanocytic differentiation such as HMB45, MelanA, and S100, and for epithelial markers such as

Fig. 9.18: High-power image of atypical fibroxanthoma demonstrating pleomorphic spindle cells and atypical mitotic figures.

Chapter 9: Pathology of Cutaneous Malignancies of the Head and Neck

185

CK5/6, p63, and pancytokeratin, although rare cases have been reported as positive for some of these markers.2,6 It has been reported that D2-40 may be a useful marker for AFX, being positive in up to half of cases,6,7 but this marker may also be seen in other tumors. Smooth muscle actin, CD31, and EMA have been reported as positive in 70%, 45%, and 16%, respectively.6 By electron microscopy, the tumor shows fibrohis­ tiocytic features.8

Complete excision should be advised in all cases. In assessing risk for recurrence or metastases, the features of concern include invasion into subcutis or deeper struc­ tures, necrosis, lymphvascular invasion and perineural invasion.2 Complete excision and close follow-up are warranted in patients whose tumors exhibit any of these features.

Differential Diagnosis

Clinical Background

As mentioned above, the diagnosis of AFX is one of exclusion. The most important entities on the differential include spindle cell melanoma, spindle cell SCC, neural tumors such as schwannoma, AS, other fibrohistiocytic lesions, and other sarcomas. The distinction from melanoma and SCC is usually straightforward by immunohistochemistry. Melanoma is usually positive for one or more melanocytic markers such as S100, HMB45, and MelanA, while AFX is negative for these. Similarly, SCC will show some immunohistoche­ mical evidence of epithelial origin, including positivity for pancytokeratin, CK5/6, EMA, and p63, which are usu­ ally negative in AFX. Angiosarcoma is variably positive for CD31, CD34, and D2-40. Although CD31 and D2-40 are positive in a subset of AFX, the expression is typically less diffuse and strong than in AS. Also, morpho­logic evi­ dence of vascular differentiation can help in this distinction. Caution should be used when interpreting positive CD10 as diagnostic of AFX, as some positivity can be seen in other tumors, including melanoma, carcinoma, and leiomyosarcoma.6 Above all, the diagnosis of AFX requires a panel of immunohistochemical stains as well as a thorough search for morphologic clues to other diagnoses. Helpful clues in the differential diagnosis of AFX are summarized in Table 9.16.

Kaposi sarcoma is a typically low-grade malignancy that arises in a well-defined subset of patients in four specific clinical scenarios. Perhaps most well-known is the socalled epidemic form, where KS is associated with HIV infection and is considered an AIDS-defining illness. The other clinical settings include the “classic” form, typically in older men of Mediterranean descent; the “endemic” African form; and those cases associated with immunosuppression. Kaposi sarcoma can involve many visceral organs but is typically found on the skin and mucosal sites. There is some variation in site of presentation depending on the clinical form. It progresses clinically through patch, plaque, and tumor stages. In the patch stage, the lesions are red-purple in color and bruiselike. With progression, nodularity develops and ulceration may occur. In 1994, the etiology of KS was identified as HHV-8 or KSHV, a previously unknown human herpes virus.1 In addition to its association with KS, this virus has also been implicated in primary effusion lymphomas and in multicentric Castleman’s disease.2 The lesional cell in KS is believed to be a lymphatic endothelial cell.3-5

Prognosis Despite its frightening morphology, AFX is an indolent tumor. Some tumors recur, usually those that were inadequately excised. Metastases are very rare.1 The risk of aggressive behavior is increased in the pleomorphic dermal sarcomas, in which a 28% recurrence risk and 10% metastatic risk have been noted in one study.2 It should be noted, however, that this study found that the majority of metastases were to the skin and no tumor-related deaths occurred, even among pleomorphic dermal sarcoma cases.2

KAPOSI SARCOMA

Histologic Features The morphology of KS depends on the stage of the lesion. At the earliest, patch stage, the findings may be subtle, with a proliferation of mildly atypical spindle cells as well as newly formed vascular channels within the dermis. The initial biopsy impression may simply be that of a “busy dermis.” Some helpful clues to the diagnosis include the “promontory sign,” where ectatic, abnormally formed vascular spaces are present around pre-existing normal vessels, as well as the presence of a lymphoplasmacytic inflammatory infiltrate. As the lesions progress, they develop increased cel­ lularity and the formation of vascular channels may be less distinct (Fig. 9.19). Intracytoplasmic lumina may

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be seen, and extravasated blood or hemosiderin may be found. The cells also become plumper and may show increased atypia. Hyaline globules may be found within the cell cytoplasm. Several less common morphologic forms of KS have been described including glomeruloid, telangiectatic, ecchymotic, KS with myeloid nodules, and pigmented forms6 as well as vesiculobullous lesions.7

raise the differential of other spindle cell neoplasms such as atypical fibroxanthoma, AS, leiomyosarcoma, and spindle cell melanoma or carcinoma. The immunohisto­ chemical stains of diagnostic use in these other entities are generally negative in KS (excepting the overlap in staining by vascular markers in AS). Most helpful is HHV-8 immunostaining, which is negative in all entities on the differential diagnosis.

Ancillary Studies

Prognosis

Consistent with their lymphatic endothelial origin, the lesional cells of KS are positive for immunohistochemical markers such as D2-40, CD31, and CD34, as well as less commonly used immunostains such as Factor VIII and Ulex europaeus agglutinin-1.8 The most specific marker is an antibody against latent nuclear antigen (LNA-1) of HHV-8 (Fig. 9.20), which is positive in the vast majority of cases of KS (although there may be fewer positive cells in early, patch stage cases).2,8

The prognosis of KS depends on the clinical setting, with the classic form typically behaving indolently. Highly active antiretroviral therapy used in the treatment of HIV produces improvement or resolution of KS lesions and has also decreased the overall incidence of KS in the HIV-positive population.9 In immunosuppressed indi­ viduals and some cases of African KS, the prognosis is poorer than in other forms.

Differential Diagnosis In many cases, clinical suspicion is raised for KS based on history, including HIV-positive status or history of immu­nosuppression. The histologic differential diagnosis depends on the stage of lesion biopsied. Early, patch stage cases may resemble interstitial histiocytic dermatoses or fibrosing disorders. More cellular plaque or tumor lesions may

Fig. 9.19: Kaposi sarcoma, tumor stage, with a nodular proliferation of spindle cells without well-formed vascular channels.

ATYPICAL INTRADERMAL SMOOTH MUSCLE NEOPLASM Clinical Background Atypical intradermal smooth muscle neoplasm is the cur­ rently favored term to denote the rare neoplasms arising from dermal smooth muscle. The term AISMN is applied to those tumors previously called cutaneous leiomyosarcoma,

Fig. 9.20: HHV-8 positivity in Kaposi sarcoma.

Chapter 9: Pathology of Cutaneous Malignancies of the Head and Neck with the new nomenclature preferred as it more accurately reflects the low malignant potential of these neoplasms, particularly in comparison to leiomyosar­co­ mas of the deeper tissues.1 Only 4% of AISMNs occur in the head and neck region.1 Peak incidence has been reported in the fifth to seventh decades with 90% of the patients being ≥ 40 years of age. There is a striking male-to-female preponde­ ra­ nce.1,2 Most patients present with a solitary, slow-growing cutaneous nodule or mass, measuring 0.5–3 cm in size, which may be painful or asymptomatic.1,3 The majo­rity of lesions are grossly white or tan with infiltrative margins.1

Histology and Ancillary Studies Features Histologically, the majority of AISMNs are confined to the dermis. Some tumors show limited superficial exten­ sion into the fibrous septae or focal growth into the super­ ficial subcutis with pushing borders. The growth pattern is often diffusely infiltrative with fascicles of atypical spin­ dle cells arranged irregularly between dermal collagen bundles; however, some lesions show a combination of diffuse and nodular growth patterns.1 The lesional cells are variably atypical spindle cells that resemble the smooth muscle of the arrector pilae muscles. Ninety-seven percent of primary AISMNs are grade I lesi­ ons, according to the Fédération Nationale des Centres de Lutte Contre le Cancer grading system.1 Criteria for diagnosis of AISMN include primarily dermal cutaneous location with minimal subcutaneous extension, hyper­ cellularity, increased nuclear to cytoplasmic ratio, nuc­lear atypia, and presence of at least 1 mitosis/10 high power fields.4 Although presence of typical or atypical mitotic figure(s) is a very valuable diagnostic feature, it can ren­ der a diagnosis of AISMN only in combination with other morphologic features and immunohistoche­ mical evid­ ence of smooth muscle differentiation.1 Immunohistochemistry for smooth muscle actin and muscle specific actin, when used in combination, identi­ fies smooth muscle differentiation in 100% of the cases. All tumors are immunopositive for smooth muscle actin.1,4 These tumors are also typically positive for desmin and caldesmon.

Differential Diagnosis The differential diagnosis of AISMN includes all of the spindle cell neoplasms that can arise in the skin (see

187

Table 9.16), as well as benign proliferations of smooth muscle such as leiomyoma. A limited panel of key immunohistochemical stains (such as CD34, S100, and CK 5/6) should be used to distinguish AISMN from other spindle cell neoplasms of the skin.4 AISMNs are distinguished from benign leiomyomas by the presence of one or more mitotic figures; typically, AISMN also show a greater degree of cytologic atypia. It is very important to differentiate between AISMN and leiomyosarcoma of subcutaneous and deep soft tissue, because the former shows dramatically better survival and carries no, or an extremely low, risk of metastasis while the latter has greatly higher probability of metastasis and recur­ rence.4 It is also essential to distinguish between primary cuta­neous leiomyosarcoma and metastatic leiomyo­sarcoma to skin.5 Metastatic leiomyosarcoma to the skin indicates a high stage disease while primary cuta­neous leiomyo­sarcoma confined to the dermis or with minimal involve­ment of the subcutis has an excellent prognosis.1,2

Prognosis Despite their very low metastatic capacity, AISMNs are characterized by limited aggressiveness and the poten­ tial to invade underlying tissues.2,6 There is also a low rate of local recurrences, mainly due to failure to achieve nega­ tive margins.1,2 In fact, “true” recurrences in lesions excised with clear margins have not been reported. Recurrent tumors usually show more aggressive histolo­gic features such as more mitotic figures and cytologic atypia, as well as more frequent superficial subcutaneous extension, nec­ro­sis, and diffuse/nodular or purely nodular growth pattern.1 The single most important predictor of recur­rence in AISMN is margin status. Wide local excision is currently viewed as appropriate treat­ment for AISMN and sufficient to prevent recurrence.1

Radiation-Induced Leiomyosarcoma Radiation-induced leiomyosarcoma is an aggressive tumor with poor prognosis that occurs in the head and neck as a consequence of radiation therapy, e.g. for nasophar­yn­ geal carcinoma.7-9 The incidence of this tumor in radiated patients ranges from 0.035% to 0.2%.9 Dr Sanaz Sanii is gratefully acknowledged for her contribution to the AISMN portion of this chapter.

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Head and Neck Surgery

PART C REFERENCES 1. Kornik RI, Muchard LK, Teng JM. Dermatofibrosarcoma protuberans in children: an update on the diagnosis and treatment. Pediatr Dermatol. 2012;29(6):707-13. 2. Abbott JJ, Oliveira AM, Nascimento AG. The prognostic significance of fibrosarcomatous transformation in derma­ tofibrosarcoma protuberans. Am J Surg Pathol. 2006;30: 436-43. 3. Goldblum JR, Reith JD, Weiss SW. Sarcomas arising in der­ matofibrosarcoma protuberans: a reappraisal of biologic behaviour in eighteen cases treated by wide local exci­ sion with extended clinical follow up. Am J Surg Pathol. 2000;24(8):1125-30. 4. Barnes L, Coleman JA, Johnson JT. Dermatofibrosarcoma protuberans of the head and neck. Arch Otolaryngol. 1984; 110:398-404. 5. Connelly JH, Evans HL. Dermatofibrosarcoma protuber­ ans: a clinicopathologic review with emphasis of fibrosar­ comatous areas. Am J Surg Pathol. 1992;16(10):921-5. 6. Loss L, Zeitouni NC. Management of scalp dermatofibro­ sarcoma protuberans. Dermatol Surg. 2005;31:1428-33. 7. Dupree WB, Langloss JM, Weiss SW. Pigmented derma­ tofibrosarcoma protuberans (Bednar tumor): a pathologic, ultrastructural and immunohistochemical study. Am J Surg Pathol. 1985;9(9):630-9. 8. Erdem O, Wyatt AJ, Lin E, et al. Dermatofibrosarcoma pro­ tuberans treated with wide local excision and followed at a cancer hospital: prognostic significance of clinicopatho­ logic variables. Am J Dermatopathol. 2012;34:24-34. 9. Szollosi Z, Nemes Z. Transformed dermatofibrosarcoma protuberans: a clinicopathologic study of 8 cases. J Clin Pathol. 2005;58:751-6. 10. Llombart B, Sanmartin O, Lopez-Guerrero JA, et al. Dermatofibrosarcoma protuberans: clinical, pathologi­ cal, and genetic (COL1A1-PDGFB) study with therapeutic implications. Histopathol. 2009;54:860-72. 11. Bandarchi B, Ma L, Marginean C, et al. D2-40, a novel immunohistochemical marker in differentiating derma­ tofibroma from dermatofibrosarcoma protuberans. Mod Pathol. 2010;23:434-8. 12. Segura S, Salgado R, Toll A. Identification of t(17;22) (q22;q13) (COL1A1-PDGFB) in dermatofibrosarcoma pro­ tuberans by fluorescence in situ hybridization in paraffinembedded tissue microarrays. Hum Pathol. 2011;42:176-84. 13. Minoletti F, Miozzo M, Pedeutour F, et al. Involvement of chromosomes 17 and 22 in dermatofibrosarcoma protu­ berans. Genes Chromosomes Cancer. 1995;13:62-65. 14. Patel KU, Szabo SS, Hernandez VS, et al. Derma­ to­ fi­ brosarcoma protuberans COL1A1-PDGFB fusion is identified in virtually all dermatofibrosarcoma protuberans cases when investigated by newly developed multiplex reverse transcription polymerase chain reaction and fluorescence in situ hybridization assays. Hum Pathol. 2008;39:184-93. 15. Takahira T, Oda Y, Tamiya S, et al. Microsatellite insta­ bility and p53 mutation associated with tumor progres­ sion in dermatofibrosarcoma protuberans. Hum Pathol. 2004;35:240-5.

16. Wood L, Fountaine TJ, Rosamilia L, et al. Cutaneous CD34+ spindle cell neoplasms: histopathologic features distinguish spindle cell lipoma, solitary fibrous tumor and dermatofibrosarcoma protuberans. Am J Dermatopathol. 2010;32:764-8. 17. Voth H, Landsberg J, Hinz T, et al. Management of der­ matofibrosarcoma protuberans with fibrosarcomatous transformation: an evidence-based review of the literature. JEADV. 2011;25:1385-91. 18. Mark RJ, Bailet JW, Tran LM, et al. Dermatofibrosarcoma protuberans of the head and neck: a report of 16 cases. Arch Otolaryngol Head Neck Surg. 1993;119:891-6.

Angiosarcoma 1. Deyrup AT, McKenney JK, Tighiouart M, et al. Sporadic cutaneous angiosarcomas: a proposal for risk stratification based on 69 cases. Am J Surg Pathol. 2008;32:72-77. 2. Donghi D, Kerl K, Dummer R, et al. Cutaneous angiosar­ coma: own experience over 13 years. Clinical features, disease course and immunohistochemical profile. JEADV. 2010;24:1230-4. 3. Bacchi CE, Silva TR, Zambrano E, et al. Epithelioid angio­ sarcoma of the skin: a study of 18 cases with emphasis on its clinicopathologic spectrum and unusual morphologic features. Am J Surg Pathol. 2010;34:1334-43. 4. Kohler HF, Neves RI, Brechtbuhl ER, et al. Cutaneous angiosarcoma of the head and neck: report of 23 cases from a single institution. Otolaryngol Head Neck Surg. 2008;139(4):519-24. 5. Mark RJ, Tran LM, Sercarz J, et al. Angiosarcoma of the head and neck: the UCLA experience 1955 through 1990. Arch Otolaryngol Head Neck Surg. 1993;119:973-8. 6. Orchard GE, Zelger B, Wilson Johnes E, et al. An immuno­ cytochemical assessment of 19 cases of cutaneous angio­ sarcoma. Histopathology. 1996;28:235-40. 7. Prescott RJ, Banerjee SS, Eyden BP, et al. Cutaneous epithe­ lioid angiosarcoma: a clinicopathologic study of four cases. Histopathology. 1994;25:421-9. 8. McKay KM, Doyle LA, Lazar AJ, et al. Expression of ERG, an Ets family transcription factor, distinguishes cutaneous angiosarcoma from histological mimics. Histopathology. 2012;61:986-91. 9. Rongioletti F, Albertini AF, Fausti V, et al. Pseudolym­ phomatous cutaneous angiosarcoma: a report of 2 new cases arising in an unusual setting. J Cutan Pathol. 2013; 40:848-54. 10. Guadagnolo BA, Zagars GK, Araujo D, et al. Outcomes after definitive treatment for cutaneous angiosarcoma of the face and scalp. Head Neck. 2011;661-7. 11. Shon W, Jenkins SM, Ross DT, et al. Angiosarcoma: a study of 98 cases with immunohistochemical evaluation of TLE3, a recently described marker of potential taxane responsiveness. J Cutan Pathol. 2011;38:961-6. 12. Lim S-Y, Pyon J-K, Mun G-H, et al. Surgical treatment of angiosarcoma of the scalp with superficial parotidectomy. Ann Plast Surg. 2010;64:180-2.

Chapter 9: Pathology of Cutaneous Malignancies of the Head and Neck

Atypical Fibroxanthoma 1. Fretzin DF, Helwig EB. Atypical fibroxanthoma of the skin: a clinicopathologic study of 140 cases. Cancer. 1973;31(6):1541-52. 2. Miller K, Goodlad JR, Brenn T. Pleomorphic dermal sarcoma: adverse histologic features predict aggressive behaviour and allow distinction from atypical fibroxanthoma. Am J Surg Pathol. 2012;36:1317-26. 3. Dei Tos AP, Maestro R, Doglioni C, et al. Ultravioletinduced p53 mutations in atypical fibroxanthoma. Am J Pathol. 1994;145(1):11-17. 4. McCoppin HH, Christiansen D, Stasko T, et al. Clinical spectrum of atypical fibroxanthoma and undifferentiated pleomorphic sarcoma in solid organ transplant patient recipients: a collective experience. Dermatol Surg. 2012; 38:230-9. 5. Stefanato CM, Robson A, Calonje JE. The histopathologic spectrum of regression in atypical fibroxanthoma. J Cutan Pathol. 2010;37:310-5. 6. Buonaccorsi JN, Plaza JA. Role of CD10, wide-spectrum keratin, p63 and podoplanin in the distinction of epi­ thelioid and spindle cell tumors of the skin: an immu­ nohistochemical study of 81 cases. Am J Dermatopathol. 2012;34:404-11. 7. Cuda J, Mirzamani N, Kantipudi R, et al. Diagnostic utility of Fli-1 and D2-40 in distinguishing atypical fibroxan­ thoma from angiosarcoma. Am J Dermatopathol. 2013; 35:316-8. 8. Barr RJ, Wuerker RB, Graham JH. Ultrastructure of atypical fibroxanthoma. Cancer. 1977;40:736-43.

Kaposi Sarcoma 1. Chang Y, Cesarman E, Pessin MS, et al. Identification of Herpesvirus-like DNA sequences in AIDS-associated Kaposi’s sarcoma. Science. 1994;266:1865. 2. Dupin N, Fisher C, Kellam P, et al. Distribution of human herpesvirus-8 latently infected cells in Kaposi’s sarcoma, multicentric Castleman’s disease, and primary effusion lymphoma. Proc Natl Acad Sci USA. 1999;96:4546-51. 3. Gessain A, Duprez R. Spindle cells and their role in Kaposi’s sarcoma. Int J Biochem Cell Biol. 2005;37:2457-65. 4. Dubina M, Goldenberg G. Positive staining of tumor-stage Kaposi sarcoma with lymphatic marker D2-40. J Am Acad Dermatol. 2009;61:276-80. 5. Wang H-W, Trotter MWB, Lagos D, et al. Kaposi sarcoma herpesvirus-induced cellular reprogramming contributes

6.

7.

8. 9.

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to the lymphatic endothelial gene expression in Kaposi sarcoma. Nat Genet. 2004;36:687-93. O’Donnell PJ, Pantanowitz L, Grayson W. Unique histo­ logic variants of cutaneous Kaposi sarcoma. Am J Derma­ topathol. 2010;32:244-50. Kandemir NO, Barut F, Gun BD, et al. Histopathological analysis of vesicular and bullous lesions in Kaposi sar­ coma. Diagn Pathol. 2012;7:101. Pantanowitz L, Otis CN, Dezube BJ. Immunohistochem­is­try in Kaposi’s sarcoma. Clin Exp Dermatol. 2009;35:68-72. Nguyen HQ, Magaret AS, Kitahata MM, et al. Persistent Kaposi sarcoma in the era of highly active antiretroviral therapy: characterizing the predictors of clinical response. AIDS. 2008;22:937-45.

Atypical Intradermal Smooth Muscle Neoplasm 1. Kraft S, Fletcher CD. Atypical intradermal smooth muscle neoplasms: clinicopathologic analysis of 84 cases and a reappraisal of cutaneous “leiomyosarcoma.” Am J Surg Pathol. 2011;35(4):599-607. 2. Massi D, et al. Primary cutaneous leiomyosarcoma: clinic­ opathological analysis of 36 cases Histopathology. 2010; 56(2):251-62. 3. LeBoit P, Burg G, Weedon D, et al. Pathology and Genetics of Skin Tumours (IARC WHO Classification of Tumours). Lyon: France World Health Organization; 2006. 4. Hall BJ, et al. Atypical intradermal smooth muscle neo­ plasms (formerly cutaneous leiomyosarcomas): case series, immunohistochemical profile and review of the literature. Appl Immunohistochem Mol Morphol. 2013; 21(2):132-8. 5. Wang WL, et al. Sarcoma metastases to the skin. Cancer. 2012;118(11):2900-4. 6. Fauth CT, et al. Superficial leiomyosarcoma: a clinico­ pathologic review and update. J Cutan Pathol. 2010;37(2): 269-76. 7. Pfeiffer J, et al. Radiation-induced leiomyosarcoma of the oropharynx. Diagn Pathol. 2006;1:22. 8. Chan JY, et al. Postradiation sarcoma after radiotherapy for nasopharyngeal carcinoma. Laryngoscope. 2012;122(12): 2695-9. 9. Santos Gorjon P, et al. Radiation-induced leiomyosarcoma of the posterior neck region. Acta Otorrinolaringol Esp. 2013;64(3):233-6.

CHAPTER Merkel Cell Carcinoma and Other Rare Skin Cancers

10

Sydney Ch’ng, Irene Low, Ashlin Alexander, Jonathan R Clark In addition to the common skin malignancies already dis­ cussed, there are other rarer but nevertheless clinically important cancers that show a predilection for the head and neck region. These include epithelial malignancies such as adnexal carcinomas of sebaceous or eccrine origin; Merkel cell carcinomas (MCC); and mesenchymal malignancies, including dermatofibrosarcoma protube­ rans (DFSP), atypical fibroxanthomas (AFX), angiosarco­ mas, and Kaposi sarcomas. These will be described in some detail in the following chapter.

MERKEL CELL CARCINOMA Definition Merkel cell carcinoma, previously known as primary cuta­ neous neuroendocrine carcinoma and trabecular carci­ noma, is a highly aggressive cutaneous malignancy. A German anatomist, Friedrich Merkel, first described Merkel cells in 1875. They are widely distributed among nerve endings in the epidermis, especially in glabrous skin, and serve specialized sensory functions as mecha­ noreceptors and chemoreceptors. Although they were widely considered to be of neural crest origin, recent mam­ malian studies have suggested that Merkel cells probably arise from pluripotent keratinocytes.

Etiology The chief etiologic factors known to be associated with MCC include Merkel cell polyomavirus (MCPyV), solar radiation, and immunosuppression. First identified in

2008, MCPyV viral genome is detected in up to 80% of North American MCC specimens. Recent studies have demonstrated a high prevalence of MCPyV infection, par­ ticularly of the skin, within the general population. Onco­ genesis requires host integration of clonal viral DNA resulting in expression of MCC-specific viral oncoprotein. In Australia, however, early evidence suggests that the prevalence of MCPyVin MCC is significantly lower (24%), and therefore, solar radiation may play a larger causative role in the Australian cohort of patients, in which wide­ spread actinic skin damage and synchronous or metach­ ronous skin cancers are common. The incidence of MCC is increased five-fold in organ transplant recipients and 11-fold in patients with autoimmune deficiency syn­ drome. Their heightened susceptibility to infections is likely a contributing factor.

Clinical Presentation MCC presents most commonly on the head and neck (50%), as an asymptomatic, flesh-colored, red or viola­ ceous nodule on sun-exposed skin (Fig. 10.1). The primary tumor’s clinical features often appear relatively innocuous and may be dismissed initially as a benign lesion. As such, it is frequently metastatic at presentation and has a high propensity to recur locally, regionally, or systemically after primary treatment.

Diagnosis MCC shows histological features that are shared with neuroendocrine carcinomas in other sites. Three main

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Head and Neck Surgery

Fig. 10.2: Merkel cell carcinoma is characterized by solid nests and sheets of round cells showing very high nuclear:cytoplasmic ratio. The neoplastic nuclei typically demonstrate finely granular chromatin pattern with inconspicuous nucleoli. Mitotic figures are readily identified.

Fig. 10.1: A Merkel cell carcinoma presents as a red, firm, painless nodule on the right temple of this elderly patient, abutting a skin graft from previous unrelated skin cancer surgery.

histologic variants, which include the intermediate, small cell, and trabecular forms, have been described, but distinction between these is of no specific clinical value. MCC most commonly exhibits a solid and diffuse growth pattern and is composed of sheets of round cells with small- to intermediate-sized nuclei showing a characte­ ristically finely dispersed chromatin pattern, inconspic­ uous nucleoli, and scanty cytoplasm (Fig. 10.2). Frequent mitoses are encountered and occasional areas of necrosis can be seen. In some cases, a distinctly organoid growth pattern can be appreciated, which is referred to as the trabecular variant. Diffuse immunohistochemical positi­ vity for neuroendocrine markers, such as chromogranin and synaptophysin, is characteristic of MCC, along with dot-like positivity for cytokeratins. A novel antibody against MCPyV has been shown to be highly specific in supporting the diagnosis of MCC.

Differential Diagnosis Histologically, MCC closely resembles metastatic small cell carcinoma of pulmonary origin. However, distincion

is usually straightforward on immunohistochemistry test­ ing, as the cells of MCC typically express dot-like positivity with cytokeratin-20 and negative staining pattern for thy­ roid transcription factor (TTF1).1 Metastatic neuroendo­ crine carcinomas from other sites are less common and require clinical correlation for exclusion. Other important differential diagnoses that should be excluded via ancillary studies include lymphomas and round cell sarcomas.

Treatment Standard therapy of MCC involves a combination of surgery and radiotherapy. However, as MCC is exquisitely radiosensitive, there is an increasing trend toward mini­ mizing or omitting surgery in the management of a subset of patients, particularly those who are elderly. Combined modality treatment has shown improvement in locoregional disease control, and disease-free survival. There is no consensus on what constitutes the optimal surgical margin, but a macroscopic margin of at least 1 cm in the head and neck region is considered acceptable. However, it is interesting to note that surgical margin sta­tus does not correlate with clinical outcome, a counterintuitive fact that may be explained in part by the radiosensitivity of MCC. Adequate radiotherapy is therefore particularly important in the control of microscopic disease.2 The dosage of adjuvant radiotherapy for the primary site and lymph node basin is similar to that employed for cutaneous squamous cell carcinoma (SCC).

Chapter 10: Merkel Cell Carcinoma and Other Rare Skin Cancers The value of sentinel node biopsy (SNB) is increasingly being recognized and incorporated into standard treat­ ment protocols. As such, microscopic nodal metastasis is now regarded as N1a tumor in the current TNM staging classification (Table 10.1). In particular, SNB is helpful in minimizing the morbidity of neck dissection and irradi­ ation and allow selective radiotherapy targeting only the primary site in node-negative patients.

Prognosis Staging The seventh edition of the American Joint Committee on Cancer TNM staging system provides for a separate classi­ fication specific to MCC3 (Table 10.1).

Survival Outcome MCC is a highly aggressive nonmelanoma skin cancer with poor prognosis. Local and regional controls at 5 years are 84% and 69%, respectively, whereas 5-year diseasespecific and overall survivals are 62% and 49%, respectively. The most significant adverse prognostic factors are age >70 years and higher disease stage.2 Table 10.1: A separate staging chapter has been dedicated to MCC in the seventh edition of AJCC TNM staging system3

T1

≤2 cm

T2

>2–5 cm

T3

>5 cm

T4

Deep extradermal structures, e.g. bone and muscle

N1a

Microscopic metastasis

N1b

Macroscopic metastasis

N2

In-transit metastasis

M1a

Skin, subcutaneous, nonregional lymph node

M1b

Lung

M1c

Other sites

Stage I

T1 N0

IA

T1 pN0

IB

T1 cN0

IIA

T2,3 pN0

IIB

T2,3 cN0

IIC

T4 N0

IIIA

Any T N1a

IIIB

Any T N1b, 2

IV

Any T Any N M1

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Epidemiology The age-adjusted incidence is 0.15/100,000. It is princi­ pally a disease of Caucasians and is very uncommon before the age of 50 years.

SEBACEOUS CARCINOMA Definition Sebaceous carcinoma is a malignancy derived from epi­thelial cell lining of the sebaceous gland.

Etiology The etiology of sebaceous carcinoma is unknown in the majority of cases. There is, however, an important subset of cases in which an association with Muir–Torre syndrome can be demonstrated. This is an autosomal dominant here­ ditary syndrome characterized by germline mutations involving one of the DNA mismatch repair genes, parti­ cularly MLH1 or MSH2, which result in high-level micro­ satellite instability in the associated tumors.4 In addition to the development of multiple sebaceous tumors that charac­ terize this syndrome, most patients also develop visceral neoplasms, particularly carcinomas involving the colorectal tract.

Clinical Presentation Seventy-five percent of sebaceous carcinomas arise from the eyelid skin. It is the fourth commonest periocular malignancy after basal cell carcinoma (BCC), SCC, and melanoma. It typically presents as a nondiscrete, firm, slowly enlarging nodule involving the eyelid. Outside of the periocular region, it is relatively uncommon and pre­ sentation with multiple sebaceous neoplasms in any patient should prompt further investigation for underlying Muir-Torre syndrome.

Diagnosis Histologically, sebaceous carcinoma is composed of lobules and sheets of polygonal cells showing varying degrees of sebaceous differentiation characterized by voluminous, finely vacuolated cytoplasm. These vacuoles contain lipid, which can be demonstrated on frozen tissue sections using oil red O histochemical stain. The malignant cells, which may show mild to significant cytologic atypia, usually demonstrate infiltrative growth into subcutaneous tissue and

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Head and Neck Surgery

underlying muscle. It is the infiltrative character that aids in the distinction of sebaceous carcinoma from its benign counterparts such as sebaceous adenoma and sebaceoma (Fig. 10.3). Positive immunohistochemistry staining for epithelial membrane antigen and Ber-EP4, with negative staining for carcinoembryonic antigen, may be helpful in confirming the diagnosis.4

Epidemiology

Differential Diagnosis

ECCRINE CARCINOMA Definition

Due to its site predilection, sebaceous carcinoma may be mistaken clinically for various benign conditions, such as chalazion, keratoconjunctivitis, and blepharo­conjun­ c­ tivitis, as well as much more common cutaneous malig­ nancies such as BCC and SCC. Histologically, well-differentiated sebaceous carcinoma needs to be dis­ tin­guished from sebaceous adenoma and sebaceoma.

Treatment The primary treatment modality for sebaceous carcinoma is complete surgical excision, although what constitutes an adequate margin clearance remains controversial. There is some evidence suggesting that Mohs’ surgery provides effective local control. Radiotherapy is used in an adjuvant or palliative setting but is not considered curative.

Prognosis Sebaceous carcinoma is an aggressive tumor. Local recur­ rence rate has been quoted at between 9% and 36%, whereas metastasis occurs in 14–25% of patients.

Sebaceous carcinoma generally affects older patients of 60–80 years of age. Presentation in the younger age group, particularly with multiple sebaceous neoplasms, should always prompt further investigation for possible MuirTorre syndrome.

Eccrine carcinomas are rare malignancies derived from epithelial lining of eccrine sweat glands.

Etiology The etiology of eccrine carcinomas is unknown, although it has been suggested that ultraviolet radiation plays a les­ ser role compared with other common cutaneous malig­­nancies such as BCC and SCC.

Clinical Presentation Among the numerous different subtypes of eccrine carci­ noma that can affect the head and neck region, microcystic adnexal carcinoma (MAC) is relatively more common and also one of the most important. It occurs most commonly on the face and lip as a slow-growing plaque or depressed, scar-like lesion. Other rare eccrine carcinomas that show a predilection for the head and neck include mucinous eccrine carcinoma and eccrine spiradenocarcinoma. The former typically presents on the scalp and eyelids as a soli­ tary, painless nodule with smooth, tan or reddish surface and soft consistency. Spiradenocarcinoma is often asso­ ciated with a longstanding history of a pre-existing benign spiradenoma.1

Diagnosis

Fig. 10.3: Sebaceous carcinoma cells characteristically show finely vacuolated cytoplasm, which is lipid laden, a feature that dis­ti­nguishes them from squamous cell carcinomas. A diagnosis of malignancy is made when the neoplastic sebaceous cells show an infiltrative growth pattern.

Histologically, MAC is composed of deceptively bland epithelial cells forming small ducts, cords, and nests, which characteristically show a deeply infiltrative growth pattern, and are associated with prominent stromal scle­ rosis. Perineural infiltration is almost invariably present. Mucinous eccrine carcinoma typically comprises discrete pools of extracellular mucin, within which are apparently free-floating clusters and islands of malignant epithelial cells. Spiradenocarcinoma may show a wide spectrum of histologic features; the diagnosis can only be made with certainty if it is associated with a recognizable area of pre­ existing spiradenoma.5

Chapter 10: Merkel Cell Carcinoma and Other Rare Skin Cancers

Differential Diagnosis The principal differential diagnosis of MAC is morphea­ form BCC and, rarely, metastatic extracutaneous carci­ noma such as infiltrating ductal carcinoma from the breast. Mucinous carcinoma of primary cutaneous origin on the other hand is much less common, and exclusion of metastatic carcinoma, particularly from the breast, lung, and gastrointestinal tract, is mandatory prior to rendering a diagnosis of primary eccrine mucinous carcinoma.5

Treatment As with other adnexal cutaneous malignancies, complete surgical excision is the mainstay of treatment in eccrine carcinomas irrespective of histological subtype. The role of radiotherapy and chemotherapy is poorly defined, although there is some evidence for using radiation as an adjunct therapy in patients presenting with multiple local recurrences.

Prognosis

195

and platelet-derived growth factor beta gene (PDGFB). The resulting transcriptional upregulation of PDGFB gene leads to autocrine activation of platelet-derived growth factor receptor (PDGFR), which directly stimulates tumor growth.

Clinical Presentation DFSP most commonly affects the trunk (50–60%), with the proximal extremity (20–30%) and head and neck region (10–15%) being the other main sites of predilection. The tumor typically presents as an aggregate of red, vio­laceous, or flesh-colored nodules within a plaque-like area, and the surrounding skin may exhibit prominent telangiectasia (Fig. 10.4). Although metastatic disease at presentation is rare, pulmonary metastasis can occur and should be excluded in clinically advanced cases.

Diagnosis Histologically, DFSP can be classified into classical and fibrosarcomatous (FS) forms. The classical form, which is

Repeated local recurrence is common with both MAC and mucinous carcinoma, particularly where complete surgical excision cannot be achieved due to anatomical barriers. Metastatic rate and disease-related mortality, however, is generally low. Spiradenocarcinoma, on the other hand, is a highly aggressive malignancy that frequently presents with widespread metastases to lymph nodes, bone, and lung.6

Epidemiology Eccrine carcinomas are rare malignancies, and their over­ all incidence is not well established, although the inci­ dence rate of MAC is considerably higher than other forms of eccrine carcinomas discussed above. MAC is reported to show a modest predilection for middle-aged females.1

DERMATOFIBROSARCOMA PROTUBERANS Definition Dermatofibrosarcoma protuberans is a rare, low-grade mesenchymal malignancy of presumed fibroblastic origin.

Etiology The vast majority of DFSP harbors a recurrent transloca­ tion between chromosomes 17 and 22, which results in fusion of the alpha chain type 1 collagen gene (COL1A1)

Fig. 10.4: Dermatofibrosarcoma protuberans is a locally aggressive tumor that begins as a skin-colored, slow-growing asymptomatic plaque.

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Head and Neck Surgery

most common, is characterized by a poorly circumscribed dermal lesion composed of short fascicles of cytologi­ cally uniform spindled cells arranged in a prominent storiform pattern, and showing typical infiltration into subcutaneous fat in a manner reminiscent of honeycomb (Fig. 10.5). In rare cases, classical DFSP is associated with a higher grade component in which the tumor cells show increased cytologic atypia and form fascicular arrangements showing “herringbone” pattern rather than a storiform architecture (Fig. 10.6). In these instances, a diagnosis of FS-DFSP is rendered.7

Differential Diagnosis In some instances, DFSP may be difficult to distinguish from the cellular variant of benign fibrous histiocytoma on routine histology alone. Diffuse, strong staining for CD34 immunohistochemistry and negative staining for Factor XIIIa is more in keeping with DFSP, while the con­verse is true of benign fibrous histiocytoma.7

Treatment Wide local excision with at least a 2-cm circumferential margin, including the underlying deep fascia, is gener­ ally accepted as adequate local treatment. Mohs’ surgery may be an effective option in early disease, particularly on the head and neck. However, evidence for its use is limited in recurrent lesions. Adequate surgical clearance may be difficult to achieve, particularly in the head and neck region, and radical excision may lead to unfavorable

Fig. 10.5: Conventional dermatofibrosarcoma protuberans is characterized by uniform spindle cells arranged in storiform architecture and infiltrating dermis and subcutis in a typical “honeycomb” fashion.

aesthetic results, a fact that needs to be clearly communi­ cated given the typically younger patient group. DFSP is a radiosensitive tumor and as such adjuvant radiotherapy is recommended in cases of microscopically positive or close margins, large primary tumor, and known recurrent disease. Targeted molecular therapy using the tyrosine kinase inhibitor imatinib has been approved in unrese­c­ table, recurrent, and metastatic DFSP.

Prognosis The classic, low-grade form, which accounts for 85–90% of DFSP, recurs in 15–20% of cases. Distant metastasis is rare at  50 years.

Epidemiology DFSP presents most commonly between 20 and 50 years of age, although presentation at either extreme of the age spectrum can occur, including occasional con­ genital cases.

ATYPICAL FIBROXANTHOMA Definition Atypical fibroxanthoma is a cutaneous pleomorphic spin­ dle cell neoplasm occurring in actinically damaged skin.

Fig. 10.6: Dermatofibrosarcoma protuberans (DFSP) with fibrosarcomatous transformation typically comprises spindle cells arranged in fascicles and shows a greater degree of cytological atypia compared with conventional DFSP.

Chapter 10: Merkel Cell Carcinoma and Other Rare Skin Cancers

197

It is generally accepted that AFX lies within the spectrum of disease nowadays referred to as undifferentiated pleo­ morphic sarcoma (UPS, formerly known as malignant fibrous histiocytoma or MFH).

ci­rcumscribed, with ulceration of the overlying epidermis being a common finding.

Etiology

AFX should be distinguished histologically from other cutaneous malignancies that may show spindle cell mor­ phology, particularly poorly differentiated or sarcomatoid SCC and spindle cell melanoma. Specific sar­comas that can occur in superficial settings, such as leiomyosarcomas and angiosarcomas, should also be considered, although these are considerably rarer than AFX. As such, a compre­ hensive panel of immunohistochemistry markers is usually required to unequivocally establish the diagnosis of AFX. Of note, it is now widely accepted that AFX and UPS are essentially indistinguishable in their cellular composition. Histologic distinction between these diagnostic catego­ries is made primarily on the basis of tumor depth; dermal­ confined tumors show negligible metastatic potential if completely excised, while deeply invasive tumors are likely to behave as superficial sarcomas. Therefore, in the pre­ sence of significant subcutaneous infiltration, and par­ti­ cularly if there are other associated signs such as perineural invasion, lymphovascular invasion, or exte­nsive necrosis, a diagnosis of superficial UPS is more appropriate.8

Solar exposure is the main etiologic factor in AFX. UVB signature DNA mutations are commonly found in tumor specimens.

Clinical Presentation AFX typically presents as a rapidly growing exophytic nodule that often exhibits ulceration and hemorrhage. It shows a predilection for sun-exposed skin of the head and neck region and is typically seen on a background of longstanding solar damage. If strictly defined as a dermal tumor, metastatic disease in AFX is an exceptionally rare occurrence. On the other hand, metastases are usually seen in the context of more deeply invasive tumors that are better classified as superficial UPS at the outset.

Diagnosis Histologically, AFX is composed of varying proportions of spindled and/or epithelioid cells arranged in fascicu­ lar, storiform, or solid sheet-like architecture (Figs. 10.7A and B). The tumor cells characteristically exhibit strik­ ing degrees of cellular pleomorphis with accompanying brisk mitotic activity.8 By definition, the tumor should be en­tirely confined within the dermis, and typically well

A

Differential Diagnosis

Treatment Surgical excision with a 1-cm margin or Mohs’ surgery is the standard of care in AFX. Radiotherapy is used in patients where an adequate margin cannot be achieved due to anatomical constraints.

B

Figs. 10.7A and B: Atypical fibroxanthoma at low power shows a polypoid growth arising from sun-damaged skin (A). At high power, the cells are spindled, with notable pleomorphism (B). When strictly defined as a dermal lesion, AFX has negligible metastatic potential.

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Head and Neck Surgery

Fig. 10.8: Regardless of treatment modality, cutaneous angiosarcoma has a high propensity for recurrence. In this patient, an angiosarcoma presents with ecchymotic extension from the obvious ulcerated nodular lesion, making determination of margin extremely difficult.

Fig. 10.9: A moderately differentiated angiosarcoma composed of anastomosing vascular channels that are lined by cytologically malignant endothelial cells.

Prognosis

Clinical Presentation

In contrast to deeply invasive UPS, which is associated with frequent metastasis and high mortality, AFX has an excellent prognosis upon complete surgical excision. Local recurrence rate is in the order of 6–10% while meta­ stasis is exceptionally rare.

Angiosarcoma typically begins as a poorly defined dis­ colored plaque resembling a bruise. As the lesion enlar­ges, it can become raised and multinodular, and occasionally may ulcerate (Fig. 10.8). In some instances, a “brawny” al­­teration to the skin appearance simulating erysipelas is seen.

Epidemiology AFX arises most commonly in the elderly Caucasian population, with around two thirds of cases occurring in men.

CUTANEOUS ANGIOSARCOMA Definition Angiosarcoma is a malignant neoplasm derived from en­dothelial cell lining of blood and lymphatic vessels.

Etiology Cutaneous angiosarcoma arises characteristically in one of three well-defined clinical contexts. The most common occurrence is in the head and neck, particularly the scalp or face, of elderly male patients. The precise etiology in this setting is unclear. The second group arises in the setting of chronic cutaneous lymphedema (so-called Stewart-Treves syndrome), and a third group is seen in association with prior radiation therapy.9

Diagnosis Well-differentiated cutaneous angiosarcoma is typically composed of interanastomosing vascular channels that form a poorly circumscribed lesion and infiltrate in a dissecting manner throughout the dermis and subcutis. The constituent endothelial cells range from spindled to epithelioid in morphology and may be deceptively bland in their cytological appearances. Poorly differen­ tiated angiosarcomas, on the other hand, tend to show a greater degree of cytological atypia, with the cells form­ing solid masses that lack overt vasoformative characte­ristics (Fig. 10.9).10

Differential Diagnosis Poorly differentiated angiosarcoma can be difficult to reli­ ably distinguish on morphology alone from other poorly differentiated malignancies, including cutaneous carci­ noma, melanoma, and pleomorphic sarcomas. Immuno­ histochemistry markers using CD31 and CD34, as well

Chapter 10: Merkel Cell Carcinoma and Other Rare Skin Cancers as novel markers, such as WT1 and ERG, are very useful in confirming endothelial lineage in these cases.10 Con­ versely, some angiosarcomas can be so well differentiated that they closely mimic benign vascular proli­ferations. In these instances, microscopic evidence of overt infiltra­ tion or permeative growth into adjacent soft tissue is sup­ portive of a malignant diagnosis.

Treatment Surgical excision with wide radial margins (at least 3 to 5 cm) and excision of full thickness scalp with underly­ ing pericranium is recommended. However, taking into ac­count anatomical constraints, disfiguring surgery should be avoided where possible, as most tumors recur regard­ less of the extent of excision. Surgery combined with post­ operative radiotherapy encompassing the entire scalp has been found to improve outcome. Adjuvant chemo­ therapy is generally reserved for advanced cases.

Prognosis Despite aggressive therapy, local recurrences and meta­ stases are very common in cutaneous angiosarcomas, particularly to lymph nodes and pulmonary sites. The prognosis is very poor, with a 5-year survival of app­ roximately 15%.10

Epidemiology Angiosarcomas are rare and account for barely 1% of all sarcoma diagnoses overall. Around one third of cutaneous angiosarcomas arise without association with lymphe­ dema or prior irradiation. Of these, by far the majority present in the head and neck region, and they show a marked tendency to affect elderly male patients.10

199

immunosuppression-associated form, seen particularly in recipients of solid organ transplants; and (4) endemic African form, which arises largely in sub-Saharan central Africa and usually involves lymph nodes, along with extremities and viscera, of children and young adult.11 In 1994, a distinctive subtype of human herpesvirus, HHV-8, was discovered in association with Kaposi sar­ coma. This oncovirus is ubiquitous in all forms of Kaposi sarcoma, and also seen in specific forms of high-grade lymphoma involving body cavities.10

Clinical Presentation Cutaneous involvement by Kaposi sarcoma typically pre­ sents as multiple reddish-blue macules or flat plaques that sometimes coalesce. As the lesions progress, most become nodular and can ulcerate or fungate.

Diagnosis Histological appearances of Kaposi sarcoma vary depen­ ding on the stage of the lesion. Three progressive stages are described, namely, the patch stage, plaque stage, and nodular stage. The first two stages overlap morphologically and are characterized by increased vascularity within the dermis, with the vessels being formed by relatively bland endothelial cells. The changes may be very subtle, particularly in the patch stage, and may be easily mistaken for reactive conditions. In the nodular stage, Kaposi sarcoma shows distinctive morphological features comprising a generally circumscribed proliferation of monomorphic spindled cells interspersed by slit-like spaces containing red blood cells (Fig. 10.10).

KAPOSI SARCOMA Definition Kaposi sarcoma is a low-grade malignant vascular neo­ plasm thought to derive from endothelial cells lining lymphatic channels.

Etiology Kaposi sarcoma occurs in four distinct clinical groups: (1) classic form, which typically arises in elderly males of Mediterranean and Eastern European origin, and shows particular predilection for the distal extremities; (2) AIDSassociated form presenting in mucocutaneous sites; (3)

Fig. 10.10: Kaposi sarcoma in both cutaneous and visceral sites typically comprises compact cellular sheets of spindled cells, which are interspersed with slit-like lumina containing red blood cells.

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Head and Neck Surgery

Differential Diagnosis

Epidemiology

Early manifestations of Kaposi sarcoma can be histologi­ cally subtle and must be differentiated from telangie­cta­ sias, purpuric dermatoses, and low-grade angiosarcomas. Nodular stage Kaposi sarcoma with predominantly spin­dled cell morphology needs to be distinguished from spi­ndle cell melanoma and carcinoma, along with other cutaneous mesenchymal proliferation such as smooth muscle and fibrohistiocytic neoplasms. Immunohistoche­mistry confi­r­ mation using the HHV-8 antibody is very helpful.10

Kaposi sarcoma occurring in the head and neck is almost always seen in the setting of immunosuppression or AIDS. With the advent of HAART, incidence of the latter form of disease has reduced markedly in recent decades.11

Treatment The primary aims of treatment in Kaposi sarcoma are those of symptom palliation, tumor shrinkage to prevent local complications, and prevention of disease progres­ sion. In most instances, the disease is localized and can be adequately treated by surgical excision and/or local radiotherapy alone. Chemotherapy is indicated in cases of systemic involvement.12 Antiviral therapy, such as gan­ ciclovir, may be helpful in preventing the onset of Kaposi sarcoma by inhibiting HHV-8 viral replication, but it is ineffective in primary treatment of the disease once it has developed. In patients receiving immunosuppressive therapy, reduction or cessation of treatment may be necessary. In AIDS patients, highly active antiretroviral therapy (HAART) has been shown to markedly reduce the incidence and severity of Kaposi sarcoma.

Prognosis The prognosis in Kaposi sarcoma is largely dependent on the clinical setting in which it occurs. The classic form is essentially indolent, while the endemic African form, particularly in cases with lymph nodes and visceral involvement in younger patients, is a highly aggressive and often fatal disease. Outcome in AIDS-related and immunosuppression-related forms is dependent on thera­ peutic success in controlling/reversing the underlying cause of immune compromise.

REFERENCES 1. Patterson JW, Wick MR. Neoplasms and pseudoneoplas­ tic proliferations of the sweat glands, and primary neuro­ endocrine (Merkel cell) carcinoma. In: AFIP Atlas of tumor pathology – nonmelanocytic tumors of the skin. Washington, DC: ARP Press; 2006. 2. Clark JR, Veness MJ, Gilbert R, O’Brien CJ, Gullane PJ. Merkel cell carcinoma of the head and neck: is adjuvant radiotherapy necessary? Head Neck. 2007;29:249-57. 3. Edge SE, Byrd DR, Compton CC, et al. American Joint Committee on Cancer (AJCC) Staging Manual, 7th edn. New York: Springer; 2009. 4. Patterson JW, Wick MR. Tumors and tumor-like conditions with sebaceous differentiation. In: AFIP Atlas of tumor pathology—nonmelanocytic tumors of the skin. Washington, DC:ARP Press; 2006. 5. Brenn T, McKee PH. Tumors of the sweat glands. In: McKee PH (ed), Pathology of the skin with clinical correlations, vol. 2. Philadelphia, PA: Elsevier Mosby; 2005. 6. Requena L, Kutzner H, Hurt MA, et al. Malignant tumours with apocrine and eccrine differentiation. In: Le Boit P (ed), WHO classification of tumours—pathology & genetics of skin tumours. Lyons, France: IARC Press; 2006. 7. Weiss S, Goldblum J. Fibrohistiocytic tumors of intermediate malignancy. In: Enzinger and Weiss’s soft tissue tumors. Philadelphia, PA: Elsevier Mosby; 2007. 8. Weiss S, Goldblum J. Malignant fibrous histiocytoma (ple­o­ morphic undifferentiated sarcoma). In: Enzinger and Weiss’s soft tissue tumors. Philadelphia: Elsevier Mosby; 2007. 9. Sangueza OP, Kasper RC, LeBoit P, et al. Vascular tumours. In: Le Boit P (ed), WHO classification of tumors – Pathology & genetics of skin tumors. Lyon, France: IARC Press; 2006. 10. Weedon D. Chapter 38—Vascular tumors. In: Weedon’s skin pathology. Philadelphia, PA: Churchill Livingstone Elsevier; 2010. 11. Lamovec J, Knuutila S. Kaposi sarcoma. In: Fletcher CDM (ed), WHO classification of tumours—pathology and genetics of tumors of soft tissue and bone. Lyon, France: IARC Press; 2002. 12. Pantanowitz L. Kaposi sarcoma—appraisal of therapeutic agents. Cancer. 2008;112:962-5.

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CHAPTER

Surgical Anatomy and Embryology of the Thyroid and Parathyroid Glands

11

Lorne Rotstein, Karen Devon

INTRODUCTION With respect to embryology and anatomy, the thyroid and parathyroid glands ought to be considered a single unit. A thorough understanding of this embryology and anatomy is essential to the performance of safe, complication-free surgery while treating diseases of these endocrine glands.

THYROID EMBRYOLOGY The thyroid gland has a dual origin with the follicular gland portion derived from the pharynx, whereas the parafol­ licular C cells stem from the neural crest. The majority of the thyroid originates from the epithelium of the floor of the pharynx (pharyngeal endoderm) at the site that eventually becomes the foramen cecum, which separates the base of the tongue from the oral tongue.1 The primordial thyroid enlage descends in the midline of the neck at approxi­ mately day 24 of gestation, leaving the pharyngeal diver­ ticulum attached to the oropharynx by a tract called the thyroglossal duct. The parafollicular C cells (the source of calcitonin) arising in the neural crest in the ultimo branchial bodies of the fourth and fifth branchial pouches laterally, later fuse with the central component so that the bulk of C cells are found within the lateral component of the thyroid gland.2 The path of migration of the thyroid from foramen cecum to its eventual location in the lower central neck is the thyroglossal tract. The thyroglossal tract fibroses and atrophies after birth, however, can lead to a number of developmental anomalies. Persistence of the thyroglossal duct or part thereof may result in formation of thyroglossal fistulae or cysts anywhere in the midline of

the neck from the base of the tongue to the sternal notch3 (Fig. 11.1). Because the thyroid enlage descends at the time of formation of the hyoid bone, the thyroglossal tract may be anterior, posterior, or pass through the central portion of the hyoid bone, thereby necessitating excision of this bone when following the tract superiorly to the foramen cecum at the time of thyroglossal cystectomy.4 Similarly, midline ectopic thyroid rests can occur anywhere from the foramen cecum to the pericardium.5 The pyra­ midal lobe of the thyroid, present in 30% to 50% of indi­ viduals is a vestige of the tract.5 Failure to recognize and excise the pyramidal lobe at the time of thyroidectomy is a potential cause of persistence of disease in goiter,

Fig. 11.1: Thyroid migration potential sites for embryological rests.

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Graves’ disease, and malignancy.6,12 Complete failure of descent of the thyroid will result in the development of a lingual thyroid gland at the base of the tongue.5 Lingual thyroid tissue may be mistaken for an epithelial malig­ nancy, yet may also be the only thyroid tissue present in the patient.7 An intact mucosal surface and a symmetrical appearance to this tissue should help differentiate the two entities. Lingual thyroid is rarely symptomatic and does not usually require treatment; however, in symptomatic patients, thyroid hormone suppression or laser ablation should be considered.7 Aberrant midline thyroid tissue, which may be found as far inferiorly as the pericardium in the superior mediastinum, does not usually require treatment.8 Elective excision of thyroglossal duct cysts is usually advised due to the potential for infections from bacterial entry via the thyroglossal tract.9,10 However, not all masses in the midline in the region of the hyoid are thyroglossal cysts. The differential diagnosis includes ectopic thyroid tissue, metastatic thyroid cancer in central nodes, and thyroglossal cancer.11 Thyroglossal cysts often contain thyroid epithelial cells, and malignancies can develop primarily in these structures.11 Ultrasound is used to confirm that a putative thyroglossal cyst is indeed cystic and that the thyroid is present and in a normal position.13 In adults, fine needle aspiration biopsy is also recommended to confirm the diagnosis and rule out malignancy.13 Aberrant thyroid tissue may also be found lateral and inferior to the thyroid gland itself as well as in the anterior superior mediastinum. These so-called thyrothymic thyroid “rests” may be encountered during thyroidectomy and are not easily differentiated clinically or pathologically from metastatic, well-differentiated thy­ roid cancer in lymph nodes.14 In the past, the finding of normal thyroid tissue loca­ ted lateral to the jugular vein, otherwise known as lateral aberrant thyroid, was controversial. We now know that these are almost always metastatic, well-differentiated thy­ roid cancers within lymph nodes, associated with an oc­cult intrathyroidal primary.15

parathyroid gland compared with the superior gland16 (Fig. 11.2.) The ultimate anatomic locations of the para­ thyroid glands are discussed later in the chapter. As the fourth pharyngeal pouch migrates with the thyroid gland and the ultimobranchial bodies, the superior parathyroids remain juxtaposed to the posterior aspect of the midportion of the thyroid gland. Therefore, over 85% of the time the location of the superior parathyroid is adjacent to the posterior aspect of the thyroid gland, 1 to 2 cm superior to the intersection of the recurrent laryngeal nerve and inferior thyroid artery.8,19 Ectopic superior parathyroid glands are therefore usually loca­ ted posterior to the thyroid gland. One percent is found above the upper pole, whereas 2–4% are found more posteriorly than expected in a retropharyngeal or retro­ e­sophageal location.20 Very rarely, at the time of the ultimobranchial fusion with the medial thyroid precursor, the precursor of the superior parathyroid can become incorporated into the thyroid forming true intrathyroidal superior parathyroids. Intrathyroidal inferior glands are marginally more common, occurring in 3% versus 1% of the population.20 Supernumerary parathyroid glands may develop within the thymus from accessory parathyroid tissue.20 The presence of tiny supernumerary glands is not uncommon (13%), but most weigh  1 cm superior to the upper pole of the thyroid gland, approximately 10% (Type 2) cross at the level of the upper pole of the thyroid, and another 5% (Type 3) actually loop below the upper pole of the thyroid gland (Fig. 11.4). Type 2 and 3 are at high risk of injury during superior thyroid artery ligation.27 Therefore, one should always attempt to identify the EBS­ LN nerve before ligating the superior thyroid artery and to ligate the artery as close as possible to the upper pole of the thyroid gland.29 Careful identifica­tion of the EBSLN requires opening of the plane between the cricothyroid muscle and the medial aspect of the upper portion of the thyroid gland while retracting the thyroid lobe laterally.30 Using this maneuver, the EBSLN can be successfully identified in 95% of cases. Continuous laryngeal nerve monitoring has also been shown to be a helpful way to identify the EBSLN.31,32 The recurrent laryngeal nerves arise embryologically in the sixth branchial arches. They branch off of the vagi

Fig. 11.4: Anatomical classification of external branch of superior laryngeal nerve. Types 2 and 3 at risk with mobilization of superior pole of thyroid.

below the level of the fourth aortic arch. The subclavian artery on the right, and the true aortic arch on the left are also derived from the fourth aortic arch. When the heart and attached structures descend into the thorax during embryologic development, these arteries pull the recurrent laryngeal nerves inferiorly in a loop, thereby producing the recurrent structure.13,33 Anomalous development of the right subclavian artery as a branch from the distal left-sided aortic arch may result in the atrophic disruption of the fourth aortic arterial arch so that the right laryngeal nerve is not dragged inferiorly and is therefore nonrecurrent.33 This occurs in 0.5–1% of cases and portends a tenfold increased risk of injury at the time of thyroidectomy. There are anecdotal reports by Katz and Nemiroff of nonrecurrent laryngeal nerves coexisting with a small recurrent ipsilateral recurrent laryngeal nerve in the normal position.34 The identification of a narrower than expected recurrent laryngeal nerve in the normal location should alert the surgeon that there may be a larger nonrecurrent trunk concomitantly.34 A non­recurrent laryngeal nerve on the left side is exceedingly rare and always associated with situs inversus and an anomalous left subclavian artery.35 The right recurrent laryngeal nerve enters the neck from the thorax more laterally than the left side and therefore has a more oblique course. On both sides as the recurrent laryngeal nerves course upward in the neck from lateral to medial, they assume a position in the tracheo­ esophageal grove approximately 60% of the time. Another 5% of the time they are more lateral to the trachea and 30% of the time can be found immediately posterior to the thyroid gland itself.36 As previously mentioned, the recurrent laryngeal nerve may be deep to or superficial to the inferior thyroid artery. There is significant variability in the relationship of the nerves and arteries between the two sides; therefore, the inferior artery cannot be relied upon as a landmark for identification of the recurrent

Chapter 11: Surgical Anatomy and Embryology of the Thyroid and Parathyroid Glands

Fig. 11.5: Lateral view of thyroid at surgery.

laryngeal nerve during surgery. The recurrent laryngeal nerve finally enters the larynx by coursing just under the lower border of the inferior constrictor muscles and thereafter out of the thyroid surgical field.36 The average diameter of the recurrent laryngeal nerve diameter is 2 mm, but it may be thinner or wider depending on the patient’s body habitus. The recurrent laryngeal nerve com­ monly branches proximal to the laryngeal entry point, but only about 30% of patients have true branching of the motor com­ponent of the nerve. Many of the other smaller branches are purely sensory.36 Most motor-related bifurcations arise above the level of the intersection of the recurrent laryngeal nerve and the inferior thyroid artery. The recurrent laryngeal nerve therefore should be initially identified low in the neck below of the level of potential branching, and the nerve should be traced upward along its medial aspect so that potential branches can be identified and preserved.22 As a corollary, if an identified recurrent laryngeal nerve is unexpectedly thin, one ought to look closely for evidence of branching prior to divid­ ing any other longitudinal structures in the area. The ligament of Berry (or posterior suspensory ligament of the thyroid) is the fibrous attachment between the laryn­ gotracheal complex and the thyroid gland and extends from the posterior lateral aspect of the cricoid and first and second tracheal rings to the juxtaposed deep surface of the medial thyroid lobe.37 The relationship between

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the ligament of Berry and the recurrent laryngeal nerve is variable, but classically the nerve is described as coursing superiorly in a position deep to the ligament. Various investigators however have demonstrated that the nerve courses directly through the ligament up to 38% of the time.37 Dissection of this dense ligamentous tissue off the medial aspect of the recurrent laryngeal nerve can be a significant challenge. Adding to this challenge, the recurrent laryngeal nerve can take a slight lateral bend or genu at the upper aspect of the ligament of Berry before entering the larynx (Fig. 11.5). These factors—density of the ligament of Berry, potential for nerve bifurcation, possible nerve genu, close approximation of the thyroid, multiple tiny arteries in the ligament—all make this small triangle the most difficult technical component of thyroidectomy, necessitating careful dissection and hemostasis and avoi­ dance of indiscriminate cauterization. Another area of difficult dissection is related to the tubercle of Zuckerkandl, which may occur anterior and lateral to the nerve as a small outpouching of thyroid, or completely envelop the recurrent nerve such that it passes through a window between the tubercle and thyroid gland proper.16 The safest place for dissection is directly on the medial aspect of the medial-most branch of the recurrent laryngeal nerve until it is seen to enter the larynx.

PARATHYROID ANATOMY Location The superior parathyroid (P4) is derived from the fourth branchial arch and is relatively constant in position, almost always found adjacent to the posterior surface of the upper thyroid, close to the intersection of the inferior thyroid artery and the recurrent laryngeal nerve.16,18 Eighty percent of P4s are within 2 cm of this point (Fig. 11.6). In under 1% of cases, the P4 may actually be above the upper pole of the thyroid or rarely retropharyngeal or retro­ esophageal. Although the locations of parathyroid glands vary greatly,20 there is often symmetry of the parathyroid glands in any given patient (80% in the superior, 70% in the inferior glands). This can be helpful during identi­ fication of normal parathyroids. When parathyroid gla­nds are pathologic, symmetry is less likely.19 Abnormal patho­ logic parathyroid glands are more likely to migrate, presumably related to their increased weight. Owing to its embryological descent with the thymus, the inferior parathyroid gland (P3) is more likely to be in an ectopic location. However, most P3s are found adjacent to the

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Fig. 11.6: Localization of superior parathyroid gland.

thyrothymic ligament either juxtaposed to the inferior pole of the thyroid or in the superior portion of the thymus gland.20 P3s are found in the same plane as the thyroid gland rather than posteriorly like P4s. Ectopic P3s can be found throughout the area of embryologic descent of the thymus from the angle of the mandible, to the carotid sheath, down to the pericardium. However, typically ectopic P3s are located within the thymus tissue in the anterior superior mediastinum.20 True intrathyroidal P3s are rare (1–3%) but found slightly more commonly than true intrathyroidal P4s; therefore, thyroid lobectomy for a missing parathyroid is usually reserved for when the missing gland is an inferior one (and thyroid imaging suggests nodularity).38 Understanding the blood supply of the parathyroid glands is crucial to avoid devascularization during thyroidectomy (Fig. 11.7). Both the P3 and the P4 are supplied directly by branches of the inferior thyroid artery running from lateral to medial. Proximate ligation of the inferior thyroid artery will lead to inadvertent devascularization; therefore, careful dissection of the parathyroid glands off of the thyroid capsule while preservating their blood supply is critical in preventing postoperative hypocalcemia. Two to three percent of P3s are actually supplied by the superior thyroid artery, making devascularization unavoidable in that circumstance.38 Parathyroid glands, which are known to be devascularized during surgery, should be auto­ transplanted.

Fig. 11.7: Superior and inferior parathyroid glands. Both derive their blood supply from branches of the inferior thyroid artery.

REFERENCES 1. Gray SW, Skandalakis JE, Akin JT, Jr. Embryological consi­ derations of thyroid surgery: developmental anatomy of the thyroid, parathyroids and the recurrent laryngeal nerve. Am Surg. 1976;42(9):621-8. 2. Wolfe HJ, DeLellis RA, Voelkel EF, et al. Distribution of calcitonin-containing cells in the normal neonatal human thyroid gland: a correlation of morphology with peptide content. J Clin Endocrinol Metab. 1975;41(06):1076-81. 3. Ellis PD, van Nostrand AW. The applied anatomy of thyro­ glossal tract remnants. Laryngoscope. 1977;87:765-70. 4. Hirshoren N, Neuman T, Udassin R, et al. The imperative of the Sistrunk operation: review of 160 thyroglossal tract remnant operations. Otolaryngol Head Neck Surg. 2009;140 (3):338-42. 5. Noyek AM, Friedberg J. Thyroglossal duct and ectopic thyroid disorders. Otolaryngol Clin North Am. 1981;14: 187-201. 6. Bliss RD, Gauger PG, Delbridge LW. Surgeon's approach to the thyroid gland: surgical anatomy and the importance of technique. World J Surg. 2000;24:891-7. 7. Kansal P, Sakati N, Rifai A, et al. Lingual thyroid. Diagnosis and treatment. Arch Intern Med. 1987;147:2046-8. 8. Kozol RA, Geelhoed GW, Flynn SD, et al. Management of ectopic thyroid nodules. Surgery. 1993;114(6):1103-6. 9. Allard RH. The thyroglossal cyst. Head Neck Surg. 1982;5: 134-46. 10. Hirshoren N, Neuman T, Udassin R, et al. The imperative of the Sistrunk operation: review of 160 thyroglossal tract remnant operations. Otolaryngol Head Neck Surg. 2009; 140(3):338-42.

Chapter 11: Surgical Anatomy and Embryology of the Thyroid and Parathyroid Glands 11. Kennedy TL, Whitaker M, Wadih G. Thyroglossal duct carcinoma: a rational approach to management. Laryn­ goscope. 1998;108:1154-8. 12. Lennquist S, Persliden J, Smeds S. The value of intraoperative scintigraphy as a routine procedure in thyroid carcinoma. World J Surg. 1988;12(5):586-92. 13. Organ GM, Organ CH, Jr. Thyroid gland and surgery of the thyroglossal duct: exercise in applied embryology. World J Surg. 2000;24(8):886-90. 14. Sackett WR, Reeve TS, Barraclough B, et al. Thyrothymic thyroid rests: incidence and relationship to the thyroid gland. J Am Coll Surg. 2002; 195(5):635-40. 15. Attie JN, Setzin M, Klein I. Thyroid carcinoma presenting as an enlarged cervical lymph node. Am J Surg. 1993(4):428-30. 16. Henry JF. Applied embryology of the thyroid and parathyroid glands. In: Randolph GW (ed), Surgery of the thyroid and parathyroid glands. Philadelphia, PA: Saunders;2003:12-20. 17. Henry JF. Surgical anatomy and embryology of the thyroid and parathyroid glands and recurrent and external laryngeal nerves. In: Clark OH, Duh QY (ed), Textbook of endocrine surgery. Philadelphia, PA: WB Saunders; 1997:8-14. 18. Norris EH. The parathyroid glands and the lateral thyroid in man: their morphogenesis, histogenesis, topographic anatomy and prenatal growth. Contrib Embryol Carnegie Instn. 1937;26:247-94. 19. Herrera MF, Gamboa-Dominguez A. Parathyroid embr­ yology, anatomy, and pathology. In: Clark OH, Duh QY (ed), Textbook of endocrine surgery. Philadelphia, PA: WB Saunders; 1997:277-83. 20. Wang C. The anatomic basis of parathyroid surgery. Ann Surg. 1976;183:271-5. 21. Pattou F, Pellissier L, Noel C, et al. Supernumerary para­ thyroid glands: frequency and surgical significance in the treatment of renal hyperparathyroidism. World J Surg. 2000;24:1330-4. 22. Lore JM, Jr. Practical anatomical considerations in thyroid tumor surgery. Arch Otolaryngol. 1983;109(9):568-74. 23. Nobori M, Saiki S, Tanaka N, et al. Blood supply of the parathyroid gland from the superior thyroid artery. Surgery. 1994;115(4):417-23. 24. Hunt PS, Poole M, Reeve TS. A reappraisal of the surgical anatomy of the thyroid and parathyroid glands. Br J Surg. 1968;55: 63-6.

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25. Frazell EL, Foote FW. Papillary thyroid cancer. Pathologic findings in cases with and without evidence of cervical lymph node involvement. Cancer. 1955;8:1164-6. 26. Noguchi S. Noguchi A. Murakami N. Papillary carcinoma of the thyroid. I. Developing pattern of metastasis. Cancer. 1970;26(5):1053-060. 27. Cernea CR, et al. Surgical anatomy of the external branch of the superior laryngeal nerve. Head Neck. 1992;14:380. 28. Arnold GE. Physiology and pathology of the cricothyroid muscle. Laryngoscope. 1961;71:687. 29. Morton RP, Whitfield P, Al-Ali S. Anatomical and surgical considerations of the external branch of the superior laryngeal nerve: a systematic review. Clin Otolaryngol. 2006; 31:368-74. 30. Cernea CR, et al. Identification of the external branch of the superior laryngeal nerve during thyroidectomy. Am J Surg. 1992;164:634. 31. Friedman M, Toriumi DM. Functional identification of the external laryngeal nerve during thyroidectomy. Laryngo­ scope. 1986;96:1291. 32. Barczynski M, Konturek A, et al. A randomized controlled trial of visualization versus neuromonitoring of the external branch of the superior laryngeal nerve during thyrodectomy. World J Surg. 2012;36:1340-7. 33. Gray SW, Skandalakis JE, Akin JT, Jr. Embryological consi­ derations of thyroid surgery: developmental anatomy of the thyroid, parathyroids and the recurrent laryngeal nerve. Am Surg. 1976;42(9):621-8. 34. Katz AD, Nemiroff P. Anastamoses and bifurcations of the recurrent laryngeal nerve—report of 1177 nerves visualized. Am Surg 1993;59(3):188-91. 35. Henry JF, Audiffret J, Denizot A, et al. The nonrecurrent inferior laryngeal nerve: review of 33 cases, including two on the left side. Surgery. 1988;104(6):977-84. 36. Shindo ML, Wu JC, Park EE. Surgical anatomy of the re­current laryngeal nerve revisited. Otolaryngol Head Neck Surg. 2005;133(4):514-9. 37. Wafae N, Vieira MC, Vorobieff A. The recurrent laryngeal nerve in relation to the inferior constrictor muscle of the pharynx. Laryngoscope. 1991;101(10):1091-3. 38. Randolph GW, Urken ML. Surgical management of pri­mary hyperparathyroidism. In: Randolph GW (ed), Surgery of the thyroid and parathyroid glands. Philadelphia, PA: Saunders; 2003:507-28.

CHAPTER Pathology of Thyroid and Parathyroid Neoplasms

12

Sylvia L Asa, Ozgur Mete

THYROID PATHOLOGY The thyroid gland is composed of two hormone-pro­ ducing cell types as well as a cadre of stromal cells, inclu­ ding fibroblasts and endothelium. Follicular cells are responsible for thyroid hormone synthesis, and parafol­ licular C cells produce the calcium-regulating hormone calcitonin. The follicular cells represent the vast majority of the pare­nchyma, whereas C cells are scattered in and around follicles, mainly at the junctions of the upper third and lower two thirds of each thyroid lobe.1-3 Other structures in the thyroid include congenital remnants such as the residual thyroglossal duct in the midline and solid cell nests (ultimobranchial remnants) that are deri­ ved from the embryologically relevant branchial clefts, mainly at the same location as the C cells that derive from them. Intrathyroidal thymus, parathyroid, and salivary gland structures all can give rise to pathology that presents as a thyroid neoplasm.

CLASSIFICATION OF THYROID PATHOLOGY Thyroid pathologies can give rise to functional changes such as hypothyroidism or hyperthyroidism, or to struc­ tural problems such as goiter or nodules. These disorders may be congenital, may have a genetic basis, and may be inflammatory or neoplastic. This chapter will focus on thyroid nodules that are very common; approximately 20% of the population have a palpable thyroid nodule and almost 70% of individuals have ultrasound detectable nodules.4 Thyroid nodules are more prevalent in women

than in men; multiple nodules are more common than solitary nodules. The critical clinical issue is the identi­ fication of the subset of these common lesions that re­qui­ res therapeutic intervention. The differential diagnosis of the thyroid nodule in­clu­ des nonneoplastic and neoplastic, benign, and malignant entities.1,5-7 Thyroid nodules derived from follicular cells may be benign or malignant. Adenomas are com­mon; they may arise in the setting of a multinodular gland (follicular nodular disease) or may be solitary, may be hormonally hypoactive, or may secrete excess thyroid hormone, resulting in clinical or subclinical hyperthy­ roidism.8,9 Malignant neoplasms composed of thyroid folli­ cular epithelial cells are the most common endocrine malignancy; they vary from the most indolent carcinomas to the most aggressive and rapidly lethal malignan­cies.10,11 Tumors of other cells and structures in the thyroid are more rare but must be considered in the diagnosis of the thyroid nodule. The classification of the most common thyroid nodules is shown in Table 12.1.

Congenital Lesions Thyroglossal Duct Cyst Thyroglossal duct cyst is a remnant of the thyroglossal duct that is the embryologic tract of thyroid development, and the remnants can be found anywhere along the ante­ rior neck from the base of the tongue to the mediastinum. The remnants can undergo cystic enlargement, resulting in a mass.12,13 The most common site of this pathology is adjacent to the hyoid bone.14 The colloid-filled structures

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Table 12.1: Classification of thyroid nodules

Congenital lesions Thyroglossal duct cyst Pharyngeal/esophageal diverticula Pyriform sinus fistula Benign follicular epithelial proliferations Follicular nodular disease Follicular adenoma Malignant thyroid neoplasms of follicular epithelium Well-differentiated carcinoma of follicular epithelium Papillary thyroid carcinoma Follicular thyroid carcinoma Poorly differentiated carcinoma of follicular epithelium Poorly differentiated thyroid carcinoma Anaplastic (undifferentiated) thyroid carcinoma Primary neuroendocrine neoplasms of the thyroid gland Thyroid C-cell lesions Medullary thyroid carcinoma Mixed (composite) follicular epithelial and medulary carcinoma Other primary neuroendocrine neoplasms Thyroid paraganglioma Intrathyroidal parathyroid adenoma Intrathyroidal parathyroid carcinoma Other intrathyroidal primary neoplasms Salivary gland tumors Mucoepidermoid carcinoma Sclerosing mucoepidermoid carcinoma with eosinophilia Thymic tumors Thymoma Thymic carcinoma Squamous cell carcinoma Hematolymphoid neoplasms Mesenchymal neoplasms Teratoma Secondary (metastatic) neoplasms

are lined by follicular, squamous, or ciliated respiratory type epithelial cells, and their fibrous walls contain thy­ roid follicles (Fig. 12.1). Malignant transformation (most commonly a well-differentiated thyroid carcinoma, rarely squamous cell carcinoma) may occur in these lesions15 anywhere along the tract.16 The important differential

Fig. 12.1: Thyroglossal duct cyst. The colloid-filled cystic structures are characteristically lined by follicular, squamous, or ciliated respiratory-type epithelial cells, and their fibrous walls contain thyroid follicles.

dia­gnosis of primary thyroid carcinoma arising in a thyro­ glossal duct is metastatic carcinoma in an obliterated midline lymph node, a not infrequent diagnostic dilemma.8 Rare pharyngeal or esophageal diverticula and pyri­ form sinus fistula may present as a thyroid mass.17

Benign Follicular Epithelial Proliferations Follicular Nodular Disease The most common thyroid nodules are benign, colloid­ rich, macrofollicular proliferations of thyroid follicular epithelium that are usually multifocal (Figs. 12.2A and B). These so-called “hyperplastic” or “colloid” nodules, also known as “adenomatoid” or “adenomatous” nodules1-3 are common, present in almost every thyroid gland at autopsy. When clinically diagnosed due to thyroid enlargement, they are known as “sporadic nodular goiter”. The pathogenesis of this disorder is completely unknown. The various terminologies are confusing, since they imply either a hyperplastic etiology or a neoplastic one. Molecular studies have shown that the nodules may be either polyclonal or monoclonal. Polyclonality sup­ ports a hyperplastic and possibly reactive pathogenesis, but many nodules in the same glands that harbor hyper­ plastic lesion are clonal proliferations,18-20 i.e. follicular adenomas. Some exhibit loss of heterozygosity,18 and there is often loss of the same informative allele in multi­ple discrete nodules.18 These data suggest a mix of hyperplastic and neoplastic processes. No environmental,

Chapter 12: Pathology of Thyroid and Parathyroid Neoplasms hormonal, or genetic abnormality has been identified to explain this phenomenon. We have therefore proposed the terminology “follicular nodular disease” to reflect the enigmatic nature of this common disorder.8,21 These lesions have variable morphologic features (Figs. 12.2A and B). While usually obviously benign, they may have areas of hypercellularity and microfollicular architecture. They often exhibit focal degeneration with hemorrhage and fibrosis. Degeneration results in reactive cytologic atypia; fibrosis can create pseudocapsules and the pattern can resemble capsular invasion. These features can be worrisome and raise the possibility of malignancy. Follicular nodular disease is commonly associated with chronic lymphocytic thyroiditis. Focal inflammation may be reactive in the setting of sporadic nodular goiter, but in patients with autoimmune thyroiditis, such as Hashimoto’s thyroiditis, the primary pathology is inflam­ matory and the follicular proliferations are almost cer­ tainly secondary to thyroid damage. The nodules that develop in thyroiditis may be obviously benign, but there is often atypia that results in significant diagnostic dilem­ mas, especially the distinction of follicular variant and oncocytic papillary carcinomas from reactive changes in benign follicular nodules. It has been suggested that a spectrum of distinct cytological and architectural changes can be used to characterize reactive atypia, dysplasia, and ultimately the development of malignancy in chronic lymphocytic thyroiditis. We have therefore proposed the concept of follicular epithelial dysplasia, analogous to changes seen in other types of epithelium in the setting of inflammation.22 Since malignant transformation in the thyroid is likely due to stepwise progression of molecular changes,23 it is not surprising that benign follicular epithe­ lial proliferations, either in follicular nodular disease or in thyroiditis, can exhibit unifocal or multifocal malignant transformation.21,24 An unusual tumor associated with chronic lympho­ cytic thyroiditis is the branchial cleft-like cyst,25 a benign cystic lesion with a squamous epithelial lining and abun­ dant lymphoid tissue, including lymphoid aggregates with large reactive germinal centers, in the surrounding stroma.

Follicular Adenomas Follicular adenomas are benign neoplasms of follicular epithelial differentiation. They usually have follicular architecture and are well delineated with either a defined fibrous capsule or a thin layer of connective tissue that defines the edge of the lesion (Fig. 12.2C). They can be

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subclassified on the basis of the size of follicles, abun­ dance of colloid, and degree of cellularity1,6; however, there is no known significance of the macrofollicular, microfollicular, fetal, or embryonal subtypes (Fig. 12.2D). Traditionally, there has also been a category of “atypical” adenoma that is characterized by cytologic atypia, but many experts have reclassified most of these lesions as encapsulated noninvasive follicular variant papillary thy­ roid carcinomas. The definition of follicular adenoma was a solitary neoplasm of follicular epithelium that lacks the nuclear atypia of papillary carcinoma (Fig. 12.2D) and does not exhibit capsular or vascular invasion that defines follicular carcinoma (Figs. 12.3A and B). However, the clonal nature of many nodules in follicular nodular disease results in reclassification of those lesions as follicular adenomas; therefore, the solitary nature of the tumor is no longer a valid criterion. A subset of benign neoplasms of follicular epithelial differentiation that may be either solitary or associated with follicular nodular disease have a papillary architecture that resembles the hyperplasia of Graves’ disease.8,21 They have intrafollicular papillary architecture, peripheral scalloping of the colloid unassociated with dark colloid formation, and postbiopsy apical hemosiderin uptake, all morphological features of hyperactivity; the nonlesioal thyroid parenchyma often shows involution. These tumors may be associated with clinical or subclinical hyperthyroidism; if radioiodine scanning is performed, the lesions are “warm” or “hot”, indicating excessive iodine uptake.9 They are clonal and often contain activating mutations of the thyroid-stimulating hormone receptor (TSHR) or the GNAS (Gsα protein) genes that mediate TSH receptor signaling,26-31 mutations that result in constitutive activation of adenylate cyclase, high intracellular cyclic AMP levels, and increased thyroid hormone synthesis and secretion. Multiple nodules with similar morphologies can also be encountered in some familial syndromes including McCune-Albright syndrome, usually due to a mosaic mutation in the guanine nucleotide-binding protein (G protein) stimulatory alpha subunit or Gsα (GNAS1) gene. In addition patients with Carney complex due to mutations in the PRKAR1A gene can also present with multiple functioning nodules displaying similar morphological features. These nodules have been classified as “papillary hyperplastic nodules”, “follicular adenomas with papillary hyperplasia”, or “follicular adenomas with papillary architecture” but truly represent “papillary adenomas”.8,21

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A

B

C

D

Figs. 12.2A to D: Benign follicular epithelial proliferations. (A) Follicular nodular disease is a multifocal proliferation of follicular epithelium (arrows) that has variable morphology, varying from colloid-rich hypocellular areas to cellular lesions resembling adenomas. (B) Many of the nodules in follicular nodular disease are poorly defined, colloid-rich and hypocellular with eccentric “Sanderson’s polsters.” (C) Follicular adenomas are encapsulated, well-differentiated follicular neoplasms that do not show capsular or vascular invasion; (D) their nuclei are small, round, and uniform.

Malignant Thyroid Neoplasms of Follicular Epithelium Well-Differentiated Carcinoma of Follicular Epithelium Differentiated thyroid cancer is the most common endo­ crine malignancy and one of the few tumors that are in­creasing in incidence.32 While some of the increase may be due to radiologic detection of small tumors that are of no clinical consequence, the increasing incidence of large tumors and increasing lethality of thyroid carcinoma suggest that other factors are also implicated.33

Papillary thyroid carcinoma: It is a well-differentiated malignancy of thyroid follicular epithelium that is characterized by papillary architecture, stromal fibrosis, and psammoma bodies. It is usually unencapsulated and infiltrative with local invasion, and a high incidence of lymphatic involvement giving rise to locoregional lymph node metastases.1-3 The cytologic features of papillary carcinoma are the hallmark of this diagnosis (Figs. 12.4A to D). The columnar epithelial cells lining the papillae (Fig. 12.4A) have enlarged, crowded, oval nuclei that are hypochromatic due to peripheral margination of chromatin and clearing of nucleoplasm.34 There is convolution of the nuc­lear membrane, resulting in nuclear grooves that

Chapter 12: Pathology of Thyroid and Parathyroid Neoplasms

A

213

B

Figs. 12.3A and B: Follicular thyroid carcinoma. (A) Follicular carcinoma resembles follicular adenoma but exhibits invasive behavior; this lesion exhibits angioinvasion proven by thrombus formation associated with intravascular tumor cells. (B) Transcapsular mushroomlike invasion is unequivocal evidence of capsular invasion in a well-differentiated thyroid carcinoma.

A

B

C

D

Figs. 12.4A to D: Papillary carcinoma. (A) The identification of even a single true papillary structure in a papillary carcinoma a warrants classification of this lesion as classical variant. (B) Follicular variant papillary carcinomas consist entirely of follicular structures. (C) Oncocytic change can be seen in all thyroid lesions; the nuclear features of papillary carcinoma characterized by enlarged nuclei with irregular contours and focal clearing warrant classification of this lesion as oncocytic follicular variant papillary carcinoma. (D) Tall cell variant papillary carcinomas are defined as neoplasms with complex papillary architecture that are composed of cells with a heightto-width ratio that exceeds 3:1.

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create a “raisinoid” or “cerebriform” appearance and, when profound, result in intranuclear cytoplasmic pseudoinclusions.35 These nuclear features were also identified in a subgroup of thyroid tumors that had follicular architecture,36 some noninvasive and classified as adenomas, and others, which exhibited invasion, but had been diagnosed as follicular carcinoma. The association of these nuclear features with lymph node metastasis led to reclassification of these lesions as “follicular variant papillary thyroid carcinoma”37,38 (Fig. 12.4B). Currently, there is controversy concerning the threshold for identifying nuclear enlargement, irregularity, and convolutions to reach a diagnosis of papillary thyroid carcinoma, resulting in significant intra- and interobserver variability of diagnosis. Follicular thyroid carcinoma: It is characteristically a well-delineated and encapsulated lesion with follicular architecture; traditionally, these lesions were distinguished from follicular adenomas by the identification of capsular and/or vascular invasion (Figs. 12.3A and B). Unlike papil­lary carcinomas, follicular carcinomas have a pro­ pensity to spread hematogenously and give rise to distant metastases. The incidence of follicular thyroid carci­ noma has been reducing over time, concurrent with increasing diagnosis of papillary thyroid carcinoma;39 much of this change in diagnosis may be due to increa­sing recognition of the cytologic features of papillary thyroid carcinoma and reclassification of follicular neo­ plasms as follicular variant papillary thyroid carcinoma. The molecular profile of differentiated thyroid cancer has raised questions about the validity of traditional morphologic classification.3,23 Classical papillary carcinomas with even minimal papillary architecture, stromal fibrosis, and psammoma bodies have a high incidence of mutations in B-type Raf kinase (BRAF), most commonly the BRAFV660E mutation. In contrast, follicular thyroid carcinomas and follicular variant papillary thyroid carcinomas with pure follicular growth patterns have a high incidence of rat sarcoma (RAS) mutations.40-50 Gene rearrangements are also found in these tumors, most commonly rearrangements involving the rearranged during transcription (RET) proto-oncogene [RET-papillary thyroid cancer (PTC)], but also involving “TRK”, paired box gene 8–peroxisome proliferator-activated receptor gamma (PAX8-PPARγ), anaplastic lymphoma receptor tyrosine kinase “ALK”, and A-kinase anchor protein 9 “AKAP9BRAF”. 23,46,47,51 The mutations and rearrangements are generally mutually exclusive and nonoverlapping. The rarer genetic alterations exhibit geographic and temporal variations.23,47,51

These molecular data validate the original classification of differentiated thyroid carcinoma as either papillary or follicular types. The recognition of follicular variant papil­ lary thyroid carcinoma identified the malignant potential of follicular neoplasms that did not have invasive behavior and paved the way for nuclear criteria for the diagnosis of malignancy in follicular lesions rather than relying on capsular and/or vascular invasion alone.1-3

Variants of Differentiated Thyroid Carcinomas Both papillary and follicular thyroid carcinomas have several variants that are distinguished on the basis of size, cytologic features, architecture, and sometimes a combi­ nation of architectural and cytologic features. Microcarcinoma is defined as a lesion that measures ≤ 1.0 cm in maximum dimension; microcarcinomas are very common as incidental findings both at autopsy and in surgical thyroidectomy specimens operated for reasons other than papillary carcinoma);52 this suggests that their diagnosis is of no real clinical significance with the rare exception of those that present with metastatic disease.53-55 These lesions are being increasingly diagnosed on radiologic investigation for other reasons,33 and there is controversy regarding the approach to management. Once biopsied and diagnosed, it is difficult to encourage patients to ignore the finding; therefore, a rational con­sen­ sus to biopsy of incidental small thyroid lesions is required. Oncocytic, oxyphilic, or Hurthle cell papillary, follicu­ lar variant papillary, or follicular carcinomas are compo­sed of cells that have increased numbers of swollen mito­ chondria that result in enlarged, granular amphophilic cytoplasm; they also often have large, cherryred nucleoli that can camouflage other nuclear features (Fig. 12.4C). Mitochondrial gene mutations are thought to underlie this phenomenon, and these coexist with the mutations that are considered to be drivers of neoplastic transfor­ mation (e.g. BRAF, RET/PTC, RAS). The mitochondrial events are not considered to alter growth and/or inva­ sion,56,57 but they may affect iodine uptake, since these lesions are thought to be relatively resistant to radioactive iodine treatment. The criteria for diagnosing oncocytic lesions should be the same as those applied to follicular lesions that are not composed of oncocytic cells;58,59 the lesions can be hyperplastic, reactive (in thyroiditis), benign neoplasms (oncocytic follicular adenoma), or malignant neoplasms of any type. Warthin-like papillary carcinoma is an example of an oncocytic classic variant papillary thyroid carcinoma with a distinct morphology that mimics

Chapter 12: Pathology of Thyroid and Parathyroid Neoplasms Warthin’s tumor of salivary glands; it has true papillary architecture, the epithelial cells have florid oncocytic change, and the stroma is heavily infiltrated by chronic inflammatory cells. Clear cell tumors are composed of large cells with clear cytoplasm; these are usually associated with oncocytic change and result from massive dilation of mitochondria, but in some tumors, the change is due to lipid accumu­ lation. Focal clear cell change is not uncommon in some oncocytic follicular epithelial neoplasms, but when an excess of 75% of the tumor shows clear cell differentia­ tion, the lesion is classified as a clear cell variant of thyroid carcinoma.1-3,59 Tall cell, columnar cell, and hobnail variants of papil­ lary carcinoma have unique cytologic features and are clinically significant since they also have more aggressive behavior than conventional types.60-68 Tall cell papillary carcinomas (Fig. 12.4D) are defined as tumors with comp­ lex papillary architecture that are composed of cells with a height-to-width ratio that exceeds 3:1; they are more locally invasive,62,66,68 but the molecular basis for this is not clear, since they harbor the same BRAFV600E mutations as other classical variant papillary carcinomas. Columnar cell tumors have more crowded elongated cells with pse­ u­ dostratification, resembling respiratory epithelium or colo­ nic adenomas, they have subnuclear cytoplasmic vacuoles that can yield a resemblance to secretory endo­ metrium,69 they are rare, and the molecular basis for aggressive beha­vior is not known. Papillary carcinomas composed of “hobnail” cells are also more aggressive, but the reasons for their unusual morphology and aggressive behavior are not known.68 Architectural variants include macrofollicular, diffuse sclerosing, solid, cribriform-morular, and villous variants. The macrofollicular variant is of importance to patholo­ gists mainly because of the bland appearance of the tumor at low magnification; the abundance of colloid and resulting relative hypocellularity can be misleading, resembling folli­cular nodular disease or adenoma. It is important to always examine the cytology of these lesions at high magnification. The diffuse sclerosis variant is almost exclusively found the pediatric population; it lacks a dominant noule and instead causes diffuse thyroid enlargement.70-73 There is squamous metaplasia, and psammoma bodies are cons­ picuous. Lymphatic invasion and intrathyroidal lymphatic dissemination is prominent, and these tumors almost al­ways have lymph node metastases at the time of diagnosis; almost 25% have lung metastases as well.

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The solid variant of papillary carcinoma has, as its name suggest, a solid growth pattern that lacks follicles and colloid. This tumor can be mistaken for poorly differentiated thyroid carcinoma (see below),3 but the tumor cells remain well differentiated and there is no tumor cell necrosis that is a feature of the more aggressive lesions. This variant of papillary carcinoma may have a more aggressive behavior.74,75 The controversial hyalinizing trabecular tumor76-78 was initially described as a benign “hyalinizing trabecular adenoma”79 and “paraganglioma-like adenoma of thyroid”.80 However, malignant behavior was quickly recognized.1,81-83 Although their architecture is solid, trabecular, and nesting rather than papillary or follicular, and there is prominent intracellular and stromal hyaline deposition, these tumors share many features with papillary carcinoma: clinically, they are associated with Hashimoto’s thyroiditis and have been reported in patients with a history of neck irradi­ ation.84 Morphologically, they form psammoma bodies, and their nuclear features are identical to those of papi­ llary carcinoma;79 at the molecular level, they exhibit the same genetic alterations with frequent RET/PTC rearrangements.85,86 For these reasons, many experts consi­ der these to be variants of papillary thyroid carcinoma.3,87,88 The cribriform-morular variant and the villous variant have clinical implications regarding the diagnosis of other nonthyroid disease. The former has a striking cribriform pattern of papillae admixed with solid squamoid-like whorls known as morula. The latter has elongated complex papillary fronds that mimic villous adenomas of the bowel. In both, the tumor cells are generally cuboidal or tall, with nuclear pseudostratification. There is no evidence that these variants have different behaviors than other forms of papillary carcinoma, but they are often associated with germline genetic alterations that are of clinical importance. Cribriform-morular papillary carcinoma is almost always identified in patients with germline mutations of the adenomatous polyposis coli (APC) gene who have familial predisposition to develop polyposis coli. It is therefore not surprising that alteration of Wnt signaling is a feature of these tumors; this can be verified using immunohistochemistry that confirms nuclear and cytoplasmic translocation of beta-catenin in these neoplasms.89-91 Only rarely do tumors of this type exhibit sporadic mutation in CTNNB1 unassociated with germline or familial disease.92 The villous variant of papil­ lary carcinoma is associated with Marfan syndrome, an autosomal dominant hereditary disorder due to mutations in genes responsible for transforming growth factor beta

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(TGF-β) signaling, most often in the FBN1 gene that encodes fibrillin-1.93 Altered TGF-β signaling weakens connective tissue integrity in Marfan syndrome and may account for the unique villous morphology of this tumor variant.

Poorly Differentiated Carcinoma of Follicular Epithelium Poorly differentiated carcinoma, also known as “insular” carcinoma,94 is an aggressive malignancy of thyroid fol­ licular differentiation that is intermediate between well differentiated and anaplastic undifferentiated carcinoma. Poorly differentiated thyroid cancers retain some featu­ res of differentiation; they express thyroid transcription factor I (TTF-1) and thyroglobulin but fail to form follicles or papillae and the tumor cells lose their polarity.1-3 These aggressive lesions do not usually take up radioactive io­dine with the affinity that is seen in differentiated thy­ roid carcinomas, consistent with lack of expression of the sodium iodide symporter (NIS). In contrast, they are more readily localized with fludeoxyglucose positron emission tomography (FDG-PET) scans,95 consistent with higher proliferative activity. The Turin consensus96 defined this entity as a neo­ plasm composed of thyroid follicular epithelial cells (based on TTF-1 and thyroglobulin expression) with (1) a solid/trabecular/insular growth pattern (Fig. 12.5A), (2) absence of nuclear features of papillary carcinoma, and (3) presence of at least one of the following: convoluted nuclei, mitotic activity of > 3/10 high-power fields, and necrosis. The necrosis is usually single cell necrosis rather

A

than the geographic type of necrosis that is seen in anaplas­ tic car­cinomas. Most of these lesions were previously classi­ fied as “follicular” or “Hurthle cell” carcinomas in the past. They are usually widely invasive and angioinvasive;97 the latter explains the high incidence and the prevalence of distant metastases of follicular carcinoma prior to 1984 when this interme­diate category was proposed. Poorly differentiated carcinomas often arise in multi­ nodular goiters and usually harbor foci of well-differen­ tiated carcinoma (either papillary or follicular), suggesting that they arise by progression of molecular dysregulation. Consistent with this theory, they can harbor multiple mutations, including BRAF, RAS, CTNNB1, and phosphati­ dylinositol-4,5-biphosphate 3-kinase, catalytic sub­unit alpha (PIK3CA).98-101

Anaplastic Thyroid Carcinoma Dedifferentiated or anaplastic thyroid carcinoma is for­ tunately rare, representing  13% of deaths from thyroid cancer.102 This is partially because of the aggres­ siveness of the tumor compared to differentiated thyroid carcinoma, but also because medullary carcinoma does not take up iodine; therefore, this highly effective targeted therapy is not indicated. Medullary carcinomas (Fig. 12.6) are usually com­ posed of solid sheets and nests of dyscohesive or weakly cohesive cells; they may be spindle-shaped, epithelioid, plasmacytoid, oncocytic, clear, squamoid, mucinous, or small cell like. The nuclei are eccentric with prominent nucleoli and coarse granular chromatin that has a “salt and pepper” appearance; occasional binucleate and giant cells are seen.103 Fixation artifact may cause a pseudopapillary appearance, mimicking papillary carcinoma.104 As they grow, these tumors surround nonneoplastic follicles, ren­dering a pseudofollicular appearance that can result in misdiagnosis. Dedifferentiation of these neuroendocrine tumors results in the appearance of a small cell carcinoma; this can mimic lymphoma. The stroma may contain amyloid; in some tumors, amyloid is seen only focally as an intracytoplasmic feature. Amyloid exhibits apple-green birefringence with polarized light and can be highlighted by Congo red staining. The diagnosis of medullary carci­ noma is confirmed by immunolocalization of calcitonin, chromogranin, and carcinoembryonic antigen (CEA) in addition to cytokeratins (mainly CK7 and CK18 and TTF-1). With dedifferentiation, calcitonin positivity may be reduced and CEA increases; this may be reflected in

217

circulating levels of these tumor markers.105,106 Calcitonin gene-related peptide is also localized in medullary thyroid carcinomas. They may also express other peptides, such as somatostatin, derivatives of the pro-opiomelanocor­tin molecule (adrenocorticotropic hormone, melanocyte-sti­ mula­ting hormone, β-endorphin and enkephalin), serot­ o­ nin, glucagon, gastrin, cholecystokinin, vasoactive intes­tinal peptide (VIP), bombesin, and α-human chori­ onic gonadotropin (HCG);1,107-109 these hormones can be asso­ciated with ectopic syndromes. Expression of somatostatin receptors is a feature of most neuroendocrine cells including thyroid C cells.110 This feature makes these tumors candidates for localiza­ tion with labeled somatostatin analogs;111 therapeutic long-acting somatostatin analogs have applications in the management of hormonal syndromes that are debili­ tating in patients with disseminated disease.112 Another unique aspect of medullary thyroid carci­ noma is its hereditary nature. The diagnosis may have implications for both the patients, who may have other endocrine tumors, and members of his/her family.113 Familial medullary carcinoma is an isolated disorder in familial medullary thyroid carcinoma (FMTC), or may be associated with pheochromocytomas and parathyroid disease in multiple endocrine neoplasia (MEN) type IIA; in MEN IIB, thyroid and adrenal proliferative disorders are associated with mucosal ganglioneuromas and a Marfanoid habitus. These disorders are all attributed to activating mutations of the RET proto-oncogene, usually in exons 10 and 11 FMTC or MEN IIA and at codon 918 in MEN IIB.114,115 This represents an example of inheritance of an activated oncogene and is a rare situation in which the genetic alterations provide almost 100% predictability of cancer development.102,116,117 For this reason, members of kindreds with FMTC or MEN IIA are advised to undergo genetic screening early in life, and affected individuals are advised to have prophylactic thyroidectomy in childhood to prevent the development of cancer.102 MEN IIB due to a codon 918 mutation is usually a de novo germline disorder. It is important to analyze the germline DNA from blood rather than tumor tissue when evaluating RET mutations and determining the possibility of familial disease, since sporadic medullary carcinomas can have RET mutations; sporadic mutations are most often identified in codon 918, but other mutations have been reported.102,115,117,118 The identification of this mutation may have prognostic value119 and may suggest a role for novel targeted therapies. Other mutations in commonly affected oncogenes and tumor suppressors are rare in this malignancy.120-122

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The FMTC is usually multicentric and associated with underlying C-cell hyperplasia.24,123,124 Increased num­ bers of C cells (> 7 cells per cluster), complete folli­cles surrounded by C cells, and identification of C cells out­ side their usual location in the upper lateral lobes are the criteria for the diagnosis of C-cell hyperplasia (Fig. 12.6B). Although rare, other causes of C-cell hyperplasia that are not associated with medullary thyroid carcinoma include chronic hyper­calcemia, follicular nodular disease, thyroiditis, and phosphatase and tensin homolog (PTEN)hamartoma tumor syndrome.24,125-129

They can be distinguished by the identification of S-100 positive sustentacular cells and staining for tyrosine hyd­ roxylase; they are negative for keratins, calcitonin, and CEA as well as thyroglobulin.136,137 Although usually benign, they may exhibit extrathyroidal extension.

Intrathyroidal Parathyroid Lesions

Mixed Follicular-C Cell Lesions

The proximity of the parathyroid glands to thyroid and the frequent intrathyroidal location of parathyroid tissue is well known; lesions of these glands can present as a thyroid nodule. The pathology of parathyroid adenomas, parathyroid carcinomas, and parathyroid cysts is discussed below under section “Parathyroid Pathology”.

Mixed follicular-C cell lesions are rare. The validity of mono-morphous tumors with genuine dual differentiation is controversial.130,131 Composite tumors do occur; they are composed of two intermixed well-differentiated com­ ponents, thyroglobulin-immunoreactive follicular cells, usually with cytologic features of papillary carcinoma, and parafollicular C cells that are immunoreactive for calcitonin and CEA.132,133 These are likely to be collision tumors, since papillary carcinomas are relatively common52 and may occur coincidentally with medullary carcinoma. The two tumors may develop separately and metastasize together to a regional node.134,135

Primary thyroid neuroendocrine carcinomas: They can very rarely be negative for calcitonin. In this scenario, the possibility of a metastatic neuroendocrine carcinoma must be excluded138 using markers of gastroenteropan­ creatic differentiation, such as CDX2, cytokeratins 7 and 20, or specific hormones that are associated with origin in the gastrointestinal tract; TTF-1 is not helpful, since lung endocrine tumors, occasional prostate endocrine tumors along with all high-grade neuroendocrine carcinomas of various sites also express this transcription factor. The biological behavior of these extremely rare non-C-cell thyroid neuroendocrine tumors is not known.

Intrathyroidal Paragangliomas

Other Intrathyroidal Primary Neoplasms

These are extremely rare tumors that present as a solitary nodule and can be misdiagnosed as medullary carcinoma.

Other tissues in and around the thyroid can give rise to primary tumors that can be mistaken for thyroid tumors.

A

B

Figs. 12.6A and B: Thyroid C-cell lesions. (A) Medullary thyroid carcinoma arises from parafollicular C cells and is usually composed of solid sheets and nests of dyscohesive or weakly cohesive endocrine cells displaying spindle-shaped, epithelioid, or plasmacytoid appearance. Some tumors may show oncocytic, clear, squamoid, mucinous, or small cell-like cytology. (B) C-cell hyperplasia is usually associated with inherited medullary thyroid carcinoma as in this case; however, this lesion may be reactive.

Chapter 12: Pathology of Thyroid and Parathyroid Neoplasms

Salivary Gland Tumors Although it is rare to see salivary gland remnants in the thyroid, these do occur, and are thought to be the origin of primary thyroid mucoepidermoid carcinoma, a common neoplasm of the salivary glands. Some authors believe they arise in the ultimobranchial body rests that are common in normal thyroids;139 alternatively, expression of TTF-1 and thyroglobulin in these tumors, and occasional association with papillary carcinoma (that could also be coincidental) has led some to speculate that derive from follicular epithelium.140-142 Like other thyroid tumors, they are more common in women, and they are often associated with thyroiditis. These tumors, composed of squamous cells, mucus-secreting cells, and “intermediate” cells, are usually indolent, even when they spread to local lymph nodes.140 An unusual variant of intrathyroidal mucoepidermoid carcinoma, sclerosing mucoepidermoid carcinoma with eosinophilia (SMECE), is characterized by stromal sclero­ sis, squamous, and glandular differentiation, an inflam­matory infiltrate rich in eosinophils;141 unlike conventional thyroid mucoepidermoid carcinoma, SMECE is negative for thyroglobulin.140,141

Thymic Tumors Intrathyroidal thymus is a common finding; therefore, it is not surprising that thymic tumors occur within the thyroid gland.143-153 It has also been suggested that they may arise from the branchial pouch developmental remnants in the thyroid known as solid cell nests or ultimobranchial body rests.146,148,154,155 There are three morpho­logic types: thymomas that may be benign, locally inva­sive or metastasize, thymic carcinomas, and thymic neuroendocrine tumors. Thyroid thymomas: They present as a mass lesion and are more common in women; they are rarely associated with myasthenia-like symptoms.150 They are composed of lymphoid cells admixed with epithelioid or spindle-shaped epithelial cells that exhibit minimal atypia. Lymphocyte­ rich thymomas may be misdiagnosed as lymphocytic thyroiditis or even lymphoma;149-153 the identification of an immature T-cell phenotype is helpful to confirm the diagnosis.152 Thymic carcinomas: They are composed of malignant epithelial cells of thymic derivation. Two unusual variants have been described in thyroid. The spindle epithelial tumor with thymus-like differentiation occurs mainly in children and young adults.142,147,148,154,155 This low-grade

219

malignancy may develop delayed hematogenous metas­ tases. Histologically, the tumor is mono- or biphasic. In the classical biphasic form, spindle-shaped tumor cells forming interlacing fascicles with fibrous stroma inter­ mixed with cuboidal to columnar epithelial cells that form tubules, papillae, cords, and glandular spaces with foci of squamous metaplasia. Mitotic activity and focal necrosis are rare.156 Immunohistochemistry is helpful to exclude the diagnosis of anaplastic carcinoma, spindle cell variant of medullary carcinoma, and other sarcomas. The tumor cells are positive for cytokeratins, smooth muscle actin, muscle-specific actin and MIC-2, and negative for thyroglobulin, calcitonin, chromogranin, S-100, and CD5.142 Since the lesion can mimic synovial sarcoma, testing for the t(X;18) translocation can be helpful since the SYT/ SSX fusion product is a characteristic feature of synovial sarcoma. Carcinoma showing thymus-like diffe­rentiation is another rare, low-grade malignant neoplasm of the thyroid that is thought to be of thymic origin and/or diffe­ rentiation. Solid sheets, tubules, papillae, or cords of cuboidal to columnar epithelial cells resembling medullary or squamous cell carcinoma are infiltrated by lymphoid cells. The epithelium is positive for cytokeratins p63, highmolecular weight keratins, and CD5, but negative for TTF-1, thyroglobulin, calcitonin, chromogranin, and S-100.155,157 Positivity for CEA can lead to confusion with medullary thyroid carcinoma.146,155

Squamous Cell Carcinoma Primary squamous cell carcinoma of thyroid: It is a rare mimic of anaplastic thyroid carcinoma clinically.142,158,159 These tumors may arise from malignant transformation of squamous metaplasia in papillary carcinoma.160-162 The morphology of primary squamous carcinoma of the thyroid is not distinctive; it is identical to squamous carcinoma arising elsewhere; therefore, it is impossible to distinguish from direct extension of an oropharyngeal primary or a metastatic squamous carcinoma (Fig. 12.7C).

Hematolymphoid Neoplasms Primary thyroid lymphoma: It accounts for 60 years of age where the incidence is two to three times higher.197 Other clinical scenarios are secondary and tertiary hyper­ parathyroidism, or a mass lesion that may be solid or cystic. Some patients have familial genetic disorders, and there is some evidence of a role for radiation in the pathogenesis of parathyroid tumors,198 but the majority of cases are sporadic and of unknown etiology.

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The classical clinical manifestations of hyperparathyroidism have been summarized as “stones, bones, and groans”, reflecting the nephrolithiasis, osteopenia, and peptic ulcers/pancreatitis that characterize the disorder. However, most cases in the western world are now dete­ cted by biochemical screening; the florid clinical manifestations are becoming increasingly uncommon. Primary hyperparathyroidism may be due to idio­ pathic or familial parathyroid hyperplasia, adenoma, or carcinoma. By far the most common lesion is adenoma. Secondary hyperparathyroidism is most often due to renal failure but rarely is due to vitamin D deficiency, severe hypomagnesemia, or pseudohypoparathyroidism; it is al­most always associated with multiglandular hyperplasia. Tertiary hyperparathyroidism is usually associated with the emergence of an autonomous adenoma or carcinoma in the setting of secondary hyperplasia.

Parathyroid Adenoma Parathyroid adenomas are usually solitary benign neo­ plasms. They account for approximately 75–80% of cases of primary hyperparathyroidism. These monoclonal tu­mors199-201 exhibit loss of chromosome 11, mainly 11q13 and specifically at MEN-1 gene, and MEN-1 intragenic deletions are probably their most common genetic event.202 Another genetic alteration that has been implicated is known as the PRAD1 gene rearrangement; this is actually a family of rearrangements that place the coding regions of either the cyclin D1 gene or the INT2 gene encoding a fibroblast growth factor under the transcriptional control of the parathyroid hormone gene promoter.203 Upregula­ tion of cyclin D1 is therefore a feature of these tumors. In addition, downregulation of the cyclin-dependent kinase inhibitor p27 has been identified. Parathyroid adenomas are usually single, involving one gland; they are well-defined and often encapsulated, composed of chief cells, clear cells, and oncocytes, with mild nuclear pleomorphism. Most adenomas have a predominance of chief cells, with scattered other cell types; pure oncocytic or clear cell adenomas also occur. The identification of a rim of hypocellular nontumorous parathyroid tissue facilitates accurate diagnosis (Fig. 12.8); in the absence of this feature, hyperplasia cannot be exclu­ded and many pathologists faced with this scenario will prefer to classify the lesion as “enlarged cellular parathyroid”. With the use of intraoperative localization and intraoperative rapid parathyroid hormone assays, a restricted surgical approach is performed,204 so no biopsies of other

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Fig. 12.8: Parathyroid adenoma. The gland is enlarged and cellular with a clear rim of hypocellular nontumorous parathyroid tissue (arrow).

glands are obtained to confirm the morphologic diagnosis, but the outcome of surgery will allow the correct diagnosis, and if wrong, further surgery is required for hyperplasia, and there is no complicating fibrosis compromising the other glands.

Parathyroid Hyperplasia Parathyroid hyperplasia accounts for 10–15% of primary hyperparathyroidism. Some cases are secondary; however, familial syndromes including MEN type 1 (MEN-1) due to germline mutation of the menin tumor suppressor gene on 11q13, or MEN-2 due to an activating mutation of the ret proto-oncogene on 10q11.2, are associated with multiglandular disease that is defined as primary hyperplasia. In the former scenario, the glands show diffuse enlargement and hypercellularity, and they are usually polyclonal; in the latter, they are often composed of multiple monoclonal nodules that biologically actually represent multiple multiglandular adenomas. These glands can be involved in an asymmetric manner, and hyperplastic glands can be highly invasive of surrounding parenchyma, creating a dilemma for the pathologist who is concerned about malignancy.

Parathyroid Carcinoma Parathyroid carcinomas are rare malignancies that acco­ unt for  4 cm) tumors has also been observed. Increases in incidence are seen across racial subgroups within the USA, are experienced more markedly in women than in men, and are associated with age, with an increasing number of patients > 45 years of age presenting with disease. The explanation for these increases remains unclear. It is possible that there is a higher degree of scrutiny applied to sectioning of resected thyroid glands by modernday pathologists, although that is unlikely to be responsi­ble for the dramatic increases observed. Exposure to ionizing radiation is a well-known risk factor for WDTC, and the application of low-dose radiation in the manage­ment of several benign head and neck conditions between 1930 and 1960 may explain to some degree the fact that the greatest increase is seen in older patients. In addition, increasing use of dental X-rays and CT scans of the head and neck is exposing individuals to higher doses of ioni­ zing radiation than in the past. In addition to medical radiation exposure, industrial disasters such as the Chernobyl and Fukushima reactor

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Head and Neck Surgery

explosions led to increased radiation exposure for large re­gional populations. Other patient-related risk factors suggested include rising body mass index with insulin resistance and the increased use of fertility drugs with resulting changes in fertility patterns. Whatever the explanation, far more patients now present with WDTC than ever before. In a time of limited health-care resources, it is critical that these patients are dealt with in a clinically sound and cost-effective manner.

INVESTIGATION OF A PATIENT WITH A THYROID NODULE SUSPICIOUS FOR WELL-DIFFERENTIATED THYROID CANCER Investigation of the thyroid nodule has been discussed in Chapter 13; therefore, this section will focus on those issues most relevant to WDTC. As with all fields of medicine, a thorough clinical history is essential. Patients should be asked about how a mass was noticed, how long it has been there, and any changes observed during that time. Specific features such as a change in voice or swallowing raise the clinical sus­ picion for malignancy. Although uncommon, WDTC can be inherited, and therefore, a full family history should be obtained. Any history of exposure to radiation should also be elicited, as this is a risk factor for thyroid cancer. Any history of prior surgical intervention in the neck should be sought. Examination of the patient starts with inspection. The patient’s weight, tremor, and sweating may all suggest thyroid dysfunction. Pulse rate and rhythm may also con­ tribute. The patient should be asked to swallow and the thyroid gland observed as it moves up and down with the pretracheal fascia. Any tethering should be noted. Palpation of the thyroid and neck should be performed to identify any evidence of fixation within the central compartment, or the presence of associated lymphadenopathy. A full head and neck examination is then performed, including visualization of the vocal cords. Cord mobility should be documented preoperatively for all patients routinely. After a history and examination, routine investigations include thyroid function tests and a US examination. The US is particularly useful in identifying features that are suggestive of malignancy. Those nodules that are taller than wide, hypoechoic, or those containing micro­ calcifications are at higher risk of malignancy, when

compared with oval hyperechoic lesions. Features such as irregular borders or extrathyroid extension also suggest malignant disease. Increased internal vascularity is also a feature, which will raise the suspicion for carcinoma. During US, particular note of the regional lymphatics should be made. Lateral neck nodes can be imaged with high levels of accuracy. The sensitivity and specificity of US in the central compartment is lower, particularly for those nodes that extend toward the superior medias­tinum and posterior to great vessels; however, the US evaluation remains critical for presurgical planning. It must be noted, however, that the US examination is highly operator dependent and thus will vary with the level of expertise, experience, and interest of the sono­ grapher. Self-performed US by the clinician is ideal if sufficient experience is available through training and practice. Ideally, during a US examination, the clinician can arrange fine-needle aspiration (FNA) sampling of pri­ mary lesions and suspicious nodes. With expertise in US, FNA sampling and cytological interpretation, high rates of accuracy in terms of diagnosis can be achieved in one visit. The report of an FNA is one of the most important pieces of information obtained during a patient’s preo­ perative investigation. A number of classifications exist to aid in standardizing the descriptions of samples ob­tained, and the clinician should have a thorough under­ standing, not only of the intended definitions of the clas­ sification system employed, but also of how that affects practice locally. The Bethesda Classification System, published in 2008, aims to standardize terminology used to classify thyroid FNAs. This system contains six classes and pro­vides recommendations for clinical management based upon them (Table 14.1). In the setting of a benign or malignant diagnosis, management decisions can be made based upon these results. Nondiagnostic samples should be repeated. Those lesions that are classified as follicular lesions of undetermined significance, atypical, follicular or Hurthle cell neoplasm or suspicious for malignancy are more complex. For these results, it is important that the clinician understands the risk of malignancy for such samples based upon other features, history and clinical findings as well as local experience. Departmental audit with comparative review against surgical histopathology is important for clinicians and patients to understand how best to interpret and act upon the results obtained.

Chapter 14: Management of Well-Differentiated Thyroid Cancer Table 14.1: Bethesda classification of thyroid cytology specimens

Classification

Estimated risk of malignancy (%)

Clinical recommendation

Non-diagnostic

1–4

Repeat with ultrasound guidance

Benign

0–3

Clinical follow-up

Atypical/Follicular lesion of undetermined significance

5–15

Repeat fine-needle aspiration biopsy in 3–6 months

Follicular/Hurthle cell neoplasm

15–30

Diagnostic lobectomy

Suspicious for malignancy

60–75

Diagnostic/therapeutic surgery

Malignant

97–99

Therapeutic surgery

Options for those patients who have nondiagnostic cytology include further examination of the cytological specimen in terms of genetic expression. Genetic analysis has become available in recent years and is likely to become more significant in the future. A study of over 4800 thyroid cytological specimens identified a 12% rate of indeterminate reports. A gene-expression classifier was used to analyze for the presence of B-type Raf kinase (BRAF) and rat sarcoma (RAS) mutations and rearran­ ged during transcription (RET)/papillary thyroid cancer (PTC) and paired box gene 8 (PAX8)/PPARy (peroxisome pro­ liferator-activated receptor gamma)1 gene rearrange­ ments.2 These novel investigations have the potential to identify patients who are at very low risk of malignancy, with a negative predictive value of up to 95% in indeter­ minate cytological specimens preoperatively. This infor­ mation can be used to select the patients most appropriate for observation. Having gained information from the history, physical examination, US, and FNA, the clinician must now con­ sider the need for further investigation. The vast majority of patients will be adequately investigated at this point. However, a small group of patients with extensive nodal disease or the suspicion of locally advanced tumors will be candidates for cross-sectional imaging. Traditionally, CT has been preferred, as it is widely available, fast, relatively cheap and gives excellent detail in regard to the local extent of the primary tumor as well as nodal disease. However, contrast enhancement, which is required for optimal resolution, involves the administra­ tion of iodine. This reduces the efficacy of radioactive iodine (RAI), administered soon after surgery, and introduces a

243

delay between surgery and adjuvant therapy with RAI. While such a delay is not ideal, the surgeon must remember that RAI will not make up for inadequate surgery, and it is imperative that the surgeon has accurate presurgical information on the extent of the tumor to allow selection of the procedure most likely to result in complete disease extirpation. If the tumor is incompletely excised, RAI will not be able to salvage the situation, as its role in postoper­ ative management is in dealing with microscopic deposits, not gross disease. In addition, a 6-week delay in the administration of RAI does not have a major impact on outcome. For these reasons, if there is any suspicion of advanced disease, the surgeon should not compromise and proceed with cross-sectional contrast-enhanced imag­ ing of the accurate anatomic extent of the primary and regional lymph nodes. PET scanning has not been widely adopted in the initial investigation of WDTC. Most lesions are not PET avid but do concentrate iodine on RAI scanning. There­ fore, PET offers little additional information over routine investigation. Longstanding or recurrent WDTC, however, may undergo dedifferentiation to more aggressive histo­ logical subtypes. Such changes are heterogeneous through­ out a tumor mass. In the setting of locally advanced disease, particularly for poorly differentiated lesions, PET avidity increases and RAI avidity decreases. PET in this setting will help identify disease extent and may also give useful information about the biological behavior of a tumor, particularly when an FNA suggests WDTC but the clinical features suggest more aggressive disease. In this setting, significant uptake on a PET scan suggests dedifferentiation, confirming clinical suspicion.

Prognosis and Risk Stratifications Having completed the process of preoperative evaluation, patients should be described in terms of the extent of local, regional, and distant disease. This information will allow the clinician and patient to appreciate the burden of disease and also provide insight into the likelihood of cure from initial therapy and chances of recurrence. It is now well recognized that the risk of death from disease is low for the majority of patients who present with WDTC. Many long-term retrospective studies have reported survival of over 95% at 10 years.3-5 Those patients at highest risk can be predicted using one of the many risk stratification systems available. It has long been recognized that older patients are at higher risk of death. Classically, 45 years has been used as

244

Head and Neck Surgery

a cutoff in most systems. Primary tumor size > 4 cm and gross extrathyroid extension are also independent risk factors for death as is the presence of distant metastases. In contrast to these well-documented risk factors, the presence of nodal disease has been more controversial. Papillary thyroid cancer metastasizes early and often. Even when lymph nodes are ultrasonically and macro­ scopically normal, occult disease is present in up to 40% of cases. Lymph node metastases are more common in young patients, but these have no impact on outcome. Thus, nodal metastases have not been generally con­ sidered an important prognostic factor. However, as the understanding of this disease evolved, investigators recognized that there is a significant difference in the outcome in patients with occult disease removed during elective neck dissection, and those who present with overt nodal disease and undergo therapeutic neck dissection, particularly in older patients. For young patients, the presence of regional disease does not predict survival. However, for older patients, positive nodal disease does predict outcome, with lower disease-specific survival in those patients with clinically apparent, bulky nodal metastases. Thus, there may be a consideration for elective node dissection in older patients, who are at a higher risk for lymph node metastases. Completeness of resection is also critical in terms of optimizing survival. Those patients who have gross residual disease after surgery are at high risk of both recurrence and death. This underlines the importance of accurate presurgical planning and meticulous surgical technique. As very few patients die of disease, estimating the risk of recurrence has more clinical utility. Many of the risk factors that are important in estimating the risk of death are also important for estimating the risk of recurrence (completeness of resection, distant metastases). However, nodal disease has a more important role in this setting, placing both young and old at higher risk of developing recurrent disease in the future. After risk stratification, most patients will be offered surgery. The resection of primary nodal disease will then provide tissue for histopathological analysis. The data used to generate the aforementioned risk stratification systems were based upon histological diagnosis of specimens after surgery, and not only clinical staging, and therefore the issue of risk stratification/prediction should be restratified when the formal pathological result is available. A few points are worth expanding on at this point, prior to discussion of appropriate therapy. As mentioned above, nodal disease is often occult and may only be

re­cognized on histological review. Given the importance of nodal metastases on recurrence and death in select populations, some authors have argued that elective nodal dissection facilitates more accurate surgical staging, which would allow those at higher risk to be identified and treated with adjuvant therapy (RAI). Although this approach certainly results in upstaging of a significant number of patients above the age of 45 years considered free of clini­ cally apparent regional disease (up to one third), there is no evidence that this translates to improved outcome. The primary nodal basin for WDTC is the central neck. However, a significant number of patients will also harbor occult metastases in the lateral neck. Despite this, it is wi­dely accepted that lateral neck dissection is not indica­ ted for clinically node negative patients. The reasons for this are twofold: significant morbidity related to lateral neck dis­section and no demonstrable improvement in outcome. The position in relation to the central neck remains more controversial. Many patients will have histologi­ cally identifiable metastases, but resecting this clinically normal appearing nodal tissue has never been convinc­ ingly shown to reduce recurrence or to improve survival. The central neck must be entered to remove the thyroid, and central compartment node dissection at the same time is easy. Also, reoperative neck surgery is associated with higher rates of morbidity. These arguments support elective node dissection, but removal of nodal tissue does however jeopardize the parathyroid glands and their blood supply, as well as recurrent laryngeal nerves (RLNs), increasing the risk of iatrogenic injury. There is no definitive evidence that elective central neck dissection improves outcome, but there remain strong advocates of this procedure. Guidelines from the American Thyroid Association (ATA) on the management of WDTC have taken a middle ground, suggesting that those patients at higher risk of metastases (larger tumors, extrathyroid extension) should be considered for elective central compartment dissection.6 It is likely that no consensus on this point will ever be reached. Surgeons contemplating this question must consider whether they think it is more reasonable to leave occult disease behind but reduce the morbidity of surgery, or resect occult disease while recognizing that there is no proven benefit and putting their patients at higher risk of immediate postoperative morbidity. In relation to extrathyroid extension, one can consi­ der three subtypes. There are patients who present with

Chapter 14: Management of Well-Differentiated Thyroid Cancer obvious/gross extension beyond the thyroid gland. These patients are at higher risk of recurrence and death. There are also patients with well-encapsulated lesions and no extension, who have an excellent outcome. The confusion arises when the lesion is clinically encapsulated and contained within the thyroid, but the pathologist reports microscopic extrathyroid extension. Such patients may be considered T1/T2 based on clinical suspicion, or ups­taged to pT3 based on pathological findings. In fact, there is very little evidence that these patients’ outcome is influen­­ ced by the sole finding of microscopic extrathyroid ex­ten­sion. Such patients do well, and recurrence is ex­tre­ mely rare, assuming appropriate surgery is performed. It is also not clear that any adjuvant therapy is indicated based solely on the presence of microscopic extrathyroid extension. Again the position with regard to microscopic extra­ thyroid extension is likely never to be answered in a ran­ do­mized, prospective manner; however, it is at least fair to say that the presence of gross extrathyroid extension is a predictor of poor outcome. In terms of margins, again there is confusion about nomenclature. Many resections are considered R0/R1/R2 dependent on clinical and histological descriptions. The thyroid, however, does not have a well-defined capsule and low-grade disease that abuts the outer edge of the capsule may be considered R1 (positive margin with chance of microscopic residual disease) after appropriate surgery. The concept of “clear” margins is poorly understood in mucosal head and neck disease, and even less wellde­fined in thyroid surgery. The vast majority of patients who have adequate tissue planes around the tumor can safely be considered free of disease after surgery and will be­have in an R0 manner. When considering the details of staging, the preope­ rative workup, the histopathological report and the opi­ni­ on of the surgeon in terms of their comfort with the surgical extent of disease must all be taken into account. The surgeon is best placed to assess risk, based upon the extent of overt disease and the completeness of resection. After surgery, a patient can be grouped as low risk when they are young and have no adverse risk factors and high risk if they are old with the presence of risk factors. Older patients with low-risk tumors and younger patients with high-risk tumors form an intermediate risk group (Table 14.2).7

245

Table 14.2: GAMES risk stratification

Risk level Low risk High risk

Patient factor Tumor factor Age < 45 years Papillary Ca

M0

No ETE ETE

Size 4 cm

Age > 45 years Follicular Ca/ M1 Hurthle cell Ca Low risk case Low-risk patient Low-risk tumor Intermediate risk case Low-risk patient High-risk tumor High-risk patient Low-risk tumor High-risk case High-risk patient High-risk tumor

GAMES (Grade, Age, Metastases, Extra thyroid extension, Size) is the Memorial Sloan Kettering Cancer Center’s risk stratification system to predict survival of patients with well-differentiated thyroid cancer. (ETE: Gross extrathyroid extension).

SURGICAL MANAGEMENT OF WELLDIFFERENTIATED THYROID CANCER Surgery remains the mainstay of therapy for WDTC. The goal of surgery is to remove all gross disease in one pro­ cedure while minimizing the chance of recurrence and preventing iatrogenic injury. For the purposes of this chapter the discussion will focus first on surgery for the thyroid gland and then on management of the neck. In practice, of course, both aspects will be addressed during one procedure. In considering appropriate surgery, the clinician must consider the preoperative workup and the risk of both recurrence and death for an individual patient. For the overwhelming majority of patients, the risk of death is almost zero and the risk of recurrence is low. The man­ agement plan must be acceptable to the surgeon, the trea­ting endocrinologist, and the patient. It is critical that all parties agree to the proposed procedure to avoid postoperative disagreement, and particularly confusion on the part of the patient. In terms of primary thyroid surgery, if the tumor is unifocal and intrathyroidal, the minimum procedure should be an extracapsular thyroid lobectomy. There is no place for subtotal or near-total thyroid surgery, done through the thyroid gland, which deliberately leaves thyroid tissue behind, as this violates the tracheoesophageal groove and at the same time increases the chance of ipsilateral recurrence. Revision surgery in this setting is more technically challenging and has a higher rate of iatro­genic injury than primary surgery. There are only three procedures considered onco­ logically sound in the presence of WDTC: isthmusectomy, lobectomy, and total thyroidectomy. Reasons for selecting

246

Head and Neck Surgery

each procedure are complex, multifactorial, and depen­ dent not only on evidence but also on the clinician’s and patient’s preference. Thyroid isthmusectomy is suitable for a small subset of patients with WDTC (around 1%). Only patients with uninodular disease confined to the thyroid isthmus, no evidence of nodal metastases, and no evidence of extra­ thyroid extension, with both thyroid lobes sonogra­phically normal, are candidates for this procedure. Those patients who meet all of the above criteria benefit from a very short procedure and a small incision. The main benefit, however, is that the tracheoesophageal groove is not disturbed. This means the chance of damage to the RLN and parathyroid glands is almost zero. Well-selected patients can be cured of their disease with this simple and safe procedure. However, the majority of patients will present with lateralized disease in the thyroid lobe. These patients should be risk assessed. Those patients who are deemed to be in a high-risk category are likely to be candidates for post­ operative RAI. This group includes those patients with large primary tumors, gross extrathyroid extension, bulky nodal disease, or distant metastases. Removal of the entire thyroid gland for these patients is important to facilitate postoperative RAI. For those patients who have uninodular disease and are considered low risk, thyroid lobectomy provides ex­cellent oncological outcomes with the benefit of protect­ing one entire lobe, and with it the RLN and parathyroids on that side.8 In turn, this prevents chronic hypocalcemia and lowers the rate of RLN injury. Prior to performing thyroid lobectomy, it is impor­ tant that the patient and endocrinologist involved with the case agree that adjuvant RAI will not be indicated and are comfortable with this approach. The patient will require postoperative surveillance of the contralateral lobe and should be warned that such surveillance may detect nodular disease in the contralateral gland, or suspi­ cious nodes in the central compartment during follow-up. Approximately 5–10% will need further surgery to the central compartment at some point for diagnostic or thera­ peutic purposes. In well-selected patients, most of these procedures will be completion thyroidectomy for nodular disease. Around half of these will yield a malignancy. Only 1–2% of patients will require surgery to the central compartment lymph nodes during follow-up. For patients with high-risk features, those with proven bilateral malignancy and with multinodular disease, total

thyroidectomy is the procedure of choice. This removes all of the thyroid gland including the pyramidal lobe and tissue on the Berry’s ligament, thereby facilitating effective adjuvant RAI and minimizing any chance of recurrence. With such an approach, those patients considered high risk will have around a 10% chance of recurrence at 5 years. Local recurrence rates are almost 0% with regional recur­ rence being more common (7%) than distant recurrence (5%). An algorithm for selecting the appropriate primary procedure is shown in Figure 14.1. It is worth highlighting some issues in relation to primary surgery. There has been a trend toward total thy­ roidectomy in recent years. The reasons for this are mul­ tifactorial. The increased availability of high-resolution US has resulted in an increased preoperative recognition of small contralateral nodules in patients otherwise consi­ dered to have normal opposite lobes. These nodules, if not removed, will require regular assessment with US follow-up and periodic needle biopsies, and therefore, it

Fig. 14.1: Algorithm for selecting the appropriate primary surgery in well-differentiated thyroid cancer.

Chapter 14: Management of Well-Differentiated Thyroid Cancer

247

is considered prudent to remove them for formal analysis and to avoid long-term monitoring. In addition, there is “evidence” that total thyroidectomy results in improved oncological outcome. However, care­ ful scrutiny of the data presented by authors arguing for total thyroidectomy reveals that with a lack of histological, surgical, and follow-up details, these claims are unproven.9 In fact, the results from several large institutional series with highly accurate details collected by clinicians rather than clinical coders suggest that there is no difference in outcome for well-selected patients undergoing total thyroidectomy and thyroid lobectomy.10,11 There is also evidence to suggest that in comparison with lobectomy, total thyroidectomy is associated with higher rates of chronic hypocalcemia, RLN injury, and even postopera­ tive tracheostomy due to bilateral nerve injury.12 Having decided upon the primary surgery of choice, management of the neck can be straightforward. Those

patients selected for isthmusectomy or lobectomy will be low risk, without evidence of nodal disease, and will require surgery for the primary lesion alone. Preoperative US dedicated to the mapping of lymph glands and iden­ tification of nodes suspicious for metastasis is very important. Occasionally, preoperative US-guided FNA of such suspicious nodes is beneficial in planning the extent of neck surgery. Cytology and thyroglobulin (Tg) mea­ surement of the FNA specimen in this setting can be quite helpful. The primary lymphatic drainage of the thyroid is to the central neck, with subsequent spread to the lower lateral (level IV and V) and then the upper lateral levels (II and III). The patterns and frequency of lymph node metastases are shown in Figure 14.2. In those patients with evidence of nodal disease, thera­peutic neck dissection is indicated. When disease is limited to the central compartment, clearance of levels

Fig. 14.2: Patterns and frequency of lymph node metastasis from thyroid cancer.

Fig. 14.3: Extent of lymph node dissection required for central neck dissection.

248

Head and Neck Surgery

VI and VII is recommended. This procedure involves removal of all nodal tissue from the hyoid to the innomi­ nate artery and from carotid to carotid laterally (Fig. 14.3). The RLNs should be carefully dissected, and an attempt should be made to preserve the parathyroid glands, along with their blood supply, recognizing that in the setting of bulky disease, it is more important to extirpate gross disease than preserve the inferior parathyroids. Although it is easy to preserve the superior parathyroids with their blood supply intact, often the inferior parathyroids are devascularized and may require autotransplantation in adja­cent muscles. In those patients with proven lateral neck disease, comprehensive neck surgery is indicated. Rates of meta­ stasis in level I are low, and in the absence of proven disease at this level, most authors would agree that this should be spared. In addition, disease at levels IIb and Va is also uncommon, and elective dissection of these levels is associated with higher rates of accessory nerve dysfunction. Assuming there is no overt disease superior to the accessory nerve, it is reasonable to spare these areas from routine dissection.

Fig. 14.4: Extent of lymph node dissection required for lateral neck dissection. Usually, levels IIa, III, IV, and Vb are included. Levels I, IIb, and Va should only be routinely dissected if there is adjacent gross disease.

Levels IIa through Vb, however, should be compre­ hensively dissected for proven lateral neck disease (Fig. 14.4). Disease at one level is commonly associated with disease throughout levels II–V.13 Particular attention to nodal tissue posterior to the great vessels in level IV should be paid as this is a common site for recurrent nodal disease. Neck dissection done for metastatic thyroid cancer requires meticulous attention to detail. Disease is often found in the root of the neck, and the potential for significant vas­cular and lymphatic injury is high. Controversy exists over the role of prophylactic neck dissection. In terms of the lateral neck, as described ear­ lier, most authors have abandoned prophylactic dissec­ tion.14 Although occult nodal disease can be proven in a minority of patients, this has no bearing on outcome, but exposes the patients to higher complication rates. In contrast to the lateral neck, the central neck re­ mains controversial. Access to levels VI and VII is straightforward during thyroid surgery. Assessment of the central neck with US is also unreliable. When performed, prophylactic central compartment node dissection re­sults in the pathological identification of subclinical metas­ tases in up to 60% of cases. This information upstages many patients and may be used to make decisions on the use of adjuvant RAI treatment.15 Although there is a seemingly sensible argument for this type of surgery, it has never been shown to benefit patients in terms of recurrence or survival. Patients with­ out gross nodal disease who do not undergo prophylactic central compartment neck dissection have very low rates of recurrence, and no improvement in survival has ever been demonstrated. Despite the fact that many of these patients harbor subclinical disease, when none die of disease and rates of recurrence are  5000 patients enrolled and followed for over a decade. Such a trial design is unlikely to be feasible; therefore, the controversy is likely to continue. In addition to the impact on oncological outcomes, although world experts report very low rates of com­ plication in large surgical series, analysis of national level data suggests that central neck surgery is associated with higher rates of morbidity in the hands of low-volume surgeons who perform the majority of procedures outside of centers of excellence.

Chapter 14: Management of Well-Differentiated Thyroid Cancer As prophylactic central neck dissection adds to the morbidity of surgery without improving outcome in properly selected patients, its routine use has not been supported by ATA or many other international guidelines.

ADJUVANT THERAPY FOR WELLDIFFERENTIATED THYROID CANCER After surgery, the histopathological specimen should be carefully scrutinized to identify the size of the primary lesion, the degree of extrathyroid extension (if present), the presence of more aggressive histological subtypes of disease, the presence of nodal metastases, the number and size of nodes involved, and the presence of extranodal extension. In addition to the histological report, the pos­t­ operative Tg should also be measured. With all of this information, decisions can be made about postsurgical therapy. Patients selected for thyroid lobectomy will be candidates to enter follow-up immediately, assuming no surprises are encountered on histo­ pathology. After total thyroidectomy, those patients who are considered at low risk, without worrying features on the pathology report and with an unmeasurable Tg (approximately 6 weeks after surgery) require no further therapy. These patients should be managed with levothy­ roxine supplementation, in an attempt to keep the T4 levels toward the upper normal range, with a low thyroid stimulating hormone (TSH), preferably below 1. This mo­del of thyroid hormone suppression has been associated with lower rates of recurrence historically. Although the data supporting this approach are not robust, it seems reasonable to suggest this in the majority of patients during follow-up. In contrast, those patients considered at high risk, based on local, regional, and distant disease extent, will be candidates for RAI. Select retrospective series have demonstrated improved outcomes for those patients with more aggressive disease who receive postoperative RAI.16 The role of RAI in these patients is to destroy any normal residual thyroid tissue, and to exert its tumoricidal effect on microscopic tumor cells in the neck or on distant metastases. It should be re-emphasized that RAI is not effective for gross residual disease and that every attempt should be made to remove all disease with the initial surgery, as incomplete surgery cannot be rescued with adjuvant RAI therapy.

249

Patients can be prepared for RAI by allowing them to become hypothyroid, thereby raising the TSH level and facilitating the uptake of iodine into any remaining thyroid cells. Alternatively, exogenous thyrotropin can be used to elevate the TSH for RAI, which has the advantage of avoiding postoperative hypothyroidism and improving patients’ postsurgical quality of life. Many patients will not fall neatly into either of these low- or high-risk categories. Older patients, those with low-volume nodal disease, and patients with large tumors limited to the thyroid gland represent a group who are at intermediate risk. For these patients, the role of adjuvant therapy is unclear. Although RAI has relatively few side effects, it is not without a potential for complications and long-term sequela. Administration itself requires some degree of patient isolation. After treatment, RAI has been associa­ ted with dry mouth and difficulty swallowing. For these reasons, the use of RAI should be limited to those patients most likely to benefit. On a population level, an association between RAI and increased rates of second malignancies has been shown, highlighting the need for some national consensus on treatment indications. For many patients, therefore, the need for RAI is unclear. Patients should understand that rates of recurrence and death after adequate surgery are very low. The chance that RAI will improve outcome in most cases is low. However, side effects from RAI are far less significant than those from external beam radiation therapy (EBRT). Discussion between the surgeon and endocrinologist should allow a treatment plan to be proposed to the patient that re­presents a balanced and reasonable approach to RAI. For a select few patients with gross extrathyroid exten­ sion, and particularly with poorly differentiated histology, EBRT may be indicated. There is no clear evidence to recommend EBRT and as it affects so few patients, it is unlikely that prospective studies will ever be completed. EBRT should be considered in unresectable disease, gross residual disease, and even potentially in patients who have a high likelihood of residual microscopic disease. The potential benefits of reducing the rate of growth of gross disease or the sterilization of a field with microsco­ pic disease should be weighed against the significant side effects of high-dose EBRT to the central compartment. Significant radiation injury to the larynx and hypopharynx and upper esophagus may result in long-term dysphagia, stricture, and possible aspiration. The majority of WDTC will progress very slowly, and cases should be dealt with on an individualized basis.

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Head and Neck Surgery

FOLLOW-UP After initial therapy for WDTC, patients enter follow-up and surveillance. The vast majority will be considered cu­red of disease. These patients have a low risk of recurrence and death from disease. Most patients are young women who require lifelong monitoring of their thyroid function. In addition, patients should be screened for recurrent di­sease. Clinical examination should be performed every 6–12 months. Traditionally, this approach resulted in excellent outcomes and very low rates of recurrent disease. In particular, very few patients develop unresectable disease while under follow-up. Over the past decade, US has become standard in the management of patients who have thyroid disease and during follow-up. Monitoring of serum Tg has also improved the accuracy of detection of extremely low-volume thyroid disease or residual thy­ roid tissue. Current guidelines recommend annual assessment with US of the neck and thyroid bed, with measurement of the serum Tg, and even TSH suppressed or thyrogen­ stimulated Tg. This allows for the identification of previ­ ously undetectable minute or microscopic “recurrences”. The majority are in the regional nodes, and most may represent disease that was present at the time of initial therapy. The need to pursue this indolent and clinically occult disease surgically must be weighed against the morbidity of surgery and the benefit of such surgery to the patient. Significant restraint and judgment need to be exercised in managing and counseling these patients. Due to the indolent nature of WDTC, patients are at risk of recurrence lifelong. Follow-up can be coordinated by the surgeon or endocrinologist, or even by a primary care physician, depending on the system in place. The demands of patients following treatment for WDTC in­clude both medical and psychological support. Many groups are now developing nurse-led survivorship pro­ grams, which allow ready access to these services in a costeffective manner.

Salvage of Recurrent Disease Recurrent disease may be identified by clinical examina­ tion, imaging, or Tg monitoring. Irrespective of the mode of presentation, patients with recurrent disease should undergo thorough workup with cross-sectional imaging to look for local, regional, and distant disease.

After workup, the recurrent disease stage can be as­sessed. Locoregional recurrence and isolated distant di­sease may be suitable for potentially curative therapy, whereas widespread metastases will not. After adequate primary surgery, extracapsular local recurrence is very uncommon. When disease is left behind after an inadequate resection (subtotal thyroidectomy), persistent disease will present with nerve dysfunction or airway involvement. These cases present a significant ma­na­gement problem. Such patients will require accurate preoperative assessment to consider their suitability for surgery and the requirement for major airway resection. Clinicians managing such patients must remember that death due to uncontrolled central neck disease is very unpleasant, with bleeding and aspiration as the ultimate mode of death. For these reasons, even in the palliative setting, major surgical procedures may be considered to avoid such devastating complications. Regional recurrence is more common, occurring in 5–10% of patients during follow-up. Previously, recurrence was identified by clinical examination and represented significant structural disease. In the modern era, lowvolume disease is identified at an early stage due to serial Tg screening and US follow-up. The challenge for clini­ cians is to identify those patients who will go on to develop meaningful clinical or progressive recurrence and there­ fore will benefit from surgical intervention. A large percentage of patients will have disease in the lymph nodes at the time of presentation, so the mere identification of malignant cells in lymph nodes should not be a trigger for surgery. Such an approach leads to the potential for multiple surgical interventions and potential morbidity, which outweighs any ill effects of the disease itself. Indeed, the approach of a disease management team should be to avoid unnecessary needle biopsy in the setting of very small volume suspicious nodes. Once an FNA is performed, confirming the presence of malignant cells, many patients will not accept a policy of monitoring the neck. Most groups now accept that nodal disease thoracic inlet diameter

II

Posterior mediastinum

Posterior to great vessels, trachea, and RLN

15%

Transcervical Sternotomy if intrathoracic goiter diameter > thoracic inlet diameter Consider sternotomy or posterolateral thoracotomy if type IIB

IIA

Ipsilateral extension

IIB

III

Contralateral extension B1

Extension posterior to both the trachea and esophagus

B2

Extension between trachea and esophagus Isolated to the mediastinum

R>>>L

No connection to  50% with levothyroxine suppression.22,34

Due to the lack of efficacy as well as potential side effects (including adverse effects on bone density and arrhythmias in elderly populations), levothyroxine therapy is only used in highly selective patient groups.35 Up to 84% of patients were ineligible for levothyroxine therapy in one consecutive Danish series.36

Radioactive Iodine The superiority of radioactive iodine over levothyroxine has been established in a randomized trial by Wesche;37 I131 induced goiter shrinkage by 44% in 2 years. Bonnema et al. found a reduction of 34% after high-dose I131 therapy in 23 patients with an initial mean goiter volume of 311 mL.38 Some patients with very large goiters are not candi­ dates for surgery. These patients may benefit with highdose I131 therapy. Tracheal cross-sectional area as well as pulmonary inspiratory capacity improves.38 The individual response to the I131 ablation is variable because a high radioiodine dose is needed to have an adequate I131 accumulation in the distinct nodular areas of the MNGs. TSH might be used to increase the uptake of the radioiodine. Several groups around the world have found iodine uptake after a single dose of recombinant human (rh) TSH to be markedly increased within the nodular areas of the MNG. However, a transient average goiter enlargement of up to 24% is seen after 0.3 mg rhTSH. This may lead to a significant cervical compression when used for augmentation of I131 therapy in patients with goiter. The use of lower doses of rhTSH needs to be explored.39

Medical Versus Surgical Management The advantages and disadvantages of surgery, radioactive iodine, and thyroxin are summarized in Table 21.5.

INDICATIONS FOR SURGERY The decision to proceed with surgery is usually made on the basis of symptoms and imaging studies. Surgery is the preferred treatment for euthyroid patents, large obstruc­ tive goiters, and substernal MNGs.32,33 Once symptoms are present, surgery is generally indicated assuming patients are fit surgical candidates. Obstructive symptoms warrant operation for sympto­ matic relief and because further thyroid growth may lead to progressive tracheal compression that may be rapidly progressively and potentially fatal. Surgery is also

Chapter 21: Surgical Management of Goiter

Symptomatic

­

­

recommended for large substernal goiters in asympto matic patients.1,10,19,41 This is, however, an area of contro versy and other experts prefer to monitor such patients.9,42 Table 21.6 outlines arguments on both sides. Table 21.7 summarizes surgical indications for MNG.

319

Radioac•  Outpatient tive Iodine management •  Few side effects during treatment •  30–40% goiter reduction in 1 year •  Repeat treatments possible

•  Gradual reduction of goiter •  Occasional goiter enlargement •  Occasional transient thyrotoxicosis •  Occasional transition into Graves’ disease •  Risk of hypothyroidism

Thyroxin

•  Lifelong treatment; low compliance •  Recurrent growth with discontinuation •  Limited goiter reduction •  Side effects—heart and bone

•  Outpatient management •  Nondestructive therapy •  Low cost

Dysphagia Thyroidectomy appears to improve dysphagia in subster nal goiters. However, the measurement is subjective and the data are mixed. Lombardi’s group suggested surgical resection offered relief from swallowing symptoms in all patients at 1 year.45 ­

•  Admission to hospital •  Higher cost •  Postoperative complications •  Hypothyroidism •  Not all patients fit for surgery

Dysphonia A mediastinal goiter study of 60 consecutive cases sugges ted dysphonia increased the likelihood of malignancy, and malignancy was associated with a significant increase in sternotomy and nerve sacrifice during surgery.18 ­

Disadvantage

•  Rapid decompression of trachea •  Rapid relief from symptoms •  Significant to complete goiter reduction •  Pathological confirmation of disease

Stang et al. found surgery offered patients symptomatic relief in those with bulky (> 100 mg) disease or tracheal compression of 35%.15

Tracheal Compression on CT Scan Shin found strong correlation between preoperative short ness of breath and tracheal compression (Fig. 21.3) on preoperative imaging for all patients.12 This is supported by Stang who suggested tracheal compression of 35% or more on CT is associated with positional dyspnea.15 ­

Advantage Surgery

Dyspnea

 

Table 21.5: Advantages and disadvantages from surgery, radioactive iodine, and thyroxin29,40

Thyroidectomy alone is effective in relieving compressive symptoms.2

Table 21.6: Arguments for and against removing a substernal goiter in asymptomatic patients

• A large goiter, a history of external radiation, or rapid growth increase32 • Some goiters will continue to grow and become more difficult to remove if obstructive symptoms do develop • Thyroxin therapy is relatively ineffective and is associated with significant morbidity in elderly patients • Forty-two percent of patients with evidence of upper airway obstruction on flow-volume loops are asymptomatic43 • The substernal component cannot be palpated or biopsied; reported cancer risk from 3% to 22%9,10 • There is a small risk of acute airway obstruction from sudden hemorrhage into the goiter

• Asymptomatic patients who are poor operative candidates • Patients without thyroid enlargement whose glands extend slightly substernally due to kyphosis • Patients with small substernal goiters   

• Patients who have serial CT scans demonstrating longterm stability of a substernal goiter • Older patients tend to experience more frequent and severe surgical complications44 

    



For observation



For operative management

320

Head and Neck Surgery

Table 21.7: Surgical indications for MNG

1. Significant regional aerodigestive tract symptoms (dyspnea, dysphagia, dysphonia) 2. Tracheal deviation on CT 3. Interval growth 4. Masses greater than 5 cm 5. Goiter with subclinical or clinical hyperthyroidism 6. Suspected or proven thyroid malignancy 7. Substernal goiter 8. Cosmetic deformity (MNG: Multinodular goiter).

Interval Growth on CT Scan The argument can be made to conservatively manage patients with stable, asymptomatic goiters. However, if a goiter demonstrates significant growth on progressive CT scans surgery is indicated. Additionally, as patients age surgical complications are more common and severe.44

Suspected Malignancy The substernal component could contain a cancer that cannot be palpated or biopsied. The reported range of cancer risk is 3–22%.9,10 Malignancy may be considered in the setting of radiographic findings of irregular or infiltrative margins, vocal cord paralysis, and nodal enlargement, especially if nodes are calcified, cystic, or enhancing.46

Cosmetic Deformity There is little research on cosmetic indications for goiter surgery, probably due to the subjective nature and insen­ sitive tools for evaluating this. It is reasonable to consider surgery in patients whose neck contour is abnormal due to the presence of goiter, given the general favorable scar and resolution of the mass effect associated with surgery.

SURGICAL MANAGEMENT Preoperative Thoracic Consultation Surgical management of patients with mediastinal goiter requires considerable experience of the surgical team, per­formed in specialized centers, and appropriate pre­ operative diagnostic management.47 Radiological evidence of extension of a substernal goiter to the aortic arch, or loss of tissue planes on CT, should raise suspicion that

Fig. 21.3: CT image demonstrating tracheal compression from large goiter.

the patient may require sternotomy for safe delivery of the gland. Surgery for these patients should be done in a specialist center by experienced thyroid surgeons, with a thoracic surgeon available if sternotomy should be required.48 The indicators for ster­notomy are shown in Table 21.8. Studies generally suggest 2–6.5% of patients with sub­ sternal goiters required sternotomy to remove a subster­ nal goiter safely.9,49 Statistically significant risk factors for sternotomy are malignancy, recurrent goiter, ectopic mediastinal goiter, posterior mediastinal location of goiter, and the presence of an goiter isolated from the orthotopic gland situated in the mediastinum.9,47,49

Airway Management Intubation Management of the airway in patients with retrosternal goiter may be difficult. Generally our anesthetic colleagues reserve fiberoptic intubation, awake or asleep, for patients at highest risk. This is typically gauged from routine anes­ thetic assessment and significant tracheal compression on imaging. Standard intubation is, however, still most often the preferred intubation method.50

Extubation Most patients after goiter surgery are extubated without difficulty. However, routinely this is best done in the operating room to ensure there is no airway compromise before being sent to the recovery room. Risk factors for

Chapter 21: Surgical Management of Goiter

Technique

Table 21.8: Indications for consideration of sternotomy

The patient rests supine on the operating table with the head elevated to decrease engorgement of the cervical veins; the neck and sternum are prepared. The skin is infiltrated with lidocaine and epinephrine mainly to avoid oozing from the skin edges. Skin is incised with the knife and subcutaneous tissue and platysma are incised with electrocautery. Care must be taken to avoid injury to the anterior jugular veins, which may be quite large in these patients. The skin flaps should be raised as high as possi ble superiorly up to the laryngeal notch, and inferiorly to the sternal notch. A self-retaining retractor or fish hooks may be used to retract the raised skin flaps. The midline fascia is incised from the thyroid notch down up to the sternal area. At this time, the operating surgeon can better ascertain the extent of the disease and feasibility of resection through the cervical incision. Next one exposes the sternomastoid muscle to identify the lateral extent of the goiter and the nature of the substernal extension. At this point, one should identify the internal jugular vein, the carotid artery, and vagus nerve, which are generally displaced considerably with large and substernal goiters. In large substernal goiters, it is often better to transect both the sternothyroid and sternohyoid muscles to improve anterior access. The numerous small veins between the strap muscles and the thyroid capsule should be carefully cauterized. The strap muscles may be retracted superiorly and inferiorly for better exposure of the substernal goiter. Extracapsular dissection of the thyroid gland should start laterally, starting with the careful ligation of the middle thyroid vein. The dissection should continue to the supe rior thyroid pole, where the overlying fascia should be incised and cricothyroid muscles exposed. The superior pole is generally pulled inferolaterally with a clamp to expose Joll’s triangle. This helps to identify the superior thyroid vessels and also to avoid injury to the superior laryngeal nerve. It is important to double ligate the superior thyroid vessels, as they tend to retract and the bleeding can be quite difficult to control. Once the superior thyroid pole is ligated, attention should turn toward identification and preservation of the superior parathyroid gland and its blood supply.

 

postoperative airway complications are generally older patients with larger goiters and tracheal compression on preoperative imaging.13 White found that while rare, presence of long-standing substernal goiter of > 5 years and causing significant tracheal compression to be a likely risk factor for tracheomalacia and tracheostomy.9

Recurrent Laryngeal Nerve (RLN) Monitoring

­

­

­

RLN monitoring is a feasible and reliable technique. It can be used to avoid bilateral nerve injury and to increase the surgeon’s confidence. However, it does not replace systematic nerve identification and a careful dissection.54 In a retrospective review of 200 consecutive thyroi dectomies, the transient nerve paralysis rate was signi ficantly lower with electrophysiologic monitoring, 1.7% compared to 11.7%, decreasing the risk of RLN paralysis by approximately 87%.55

Surgical Technique Equipment and Preparation ­

In addition to standard instrumentation, a self-retaining Mahorner or Gellpi retractor is quite helpful. Electrocau tery is routinely used along with bipolar cautery near the vital structures such as the parathyroid and RLNs. Depending on individual preference, a Harmonic scalpel or Liga-Sure can be useful. A blood transfusion is rarely necessary, but a cross-match may be considered. If at all concerned about the potential need for sternotomy, a thoracic team should be available.

­

­

1. Known or suspected malignancy extending into the mediastinum 2. Posterior mediastinal goiter associated with contralateral extension (substernal type IIB) 3. Mediastinal blood supply (especially substernal type III) 4. True superior vena cava syndrome (greater likelihood of malignancy) 5. Recurrent large, substernal goiters 6. Presence of immobile substernal component or significant substernal adhesions 7. Substernal goiter delivery associated with substantial hemorrhage 8. Intrathoracic goiter diameter > thoracic inlet diameter 9. Presence of long thin stalk from cervical to substernal goiter.



321

Identification and Preservation of Parathyroid Glands The superior thyroid pole can be pulled anteromedially to separate it from the pharyngeal musculature to allow

322

Head and Neck Surgery

inspection of the superior parathyroid glands. Superior parathyroids are more consistent in position and are seen twice more frequently in goiter surgery than its inferior counterparts.30 Inferior parathyroid glands are more varied in location due to embryology and the inferior growth of goiters. Therefore, real emphasis during thyroi­ dectomy should be on preservation of the superior para­thyroid glands. If the superior parathyroid gland is injured during the dissection or devascularized, a portion of the gland should be sent for frozen section and the remaining parathyroid tissue should be autotransplanted in the sternomastoid muscle toward the end of the surgical procedure.

substernal goiter. Bipolar electrocautery is quite helpful to control bleeding around the RLN.

Delivery of Goiter

The dissection should continue from lateral to medial iden­ tifying the trachea, esophagus, and tracheoesophageal groove area. However, this may be difficult in the presence of a large goiter. An esophageal probe or nasogastric tube is often helpful to achieve this. The dissection should continue on the lateral side of the goiter, making sure all the blood vessels are ligated carefully. Even with a large substernal goiter, it is important to recognize that the RLN is generally in its normal position in the tracheoesopha­ geal groove. The RLN can be adherent to the posterior aspect of a large goiter (Fig. 21.4). A superior approach to identifying the RLN can be useful (Fig. 21.5). Rarely in a posterior mediastinal goiter the RLN may be displaced anterior to the substernal portion of the thyroid, which clearly is at high risk of injury during the delivery of the

Since the strap muscles are already cut, finger dissection can be performed between the goiter, the sternum and the clavicle, under the strap muscles. The inferior thyroid veins are generally several small veins stemming from the lower portion of the thyroid, directly toward the media­ stinum. These vessels that are easily avulsed should be carefully identified and ligated. The Harmonic scalpel is quite helpful here or appropriate vascular clips may be used. Additionally there is often a large vein in the medial por­tion of the inferior pole of the thyroid between the trachea and the goiter. Injury to this vessel may lead to massive hemorrhage and the need for emergency thoracic exposure. It is important to now identify the position of the trachea, and dissect the contralateral side for further exposure of the substernal goiter. Careful dissection may progress from the lateral to medial side avoiding any avulsion of the vessels. While almost all substernal goiters originate in and derive the blood supply from the neck, there are rare cases of substernal and cervical goiters with aberrant intrathoracic blood supply: thyroidea ima, subclavian, internal mammary artery or aorta.55 If these vessels are encountered, they should be clamped and carefully ligated. Additionally, if the inferior parathyroid glands are identified, they should similarly be preserved along with its blood supply. Generally at this point the substernal portion of the goiter should be easily retrieved

Fig. 21.4: Adherence of the recurrent laryngeal nerve to the undersurface of the large substernal goiter.

Fig. 21.5: Superior approach to the recurrent laryngeal nerve can be helpful during goiter surgery.

Identification and Preservation of the RLN

323

Chapter 21: Surgical Management of Goiter

We suggest a conservative philosophy tailoring the extent of surgery to the initial disease with the minimum pro cedure being a total unilateral lobar resection. A total thyroidectomy is performed in patients with bilateral goiters. However, if there is any concern about the RLN on the ipsilateral side or parathyroid preservation, con tralateral surgery can be aborted or staged. Additionally, if the substernal goiter involves only one lobe of the thyroid gland and the contralateral lobe is essentially normal a lobectomy is recommended to relieve tracheal compression. The operating surgeon should make the decision regarding the extent of thyroidectomy based on the gross findings, the likelihood of malignancy, the ease of surgical procedure, and to avoid future recurrence on the contralateral side. Unless a total thyroidectomy is carried out, recurrence of the goiter is seen in 40% of patients with long-term follow-up.57,33 In a randomized study with a median followup period of 10 years, the use of levothyroxine did not protect against goiter recurrence.58

When performed by surgeons experienced with the pro cedure, total thyroidectomy results in permanent hypo thyroidism in 1–2% of patients.60 As for RLN injury, a higher rate of permanent hypoparathyroidism is seen in substernal compared to cervical thyroidectomies.2,9 ­

­

Recurrent laryngeal nerve paralysis rates vary from 1% to 2% in high volume centers. Higher rates of unintentional permanent RLN injury in substernal goiters compared to cervical goiters are generally recognized.9 One literature review of over 12,000 patients reported a significantly lower temporary and permanent RLN palsy rates with identification of the recurrent nerve when compared with reports without obligatory identification of the nerve.56 One series suggests RLN injury can be further reduced with routine RLN monitoring.12

Hematoma A review of publications containing large cohorts of > 1000 patients from single centers found hematoma rates vary between 0.3% and 1.2% and up to 6.5% when smaller studies were included.61 This included both cervical and substernal goiters. A literature review by Shaha et al. limited to only substernal goiters found a 3% hematoma rate.17 The timing of hematoma collection is usually in the first 24 hours.  

­

RLN Paralysis



­

­

­

­

­



­

Hypoparathyroidism

­

Extent of Thyroidectomy

­

were significantly greater for sternal goiters compared with simple cervical goiters.44 From the same database, complication rates were significantly lower at hospitals that performed a high volume of substernal thyroi dectomies.59

­

from the mediastinum. Careful hemostasis of facial bands arising from digital mobilization should be achieved. Delivery of the thyroid gland should only occur after the identification of both RLNs.56 If the goiter cannot be delivered, an upper partial sternotomy should be performed. Morselization performed in the past for piece meal delivery of substernal goiter has been abandoned due to the risk of hemorrhage and possible spread of carcinoma. At the conclusion of the procedure, Valsalva maneu vers should be undertaken to ensure there are no active areas of bleeding. A suction drain can be placed but is not mandatory. The divided strap muscles should be re-approximated and the midline closed with only two or three stitches so that any bleeding is not contained and be recognized quickly. The platysma should be approxi mated carefully and the skin closed in a standard fashion.

Surgery for substernal goiter appears to be associated with higher complication rates than for simple cervical goiters. A study of 34,000 patients from the New York State Statewide Planning and Research Cooperative System database found that RLN injury, postoperative bleeding, respiratory failure, blood transfusion, and mortality rates

­

About 5–10% of operations for substernal goiters are performed because of recurrent or persistent disease. The most common initial operations with recurrence or persistence appear to be subtotal or hemithyroidectomy. Total thyroidectomy for MNGs should decrease with time.9

Tracheostomy Tracheostomy is very rarely required post-thyroidectomy. The usual indications are infiltration by tumor, bilateral nerve injury, tracheal compression by hematoma, or tra ­

COMPLICATIONS OF SURGERY

Recurrence

324

Head and Neck Surgery

cheomalacia.3 A literature reviewed by White et al. found that the presence of a substernal goiter of > 5 years dura­ tion and causing significant tracheal compression was a risk factor for tracheomalacia and tracheostomy.9 It is reported to occur in 0.001–1.5% of thyroidectomies per­ formed.17 Many cases of tracheomalacia can be managed without tracheostomy and some cases may be undiagno­ sed bilateral nerve injury.

Other Low rates of wound infection, pneumothorax, atrial fibril­ lation, pleural effusion, chlye leak, and Horner’s syndrome have also been described.

CONCLUSION Multinodular goiters are a heterogenous group of disease etiologies that manifest as gross enlargement of the thyroid gland. Goiter size becomes clinically important due to increasing risk of compression of adjacent structures and risk of malignancy. Management of MNG is often surgical although other medical modalities exist. The surgeon’s role is to identify those requiring surgery, adequately image the extent of goiter preoperatively, exclude malignancy, plan for safe surgery with or without sternotomy, airway management, preservation of parathyroid glands and RLNs, and avoidance of other surgical complications.

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57. Rojdmark J, Jarhult J. High long term recurrence rate after subtotal thyroidectomy for nodular goitre. Eur J Surg. 1995;161(10):725-7. 58. Hegedus L, Nyqaard B, Hasen JM. Is routine thyroxine treatment to hinder postoperative recurrence of nontoxic goiter justified? J Clin Endocrinol Metab. 1999;84(2):756-60. 59. Pieracci FM, Fahey TJ 3rd. Effect of hospital volume of thyroidectomies on outcomes following substernal thyroidectomy. World J Surg. 2008;32(5):740-46.

60. Zambudio AR, Rodriguez J, Riquelme J, et al. Prospective study of postoperative complications after total thyroi­ dectomy for multinodular goiters by surgeons with experience in endocrine surgery. Ann Surg. 2004;240(1): 18-25. 61. Promberger R, Ott J, Kober F, et al. Risk factors for post­ operative bleeding after thyroid surgery. Br J Surg. 2012; 99(3):373-9. doi: 10.1002/bjs.7824. Epub 2012 Jan 9.

Chapter 22: Management of Primary and Secondary Hyperparathyroidism

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CHAPTER

22

Management of Primary and Secondary Hyperparathyroidism Salem I Noureldine, Sun M Ahn, Ralph P Tufano

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The normal ionized calcium concentration in the blood ranges from 1.1 to 1.35 mmol/L (4.5–5.4 mg/dL).1,2 Of the total serum calcium, about 40% is bound to protein, mainly albumin. Of the remaining 60% that is unbound, appro ximately 10% is complexed to anions while the remaining 50% of total calcium is free, ionized calcium. Free ionized calcium is the only form of calcium that is biologically active. Therefore, any changes in plasma albumin level, anion concentration, and acid–base disturbances may alter the ionized calcium concentration and thus calcium’s biologic activity. Some symptoms of hypocalcemia include ­

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CALCIUM HEMOSTASIS AND PARATHYROID HORMONE REGULATION



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Historically, hyperparathyroidism (HPT) has been divi­ ded into primary, secondary, and tertiary categories. Primary HPT, in the absence of a known or recognized stimulus, occurs in the setting of excessive parathyroid hormone (PTH) secretion by an autonomous gland resulting in hypercalcemia. In contrast to primary HPT, the abnormal parathyroid glands in secondary and tertiary HPT are not the cause of disease but rather the result of other disease processes, most commonly chronic kidney disease. In secondary HPT, the parathyroid glands undergo hyperplasia as a result of unbalanced calcium–phosphate metabolism. In tertiary HPT, a condition unique to the post renal transplant patient, parathyroid disease fails to resolve after renal function, and normal calcium–phosphate metabolism are restored.

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hyper reflexia, spontaneous twitching, muscle cramps, and numbness and tingling. Specific signs of hypocal cemia are Chvostek’s sign, or twitching of the facial muscles elicited by tapping on the facial nerve, and Trousseau’s sign, which is carpopedal spasm with inflation of a blood pressure cuff. The mechanism of hypocalcemia is thought to be due to the decrease in extracellular calcium, which leads to lowering of threshold potential and thus increased excitability of neurons and skeletal muscle cells. On the contrary, hypercalcemia manifests in constipation, polyuria, polydipsia, renal or biliary stones, bone pain, abdominal pain, nausea and vomiting, depression and anxiety, cog­ nitive dysfunction, lethargy, coma, and death. Calcium hemostasis involves a complex interaction between three hormones (PTH, calcitonin, and vitamin D and its derivatives) and their effects on three target end organs (bone, kidney, and intestine). Briefly, a small proportion of ingested elemental calcium is absorbed from the gastrointestinal tract, a process that is stimulated by the active form of vitamin D, 1,25 dihydroxychole­ calciferol. There is also continuous bone remodeling through the action of osteoblasts and osteoclasts. Bone resorption is stimulated by PTH and 1,25 dihydroxy­ cholecalciferol while inhibited by calcitonin. Finally, the renal system modulates excretion and reabsorption of calcium in the distal nephron through the action of PTH. PTH is a single chain polypeptide composed of 84 amino acids. When secreted, the PTH is immediately degraded into two fragments—the amino (N) and car­ boxyl (C) terminal fragments.3 The N terminal fragment contains the region that confers bioactivity but is short lived. The C terminal fragment has a longer half life of -

INTRODUCTION

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Head and Neck Surgery

several hours. The intact 1-84 PTH molecule has a halflife of 2–5 minutes.4 PTH is secreted in response to a decrease in serum ionized calcium level and acts on the target end organs to increase the concentration back to normal. When the calcium concentration is in the normal range, the PTH is secreted at a low, basal rate. A decline in calcium concentration from 10.5 mg/dL to 9.0 mg/dL elicits gradual increase in PTH secretion. A further decrease in calcium concentration from 9 mg/ dL to 8 mg/dL induces a marked rise in PTH secretion to a maximal rate, and there is no further rise in PTH secretion below 8 mg/dL.5 The response of the parathy­ roid glands to a decrease in calcium level is remarkably rapid, occurring within seconds. In addition to the acute changes in PTH secretion, chronic, long-term changes in calcium concentration alter PTH gene transcription, synthesis and storage of PTH, and the growth of the parathyroid glands. PTH acts by binding to the receptors on the major target end organs, kidneys, skeletal system, and intestine. The interaction with the receptor results in the production of cyclic adenosine monophosphate (cAMP) with downstream cellular responses that are specific to that organ system.6 The action on kidney and skeletal system is direct, mediated by cAMP, while the action on intestine is indirect, via activation of vitamin D. The action of PTH on the kidney is twofold. First, it stimulates calcium resorption in the distal convoluted tubule. In addition, PTH inhibits phosphate reabsorp­ tion in the proximal convoluted tubule, causing phos­ phaturia. This excreted phosphate would have otherwise complexed calcium in plasma. Thus, this action results in an increase in the plasma calcium concentration.6 The overall effect of PTH on bone is increased bone resorp­ tion through the bone remodeling effect of osteoclast and osteoblast activities. PTH acts directly on osteoblast via PTH receptor and downstream cAMP response, while its action of osteoclasts is indirect and mediated by cytokines released from osteoblasts.7 The last impor­ tant function of PTH is to increase intestinal calcium absorption via the activation of vitamin D. PTH stimu­ lates renal 1α-hydroxylase, an enzyme that con­ verts 25-hydroxycholecalciferol (calcifediol) to 1,25-dihydroxy­ ch­ olecalciferol (calcitriol). In turn, calcitriol stimulates intestinal calcium absorption.8

PARATHYROID GLAND EMBRYOLOGY, ANATOMY, AND NORMAL HISTOLOGY Paired superior and inferior parathyroid glands start to develop in the 5th week of embryology.9 They are derived

from the endoderm of the 3rd and 4th pharyn­geal pou­ ches. The inferior parathyroid glands derive from the 3rd pha­ryngeal pouch along with the thymus. They start at the region of the pharyngeal wall and migrate inferome­ dially with the thymus. They are intimately associa­ted with the tail of the thymus until the thymus separates to enter the anterior mediastinum, and the developing parathyroid tissue settles to its position on the dorsal sur­ face of the inferior pole of the thyroid gland. The second set of parathyroid glandular tissue arises from the 4th pharyngeal pouch. Around the 6th week of develop­ ment, they detach from the pha­rynx and attach to the posterior portion of the superior pole of the thyroid as the thyroid gland migrates caud­ally. This limited course results in smaller variability in the location of the supe­ rior parathyroid glands compared to inferior glands. Each gland typically weighs about 35–40 mg, measures 3–8 mm in all dimensions, and can vary in color from light yellowish tan to reddish brown.10 The inferior para­ thyroid gland is usually found within 1 cm inferior, posterior, or lateral to the inferior pole of the thyroid gland in about 50% of cases. It is typically ante­ rior to the course of the recurrent laryngeal nerve. In a large autopsy series, the authors found the remaining 17% on or within the capsule of the thyroid gland, 26% within the cervical part of the thymus, and rarely superior to the intersection between the inferior thyroid artery and the recurrent laryngeal nerve.11 In terms of the super­ numerary cases, one-third of the cases were near the orthotopic superior and inferior parathyroid glands, while the remaining two-third of the cases were associa­ted with the thyrothymic ligament or the thymus. The limited course of the superior parathyroid descent leads to a smaller variability in location compared to the inferior counterparts. In 85% of cases, they can be found at the posterior aspect of the thyroid gland within a 2 cm diameter area centered around 1 cm above the intersection of the recurrent laryngeal nerve and the inferior thyroid artery. This is at the level of the crico­ thyroid junction.10 Thus, the glands are posterior to the recurrent laryngeal nerve. Rarely, they can be located either at the level of or superior to the supe­rior pole of the thyroid gland. Finally symmetry between left and right is observed in about 80% of cases for the superior and 70% for the inferior parathyroid glands. Thus, con­ tralateral localization for comparison can be helpful when unable to locate the parathyroid gland of interest.

Chapter 22: Management of Primary and Secondary Hyperparathyroidism

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Primary Versus Secondary Hyperparathyroidism

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Hyperparathyroidism can occur as isolated sporadic disease or associated with inheritable genetic disorders. The most common form of HPT is due to the develop­ ment of a single benign adenoma. The parathyroid adeno­ mas are monoclonal or oligoclonal neoplasms, where molecular alterations lead to clonal expansion of tumor cells. These alterations have been discovered in both tumor suppressor genes and proto oncogenes. Similar to other tumors, parathyroid adenomas arise from progres­ sive accumulation of genetic alterations that lead to the development of tumorigenic phenotypes. The more common molecular changes involve muta­ tions in tumor suppressor genes. The multiple endoc­ rine neoplasia type 1 (MEN1) gene is a tumor suppressor gene shown to have somatic mutations in both copies of the gene in 20% of cases. This gene located on chro­ mosome 11q13 was initially recognized in patients with MEN1 syndrome but has been demonstrated to be an even more common event in the development of sporadic parathyroid adenomas. Chromosome 11q13 has been found to harbor a proto oncogene that has been impli­ cated in the development of parathyroid adenomas. The PRAD1, or parathyroid adenomatosis 1 oncogene, is a cyclin D1 cell cycle regulator. Activating mutations in the PRAD1 gene result in unregulated cell cycle progres­ sion from G1 to S phase and hypercellularity.

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Etiology/Pathogenesis

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The prevalence of secondary and tertiary HPT depends on the frequency of the underlying disease. Secondary HPT occurs to some degree in nearly all patients with dialysis dependent chronic kidney disease and can lead to tertiary HPT, especially if hyperphosphatemia is uncontrolled and vitamin D is not replaced adequately. Renal failure is the most common cause of secondary HPT; however, any cause of hypocalcemia or vitamin D deficiency may result in elevated levels of PTH. No recent studies have evaluated the prevalence of secon­ dary HPT; however, the incidence of parathyroidectomy in patients with chronic renal failure is estimated to be 5.28 per 1000 patient years.15 The prevalence of secondary HPT caused by vitamin D deficiency is reported to be around 30% in adults over the age of 65.16 Inadequate vitamin D intake is quite common, especially among the elderly who may have limited exposure to sunlight. The incidence is greater among the elderly African Americans than among Caucasians.17 Tertiary HPT results from progression of secondary HPT in patients with chronic renal failure and is less common than secondary HPT. However, with increased screening for primary HPT, patients are detected earlier in the course of the disease, minimizing the long term clinical effects that have been historically described.

HYPERPARATHYROIDISM

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Diseases of the parathyroid glands are an intriguing and fairly prevalent clinical entity in the United States. Primary HPT is the third most common endocrine dis­ order. Each year < 10 cases of primary HPT per 100,000 people are diagnosed in those younger than 40 years. The incidence is estimated to be four times higher in patients older than 60 years of age.12 Nonetheless, pri­ mary HPT can affect all age groups, including children; its true prevalence in children is unknown, but consi­ dered to be rare. Women seem to have a higher incidence of this disease compared to men, with a female to male ratio of 4:1; varying from close to unity in patients younger than 40 years to 5:1 in those older than 75 years.13 It has been estimated that every woman has a 1% risk of developing primary HPT during her lifetime. However, 90% of people with primary HPT remain undiagnosed.14

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Incidence

Hyperparathyroidism is divided into primary, secondary, and tertiary categories. Primary HPT, in the absence of known or recognized stimulus, occurs in the setting of excessive PTH secretion by an autonomous gland result­ ing in hypercalcemia. Secondary HPT occurs in the setting of hypocalcemia or vitamin D deficiency acting as a stimulus for PTH production, resulting in a compensatory mechanism to restore normal function. When the PTH cannot correct the plasma calcium because of organ failure or reduced calcium availability, hypocalcemia can occur. Patients might have symptoms and signs related to acute hypocalcemia or slowly developing hypocalcemia and long standing raised PTH. Tertiary HPT results from autonomous functioning glands in patients with long standing secondary HPT.

Presentation There has been a notable change in the presentation of primary HPT during recent years. Historically, patients with primary HPT presented with specific symptoms,

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Head and Neck Surgery

such as nephrolithiasis, osteitis fibrosa cystica, muscle atrophy, hyperreflexia, and overt symptoms from a hyper­calcemic crisis resulting in significant morbidity.18 Nonspecific symptoms include malaise, fatigue, depres­ sion, and other psychiatric symptoms, sleep disturbance, loss of weight, abdominal pains, constipation, and vague musculoskeletal pains. The relative portion of these vari­ ous disease presentations has continuously decreased due to the contemporary increase of the nonspecific disease presentations or unapparent symptoms.12,18,19 Con­­ temporary manifestations of primary HPT have shifted from a debilitating disorder to one that is typically asymptomatic. The term “asymptomatic HPT” has been applied when the disorder is detected during health screening and population studies or coincidentally dur­ ing medical examination. The usual presenting abnor­ mality in these patients is an abnormally elevated serum calcium level detected on routine blood chemistry scre­ ening.19,20 Despite the lack of obvious abnormalities noted at the time of diagnosis, caution should be exercised before declaring that a patient is asymptomatic. Lund­gren et al.21 have shown a greater number of missed workdays in asymptomatic postmenopausal women with primary HPT. Therefore, these patients may be more appropriately described as minimally symptomatic in that nonspecific symptoms and silent complications of HPT would be eliminated by parathyroidectomy.22 Traditionally, clinical manifestations are described according to the organ system affected. Neurologic sym­ ptoms such as sleep disturbance, depression, psychosis, fatigue, nervousness, and cognitive dysfunction may com­ monly occur to a varying degree in primary HPT. Other neurologic changes occasionally seen in patients with HPT include deafness, dysphagia, dysosmia, and dys­ esthesia.23 Many of these neuropsychiatric symptoms in patients with primary HPT are improved after parathy­ roidectomy.3,24 Cardiovascular manifestations including hypertension, valvular calcifications, and ventricular hy­pertrophy have been described in patients with asymp­ tomatic primary HPT. Convincing evidence of a definite relationship is yet to be identified.25,26 Historically, more than half of patients with HPT were found to have renal symptoms manifested by nephro­ lithiasis. Today it remains the most common clinical expression of the disease, although its frequency dec­ reased significantly to approximately 4%, after the wide­ spread use of screening tests for serum calcium levels.12 Decreased phosphorus excretion, mild metabolic acido­ sis, and a reduction in glomerular filtration rate are other

reported consequences of HPT. Nephrocalcinosis, diffuse calcification of the renal parenchyma, is a rare complica­ tion of primary HPT. Elevated levels of PTH result in high turnover of bone. Abnormalities of the skeletal system in the form of ostei­tis fibrosa cystica and brown tumors have been historically reported. With earlier disease detection, many of these manifestations are avoided. Nonetheless, there is an incr­ ease in osteoclastic and osteoblastic activity associated with HPT, resulting in compromised bone integrity. The alteration in bone integrity results in a weakened stru­c­ ture predisposing to fracture. In the contemporary asymp­ tomatic form of the disease, skeletal changes are not apparent on plain radiographs. However, with widesp­ read use of bone density scans, patterns of diminished bone densities can be identified early in the course of the disease. End organ manifestations of HPT have signi­ ficant clinical consequences on the renal and skeletal systems. Intervention in the asymptomatic patient is ai­med at minimizing the result of the sustained effect of primary HPT on these systems. Similar to primary HPT, clinical manifestations of se­condary HPT have also considerably changed over the past several decades. This is largely attributed to the im­proved vitamin D and phosphorus regulation in patients with renal failure. Symptoms such as arthritis, bone pain, myopathy, tendon rupture, and extraskeletal calcifications are now rarely encountered. Today, patients with secon­ dary HPT are usually asymptomatic. Despite these advances, several manifestations of the disease continue to require close attention. Coronary artery calcification and calciphylaxis are two complications of HPT in renal failure that contributes to a high mortality rate in this population. Coronary artery calcification has been shown to occur more commonly among younger dialysis patients.27 Calciphylaxis manifests as an ischemic region in the dermis and subcutaneous fat resulting from calci­fication of the walls of the medium-sized vessels, usually at the site of trauma such as an injection or biopsy. The ischemia leads to infarction and ulcerations that become infected, leading to sepsis and eventually death. Clinical manifestations of vitamin D deficiency from nonrenal causes include tingling, cramps, seizures, and tetany. Chronic vitamin D deficiency results in ost­eomalacia and decreased bone densities.

Evaluation Hypercalcemia is identified on a routine blood test, prompting further investigation. Total serum calcium is

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Chapter 22: Management of Primary and Secondary Hyperparathyroidism

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Traditionally, a collar incision involving bilateral cervical exploration of all four parathyroid glands and removal of any that are grossly enlarged has been the “gold standard” surgical treatment of primary HPT. In the past two decades, significant improvements in the accu­ racy and reliability of preoperative localization studies and the development of more effective imaging methods have facilitated further evolution in surgical management. This allowed a more targeted less invasive surgical approach while achieving the same, or improved, surgical outcomes as those achieved by traditional parathyroidectomy.30,31 Localization studies are categorized into preoperative studies (noninvasive and invasive) and intraoperative adjuncts. ­

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Localization Studies

Noninvasive Methods





patients, the PTH is still excessive for the calcium level.28 These patients have no obvious causes for secondary elevations of PTH, such as renal disease or vitamin D deficiency. Blood ionized calcium level may be frankly elevated when the blood total calcium is normal. Over time, clearly elevated calcium levels are often found as well. These patients must be distinguished from patient with urinary calcium loss (renal leak hypercalciuria) where PTH becomes elevated to compensate for the urinary calcium losses. Normocalcemic primary HPT was first formally recognized at the Third International Workshop on the Management of Asymptomatic Pri­ mary Hyperparathyroidism.29 At that time, however, the expert panel stated that because so little is known about this form of the disease, the guidelines for the hyperca­ lcemic form of primary HPT could not be applied with confidence. Monitoring normocalcemic primary hyper­ parathyroid patients with the same protocol for those with asymptomatic hypercalcemic primary HPT seems reasonable. If the disease evolves into the hypercalce­ mic form, then the published guidelines from the Third International Workshop would be reasonable to follow. Tertiary HPT may be difficult to distinguish from pri­ mary HPT, because the serum chemistries may be similar. Tertiary HPT usually occurs in the setting of chronic renal failure and renal transplantation. Serum calcium, phosphorus, and PTH are elevated; however, phosphorus may be low in patients after kidney transplantation.

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favored over ionized calcium in the setting of normal albumin. A thorough history is essential, because mild symptoms may be uncovered. A history of kidney stones and fractures should be assessed. Family history of HPT, hypercalcemia, kidney stones, and osteoporosis should be sought to evaluate for familial causes of primary HPT and familial hypocalciuric hypercalcemia (FHH). Nonspecific complaints such as decreased level of energy, weakness, and symptoms of depression should be iden­ tified. Medications, such as thiazide diuretics and lithium, may mimic the clinical picture of HPT. Once hypercalcemia is identified, an elevated PTH level can help distinguish causes of hypercalcemia. If PTH is elevated in the setting of hypercalcemia, the diag­ nosis of primary HPT is made. A PTH level within the normal range in the setting of hypercalcemia is sugges­ tive of primary HPT, because nonparathyroid causes of hypercalcemia should suppress PTH levels. For this and other reasons, accurate measurement of PTH is essential. Current PTH assays available for measuring the intact molecule are immunoradiometric assays that specifically measure the biologically active PTH (1 84) molecule. Other causes of hypercalcemia that mimic the biochemical profile of primary HPT are FHH, lithium, and thiazide diuretics. Other tests may be helpful but are not essential in making the diagnosis of primary HPT. Serum phos­ phorus levels may be low to low normal. 1, 25 Dihydroxy vitamin D levels may be elevated secondary to increased conversion from 25 hydroxy vitamin D as a result of the elevation in PTH. A 24 hour urine calcium excretion may be elevated in primary HPT, whereas values below 100 mg/24 hours are suggestive of FHH. Fractional excretion of calcium of < 0.01 measured on a spot urine sample is also sug­ gestive of FHH. Markers of bone turnover are elevated in primary HPT and may be followed to assess the efficacy of medical treatment. Bone densitometry should be obtai­ ned, especially in the asymptomatic patient, because diminished densities are an indication for surgery. There is no single test that establishes the diagnosis of secondary HPT; however, an elevated PTH level in the setting of low serum calcium is diagnostic. If the phosphorus is elevated, the cause is likely chronic renal failure. If the serum phosphorus is low, then other causes of vitamin D deficiency should be considered. In some patients with HPT, the serum calcium level may be normal despite an elevated PTH level, also known as normocalcemic hyperparathyroidism. In such

High-resolution ultrasound (US): Of all the imaging modalities, US is the least expensive and least invasive;

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it does not involve radiation and is readily accessible. It is performed using a high-frequency linear transducer ideally in the range of 12–15 mHz. Parathyroid glands appear as well-circumscribed and oval, hypoechoic, and usually solid nodules (Fig. 22.1). Table 22.1 summarizes the factors that limit the accuracy of US imaging. The surgeon must always keep in mind the possibility of an intrathyroidal parathyroid adenoma, which can present in up to 5% of cases,32,33 thus requiring proper patient counseling for a possible thyroid lobectomy. The sensiti­ vity of US detection of parathyroid adenomas ranges from 27% to 95%, with a specificity of 92–97%. It is the operator experience that has the greatest effect on the ability to detect and likely accounts for the wide range of reported sensitivity. Lastly, US-guided FNA can be considered to confirm intrathyroidal parathyroid adenomas or in selected cases of persistent or recurrent HPT after failed explora­tion. An elevated PTH washout concentration from the FNA can help identify parathyroid gland lesions. With the PTH washout technique, minimally invasive surgery can be implemented even with negative cytology, thus allo­w­ ing success of a targeted surgical approach in diffi­cult redo cases. Four-dimensional computed tomography (4D-CT): This is an imaging modality that is similar to CT angiography. The name is derived from 3-dimensional CT scanning with an added dimension from the changes in perfu­ sion of contrast over time. 4D-CT generates exquisitely

detailed, multilane images of the neck and allows the visualization of differences in the perfusion characteristics of hyperfunctioning parathyroid glands (i.e. rapid uptake and washout), compared with normal parathy­roid glands and other structures in the neck. The images that are generated by 4D-CT provide both anatomic information and functional information in a single study that the operating surgeon can interpret easily and may serve an important role in localization before both ini­tial and reoperative parathyroid procedures. Magnetic resonance imaging (MRI): MRI may be selecti­ vely applied for parathyroid imaging. Hyperfunctional parathyroid glands tend to be isointense to low signal intensity on T1-weighted images, high signal intensity on T2-weighted images, with intense enhancement after intravenous gadolinium administration. MRI evaluation of parathyroid localization may be more applicable for ectopic adenomas located in the mediastinum. Limita­ tions of the use of MRI include cost and patient comp­ liance with reference to a sense of close confinement during examination. Technetium sestamibi scan (Tc-99m): Tc-99m detects mitochondrial uptake of the radionuclide tracer in areas of hyperfunctioning tissue. The injected tracer is initially concentrated in normal thyroid and abnormal para­ thyroid tissues. The concentration in normal thyroid tissue decreases rapidly, leaving behind foci of relatively enhanced uptake of the tracer in abnormal thyroid and parathyroid tissues. After injection of the radiotracer, one set of images is taken within 15 minutes and then a delayed set is taken at 2 hours. Asymmetry of uptake can be noted on early images, but usually, the delayed images are necessary to locate the focus of radiotracer, which characterizes hyperfunctioning parathyroid. A lack of retention of the tracer does not exclude the diagnosis of primary HPT, as sestamibi imaging can miss Table 22.1: Factors that limit the accuracy of ultrasound imaging

Operator skill and experience Obesity Smaller gland size Concurrent thyroid pathology (i.e. thyroiditis, multinodular goiter) Fig. 22.1: Ultrasound (US) of the neck in a 67-year-old woman with hyperparathyroidism (HPT) reveals an ovoid, 2.2-cm hypoechoic nodule adjacent to but separate from the lower pole of the right lobe of the thyroid, suggestive of a parathyroid adenoma.

Reoperative cases or previous neck surgery Retrotracheal, retroesophageal, and mediastinal glands Multiglandular disease

Chapter 22: Management of Primary and Secondary Hyperparathyroidism ­

quadriplegia.42 As a consequence of these potential risks and because of improvements in noninvasive imaging studies, selective parathyroid arteriography is rarely per­ formed currently. A more selective arteriographic modality is that of super selective digital subtraction angiography.42 This is a highly sensitive method for localization of ectopic parathyroid tissue and has an indication for patients with recurrent or persistent HPT in whom previous noninva­ sive testing has failed to identify the adenoma in a usual or utopic location. ­

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small adenomas and hyperplasia. The combination of US and sestamibi scintigraphy to localize parathyroid adenomas preoperatively increases the sensitivity to 95% because each modality contributes different data to help determine the gland location (Table 22.2).34

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Selective venous sampling: This modality is performed by catheterization of veins draining the neck and media­ stinum.43 By obtaining blood samples and comparing PTH levels obtained from sampling of the iliac veins with those obtained from thyroid veins (superior, middle and inferior), vertebral veins, and the thymic vein, the anticipated localization of the adenoma will be within the area where venous PTH levels are at least twice as high as the systemic levels. Selective venous sampling has been shown to be more accurate than large vein sampling, with accuracy of 83% as contrasted to 29%, respectively.43 This modality became significantly more accurate with the utilization of improved intact PTH assays, which increased the sensitivity of venous samp­ ling to 87–95% in some investigations.44 Selective venous sampling should be reserved for patients requiring reoperation and in whom noninvasive studies are nega­ tive, equivocal, or conflicting. This modality is technically challenging and its success depends on an experienced interventional radiologist.

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Intraoperative US: The availability of high resolution US has led some surgeons to further utilize it in their operating room. Intraoperative US may be useful in a number of operative settings. Using this adjunct will allow the surgeon to scan the neck and, where possible, correlate structures with preoperative images just prior to surgery. This achieves accurate visualization of the ultimate position of both the parathyroid lesion and other structures in the neck, in particular the relation to the internal jugular vein and carotid artery. This techni­ que may also assist in precisely localizing the incision once the patient is in the neck extension position, for an ideal access for removal of parathyroid tissue. US can be combined with FNA for PTH to interrogate hypo­ echoic structures identified in the thyroid or neck intra­ operatively. ­

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Fine-needle aspiration biopsy (FNA): It may be applied with either CT or US guidance for correct needle place­ ment in suspected abnormal parathyroid tissue during localization in preparation for reoperative surgery, where radiographic findings are otherwise equivocal. FNA of enlarged parathyroid glands by CT or US guidance was initially described in the early 1980s.35,36 Investigations have shown FNA to be a specific modality in distingui­ shing between parathyroid and nonparathyroid tissues. Cytologic evaluation of tissue samples obtained by FNA biopsy is less sensitive than measuring washout PTH levels of the aspirate material, because follicular thyroid tumors may be misinterpreted as parathyroid tissue under cytologic review. PTH washout is an accurate way to localize culprit lesions in patients with findings indicating parathyroid lesions on neck US. Frasoldati et al. showed that a PTH washout result of > 101 pg/mL had a 100% sensitivity and specificity for verification of parathyroid tissue.37 Marcocci et al. regarded a PTH washout value of > 50 pg/mL as positive for sampling in parathyroid tissue,38 whereas Maser et al. reported that a PTH washout value of > 1,000 pg/mL indicates sampling of parathyroid tissue.39 Sacks et al. reported 45 patients with PHPT who underwent FNA of suspected parathyroid adenomas. Thirty seven of the 45 patients had elevated PTH levels, with a specificity of 100% at the time of operation.40 We recommend against this practice in the primary surgical setting.

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Invasive Methods

Selective arteriography: Selective angiographic injection of the inferior thyroid arteries will demonstrate a vascular blush that may be present in up to 25–70% of parathy­ roid adenomas.41 Significant complications attributable to this technique have been reported and include central nervous system embolic infarction and potential Table 22.2: Positive predictive values for various preoperative diagnostic modalities

Ultrasound

Sestamibi

CT

MRI

PET

60–92%

78–100%

36–100%

51–100%

70–74%

(PET: Positron emission tomography; CT: Computed tomogra­ phy; MRI: Magnetic resonance imaging).

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Head and Neck Surgery

Methylene blue injection: In rare circumstances, methylene blue has been used by some surgeons, due to the dye's ability to preferentially stain the parathyroid glands when perioperative adjuncts have been misleading. The ratio­ nale for using methylene blue is to facilitate correct parathyroid gland identification and thus minimize the complication rate.45,46 Unfortunately, the literature is pla­gued with growing numbers of reports describing signi­ ficant side effects to its use such as, encephalopathy or central nervous system toxicity, as well as specific inte­ raction with serotonin reuptake inhibitors causing severe cardiovascular changes and neurological dys­function.45,47-49 Because of these precautions and the little added value, methylene blue is no longer justified for intravenous use and should not be relied on as an option in intra­ operative identification of parathyroid tissue. Radioguided Tc-99m sestamibi: Tc-99m sestamibi uptake by parathyroid tissue is a function of metabolic activity. This forms the basis for utilizing sestamibi scans to loca­ lize hypersecreting parathyroid glands in patients with primary HPT. Patients are injected with a Tc-99m sesta­ mibi isotope on the day of surgery, usually within appro­ ximately 2 hours of the operation. A hand-held gamma probe is used to direct the incision site and to localize the abnormal parathyroid glands. The initial scan provides information regarding localization of presumed adenomas and the presence of delayed uptake of nuclear material within the thyroid gland. After identification and removal of the abnormal parathyroid gland, the gamma probe may be used to confirm high metabolic activity within the resected tissue as compared with the radioactivity of the surgical bed, thus validating that no additional hyperactive glands remain behind. Potential advantages of radioguided parathyroid identification in­clude facili­ta­ tion of targeted parathyroidectomy, shorter operating time and verification of successful surgery. Absolute contra­ indications for radioguided parathyroi­ dectomy include pregnancy and allergy or sensitivity to Tc-99m sestamibi. The Twenty percent rule, published by Murphy and Norman,50 which suggests that any exci­sed tissue contain­ ing > 20% of background radioactivity in a patient with a positive Sestamibi scan, results in finding a solitary parathyroid adenoma. This protocol, however, has limited ability to exclude non parathyroid tissue or multiglandu­ lar disease, and that the signal is proportional to the gland size.51-54 The overall accuracy of radioguided parathyroidec­ tomy is 83% with a conversion rate to bilateral neck

exploration of 10% for single gland disease, 50% for multiglandular disease and 50% for hyperplasia.53,55 The gamma probe is considered unhelpful in up to 48% of cases.52,56 The limitations include logistic difficulties with timing isotope injection, equipment problems, confu­sing counts, and easily identified abnormal glands. Therefore, most parathyroid surgeons will only consider intraope­ rative radioguided parathyroidectomy in patients with an ectopic parathyroid adenoma or previous thyroidectomy where confusing background counts are not a concern. Frozen section analysis: The histological identification of parathyroid tissue relies on the identification of three types of cells that comprise the parathyroid tissue; (i) chief, (ii) oxyphil, and (iii) water clear cells. Chief cells be similar to thyroid follicular cells and oxyphil cells are indistinguishable from thyroid Hurthle cells, thus the distinction of parathyroid from thyroid tissue is more challenging. However, follicles and colloid like material are uncommon in parathyroid specimens. Fro­ zen section is an unreliable method for distinguishing between multiglandular disease and adenomas.57 The distinction between hyperplasia and adenoma is not based on pathologic criteria, rather on the operative find­ ings. If the pathologist receives a biopsy from a single parathyroid gland for frozen section interpretation, the possible diagnosis would be, hypercellular parathyroid tissue. An adenoma can be diagnosed with confidence if only one gland of the four glands is enlarged and hypercellular. Therefore, without biopsies from all four glands, the pathologist is unable to determine the cellu­lar constituency of the remaining parathyroid glands. Never­ theless, the use of frozen section to distinguish parathyroid tissue from non-parathyroid tissue has an accuracy of 99.2%.58 There is also a role for frozen section in subtotal or total parathyroidectomy for multiglan­ dular disease, secondary or tertiary HPT. In these cases the surgeon may choose cryopreservation or implanta­ tion of parathyroid tissue, as the correct identification of parathyroid tissue is crucial. In these instances, the use of frozen section is more common in order to positively diagnose parathyroid tissue prior to implantation. Need­ less to say, documentation of prior removal of four normal parathyroid glands is very worrisome for a missed super­ numerary parathyroid adenoma. Failure to perform auto­ transplantation of parathyroid tissue follo­wing removal of the remaining parathyroid gland would result in per­ manent hypoparathyroidism. This unders­cores the need to thoroughly evaluate the prior operative and pathology

Chapter 22: Management of Primary and Secondary Hyperparathyroidism

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Familial HPT and MEN HPT is associated with two MEN syndromes: MEN1 and MEN2A. Patients with MEN1, Wermer’s syndrome, exhibit parathyroid hyperplasia, pancreatic neuroendo­ crine tumors and pituitary tumors. HPT is a common initial manifestation of the syndrome, with > 90% of affected individuals exhibiting HPT. It has an autosomal dominant inheritance pattern with variable penetrance. MEN1 is thought to be caused by mutation in the tumor suppressor gene MEN1, where both copies of the gene -

 

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Intraoperative PTH (IOPTH) assay: To further improve the surgical success of targeted parathyroidectomy and to minimize the possibility of persistent or recurrent HPT after surgery, some have advocated the use of surgical adjuncts such as IOPTH monitoring. In 1990, Dr. George Irvin of the University of Miami revolutionized parathy­ roid surgery by measuring IOPTH levels and confirming removal of hypersecreting parathyroid glands. IOPTH is useful in assessing the adequacy of resection by functional means without the need to expose all the para­ thyroid glands. Before exiting the operating room, the surgeon can confirm that the patient will be eucalcemic by demonstrating an appropriate reduction in IOPTH levels after excision of all hyperfunctioning parathyroid tissue. The ability to confirm complete removal of all hypersecreting glands and predict operative success minimizes operative time, diminishes the need for bila­ teral neck exploration, and improves cure rates.59 IOPTH is based on the short half life of circulating PTH. PTH is cleared from the blood in an early rapid phase with a half life variously reported as 1.5–21.5 minutes in patients with normal renal function. PTH levels are mea­ sured preoperatively and at set post excision times. Due to the different IOPTH decrease criteria for a successful operation, several studies aimed to identify the optimal criteria and its predictive cure rate. A decline of > 50% in PTH level from the highest preincision or pre excision level is associated with predictive cure in 94 97% of cases.60 62 We prefer a PTH drop of at least 50% and into the normal range before concluding the procedure. The single criterion of PTH drop into the normal range is somewhat problematic as some patients have a normal or slightly elevated baseline level and thus some

institutions adjusted their criteria and required a 50% PTH drop with and/or normalization of PTH levels. The use of IOPTH is recommended for patients undergoing targeted parathyroidectomy. Different criteria may be utilized with similar accuracy rates (Table 22.3).63 When used correctly, we believe that IOPTH is the most accurate adjunct available to the surgeon performing parathyroid surgery. Nonetheless, when there are concor­ dant Sestamibi scans and US localization, IOPTH appears to add little benefit to the cure rate.64 68 Of note, there is a distinct entity of parathyroid disease that manifests normal PTH levels and can therefore be referred to as normohormonal primary HPT. Interestin­ gly, a normohormonal parathyroid disorder may occur with iPTH levels as low as 5–15 pg/mL, which is at the lowest reference point of most iPTH assays or below the detectable range. Awareness of this unusual phenotype may facilitate earlier diagnosis and surgery. Nonetheless, it is particularly difficult to apply this intraoperative adjunct to decide the surgical cure of the patient when the serum PTH level is within the normal range. Very few studies have focused on this issue, and we believe the utility of IOPTH monitoring in this subset of patients needs to be further studied.69 71

reports, and to discuss the case directly with the surgeons involved in the prior operations when possible.

Table 22.3: Different available criteria for successful parathyroidectomy using IOPTH

% drop

Compared to

Miami

10

≥ 50%

Pre incision Pre excision

Vienna

10

≥ 50%

Preincision

10 10

> 70% > 80%

PTH levels

-

Minute

Ann Arbor

And

Wisconsin (PTH: Parathyroid hormone).

50%

 

 

And PTH 100–200 ng/L And PTH > 200 ng/L

 

Or

Baseline

5 or 10 5, 10, or 15

12–75 pg/mL ≥ 50%  

Rotterdam

 

-

And/Or

 

Institute

335

Preincision, T5 if higher

336

Head and Neck Surgery

are sequentially inactivated to result in neoplasia. This gene, which encodes a 610-amino acid nuclear protein menin, is located on chromosome 11q13. In addition to parathyroid adenoma, mutations in MEN1 have been identified in cases of gastrinomas, insulinomas, lung carcinoids, and pituitary tumors. The exact function of menin is still under investigation but is thought to func­ tion as a nuclear transcription factor that regulates target gene expression. The surgical approach should consist of a routine bilateral neck exploration with identification of all four parathyroid glands. The extensiveness of surgical resec­ tion of the parathyroid glands is controversial, with advocates of both subtotal and total parathyroidectomy.72 Some authors have reported their experience with sub­ total parathyroidectomy in patients with MEN1 with differing degrees of surgical success.73,74 The difference in success rates is attributed to the persistent exposure of a trophic mitogenic humoral factor in patients with MEN1 disease.75 As a consequence, any parathyroid rem­ nant remaining after subtotal parathyroidectomy will be exposed to this humoral factor, thus potentially increasing the chance of recurrence. Total parathyroidec­ tomy with autotransplantation of fragmented parathy­roid tissue has therefore been advocated by others as the procedure of choice for hyperparathyroid patients with MEN1.76,77 Nonetheless, MEN1-associated HPT is asso­ cia­ ted with the finding of supernumerary parathy­ roid glands. This factor contributes to the potential for missed glands at the time of initial operation, thus inc­re­asing the risk of recurrence.31 MEN2A or Sipple’s syndrome is a triad of HPT, med­ ullary thyroid cancer, and pheochromocytoma. While essentially all individuals with MEN2A develop medul­ lary thyroid cancer, the penetrance of HPT is variable, with about 20–35% being affected while approximately 70% are affected with pheochromocytoma. Therefore, when planning parathyroid exploration for HPT suspec­ ted to be associated with MEN2A, the diagnosis of pheochromocytoma must be explored to prevent intra­ operative hypertensive crisis. Contrary to MEN1, HPT in MEN2A is caused by activating point mutations in the RET proto-oncogene, which is inherited as an auto­ somal dominant trait. RET proto-oncogene encodes a tyrosine kinase plasma membrane receptor, although the exact function is poorly characterized. The inci­ dence of multiglandular disease is much lower in patients

with MEN2A, and thus, subtotal parathyroidectomy with removal of only the obviously enlarged parathyroid glands is the approach of choice.

Histopathology of the Parathyroid Glands The parathyroid glands are enveloped in their own thin collagenous connective tissue capsule that extends into the gland, separating the parenchyma into elongated chords or clusters of functional secretory cells. Along this septum, blood vessels, nerves, and lymphatics tra­vel into the interior of the gland. The major functional parenchymal cells of the parathyroids are the chief cells. These cells measure 5–8 µm in diameter. The chief cells contain cytoplasmic secretory granules that arise from the Golgi complex. These granules contain PTH. With the increase in age, the secretory cells may be replaced by adipose cells, which can comprise up to 60% of the gland in older individuals. The second cell type comprising the parathyroid gland parenchyma is the oxyphilic cell. These cells are less numerous yet larger in diameter and stain more deeply with eosin than chief cells. Of note, these cells are considered to be mitochondrial rich, which may explain the increased ability of diseased parathyroid glands, with high oxyphilic cell concentrations, to concentrate TC-99m on sestamibi scan.72

Parathyroid Adenoma Parathyroid adenoma may occur in any of the four para­ thyroid glands; however, it may involve the inferior parathyroid glands more commonly than the superior ones.31 Grossly, parathyroid adenomas are usually oval or bean-shaped, soft in consistency, and have a reddishbrown color.78,79 Under light microscopy, parathyroid adenomas appear similar to normal parathyroid glands, exhibiting a thin fibrous capsule with a cellular frame­ work invested by a rich capillary network. Other growth patterns include follicular, pseudopapillary, and acinar patterns. Chief cells comprise the dominant cell types in most parathyroid adenomas and frequently exhibit nuclear pleomorphism, multinucleation, and giant cell formation.79,80 The chief cells in parathyroid adenomas can be larger than ones usually found in normal parathy­roid glands.81 Variations in parathyroid adenomas may occur and include the following subtypes: oncocytic adenoma, lipoadenoma, large clear cell adenoma, water-clear cell adenoma, and atypical adenoma. Atypical adenoma is

Chapter 22: Management of Primary and Secondary Hyperparathyroidism

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Parathyroid Gland Hyperplasia

common distant metastasis, yet, advanced metastases to the cervical and mediastinal lymph nodes, lungs, bone, liver, kidney and adrenal glands may occur.91,92 On microscopy, the entire parathyroid gland is trave­ rsed by broad fibrous bands that seem to originate from the capsule and extend inwards, giving a lobulated app­ earance. Mitosis can be seen in most instances. Increased mitotic activity in unequivocal parathyroid carcinoma is an indicator or poor prognosis. Parathyroid carcinoma usually grows slowly and can be an indolent tumor.

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typically used to describe parathyroid adenomas that exhibit atypical cytologic features without vascular and soft tissue invasion, or metastases.82 It is important to differentiate these lesions from parathyroid carcinomas.

337



Parathyroid carcinoma is a rare malignant neoplasm that is derived from the parenchymal cells. These carci­ nomas are usually large tumors; up to 50% can be palpable at the time of presentation with a mean diameter of 3 cm.88,89 Parathyroid carcinomas are firm or hard in consistency and have a grayish white surface color. Adherence to surrounding tissue is common and exten­ sion to involve the soft tissues around the thyroid gland may be noted.90 Metastasis at the time of presentation is unusual and is rarely found in regional lymph nodes. Parathyroid carcinoma is more often associated with local infiltra­ tion, with invasion into adjacent structures such as the thyroid gland, strap muscles, trachea and the recurrent laryngeal nerve. Pulmonary metastases are the most

Indication for Exploration

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In general, patients should be evaluated for the risk of complications developing on the basis of disease seve­ rity at the time of diagnosis, including those previously diagnosed and whom complications have developed over a short interval since diagnosis, and are at a high risk of further morbidity. Patient’s age should not repre­ sent an exclusive determinate of candidacy for surgery. The overall medical state and the potential for pursuing an active lifestyle should play a more prominent role in determining the recommendation for treatment. The severity of hypercalcemia represents a conside­ ration in the decision to offer surgery. A major factor to be considered in determining the need for surgical intervention is the potential of long term benefits and predictions for cure. In 85 90% of patients, HPT occurs as a result of a single adenoma. Surgical removal of the adenoma is curative in over 95% of patients. The long term benefit and potential for cure is also high. The decision to perform surgery on a patient with primary HPT and metabolic complications is straight­ forward. The decision is less clear and challenging in asymptomatic patients and must be guided by the poten­ tial benefits of surgery, the patient’s risk of complica­ tions developing from the disease and the wishes of the patient and the surgeon experience. The Third Interna­ tional Workshop from the 2008 National Institutes of Health provided the following recommendations on the management of asymptomatic primary HPT29: • Serum calcium is greater than 1 mg/dL above the upper limit of normal • Creatinine clearance below 60 mL/min/1.73 m2 • Patients are younger than 50 years of age • Bone mineral density measurement is reduced > 2.5 standard deviations at spine, hip or radius, or presence of fragility fracture  

Parathyroid Carcinoma

SURGICAL MANAGEMENT



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Primary parathyroid hyperplasia is a proliferation of the parenchymal cells in multiple parathyroid glands in the absence of a known stimulus for PTH secretion. There are two types of parathyroid hyperplasia: chief cell hyper­ plasia and water cell or clear cell hyperplasia.83,84 In chief cell hyperplasia, the dominant cell types are chief cells. The cellular proliferations may also give rise to nodular formation, and this can cause asymmetric gland enlargement.83,84 Cytoplasmic fat in the chief cells is reduced. Abnormal nuclei or mitosis are rare.84 Clear cell hyperplasia is a rare form of hyperplasia that is characterized by proliferation of vacuolated clear cells in multiple parathyroid glands. These glands tend to be larger and more irregular in shape, with lobular extensions to surrounding soft tissue. The histologic appea­ rance of clear cell hyperplasia bears a resemblance to that of renal cell carcinoma.85 Secondary parathyroid hyperplasia, as a conseque­ nce of renal failure, cannot be distinguished from pri­ mary hyperplasia. One exception is that with disease progression, asymmetry of glands becomes more evident in renal induced disease. The degree of glandular enlarge­ ment tends to reflect the severity of the underlying renal disorder.86,87

338

Head and Neck Surgery

• Patient requests surgery, or patient is unsuitable for long-term surveillance. If any one of these criteria is met, the patient is con­ sidered to be a candidate for parathyroid surgery. Surgery for secondary HPT is reserved for patients with disease that is refractory to medical management (Table 22.4). Indications for parathyroidectomy include hypercalce­ mia and/or hyperphosphatemia that cannot be managed with dialysis or medical therapy, manifestations of mea­ bolic bone disease, intractable pruritus or calciphylaxis.

Surgical Technique The optimal approach in managing primary HPT is one in which normocalcemia is achieved, while minimi­zing the potential surgical morbidity. The approach selected should also be individualized to the patient and disease entity, single vs. multiple gland disease, and should be time and cost effective.

Focused Surgery This approach uses both preoperative nuclear medicine and radiological studies, and the implementation of IOPTH assay for the surgical management of primary HPT secondary to anticipated parathyroid adenoma. If the preoperative scan identifies a discrete focus sugge­ stive of adenoma, a directed exploration to the side loca­ lized is performed, and biochemical confirmation of removal of all hyperfunctioning parathyroid tissue is obtained through the use of IOPTH. A 50% or greater decrease in the postexcision PTH level compared with the pre-excision level, provides biochemical confirma­ tion of removal of all hyperfunctioning parathyroid tissue. This allows the surgeon to confidently conclude the procedure without identification or biopsy of any other parathyroid glands.

In the past two decades, significant improvements in the accuracy and reliability of preoperative localization studies have facilitated further evolution in surgical manage­ment, allowing a more targeted minimally invasive surgical approach.30 The first unilateral appro­ ach for solitary parathyroid adenomas was reported by Tibblin et al. in 1982.93 Since then, several techniques have been described, including radio-guided parathyroidectomy, endoscopic parathyroidectomy with gas insufflation and video-assisted parathyroidectomy without gas insuff­ lation. Robotic-assisted transaxillary parathyroidectomy using the da Vinci Si surgical system (Intuitive Surgical, Sunnyvale, CA, USA) has also been described recently in a few case reports and small series.30,94-96 The conflu­ ence of improved adenoma locali­zation using different preoperative localization studies and the concomitant advent of minimally invasive technology, have led to fewer complications, shorter opera­tive time, shorter hospitali­ zation, quicker recovery and greater patient satisfaction.97 Targeted parathyroidectomy has become the preferred procedure over bilateral neck exploration for PHPT by most surgeons. When a parathyroid adenoma is localized preoperatively, it can be removed without visuali­ zing the other glands. Mini­mal access techniques have therefore replaced a bilateral neck exploration in patients with localized disease, although a traditional cervical incision with bilateral neck exploration remains the opti­ mal surgery for non-localized disease. We and most parathyroid surgeons would absolu­ tely recommend against unilateral exploration or remote access techniques in patients with suspected multiglan­ dular disease, since bilateral exploration can be peformed safely through a very small cervical incision. Moreover, when localization studies are inconclusive or equivocal, a traditional bilateral neck exploration is to be perfor­med. Both sides of the neck are to be explored in an attempt

Table 22.4: Indications for parathyroidectomy in patients with secondary hyperparathyroidism that is refractory to medical treatment

Hypercalcemia Normocalcemia with hyperphosphatemia and soft tissue calcifications Normocalcemia with high total alkaline phosphatase and evidence of renal osteodystrophy, spontaneous fractures or other mus­ culoskeletal symptoms Normocalcemia and pruritus with associated high PTH-values Presence of calciphylaxis Normocalcemia and anemia resistant to erythropoietin (PTH: Parathyroid hormone; HPT: Hyperparathyroidism).

Chapter 22: Management of Primary and Secondary Hyperparathyroidism

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Despite the many advances in focused parathyroidec­ tomy, the four gland exploration remains necessary in the 10–15% of patients with negative or equivocal preopera­ tive scans. This traditional approach is also necessary for patients with familial HPT, MEN syndromes and second­ ary or tertiary HPT.98 Four gland exploration requires bilateral neck exploration with identification of all four parathyroid glands and removal of all enlarged ones. Exploration of the neck is performed via a low tran­ sverse cervical (Kocher) incision, usually over a natural skin crease, and is carried down through the platysma. After incising the platysma, the cranial skin platysma flap is dissected upward to the notch of the thyroid car­ tilage and the caudal platysma flap is dissected inferiorly to the suprasternal notch. The midline raphe of the strap muscles is identified and separated from the thyroid notch to the suprasternal notch, thus allowing the sterno­ hyoid muscles to be retracted laterally. The sternothy­ roid muscle is then separated over the thyroid lobe on the side of the neck to be explored first, carefully eva­ luating the muscle away from the thyroid capsule. The thyroid lobe on the side being explored is then retracted anteromedially to access the potential space posterior to the thyroid lobe. Blunt dissection of the tissue is carried on to evaluate the area where both normal and abnormal parathyroids generally reside. Access to the paraesophageal and retroesophageal spaces is created by opening the pretracheal fascia connecting the carotid sheath and the thyroid gland. Identification and dissec­ tion of the recurrent laryngeal nerve is then under taken to prevent injury. Depending on the surgical preference, the usual trend is to identify the inferior parathyroid glands first. They tend to be larger and more anterior. Typically, the infe­ rior parathyroid glands are found adjacent to the inferior pole of the thyroid gland or within the thyrothymic liga­ ment, inferior to the thyroid gland. They may also be located anterior and slightly medial to the juxtaposition of the inferior thyroid artery and recurrent laryngeal nerve. The superior parathyroids are most commonly found along the posterior capsule of the thyroid gland at a point slightly lateral and posterior to the juxtaposition between the recurrent laryngeal nerve and inferior thyroid artery.



Surgery for Secondary Hyperparathyroidism Subtotal parathyroidectomy, removal of 3½ glands, and total parathyroidectomy with reimplantaion of parathy­ roid tissue are both considered standard surgical proce­ dures for the treatment of secondary HPT. Both subtotal and total parathyroidectomy with reimplantation leave behind vital parathyroid tissue in the same pathophy­ siologic environment that provides a continued growth stimulus of the parathyroid remnant. Therefore, unless renal transplantation occurs, these patients are at high risk of recurrent disease (5–80%).72 Given this high risk of recurrent disease, total parathyroidectomy with reim­ plantation of this remnant, away from the dialysis arterio­ venous fistula if possible, has been entertained as an alternative strategy for patients who are not candidates for renal transplantation. Under general anesthesia, the patient’s neck is slightly extended and a Kocher incision is made through the skin, subcutaneous tissues, and platysma muscle. Sub­ platysmal flaps are then raised superiorly to the thyroid notch and inferiorly to the sternal notch. The thyroid gland is then mobilized medially. If necessary, the mid­ dle thyroid vein can be divided to assist with exposure. The recurrent laryngeal nerve should be identified in or near the tracheoesophageal groove. All four parathyroid glands are then identified. If a gland is not found in its orthotopic location or within the thymus, the relatively avascular paraesophageal, paralaryngeal, retroesophageal, ­

Neck Exploration

Dissection of the superior parathyroid glands should be initiated at the outermost tip of the gland to prevent injury to the parathyroid vessels. The dissection of the inferior parathyroid glands should begin at the caudal end of the parathyroid gland, as the vascular pedicle generally enters on the upper or cranial side of the inferior parathyroid gland. Once identified, the abnormal parathyroid gland is removed and sent to pathologic analysis. A comprehensive search is conducted to locate and examine the second gland on the same side. In an event that the second gland on the side explored first is found to be abnormal, or if it appears enlarged, all four glands should identified and histologically examined. In this instance, the presumptive diagnosis is hyperplasia that will require subtotal parathyroidectomy. Failure to identify a missing gland suspected of being an adenoma, or in the case of hyperplasia, failure to locate all glands mandates a thorough dissection in an effort to locate abnormally located or ectopic parathyroid tissue.



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to identify at least four parathyroid glands, independent of whether the first side explored yields an enlarged parathyroid gland or not.

339

340

Head and Neck Surgery

and retropharyngeal regions should be carefully examined. If a gland is not located in these locations, the carotid sheath be incised and examined and thyroid lobec­ tomy may be considered. Intraoperative US is useful for identi­fying the occasional intrathyroidal or subcapsular parathyroid gland. Occasionally, a parathyroid gland is located in a subcapsular position within the thyroid gland. Incision of the thyroid capsule will expose the parathyroid gland and facilitate removal. In patients undergoing subtotal parathyroidectomy, the smallest gland is subtotally resected leaving a 40–60 mg remnant without macroscopic nodules that is marked with a non-absorbable suture. In patients who will undergo prolonged dialysis, a smaller remnant (20–30 mg) may be chosen in anticipation of recurrent disease. On the other hand, if the patient is to undergo renal trans­ plantation, a larger remnant (50–60 mg) should be left in situ to avoid post-transplantation hypocalcemia. The location of this remnant should be clearly described in relation to the recurrent laryngeal nerve and other stru­ ctures. Once this remnant is deemed viable, the remain­ing three parathyroid glands are resected. Comp­ lete removal of the gland should be achieved with gentle dis­section and clipping of the vascular pedicle. A succes­ s­ ful subtotal parathyroidectomy depends on the size and viability of the remnant. Remnants that are nodular are more likely to grow and cause recurrent disease. In total parathyroidectomy, all four (or more) glands are completely resected. In either situation, a small por­ tion of all four glands should be sent to pathology for frozen section analysis to confirm parathyroid tissue. Any remaining resected parathyroid tissue should be placed in cold sterile saline for subsequent cryopreser­ vation, especially in patients undergoing total parathy­ roidectomy without autotransplantation or in patients who are candidates for renal transplantation. Transcervical thymectomy should be considered to remove any supernumerary and/or ectopic glands. Up to 15% of patients with secondary HPT harbor enlarged glands within the thymus. After mobilization of the cervi­ cal portion of the thymic tongue, traction can be app­lied and thymectomy of at least the upper part of the thymus bilaterally can be performed usually with blunt dissection through the existing incision without the need for sternotomy. In addition, a central neck dissection involving the removal of all fatty tissue behind the thy­roid, along the esophagus, and along both recurrent lary­n­ geal nerves should be considered, especially if all four

glands have not been found. Care should be taken to avoid jeopardizing the circulation to any remnant para­ thyroid glands. In patients undergoing total parathyroidectomy with reimplantaion, success is dependent on the absence of nodularity of the grafted parathyroid tissue and the num­ ber and weight of the implanted fragments. Reimplan­ ta­ tion is usually performed in the non-access-bearing forearm. Other sites that can be utilized include the sternocleidomastoid muscle or subcutaneous tissues of the forearm, abdominal wall, or sternum. The parathyroid autograft is prepared by taking non-nodular parathyroid tissue (40–60 mg) and cutting it into approximately fifteen to twenty 1-mm3-sized fragments. A longitudinal incision is made over the brachioradialis muscle and a pocket is or pockets are created by blunt dissection in the muscle. The parathyroid fragments are then placed within the pocket. Care must be taken to confirm hemostasis as formation of a hematoma may prevent vascularization of the graft. The muscle pocket is then closed with nonabsorbable suture. One advantage of using the brachio­ radialis muscle is that it allows for easier management of recurrent disease.

Mediastinal Exploration The most common location for an adenoma is in a cer­ vical location (30–54%), followed by mediastinal (16– 34%), retroesophageal (14-39%), thymus (12%), upper cervical (8%), aortic arch (5%), and intrathyroidal (1%).99 The percentage of individuals with more than four par­ athyroid glands is estimated to range from 5% to 13%.100,101 These supranumerary glands are often found within the mediastinum. In challenging cases, the surgeon must have a syste­ m­ atic approach to the surgical identification of the parathyroid glands. An inferior gland is often located in the thyrothymic ligament or thymus. Most parathyroid adenomas within the thymus can be removed through a cervical incision. A superior gland is often located in the tracheoesophageal groove, and rarely within the carotid sheaths. The retroesophageal space should be ins­ pected and finally consideration given to performing a thyroid lobectomy on the side of the missing gland. The mediastinum should not be explored on the first operation unless there is preoperative localization of an adenoma within the thorax. Most mediastinal glands can be removed from a cer­ vical approach. However, a mediastinal gland that cannot be safely removed through a cervical incision will

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Chapter 22: Management of Primary and Secondary Hyperparathyroidism



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1. Pellitteri P, Sofferman R, Randolph G. Surgical Management of Parathyroid Disorders. Cummings Otolaryngology— Head & Neck Surgery. 5th ed: Elsevier; 2010.



REFERENCES

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Discloser statement: The authors declare that no competing financial interest exists.



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One of the most important aspects of postoperative care is monitoring of the serum calcium level. The incidence of hypocalcemia after parathyroidectomy ranges from 26% to 47%, as defined either by laboratory values or symp­ toms.102 104 Once discharged home, we advise symptomatic patients to take 1300 mg of calcium carbonate orally three to four times daily, with additional tablets as needed. Hungry bone syndrome may occur, manifested by marked hypocalcemia and hypophosphatemia that may be refractory to supplementation. Patients at higher risk of developing hungry bone syndrome include patients with long standing primary or secondary HPT, those with markedly high calcium levels prior to surgery (2 mg/dL above normal), increased alkaline phosphatase levels or extensive bony resorption on radiographic studies. This syndrome is likely due to the rebound uptake of calcium and phosphate by bones that have been pre­ viously starved of these metabolites. The majority of patients are discharged home either from the postoperative care unit or on the morning of postoperative day one. The main life threatening comp­ lication following parathyroid surgery is an expanding neck hematoma. This requires immediate opening of the sutures at the bedside followed by emergent transpor­ tation to the operating room for definitive hemostasis and reclosure. The first outpatient follow up is at 1 week to 1 month for pathology review, wound inspection, and further instruction on wound care. Duration and extent of vitamin D and calcium supplementation are based on preoperative bone mineral density determination and interdisciplinary management with an endocrinologist.





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POSTOPERATIVE MANAGEMENT

2. Daniels R. Delmar’s Guide to Laboratory and Diagnostic Tests. 2nd edn. Independence, KY: Cengage Learning; 2010. 3. Habener JF, Segre GV, Powell D, et al. Immunoreactive parathyroid hormone in circulation of man. Nat New Biol. 1972;238(83):152 4. 4. Martin KJ, Hruska KA, Freitag JJ, et al. The peripheral metabolism of parathyroid hormone. N Engl J Med. 1979;301(20):1092 8. 5. Habener JF, Rosenblatt M, Potts JT, Jr. Parathyroid hor­ mone: biochemical aspects of biosynthesis, secretion, action, and metabolism. Physiol Rev. 1984;64(3):985 1053. 6. Michalangeli VP, Hunt NH, Martin TJ. States of activation of chick kidney adenylate cyclase induced by parathyroid hormone and guanyl nucleotides. J Endocrinol. 1977; 72(1):69 79. 7. McSheehy PM, Chambers TJ. Osteoblastic cells mediate osteoclastic responsiveness to parathyroid hormone. Endocrinology. 1986;118(2):824 8. 8. Mawer EB, Backhouse J, Hill LF, et al. Vitamin D metabo­ lism and parathyroid function in man. Clin Sci Mol Med. 1975;48(5):349 65. 9. Fancy T, Gallagher D, 3rd, Hornig JD. Surgical anatomy of the thyroid and parathyroid glands. Otolaryngol Clin North Am. 2010;43(2):221 7, vii. 10. Wang C. The anatomic basis of parathyroid surgery. Ann Surg. 1976;183(3):271 5. 11. Akerstrom G, Malmaeus J, Bergstrom R. Surgical anatomy of human parathyroid glands. Surgery. 1984;95(1):14 21. 12. Heath H, 3rd, Hodgson SF, Kennedy MA. Primary hyperpara­ thyroidism. Incidence, morbidity, and potential economic impact in a community. N Engl J Med. 1980;302(4):189 93. 13. Christensson T, Hellstrom K, Wengle B, et al. Prevalence of hypercalcaemia in a health screening in Stockholm. Acta Med Scand. 1976;200(1 2):131 7. 14. Ljunghall S, Hellman P, Rastad J, et al. Primary hyper­ parathyroidism: epidemiology, diagnosis and clinical picture. World J Surg. 1991;15(6):681 7. 15. Malberti F, Marcelli D, Conte F, et al. Parathyroidectomy in patients on renal replacement therapy: an epidemiologic study. J Am Soc Nephrol. 2001;12(6):1242 8. 16. Harris SS, Soteriades E, Dawson Hughes B. Secondary hyperparathyroidism and bone turnover in elderly blacks and whites. J Clin Endocrinol Metab. 2001;86(8):3801 4. 17. Thomas MK, Lloyd Jones DM, Thadhani RI, et al. Hypo­ vitaminosis D in medical inpatients. N Engl J Med. 1998; 338(12):777 83. 18. Silverberg SJ, Bilezikian JP. Evaluation and management of primary hyperparathyroidism. J Clin Endocrinol Metab. 1996;81(6):2036 40. 19. Silverberg SJ, Bilezikian JP. Primary hyperparathyroidism: still evolving? J Bone Miner Res. 1997;12(5):856 62. 20. Lundgren E, Ljunghall S, Akerstrom G, et al. Case control study on symptoms and signs of "asymptomatic" primary hyperparathyroidism. Surgery. 1998;124(6):980 5; discus­ sion 5 6. 21. Lundgren E, Szabo E, Ljunghall S, et al. Population based case control study of sick leave in postmenopausal women before diagnosis of hyperparathyroidism. BMJ. 1998;317 (7162):848 51.



require either median sternotomy if the gland is anterior or a thoracotomy if the gland is posterior. Recently, these glands can also be resected thoracoscopically. The endocrine surgeon should be guided by the preoperative imaging results. Inferior glands are generally within the thymus, but occasionally have migrated to the pericar­ dium. Superior glands are generally found in the trache­ oesophageal groove.

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Head and Neck Surgery

22. Talpos GB, Bone HG, 3rd, Kleerekoper M, et al. Randomized trial of parathyroidectomy in mild asymptomatic primary hyperparathyroidism: patient description and effects on the SF-36 health survey. Surgery. 2000;128(6):1013-20;dis­ cussion 20-1. 23. McLeod MK, Monchik JM, Martin HF. The role of ion­ ized calcium in the diagnosis of subtle hypercalcemia in symptomatic primary hyperparathyroidism. Surgery. 1984; 95(6):667-73. 24. Chan AK, Duh QY, Katz MH, Siperstein AE, Clark OH. Clinical manifestations of primary hyperparathyroidism before and after parathyroidectomy. A case-control study. Ann Surg. 1995;222(3):402-12; discussion 12-4. 25. Silverberg SJ. Natural history of primary hyperparathyroid­ ism. Endocrinol Metab Clin North Am. 2000;29(3):451-64. 26. Silverberg SJ. Non-classical target organs in primary hyperparathyroidism. J Bone Miner Res. 2002;17 Suppl 2: N117-25. 27. Goodman WG, Goldin J, Kuizon BD, et al. Coronary­ artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med. 2000;342(20):1478-83. 28. Clark OH. Symposium: Parathyroid disease—part 1. Con­ temp Surg. 1998; 52:137-52. 29. Bilezikian JP, Khan AA, Potts JT, Jr. Guidelines for the management of asymptomatic primary hyperparathyroi­ dism: summary statement from the third international workshop. J Clin Endocrinol Metab. 2009;94(2):335-9. 30. Palazzo FF, Delbridge LW. Minimal-access/minimally inva­ sive parathyroidectomy for primary hyperparathyroidism. Surg Clin North Am. 2004;84:717-34. United States. 31. Pellitteri PK. Directed parathyroid exploration: evolution and evaluation of this approach in a single-institution review of 346 patients. Laryngoscope. 2003;113(11):1857-69. 32. Thompson NW, Eckhauser FE, Harness JK. The anatomy of primary hyperparathyroidism. Surgery. 1982;92(5):814-21. 33. Bruining HA, van Houten H, Juttmann JR, et al. Original scientific reports. Results of operative treatment of 615 patients with primary hyperparathyroidism. World J Surg. 1981;5(1):85-90. 34. Ruda JM, Hollenbeak CS, Stack BC, Jr. A systematic review of the diagnosis and treatment of primary hyperparathy­ roidism from 1995 to 2003. Otolaryngol Head Neck Surg. 2005;132(3):359-72. 35. MacFarlane MP, Fraker DL, Shawker TH, et al. Use of pre­ operative fine-needle aspiration in patients undergoing reoperation for primary hyperparathyroidism. Surgery. 1994;116(6):959-64; discussion 64-5. 36. Stephen AE, Milas M, Garner CN, et al. Use of surgeonperformed office ultrasound and parathyroid fine needle aspiration for complex parathyroid localization. Surgery. 2005;138(6):1143-50; discussion 50-1. 37. Frasoldati A, Pesenti M, Toschi E, et al. Detection and diag­ nosis of parathyroid incidentalomas during thyroid sonog­ raphy. J Clin Ultrasound. 1999;27:492-8. United States: 1999 John Wiley & Sons, Inc.; 1999.

38. Marcocci C, Mazzeo S, Bruno-Bossio G, et al. Preoperative localization of suspicious parathyroid adenomas by assay of parathyroid hormone in needle aspirates. Eur J Endocrinol. 1998;139(1):72-7. 39. Maser C, Donovan P, Santos F, et al. Sonographically guided fine needle aspiration with rapid parathyroid hormone assay. Ann Surg Oncol. 2006;13(12):1690-5. 40. Sacks BA, Pallotta JA, Cole A, Hurwitz J. Diagnosis of para­ thyroid adenomas: efficacy of measuring parathormone levels in needle aspirates of cervical masses. AJR Am J Roentgenol. 1994;163(5):1223-6. 41. Sachs BA, Pollatta J. Angiographic ablation of parathy­ roid adenomas. In: Kadir S (ed.), Current Practice of Interventional Radiology. Philadelphia: BC Decker; 1991. 42. Miller DL, Chang R, Doppman JL, Norton JA. Localization of parathyroid adenomas: superselective arterial DSA versus superselective conventional angiography. Radio­ logy. 1989;170(3 Pt 2):1003-6. 43. Sugg SL, Fraker DL, Alexander R, et al. Prospective evalua­ tion of selective venous sampling for parathyroid hormone concentration in patients undergoing reoperations for pri­ mary hyperparathyroidism. Surgery. 1993;114(6):1004-9; discussion 9-10. 44. Jones JJ, Brunaud L, Dowd CF, et al. Accuracy of selective venous sampling for intact parathyroid hormone in difficult patients with recurrent or persistent hyperparathyroidism. Surgery. 2002;132(6):944-50; discussion 50-1. 45. Pollack G, Pollack A, Delfiner J, et al. Parathyroid surgery and methylene blue: a review with guidelines for safe intraoperative use. Laryngoscope. 2009;119(10):1941-6. 46. Kuriloff DB, Sanborn KV. Rapid intraoperative localization of parathyroid glands utilizing methylene blue infusion. Otolaryngol Head Neck Surg. 2004;131(5):616-22. 47. Han N, Bumpous JM, Goldstein RE, Fleming MM, Flynn MB. Intra-operative parathyroid identification using methylene blue in parathyroid surgery. Am Surg. 2007;73(8):820-3. 48. Ahmed TS. Methylene blue toxicity following infusion to localize parathyroid adenoma. J Laryngol Otol. 120. England2006. p. 708; author reply -9. 49. Vutskits L, Briner A, Klauser P, et al. Adverse effects of methylene blue on the central nervous system. Anesthesiology. 2008;108(4):684-92. 50. Murphy C, Norman J. The 20% rule: a simple, instanta­ neous radioactivity measurement defines cure and allows elimination of frozen sections and hormone assays during parathyroidectomy. Surgery. 1999;126(6):1023-8; discus­ sion 8-9. 51. Rubello D, Casara D, Giannini S, et al. Importance of radioguided minimally invasive parathyroidectomy using handheld gamma probe and low (99m)Tc-MIBI dose. Technical considerations and long-term clinical results. Q J Nucl Med. 2003;47(2):129-38. 52. Jaskowiak NT, Sugg SL, Helke J, Koka MR, Kaplan EL. Pitfalls of intraoperative quick parathyroid hormone moni­ toring and gamma probe localization in surgery for pri­ mary hyperparathyroidism. Arch Surg. 2002;137(6):659-68; discussion 68-9.

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Chapter 22: Management of Primary and Secondary Hyperparathyroidism

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68. Haciyanli M, Lal G, Morita E, et al. Accuracy of preopera­ tive localization studies and intraoperative parathyroid hor­ mone assay in patients with primary hyperparathyroidism and double adenoma. J Am Coll Surg. 2003;197(5):739 46. 69. Lafferty FW, Hamlin CR, Corrado KR, et al. Primary hyper­ parathyroidism with a low normal, atypical serum para­ thyroid hormone as shown by discordant immunoassay curves. J Clin Endocrinol Metab. 2006;91(10):3826 9. 70. Norman J, Goodman A, Politz D. Calcium, parathyroid hor­ mone, and vitamin D in patients with primary hyperpara­ thyroidism: normograms developed from 10,000 cases. Endocr Pract. 2011;17(3):384 94. 71. Wallace LB, Parikh RT, Ross LV, et al. The phenotype of primary hyperparathyroidism with normal parathyroid hormone levels: how low can parathyroid hormone go? Surgery. 2011;150(6):1102 12. 72. Pellitteri PK, Patel P. Surgical management of primary hyperparathyroidism. In: Pellitteri PK, McCaffery TV (eds), Endocrine Surgery of the Head and Neck. Clifton Park, NY: Delmar Thomson; 2003. pp. 359 76. 73. Kraimps JL, Duh QY, Demeure M, Clark OH. Hyperpara­ thyroidism in multiple endocrine neoplasia syndrome. Surgery. 1992;112(6):1080 6; discussion 6 8. 74. Prinz RA, Gamvros OI, Sellu D, Lynn JA. Subtotal parathyroidectomy for primary chief cell hyperplasia of the multiple endocrine neoplasia type I syndrome. Ann Surg. 1981;193(1):26 9. 75. Brandi ML, Aurbach GD, Fitzpatrick LA, et al. Parathyroid mitogenic activity in plasma from patients with familial multiple endocrine neoplasia type 1. N Engl J Med. 1986; 314(20):1287 93. 76. Wells SA, Jr., Ellis GJ, Gunnells JC, et al. Parathyroid auto­ transplantation in primary parathyroid hyperplasia. N Engl J Med. 1976;295(2):57 62. 77. Wells SA, Jr., Farndon JR, Dale JK, et al. Long term evalu­ ation of patients with primary parathyroid hyperplasia managed by total parathyroidectomy and heterotopic autotransplantation. Ann Surg. 1980;192(4):451 8. 78. Williams ED. Pathology of the parathyroid glands. Clin Endocrinol Metab. 1974;3(2):285 303. 79. Fialkow PJ, Jackson CE, Block MA, et al. Multicellular origin of parathyroid "adenomas". N Engl J Med. 1977;297(13): 696 8. 80. van Heerden JA, Grant CS. Surgical treatment of primary hyperparathyroidism: an institutional perspective. World J Surg. 1991;15(6):688 92. 81. Lloyd HM, Jacobi JM, Cooke RA. Nuclear diameter in parathyroid adenomas. J Clin Pathol. 1979;32(12):1278 81. 82. Levin KE, Galante M, Clark OH. Parathyroid carcinoma versus parathyroid adenoma in patients with profound hypercalcemia. Surgery. 1987;101(6):649 60. 83. DeLellis RA: Tumors of the Parathyroid Glands, Third Series, Fascicle 6. Washington, DC: Armed Forces Institute of Pathology; 1993. p. 25. 84. Ghandur Mnaymneh L, Kimura N. The parathyroid ade­ noma. A histopathologic definition with a study of 172 cases of primary hyperparathyroidism. Am J Pathol. 1984;115(1):70 83.



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53. Chen H, Mack E, Starling JR. Radioguided parathyroidec­ tomy is equally effective for both adenomatous and hyper­ plastic glands. Ann Surg. 2003;238(3):332 7; discussion 7 8. 54. Ugur O, Bozkurt MF, Hamaloglu E, et al. Clinicopathologic and radiopharmacokinetic factors affecting gamma probe guided parathyroidectomy. Arch Surg. 2004;139(11):1175 9. 55. Chen H, Mack E, Starling JR. A comprehensive evaluation of perioperative adjuncts during minimally invasive parathyroidectomy: which is most reliable? Ann Surg. 2005;242(3):375 80; discussion 80 3. 56. Inabnet WB, 3rd, Kim CK, Haber RS, Lopchinsky RA. Radioguidance is not necessary during parathyroidectomy. Arch Surg. 2002;137(8):967 70. 57. Hosking SW, Jones H, du Boulay CE, et al. Surgery for parathyroid adenoma and hyperplasia: relationship of histology to outcome. Head Neck. 1993;15(1):24 8. 58. Westra WH, Pritchett DD, Udelsman R. Intraoperative con­ firmation of parathyroid tissue during parathyroid explora­ tion: a retrospective evaluation of the frozen section. Am J Surg Pathol. 1998;22(5):538 44. 59. Chen H, Pruhs Z, Starling JR, et al. Intraoperative para­ thyroid hormone testing improves cure rates in patients undergoing minimally invasive parathyroidectomy Sur­ gery. 2005;138(4):583 7; discussion 7 90. 60. Carneiro DM, Solorzano CC, Nader MC, et al. Comparison of intraoperative iPTH assay (QPTH) criteria in guiding parathyroidectomy: which criterion is the most accurate? Surgery. 2003;134(6):973 9; discussion 9 81. 61. Irvin GL, 3rd, Solorzano CC, Carneiro DM. Quick intra­ operative parathyroid hormone assay: surgical adjunct to allow limited parathyroidectomy, improve success rate, and predict outcome. World J Surg. 2004;28(12):1287 92. 62. Chiu B, Sturgeon C, Angelos P. Which intraoperative para­ thyroid hormone assay criterion best predicts operative success? A study of 352 consecutive patients. Arch Surg. 2006;141(5):483 7; discussion 7 8. 63. Mazeh H, Chen H. Intraoperative adjuncts for parathyroid surgery. Exp Rev Endocrin Metab. 2011;6(2):245 53. 64. Stalberg P, Sidhu S, Sywak M, et al. Intraoperative para­ thyroid hormone measurement during minimally invasive parathyroidectomy: does it "value add" to decision mak­ ing? J Am Coll Surg. 2006;203(1):1 6. 65. Gawande AA, Monchik JM, Abbruzzese TA, et al. Reas­ sessment of parathyroid hormone monitoring during parathyroidectomy for primary hyperparathyroidism after two preoperative localization studies. Arch Surg. 2006; 141(4):381 4; discussion 4. 66. Mihai R, Palazzo FF, Gleeson FV, Sadler GP. Minimally invasive parathyroidectomy without intraoperative para­ thyroid hormone monitoring in patients with primary hyperparathyroidism. Br J Surg. 2007;94(1):42 7. 67. Pang T, Stalberg P, Sidhu S, et al. Minimally invasive parathyroidectomy using the lateral focused mini incision technique without intraoperative parathyroid hormone monitoring. Br J Surg. 2007;94(3):315 9.

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85. LiVolsi VA, Asa SL: The Parathyroid Glands in Endocrine Pathology, Philadelphia: Churchill-Livingstone; 2002. 86. Grimelius L, Akerstrom G, Johansson H, et al. The Para­ thyroid Glands. In: Kovacs K, Asa SL (eds), Functional Endocrine Pathology. Boston: Blackwell Scientific Publi­ cations; 1991. pp. 375-95. 87. Shelling DH. The parathyroids in health and disease. St. Louis: C.V. Mosby; 1935. 88. van Heerden JA, Weiland LH, ReMine WH, Walls JT, Purnell DC. Cancer of the parathyroid glands. Arch Surg. 1979;114(4):475-80. 89. Wang CA, Gaz RD. Natural history of parathyroid carci­ noma. Diagnosis, treatment, and results. Am J Surg. 1985; 149(4):522-7. 90. Smith JF, Coombs RR. Histological diagnosis of carcinoma of the parathyroid gland. J Clin Pathol. 1984;37(12):1370-8. 91. Sandelin K, Tullgren O, Farnebo LO. Clinical course of metastatic parathyroid cancer. World J Surg. 1994;18(4):5948; discussion 9. 92. Schantz A, Castleman B. Parathyroid carcinoma. A study of 70 cases. Cancer. 1973;31(3):600-5. 93. Tibblin S, Bondeson AG, Bondeson L, Ljungberg O. Surgical strategy in hyperparathyroidism due to solitary adenoma. Ann Surg. 1984;200(6):776-84. 94. Tolley N, Arora A, Palazzo F, et al. Robotic-assisted para­ thyroidectomy: a feasibility study. Otolaryngol Head Neck Surg. 2011;144:859-66. England. 95. Katz L, Abdel Khalek M, Crawford B, Kandil E. Roboticassisted transaxillary parathyroidectomy of an atypical ade­ noma. Minim Invasive Ther Allied Technol. 2012;21(3):201-5.

96. Landry CS, Grubbs EG, Morris GS, et al. Robot assisted transaxillary surgery (RATS) for the removal of thyroid and parathyroid glands. Surgery. 2011;149:549-55. United States. 97. Ikeda Y, Takami H. Endoscopic parathyroidectomy. Biomed Pharmacother. 2000;54 Suppl 1:52s-6s. 98. The American Association of Clinical Endocrinologists and the American Association of Endocrine Surgeons position statement on the diagnosis and management of primary hyperparathyroidism. Endocr Pract. 2005;11(1): 49-54. 99. Wang CA. Parathyroid re-exploration. A clinical and patho­ logical study of 112 cases. Ann Surg. 1977;186(2):140-5. 100. Pattou FN, Pellissier LC, Noel C, et al. Supernumerary parathyroid glands: frequency and surgical significance in treatment of renal hyperparathyroidism. World J Surg. 2000;24(11):1330-4. 101. Hooghe L, Kinnaert P, Van Geertruyden J. Surgical anatomy of hyperparathyroidism. Acta Chir Belg. 1992;92(1):1-9. 102. Mittendorf EA, Merlino JI, McHenry CR. Post-para­ thyroidectomy hypocalcemia: incidence, risk factors, and management. Am Surg. 2004;70(2):114-9; discussion 9-20. 103. Kald BA, Mollerup CL. Risk factors for severe postoperative hypocalcaemia after operations for primary hyperparathy­ roidism. Eur J Surg. 2002;168(10):552-6. 104. Westerdahl J, Lindblom P, Valdemarsson S, Tibblin S, Bergenfelz A. Risk factors for postoperative hypocalcemia after surgery for primary hyperparathyroidism. Arch Surg. 2000;135(2):142-7.

345

Chapter 23: Management of Recurrent Hyperparathyroidism

CHAPTER

Management of Recurrent Hyperparathyroidism

23

Salem I Noureldine, Phillip K Pellitteri, Ralph P Tufano

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Diseases of the parathyroid glands are an intriguing and fairly prevalent clinical entity in the United States. Each year < 10 cases of primary hyperparathyroidism (HPT) per 100,000 people are diagnosed in those younger than 40 years. The incidence is estimated to be four times higher in patients older than 60 years of age.1 Surgery for primary HPT performed by an experienced surgeon is curative at the initial operation in > 95% of cases.2 In contrast, the success rate for surgeons who perform < 10 parathyroidec­ tomy procedures per year is only 70%.3 The majority of parathyroid operations in the United States are not, in fact, performed by experienced parathyroid surgeons.4 Consequently, the disease is not cured for some patients following surgery. Those not cured either remain hyper­ calcemic in the immediate postoperative period or redevelop hypercalcemia after a long period of normo­ calcemia. Hypercalcemia persisting or recurring within 6 months after initial parathyroidectomy is referred to as persistent HPT. Persistent HPT is usually due to a missed parathyroid adenoma, and is the most common indica­ tion for parathyroid reoperation. Hypercalcemia recurring > 6 months after an apparently curative initial para­ thyroidectomy is referred to as recurrent HPT. Recurrent HPT is most frequently due to the biology of the underlying disease process. Regardless of terminology, in both cases, the patient is at continued risk of metabolic complications from hypercalcemia and may continue to have discomfort from the associated symptoms. Despite the advances in preoperative imaging and adjunctive intraoperative tools, the incidence of persistent or recurrent HPT has been reported to be as high as

30%.5 7 It has been also estimated that 2–10% of surgical failures may be attributed to an incorrect preoperative diagnosis.8,9 Accordingly, the key requirement for success in reoperative parathyroidectomy is a proper diagnosis. By definition, HPT (primary or secondary) must be confir­ med with an elevated serum calcium concentration and an elevated or inappropriately high parathyroid hormone (PTH) level. Patients may also present with elevated PTH with serum calcium levels at the upper limit of normal. Checking an ionized calcium level can help confirm the diagnosis of HPT in most of these patients. Elevated serum chloride and decreased serum phosphate levels are frequently noted. In addition, if not previously performed, benign familial hypocalciuric hypercalcemia is ruled out with an appropriately elevated 24 hour urinary calcium measurement. If all these parameters are not present, other causes of hypercalcemia must be con­ sidered (i.e. patients with normocalcemic HPT caused by hypoalbuminemia, hyperphosphatemia, vitamin D deficiency, or hypomagnesemia), because a repeat para­ thyroidectomy is almost guaranteed to be unbeneficial in these circumstances. The diagnosis of HPT has been faci­ litated by the development of immunometric assays.10,11 Clinical analysis with immunometric PTH assays typically distinguishes hypercalcemic patients with HPT from patients with other causes of hypercalcemia. Diagnostic errors of HPT can result from medications (i.e. calcium, vitamin D, furosemide, thiazide diuretics, calcitonin, or lithium), malignancy (i.e. bone metastases or humoral hypercalcemia), granulomatous disease, acuterenal fai­ lure, bone disease (i.e. Paget disease or immobilization), hyperthyroidism, or adrenal insufficiency. -

INTRODUCTION

346

Head and Neck Surgery

The indications for surgical intervention in reoper­ ative cases must be solid, because the morbidity and technical difficulty is increased. Reoperations are unfor­ tunately associated with a lower success rate than initial operations. Nonetheless, in experienced hands, the suc­ cess rate of reoperative parathyroidectomy for persistent and recurrent HPT is reported to be > 80–90%.12 However, the ideal period to cure the patient is during the initial operation, when the risks of surgical complications are least possible and the likelihood of cure is greatest. This chapter will highlight the reasons for persistent and recurrent HPT, discuss the indications for reoperative surgery, and outline a perioperative scheme for managing persistent and recurrent HPT.

CAUSES OF FAILED PRIMARY EXPLORATION A missed single adenoma represents the most common finding yielded on parathyroid re-exploration conducted by the experienced parathyroid surgeon. Akerstrom et al.13 reported on 84 parathyroid re-explorations in 69 patients with primary HPT. Thirty-seven of these patients had missed adenomas and 4 had “double” adenomas and only 1 adenoma was resected on the initial exploration. The majority of the remaining patients had persistent HPT secondary to inadequate resection of parathyroid hyper­ plasia, with only four patients demonstrating recurrent “single” adenomas. Rotstein et al.14 summarized their experience with 28 reoperations for primary HPT. Solitary adenoma was identified in 24 patients with 2 patients each having hyperplasia and carcinoma. Norman and Denham15 used the technique of minimally invasive radioguided parathyroidectomy for reoperative disease and recovered 23 solitary adenomas from 24 patients. Jaskowiak et al.16 reviewed the NIH experience of 288 patients with persi­ s­ tent/recurrent HPT; 222 (77%) of these patients were ulti­mately demonstrated to have solitary adenomas. In patients with renal failure induced HPT, hyperpla­ sia is the expected histopathology. Cattan et al.17 explored 89 patients for persistent or recurrent secondary HPT; 53 of these patients had undergone subtotal parathyroi­ dec­tomy, whereas 36 had prior total parathyroidectomy with autotransplantation. Hypertrophy of the remnant was identified as the principal cause of recurrence in the sub­total group. In the group receiving total parathyroidec­ tomy, recurrence was located in the autotransplant in one half; hyperplastic disease was identified in the neck or mediastinum in the remaining half.

When considering the possibility that failure to iden­ tify a single adenoma may be due to ectopic gland posi­ tion, consideration of the surgical embryo-anatomic relationships in the central neck is of primary importance. Parathyroid tissue originates from primordial pharyngeal endoderm formed in the third and fourth pharyngeal pouches during the fifth week of embryologic develop­ ment (Fig. 23.1). The epithelial lining of the dorsal wing of the third pharyngeal pouch differentiates into primordial parathyroid glandular tissue, where the ventral portion of the pouch differentiates into the thymus. As the thymus migrates medially and inferiorly, it pulls the inferior para­ thyroid gland (parathymus) with it into the thymic tail. Eventually, the main portion of the thymus migrates to its final position in the upper thoracic region, and its tail involutes, leaving the developing parathyroid gland to come to its position on the dorsal surface of the inferior pole of the thyroid gland. This glandular tissue eventually forms the inferior parathyroid gland. Simultaneously, the epithelium of the dorsal wing of the fourth pharyngeal pouch begins to differentiate into parathyroid glandular tissue. After separation from the regressing pouch, it becomes associated with the lateral portion of the caud­ally migrating thyroid and carries a short distance medially and inferiorly until it resides posterior to the superior pole of the thyroid gland. This tissue eventually develops into the superior parathyroid gland. This embryologic pattern of development has significant implications for the identi­ fication of ectopic or normal glandular variance during the course of parathyroidectomy. The longer embryologic migration results in an extensive area of potential dis­persal for the normal inferior parathyroid gland. In 61% of cases, the glands are situated at the level of the inferior poles of the thyroid lobes on the posterior, lateral, or anterior aspects. In 26% of cases, they are situated in the thyro-thymic ligament, or on the upper, cervical portion of the thymus. Less commonly, in 7% of cases, they are situated higher up at the level of the middle third of the posterior aspect of the thyroid lobes and may be confused with the superior parathyroid gland. Because of the embryonic descent of the thymus extending from the angle of the mandible to the pericardium, anomalies of migration of the parathy­ mus are responsible for high or low ectopic locations of the inferior parathyroid gland. The incidence of higher ectopia along the carotid sheath, from the angle of the mandible to the lower pole of the thyroid, does not seem to exceed 1–2%.18 Alternatively, if separation from the thymus is delayed, the inferior parathyroid gland may be

Chapter 23: Management of Recurrent Hyperparathyroidism

347

Fig. 23.2: Intrathymic parathyroid adenoma within mediastinum.

Fig. 23.1: Embryonic development of the parathyroid glands.

pulled inferiorly into the anterior mediastinum to a vary­ ing degree. In this circumstance, the glands are usually within the thymus at the posterior aspect of its capsule, or still in contact with the great vessels of the mediasti­ num (Fig. 23.2). Lower ectopic regions such as these are noted in 3.9–5% of instances.19 The migration of the ulti­ mobranchial bodies of the thyroid glands serve as a mig­ ratory tract for the superior parathyroid glands, which travel toward the lateral part of the main medial thyroid rudiment. In contrast to the inferior glands, the superior

parathyroids have a relatively limited descent within the neck. They remain in contact with the posterior part of the middle third of the thyroid lobes. This limited embryo­ nic migration explains why they remain relatively stable in their regional distribution when not pathologic. They are most commonly grouped at the posterior aspect of the thyroid lobes, in an area 2 cm in diameter, whose center is situated approximately 1 cm above the crossing of the inferior thyroid artery and the recurrent laryngeal nerve.20,21 As a consequence of the extensive descent of the inferior parathyroid gland, the migration of the para­ thymus results in the inferior and superior glands crossing during development. The embryonic intersection of these glands explains why they are grouped at the level of the inferior thyroid artery, at the junction of the middle and inferior thirds of the thyroid lobe, and in many respects quite close, depending on the degree of migration of the inferior parathyroid gland. Because of the limited migra­ tory descent of the superior parathyroid gland, the area within which these glands disperse is limited and thus congenital ectopic positions of the superior gland are unu­ sual. In 13% of instances, the superior glands are located

348

Head and Neck Surgery

on the posterior aspect of the superior pole of the thyroid lobe in a lateral laterocricoid, lateral pharyngeal, or cri­ cothyroid position. In 30 distinct benign and malignant

neoplasms being recognized by the World Health Organization (WHO, Table 26.1).1 The majority (65–80%) of salivary gland tumors arise in parotid glands, 10% in submandibular glands, and the remainder in sublingual glands and minor salivary glands. The most common salivary gland tumor is pleomorphic adenoma (PA) (benign mixed tumor), and the most common malignancy is mucoepidermoid carcinoma (MEC). Typical prognostic factors for salivary gland malignancy include clinical and pathological stage2 (Table 26.2); tumor grade; tumor location; and facial nerve involvement. Prognostic factors pertinent to specific entities are described in individual sections.

Histological Grading of Malignant Salivary Gland Tumors The histological grading of malignant salivary gland tumors is relatively complex, and may pose a challenge to newcomers not familiar to the field.3 Several entities, namely MEC, adenoid cystic carcinoma (AdCC), and adenocarcinoma not otherwise specified, have their own three-tiered grading system and will be discussed later in Sections Mucoepidermoid Carcinoma; Adenoid Cystic Carcinoma; and Adenocarcinoma, Not Otherwise Specified. In most other instances, the histologic types of the tumors define the grade. Entities that are typically considered as low-grade malignancy include acinic cell carcinoma, polymorphous low-grade adenocarcinoma (PLGA), basal cell adenocarcinoma, epithelial-myoepithelial carcinoma (EMC), clear cell carcinoma (CCC), low-grade

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Figs. 26.1A to D: Histology of normal salivary glands. (A and B) The parotid gland is composed of lobules of serous acini (SA) admixed with ductal system (D) and adipose tissue (A). The intercalated ducts (arrowhead) lie in contact with the serous acini, and comprise a single layer of cuboidal epithelium with scattered basally located elongated myoepithelial cells (arrows). The striated ducts (SD) are lined by columnar epithelium with abundant eosinophilic cytoplasm enriched in mitochondria. (C) Sublingual glands are composed of exclusively mucinous acini (MA). The excretory duct (ED) contains pseudostratified columnar epithelium. (D) Submandibular glands and minor salivary glands contain an admixture of mucous and serous acinic cells. In mixed units, serous cells form a crescent (white arrows) surrounding the centrally located mucous cells (M).

cribriform cystadenocarcinoma [low-grade salivary duct carcinoma (LG-SDC)], and myoepithelial carcinoma. The high-grade tumors include SDC, oncocytic carcinoma, small cell carcinoma, large cell carcinoma (LCC), carcinosarcoma, and malignant sebaceous tumors. In addition, it is now well-accepted that many low-grade salivary gland carcinomas can rarely undergo so-called “highgrade transformation” (or “dedifferentiation”), in which a component of undifferentiated carcinoma with marked nuclear pleomorphism, necrosis, and frequent mitosis is juxtaposed to the typical low-grade carcinoma.4 Highgrade transformation is associated with aggressive clinical behaviors, and has been reported in an expanding

collection of carcinomas, including acinic cell carcinoma, AdCC, EMC, PLGA, myoepithelial carcinoma, MEC, and CCC.

Utilities of Diagnostic Molecular Pathology in Salivary Gland Neoplasms In the past decade, significant advances in diagnostic molecular pathology have expanded our knowledge in the field of salivary gland tumors, leading to redefinition of several entities.5 Clear cell carcinoma and mammary analog secretory carcinoma are two examples of such changes.

Chapter 26: Pathology of Salivary Gland Neoplasms Table 26.1: World Health Organization (WHO) Histological classification of tumors of the salivary gland tumors (2005)

Benign epithelial tumors Pleomorphic adenoma Myoepithelioma Basal cell adenoma Warthin tumor Oncocytoma Canalicular adenoma Sebaceous adenoma Lymphadenoma Ductal papillomas Cystadenoma Malignant epithelial tumors Acinic cell carcinoma Mucoepidermoid carcinoma Adenoid cystic carcinoma Polymorphous low-grade adenocarcinoma Epithelial-myoepithelial carcinoma Clear cell carcinoma, not otherwise specified Basal cell adenocarcinoma Sebaceous carcinoma Sebaceous lymphadenocarcinoma

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of clear cells but lacks characteristic features of other carcinomas; hence the name “not otherwise specified.” It was not until 2011 that a characteristic t(12;22) (q13;q12) translocation was discovered in CCC. This recurrent translocation has since been detected in nearly 100% of clear cell carcinoma, and is now being utilized as a diagnostic tool for this specific entity (see Section Hyalinizing Clear Cell Carcinoma). Mammary analog secretory carcinoma of the salivary gland is a new entity that was first described and defined in 2010, partially based on the presence of a recurrent fusion involving chromosome 12p13 ETV6 locus and chromosome 15q25 NTRK3 locus (see Section Mammary Analog Secretory Carcinoma). The most common encountered genetic alterations in salivary gland tumors are listed in Table 26.3. In addition to the diagnostic roles, molecular testing has been implied as a tool to identify potential predictive factors for targeted therapies. Human epithelial growth factor receptor 2 (Her2) expression, for example, has been detected in over 90% of SDC. Among them, 15% has Her2 amplification by fluorescent in situ hybridization (FISH). Ongoing trials using trastuzumab (Herceptin), a monoclonal Her2 antibody, to treat metastatic SDC with Her2 amplification have yielded promising results.

Cystadenocarcinoma Low-grade cribriform cystadenocarcinoma Mucinous adenocarcinoma

BENIGN EPITHELIAL TUMORS

Oncocytic carcinoma

Pleomorphic Adenoma6

Salivary duct carcinoma

Synonyms

Adenocarcinoma, not otherwise specified Myoepithelial carcinoma Carcinoma ex pleomorphic adenoma Carcinosarcoma Metastasizing pleomorphic adenoma Squamous cell carcinoma Small cell carcinoma Large cell carcinoma Lymphoepithelial carcinoma Sialoblastoma Soft tissue tumors Hematolymphoid tumors Secondary tumors

In the most recent WHO classification (2005), CCC is a diagnosis of exclusion defined as a carcinoma composed

Benign mixed tumor

Definition Pleomorphic adenoma is a benign tumor composed of cells demonstrating variable ductal and myoepithelial differentiation, intermingled with mesenchymal components.

Clinical and Epidemiological Features Pleomorphic adenoma is the most common salivary gland neoplasm in the adult and pediatric populations, accounting for about 60% of all salivary gland tumors. Eighty percent of PAs arise in the parotid glands, 10% in submandibular glands, and the remaining arise in minor salivary glands. Pleomorphic adenoma typically presents as an indolent painless solitary mass.

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Table 26.2: American Joint Committee on Cancer (AJCC) staging of major salivary gland malignancy*

Primary tumor (T) TX:

Primary tumor cannot be assessed

T0:

No evidence of primary tumor

T1:

Tumor 2 cm or less in greatest dimension without extraparenchymal extension

T2:

Tumor > 2 cm but no > 4 cm in greatest dimension without extraparenchymal extension

T3:

Tumor > 4 cm and/or tumor having extraparenchymal extension

T4a: Moderately advance disease: tumor invades skin, mandible, ear canal, and/or facial nerve T4b: Very advanced disease: tumor invades skull base and/or pterygoid plates and/or encases carotid artery Regional lymph node (N) NX:

Regional lymph nodes cannot be assessed

N0:

No regional lymph node metastasis

N1:

Metastatic in a single ipsilateral lymph node, 3 cm or less in greatest dimension

N2:

Metastasis in a single ipsilateral lymph node, > 3 cm but not > 6 cm in greatest dimension (N2a), or in multiple ipsilateral lymph nodes, none > 6 cm in greatest dimension (N2b), or in bilateral or contralateral lymph nodes, none > 6 cm in greatest dimension (N2c)

N3:

Metastasis in a lymph node, > 6 cm in greatest dimension

Distant metastasis (M) M0: No distant metastasis M1: Distant metastasis *Malignant salivary gland tumor arising in the minor salivary glands is staged according to carcinoma of the site of origin.

Table 26.3: Common genetic alternations in salivary gland neoplasms

Percentage of cases with alteration

Tumor type

Chromosomal abnormality Genes/proteins

Pleomorphic adenoma

Translocation involving 8q12

PLAG1

40%

Pleomorphic adenoma

Translocation involving 12q13-15

HMGA2

8%

Mucoepidermoid carcinoma

t(11;19) (q21;p13)

MECT1-MAML2

70%

Adenoid cystic carcinoma

t(6;9) (q22–23;p23–24)

MYB-NFIB

57%

Clear cell carcinoma

t(12;22) (q13;q12)

ATF1-EWSR1

82%

Salivary duct carcinoma

17q12

Her2 amplification and expression

Amplification: 15% Expression: 90%

Carcinoma ex pleomorphic adenoma

8q12

PLAG1

60%

Mammary analog secretory carcinoma

t(12;15) (p13;q25)

ETV6-NTRK3

~100%

Pathological Findings •

Macroscopic appearance: The common appearance of PA is a well-circumscribed, partially encapsulated mass with a bosselated outer surface. It may have a homogenous tan-white surface, sometimes with a glistening gelatinous texture. Recurrent PAs often present as multifocal nodules.

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Architecture and cytology: Pleomorphic adenomas are composed of an admixture of ductal epithelium, modified myoepithelial cells, and mesenchymal stroma (Figs. 26.2A to F). Architectural pleomorphism is common in this tumor and can be observed in different areas of the same tumor. The epithelial cells contain eosinophilic cytoplasm, and form ducts and tubules. The myoepithelial cells can have spindle,

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Figs. 26.2A to F: Pleomorphic adenoma (benign mixed tumor). (A) Pleomorphic adenoma typically is as a well-circumscribed lobulated mass. (B) Pleomorphic adenoma is composed of three components: modified myoepithelial cells (My.), ductal elements (Du.), and stromal component (St.). In this case, the stromal component is myxoid, which stains lightly blue (basophilic) on hematoxylin and eosin. (C–E) Metaplastic changes, e.g. acinic metaplasia (panel C, arrow), lipomatous differentiation (panel D, arrows), chondroid differentiation (panel E, labeled as Ch) and squamous metaplasia with keratinization (panel E, arrows), are common in pleomorphic adenoma. (F) Vascular permeation by pleomorphic adenoma can rarely be seen in the periphery of the tumor, which is not indicative of malignancy.

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epithelioid, clear cell, or plasmacytoid appearance with small hyperchromatic nuclei. The stromal component can be mucoid, myxoid, chondroid, or hyalinized. Metaplastic and degenerative changes are commonly seen in PAs, which include squamous metaplasia, mucinous metaplasia, sebaceous differentiation, lipomatous differentiation and osseous metaplasia, as well as infarction and necrosis. Atypical histological features, such as capsular infiltration, hypercellularity, cellular atypia, and vascular invasion, can be seen in PAs. Such features are not indicative of malignancy; on the other hand, the presence of anaplasia, atypical mitoses, and broad zones of hyalinization are concerning features, and should promote a search for carcinoma ex PA. Special stains, immunoprofile, and molecular studies: The ductal epithelial cells are positive for a variety of keratins including pankeratins (AE1:AE3), keratin 7 (CK7), keratin 19 (CK19), carcinoembryonic antigen (CEA), and epithelial membrane antigen (EMA). Myoepithelial cells are positive for myoepithelial markers such as high-molecular-weight keratin, keratin 14 (CK14), p63, calponin, S100, smooth muscle actin, smooth muscle myosin heavy chain, muscle specific actin, and glial fibrillary acidic protein. About 40% of PAs carry a rearrangement involving chromosome 8q12 PA gene 1 (PLAG1) locus. In addition, 8% of PAs have a translocation involving the high-mobility group protein gene (HMGA2) on chromosome 12.

Clinical and Epidemiological Features Myoepithelioma accounts for 1–2% of all salivary gland neoplasia, and typically presents as a slow-growing painless mass. The most common affected site is the parotid gland, followed by minor salivary glands of the hard and soft palate. Submandibular glands and other minor salivary glands can also be involved. Myoepithelioma occurs over a wide age range, from 9 to 85 years old, with most cases presenting in the fifth to sixth decades of life. There is no documented gender predilection.

Pathological Findings •

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Prognosis A PA is a benign tumor with an excellent prognosis. The five-year recurrence rate is 3% following complete resection with adequate margins. The rate of local recurrence is much higher, in the range of 20–45%, after enucleation.

Myoepithelioma7 Synonyms Myoepithelial adenoma, benign myoepithelial tumor

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Macroscopic appearance: It usually presents as a well-circumscribed, tan-yellow, solid mass with a glistening cut surface. Architecture: Myoepithelioma is an encapsulated cellular neoplasm with various growth patterns, e.g. solid, nodular, trabecular, reticulated, and pseudoglandular architecture (Figs. 26.3A to F). Cytology: Neoplastic myoepithelial cells exhibit spindle, plasmacytoid, epithelioid, oncocytic, and/or clear cell morphology. The spindle cells have elongated eosinophilic cytoplasm and uniform, centrally located nuclei, arranged in interlacing fascicles. The plasmacytoid cells are polygonal cells with eccentric round nuclei, dense chromatin, and plasmacytoid hypereosinophilic cytoplasm, and are arranged as single cells, islands, cords, or sheets, usually admixed with a background of mucoid or myxoid matrix. The epithelioid cells usually grow as trabeculae, cords, or solid sheets of polygonal cells with eosinophilic cytoplasm and centrally located nuclei. The clear cells are polygonal cells with clear cytoplasm, which contain periodic acid-Schiff (PAS)-reactive and diastase sensitive glycogen. Immunoprofile: Myoepithelioma is positive for a wide array of keratins, particularly high-molecular weight keratins and at least one myoepithelial marker.

Definition

Prognosis

Myoepithelioma is a benign salivary gland tumor composed predominantly, or exclusively, of cells with myoepithelial differentiation; it has little (< 5%) or no ductal epithelial differentiation.

Myoepithelioma is a benign neoplasm in which complete surgical excision is considered curative. Local recurrence is usually related to inadequate incomplete excision.

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Figs. 26.3A to F: Myoepithelioma. Myoepithelioma is a benign salivary gland tumor composed of exclusively myoepithelial cells, organized in reticulated (A), trabecular (C), or solid (E) architecture, sometimes within a background of myxoid stroma (A). The myoepithelial cells can be plasmacytoid with eccentric nuclei and hypereosinophilic cytoplasm (B); clear cells with centrally located oval to round nuclei and abundant clear cytoplasm (D); or spindle with elongated nuclei (F).

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Basal Cell Adenoma

Prognosis

Definition

Basal cell adenoma is a benign salivary gland neoplasm amendable for curative surgery with little risk of recurrence. The exception is the membranous variant, which bears a 25% recurrence risk, and minimal but reported risk of malignant transformation.

Basal cell adenoma (BCA) is a benign salivary gland neoplasm characterized by a proliferation of basaloid cells in the absence of the typical chondromyxoid mesenchymal stromal component of PA. Four histological variants of BCA have been described: solid, tubular, trabecular, and membranous (synonym: dermal analog tumor).

Clinical and Epidemiological Features Basal cell adenomas account for ~2% of salivary gland tumors. They most frequently occur in the parotid glands (70–75%), while the rest affect submandibular glands and minor salivary glands of the upper lip and buccal mucosa. Basal cell adenomas typically present as asymptomatic mobile slow growing masses. The membranous variant is a distinct variant that mostly affects male patients, and may present as multifocal disease with associated cutaneous adnexal tumors, e.g. cylindroma, eccrine spiradenoma, and trichoepithelioma.

Pathological Findings •

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Macroscopic appearance: Basal cell adenoma is usually an encapsulated, or well-circumscribed, mobile, pink-brown, solid mass. Architecture: The neoplastic cells are arranged in solid nests (solid variant), tubules (tubular variant), trabeculae (trabecular variant), or ‘jigsaw puzzle’ like pattern surrounded by eosinophilic hyalinized basal membrane-like material (membranous variant) (Figs. 26.4A to D). Cytological features: Basal cell adenomas are classically composed of two types of cells. Peripheral cells with hyperchromatic nuclei and scanty cytoplasm. These cells line the outer surface of the cell nests, and arrange in a palisading pattern. The second types of cells have pale nuclei, more abundant cytoplasm, and are usually more centrally located. Small ductal structures, squamous metaplasia, or keratin eddies may be seen within the nests. Special stains and immunoprofile: The peripheral cells can be positive for myoepithelial markers, and the central cells may be immunoreactive to CK7, cytokeratin, CEA, and EMA. The hyalinized material in the membranous variant is PAS-positive and diastase resistant.

Warthin Tumor8 Synonyms Adenolymphoma, cystadenolymphoma, papillary cystadenoma lymphomatosum.

Definition Warthin tumor is a common benign salivary gland tumor characterized by a double layer of oncocytic epithelium and myoepithelial cells, a papillary or cystic architecture, and a reactive lymphoid stroma with germinal centers.

Clinical and Epidemiological Features Warthin tumor is the second most common salivary gland tumor after PA, accounting for 4–13% of all salivary gland neoplasms. It has a strong association with cigarette smoking. Ninety-eight percent of patients with a Warthin tumor have a smoking history, and the relative risk of smokers developing this tumor is about eight times compared to that in nonsmokers. A notable change of male-to-female ratio from 10:1 in 1953 to 1.2:1 in 1996 has been observed and is possibly associated with the increased number of female smokers. Warthin tumors occur almost exclusively in parotid glands (93–100%); however, cases of Warthin tumors arising in minor salivary glands have also been reported. About 10–20% of patients present as bilateral or multicentric disease.

Pathological Findings •

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Macroscopic appearance: Warthin tumors are wellcircumscribed, partly cystic masses. The cystic space may contain mucoid or brown viscous fluid. Architecture: Warthin tumor typically contains cystic regions lined by epithelium with papillary projections, and a lymphoid stroma (Figs. 26.5A to D). The epithelial lining is comprised of a double layer of oncocytic epithelium: the inner tall columnar luminal cells and the outer cuboidal basal cells. There is also an inconspicuous layer of myoepithelial cells. The stromal component has variable amounts of reactive lymphoid tissue, commonly with germinal centers.

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Figs. 26.4A to D: Basal cell adenoma. (A) A basal cell adenoma arises within the parotid gland (top right, P) as a well-circumscribed mass with a thin fibrous capsule (arrowheads). Basal cell adenoma is composed of basaloid neoplastic cells arranges as trabeculae (D), solid nests (B), or “jigsaw puzzle” like pattern surrounded by eosinophilic hyalinized basal membrane-like material (membranous variant, C). (D) The neoplastic cells have hyperchromatic nuclei and scanty cytoplasm. A second population of cells with more abundant cytoplasm forming ductal structures is also present (arrows).

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Cytological features: The epithelial lining of Warthin tumors has a prominent oncocytic appearance with abundant eosinophilic granular cytoplasm. Necrosis and metaplastic changes, e.g. mucinous, sebaceous, and squamous metaplasia, can be seen in 6–7% of Warthin tumors, usually in the setting of inflammation, infarction, or post-fine needle aspiration. Immunoprofile: The epithelial linings are positive for low-molecular-weight cytokeratin (LMWCK), e.g. CK7, CK8, and CK18.

Prognosis Complete excision, with a recurrence rate of ~5%, is the treatment of choice for Warthin tumors. Malignant

transformation in the epithelial component to squamous cell carcinoma or MEC, or in the lymphoid component to low-grade B-cell lymphoma, is rare, affecting < 1% of Warthin tumors.

Oncocytoma Definition Oncocytoma is a benign neoplasm composed of exclusively of oncocytes, which are large polygonal epithelial cells with abundant eosinophilic granular cytoplasm enriched in mitochondria.

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Figs. 26.5A to D: Warthin tumor. (A and B) Warthin tumor typically is a well circumscribed, partially cystic mass with abundant lymphoid stroma (LS). Intracystic papillary projections may be seen. (C) The epithelial lining is composed of a double layer of oncocytic cells. There is also an inconspicuous layer of myoepithelial cells (white arrow). (D) Mucinous metaplasia with mucocytes (black arrowhead) and squamoid metaplasia (black arrow) may be present focally.

Clinical and Epidemiological Features

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Oncocytomas account for 1% of salivary gland tumors. Eighty-five percent of oncocytomas occur in the parotid glands, and the remainder arise in the submandibular and minor salivary glands. Approximately 20% of the patients with oncocytoma have a history of previous radiation therapy or occupational radiation exposure to the affected region. Seven percent of oncocytomas are bilateral.

Pathological Findings •

Macroscopic appearance: Oncocytoma is an encapsulated solid mass with an orange or light-brown cut surface.

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Architectural and cytological features: The cells are arranged as solid sheets, trabeculae, or loose clusters. The typical oncocytic cells have abundant granular cytoplasm, and centrally located round to oval nuclei with vesicular chromatin and small nucleoli (Figs. 26.6A to C). A clear cell variant of oncocytoma has been previously described, composed of cells with clear cytoplasm, which is attributed to cytoplasmic glycogen and/or fixation artifacts. Special stains and immunoprofile: Phosphotungstic acid hematoxylin stain can demonstrate mitochondria as blue-black cytoplasmic granules. The tumor cells are immunoreactive for cytokeratins, p63, and EMA.

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Figs. 26.6A to C: Oncocytoma. An oncocytoma is typically present as a solid and lobulated mass separated from surrounding parotid glands (P) by a fibrous capsule (A). The neoplastic cells are arranged as solid sheets or trabeculae (B). The oncocytes have abundant granular cytoplasm, and centrally located round to oval nuclei with vesicular chromatin and conspicuous nucleoli (C).

Prognosis Complete surgical resection is the treatment of choice with extremely rare local recurrence. Transformation to an oncocytic carcinoma is a rare but well-recognized phenomenon (see Oncocytic Carcinoma).

buccal mucosa (~10%). It comprises 1% of all salivary gland neoplasms, and 4% of minor salivary gland tumors. Canalicular adenomas mostly affect elderly individuals, with a peak incidence in the seventh decade.

Pathological Findings

Canalicular Adenoma

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Definition Canalicular adenoma is a benign tumor composed of branching and anastomosing cords of columnar epithelium and a pauci-cellular vascular stroma.

Clinical and Epidemiological Features This tumor has a predilection for the minor salivary glands of the upper lip (80% of cases), followed by those of the

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Macroscopic appearance: Canalicular adenoma usually presents as a well-circumscribed and/or encapsulated solid tan nodule. Architecture and cytological features: The typical growth pattern of canalicular adenoma is parallel rows of columnar basaloid epi1thelial cells, forming branching and interconnecting tubules, cysts, and canaliculi (Figs. 26.7A to C). The stroma in between is paucicellular, edematous, and highly vascular.

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Immunoprofile: The epithelial cells are positive for cytokeratins and S100, and negative for myoepithelial markers.

Prognosis Canalicular adenoma has an excellent prognosis following complete resection with an adequate margin. Recurrences are rare, and may reflect multifocal primary disease.

Sebaceous Adenoma and Lymphadenoma Definition

Clinical and Epidemiological Features Sebaceous adenomas and lymphadenomas are rare, representing 0.1% of all salivary gland tumors. Half of the sebaceous adenomas occur in the parotid glands, while the rest involve buccal mucosa, retromolar region, and submandibular glands. Ninety percent of the sebaceous lymphadenoma occur in the parotid gland. The proposed histological origin of sebaceous lymphadenoma is the entrapped salivary gland tissues within an intraparotid lymph node.

Pathological Findings •

Macroscopic appearance: These tumors are typically well-circumscribed, partially or completely encapsulated, solid or partially cystic, grey-beige masses. Architecture and cytological features: The tumor is composed of nests and cysts of sebaceous cells (Figs. 26.8A to C). These cells have vacuolated lipid-containing

Sebaceous adenoma is a rare benign tumor containing nests and cysts of benign sebaceous cells. Sebaceous lymphadenoma is a similar benign entity, composed of intermixed islands of benign sebaceous cells with lymphoid stroma and lymphoid follicles.

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Figs. 26.7A to C: Canalicular adenoma. Canalicular adenoma is a well-circumscribed solid nodule (A) composed of anastomosing tubules and beaded canaliculi with a pauci-cellular vascular stroma (B). The canaliculi are lined by parallel rows of columnar basaloid epithelium (C).

Chapter 26: Pathology of Salivary Gland Neoplasms cytoplasm, and centrally located small nuclei. Cytological atypia, mitotic activity, and necrosis are typically absent. Sebaceous adenoma contains fibrous stroma, while sebaceous lymphadenoma has dense lymphoid stroma with lymphoid follicles.

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Clinical and Epidemiological Features All three entities are predisposed to minor salivary glands. However, cases of intraductal papilloma and sialadenoma papilliferum arising from major salivary glands, especially parotid glands, have also been reported.

Prognosis Complete surgical resection is curative, with no risk of recurrence.

Pathological Findings •

Ductal Papillomas Definition Ductal papillomas are comprised of three distinct benign papillary epithelial tumors of salivary duct origin classified as (1) inverted ductal papilloma; (2) intraductal papilloma; and (3) sialadenoma papilliferum.

Inverted ductal papilloma occurs exclusively in the minor salivary gland, usually at the junction of salivary duct and mucosal epithelium. It has an inverted (endophytic) growth pattern, in which the epithelium “pushes” downward into the submucosa as bulbous fronds. The epithelium has columnar or cuboidal cells lining the luminal surface and a centrally located basaloid or epidermoid (squamoid) epithelium admixed with scattered mucous cells.

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Figs. 26.8A to C: Cystic sebaceous lymphadenoma. (A and B) A sebaceous lymphadenoma arises within the parotid gland (P). The cyst is lined by squamous epithelium with abundant nests of sebaceous cells (arrowheads) within the wall of the cyst, surrounded by a dense layer of lymphoid stroma (LS). (C) The sebaceous cells have vacuolated lipid-containing cytoplasm, and centrally located small nuclei with minimal cytological atypia.

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Intraductal papilloma usually present as a unicystic lesion with numerous intraluminal branching papillae. The epithelial lining of the cystic space and papillae is an admixture of cuboidal to columnar ductal epithelial cells and goblet cells. Mitotic activity or cytological atypia are typically absent. Sialadenoma papilliferum is a biphasic tumor, composed of an exophytic papillary or verrucous proliferation of benign squamous mucosa, and an endophytic proliferation of ductal epithelium in the forms of cysts and ducts, sometimes with intraluminal papillary projections. The endophytic component is lined by a double-layered ductal epithelium: a luminal columnar ductal epithelium and a basal cuboidal cell layer. Interspersed mucous cells may be seen in the exophytic or endophytic component.

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Architecture and cytological features: The cysts are lined by a mixture of various types of epithelial cells, including cuboidal ductal epithelium, oncocytes, mucous cells, sebaceous, and squamous (epidermoid) cells. The papillary variant of cystadenoma contains multiple intracystic papillae with fibrovascular cores. Cystadenoma is devoid of solid growth pattern, cytologic atypia, lymphoid stroma, or complex intraluminal papillary architecture, which is a helpful hint to differentiate this particular entity from other benign or malignant salivary tumors with cystic architecture.

Prognosis Cystadenoma is a benign neoplasia in which a complete surgical resection is considered curative. Rare recurrence or malignant transformation has been reported in the literature.

Prognosis Inverted papillomas and intraductal papillomas follow a benign clinical course with little or no risk of recurrence after complete resection. The recurrence rate of sialadenoma papilliferum is higher, in the range of 10–15%.

Cystadenoma Synonyms

MALIGNANT EPITHELIAL TUMORS Acinic Cell Carcinoma3,4,9 Definition Acinic cell carcinoma is a malignant salivary gland neoplasm with at least some of the neoplastic cells recapitulating the appearance of serous acinar cells with cytoplasmic zymogen granules.

Cystic duct adenoma, oncocytic cystadenoma

Definition Cystadenoma is a benign multi- or unicystic epithelial tumor lined by variable-appearing epithelial cells, often with papillary projections.

Clinical and Epidemiological Features Cystadenoma comprises 4–5% of benign salivary tumors. It involves the minor salivary glands, parotid glands, and submandibular glands in a descending order of incidence, accounting for 50%, 45%, and < 10% of the tumors. Cystadenoma affects women more commonly, and typically presents as a slow-growing painless mass.

Pathological Findings •

Macroscopic appearance: Cystadenomas are typically well circumscribed, partially encapsulated, multicystic, or unicystic (Figs. 26.9A to C).

Clinical and Epidemiological Features Acinic cell carcinomas represent approximately 6% of salivary gland neoplasms and 18% of salivary gland malignancies. > 80% of tumors arise in the parotid gland, 15% in minor salivary glands, and 5% in the submandibular and sublingual glands. Acinic cell carcinomas affect women more commonly (M: F = 1:1.5) with a broad age distribution (mean, 44 years). About 4% of the cases occur in children, making them the second most common malignant salivary gland tumor in this age group. Up to half of patients have pain or tenderness clinically, and facial paralysis has been reported in 5–10% of patients.

Pathological Findings •

Macroscopic appearance: The typical appearance of acinic cell carcinoma is a small (< 3 cm), wellcircumscribed, soft to rubbery to firm tumor. However, large tumors measuring up to 13 cm have been reported.

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Figs. 26.9A to C: Oncocytic cystadenoma. (A) An oncocytic cystadenoma arises within the sublingual gland (S) as a multicystic lesion. (B) The cysts are lined by single or multiple layers of oncocytic cells. Occasional simple papillary projections (arrows) with fibrovascular cores can be seen. (C) The lining of the cysts is composed of cuboidal oncocytic cells, with abundant eosinophilic granular cytoplasm, centrally located round nuclei, and prominent nucleoli.

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Architecture: Acinic cell carcinomas have various growth patterns, including solid, microcystic, papillary-cystic, and follicular patterns. Many tumors have prominent lymphoid infiltrate, and some have germinal center formation. Cytological features: The presence of neoplastic acinic cells with abundant basophilic cytoplasmic zymogen granules is pathognomonic for this entity (Figs. 26.10A to D). Other cell types such as vacuolated cells, clear cells, nonspecific glandular cells, and intercalated duct-like cells can also be found. Special stains, immunoprofile, and molecular studies: The characteristic acinic cells have PAS-positive, diastase-resistant cytoplasmic granules. They are also positive for 1-antitrypsin, 1-antichymotrypsin, and CEA. No consistent cytogenetic alteration has been reported. High-grade transformation: Although a rare event, high-grade transformation (previously known as

“dedifferentiation”) is a well-documented phenomenon in acinic cell carcinomas. Histologically, sheets of undifferentiated carcinoma with marked nuclear pleomorphism, necrosis, and frequent mitosis are juxtaposed with conventional acinic cell carcinoma. The high-grade transformation is associated with a more aggressive clinical behavior.

Prognosis and Prognostic Factors Acinic cell carcinoma is an indolent malignancy with a 5-year disease-free survival rate of 91%. The recurrence rate is about 35% following surgical resection. In addition to staging, adverse prognostic factors include tumor size larger than 3 cm; submandibular tumor or involvement of the deep lobe of parotid; multiple recurrences; neural invasion; high mitotic or proliferative index; focal necrosis; and high-grade transformation.

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Figs. 26.10A to D: Acinic cell carcinoma. (A) This acinic cell carcinoma is a well-circumscribed, partially encapsulated, solid tumor. The most common growth patterns seen in acinic cell carcinoma are solid with sheets of neoplastic cells (B) and microcystic with numerous small cystic spaces (C). Prominent lymphoid infiltrate with germinal center (GC) formation is a common finding in acinic cell carcinoma (C). (D) Neoplastic cells with abundant basophilic zymogen granules (arrows) are pathognomonic for this tumor. Vacuolated cells with eosinophilic to clear cytoplasm (arrowheads) are also common in this entity.

Mucoepidermoid Carcinoma3,10–15 Definition Mucoepidermoid carcinoma is a malignant glandular epithelial neoplasm composed of an admixture of epidermoid, intermediate, and mucous cells.

glands, involving parotid glands (45%), submandibular glands (7%), or sublingual glands (1%) in a descending order of incidence. The most common site of minor salivary gland involvement is the palate, followed by the buccal mucosa and the lips.

Pathological Findings Clinical and Epidemiological Features Mucoepidermoid carcinoma is the most common salivary gland malignancy in adults and children, representing about 30% of both major and minor salivary gland malignancy. Fifty-three percent occur in major salivary

•

•

Macroscopic appearance: Mucoepidermoid carcinoma may be encapsulated, well-circumscribed, or infiltrative. Cysts can be of variable size at presentation. Cytological features: The characteristic features for MECs are the presence of three types of cells: squamoid

Chapter 26: Pathology of Salivary Gland Neoplasms (epidermoid), mucous, and intermediate cells (Figs. 26.11A to D). Mucous cells are usually found within the cystic lining. They have large pale mucin-containing cytoplasm, and basally displaced small nuclei. Epidermoid cells are polygonal cells with abundant eosinophilic cytoplasm and vesicular nuclei. They form nests, or solid sheets, with a pavement-like arrangement. Despite the squamoid appearance, the epidermoid cells usually lack intercellular bridges, keratin pearls, or extensive keratinization. The intermediate cells can be basaloid with small hyperchromatic nuclei; or large polyclonal with vesicular nuclei and abundant cytoplasm. The cells typically arrange in clusters or sheets, admixed with other cell types.

•

•

•

A

B

C

D

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Architectural features: Mucoepidermoid carcinomas are often multicystic with a solid component. The percentage of cystic component is an important prognostic factor that has been incorporated into the grading system of MECs. Histological grading: The two most commonly adopted grading schemes for MECs are the Armed Forces Institute of Pathology (AFIP) grading scheme (Table 26.4) and the Brandwein grading scheme (Table 26.5). Histological variants: Three histological variants of MECs have been described, i.e. clear cell variant containing predominantly clear cells with intracytoplasmic glycogen; oncocytic variant with abundant oncocytic cells; and sclerosing variant with marked

Figs. 26.11A to D: Mucoepidermoid carcinoma (MEC). A MEC of parotid gland (P) is composed of a mixture of cystic (A and B) and solid (A and C) components. Three types of cells are typically present in MEC, including mucocytes with abundant intracellular mucin and peripherally located small nuclei (arrows); squamoid cells with eosinophilic cytoplasm and vesicular nuclei in a pavement-like arrangement (S); and intermediate cells with clear to eosinophilic cytoplasm and small pyknotic nuclei (I). (D) A mucicarmine stain highlights the intracellular mucin of the mucocytes in pink.

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Table 26.4: Armed Forces Institute of Pathology (AFIP) grading scheme for mucoepidermoid carcinoma

Table 26.5: Brandwein grading scheme for mucoepidermoid carcinoma

Features

Point

Features

Point

Intracystic component < 20%

2

Intracystic component < 25%

2

Neural invasion

2 3

Tumor front invades in small nest and islands

2

Necrosis Four or more mitoses per 10 high power fields

3

Pronounced nuclear atypia

2

Lymphovascular invasion

3

Anaplasia

4

Perineural invasion

3

Tumor grade

Total point

Mortality

Bone invasion

3

Low grade

0–4

3%

Necrosis

3

Intermediate grade

5–6

10%

3

High grade

7 or more

46%

Four or more mitoses per 10 high power fields Tumor grade

Total point Mortality

Low grade

0

0%

Intermediate grade

2–3

5%

High grade

4 or more

56%

•

sclerosing stroma accompanied by peripheral infiltration of lymphocytes, plasma cells, and eosinophils. Residual foci of typical MECs are usually required to make a diagnosis of these rare variants. It remains unclear whether these variants bear any prognostic significance. Immunoprofile: The cytoplasmic mucin of mucous cells can be demonstrated by mucicarmine or Alcian blue staining. About 70% (range 38–82%) of MECs carry a t(11;19) MECT1-MAML2 translocation, which can be detected using reverse transcription-polymerase chain reaction or FISH techniques.

Prognosis and Prognostic Factors Histological grade and tumor stage are the two wellestablished prognostic factors in MEC. The overall survival of patients with low- to intermediate-grade MECs is 95 months, while it decreases to 51 months in patients with high-grade MECs. It is now generally accepted that low-grade MECs require only surgical resection with adequate margins, while high-grade tumors will be treated with a combination of surgery, adjuvant radiation, and neck dissection. Additional adverse prognostic factors include perineural invasion, positive surgical margins, and submandibular location of the tumor. Presence of t(11;19) translocation is more prevalent in the low- to intermediate-grade MEC, and may predict a significantly better survival with an overall survival of 10 years in fusionpositive MECs compared to 1.6 years in fusion-negative cases.

Adenoid Cystic Carcinoma3,4,16,17 Definition Adenoid cystic carcinoma is a basaloid salivary gland malignancy that consists of epithelial and myoepithelial cells arranged in variable architectural configurations including tubular, cribriform, and solid patterns.

Clinical and Epidemiological Features Adenoid cystic carcinoma comprises approximately 10% of all salivary gland malignancies. The most frequent sites of involvements are the parotid glands, accounting for 5% of all parotid gland tumors; submandibular glands, accounting for 15% of submandibular gland tumors; and minor salivary glands throughout the oral cavity and upper aerodigestive tract accounting, for 30% of minor salivary gland tumors. Adenoid cystic carcinoma has a tendency to invade nerves, and typically has a long protracted relentless clinical course with multiple recurrences and a dismal long-term overall survival rate (10% in 10–15 years).

Pathological Findings •

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Macroscopic appearance: Typically, AdCC is a tan, rubbery to firm mass. The tumor border ranges from encapsulated, well circumscribed, to infiltrative. Architecture: Three well-recognized patterns are commonly seen in AdCC. The tubular pattern in which

Chapter 26: Pathology of Salivary Gland Neoplasms

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an inner layer of epithelial ductal cells and an outer layer of myoepithelial cells are arranged as tubules. The classical cribriform pattern, in which the admixed myoepithelial and epithelial cells are arranged in a “Swiss cheese”-like appearance surrounding spaces filled with basophilic mucopolysarccharide or hyalinized eosinophilic basement membrane-like material. The solid pattern contains solid sheets or large nests of neoplastic cells (Figs. 26.12A to F). Cytological features: Adenoid cystic carcinoma typically contains basaloid cells with indistinct cell border, scanty cytoplasm, and uniform hyperchromatic angulated nuclei. The solid variant of AdCC may have cells with greater nuclear pleomorphism, larger nuclei and nucleoli and elevated mitotic activity. Grading scheme: Table 26.6 outlines the most commonly used grading scheme of AdCC. Adenoid cystic carcinoma with high-grade transformation: High-grade transformation of AdCC is a rare phenomenon that is indicative of a highly aggressive clinical course with 57% risk of lymph node metastases. Histologically, it is characterized by two juxtaposed carcinoma components: a conventional AdCC, and a transformed pleomorphic adenocarcinoma, or undifferentiated carcinoma, of a pure ductal phenotype. Immunoprofile and molecular characteristics: The ductal cells are positive for cytokeratins, S100, and EMA, while the myoepithelial cells are immunoreactive to the myoepithelial markers. Fifty-seven percent of AdCCs harbor t(6;9) MYB-NFIB translocation, and 30% have mutations in the fibroblastic growth factor (FGF)-insulin-like growth factor (IGF)-PI3K pathway.

Polymorphous Low-Grade Adenocarcinoma4,7,18 Definition Polymorphous low-grade adenocarcinoma is a lowgrade ductal malignancy characterized by an infiltrative growth of uniform neoplastic cells arranged in diverse architectural patterns (hence the term, “polymorphous”).

Clinical and Epidemiological Features The majority of PLGA occur in minor salivary glands of the oral cavity, accounting for 26% of oral salivary gland malignancy. After MEC, it is the second most common salivary gland malignancy occurring in the oral cavity. Sixty percent of PLGA involves the palate. PLGA occurs only exceptionally in the major salivary glands, lacrimal glands, or minor salivary glands of the nasal cavity and nasopharynx. The male to female ratio of PLGA is 2:1.

Pathological Findings •

•

Prognosis and Prognostic Factors Stage is the most consistent predictor for AdCC. It has long been shown that the solid pattern of AdCC is correlated with a poor prognosis. However, it remains controversial whether histologic grade is an independent prognostic factor for poor prognosis, or rather, merely a histologic factor that is associated with high-stage tumor, and, thus, indirectly links to adverse clinical outcome. Regardless of the histologic grade, AdCC is generally considered to be a malignancy with a high risk of recurrence, and is treated with wide local or radical surgical resections followed by adjuvant radiation therapy. The overall survival rate after 10–15 years is 10%, and the incidence of distal metastasis is 25–55%. Additional adverse prognostic factors reported include the tumor site and status of surgical margins.

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Macroscopic appearance: The tumor usually presents as a raised beige-tan, nonencapsulated, round, or lobulated mass. The overlying mucosa can be intact or sometimes ulcerated. Architecture: One predominant histologic feature of PLGA is the diverse architectural arrangements that range from lobular, solid, papillary, papillarycystic, cribriform, trabecular, fascicular, tubular, to ductal structures (Figs. 26.13A and B). Single cell filing, in which the neoplastic cells are arranged as single rows resembling breast lobular carcinoma, is a frequent finding in PLGA, hence the synonym, “lobular carcinoma.” The stroma of PLGA is usually hyalinized and/or mucoid. Mitoses and necrosis are rare in PLGAs. Perineural invasion is seen in 30% of PLGAs, typically in the form of concentrically arranged cords of neoplastic cells surrounding nerves giving a target-let appearance. Cytological features: Despite the architectural polymorphism, the neoplastic cells of PLGA have a characteristic uniform appearance with small-to-medium sized oval-to-spindle nuclei, pale-staining (vesicular) nuclei, and amphophilic to eosinophilic cytoplasm. Occasionally, clear, oncocytic, squamous, mucus, or acinic cell changes may present in PLGA. However, such changes typically present focally and are not the predominant features.

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A

B

C

D

E

F

Figs. 26.12A to F: Adenoid cystic carcinoma (AdCC). (A and B) The tubular pattern of AdCC is composed of an inner layer of epithelial ductal cells and an outer layer of myoepithelial cells arranged as tubules. The neoplastic cells are basaloid with indistinct cell border, scanty cytoplasm, and uniform hyperchromatic angulated nuclei. (C and D) The cribriform pattern contains admixed myoepithelial and epithelial cells arranging in a “Swiss cheese” appearance, surrounding spaces filled with basophilic mucopolysaccharide or hyalinized eosinophilic basement membrane-like material. (E) Basaloid neoplastic cells form solid nests in solid variant of AdCC. (F) Perineural invasion, in which nests of tumor cells wrap around nerves (Ne), is a common finding in AdCC.

Chapter 26: Pathology of Salivary Gland Neoplasms •

High-grade transformation in the form of poorly differentiated adenocarcinoma or undifferentiated carcinoma, similar to that described in acinic cell carcinoma and AdCC, has been reported in six cases of PLGA. All six cases have extensive local disease and/ or metastases to regional lymph nodes without evidence of distant metastasis. Immunoprofile: PLGA typically lacks the myoepithelial cells with none, or only rare cells, staining with myoepithelial markers. The majority of neoplastic cells in PLGA are positive for S100, cytokeratins, EMA, and CEA, suggestive of a ductal phenotype.

•

Prognosis and Prognostic Factors The overall prognosis of PLGA is excellent. The risk of local recurrence following surgical resection is 9–17%. Involvement of regional lymph nodes is reported in 5–15% of cases. Distant metastasis and disease-specific mortality are rare. There are reports suggesting that the increased

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percentage of papillary architecture is associated with higher risk of lymph node metastases.

Epithelial-Myoepithelial Carcinoma4,19 Definition Epithelial-myoepithelial carcinoma is a low-grade salivary gland malignancy characterized by the presence of two cell types: an inner layer of ductal epithelial cells and an outer layer of clear myoepithelial cells.

Clinical and Epidemiological Features Epithelial-myoepithelial carcinoma represents approximately 1% of the salivary gland tumors. It occurs predominantly in the major salivary glands with 60–80% of cases in the parotid glands, although the minor salivary glands throughout the upper aerodigestive tract can also be involved.

Pathological Findings Table 26.6: Grading scheme of adenoid cystic carcinoma

Grade

Perzin et al.16 and Szanto et al.17

Low grade

Predominantly tubular pattern without solid component

Intermediate grade

Predominantly cribriform pattern. Tumor may have solid component but should be < 30% of the entire tumor volume

High grade

Solid component > 30% of the entire tumor volume

A

•

•

Macroscopic appearance: Epithelial-myoepithelial carcinoma is usually an unencapsulated, but wellcircumscribed, lobulated, solid, tan-yellow mass. Mucosal ulceration and infiltrative border can be observed in EMCs involving minor salivary glands. Architectural and cytological features: The hallmark of EMCs is the bi-layered duct-like structure that resembles the normal salivary duct (i.e. organoid). The inner layer is composed of dark stained cuboidal to

B

Figs. 26.13A and B: Pleomorphous low-grade adenocarcinoma (PLGA). (A) A PLGA arises from the minor salivary glands of hard palate. PLGA can have a diverse architectural arrangements, including papillary-cystic (top), cribriform and microcystic (bottom). Sq: overlying benign squamous mucosa. (B) The nuclei of PLGA have a characteristic uniform appearance with oval nuclei, pale-staining (vesicular) chromatin, and nuclear membrane condensation.

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columnar cells with basaloid nuclei and eosinophilic, finely granular cytoplasm. The outer layer contains single or multiple layers of polygonal cells with vesicular nuclei and clear cytoplasm. Other growth patterns, such as papillary-cystic and solid, can also be seen. The typical bilayered appearance may be lost in the solid areas, which usually contain exclusively clear cells (Figs. 26.14A to F). Oncocytic and apocrine EMCs are rare variants of EMCs, accounting for 8% of all EMC cases. High-grade transformation (“dedifferentiation”) is a rare occurrence in EMCs and has been reported in 22 patients in the literature. Contrary to the transformed AdCC, which usually show a ductal differentiation, the transformed high-grade carcinoma component of EMC preferably exhibits a myoepithelial phenotype with spindle, clear cell, or plasmacytoid appearance. Immunoprofile: The inner layer shows a ductal phenotype and is usually positive for cytokeratin, EMA, and S100. The outer layer, or solid clear cell component, demonstrates myoepithelial differentiation with positivity for at least one of the myoepithelial markers.

Clinical and Epidemiological Features Clear cell carcinoma typically affects patients in their 60s with an overall equal gender distribution. Most CCCs (70–80%) occur in the oral cavity with a presumed minor salivary gland origin; the most common sites are palate, tongue base, and mobile tongue. Rare cases arising from major salivary glands, nasopharynx, or larynx have also been reported.

Pathological Findings •

•

Prognosis and Prognostic Factors Epithelial-myoepithelial carcinoma is considered to be a low-risk malignancy with a five-year overall survival rate of 80–94%, about 40% risk of local recurrence, and 14– 20% risk of metastasis to regional lymph nodes or distant sites. Adverse prognostic factors, in addition to stage, include positive surgical resection margin, minor salivary gland location, nuclear atypia in > 20% of the tumor, and high proliferative index. High-grade transformation, if present, is indicative of aggressive behavior with a drastically increased risk of metastases (50% risk to lymph nodes and 30% risk to distant organs).

Hyalinizing Clear Cell Carcinoma20,21 Synonyms Clear cell carcinoma, not otherwise specified

Definition Clear cell carcinoma is a malignant low-grade epithelial neoplasm composed of a monomorphous population of neoplastic cells with clear or eosinophilic cytoplasm in a hyalinized fibrous background. The majority of CCCs (82–92%) carry a unique molecular signature of t(12; 22) ATF1-EWSR1 fusion.

•

•

Macroscopic appearance: Clear cell carcinoma usually presents as an unencapsulated, poorly circumscribed, solid tumor with a white-tan cut surface. Tumor size ranges between 1.0 and 4.5 cm. Architecture: Microscopically, CCC is typically an infiltrative tumor with frequent perineural invasion. The neoplastic cells are arranged in single cells, nests, cords, or interconnecting trabeculae separated by collagenous stroma. At the central portion of the tumor, hyalinized basement membrane-like material can be seen surrounding or admixed within the cell nests, mimicking the cribriform growth pattern of AdCC (Figs. 26.15A to C). Cytological features: Despite the name, a predominance of cells with clear cytoplasm is only seen in a minority of cases. The tumor cells often have pale eosinophilic cytoplasm, monotonous small nuclei, and inconspicuous nucleoli. The mitotic activity is typically low (0-1/10 HPFs), and necrosis is usually absent. Special stains, immunoprofile, and molecular studies: The clear cytoplasm of the neoplastic cells contains PAS-positive and diastase-sensitive glycogen. Clear cell carcinoma is usually positive for high-molecularweight cytokeratin (HMWCK) 34E12 and p63, suggestive of squamous differentiation. Most cases are negative for myoepithelial markers. Reverse transcription-polymerase chain reaction and FISH study using a dual-color EWSR1 break-apart probe are useful tools to confirm the presence of t(12;22) fusion, which distinguishes CCC from other neoplasms with clear cell features.

Prognosis Clear cell carcinoma is a low-grade salivary gland malignancy with a good overall outcome. Only one case of disease-specific mortality is documented in the literature. The reported rate of local recurrence is 12–17%.

Chapter 26: Pathology of Salivary Gland Neoplasms

A

B

C

D

E

F

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Figs. 26.14A to F: Epithelial-myoepithelial carcinoma (EMC). (A and B) EMC is composed of bilayered duct-like structure that resemble normal salivary duct. Other less common architectures of EMCs include (C) papillary-cystic pattern, in which a bilayered epithelium overlying true papillae with fibrovascular core, and (D) solid pattern, which typically contains predominantly clear cells with myoepithelial differentiation. (E and F) The luminal layer is composed of dark stained cuboidal to columnar epithelial cells (e) with basaloid nuclei and eosinophilic cytoplasm. The basal layer contains a single layer of myoepithelial cells (m) with vesicular nuclei and clear cytoplasm. Mitoses (arrowheads) are present.

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A

B

C

Figs. 26.15A to C: Hyalinizing clear cell carcinoma. (A and B) Hyalinizing clear cell carcinoma is composed of nests, cords, and interconnecting trabeculae of neoplastic cells, separated by abundant hyalinized collagenous stroma (arrow heads). (C) The neoplastic cells contain ample clear to pale eosinophilic cytoplasm.

Basal Cell Adenocarcinoma22

Pathological Findings

Synonyms

•

Malignant basal cell adenoma, basal cell carcinoma, malignant basal cell tumor.

•

Definition Basal cell adenocarcinoma is the malignant counterpart of BCA that can be distinguished from BCA by invasion of local structures, perineural invasion, or lymphovascular invasion, and potential for metastases.

Clinical and Epidemiological Features More than 90% of basal cell adenocarcinomas occur in the parotid glands, especially the superficial lobe. The submandibular glands and minor salivary glands of the oral cavity are rarely affected.

Macroscopic appearance: Basal cell adenocarcinoma is a solid, tan to gray, unencapsulated mass with a well-circumscribed or variably infiltrative border. Architectural and cytological features: Basal cell adenocarcinoma resembles BCA architecturally and cytologically. The tumor is composed of solid, membranous, trabecular and tubular patterns of basaloid cells (as described in Section Basal Cell Adenoma; Figs. 26.16A to C). The degree of cytological atypia, the level of mitotic activity, and the presence of necrosis vary between cases. However, such features are neither diagnostic nor necessary for a diagnosis of malignancy. A malignant diagnosis is rendered solely based on invasion, including infiltration into parotid parenchyma or adjacent structures (e.g. dermis, skeletal muscle, and periglandular fat), and/or perineural or lymphovascular invasion.

Chapter 26: Pathology of Salivary Gland Neoplasms

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A

B

C

Figs. 26.16A to C: Basal cell adenocarcinoma. (A) A basal cell adenocarcinoma of the parotid gland shows invasion into the subcutaneous adipose tissue. (B) The neoplastic cells are arranged as tubules and trabeculae surrounded by hyalinized material, architecturally resembling basal cell adenoma. (C) Basal cell adenocarcinoma may demonstrate nuclear pleomorphism, vesicular chromatin pattern, inconspicuous nucleoli, and increased mitotic activity (arrow).

•

Immunoprofile of basal cell adenocarcinoma is similar to basal cell adenoma.

Prognosis Basal cell adenocarcinoma is considered to be a low-risk salivary gland malignancy that has a tendency to recur locally, but rarely metastasize.

Malignant Sebaceous Tumors: Sebaceous Carcinoma and Sebaceous Lymphadenocarcinoma Sebaceous carcinoma is malignant counterpart of sebaceous adenoma, composed of sebaceous cells of varying maturation, demonstrating pleomorphism, nuclear atypia and invasiveness. It represents < 1% of salivary gland tumors, and affects mostly adults in their third to seventh decade of life. The location of the tumor is similar to that of sebaceous adenoma with 90% of cases occurring in the

parotid glands. Histologically, the tumor is composed of sheets and nests of cells with abundant clear to eosinophilic cytoplasm and pleomorphic hyperchromatic nuclei (Figs. 26.17A to C). Squamous differentiation, basaloid differentiation, and necrosis are common in these tumors. The 5-year overall survival rate following complete excision is 62%. Sebaceous lymphadenocarcinoma is an extremely rare tumor, which refers to carcinoma arising in a sebaceous lymphadenoma (synonym: carcinoma ex sebaceous lymphadenoma). This tumor arises exclusively in the parotid glands and periparotid lymph nodes as sebaceous lymphadenoma. The carcinoma component ranges from sebaceous carcinoma to poorly differentiated carcinoma.

Cystadenocarcinoma Definition Cystadenocarcinoma is a group of rare malignant epithelial salivary gland tumors characterized by an infiltrative growth pattern and a predominantly cystic growth pattern,

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A

B

C

Figs. 26.17A to C: Sebaceous carcinoma. (A) A sebaceous carcinoma of the parotid gland (P) is an infiltrative tumor composed of sheets and large nests of neoplastic cells. (B and C) The neoplastic cells show definite sebaceous differentiation with lipid-rich vacuolated cytoplasm. Necrosis (N), mitoses (arrowhead), and squamous differentiation with eosinophilic cytoplasm and keratinization (arrow) are common.

frequently accompanied by intracystic papillary growth. By definition, cystadenocarcinoma lacks peripheral myoepithelial cells and diagnostic features of another type of cystic salivary gland malignancy.

Clinical and Epidemiological Features Cystadenocarcinoma is a rare tumor, accounting for 1.5 mm into the extracapsular tissue (Ca-ex-PA: Carcinoma ex pleomorphic adenoma).

Clinical and Epidemiological Features Carcinoma ex pleomorphic adenoma accounts for 3.6% of all salivary gland tumors, 12% of salivary gland malignancy, and 6.2% of all PAs. The incidence of Ca-exPA increases with a prolonged history of PA, from 1.5% at 5 years to 10% after 15 years. The typical clinical presentation is a mass that grows rapidly over months. Twenty percent of the patients report a history of long-standing or recurrent PAs. A third of the patients have symptoms suggestive of facial nerve involvement. Carcinoma ex pleomorphic adenoma affects predominantly the parotid glands (82%), followed by the submandibular glands (18%). Cases from the sublingual or minor salivary glands have been reported, but are exceedingly rare.

Pathological Findings •

•

•

Macroscopic appearance: The gross appearance of PA was described previously. The carcinoma component is usually infiltrative and firm, sometimes accompanied by necrosis and hemorrhage. Architectural and cytological features: By definition, Ca-ex-PA must have two components: the carcinoma and evidences of an antecedent or coexistent benign PA. The carcinoma component may show epithelial or myoepithelial differentiation. About 90% of the carcinomas are high grade. The most common types are adenocarcinoma not otherwise specified, SDC, and myoepithelial carcinoma. Other less common types that have been reported are AdCC, MEC, acinic cell carcinoma, EMC, basal cell carcinoma, carcinosarcoma, squamous cell carcinoma, and CCC. Invasiveness of Ca-ex-PA: Carcinoma ex pleomorphic adenoma can be divided into three categories based on the existence and extent of capsular invasion (Table 26.8 and Figs. 26.22A to D). About 30% of Ca-ex-PAs are noninvasive or minimally invasive. The rest (~70%) belong to invasive Ca-ex-PA.

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Prognosis Patients with Ca-ex-PAs have poor overall survival compared to those with most other salivary gland malignancies. The 5-year disease specific survival rate is about 37–44%. The risk of local recurrence is 55%, and distal metastases are reported in 42% of patients. The degree of capsular invasion predicts clinical outcome. The noninvasive or minimal invasive Ca-ex-PAs have a 5-year survival that exceeds 90% but also have an increased risk of local recurrence compared to those with benign PAs. The overall survival decreases drastically to < 20% in invasive or widely invasive Ca-ex-PAs. Additional adverse prognostic factors include high histological grade of the carcinoma component, high mitotic rate (≥ 5/10 HPFs) or atypical mitosis, vascular invasion, lymph node involvement, hematogenous metastasis, and completeness of surgical resection.

Carcinosarcoma Carcinosarcoma is a high-grade malignancy composed of a mixture of malignant epithelial (carcinomatous) and mesenchymal (sarcomatous) components. It is exceedingly rare with < 100 cases reported in the literature. Two thirds of the cases occur in the parotid glands, while the rest affect mostly the submandibular glands and palate. Carcinosarcoma may occur de novo or in association with a history of PA (so-called carcinosarcoma ex PA). The most common sarcomatous component is chondrosarcoma or osteosarcoma, while the most common carcinomatous component is adenocarcinoma not otherwise specified, or undifferentiated carcinoma (Figs. 26.23A to C). Other types of carcinoma, such as AdCC, EMC, and cystadenocarcinoma, have also been reported as the carcinomatous element of carcinosarcoma. Carcinosarcoma is a highly aggressive malignancy with an overall length of survival of 30 months after diagnosis, and a disease-specific mortality rate of 60%. Local recurrence, regional metastasis to lymph nodes, and distal metastasis to lungs, bone, and brain involving either or both components are common.

Metastasizing Pleomorphic Adenoma Metastasizing PA refers to regional or distal metastasis of a histologically benign PA. The entity is extremely rare, with < 50 cases reported in the literature. The metastatic PA resembles the primary tumor, containing the typical mixture of mesenchymal, epithelial, and myoepithelial

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A

B

C

D

Figs. 26.22A to D: Carcinoma ex pleomorphic adenoma (Ca-Ex-PA; malignant mixed tumor). (A) A high-grade myoepithelial carcinoma (MC) with plasmacytoid neoplastic cells of myoepithelial phenotype arises within a pleomorphic adenoma (PA). (B) The carcinoma component in this Ca-Ex-PA is a high-grade salivary duct carcinoma with pleomorphic bizarre nuclei and abundant eosinophilic cytoplasm. (C) Ca-Ex-PA in-situ: frankly malignant neoplastic cells with large nuclei and prominent nucleoli are centrally located and surrounded by an intact layer of benign myoepithelial cells (arrows). (D) The carcinoma component (salivary duct carcinoma—SDC) is confined within the pre-existing capsule of pleomorphic adenoma (arrowheads), which fulfills the criteria of an intracapsular Ca-Ex-PA.

elements of PA. The pathogenesis of metastasizing PA is unclear. It is postulated that the tumor gains vascular access through multiple recurrence or surgical manipulation. The treatment of choice is complete surgical resection of all metastatic foci. The reported mortality of this entity ranges from 20% to 40%.

Squamous Cell Carcinoma Definition Squamous cell carcinoma is a rare salivary gland malignancy composed of epithelial cells, of squamous differentiation, in the form of keratinization and/or intercellular

bridges. A diagnosis of primary squamous cell carcinoma of the salivary glands can only be made after excluding the possibility of metastatic disease or direct extension of carcinoma from an adjacent site, such as skin and mucosa. For this reason, primary squamous cell carcinoma can only be diagnosed in the major salivary glands (80% in parotid glands and 20% in submandibular glands) since squamous cell carcinoma involving the minor salivary glands cannot be distinguished from tumors of mucosal origin.

Clinical and Epidemiological Features Primary squamous cell carcinoma accounts for < 1% of salivary gland tumors. Prior radiation therapy to the head

Chapter 26: Pathology of Salivary Gland Neoplasms

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A

B

C

Figs. 26.23A to C: Carcinosarcoma. (A-C) A carcinosarcoma arises from the parotid gland. The carcinoma component is a high-grade adenocarcinoma, not otherwise specified, with neoplastic epithelial cells forming glands, small cords, and nests. The sarcoma component is an osteosarcoma, osteoblastic variant (Os). Hyperplastic osteoblast-like neoplastic cells lay down hypereosinophilic neoplastic bone matrix, forming lace-like woven bone.

and neck region has been reported as an associated risk factor with a latent period of 10–30 years.

Pathological Findings Squamous cell carcinoma presents as an infiltrative solid mass, sometimes with focal necrosis. Histologically, it is composed of sheets or nests of neoplastic cells with intracellular keratin, keratin pearls and intercellular bridges, accompanied by a desmoplastic stromal reaction, which is a fibroblastic and inflammatory reaction of the stroma to the invasive tumor (Figs. 26.24A and B). Perineural invasion is common. Immunophenotypically, squamous cell carcinoma is positive for p63 and high-molecularweight keratin CK5/6 and 34E12.

Prognosis Primary squamous cell carcinoma of the salivary glands is considered to be a high-grade aggressive malignancy,

with a 5-year disease specific mortality rate of 75%, a local-regional recurrence rate of 50%, and an incidence of distal metastasis of 25%. In addition to stage and facial paralysis, the reported adverse prognostic factors include the presence of fixation, ulceration, and older age.

Small Cell Carcinoma31,32 Definition Small cell carcinoma of the salivary gland is a salivary malignancy composed of small anaplastic cells with epithelial and neuroendocrine differentiation.

Clinical and Epidemiological Features Salivary gland small cell carcinomas are rare, constituting < 1% of all salivary gland tumors and 2% of all salivary gland malignancies. Eighty percent of cases occur in the parotid glands, while the rest involve submandibular and

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A

B

Figs. 26.24A and B: Squamous cell carcinoma. (A and B) A keratinizing squamous cell carcinoma involves the parotid gland (P). The neoplastic cells show squamous differentiation with keratinization and keratin pearls (K) and intercellular bridges (arrowhead).

minor salivary glands. They usually present as a rapid growing mass, occurring within months, with frequent facial nerve and cervical lymph node involvement.

Approximately half of the patients develop local recurrence and metastasis. Tumor size appears to be a prognostic factor. Tumors > 3–4 cm are associated with increased incidence of local failure and reduced survival.

Pathological Findings •

•

•

Macroscopic appearance: Small cell carcinoma usually presents as a white firm mass with an infiltrative border, often with invasion into adjacent salivary glands or soft tissue. Architecture and cytology: Small cell carcinoma is comprised of sheets, or nests, of undifferentiated neoplastic cells with round, oval to spindle nuclei, fine disperse chromatin, absent or inconspicuous nucleoli, and scanty cytoplasm. The size of the nuclei is less than two to three times the diameter of normal small lymphocytes. Nuclear molding and crush artifact are frequently present in this tumor (Figs. 26.25A to C). Mitotic figures are numerous, typically over 10 per 10 high power fields. Immunoprofile: Small cell carcinoma is usually positive for pan-cytokeratin and LMWCK with a characteristic paranuclear dot-like staining pattern. At least one of the neuroendocrine markers (e.g. synaptophysin, chromogranin, or CD56) is positive in neoplastic cells. A certain percentage of small cell carcinomas also show positivity for CK7, CK20, NSE, neurofilament, and CD57.

Prognosis Small cell carcinoma has a poor overall prognosis with a 5-year survival rate ranging from 13% to 46%.

Large Cell Carcinoma Synonym Large cell undifferentiated carcinoma

Clinical and Epidemiological Features Large cell carcinoma is an exceptionally rare, high-grade salivary gland malignancy, comprising < 1% of malignant salivary gland tumors. The parotid gland is the most commonly affected site, but the submandibular glands and minor salivary glands can also been affected.

Pathological Findings Macroscopically, LCC presents as an infiltrative solid mass with frequent necrosis and hemorrhage. Histologically, LCC is composed of large neoplastic cells with abundant cytoplasm, bizarre pleomorphic nuclei, and prominent nucleoli (Figs. 26.26A and B). Tumor giant cells can be present. Necrosis, brisk mitoses and atypical mitoses, perineural invasion, and vascular permeation are common. The neoplastic cells are arranged as trabeculae, sheets, or dyscohesive single cells. Large cell carcinomas are carcinoma with the neoplastic cells positive for cytokeratins and EMA. A certain percentage of LCCs show neuroendocrine differentiation with expression of synaptophysin, chromogranin, or CD56.

Chapter 26: Pathology of Salivary Gland Neoplasms

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Figs. 26.25A to C: Small cell carcinoma. (A) A small cell carcinoma of the parotid gland demonstrates an infiltrative growth pattern. (B) The tumor is composed of solid sheets or large nests of dyscohesive neoplastic cells with spindle to oval nuclei and scanty cytoplasm. (C) The nuclei of small cell carcinoma typically contain vesicular “salt and pepper” chromatin and indistinct nucleoli. Nuclear molding (black arrows), in which the adjacent nuclei take the conformity of each other, is a phenomenon commonly seen in small cell carcinoma. Mitotic figures (black arrowheads) are frequent findings in small cell carcinoma.

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B

Figs. 26.26A and B: Large cell carcinoma. (A) A large cell undifferentiated carcinoma of the parotid gland (P) is present as an infiltrative mass (P). (B) The neoplastic cells have abundant eosinophilic cytoplasm, large oval to irregular nuclei, coarse chromatin, conspicuous nucleoli, and no definite differentiation. An atypical multipolar mitosis is also present (arrowhead).

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Head and Neck Surgery In situ hybridization for EBV-encoded RNA is usually strongly and diffusely positive in the neoplastic cells of endemic cases.

Prognosis Large cell carcinomas are aggressive malignancy with a 5-year overall survival rate of 54%. Local recurrence and metastasis are reported in 50% of LCCs, with hematogenous spread being more common than lymph node metastasis.

Lymphoepithelial Carcinoma Definition Lymphoepithelial carcinoma (LEC) is a large cell undifferentiated carcinoma accompanied by a prominent nonneoplastic lymphoplasmacytic infiltrate, morphologically resembling nasopharyngeal undifferentiated carcinoma.

Clinical and Epidemiological Features Lymphoepithelial carcinomas of the salivary glands are rare, representing < 1% of all salivary gland tumors. Lymphoepithelial carcinomas show a unique ethnic and demographic distribution, similar to that of nasopharyngeal undifferentiated carcinoma, affecting southeastern Chinese, Japanese, and Inuits in the Arctic regions. Nearly all tumors in patients from the endemic regions show an association to Epstein–Barr virus (EBV), while LECs from nonendemic regions typically lacks EBV. Eighty percent of the tumors affect parotid glands, while the rest occur in the submandibular glands or rarely minor salivary glands.

Pathological Findings •

•

•

Macroscopic appearance: Lymphoepithelial carcinomas are present as solid masses that can be well-circumscribed or infiltrative, fish-fleshy to firm. Architectural and cytologic features: The neoplastic cells have an indistinct cell border, marked nuclear pleomorphism, vesicular nuclei, prominent nucleoli, and brisk mitotic activity. They form infiltrative syncytial sheets or islands separated by a prominent lymphoid stroma with or without germinal center formation (Figs. 26.27A to D). Focal squamous differentiation in the form of intercellular bridges and intracytoplasmic keratin may be seen. Immunoprofiles and molecular studies: The neoplastic cells are positive for pan-cytokeratin and EMA.

Prognosis Lymphoepithelial carcinomas are typically treated with a multimodality approach combining surgical resection and radiation therapy. The reported 5-year overall survival is 75–85%.

Sialoblastoma Definition Sialoblastoma is a rare congenital or neonatal low-grade salivary gland malignancy that recapitulates the primitive salivary gland development.

Clinical and Epidemiological Features Sialoblastoma usually affects major salivary glands (75% in parotid glands and 25% in submandibular glands). It typically presents at or shortly after birth, but may also occasionally occur in children < 2 years of age.

Pathological Findings • •

Macroscopic appearance: Sialoblastoma is a partially circumscribed, nodular to multilobulated solid mass. Architectural and cytological features: Sialoblastoma is composed of primitive basaloid epithelial cells with scanty cytoplasm, bland monotonous round to oval nuclei, fine chromatin, and small nucleoli. The cells forms solid organoid nests, sometimes with peripheral palisading. Myoepithelial, ductal, squamous, acinic, and sebaceous differentiation may be seen. Increased mitotic activity, necrosis, and nuclear pleomorphism are present in a small percentage of cases.

Prognosis and Prognostic Factors Surgical resection is the treatment of choice and is curative in the majority of cases. Local recurrence occurs in 22% of cases, and the risk of lymph node metastases is about 9%.

Chapter 26: Pathology of Salivary Gland Neoplasms

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D

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Figs. 26.27A to D: Lymphoepithelial carcinoma. (A and B) Lymphoepithelial carcinoma is composed of an intimate admixture of two components: a prominent nonneoplastic lymphoid stroma (L); and a high-grade carcinoma (C) with indistinct cell border, marked nuclear pleomorphism, vesicular nuclei, prominent nucleoli, and brisk mitotic activity (arrowheads). (C) Immunohistochemistry for pancytokeratin AE1/AE3 highlights the nest of carcinoma in brown, while the background lymphoid tissue does not stain showing only blue counterstain. (D) In situ hybridization for EBV (EBER) is strongly and diffusely positive in lymphoepithelial carcinoma (blue color).

Mammary Analog Secretory Carcinoma33–35 Definition Mammary analog secretory carcinoma (MASC) is a malignant duct-derived salivary neoplasm, bearing strong morphological similarities to breast secretory carcinoma and a characteristic t(12; 15) ETV6-NTRK3 translocation.

Clinical and Epidemiological Features This rare entity was first described in 2010; the exact incidence is unclear as < 100 cases are reported in the

literature. The average age of presentation is 46 years (range 21–75) with a slight male predominance (M:F = 1.4:1). The majority of cases (approximately 70%) occur in parotid glands, but cases from minor salivary glands have also been reported.

Pathological Findings •

•

Macroscopic appearance: Mammary analog secretory carcinoma is a well-circumscribed but unencapsulated, white to tan, rubbery tumor. Architecture: Mammary analog secretory carcinoma usually has a lobulated growth pattern separated by fibrous septae. The neoplastic cells are arranged in solid sheets, microcysts or tubules with prominent

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Head and Neck Surgery

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Figs. 26.28A to D: Mammary analog secretory carcinoma (MASC). (A) An MASC of the parotid gland is present as a well circumscribed, partially encapsulated mass with a lobulated growth pattern. (B) The neoplastic cells are arranged in microcystic (bottom left) and macrocystic-papillary architectures (right). (C) The neoplastic cells have vacuolated cytoplasm, monotonous vesicular nuclei and inconspicuous nucleoli. (D) PAS-diastase stain highlights the foamy cystic content in magenta color.

•

•

bubbly secretion within the cystic space. Less commonly, a solid or macrocystic pattern can be seen (Figs. 26.28A to D). Cytological features: The neoplastic cells have vacuolated cytoplasm, monotonous vesicular nuclei, and inconspicuous nucleoli. Mitotic index is usually low. Special stains, immunoprofile, and molecular studies: The foamy cystic content is positive for PAS, PAS-D, mucicarmine, and mammaglobin. Neoplastic cells are typically positive for LMWCK, S100, as well as markers that are commonly expressed in breast neoplasia, e.g. mammaglobin and GCDFP-15. The signature t(12,15) translocation can be confirmed by FISH using dual-color ETV6 break-apart probe.

Prognosis Twenty-two percent of the patients have lymph node metastasis at the time of presentation. Up to 5% of MASCs develop hematogenous metastases. The reported diseasefree survival following complete surgical resection is 92 months. To date, no prognostic factors have been identified.

REFERENCES 1. Barnes L, Eveson JW, Reichart P, et al. World Health Organization classification of tumours: pathology and genetics of head and neck tumours, 3rd edition. Switzerland: International Agency for Research on Cancer (IARC); 2005;211-84.

Chapter 26: Pathology of Salivary Gland Neoplasms 2. Edge SB, Byrd DR, Compton CC, et al. AJCC Cancer Staging Manual, 7th edition. New York: Springer; 2009. 3. Seethala RR. Histologic grading and prognostic biomarkers in salivary gland carcinomas. Adv Anat Pathol. 2011;18:29-45. 4. Nagao T. “Dedifferentiation” and high-grade transformation in salivary gland carcinomas. Head Neck Pathol. 2013;7 (Suppl 1):S37-S47. 5. Weinreb I. Translocation-associated salivary gland tumors: a review and update. Adv Anat Pathol. 2013;20:367-77. 6. Matsuyama A, Hisaoka M, Nagao Y, et al. Aberrant PLAG1 expression in pleomorphic adenomas of the salivary gland: a molecular genetic and immunohistochemical study. Virchows Arch. 2011;458:583-92. 7. McHugh JB, Visscher DW, Barnes EL. Update on selected salivary gland neoplasms. Arch Pathol Lab Med. 2009;133: 1763-74. 8. Iwai T, Baba J, Murata S, et al. Warthin tumor arising from the minor salivary gland. J Craniofac Surg. 2012;23:e374-6. 9. Neskey DM, Klein JD, Hicks S, et al. Prognostic factors associated with decreased survival in patients with acinic cell carcinoma. JAMA Otolaryngol Head Neck Surg. 2013; 139:1195-1202 10. McHugh CH, Roberts DB, El-Naggar AK, et al. Prognostic factors in mucoepidermoid carcinoma of the salivary glands. Cancer. 2012;118:3928-36. 11. Bell D, El-Naggar AK. Molecular heterogeneity in mucoepidermoid carcinoma: conceptual and practical implications. Head Neck Pathol. 2013;7:23-7. 12. Chiosea SI, Dacic S, Nikiforova MN, et al. Prospective testing of mucoepidermoid carcinoma for the MAML2 translocation: clinical implications. Laryngoscope. 2012;122:1690-94. 13. Seethala RR, Dacic S, Cieply K, et al. A reappraisal of the MECT1/MAML2 translocation in salivary mucoepidermoid carcinomas. Am J Surg Pathol. 2010;34:1106-21. 14. Brandwein MS, Ferlito A, Bradley PJ, et al. Diagnosis and classification of salivary neoplasms: pathologic challenges and relevance to clinical outcomes. Acta Otolaryngol. 2002;122:758-64. 15. Goode RK, Auclair PL, Ellis GL. Mucoepidermoid carcinoma of the major salivary glands: clinical and histopathologic analysis of 234 cases with evaluation of grading criteria. Cancer. 1998;82:1217-24. 16. Perzin KH, Gullane P, Clairmont AC. Adenoid cystic carcinomas arising in salivary glands: a correlation of histologic features and clinical course. Cancer. 1978;42:265-82. 17. Szanto PA, Luna MA, Tortoledo ME, et al. Histologic grading of adenoid cystic carcinoma of the salivary glands. Cancer. 1984;54:1062-9. 18. Paleri V, Robinson M, Bradley P. Polymorphous lowgrade adenocarcinoma of the head and neck. Curr Opin Otolaryngol Head Neck Surg. 2008;16:163-9. 19. Seethala RR. Oncocytic and apocrine epithelial myoepithelial carcinoma: novel variants of a challenging tumor. Head Neck Pathol. 2013;7(Suppl 1):S77-S84. 20. Tanguay J, Weinreb I. What the EWSR1-ATF1 fusion has taught us about hyalinizing clear cell carcinoma. Head Neck Pathol. 2013;7:28-34.

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21. Weinreb I. Hyalinizing clear cell carcinoma of salivary gland: a review and update. Head Neck Pathol. 2013;7 (Suppl 1):S20-S29. 22. Ward BK, Seethala RR, Barnes EL, et al. Basal cell adenocarcinoma of a hard palate minor salivary gland: case report and review of the literature. Head Neck Oncol. 2009;1:41. 23. Kuo YJ, Weinreb I, Perez-Ordonez B. Low-grade salivary duct carcinoma or low-grade intraductal carcinoma? Review of the literature. Head Neck Pathol. 2013;7(Suppl 1):S59-S67. 24. Zhou CX, Shi DY, Ma DQ, et al. Primary oncocytic carcinoma of the salivary glands: a clinicopathologic and immunohistochemical study of 12 cases. Oral Oncol. 2010;46:773-8. 25. Guclu E, Oghan F, Ozturk O, et al. A rare malignancy of the parotid gland: oncocytic carcinoma. Eur Arch Otorhinolaryngol. 2005;262:567-9. 26. Simpson RH. Salivary duct carcinoma: new developments– morphological variants including pure in situ high grade lesions; proposed molecular classification. Head Neck Pathol. 2013;7(Suppl 1):S48-S58. 27. Savera AT, Sloman A, Huvos AG, et al. Myoepithelial carcinoma of the salivary glands: a clinicopathologic study of 25 patients. Am J Surg Pathol. 2000;24:761-74. 28. Antony J, Gopalan V, Smith RA, et al. Carcinoma ex pleomorphic adenoma: a comprehensive review of clinical, pathological and molecular data. Head Neck Pathol. 2012; 6:1-9. 29. Di Palma S. Carcinoma ex pleomorphic adenoma, with particular emphas2is on early lesions. Head Neck Pathol. 2013;7(Suppl 1):S68-S76. 30. Katabi N, Gomez D, Klimstra DS, et al. Prognostic factors of recurrence in salivary carcinoma ex pleomorphic adenoma, with emphasis on the carcinoma histologic subtype: a clinicopathologic study of 43 cases. Hum Pathol. 2010;41:927-34. 31. Servato JP, da Silva SJ, de Faria PR, et al. Small cell carcinoma of the salivary gland: a systematic literature review and two case reports. Int J Oral Maxillofac Surg. 2013;42:89-98. 32. Meacham R, Matrka L, Ozer E, et al. Neuroendocrine carcinoma of the head and neck: a 20-year case series. Ear Nose Throat J. 2012;91:E20-E24. 33. Chiosea SI, Griffith C, Assaad A, et al. Clinicopathological characterization of mammary analogue secretory carcinoma of salivary glands. Histopathology 2012;61:387-94. 34. Skalova A, Vanecek T, Sima R, et al. Mammary analogue secretory carcinoma of salivary glands, containing the ETV6-NTRK3 fusion gene: a hitherto undescribed salivary gland tumor entity. Am J Surg Pathol. 2010;34:599-608. 35. Skalova A. Mammary analogue secretory carcinoma of salivary gland origin: an update and expanded morphologic and immunohistochemical spectrum of recently described entity. Head Neck Pathol. 2013;7(Suppl 1):S30-S36.

Chapter 27: Salivary Gland Neoplasms

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CHAPTER

Salivary Gland Neoplasms

27

Yekaterina A Koshkareva, Robert L Ferris

INTRODUCTION

Salivary gland carcinomas comprise approximately 7% of epithelial cancers of the head and neck in the United States,1 with an annual incidence of between 0.3 and 3 cases per 100,000 population.2 European reports show a similar incidence.3 The exact incidence of benign salivary

neoplasms is less clear, as many of them escape clinical attention, resulting in great under-reporting. When all sali­ vary gland tumors are taken into account, the incidence ranges between 0.4 and 13.5 cases per 100,000 population.4 Salivary neoplasms originate from both major parotid and submandibular glands and minor salivary glands of the upper aerodigestive tract. The anatomic distribution of the salivary gland tumors is derived from several major studies and depicted in Figure 27.1.5-7 Over 75% of salivary gland tumors originate in the parotid gland, with submandibular and minor glands comprising the rest. Approximately 80% of parotid gland lesions are benign. This tendency is less likely in submandibular glands. Over half of the minor salivary gland lesions are malignant, especially outside of oral cavity (Fig. 27.2).5-13 Most salivary tumors are found in the parotid, and most parotid tumors are benign, making a benign parotid tumor the most commonly encountered salivary gland neoplasm.

Fig. 27.1: Anatomical distribution of salivary neoplasms (total of 8863 cases).

Fig. 27.2: Relative proportion of benign versus malignant salivary neoplasms at various anatomic sites.

A vast array of both benign and malignant neoplasms originate from the major and minor salivary glands. They are relatively rare, diverse in histologic makeup, and involve a variety of anatomic sites. The aim of this chapter is to provide a comprehensive description of etiology, incidence, pathology, and presentation of salivary tumors, as well as a summary of available treatment options and outcomes.

INCIDENCE

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Head and Neck Surgery

ETIOLOGY Little is known about the etiology of salivary gland neo­ plasms. Both hereditary and environmental risk factors have been proposed. The Inuit population has a higher incidence of salivary gland tumors.14 Exposure to ionizing radiation is the only well-established risk factor, based on the descriptive studies of atomic bomb explosion sur­ vivors in Hiroshima and individuals who received low-dose head and neck irradiation.15-20 Rubber and nickel industry workers might be at a higher risk of develop­ ment of salivary gland neoplasms.21 Tobacco smoking and Warthin’s tumor have been linked as well.22

HISTOLOGIC CLASSIFICATION The wide range of histologic diversity between the salivary gland tumors and even within a single tumor itself makes the pathologic diagnosis challenging. The original classification scheme described by Foote and Frazell has been refined, leading to the current World Health Organization (WHO) classification.23 The most recent WHO classification published in 2005 recognizes 13 benign and 24 malignant tumor subtypes.24 The WHO classification is summarized in Table 27.1.

Pleomorphic adenoma, or benign mixed tumor, is the most common salivary neoplasm. It is followed by papillary cystadenoma lymphomatosum, also known as Warthin’s tumor. Other less common benign neoplasms are oncocytoma, monomorphic adenoma, and the benign lymphoepithelial lesion of Godwin.5-7,25-27 Among malignant tumors, mucoepidermoid carci­ noma, adenoid cystic carcinoma, adenocarcinoma, and malignant mixed tumor are most frequently encountered. Acinic cell carcinoma and anaplastic carcinomas are less common.5-13,26-28 Cases of primary squamous carcinoma are extremely rare, so metastatic and squamous variants of mucoepidermoid carcinoma should be ruled out prior to making this diagnosis. It should be remembered that scalp and facial skin carcinomas and melanomas drain into intraparotid lymph nodes and comprise 70–80% of metastases to the parotid gland. The metastases from infraclavicular primary sites are not as common.29-31 The frequency of encountering a certain neoplasm depends on the anatomic subsite in question. As such, mucoepidermoid carcinoma is the most commonly encountered malignancy in the parotid gland, whereas adenoid cystic in the submandibular. In minor salivary glands both entities occur at approximately same rate,

Table 27.1: Histologic classification of salivary gland neoplasms

WHO classification system

Benign epithelial tumors

Malignant epithelial tumors

Pleomorphic adenoma Myoepithelioma Basal cell adenoma Warthin’s tumor Oncocytoma Canalicular adenoma Sebaceous adenoma Lymphadenoma Sebaceous Nonsebaceous Ductal papillomas Inverted ductal papilloma Intraductal papilloma Sialadenoma papilliferum Cystadenoma

Acinic cell carcinoma Mucoepidermoid carcinoma Adenoid cystic carcinoma Polymorphous low-grade adenocarcinoma Epithelial–myoepithelial carcinoma Clear cell carcinoma, not otherwise specified Basal cell adenocarcinoma Sebaceous carcinoma Sebaceous lymphadenocarcinoma Cystadenocarcinoma Low-grade cribriform cystadenocarcinoma Mucinous adenocarcinoma Oncocytic carcinoma Salivary duct carcinoma Adenocarcinoma, not otherwise specified Myoepithelial carcinoma Carcinoma ex pleomorphic adenoma Carcinosarcoma Metastasizing pleomorphic adenoma Squamous cell carcinoma Small cell carcinoma Large cell carcinoma Lymphoepithelial carcinoma Sialoblastoma

Chapter 27: Salivary Gland Neoplasms followed by adenocarcinoma. The relative incidence rates of various malignant tumors by salivary gland site, according to the National Cancer Institute Surveillance, Epidemiology and End Results (SEER) Program data from 1992 to 2006, are presented in Figures 27.3A to C. As mentioned, the authors caution the audience regarding possible misclassification of squamous cell carcinomas in the database, as the majority are either intraparotid metastases from other primary sites or misdiagnosed high-grade mucoepidermoid carcinomas.

BENIGN TUMORS Pleomorphic Adenoma

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There are multiple finger-like projections into the capsule and the tumor itself may bulge through the capsule. Although it is a benign tumor, surgical removal is indi­ca­ted due to its risk of malignant transformation and ten­dency to recur. Approximately 3% of parotid pleomor­phic adenomas recur after 5 years; this rate doubles at 10 years.33 Recurrences tend to occur in younger patients and are multifocal.34,35

Warthin’s Tumor (Papillary Cystadenoma Lymphomatosum, Adenolymphoma)

This neoplasm was formerly known as benign mixed tumor because it contains both epithelial/myoepithelial and mesenchymal or stromal components. It is the most common salivary gland tumor. Pleomorphic adenomas are encapsulated, but the capsule thickness varies and may be completely absent, especially in predominantly mucoid tumors and tumors arising in minor salivary glands.32

This tumor is also known as cystadenolymphoma, due to solid and cystic areas composed of epithelial and lym­ phoid elements. It is seen in the parotid almost exclu­ sively, due to its histologic origin within the intraparotid lymph nodes. Warthin’s tumor tends to occur in the tail of the parotid and affect older male patients and smokers, and has also been reported to be bilateral or multifocal in a small number of cases.36,37

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Figs. 27.3A to C: Overview of incidence of malignant tumors of (A) parotid (4265 cases), (B) submandibular glands (845 cases), and (C) sublingual glands (58 cases) according to the National Cancer Institute’s SEER database, between 1992 and 2006. *Authors admit to possible misclassification of squamous cell carcinomas in the database, as the majority are either intraparotid metastases from other primary sites or misdiagnosed high-grade mucoepidermoid carcinomas.

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Oncocytoma This is a rare benign encapsulated tumor made up of oncocytic cells (epithelial cells with eosinophilic granular cytoplasm and increased mitochondrial content). They are almost always solitary, slow growing, and usually found in the parotid.

Monomorphic Adenomas These tumors are of various types depending on the histological pattern and the cell of origin, with basal cell adenoma being the most common. They mostly occur in major salivary glands and affect males in their 1950–1970s.

MALIGNANT TUMORS Mucoepidermoid Carcinoma As noted above, mucoepidermoid carcinoma is the most common malignant neoplasm of the parotid gland, and the most prevalent salivary cancer overall. As the name implies, this multicystic neoplasm is made of mucous and epidermoid cells. These tumors are categorized as low-grade, intermediate-grade, and high-grade based on histologic features, such as percent of cystic component, neural invasion, necrosis, mitoses, and presence of ana­ plasia.38 Low-grade lesions with well-defined glandular elements metastasize infrequently and have an excel­lent overall prognosis. Alternatively, high-grade mucoepider­ moid carcinoma may be devoid of glandular structure. They are aggressive, with as high as 70% rate of regional metastases.39 Intermediate-grade lesions display histo­ logic features and clinical behavior between the spectrum described above. A 5-year disease-free interval suggests cure, as the natural history of mucoepidermoid carcinoma is less protracted than that of other types of salivary cancer.

Adenoid Cystic Carcinoma Adenoid cystic carcinomas comprise about 10% of the epithelial salivary tumors. As previously stated, it is the most common malignancy of the submandibular gland, and it occurs equally frequently with mucoepidermoid carcinoma in minor salivary sites (hard palate being most common). The most common presenting symptom is a slow growing mass, followed by pain due to predilection for nerve invasion and lack of encapsulation.40 This neo­ plasm is unique due to its protracted natural history, with poor long-term outcomes due to local recurrence.

Patients with adenoid cystic carcinoma require extensive follow-up, as disease-related deaths have been reported even 20 or more years after treatment.41,42 There is a ten­ dency for pulmonary metastases; however, prolonged survival has been observed in many of these patients.43 Adenoid cystic carcinoma can present in the following three histologic patterns: solid, tubular, and cribriform. Generally, predominantly tubular and cribriform tumors tend to be less aggressive than tumors with > 30% solid component.40 Favorable outcomes have been documen­ ted in patients with tubular histopathology tumors.44,45 However, the differential survival based on histologic grading is no longer seen at 10 years after the treatment, suggesting that the histologic pattern affects the diseasefree survival primarily and not the overall outcome.46-48

Adenocarcinoma, Not Otherwise Specified These tumors have ductal differentiation, but lack any other defining histomorphological details.49 High-grade lesions are associated with a much worse prognosis than low-grade lesions. There is a significant decline in survival from 5 to 10 years after treatment. This suggests that long-term follow-up is warranted for patients with this pathology.50,51

Salivary Duct Carcinoma Salivary duct carcinoma (SDC) is a rare salivary tumor and one of the most aggressive, with a poor prognosis. It tends to affect men (4:1), usually over 50 years of age. More than 80% of cases involve the parotid gland and present with a rapidly growing mass.52,53 Most patients present with stage III or IV disease, as over 50% have cervical lymph node involvement. One-third of patients suffer recurrence, 46% develop distant metastases, and 65% die of the disease, usually within 4 years of diagnosis.54

Carcinoma Ex Pleomorphic Adenoma This malignancy arises within a pleomorphic adenoma. The malignant component is usually a poorly differen­ tiated adenocarcinoma or an undifferentiated carcinoma. The ratio of benign to malignant components is variable. It is subdivided into noninvasive, minimally invasive, or invasive.55 Naturally, noninvasive variants behave more like a pleomorphic adenoma, whereas the invasive coun­ terpart is more aggressive, with recurrence rate of 23% and metastatic rate over 40%.56-57

Chapter 27: Salivary Gland Neoplasms

Acinic Cell Carcinoma This neoplasm affects all age groups and is rarely seen outside of the parotid gland. It is considered a low-grade malignancy and is known for its indolent course. However, higher grade variants exist (papillocystic). Despite its overall good prognosis, there is potential of local recur­ rence or distant metastases, especially in advanced-stage or improperly treated tumors.58-60

Grading of Malignant Salivary Gland Neoplasms As expected, abundance and diversity of advanced-stage malignancies already pose a significant diagnostic chal­ lenge. In hopes to simplify prognostic and management algorithms, it was proposed to grade salivary tumors based on their clinical behavior. It has been demonstra­ ted that histologic type is a predictor of local, regional, and distal control and outcome.61 However, the “outliers” do exist, proving that the system is not perfect. According to Seethala, the intrinsic flaw of the existing system is that due to an insufficient sample sizes, the grading is not standardized, making it less reproducible. Also, the tumors that have been perceived as “high risk” histori­ cally, such as SDC or squamous cell carcinoma, are not graded at all.62 To complicate the assignment of tumor grade fur­ ther, heterogeneity exists within the histologic groups themselves, and there are aggressive variants within the low-risk tumor groups as well as indolent variants among the high-risk tumors. For instance, for mucoepidermoid carcinoma, grading is the most important prognostic and therapeutic factor. Low-grade tumors have an overall survival of over 90% and can be managed purely surgi­ cally. For high-grade tumors, however, overall survival drops to below 50% and adjuvant radiation and neck dissections are required.62 The 2005 WHO classification of salivary gland malig­ nancies into low- and high-risk groups based on the histology and grading is presented in Table 27.2.63 In hopes of improving the existing system, Jouzdani et al. identified a separate intermediate-risk category and demons­ trated that it has its own behavioral pattern. According to the constructed Cox models, one step elevation from low- to intermediate- to high-risk level resulted in 2.6 increase in risk of nonspecific death and 2.3 increase in the risk of disease recurrence. Three-grade histological classification is presented in Table 27.3.64

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Table 27.2: Risk classification of salivary gland malignancies by the World Health Organization

Low risk

High risk

Acinic cell carcinoma

Sebaceous carcinoma and lymphadenocarcinoma

Low grade mucoepidermoid carcinoma* Epithelial–myoepithelial carcinoma Polymorphous low-grade adenocarcinoma Clear cell carcinoma Basal cell adenocarcinoma Low-grade salivary duct carcinoma (low-grade cribriform cystadenocarcinoma) Myoepithelial carcinoma Oncocytic carcinoma Carcinoma ex pleomorphic adenoma (intracapsular/ minimally invasive or with low-grade histology) Sialoblastoma Adenocarcinoma NOS and cystadenocarcinoma, low grade*

High grade mucoepidermoid carcinoma* Adenoid cystic carcinoma† Mucinous adenocarcinoma Squamous cell carcinoma Small cell carcinoma Large cell carcinoma Lymphoepithelial carcinoma Metastasizing pleomorphic adenoma Carcinoma ex pleomorphic adenoma (widely invasive or high-grade histology) Carcinosarcoma Adenocarcinoma and cystadenocarcinoma, NOS, high grade*

*Intermediate-grade classification is controversial for these tumors. For mucoepidermoid carcinoma, it depends on the grading algorithm used. For adenocarcinoma NOS (not otherwise specified), intermediate grade should be placed in the high-risk group based on the data available. †All adenoid cystic carcinomas are considered high-risk of local recurrence, but only solid adenoid cystic carcinoma (i.e. high grade) is high risk of nodal metastasis.

CLINICAL PRESENTATION AND EVALUATION History The most common presenting symptom of a neoplasm arising in major salivary glands is an asymptomatic swel­ ling, often for many months and even years. For minor salivary glands, the symptoms vary according to the anatomic location. Involvement of the paranasal sinuses results in facial pain and swelling. Nasal cavity process leads to nasal obstruction and epistaxis. Oral cavity minor salivary gland involvement causes painless swelling and ill-fitting dentures. Lastly, laryngeal site tumors tend

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Head and Neck Surgery

Table 27.3: Three-grade histological classification of salivary gland malignancies by Jouzdani et al.64

Low risk

Intermediate risk

High risk

Low grade mucoepidermoid

Intermediate grade mucoepidermoid

High grade mucoepidermoid

Acinic cell carcinoma

Tubular and cribriform adenoid cystic carcinoma

Undifferentiated, solid adenoid cystic carcinoma

Myoepithelial carcinoma Mucinous adenocarcinoma

Salivary duct carcinoma

Basal cell carcinoma Polymorphous low-grade adenocarcinoma

Adenocarcinoma NOS*

Low-grade cribriform cystadenocarcinoma

Oncocytic carcinoma

Mammary analogue secretory carcinoma

Carcinosarcoma

Cystadenocarcinoma

Large cell carcinoma

Clear cell carcinoma

Sebaceous carcinoma

Epithelial myoepithelial carcinoma

Lymphoepithelial carcinoma

Squamous cell carcinoma Small cell carcinoma

Dedifferentiated acinic cell carcinoma Dedifferentiated basal cell adenocarcinoma

(*NOS: Not otherwise specified). to cause hoarseness and sore throat. Periodicity of swel­ ling as well as the associated factors should be carefully assessed. For instance, episodic swelling of parotid or submandibular glands accompanied by pain and with a temporal relation to gustatory stimuli is suggestive of ductal obstruction. Pain is reported in 2.5–4% of patients with benign parotid tumors, and 10–29% of patients with parotid cancer, perhaps indicative of perineural invasion (PNI) by tumor cells.53,65-68 Pain is also reported in a few patients with benign submandibular neoplasms, and up to 50% of patients with malignant submandibular tumors.9,69,70

Physical Findings As with any tumor, it is of paramount importance to document the exact location and size of the lesion. This is particularly true of salivary neoplasms, since malignant lesions tend to be larger at presentation and involve minor salivary glands. As noted above, both benign and malignant salivary tumors present as a palpable mass. A few physical find­ ings raise the index of suspicion for a malignant process. Facial nerve involvement almost always indicates malig­ nancy. However, facial nerve weakness or paralysis is present in less than a quarter of cases.71-73 This finding is usually associated with a poor prognosis, and is most

commonly encountered in patients with adenoid cystic carcinoma, undifferentiated carcinoma, and squamous carcinoma.71,74,75 Cervical lymphadenopathy is another strong predic­ tor of malignancy. Cervical node involvement is evident at presentation in approximately 13–25% of patients with parotid cancer,53,67,72 14–33% of patients with submandi­ bular gland cancer,69,76,77 and 14% in patients with minor salivary gland cancer.13 Squamous carcinoma, highgrade mucoepidermoid carcinoma, high-grade adeno­ carcinoma, and malignant mixed tumor are more likely to present with regional lymph node metastases.66,67,69 Finally, tumor fixation to either skin or deep structures suggests malignant disease. In patients with untreated parotid cancer, fixation to the skin was noted in 9% at Memorial Sloan-Kettering Cancer Center (MSKCC), while fixation to deep tissues was noted in 13% at the MD Anderson Hospital and 17% at MSKCC.67,72

Diagnostic Imaging As a general guideline, imaging studies should only be obtained if the patient management will be affected, as comprehensive history and physical examination are usually sufficient to establish the diagnosis and extent of a tumor in the major salivary glands. If palpation of a major salivary gland lesion suggests gross extension

Chapter 27: Salivary Gland Neoplasms outside of the gland or fixation to adjacent structures, imaging is warranted to better delineate the extent of disease and identify other structures involved. This is particularly true of deep-lobe parotid tumors extending into parapharyngeal space. Most minor salivary gland tumors require radiographic evaluation to define the full extent of disease and involvement of adjacent structures. Several imaging modalities are available as adjuncts in evaluating a salivary gland tumor. In cases of suspected obstructive inflammatory disease in the submandibular gland, plain radiographs may identify a calculus in the gland itself or the Warthin’s duct. If expertise exists, ultra­ sonography is an appropriate initial step in evaluation of the major salivary glands, due to its noninvasiveness, low cost and ability to localize the tumor within the gland and identify cystic structures. Heterogeneous echogeni­ city, ill-defined margins, involvement of adjacent struc­ tures are signs of a malignant process.78-80 Computed tomography (CT) scan is the study of choice the evalua­ tion of cortical bone involvement. Magnetic resonance ima­ging (MRI) better visualizes soft tissue details of the minor salivary gland processes, deep parotid tumors and PNI. Irregular borders, extraglandular extension, and hypointensity on T2-weighed images are suggestive of malignancy.78,80,81 Additionally, MRI may also assist in differentiation between tumor and opacification of an obstructed sinus by fluid in paranasal sinuses location. Combined 18F-fluorodeoxyglucose positron emission tomography (FDG-PET)/CT has assumed an important role in head and neck oncology. However, its applica­ tions are limited in salivary gland neoplasms. It was shown to be superior to CT alone in delineating the tu­mor extent, nodal involvement and distal metastases.82-84 However, it is not particularly useful in distinguishing between malignant and benign entities, as pleomorphic adenomas and Warthin’s tumors demonstrate high glu­ cose uptake.85

Fine-Needle Aspiration Cytology Unlike the minor salivary glands, open incisional biopsy is not recommended for parotid and submandibular gla­ nds due to the risk of tumor seeding and injury to the facial nerve and its branches. Fine-needle aspiration cytology (FNAC) provides an opportunity to obtain a preliminary diagnosis of a major salivary gland lesion, which could be helpful in treatment guidance. Up to onethird of patients can be spared an unnecessary operation.86 Despite the extensive experience with FNAC and multi­ple

457

literature reports, there are no guidelines for the FNAC application. In a recent meta-analysis by Schmidt et al., the sensitivity and specificity for diagnosis of neoplasia were 71% and 100%, respectively. The sensiti-vity and specificity for diagnosis of malignancy were 76% and 97%, respectively. For differentiation between a benign and malignant salivary lesion, the positive and negative predictive values were 90% and 94%, respec­tively.87 In a systematic review by Colella et al., the concordance rates between cytologic and surgical pathology diag­no­ ses were 95.61% for benign and 79.95% for malignant salivary tumors. Furthermore, the cytologic diagnosis was histologically confirmed in only 63% of mucoepi­ dermoid carcinomas and 70% adenoid cystic carcino­ mas.88 In summary, FNAC is a safe, fast and welltolerated procedure, which is reliable in distinguishing between benign and malignant lesions, but is not as useful in differentiating between the various malignancies. Explanations for limitations of FNAC are the absolute necessity of an experienced cytopathologist and the lack of histologic architecture within the sample. Core needle biopsy (CNB) technique addresses some of the limitations of FNAC. It utilizes a larger needle (14–21 gauge) and provides a larger tissue sample, which eli­ minates the need for a cytopathologist to assess the specimen adequacy. Also, histologic architecture of the sample is preserved, facilitating the diagnosis. Lastly, CNB specimens are formalin-fixed and paraffin-embedded, which improves the immunohistochemical staining. According to the recent meta-analysis by Schmidt et al. reports, CNB sensitivity was 92% and specificity was 100%. CNB had a 1.2% sample inadequacy rate. When compared to FNAC, CNB had a higher diagnostic accu­ racy. The main complication reported was hematoma formation at a rate of 1.7%, none of which required treatment. In theory, CNB is more painful and there is a greater risk of facial nerve damage (no cases of perma­ nent CN VII weakness have been reported so far).89 Regardless of the biopsy technique employed, caution must always be taken in analyzing the results if the aspiration diagnosis is inconsistent with the clinical presentation.

Staging As with any malignancy, clinical staging of salivary cancer is essential to describe the extent, estimate prognosis, design management strategy and compare treatment results. The current AJCC staging systems are presented

458

Head and Neck Surgery

in Table 27.4.90 While there is no separate staging system for minor salivary cancer as of now, a study from Memo­ rial Hospital demonstrated that the staging system used for squamous carcinoma at various upper aerodigestive tract sites has similar prognostic value for minor salivary cancer arising in the same anatomic locations.91

Molecular Alterations in Salivary Malignancy The goal of molecular cancer analysis is to identify the diagnostic and predictive of behavior markers and inc­ rease the number of potential targets and therapies. The epidermal growth factor receptor (EGFR), a transmem­ brane receptor involved in signal transduction, has been

Table 27.4: AJCC staging systems for salivary gland cancer

Primary tumor (T) TX: Primary tumor cannot be assessed T0: No evidence of a primary tumor T1:Tumor ≤ 2 cm in greatest dimension without extraparenchymal extension T2:Tumor > 2 cm but ≤ 4 cm in greatest dimension without extraparenchymal extension but  4 cm and/or tumor having extraparenchymal extension T4a: Moderately advanced disease. Tumor invades skin, mandible, ear canal, and/or facial nerve T4b: Very advanced disease. Tumor invades skull base and/ or pterygoid plates and/or encases carotid artery Regional lymph nodes (LN) (N) NX: Regional LNs cannot be assessed N0: No regional LN involvement N1: Metastasis in single LN  3 cm but  3 cm but  6 cm N3: Metastasis in LN > 6 cm Distant metastasis (M) MX: Distant metastasis cannot be assessed M0: No distant metastasis M1: Distant metastasis Stage grouping I: T1/N0/M0 II: T2/N0/M0 III: T3/N0/M0 T1-3/N1/M0 IVA: T4a/N0-1/M0 T1-4a/N2/M0 IVB: T4b/any N/M0 Any T/N3/M0 IVC: Any T/any N/M1

asso­ciated with aggressive malignant behavior.92,93 EGFR is commonly expressed (> 50% frequency) in both muco­ epi­dermoid carcinoma and SDC, but less common in ade­noid cystic carcinoma.94-97 HER-2, another transmembrane glycoprotein rece­ptor involved in cell growth and differentiation, com­monly overexpressed in aggressive breast carcinoma. Over­ expres­ sion of HER-2 is more likely in salivary gland cancers of excretory duct origin, such as SDC and muco­ epidermoid carcinoma.95,98-100 It has been correlated with lymph node involvement and worse overall survival.93 HER-2 targeted treatment has not been shown to pro­vide significant clinical benefit.101 C-Kit is a proto-oncogene encoding a transmembrane receptor type tyrosine kinase involved in growth stimu­ lation and differentiation. Its expression, but not genetic mutations at exons 11 and 17, has been demonstrated in adenoid cystic carcinomas.102,103 Absence of C-Kit expres­ sion correlates with poor prognosis.92 A number of genetic alternations were found in salivary gland tumors in the last decade. Translocation t(11:19)(q21;p13) is found in mucoepidermoid carci­ noma. It is responsible for MECT1-MAML2 fusion gene, which disrupts the NOTCH pathway. Presence of this translocation is predictive of favorable prognosis.104 Translocation t(6;9)(q22-23;p23-24) is found in adenoid cystic carcinoma. Its fusion product between transcrip­ tion factors MYB and NFIB has been correlated with worse outcomes.105

OVERVIEW OF PAROTID AND SUBMANDIBULAR GLAND SURGERY AND COMPLICATIONS Surgical resection is the standard of care for both benign and malignant salivary tumors. The anatomic and tech­ nical details of the parotidectomy and submandibular gland dissection can be found elsewhere.

Complications of Parotidectomy The most feared and devastating complication of paro­ tidectomy is facial nerve injury. Some degree of facial weakness is seen in 13 to 100% of patients after a parotid surgery, depending on the underlying pathology, extent of operation, location of tumor and whether it is a re­vi­ sion.106 To establish the baseline presence and degree of weakness, facial function should be assessed once the

Chapter 27: Salivary Gland Neoplasms patient is extubated and able to follow commands. Most cases of facial nerve dysfunction are due to stretching, compression, entrapment, thermal and ischemic inju­ ries.107 The extent and duration of surgery, close contact of tumor with the facial nerve, histopathology and the size of the lesion were found to be predictive of post-parotidectomy facial nerve weakness by various groups.108,109 The rate of permanent paralysis is below 5%, with most recoveries occurring within 12 months.106,108,109 If facial nerve transection occurs intraoperatively, primary tension-free repair with fine permanent interrupted sutures under magnification is advocated.110 Greater auri­ cular or sural nerves can be used as the interposition grafts if tension-free primary repair is not attainable. Over 60% of patients with facial nerve grafting are able to achieve the best outcome, defined as House-Brachmann Grade III. Most Grade III and Grade IV recoveries occur within 6 months.111 According to the review by Eisele et al., majority of the otolaryngologists/head and neck surgeons in the United States and the United Kingdom report using nerve monitoring during parotid surgery. Many agree that it can be of benefit in a reoperative setting, radiated field, distorted anatomy, and minimally invasive procedures. However, there is no objective evidence, as the existing literature is scarce, heterogenous, and grossly underpowered to make any meaningful conclusions.107 Hemorrhage is another serious and fortunately rare complication. Most instances are a result of suboptimal intraoperative hemostasis and usually manifest within the first 24 hours.112 Anticoagulation and antiplatelet agents tend to increase the risk of bleeding and should be dis­ continued prior to surgery. Should the hematoma deve­lop, prompt operative exploration and evacuation are war­ ranted. Frey syndrome (gustatory sweating) is a common post-parotidectomy condition. The pathophysiologic mechanism involves aberrant communication of parasym­ pathetic secretomotor fibers supplying parotid gland and sympathetic fibers supplying cutaneous sweat glands and blood vessels, which results in sweating and flush­ ing with salivation provoking stimuli. If tested with a starch iodine test, between 43% and 96% of patients will test positive. However, only 14% to 43% are of patients are symptomatic (on average within 5 months). Less than 10% of parotidectomy patients suffer from severe gusta­ tory sweating.113,114 The topic of prevention has been investigated extensively. Intraoperative preventive tech­ niques, such as superficial musculoaponeurotic system

459

(SMAS), superficial temporal artery fascial (STAF), and sternocleidomastoid (SCM) flaps and AlloDerm inter­ po­ sitional grafts, have been described.115-118 A recent meta-analysis by Curry et al. confirmed the benefit of intra­operative techniques aimed to prevent symptomatic Frey syndrome.119 Once the clinical presence of the synd­ rome is confirmed, it can be treated with topical anti­pers­ pirants or superficial Botulinum toxin A administration.120 The transected edge of the parotid gland may secrete saliva and collect under the skin (sialocele) or drain through the skin (fistula). As expected, the drainage increases with meals and mastication. The incidence of complication is between 4% and 14%.121,122 The condition is mostly self-limited and resolves with repeated aspi­ ration and compression dressings. Administration of oral anticholinergics may be considered to decrease the sali­ vary flow. In settings of conservative management failure, tympanic neurectomy, Botulinum toxin A injection, and completion parotidectomy should be considered.123 The excision of parotid gland leaves a depression in the surgical bed, anterior to the ear and over the mandi­ble angle. This cosmetic alteration is rather a conseque­nce, not a complication of parotidectomy, and it can be quite esthetically bothersome to the patient. A variety of flap (SMAS, STAF, SCM), graft (AlloDerm and dermofat) and lipofilling techniques have been shown to minimize the post-parotidectomy facial depression.115-118,124 In most situ­ ations, the defect smoothes out over several months. Hypoesthesia of the greater auricular nerve is another common consequence, not a complication, of paroti­ dectomy. The numbness around the ear lobule improves to various degree within 1 year of the operation. Preser­ vation of the posterior branches of the greater auricular nerve has been recommended for a faster and more complete recovery.125

Complications of Submandibular Gland Resection As with parotid surgery, most serious and devastating complication is nerve injury. Marginal mandibular branch of the facial nerve is the most commonly affected. The incidence of transient and permanent weakness is approximately 9% and 90%) being low grade lesions that exhibit an indolent course. Total laryngectomy is virtually always curable but a more conservative approach as suggested by the Mayo Clinic report appears more appropriate given the excellent survival rates,31,32 In their series, only 14% received total laryngectomy. Recurrence rates are higher in patients undergoing less than total laryngectomy (“complete external removal” associated with a 27% recurrence rate and “subtotal external removal” associated with a 67% recurrence rate); however, acceptable 5 year (90.1%) and 10 year survival (80.9%) rates can be achieved after salvage surgery.

Ewing’s Sarcoma

­

Chondrosarcoma of the Larynx

particle beam therapy or stereotactic photon treatment with or without intensity modulated RT. A number of small series have shown that a combination of surgical debulk­ ing and high dose precision RT results in durable local control in a large proportion of skull base chondrosarco­ mas (in excess of 80%) with modest late toxicity. The outcome of lesions < 25 mL in volume is particularly good, especially if adequate doses are administered with a combination of photons and protons to approximately 70 cobalt gray equivalent.33 Other authors have reported similar results in smaller series with either protons or fractionated stereotactic radiation therapy,34,35 and more recently carbon ions.36



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chemotherapy has a role.17 Postoperative RT should be considered in patients with positive margins.18 20 RT as single modality treatment is also capable of long term control of chondrosarcomas in regions not easily amenable to surgical resection such as the clival region. Ten year control rates between 70% and 80% have been reported using proton beam RT as single modality therapy.16,23 At the Princess Margaret Cancer Center, RT as primary treatment is offered to patients with unresectable disease or when resection would be associated with considerable morbidity. A large NCDB analysis reported that decreased survi­ val was associated with advanced stage, higher grade, and the myxoid or mesenchymal histological subtypes. In this series, the overall 5 year disease specific rates exceeded 80%. The beneficial outcomes are clearly rela­ ted to the fact that grade 1 (50%) and grade 2 (37%) were the predominant subtypes, which demonstrate superior survival outcomes (93.2%) compared with higher grade tumors (67.3%) (p = 0.0265).29

Chapter 30: Bone Sarcomas of the Head and Neck Pos­toperative RT should be offered to patients with posi­ tive margins after surgery. High-volume disease is an indication for combined treatment (surgery and RT), whereas small-volume disease is managed with RT as single-modality treatment unless disease is very limited and surgery can be accomplished with wide margins, thereby obviating the need for RT.

Metastatic Disease Treatment of metastatic bone disease is always pallia­ tive. In OS, the median survival postmetastasectomy for limited pulmonary metastases was 20 months, with 11% surviving 60 months in a series from Memorial Sloan Kettering Cancer Center.40 The Inter­national Registry of Lung Metastases reported on 5206 patients with pulmo­ nary metastases resection, 2173 of whom had bone or STS. Patients with single metastases and long diseasefree intervals were recognized as having better outcome.41 Advanced OS remains difficult to treat, and chemotherapy alone does not appear to be curative for inoperable metastatic disease. There have been no controlled studies designed to demonstrate the benefit of chemotherapy at recurrence in terms of adding to salvage rates. Also, unlike the case for many STS cases, many patients with OS will already have been treated with active agents.

REFERENCES 1. O’Sullivan B, Chung P, Euler C, et al. Soft tissue sarcoma. In: Gunderson LL, Tepper JE (eds). Clinical radiation oncology, 2nd edn. Philadelphia, PA: Churchill Livingston; 2007:1519-49. 2. Sagerman RH, Cassady JR, Tretter P, et al. Radiation induced neoplasia following external beam therapy for children with retinoblastoma. Am J Roentgenol Radium Ther Nucl Med. 1969;105:529-35. 3. Garrington GE, Scofield HH, Cornyn J, et al. Osteosarcoma of the jaws. Analysis of 56 cases. Cancer. 1967;20:377-91. 4. Koch BB, Karnell LH, Hoffman HT, et al. National cancer database report on chondrosarcoma of the head and neck. Head Neck. 2000;22:408-25. 5. Tachibana E, Saito K, Takahashi M, et al. Surgical treatment of a massive chondrosarcoma in the skull base associated with Maffucci’s syndrome: a case report. Surg Neurol. 2000;54:165-69, discussion 169-70. 6. O'Sullivan B, Irish J, Tsang R. Head and neck sarcomas and lymphomas. In: Functional preservation and quality of life in head and neck radiotherapy medical radiology. Berlin, Heidelberg: Springer; 2009:103-115. 7. Noria S, Davis A, Kandel R, et al. Residual disease following unplanned excision of soft tissue sarcoma of an extremity. J Bone Joint Surg. 1996;78:650-5.

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8. Davis AM, Kandel RA, Wunder JS, et al. The impact of residual disease on local recurrence in patients treated by initial unplanned resection for soft tissue sarcoma of the extremity. J Surg Oncol. 1997;66:81-7. 9. Brennan MF, Singer S, Maki RG, et al. Sarcomas of soft tissue and bone: soft tissue sarcoma. In: De Vita V, Hellman S, Rosenberg SA (eds). Cancer: principles and practice of oncology, 7th edn. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:1581-637. 10. Schajowicz F, Sissons HA, Sobin L. The World Health Orga­ nization’s histologic classification of bone tumors. A com­ men­tary on the second edition. Cancer. 1995;75:1208-14. 11. Cavazzana AO, Miser JS, Jefferson J, et al. Experimental evidence of neural origin of Ewing’s sarcoma of bone. Am J Pathol. 1987;127:508-18. 12. Womer RB. The cellular biology of bone tumours. Clin Orthop. 1991;262:12-21. 13. Sobin L, Wittekind C. TNM classification of malignant tumours, 6th edn. New York: Wiley-Liss; 2002. 14. Greene FL, Page D, Norrow M, et al. AJCC cancer staging manual, 6th edn. New York: Springer; 2002. 15. Oda D, Bavisotto LM, Schmidt RA, et al. Head and neck osteosarcoma at the University of Washington. Head Neck. 1997;19:513-23. 16. Kassir RR, Rassekh CH, Kinsella JB, et al. Osteosarcoma of the head and neck: meta-analysis of nonrandomized studies. Laryngoscope. 1997;107:56-61. 17. Smeele LE, Kostense PJ, van der Waal I, et al. Effect of che­ motherapy on survival of craniofacial osteosarcoma: a sys­ tematic review of 201 patients. J Clin Oncol. 1997;15:363-7. 18. Ha PK, Eisele DW, Frassica FJ, et al. Osteosarcoma of the head and neck: a review of the Johns Hopkins experience. Laryngoscope. 1999;109:964-9. 19. Smith RB, Apostolakis LW, Karnell LH, et al. National Cancer Data Base report on osteosarcoma of the head and neck. Cancer. 2003;98:1670-80. 20. Link MP, Goorin AM, Miser AW, et al. The effect of adju­ vant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med. 1986; 314:1600-6. 21. Souhami RL, Craft AW, Van der Eijken JW, et al. Randomised trial of two regimens of chemotherapy in operable osteosar­ coma: a study of the European Osteosarcoma Intergroup. Lancet. 1997;350:911-7. 22. Huvos AG, Rosen G, Marcove RC. Primary osteogenic sarcoma: pathologic aspects in 20 patients after treatment with chemotherapy en bloc resection, and prosthetic bone replacement. Arch Pathol Lab Med. 1977;101:14-8. 23. Coca-Pelaz A, Rodrigo JP, Triantafyllou A, et al. Chondro­ sarcomas of the head and neck. Eur Arch Otorhinolaryngol. 2014;271(10):2601-9. Epub Nov 10, 2013. 24. Pardo-Mindan FJ, Guillen FJ, Villas C, et al. A compara­ tive ultrastructural study of chondrosarcoma, chordoid sarcoma, and chordoma. Cancer. 1981;47:2611-9. 25. Kilpatrick SE, Inwards CY, Fletcher CD, et al. Myxoid chon­ drosarcoma (chordoid sarcoma) of bone: a report of two cases and review of the literature. Cancer. 1997;79:1903-10.

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Protontherapie D’Orsay experience. Int J Radiat Oncol Biol Phys. 2001;51:392 8. Debus J, Schulz Ertner D, Schad L, et al. Stereotactic fractionated radiotherapy for chordomas and chondro­ sarcomas of the skull base. Int J Radiat Oncol Biol Phys. 2000;47:591 6. Schulz Ertner D, Nikoghosyan A, Hof H, et al. Carbon ion radiotherapy of skull base chondrosarcomas. Int J Radiat Oncol Biol Phys. 2007;67:171 7. Whaley JT, Indelicato DJ, Morris CG, et al. Ewing tumors of the head and neck. Am J Clin Oncol. 2010;33(4):321 6. Zoubek A, Dockhorn Dworniczak B, Delattre O, et al. Does expression of different EWS chimeric transcripts define clinically distinct risk groups of Ewing tumor patients? J Clin Oncol. 1996;14:1245 51. Paulussen M, Ahrens S, Lehnert M, et al. Second malig­ nancies after Ewing tumor treatment in 690 patients from a cooperative German/Austrian/Dutch study. Ann Oncol. 2001;12:1619 30. Meyers PA, Heller G, Healey JH, et al. Osteogenic sarcoma with clinically detectable metastasis at initial presentation. J Clin Oncol. 1993;11:449 53. Friedel G, Pastorino U, Buyse M, et al. Resection of lung metastases: long term results and prognostic analysis based on 5206 cases–the International Registry of Lung Metastases. Zentralbl Chir. 1999;124:96 103. ­





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26. Mark RJ, Tran LM, Sercarz J, et al. Chondrosarcoma of the head and neck. The UCLA experience, 1955–1988. Am J Clin Oncol. 1993;16:232 7. 27. Harwood AR, Krajbich JI, Fornasier VL. Mesenchymal chondrosarcoma: a report of 17 cases. Clin Orthop. 1981; 158:144 8. 28. Harwood AR, Krajbich JI, Fornasier VL. Radiotherapy of chondrosarcoma of bone. Cancer. 1980;45:2769 77. 29. McNaney D, Lindberg RD, Ayala AG, et al. Fifteen year radiotherapy experience with chondrosarcoma of bone. Int J Radiat Oncol Biol Phys. 1982;8:187 90. 30. Krochak R, Harwood AR, Cummings BJ, et al. Results of radical radiation for chondrosarcoma of bone. Radiother Oncol. 1983;1:109 15. 31. Lewis JE, Olsen KD, Inwards CY. Cartilaginous tumors of the larynx: clinicopathologic review of 47 cases. Ann Otol Rhinol Laryngol. 1997;106:94 100. 32. Kozelsky TF, Bonner JA, Foote RL, et al. Laryngeal chon­ drosarcomas: the Mayo Clinic experience. J Surg Oncol. 1997;65:269 73. 33. Hug EB, Loredo LN, Slater JD, et al. Proton radiation therapy for chordomas and chondrosarcomas of the skull base. J Neurosurg. 1999;91:432 9. 34. Noel G, Habrand JL, Mammar H, et al. Combination of photon and proton radiation therapy for chordomas and chondrosarcomas of the skull base: the Centre de

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31

Overview of Head and Neck Lymphomas Shane A Gangatharan, Vishal Kukreti

INTRODUCTION Lymphomas represent a spectrum of disease derived from malignant lymphocytes. They are heterogeneous in presentation and natural history and thus management varies from observation to aggressive combined modality therapy. A common site of disease is the head and neck, and while curative options by surgery alone are rare, the otolaryngologist is often involved with initial presentation and obtaining tissue diagnosis. The head and neck may be involved as part of systemic disease involving multiple lymph nodes, which often becomes apparent before intrathoracic or intra-abdominal disease. Rarer forms of lymphoma are limited to specific extranodal sites in the head and neck. A recent registry study showed lymphoma accounts for 12.4% of head and neck tumors highlighting the importance of the otolaryngologist often involved in patient care at the time of diagnosis.1

CLASSIFICATION Classification of lymphoma by the WHO lists > 30 sub­ types (Table 31.1).2 General classification can be made on the basis of Hodgkin lymphoma (HL) and nonHodgkin lymphoma (NHL). HL is characterized by unique pathology. Most of the tumor consists of an inflammatory infiltrate; however, the clonal cells are B lymphocytes called Reed–Sternberg cells that are morphological abnormal and sparsely dispersed throughout (Fig. 31.1). There are different subtypes of HL based on the characteristics of these Reed-Sternberg cells dividing into classical and nodular lymphocyte-predominant Hodgkin lymphoma

(NLPHL). The appearance of the inflammatory infiltrate is further used to subclassify types of classical HL (nodular sclerosing, mixed-cellularity, lymphocyte-depleted, lym­ phocyte-rich). In contrast, NHL pathological specimens consist of sheets of monoclonal proliferations of lymphoid cells dis­rupting and invading the architecture of normal tissue. Morphology of these cells can vary from small and well-differentiated to large and blastoid. Morphological appearance, specific antigens on the cell surface, and chromo­somal changes in conjunction with clinical cor­ re­lation are used for subclassi­fication. NHL may be B lym­phocyte or T lymphocyte in origin with the former being more common.

CLINICAL FEATURES General Lymphomas commonly present due to symptoms asso­ ciated with lymphadenopathy such as masses or pain, or due to systemic “B-type” symptoms that are classified as weight loss (> 10% of body weight over 6 months), drenching nights sweats or unexplained fever. While classical nodal sites are commonly affected (Fig. 31.2), due to the highly systemic nature of lymphocytes, extra­ nodal sites may be affected and radiological appearances may mimic other nonhematological neoplasms. Where there is bone marrow involvement, presentations often include an abnormal complete blood count (CBC) with elevated white cell count and circulating lymphoma cells, or cytopenias due to reduced normal hematopoiesis. The clinical course is highly dependent on subtype.

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Head and Neck Surgery

Table 31.1: Major lymphoma subtypes

Mature B cell neoplasms

Mature T-cell and NK-cell neoplasms

Hodgkin lymphoma (HL)

Chronic lymphocytic leukemia/small lymphocytic lymphoma

T-cell prolymphocytic leukemia

Nodular sclerosis classical HL

B-cell prolymphocytic leukemia

T-cell large granular lymphocytic leukemia

Lymphocyte-rich classical HL

Splenic marginal zone lymphoma

Aggressive NK-cell leukemia

Mixed cellularity classical HL

Hairy cell leukemia

Systemic EBV positive T-cell lymphoproliferative disease of childhood

Lymphocyte-depleted classical HL

Lymphoplasmacytic lymphoma

Hydroa vacciniforme-like lymphoma

Nodular lymphocyte predominant HL

MALT lymphoma

Adult T-cell leukemia/lymphoma

Nodal marginal zone lymphoma

Extranodal NK/T-cell lymphoma, nasal type

Post-transplant lymphoproliferative disorders (PTLD)

Follicular lymphoma

Enteropathy-associated T-cell lymphoma

Early lesions

Primary cutaneous follicle center lymphoma

Hepatosplenic T-cell lymphoma

Polymorphic PTLD

Mantle cell lymphoma

Subcutaneous panniculitis-like T-cell lymphoma

Monomorphic PTLD

Diffuse large B-cell lymphoma

Mycosis fungoides

Classical Hodgkin lymphoma PTLD

Lymphomatoid granulomatosis

Sezary syndrome

Primary mediastinal large B-cell lymphoma

Primary cutaneous CD30 positive T-cell lymphoproliferative disorders

Precursor lymphoid neoplasms

Intravascular large B-cell lymphoma

Primary cutaneous gamma-delta T-cell lymphoma

B lymphoblastic leukemia/lymphoma

ALK positive large B-cell lymphoma

Peripheral T-cell lymphoma, not otherwise specified

T lymphoblastic leukemia/lymphoma

Plasmablastic lymphoma

Angioimmunoblastic T-cell lymphoma

Large B-cell lymphoma arising in HHV8 associated multicentric Castleman disease

Anaplastic large cell lymphoma, ALK positive

Primary effusion lymphoma

Anaplastic large cell lymphoma, ALK negative

Burkitt lymphoma B-cell lymphoma, unclassifiable with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma (including “double-hit” lymphoma) B-cell lymphoma, unclassifiable with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma “Grey-zone lymphoma” (EBV: Epstein-Barr virus; NK: Natural killer). Source: Adapted from Swerdlow et al.2

Chapter 31: Overview of Head and Neck Lymphomas

503

Fig. 31.1: Classical Hodgkin lymphoma histopathology. Hematoxylin and eosin (H&E) stain demonstrating large Reed-Sternberg cells (arrows) on a background of smaller inflammatory cells (eosinophils, lymphocytes, and histiocytes).

NHL Clinically, it is helpful to unify subtypes of lymphoma to classify NHL as indolent, aggressive, or highly aggressive, correlating with speed of tumor growth and cellular diffe­ rentiation. Incidence usually increases with age with the exception of the highly aggressive lymphomas—Burkitt lymphoma and acute lymphoblastic lymphoma.3

Indolent NHL

Fig. 31.2: Lymph node sites.

Indolent lymphomas are slow growing, developing over months to years. These may present as slow growing lymph nodes, or discovered incidentally with the findings of intrathoracic or intra-abdominal lymphadenopathy by body imaging. Indolent lymphoma is usually treatable; however, most cases are considered incurable and have a multiple relapsing course. If asymptomatic, therapy may not be required. The most common indolent lymphoma, follicular lymphoma (FL), has an incidence rate of 3.18 per 100000 person-years in the United States based on SEER data.3 It can involve any nodal area as well as bone marrow. Median time to first chemotherapy is 2.5 and 3 years.4 After initial therapy, median time to relapse is approximately 5 years.5 Prognosis is usually favorable with median overall survival (OS) at 10 years > 70%.6 The next common indolent lymphoma, marginal zone lym­ phoma (MZL), is divided into extranodal, nodal, and splenic by regions of involvement. Extranodal disease is the most common, known as mucosa-associated lym­phoid

tissue (MALT) as it often arises in mucosal surfaces where lymphocytes are not typically found such as the gastro­ intestinal tract, salivary glands, respiratory tract, ocular adnexa, and skin.7 Median OS at 5 years in these indolent lymphomas is > 85%.6 The exception to the concept of indolent lymphomas being incurable is that some loca­ lized indolent lymphomas (Stage I–II) may be cured with radiotherapy alone. Approximately, 50–70% of these patients will achieve long-term remission.8 The indolent disorders, small lymphocytic lymphoma (SLL) and chronic lymphocytic leukemia (CLL), represent the same histological disease. Together they have an incidence of 5.17 per 100000 person-years.3 Clinical pre­ sentations vary widely from asymptomatic disease to widespread lymphadenopathy including liver and spleen. Most cases involve the bone marrow in which the disease is termed as the lymphoproliferative disorder CLL. Where the peripheral blood lymphocyte count is 80% in patients < 40 years old17 with late relapses being uncommon. There is an endemic form of Burkitt lymphoma found in mala rial regions of Africa and Papa New Guinea occurring mainly in children in which the presentation is that of jaw or periorbital masses before rapidly disseminating.15 Other highly aggressive lymphoma includes acute lym phoblastic lymphoma that is the nodal presentation of acute lymphoblastic leukemia.  

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the disease involves nodal regions, it is termed the lym phoma SLL. It may be associated with autoimmune disease such as autoimmune hemolytic anemia and immune-mediated thrombocytopenia. OS still remains good though not as favorable as FL and MZL with median OS at 5 years 67–76%.9 Rarer indolent lymphomas include lymphoplasmacytic lymphoma and cutaneous T-cell lymphomas such as mycosis fungoides. Mantle cell lymphoma (MCL) was classically con sidered an indolent lymphoma by virtue of small lym phoma cells and slow growing nature; however, a large subset of this group presents with clinically aggressive disease requiring immediate and aggressive therapy. Similar to other indolent lymphomas presentations can vary from asymptomatic lymphocytosis to widespread lymphadenopathy with marrow involvement. There is a predilection for gastrointestinal involvement; thus, gastrointestinal symptoms in patients with MCL should be investigated with endoscopy and biopsy. The lymphoma cells share features common to CLL with the expression of B-cell antigens and CD5; thus, pathological specimens require immunohistochemical and cytogenetic studies to confirm the expression and mutation of cyclin D1, a regulatory protein of the cell cycle, specific to this disease. Duration of responses to chemotherapy is much shorter than that of other indolent lymphoma with median progression-free survival (PFS) of < 2 years.10 As a result, the strategy in younger patients is upfront intensive chemotherapy followed by autologous stem cell trans plant that demonstrates improved PFS of > 5 years and improved OS compared to chemotherapy alone.11 Longterm data is required to confirm if this therapy can result in long-term cure in a disease that was once considered incurable.



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Aggressive NHL

Special Cases of NHL

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Aggressive lymphomas develop over the course of weeks to months and always require therapy to avoid com plications of progression. Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of all lymphomas as well as all aggressive and all lymphomas with an inci dence of 7.14 per 100000 person-years in the United States.3 Any nodal area including the marrow can be involved and in one-third of cases extranodal areas are affected.12 Less commonly, the central nervous system (CNS) can be involved with either leptomeningeal disease or parenchymal brain lesions. Cure rates are highly dependent on stage and prognostic factors with median

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The recently defined category of B-cell lymphoma unclas sifiable with features intermediate between DLBCL and Burkitt lymphoma represents a heterogeneous group of lymphomas with morphological and genetic features that do not fulfill the diagnostic criteria for either DLBCL or Burkitt lymphoma. A frequent feature is the presence of the MYC gene translocation that is found in all cases of Burkitt lymphoma and 14% of DLBCL conferring worse outcomes. Prognosis of this group is variable, and of note

Chapter 31: Overview of Head and Neck Lymphomas the subgroup “double-hit” that contains mutation of MYC and the BCL2 gene has a dismal median survival of 4.5–18.5 months.18 While NHL can arise and spread from any nodal or extranodal tissue, there are certain subtypes that have a pro­pensity for specific anatomical locations (e.g. primary CNS lymphoma, primary mediastinal lymphoma) inclu­ ding the head and neck described in further detail below. Reasons for affinity to specific regions can some­times be explained in the case of chronic antigen stimu­lation by infection such as Helicobacter pylori in gastric lymphoma, and Chlamydia psittaci in the ocular adnexa; however, in most instances there is no known cause.7

HL Hodgkin lymphoma accounts for  50 or history of respiratory disease if receiving bleomycin

Lumbar puncture

Cerebrospinal fluid for cytology/flow cytometry

If neurological symptoms

Bloods

HIV serology

If risk factors for HIV

Imaging

(CT: Computed tomography; CBC: Complete blood count; LDH: Lactate dehydrogenase; ESR: Erythrocyte sedimentation rate; PET: Positron emission tomography; NHL: Non-Hodgkin lymphoma).

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Head and Neck Surgery

Dependent on chemotherapy regimen

- Febrile neutropenia

Fever > 38.3°C (or > 38°C on two occasions) in the setting of neutrophils < 0.5×109/L, or 80% aggressive NHL (DLBCL)

Parotid lymphoma

80% MALT, associated with Sjögren’s syndrome

Thyroid lymphoma

Aggressive NHL, associated with Hashimoto’s thyroiditis

Extranodal NK/T-cell lymphoma, nasal type

Aggressive, endemic to East Asia, Latin America resistant to chemotherapy alone

Laryngeal lymphoma

Rare, usually DLBCL

Ocular adnexal

Usually MALT, associated with Chlamydophila psittaci

Plasma cell neoplasm Plasmacytomas

> 80% isolated, or may be associated with multiple myeloma

Myeloid neoplasms

Occurs in setting of AML, or isolated with rapid progression

Myeloid sarcoma

(AML: Acute myeloid leukemia; DLBCL: Diffuse large B-cell lymphoma).

cytotoxic chemotherapy has demonstrated improved OS in many lymphomas.44,45 The risk of reactivation of hepatitis B is > 50% in patients receiving combined che­ motherapy and rituximab, and routine screening for hepatitis should be performed in all patients receiving this combination of therapy.

Radiotherapy Both normal and malignant hematopoietic cells are highly sensitive to the effect of ionizing radiation.46 Through volumetric planning, modern techniques allow the deli­ very of a homogenous radiation dose to tumor volume while limiting radiation to normal tissues. There is a role in indolent NHL to cure early stage disease or offer local control to symptomatic areas. In early stage, aggressive NHL and HL combined modality approach with chemo­ therapy followed by radiotherapy offers improved PFS, OS, and chance of cure. In advanced stage NHL and HL, adjuvant radiotherapy to bulky sites or areas of persistent disease may offer improved control and PFS. Toxicities are highly dependent on the location of the radiation field and organs or critical structures; thus, each case requires individual assessment prior to radiotherapy. A common acute toxicity associated with radiotherapy specifically to the head and neck region is mucositis.47

Surgery Due to residual microscopic disease, surgery alone for localized disease is often followed by relapse. Seeding from surgical procedures has not been documented. Debulking

of tumor masses as an adjunct to primary chemotherapy is unlikely to have any value; however, there have been rare reports of surgical debulking and chemotherapy achiev­ing disease control following failed initial chemo­ therapy.48 There may be a role for curative surgery alone in rare cases of indolent MALT lymphoma confined to the lungs, stomach, or spleen, however, no common head and neck areas. In pediatric populations, stage I NLPHL may be observed after complete excision, with chemotherapy reserved for relapse. This strategy may avoid chemothe­ rapy toxicities when the patient is younger.

SPECIFIC HEAD AND NECK SITES NHL or HL can occur in any nodal or extranodal region. There are specific subtypes of NHL that arise in primary extranodal tissue of the head and neck. In addition, there are also other hematological neoplasms that can occur in the head and neck including plasmacytomas and mye­ loid sarcoma (Table 31.5).

PRIMARY EXTRANODAL LYMPHOMAS Waldeyer’s Ring Half of extranodal lymphomas of the head and neck are located in Waldeyer’s ring. Most cases are aggressive NHL, particularly DLBCL (83%). The tonsils are the most common site of involvement with initial presentation being unilateral tonsil enlargement; however, 10–20% may have bilateral involvement.27 Nasopharynx is the next common area of involvement and tends to affect younger

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Head and Neck Surgery

Fig. 31.5: Noncontrast computed tomography (CT) scan of the neck with large right thyroid lymphoma (DLBCL, diffuse large B-cell lymphoma, on histopathology).

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One to five percent of thyroid cancers are lymphoma. Most are aggressive B-cell NHL51 (Fig. 31.5). There is a strong associated with Hashimoto’s thyroiditis found in 34–85% of cases. These may be localized to the thyroid gland only with as many as 50% being stage IE. Case series describe median 5 years OS of 62%.

Extranodal Nasal-Type Natural Killer/ T-Cell Lymphoma (ENKTL) This is an aggressive NHL where the pathological cell exhibits antigens common to T cells and another form of lymphocytes, natural killer (NK) cells.52 It is endemic to East Asia and Latin America and all cases are associated with EBV positivity. Nose and paranasal areas are involved in > 80% of cases; however, this can also occur in extra nasal locations such as the skin (Fig. 31.6). Histology demonstrates a destructive pattern of tumor cells with surrounding inflammatory cells and necrotic changes thus a differential diagnosis is Wegener’s granulomatosis. Though clinically aggressive, 70–80% are confined to stage I–II at diagnosis presenting initially with local symptoms ­

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MALT of the parotid is commonly associated with Sjögren’s syndrome and due to inflammation of salivary glands. Four to ten percent of Sjögren’s patients develop salivary gland lymphoma, 80% of which are MALT.50 Other lym phomas can originate from the parotid gland, these are often indolent lymphomas such as FL; however, 30% can be aggressive NHL and HL.50 Systemic spread is common and only a quarter will be localized with the parotid the only site of disease. Chemotherapy or combined chemo therapy and radiotherapy may be used in stage I–II disease. Outcomes are highly dependent on subclassification and stage with excellent disease-free survival and OS in stage I–II disease.

Thyroid

 

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Parotid

Fig. 31.6: Extranodal natural killer (NK)/T-cell lymphoma, nasal type – T2-weighted magnetic resonance imaging (MRI) scan postgadolinium contrast of the head showing invasion of the left nasofacial crease and erosion of the nasal septum.

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patients with median age of 40 years. Involvement of the base of tongue is rare. Staging of tumors of Waldeyer’s ring often demonstrates stage I–II disease that may be amenable to combined chemoradiotherapy. However, there is a predilection for lymphomas of Waldeyer’s ring to involve the gastrointestinal tract either at diagnosis or relapse in approximately 10%, thus gastrointestinal inves tigations should be considered as part of staging depending on symptoms.49 Prognosis in early stage disease is generally favorable with median 5-year OS 73% for aggressive lymphoma, 92% for indolent disease. 27

Chapter 31: Overview of Head and Neck Lymphomas

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Ocular Adnexa Eight to nineteen percent of investigated masses of the orbit and orbital adnexa are lymphoma.56,57 There are associations with C. psittaci infection causing chronic inflammation and antigen stimulation and as a result predisposing to lymphoproliferative disease. Most cases are MZL and limited to stage IE. As a result radiotherapy for local disease results in excellent long-term OS with 5 years OS of 90–100%.58

Sinonasal

Fig. 31.7: Sinonasal lymphoma—three-dimensional bone reconstruction demonstrating bone erosion secondary to tumor.

such as epistaxis and nasal obstruction. Unlike most NHL, ENKTL demonstrates high rates of chemotherapy resistance and radiotherapy followed by chemotherapy has been the mainstay of therapy for limited stage disease resulting in 5 years OS of 70–80%. Disease that spreads systemically, progresses rapidly, and is associated with poor outcome with systemic chemotherapy results in 5 years OS