Evidence in Head and Neck Cancer

HEAD AND
HEAD AND NECK CANCERS

An Imprint of Springer Publishing
NECK CANCERS
Evidence-Based Treatment
Athanassios Argiris, MD, PhD, FACP HEAD
AND NECK
Robert L. Ferris, MD, PhD, FACS
David I. Rosenthal, MD, FACR, FASTRO
Head and Neck Cancers: Evidence-Based Treatment presents a practical, state-of-the-art

resource for any clinical oncologist treating or managing patients with head and neck cancers,
CANCERS
including oropharyngeal cancer, cancer of the oral cavity, laryngeal cancer, nasopharyngeal
cancer, hypopharyngeal cancer, cancer of the sinuses and the skull base, salivary gland cancer,
and neck lymphadenopathy.
Section I of the book covers the most pertinent details on the epidemiology, biology,
diagnosis and staging of the disease including topics such as the genomic landscape of head
and neck squamous cell carcinoma and novel imaging modalities. Section II discusses the
evidence-based treatment modalities for conventional and novel chemotherapy regimens, the
evidence behind emerging radiation therapy techniques and the minimally invasive surgical
advances changing the landscape of care. The chapters in Section III are dedicated to Evidence-Based Treatment
site-specific management, including management guidelines, tables with FDA-approved
therapies and relevant ongoing clinical trials as well as instructive clinical cases with important
discussion on outcomes and follow-up care. Finally, Section IV focuses on recurrent and
metastatic disease and Section V provides the essentials on supportive care, including
managing the elderly, managing patients suffering from dysphagia and oral complications,
and must-know details of quality of life assessment and patient-reported outcomes.
Argiris • Ferris • Rosenthal

Emphasizing the practice-changing techniques and the latest evidence-based treatment
advances including targeted therapies, immunotherapy, transoral robotic surgery, and
radiation therapy precision, this comprehensive yet accessible textbook is indispensable for
any clinical oncologist of each discipline wanting a balanced and evidence-based reference
on managing patients with head and neck malignancies.
Key Features:
n Includes didactic clinical cases for each type of head and neck cancer
n Numerous tables highlight FDA-approved therapies and ongoing clinical trials
n rovides evidence-based recommendations for treating head and neck cancers at
P
each stage of the disease with conventional and novel treatment strategies Athanassios Argiris
n Covers strategies for managing acute and late complications to treatment
Includes access to the fully-searchable downloadable ebook
Robert L. Ferris
David I. Rosenthal
n
Recommended
Shelving Category:
Oncology
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HEAD
AND NECK
CANCERS
© Springer Publishing Company

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HEAD
AND NECK
CANCERS
Evidence-Based Treatment
Editors
Athanassios Argiris, MD, PhD, FACP

Professor, Department of Medical Oncology
Thomas Jefferson University
Philadelphia, Pennsylvania;
Adjunct Professor of Medicine
University of Texas Health Science Center at San Antonio
San Antonio, Texas;
Consultant Medical Oncologist
Hygeia Hospital
Athens, Greece

Director, UPMC Hillman Cancer Center
Hillman Professor of Oncology
Associate Vice-Chancellor for Cancer Research
Co-Director, Tumor Microenvironment Center
Professor of Otolaryngology, of Immunology, and of Radiation Oncology
University of Pittsburgh
Pittsburgh, Pennsylvania

Professor
Section Chief, Head and Neck Radiation Oncology
Director, Head and Neck Translational Research Department of Radiation Oncology
The University of Texas MD Anderson Cancer Center
Houston, Texas

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Library of Congress Cataloging-in-Publication Data
Names: Argiris, Athanassios, editor. | Ferris, Robert L., editor. |

Rosenthal, David I., editor.
Title: Head and neck cancers: evidence-based treatment / editors,
Athanassios Argiris, Robert L. Ferris, David I. Rosenthal.
Description: New York: Demos Medical Publishing/Springer Publishing Company,
[2018] | Includes bibliographical references and index.
Identifiers: LCCN 2018005800| ISBN 9780826137777 (alk. paper) | ISBN
9780826137784 (e-book)
Subjects: | MESH: Head and Neck Neoplasms—therapy | Head and Neck
Neoplasms—pathology
Classification: LCC RC280.H4 | NLM WE 707 | DDC 616.99/491—dc23
LC record available at https://lccn.loc.gov/2018005800
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18 19 20 21 22 / 5 4 3 2 1

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Contents
Contributors vii 7. Proton Therapy 109

Preface xiii Pierre Blanchard, G. Brandon Gunn, and
Share Head and Neck Cancers: Steven J. Frank
Evidence-Based Treatment 8. Transoral Robotic Surgery: Advances
and Applications 119
S E C TION I Meghan T. Turner, F. Christopher Holsinger,
and Robert L. Ferris
Epidemiology, Biology, Diagnosis,
and Staging 9. Induction Chemotherapy: Current and
Emerging Role in HNSCC 141
1. Head and Neck Cancer Glenn J. Hanna and Robert I. Haddad
Epidemiology 3 10. Immunotherapy for HNSCC: Rationale
Angela L. Mazul, Erich M. Sturgis, and Clinical Applications 161
Andrew F. Olshan, and Jose P. Zevallos Jennifer Moy, Jennifer M. Johnson,
2. Pathology of HNSCC 23 Jessica Moskovitz, Robert L. Ferris, and
Michelle D. Williams and Adel K. El-Naggar Athanassios Argiris
3. The Genomic Landscape of 11. Targeting the Human Epidermal

HNSCC 37 Receptor Family in HNSCC 191
Steffen Wagner, Jens P. Klussmann, and Emmanuel Seront, Sandra Schmitz, and
Ruud H. Brakenhoff Jean-Pascal Machiels
4. HPV-Related Head and Neck 12. Therapies Targeting VEGF/

Cancer Biology 53 Angiogenesis and Other Novel
Farhoud Faraji and Carole Fakhry Targets and Therapies in HNSCC 217
Sophie Stock-Martineau, Yanqun Dong,
5. Imaging of Head and Neck Cancers 77 Denis Soulières, and Thomas J. Galloway
Rathan M. Subramaniam
S E C TION II SEC TION III
Established and Emerging Site-Specific Management

Treatment Modalities
13. Oropharyngeal Cancer: HPV-Positive
6. Advances in Radiation Therapy Disease 237
Techniques for HNSCC: Image-Guided Christien A. Kluwe, Anthony J. Cmelak, and
RT Stereotactic, IMRT-VMAT, MRI-Linac Barbara A. Burtness
and Simulation 93
Jussi Sillanpaa, C. Jillian Tsai, and Nancy Y. Lee

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14. Non–HPV-Associated Oropharyngeal SEC TION IV

Cancer 253
Meghan T. Turner, Anirudh Saraswathula, and Recurrent or Metastatic Disease
F. Christopher Holsinger
15. Oral Cavity Cancer: Surgical 22. Locally Recurrent HNSCC: Salvage
Approaches and Postoperative Surgery, Reirradiation 403
Antoine Eskander, Sharon A. Spencer,
Treatment 271
Corey J. Langer, Takashi Maruo, Ryuichi Hayashi,
Antoine Eskander, Jacques Bernier, Lisa Licitra,
Sadamoto Zenda, and James W. Rocco
Paolo Bossi, and Theodoros N. Teknos
16. Nasopharyngeal Cancer 303 23. Recurrent or Metastatic HNSCC:

Wai Tong Ng, Oscar S. H. Chan, Henry C. K. Sze,
Systemic Therapy 423
Tomohiro Enokida, Susumu Okano, and
Ka On Lam, and Anne W. M. Lee
Makoto Tahara
17. Hypopharyngeal Cancer:
A Multidisciplinary Approach 321 SEC TION V
Moran Amit, Loren K. Mell, Cristina P. Rodriguez,
and Neil D. Gross Supportive Care and Special
Patient Groups
18. Laryngeal Cancer: Organ
Preservation Strategies 333
Arlene A. Forastiere, Jae Lee, Steven B. Chinn, 24. Oral Complications 445
Karim Boudadi, Avraham Eisbruch, Rajesh V. Lalla and Douglas E. Peterson
Randal S. Weber 25. Dysphagia in Patients With Head and
19. Malignancies of the Paranasal Sinuses Neck Cancer 457
and Skull Base 359 Katherine A. Hutcheson and Jan S. Lewin
Heather A. Osborn, Jong Chul Park, Nabil F. Saba, 26. Quality of Life Assessment and Patient-
Pierre Blanchard, and Derrick T. Lin Reported Outcomes in Head and
20. Evaluation and Treatment of Neck Cancer 479
Metastatic Lymphadenopathy From Minh Tam Truong and Lisa Ann Kachnic
an Unknown Primary 371 27. Management of Head and Neck
Shirin Attarian, Richard Blake Ross, Cancers in the Elderly 509
Shlomo A. Koyfman, and Missak Haigentz, Jr. Jessica L. Geiger and Julie E. Bauman
21. Salivary Gland Malignancies 385
Cristina P. Rodriguez, Jessica L. Geiger, Index 523
Jon Mallen-St. Clair, Patrick K. Ha, Sue S. Yom,
Adam S. Garden, and David J. Adelstein

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Contributors
David J. Adelstein, MD, Professor of Medicine, Cleveland Clinic Lerner College

of Medicine of Case Western Reserve University; Staff Physician, Department of
Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute,
Cleveland, Ohio
Moran Amit, MD PhD, Fellow, Department of Head and Neck Surgery, Division of
Surgery, The University of MD Anderson Cancer Center, Houston, Texas
Athanassios Argiris, MD, PhD, FACP, Professor, Department of Medical Oncology,

Thomas Jefferson University, Philadelphia, Pennsylvania; Adjunct Professor of
Medicine, University of Texas Health Science Center at San Antonio, San Antonio,
Texas; Consultant Medical Oncologist, Hygeia Hospital, Athens, Greece
Shirin Attarian, MD, Fellow, Division of Oncology, Department of Medicine,

Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, New York
Julie E. Bauman, MD, MPH, Professor of Medicine, Chief, Division of Hematology

and Oncology, Associate Director, Translational Research, University of Arizona
Cancer Center, Tuscon, Arizona
Jacques Bernier, MD, PhD, Department of Radiation Oncology, Oncology Institute

of Southern Switzerland, San Giovanni Hospital, Bellinzona, Switzerland
Pierre Blanchard, MD, PhD, Department of Radiation Oncology, The University of

Texas MD Anderson Cancer Center, Houston, Texas
Paolo Bossi, MD, Head and Neck Medical Oncology Unit, Fondazione IRCCS
Istituto Nazionale Tumori, Milan, Italy
Karim Boudadi, MD, Clinical Associate and Assistant Professor-Hematology/Medical

Oncology, Department of Oncology, Johns Hopkins University, Baltimore, Maryland
Ruud H. Brakenhoff, PhD, Professor of Head and Neck Cancer Genomics, Tumor
Biology Section, Department of Otolaryngology-Head and Neck Surgery, Cancer
Center Amsterdam, Amsterdam, the Netherlands
Barbara A. Burtness, MD, Professor of Medicine, Co-Director, Developmental

Therapeutics Research Program, Yale University School of Medicine and Yale Cancer
Center, New Haven, Connecticut

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Oscar S. H. Chan, FRCR, Honorary Associate Consultant, Department of Clinical

Oncology, Pamela Youde Nethersole Eastern Hospital, Hong Kong
Steven B. Chinn, MD, MPH, Assistant Professor Head and Neck Surgical Oncology,
Department of Otolaryngology-Head and Neck Surgery, Head and Neck Surgical
Oncology, Microvascular Reconstructive Surgery, University of Michigan, Ann
Arbor, Michigan
Anthony J. Cmelak, MD, Professor of Radiation Oncology, Senior Medical Director,

Radiation Oncology Satellites, Department of Radiation Oncology, Vanderbilt-
Ingram Cancer Center, Nashville, Tennessee
Yanqun Dong, MD, PhD, Radiation Oncology Resident, Department of Radiation

Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania
Avraham Eisbruch, MD, Professor of Radiation Oncology, Department of Radiation

Oncology, University of Michigan, Ann Arbor, Michigan
Adel K. El-Naggar, MD, PhD, Professor, Department of Pathology, Kenneth D. Muller

Professorship, The University of Texas MD Anderson Cancer Center, Houston, Texas
Tomohiro Enokida, MD, PhD, Department of Head and Neck Medical Oncology,
National Cancer Center Hospital East, Kashiwa, Chiba, Japan
Antoine Eskander, MD, ScM, FRCS(C), Assistant Professor, Department of

Otolaryngology—Head and Neck Surgery, University of Toronto, Sunnybrook Health
Sciences Centre and Odette Cancer Centre; Surgical Oncologist, Endocrine Surgery,
Michael Garron Hospital, Toronto, Ontario, Canada
Carole Fakhry, MD, MPH, Associate Professor, Department of Otolaryngology-Head

and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
Farhoud Faraji, PhD, Medical Student, MD/PhD Program, Saint Louis University
School of Medicine, St. Louis, Missouri
Robert L. Ferris, MD, PhD, FACS, Director, UPMC Hillman Cancer Center; Hillman
Professor of Oncology; Associate Vice-Chancellor for Cancer Research; Co-Director,
Tumor Microenvironment Center; Professor of Otolaryngology, of Immunology, and
of Radiation Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania
Arlene A. Forastiere, MD, Professor of Oncology, Department of Oncology, Johns

Hopkins University, Baltimore, Maryland
Steven J. Frank, MD, Professor, Department of Radiation Oncology, The University

of Texas MD Anderson Cancer Center, Houston, Texas
Thomas J. Galloway, MD, Associate Professor, Department of Radiation Oncology,

Fox Chase Cancer Center, Philadelphia, Pennsylvania
Adam S. Garden, MD, Professor, Department of Radiation Oncology, The University

of Texas MD Anderson Cancer Center, Houston, Texas
Jessica L. Geiger, MD, Assistant Professor of Medicine, Cleveland Clinic Lerner

College of Medicine of Case Western Reserve University; Associate Staff, Department
of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute,
Cleveland, Ohio

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Neil D. Gross, MD, Professor, Department of Head and Neck Surgery, Division of
Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
G. Brandon Gunn, MD, Associate Professor, Department of Radiation Oncology, The

University of Texas MD Anderson Cancer Center, Houston, Texas
Patrick K. Ha, Professor, Department of Otolaryngology, University of California San

Francisco, San Francisco, California
Robert I. Haddad, MD, Associate Professor of Medicine at Harvard Medical School,

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
Missak Haigentz, Jr., MD, Section Chief of Oncology, Morristown Medical Center,
Atlantic Health System, Morristown, New Jersey; Adjunct Clinical Professor of
Medicine (Oncology) and Otorhinolaryngology-Head & Neck Surgery, Albert
Einstein College of Medicine, Bronx, New York
Glenn J. Hanna, MD, Instructor of Medicine at Harvard Medical School, Department

of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
Ryuichi Hayashi, MD, Department of Head and Neck Surgery, National Cancer
Center Hospital East, Kashiwa, Chiba, Japan
F. Christopher Holsinger, MD, FACS, Professor and Chief, Division of Head and
Neck Surgery, Department of Otolaryngology-Head and Neck Surgery, Stanford
University Medical Center, Palo Alto, California
Katherine A. Hutcheson, PhD, Associate Professor, Department of Head and Neck

Surgery, Section of Speech Pathology and Audiology, The University of Texas MD
Anderson Cancer Center, Houston, Texas
Jennifer M. Johnson, MD, PhD, Assistant Professor, Department of Medical

Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania
Lisa Ann Kachnic, MD, FASTRO, Professor and Cornelius Vanderbilt Chair of
Radiation Oncology, Department of Radiation Oncology, Vanderbilt University
Medical Center, Nashville, Tennessee
Jens P. Klussmann, Dr. med., Professor and Chairman, Department of

Otorhinolaryngology, Head and Neck Surgery, University of Cologne, Cologne,
Germany
Christien A. Kluwe, MD, Radiation Oncology Resident, Department of Radiation

Oncology, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee
Shlomo A. Koyfman, MD, Radiation Oncologist, Department of Radiation Oncology,

Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
Rajesh V. Lalla, DDS, PhD, Associate Professor, Section of Oral Medicine; Associate
Dean for Research, University of Connecticut School of Dental Medicine, Farmington,
Connecticut
Ka On Lam, FRCR, Clinical Assistant Professor, Department of Clinical Oncology,

The University of Hong Kong, Hong Kong
Corey J. Langer, MD, FACP, Professor of Medicine at the Hospital of the University
of Pennsylvania, Department of Medicine, Division of Hematology Oncology, Penn
Medicine, Philadelphia, Pennsylvania

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Anne W. M. Lee, MD, Professor, Department of Clinical Oncology, The University of

Hong Kong and The University of Hong Kong-Shenzhen Hospital, Hong Kong
Jae Lee, MD, PhD, Clinical Resident, Department of Radiation Oncology, University
of Michigan, Ann Arbor, Michigan
Nancy Y. Lee, MD, Vice Chair, Department of Radiation Oncology; Service Chief,
Head and Neck Radiation Oncology; Director, Proton Therapy, Memorial Sloan
Kettering Cancer Center, New York, New York
Jan S. Lewin, PhD, Professor, Department of Head and Neck Surgery, Chief, Section
of Speech Pathology and Audiology, The University of Texas MD Anderson Cancer
Center, Houston, Texas
Lisa Licitra, MD, Head and Neck Medical Oncology Unit, Fondazione IRCCS Istituto
Nazionale Tumori, Milan, Italy
Derrick T. Lin, MD, FACS, Chief, Division of Head and Neck Oncology, Massachusetts
Eye and Ear Infirmary, Clinical Surgical Director, Center for Head and Neck Cancers,
Massachusetts General Hospital; Co-Director, Cranial Base Center, Massachusetts Eye
and Ear Infirmary/Massachusetts General Hospital; Daniel Miller Associate Professor of
Otolaryngology, Harvard Medical School, Boston, Massachusetts
Jean-Pascal Machiels, MD, PhD, Professor, Department of Medical Oncology and

Head and Neck Surgery, Institut Roi Albert II, Cliniques Universitaires Saint-Luc and
Institut de Recherche Clinique et Expérimentale, Université Catholique de Louvain,
Brussels, Belgium
Jon Mallen-St. Clair, MD, PhD, Attending Surgeon, Head and Neck Oncologic and
Microvascular Reconstructive Surgery, Cedars-Sinai Medical Group, Los Angeles,
California
Takashi Maruo, MD, PhD, Department of Head and Neck Surgery, National Cancer
Center Hospital East, Kashiwa, Chiba, Japan
Angela L. Mazul, PhD, MPH, Assistant Professor, Department of Otolaryngology/Head

and Neck Surgery, Washington University School of Medicine, St. Louis, Missouri
Loren K. Mell, MD, Chief, Head and Neck Malignancy Service; Associate Professor,
Department of Radiation Medicine and Applied Sciences, Moores Cancer Center,
University of California San Diego, La Jolla, California
Jessica Moskovitz, MD, Fellow, Department of Otolaryngology, University of

Pittsburgh, Pittsburgh, Pennsylvania
Jennifer Moy, MD, Physician, Department of Otolaryngology, University of

Pittsburgh, Pittsburgh, Pennsylvania
Wai Tong Ng, MD, Consultant, Department of Clinical Oncology, Pamela Youde
Nethersole Eastern Hospital, Hong Kong
Susumu Okano, MD, PhD, Department of Head and Neck Medical Oncology,
Andrew F. Olshan, PhD, Barbara Sorenson Hulka Distinguished Professor in Cancer

Epidemiology, Department of Epidemiology, University of North Carolina at Chapel
Hill, Chapel Hill, North Carolina

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Heather A. Osborn, MD, FRCSC, Assistant Professor, Department of

Otolaryngology—Head and Neck Surgery, Yale University, New Haven, Connecticut
Jong Chul Park, MD, Assistant in Medicine, Department of Hematology and

Oncology, Massachusetts General Hospital Cancer Center, Boston, Massachusetts
Douglas E. Peterson, DMD, PhD, Professor and Chair, Section of Oral Medicine,
University of Connecticut School of Dental Medicine, Farmington, Connecticut
James W. Rocco, MD, PhD, FACS, Professor and Chairman, Department of

Otolaryngology-Head and Neck Surgery, Wexner Medical Center, James Cancer
Hospital, Solove Research Institute, The Ohio State University, Columbus, Ohio
Cristina P. Rodriguez, MD, Associate Professor, Division of Medical Oncology,

Department of Medicine, University of Washington, Seattle, Washington
Richard Blake Ross, BS, Medical Student, Department of Radiation Oncology,

Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
Nabil F. Saba, MD, FACP, Professor, Hematology and Medical Oncology, Emory
University School of Medicine; Director, Head and Neck Medical Oncology Program,
Winship Cancer Institute of Emory University, Atlanta, Georgia
Anirudh Saraswathula, BA, Medical Student, Department of Otolaryngology-

Head and Neck Surgery, Stanford University School of Medicine, Palo Alto,
California
Sandra Schmitz, MD, PhD, Associate Professor, Department of Medical Oncology

and Head and Neck Surgery, Institut Roi Albert II, Cliniques Universitaires Saint-
Luc and Institut de Recherche Clinique et Expérimentale, Université Catholique de
Louvain, Brussels, Belgium
Emmanuel Seront, MD, PhD, Medical Oncologist, Institut Roi Albert II, Service
d’Oncologie Médicale, Cliniques Universitaires Saint-Luc and Institut de Recherche
Clinique et Expérimentale (Pole MIRO), Université Catholique de Louvain, Brussels,
Belgium; Service d’Oncologie Médicale, Centre Hospitalier de Jolimont, Haine Saint
Paul, Belgium
Jussi Sillanpaa, PhD, Memorial Sloan Kettering Cancer Center, Middletown,

New Jersey
Denis Soulières, MD, Hematologist and Medical Oncologist, Department of

Hematology and Medical Oncology, CHUM, University of Montreal, Montreal,
Quebec, Canada
Sharon A. Spencer, MD, Professor and Chief of Medical Services, Hazelrig Salter
Radiation Oncology Center, Department of Radiation Oncology—University of
Alabama at Birmingham School of Medicine, Birmingham, Alabama
Sophie Stock-Martineau, MD, Fellow, Department of Hematology and Medical

Oncology, CHUM, University of Montreal, Montreal, Quebec, Canada
Erich M. Sturgis, MD, MPH, Professor, Department of Head and Neck Surgery,
Division of Surgery, The University of Texas MD Anderson Cancer Center,
Houston, Texas

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Rathan M. Subramaniam, MD, PhD, MPH, FRANZCR, FACNM, Robert W. Parkey

MD Distinguished Professor of Radiology, Professor and Chief, Division of Nuclear
Medicine, Medical Director of the Cyclotron and Molecular Imaging Programs,
Program Director of Nuclear Medicine Residency and PET/CT Fellowships,
Departments of Radiology, Clinical Sciences and Advanced Imaging Research Center,
The University of Texas Southwestern Medical Center, Dallas, Texas
Henry C. K. Sze, FRCR, Associate Consultant, Department of Clinical Oncology,

Pamela Youde Nethersole Eastern Hospital, Hong Kong
Makoto Tahara, MD, PhD, Department of Head and Neck Medical Oncology,
Theodoros N. Teknos, MD, FACS, Clinical Professor, Otolaryngology, CWRU School

of Medicine; President and Scientific Director, UH Seidman Cancer Center, Cleveland,
Ohio
Minh Tam Truong, MD, Chief of Radiation Oncology, Department of Radiation

Oncology, Boston Medical Center; Associate Professor and Chair of Radiation
Oncology, Boston University School of Medicine, Boston, Massachusetts
C. Jillian Tsai, MD, PhD, Director, Head and Neck Radiation Oncology Research,
Memorial Sloan Kettering Cancer Center, New York, New York
Meghan T. Turner, MD, Assistant Professor, Department of Otolaryngology-Head

and Neck Surgery, West Virginia University School of Medicine, Morgantown, West
Virginia
Steffen Wagner, Dr. rer. nat., Group Leader, Head and Neck Cancer Research,
Department of Otorhinolaryngology, Head and Neck Surgery, University of Giessen,
Giessen, Germany
Randal S. Weber, MD, Chief Patient Experience Officer; Professor of Head and
Neck Surgery, Department of Head and Neck Surgery, The University of Texas MD
Anderson Cancer Center, Houston, Texas
Michelle D. Williams, MD, Associate Professor, Department of Pathology, The

University of Texas MD Anderson Cancer Center, Houston, Texas
Sue S. Yom, MD, PhD, Associate Professor of Clinical Radiation Oncology,

Department of Radiation Oncology, University of California San Francisco, San
Francisco, California
Sadamoto Zenda, MD, PhD, Department of Radiation Oncology, National

Cancer Center Hospital East, Kashiwa, Chiba, Japan
Jose P. Zevallos, MD, MPH, Joseph B. Kimbrough Professor of Head and Neck
Surgery, Department of Otolaryngology/Head and Neck Surgery, Washington
University School of Medicine, St. Louis, Missouri

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Preface
Head and neck cancers are challenging diseases into consideration long-term treatment effects.
that require complex management and exem- A major breakthrough worth reiterating has
plify the value of collaboration among multiple been the introduction of immunotherapy as a
specialties. Very appropriately, we the Editors standard therapy that establishes the signifi-
are representatives of each of the three major cance of host immune response in the initiation
treatment modalities. The genesis of this work and progression of squamous cell carcinoma
was driven by recognition that, despite evolu- of the head and neck. Taken together, these
tion in various approaches and new emerging developments provide the basis and justify the
data, high quality clinical care is optimal when timely publication of “Head and Neck Cancers:
there is mutual respect of each other’s discipline, Evidence-Based Treatment”.
and when each patient has a treatment recom- This textbook captures key advances and
mendation made by multidisciplinary input. aims to become a quick and handy reference
When discussing the need for a new text- tool for head and neck cancer management
book we recognized and agreed that critical issues, and features didactic patient cases in
developments have been transforming the field each site-specific management chapter. We
of head and neck oncology. Indeed, in the past anticipate that physicians involved in the care
few years there have been significant advances of these patients will find the material rele-
in our understanding of the molecular biol- vant to their clinical practice. Evidence-based
ogy, immune evasion, and genetic landscape of approaches are emphasized throughout the
head and neck cancers, as well as the multidis- textbook. The chapters have been authored
ciplinary management of these malignancies, by internationally recognized experts, with a
including immunotherapy, targeted therapies, focus on multi-modality representation. We are
precision radiation therapy, robotic surgery, thankful and much obliged to their diligent and
and supportive care capabilities. With the rising thoughtful contributions.
epidemic of human papillomavirus-associated Finally, we owe a debt of gratitude to our
oropharyngeal cancer, customizing treatment patients. Their journeys and life stories are
is of utmost importance, in particular taking teaching us to become better doctors.
Athanassios Argiris, MD, PhD, FACP


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Share
Head and Neck Cancers: Evidence-Based Treatment

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3
The Genomic Landscape
of HNSCC
Steffen Wagner
Jens P. Klussmann
Ruud H. Brakenhoff
every cell division somatic mutations occur

CANCER AND SOMATIC and accumulate (4). From the first cell division
GENETIC ALTERATIONS in the developing embryo, mutations start to
accumulate. DNA replication is not foolproof,
Since the 1990s, it was broadly accepted that causing mutations to occur from the day of
cancer arises by an accumulation of somatic conception, and when the wrong genes are
genetic changes. These genetic alterations hit, cancer may result. However, when certain
were deciphered by studying cancer and their critical genes are hit, such as TP53 and other
recognizable precursor stages at the molecular genes in cell cycle regulation or DNA mainte-
level. The number of genetic changes roughly nance, replication stress may develop and the
increases in parallel to the morphological sever- accumulation of genetic changes will dramat-
ity of the lesions, and although there seems a ically increase in such cells (5). After a cou-
certain order, the accumulation was consid- ple of mutations in critical control genes, the
ered more important than the order (1,2). carcinogenic process may drive itself (6). To
Most of these concepts are still valid in 2018, summarize, there is an intrinsic risk for cancer
although the complexity has been tremendously development by accumulating somatic muta-
enhanced by the rapidly increasing knowledge tions in every cell division, but exogenous fac-
during the past few years. The relatively simple tors that trigger or increase genetic alterations
linear genetic progression models became more boost the cancer risk.
complex and more variable (3).
Smoking and excessive alcohol consumption
are important risk factors for head and neck
squamous cell carcinoma (HNSCC), causing MUTATIONS, COPY NUMBER
gene mutations, and these tumors still form ALTERATIONS, AND
the bulk of HNSCC. However, a subgroup of EPIGENETIC CHANGES
tumors is caused by infection with the human
papillomavirus (HPV), and the incidence of Somatic genetic changes are broadly defined.
these tumors has also increased. Hence, exoge- The term “mutations” links to genes, and usu-
nous factors play an important role in HNSCC. ally relates to genetic alterations at the base
Notwithstanding these causative exogenous pair level, stretching from a single nucleo-
carcinogens, it is important to realize that by tide to small deletions and insertions (indels).

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However, many genetic changes encompass next-generation sequencing methods (7),

gains and losses of almost entire chromosomes. a major problem became apparent. Many
How critical these huge losses and gains are in somatic mutations were identified, but mostly
the development of cancer remains somewhat not in cancer driver genes but in so-called pas-
elusive, but for sure they add to the inactiva- senger genes. As indicated earlier, during every
tion of tumor suppressor genes and activation cell division cells accumulate mutations and
of oncogenes (3,7). The CDKN2A locus encod- this holds true for tumor cells as well. Hence,
ing p16INK4A is frequently lost usually by a large the number of mutations will increase, but not
chromosomal loss at 9p21 on one allele and all are in genes that drive cancer progression.
a focal loss around the CDKN2A gene, or a In 2013 this problem of drivers and passen-
mutation or epigenetic event in the gene itself, gers was comprehensively evaluated, and some
on the second allele. Hence, we can assume that solutions were suggested (11). It became appar-
these chromosomal losses clearly play a role. ent that there is a considerable mutational
The more frequent gene amplifications (up heterogeneity between tumors causing bias in
to 10–20 copies) are also relevant. There are the mutational profiles, and which is not cor-
frequent amplifications in HNSCC at chro- rected for to weigh whether a mutated gene is
mosome locus 11q13 where the CCND1 gene indeed a driver gene in a particular cancer. A
is residing encoding cyclinD1 or at the 7p12 most important factor of this mutational het-
locus of the epidermal growth factor receptor erogeneity was a consequence of the tumor type
(EGFR) gene (7), both bona fide oncogenes in and exposure to mutagens, as some tumors
HNSCC. What is less clear is the precise role of such as melanomas were shown to accumulate
the large chromosomal gains that increase gene many mutations, while others show hardly any
copy numbers just twofold. mutations. In addition, the type of mutations
Besides mutations and chromosomal alter- differs between tumors: in melanomas frequent
ations, epigenetic alterations occur frequently. TT-dimers occur causing a specific mutational
At the DNA level these encompass methyla- profile. Summarized, some mutations are just
tions at CpG sequences, most particularly in more likely to occur in a particular tumor type.
the promoter region of genes, thereby shutting Most remarkable was the observation
them off. Also, the CDKN2A gene is frequently that the number of mutations accumulates
inactivated by methylation. However, many in genome regions that replicate late during
more epigenetic alterations are described that S-phase encompassing the regions that are not
encompass, for example, histone code modifi- actively transcribed. Hence, genes in these loca-
cations. The DNA is wrapped around histone tions are found to become frequently mutated,
octamers, and these proteins play an active role but usually do not encompass cancer driver
in the expression of the genes in the vicinity of genes. The authors suggested that nucleotide
where they bind to the DNA strand. These his- shortage may play a role here.
tones can be acetylated and methylated at dif- When the authors developed a correc-
ferent amino acid residues, with major effects tion algorithm that takes all the biases into
on gene expression (8). account, and used that on the sequencing data
Last but not least are the microRNAs (miR- of 178 lung squamous cell carcinomas (SCCs),
NAs). These small noncoding RNAs of approx- the number of candidate cancer driver genes
imately 22 nucleotides can bind to the 3´ reduced from 450 to 11 (11). Hence, mutation
untranslated region (3ÚTR) in the mRNA of data should be interpreted with great caution to
genes targeting them for degradation by the RISC identify potential cancer genes. Obviously, the
complex. Hence, one miRNA may target a mul- frequency with which mutations occur in genes
titude of genes. Many changes in miRNA expres- underpins their relevance as cancer drivers, but
sion are reported in cancer, including HNSCC. in those cases that genes are mutated infre-
In addition, major changes in general miRNA quently, additional functional studies should
biogenesis have been described in cancer (9). elucidate the role of these genes.
DRIVERS AND PASSENGERS CLASSIFICATION OF HNSCC
Since modern cancer genomics was initi- The very large majority of head and neck can-
ated by large-scale Sanger sequencing of cancers (>90%) are SCCs that arise in the mucosal
cer genomes (10), and emerged rapidly by linings of the upper aerodigestive tract, and in a

’
single cell type, suggesting that it is a relatively epidemiology, health management, and clinical
homogeneous disease. However, HNSCC is a purposes. Nine subsites of head and neck can-
remarkably heterogeneous disease, and this cer are distinguished according to anatomical
led to several subclassifications of the disease localization and molecular properties (p16INK4A
in relation to anatomy, etiology, and clinical expression and HPV status) of the disease (12).
or molecular characteristics. Some of these are In Table 3.1 the major subsites of head and
overlapping. In this section, we describe these neck cancers are listed including correspond-
classifications and take one as the main topic in ing International Classification of Diseases for
the subsequent chapter. Oncology, third edition (ICD-O-3) codes and
the further molecular subclassification in the
case of oropharyngeal and hypopharyngeal
ANATOMICAL CLASSIFICATION OF
cancer.
HEAD AND NECK CANCERS BY SUBSITE
In consideration of risk factors, each subsite
In combination with histology (morphology) has its particular set of usually more than one
obtained from microscopic tumor examina- environmental factor that contributes to the
tion, anatomical classification is used routinely genetic alterations associated with carcinogene-
in cancer registries to describe the kind (mor- sis. For example, sunlight exposure is more rel-
phology, behavior, and grading) and origin evant for cancers of the lip than for laryngeal or
of neoplasms, which can be used as tool for oropharyngeal cancers, for which lifestyle factors
TABLE 3.1
The Major Sites of Head and Neck Cancer With Corresponding ICD-O-3 Codes and
Molecular Subclassification
Anatomical Subsite Molecular ICD-O-3 Codes

Classification
1 Lip and oral cavity C00.0-6, C00.8-9, C02.0-3, C02.8-9, C03.0-1, C03.9,
C04.0-1, C05.0, C05.8-9, C06.0-2, C06.8-9
2 Major salivary glands C07.9, C08.0-1, C08.8-9
3 Nasopharynx C11.0-3, C11.8-9
4 Oropharynx p16INK4A-positive, C01.9, C02.4, C05.1-2, C09.0-1, C09.8-9, C10.0,

HPV-mediated C10.2-3, C10.8-9, C11.1
5 Oropharynx and p16INK4A-negative, C01.9, C02.4, C05.1-2, C09.0-1, C09.8-9, C10.0,

hypopharynx HPV-unrelated C10.2-3, C10.8-9, C11.1 and C12.9, C13.0-2, C13.8-9
6 Nasal cavity and paranasal C30.0, C31.0-1

sinuses
7 Larynx C10.1, C32.0-2, C32.8-9
8 Mucosal melanoma of the C00.0-6, C00.8-9, C01.9, C02.0-4, C02.8-9, C03.0-1,

head and neck C03.9, C04.0-1, C04.8-9, C05.0-2, C05.8-9, C06.0-2,
C06.8-9, C09.0-1, C09.8-9, C10.0-3, C10.8-9, C11.0-
3, C11.8-9, C12.9, C13.0-2, C13.8-9, C14.0, C14.2,
C14.8, C30.0, C31.0-1, C32.0-2, C32.8-9
9 Cutaneous squamous cell C00.0-2, C44.0, C44.2-4, C44.8

carcinoma of the head and
neck
ICD-O-3, IInternational Classification of Diseases for Oncology, third edition.

’
such as tobacco and alcohol exposure or viral expression profile, the other clusters correlated
infection have the highest impact. HPV-related less well with the former studies. This could
tumors are typically found in the oropharynx illustrate the heterogeneity of HNSCC regard-
and even more particularly in the tonsils, which ing gene expression, but may also indicate dif-
is discussed in more detail in the following. ferences in collecting and processing of samples
In summary, head and neck cancers are and the used profiling platforms. However, an
diverse concerning anatomical localization and important finding of this study was that the
contributing risk factors. The current knowl- samples containing transcriptionally inactive
edge shows that HPV-related cancers in the HPV16 DNA shared characteristics with HPV-
head and neck region are primarily localized negative samples regarding gene expression and
within the oropharynx, mainly within the ton- frequency of TP53 mutations, indicating that
sil (13). Up to a certain extent, HPV-negative the presence of HPV16 DNA is not indicative
cancers of the oropharynx might be very com- for a role of the virus. Further, the so-called
parable to nonoropharyngeal head and neck disruptive TP53 mutations and an immune
cancers, but HPV-related cancers of the oro- response–related gene expression cluster were
pharynx are a true distinct disease entity, and associated with lymph node metastasis, inde-
classification on the basis of HPV status is the pendent of HPV status (19).
leading topic in this chapter. Five subtypes of HNSCC, including two
biologically distinct HPV subtypes, were iden-
tified by Keck and coworkers in 2015 in a
SUBTYPES IN HNSCC BASED
clinically homogeneous cohort of 134 locore-
ON GENE EXPRESSION
gionally advanced HNSCCs with 44% HPV-
Initially microarray hybridizations and later positive tumors. All patients were treated
RNA sequencing studies allowed research- with concurrent chemoradiotherapy. Gene
ers to identify all genes in a tissue that are expression profiling was done using Agilent
expressed. These gene expression profiles have 4x44Kv2 expression arrays and combined with
been explored in different tumor types includ- previously published and publicly available
ing HNSCC by several groups. In 2004, four data, generating a final dataset of more than
expression subtypes were defined in HNSCC 900 patients. One of the subtypes showed an
by cDNA microarray hybridization, resembling immune and mesenchymal phenotype and con-
those in lung cancer found before (14,15). In a tained both HPV-positive and HPV-negative
later study, four comparable profiles were iden- tumors, while the other subgroup resembled the
tified using Agilent 44K microarrays, and these classical expression pattern according to prior
groups were classified and termed as basal, mes- nomenclature in other cancer types and molec-
enchymal, atypical, and classical gene expres- ular characteristics (20–22), but also contained
sion subtypes (16). While HPV status was not both HPV-positive and HPV-negative tumors.
included in the earlier study, an enrichment of A basal expression subgroup encompassed the
HPV-associated gene expression was observed remaining HPV-negative samples with signifi-
in the atypical subtype with elevated expression cant enrichment of hypoxia-responsive genes
of CDKN2A, LIG1, and the transcription fac- (e.g. HIF1A, CA9, and VEGF), neuregulin sig-
tor RPA2 (16,17). The basal gene expression naling (including EGFR, AREG NRG1), and
profile showed signatures found in basal cells overexpression of epithelial marker genes like
from airway epithelium (e.g., high COL17A1 P-cadherin (CDH3) and cytokeratins (KRT1,
expression associated with the extracellular KRT9). In contrast to the basal expression
matrix production, and high TGFA, EGFR, subgroup, both HPV-positive subtypes showed
and TP63 expression) (16,18). Genes associ- low expression and no copy number events for
ated with epithelial-to-mesenchymal transition EGFR/HER ligands (23).
(EMT), mesenchymal markers, and transcrip- Several gene expression signatures have been
tion/growth factors were enriched in the mes- established from microarray and RNA-Seq
enchymal subtype, while genes enriched in the studies. However, none of these approaches
classical subtype were associated with expo- could be implemented in the standard of care
sure to cigarette smoke, xenobiotic metabolism for HNSCC so far. A recent study demonstrates
genes, and transcription factors (16). Also four the use of formalin-fixed paraffin embedded
subtypes were identified in a third study using (FFPE) oropharyngeal squamous cell carci-
Illumina Expression BeadChips (19). Although noma (OPSCC) tumor tissue for mutation and
one cluster closely matched the classical gene transcriptional profiling by using Ion Torrent

’
AmpliSeq cancer panel tNGS and NanoString and its prevalence varies between 0.1 and 0.5%
gene expression assays (24). In this pilot study, (27,28). The standard policy is to treat the
230 cancer-relevant genes were analyzed in lesion when possible and analyze the specimen
four HPV-positive and four HPV-negative or a biopsy by microscopic examination for
samples. The expression of several genes was dysplasia, graded as mild, moderate, or severe.
highly likely to correlate with HPV status (e.g. Although consensus criteria have been defined
WNT1, PDGFA, and OGG1). Further, by by the World Health Organization (WHO),
unsupervised hierarchical clustering six groups it remains problematic to make an objective
of differentially expressed genes were identified categorization of dysplasia owing to a high
in this dataset. Technical replicates of this gene inter- and intraobserver variation. Patients are
expression study proved a reproducible pattern subsequently monitored by active surveillance
of gene expression for each tumor with respect and biopsy on indication.
to the underlying biology (24) and it may be The percentage of oral leukoplakias that
assumed that the ability to use FFPE samples develop into cancer depends on various factors
will advance gene expression studies. such as the study population, the definition of
The expression profiling either by protein leukoplakia used, and the length of the obser-
or RNA expression suggests differential ben- vation time, but an annual transformation rate
efit of target specific therapies for different of 1% to 2% per year is a reasonable assump-
patient groups with HNSCC. Tumors with tion (26). Risk factors for progression are
high and amplified levels of EGFR may qualify female gender, size, and the presence and grade
for cetuximab treatment. Especially in sight of of dysplasia.
current antibody-based therapies, this might be Besides these recognizable lesions in the
of translational importance and further efforts mucosal linings, it has been well established that
are needed for biomarker development and mucosal abnormalities may exist that are only
improvement of personalized care for patients visible under the microscope. When tumors are
with HNSCC in the future. diagnosed and excised, the specimen is trans-
In summary, there are several ways to clas- ferred to the pathology laboratory to perform
sify head and neck tumors, based on anatom- definitive staging and investigate the surgical
ical subsite, based on gene expression profiles, margins for tumor invasion. The pathologist also
but most prominent at present is the classifica- scores for changes in the mucosal epithelium,
tion on the basis of HPV status, at least in the and grades these as mild, moderate, or severe
oropharynx. HPV-positive tumors are different dysplasia. Particularly severe dysplasia is con-
at the molecular level and show a very differ- sidered as a preneoplastic change in the mucosal
ent clinical behavior, which recently led to an epithelium. Already in 1953, the term “field can-
adaptation in the staging (25) and clinical tri- cerization” was proposed to describe these dys-
als to de-intensify therapy. The role of HPV in plastic changes that might also explain the high
nonoropharyngeal tumors is less clear, but all propensity that local recurrences develop after
in all we separate HNSCC primarily in HPV- HNSCC treatment and the high risk that multi-
negative and HPV-positive tumors, and discuss ple independent tumors develop in the mucosal
the genomic landscape likewise. linings of the upper aerodigestive tract (29).
In the nineties, these precancerous changes
were comprehensively studied with genetic
HPV-NEGATIVE AND markers, and it was shown that the number of
HPV-POSITIVE HNSCC: genetic changes runs more or less in parallel to
CARCINOGENESIS the severity of the lesions. This led to the first
genetic progression model of head and neck
cancer (2). Loss of heterozygosity at chromo-
HPV-NEGATIVE TUMORS
somes 3p, 9p, and 17p appeared to occur in
Most HNSCC patients present with tumors de dysplasia, apparently reflecting early carcino-
novo. However, there are precancerous lesions genesis, while other alterations at 11q, 4q, and
in the mucosal linings of the upper aerodiges- 8 were typically present in carcinomas, likely
tive tract that are either white (leukoplakia) corresponding to a relatively late phase in
or red (erythroplakia) areas of the mucosa. carcinogenesis.
These lesions may progress and develop into These genetic markers were employed to
SCCs (26). Leukoplakia is the most common study the presence of genetically altered muco-
precursor lesion of oral squamous carcinomas sal epithelial cells, also coined as “fields” in

’
relation to the field cancerization concept of The initial genetic progression model, later
Slaughter et al. (29). Indeed many more pre- adapted and simplified, are elementary linear
malignant changes characterized by tumor-as- models (3). However, the plethora of new can-
sociated genetic changes were observed, and didate cancer genes that are mutated in HNSCC
shown to be clinically relevant as they formed will make these simple linear models much
an important source of local recurrences and more complex and diverse, and the research
second primary tumors at least in surgically field has to deal with the fact that there are
treated patients (30–32). Most recent stud- likely multiple ways that lead to mucosal epi-
ies have identified these same genetic changes thelial cell transformation.
at chromosome arms 3p and 9p together with In most recent molecular profiling studies it
mutations in TP53 as the best predictors of was shown that another subgroup of tumors
malignant transformation in leukoplakia (33) exists that is characterized by very few copy
and in surgical margins (34). number alterations. This subgroup of HPV-
The tumor suppressor gene on chromosome negative and TP53 wild type tumors typically
arm 9p is CDKN2A encoding the p16INK4A displays HRAS and CASP8 mutations and a
protein, which binds and disrupts the cyclinD/ more favorable prognosis (7). In previous stud-
CDK4-6 complex that drives cells through the ies, it was shown that this group is diploid, pro-
G1-S checkpoint. The p16INK4A cell cycle inhibit- ficient in DNA mismatch repair and seems to
ing protein is frequently inactivated in HNSCC occur more frequently in females without a his-
by mutation or methylation in combination with tory of smoking and alcohol consumption (39).
chromosomal loss, or by homozygous deletion
(7,68). On chromosome 17p13 the TP53 gene
HPV-POSITIVE TUMORS
is located that is also frequently inactivated in
HNSCC, mostly by missense mutations com- HPV infection causes a subgroup of tumors,
bined with allelic loss. Somatic mutations are most particularly those arising in the orophar-
found in 60% to 80% of the tumors (7,35–37). ynx. HPV-positive OPSCCs form a separate
Hence, there is quite some information on the disease entity that led to an adapted staging
precancerous fields and the molecular changes system (25). In addition, several studies to
in these fields, although more detailed DNA de-escalate therapy have been initiated and
sequencing data are still lacking. the results are awaited. Most assays to test
Furthermore, there is only very limited for HPV in tumor specimen are based on the
data on what precedes the development of detection of viral DNA. There are many HPV
these fields. Van Houten et al. described small types that may cause cancer, but most prom-
p53-positive focal patches in tumor-adjacent inent is HPV16, particularly in the head and
mucosal epithelium (35), and showed that neck region. As mentioned earlier, the virus
these indeed contained mutations, but not encodes two oncogenes E6 and E7. The E7
related to the index tumor of these patients. protein binds the pocket proteins pRb, P130,
These mutated p53-positive patches were con- and p107 thereby creating an S-phase envi-
sidered equivalent to the “clones” or “clonal ronment in the cell. Usually an unscheduled
units” and defined as a family of daughter S-phase with high E2F activity causes p53
cells that originate from an adult stem cell activation by p14 inhibition of MDM2 and
that makes up that part of the squamous epi- induction of apoptosis, and therefore the virus
thelium, and that has now become detectable expresses the oncoprotein E6 that targets p53
by the mutation in p53. These p53 mutated for degradation. Hence, the virus hits pre-
clonal units were considered to represent the cisely the same pathways as is noted in HPV-
first oncogenic changes in the mucosa, and negative tumors: the p53–p21 pathway and
formed together with the genetically defined the p16–cyclinD1–Rb pathway. Typically in
fields the basis of the hypothetical patch– HPV-positive tumors, p16INK4A is active and
field–tumor–metastasis progression model for often overexpressed, while cyclinD1 at 11q13
HNSCC development (3). This model was is not amplified and p53 is wild type (7,40,41).
deduced from the existing descriptive studies Hence, at the genetic level, most prominent in
but recent data in engineered mouse models HPV-positive tumors is the absence of TP53
support such a model. By Axin2 lineage trac- mutations as well as the absence of the loss of
ing experiments the stem cells and the patches chromosome arms 3p and 9p and the amplifi-
they form have been shown recently, at least in cation of 11q13, while these changes are very
mouse skin (38). common in HPV-negative tumors.

’
Both E6 and E7 expression remains critical oropharynx are surrounded by large fields of
in HPV-positive HNSCC cell lines (42) and infected cells, a surrogate for the fields of genet-
the cancer-associated phenotype caused by ically altered cells that precede HPV-negative
inactivation of the p53 and pRb pathways in tumors. It was assumed that HPV infection is
oropharyngeal keratinocytes is at least cellular the first carcinogenic event in HPV-positive
immortalization (43). This phenotype would tumors, as it is in the cervix, and that HPV
also fit with the timing of the genetic events early presence and E6 transcripts could be used to
in the progression of HPV-negative HNSCC as study the presence of these fields surrounding
abrogation of the p53 and pRb pathways by HPV-positive tumors. Remarkably, in none of
loss of 9p21, the location of CDKN2A as well the analyzed tumor-free surgical margins E6
as TP53 mutations are frequently found in the transcripts could be detected. Again, strongly
precursor fields (2,30,44), and are considered suggesting that HPV-induced field canceriza-
as the earliest genetic changes. In HPV-positive tion seems not to occur in the upper aerodi-
HNSCC these same pathways are likely also gestive tract. Alternatively, HPV infection may
the first to be inactivated by the viral E6 and also not be the first carcinogenic event (49). In
E7 oncoproteins, strongly suggesting that HPV contrast to HPV-mediated carcinogenesis in the
infection is indeed the initial carcinogenic event cervix that can be followed by inspection and
as it is in cervical cancer (45). biopsies of the acetowhite lesions, there are at
The key precursor lesions in the mucosal lin- present no indications for HPV-related precan-
ings are leukoplakias, and it was therefore log- cerous changes in the upper aerodigestive tract.
ical to study HPV presence in these lesions, but Hence, the molecular pathogenesis of HPV-
the results are highly discordant. A major prob- induced squamous cancers in the upper aerodi-
lem in the different studies is the false positive gestive tract remains unsolved, and currently
results by the applied ultrasensitive HPV DNA relies on the extrapolation of data collected in
assays. Most reliable studies suggest a very low the invasive carcinomas.
prevalence of less than 1%; this is reviewed by
Ha and Califano (46). Given the second obser-
vation that 3p and 9p losses of heterozygosity
are the key genetic changes predicting malignant HPV-NEGATIVE AND HPV-
transformation of leukoplakias (33), although POSITIVE HNSCC: PROTEIN
these alterations are typically absent in HPV- EXPRESSION, GENETICS, AND
positive tumors (40), we consider progressing EPIGENETICS
leukoplakia lesions as being HPV-negative, and
they should not be considered the precursor A most interesting feature of head and neck
lesion of HPV-mediated carcinogenesis. cancers in comparison to other tumor entities is
Are there any other indications for HPV- the existence of virus and chemical agent driven
induced precancerous changes in the upper cancer within one anatomically well-defined
aerodigestive tract? They are very common sublocalization (the oropharynx) in a some-
in the cervix, and in fact the target lesion for what balanced numerical ratio. For example,
screening (45). The highest attributable fraction in lung cancer, smoking is the dominant risk
of HPV in the head and neck is found in the ton- factor while viral infection is negligible. In
sils, and therefore both precancerous changes contrast, almost 100% of cervical carcinomas
and sites of infection are expected in the ton- are associated with HPV infection. During the
sils. Several studies have been carried out with past year it became evident that HPV-related
the largest reporting on over 4,000 tonsils of OPSCCs are a distinct entity with characteristic
which over 3,300 could be analyzed. No HPV molecular and clinical features such as superior
was found (47). Hence, the precursor lesions of survival of patients. Consequently, it was to be
HPV-driven carcinogenesis in the upper aerodi- expected that HPV was introduced for classifi-
gestive tract are still an enigma. There have cation of oropharyngeal cancer in the latest ver-
been indications that tonsillar cancers may be sion of American Joint Committee on Cancer
surrounded by p16INK4A-positive mucosal fields, (AJCC) staging albeit HPV status is determined
but these might have been superficially growing only by p16INK4A immunostaining as a surrogate
tumors and without proper genetic analysis of and not in combination with HPV testing (12).
these lesions this remains unclear (48). The choice to rely on p16INK4A immunos-
Finally, it was also studied using HPV taining was that it is easier to standardize com-
assays whether HPV-positive tumors in the pared to viral oncogene (mainly E6 and E7)

’
mRNA detection, and that it is a good although expression is usually detectable in the majority
not perfect surrogate marker. Overexpression (>70%) of tumor cells by immunohistochemis-
of p16INK4A protein is indirectly linked to the try, with a strong, diffuse expression pattern in
oncogenetic activity of HPV encoded protein both nucleus and cytoplasm (classical pattern of
E7. In contrast, CDKN2A, the gene encoding HPV-induced transformation) (48,50,53,54).
p16INK4A, it is one of the most frequently inacti- Inactivation of retinoblastoma (Rb) by the HPV
vated tumor suppressor genes in HPV-negative E7 oncoprotein overcomes cell cycle arrest and
tumors (50,51). E7 enhances p16INK4A expression by inducing
epigenetic changes (55). However, it has to
DIFFERENTIAL PROTEIN be mentioned that HPV-independent p16INK4A
EXPRESSION IN HPV-POSITIVE overexpression is described for different can-
AND HPV-NEGATIVE HNSCC cers and about 5% of oropharyngeal cancers
The most prominent protein markers in (50), probably by alternative alterations in the
HNSCC include p53, EGFR, and VEGF. The p16-signaling pathway (e.g., inactivation of
53 kDa nuclear phosphoprotein p53 is coded retinoblastoma). Previous studies have shown
by the tumor suppressor gene TP53. It is one of that respective disadvantages of HPV detection
the most important tumor suppressors involved by polymerase chain reaction (PCR; low spec-
in DNA synthesis/repair and programmed cell ificity) or by p16INK4A immunohistochemistry
death and, when activated, inhibits the cell cycle (HPV-independent overexpression) can be ruled
by induction of p21. Expression of p53 is usu- out by the combination of both techniques.
ally not detected in healthy cells owing to its
MUTATIONS AND COPY-NUMBER
short half-life, but it is frequently observed in
ABERRATION (CNA) PROFILES
cancer cells. Accumulation of p53 occurs by
enhanced expression upon cellular stress, for Complex karyotypes are frequent in HNSCC,
example, induction by carcinogenic processes. including several numeric and structural alter-
However, several mutational hot spots within ations. A high variability and heterogeneity
TP53 in cancer cells have been identified, which among cells indicates selection processes and
lead to mutated protein with abrogated tumor clonal evolution in HNSCC. This led to one of
suppression function. Therefore, selection pro- the first genetic progression models for HNSCC,
cesses cause tumor cells to accumulate TP53 in which chromosomal changes (gains, losses,
mutations. Although not fully understood, the and translocations) accumulate in an ordered
consequence of more TP53 mutations/higher manner with resulting growth advantage of a
p53 expression level could be a worse progno- favored cell population (2). In a 2014 review,
sis. These findings are superimposed by effects cytogenetic aberrations in HNSCC have been
of HPV-induced carcinogenesis, and right now, summarized (56).
it is unclear whether TP53 mutations have The current knowledge indicates that cer-
prognostic impact independently from HPV tain genetic alterations are shared by HNSCC
status. Some studies do report this (52), but the irrespective of HPV status, while others are
studied cohorts are somewhat small and based restricted to either HPV-negative or HPV-
on heterogeneous patient populations. HPV- positive HNSCC (57). This has been largely con-
positive tumors rarely contain TP53 mutations firmed by data from The Cancer Genome Atlas
compared to HPV-negative tumors (40) and (TCGA) consortium. For example, amplifica-
prognosis is usually better. Although pointing tion of the 3q26-28 region, containing PIK3CA,
in the same direction, underlying mechanisms TP63, and SOX2 are frequent to both (7).
differ. In HPV-driven cancers, viral E6 oncopro- Deletion (14%) or mutation (8%) of TRAF3
tein expression impedes p53 function via bind- (tumor necrosis factor receptor–associated fac-
ing and recruitment of ubiquitinating proteins tor 3), which is involved in innate and acquired
and labeling p53 for proteasomal degradation. antiviral immune response, was found in high
Therefore, no selection pressure to acquire frequency in HPV-positive HNSCC (7). In this
TP53 mutations exists in HPV-driven can- context, higher mutation rates in CYLD (cylin-
cers. However, as already mentioned another dromatosis lysine 63 deubiquitinase) have also
protein marker (p16INK4A) is overexpressed in been identified in HPV-positive HNSCC and
HPV-related cancers. The p16INK4A tumor sup- both aberrations correlated with NFkB (nuclear
pressor protein is generally inactivated by muta- factor kappa-light-chain-enhancer of activated
tion, methylation, and losses in HPV-negative B cells) activation, episomal HPV status of
tumors. In HPV-driven tumors, p16 INK4A tumors, and improved patient survival (58).

’
Amplifications of EGFR and FGFR1 appear to Among the best known and highly validated
be restricted to HPV-negative HNSCC, which is differences between HPV-negative and HPV-
confirmed by other studies (7,59–61). positive HNSCC are somatic mutations in the
A comparison of HPV-positive and HPV- TP53 gene, which are found in 60% to 80% of
negative tumors was done for mutations and HPV-negative but are virtually absent in HPV-
CNAs in 617 cancer-associated genes in 120 positive tumors (7,35–37). This reflects the low
matched tumor/normal samples (42.5% HPV- selection pressure to acquire TP53 mutations in
positive tumors) (62). In contrast to the general HPV-positive cancers due to p53 inactivation
expectation, mutational burden did not differ by the HPV E6 oncoprotein.
between HPV positive and HPV negative. The Although the majority of HNSCCs are either
mutational spectrum of HPV-negative tumors driven by HPV or harbor TP53 mutations, a
resembles that of published lung SCC anal- remaining 20% cases seem to have p53 wild
yses with high mutation frequency in TP53, type (39). It might be that other genes in the
CDKN2A, MLL2, CUL3, NSD1, PIK3CA, p53 pathway are altered in selected cases (66)
and NOTCH genes. In HPV-positive tumors or that p53-independent tracks of malignant
a unique profile with high mutation rates in progression are followed. For example, this
DDX3X, FGFR2/3 and aberrations in PIK3CA, subgroup of HPV-negative and TP53 wild
KRAS, MLL2/3, and NOTCH1 was found (62). type tumors typically show HRAS and CASP8
A most important progress in recent years mutations, as was recently shown by molecular
was the publication of 279 head and neck can- profiling studies (7).
cer genomes characterized by next-generation HPV-driven tumors with E6 transcription
sequencing and array analysis by TCGA con- were shown to have a different genetic pattern
sortium (7). In this dataset, 36 cases were identi- (e.g., absence of chromosome arms 3p, 9p loss,
fied to be HPV positive. The analysis confirmed and 11q13 amplification) compared to HPV-
differential genetic patterns described earlier. negative HNSCC with respect to loss of hetero-
Further, frequent structural changes in TRAF3, zygosity analysis and microarray comparative
a gene at chromosomal region 14q32 and fre- genomic hybridization (40,41,67). The genes
quently involved in antiviral immune responses located at 9p and 11q13 are CDKN2A and
were found in HPV-positive tumors. In contrast, CCND1, and both are established cancer genes
amplifications of EGFR and FGFR1 appear to in HPV-negative HNSCC and often affected by
be restricted to HPV-negative HNSCC (7,59– genetic alterations (7,41,68). In HPV-positive
61). TpC mutations were found more frequent HNSCC, chromosomal instability seems to be
in HPV-positive tumors, although the total associated with HPV DNA integration into the
number of somatic mutations was not differ- host´s genome and, albeit being linked to can-
ent between HPV-positive and HPV-negative cer progression in general, is associated with
tumors. Missense mutations in PIK3CA cod- favorable prognosis in tonsillar cancer (69).
ing for the catalytic subunit of PI3-kinase were In the classical view of HPV-related carcino-
identified in HPV-positive tumors as well as genesis, integration of the viral DNA into the
amplifications of E2F1. PI3-kinase activity acti- host genome disrupts control of E6 and E7 activ-
vates AKT signaling and PIK3CA mutations ity by inactivating E2 protein by linearizing the
in HPV-positive tumors have been reported HPV genome within this E2 coding open read-
before [e.g., in 8/33 HPV-positive tumors ana- ing frame. Although this model appears to be
lyzed (63)]. Data from TCGA and other studies reasonable, in an analysis of 73 HPV-associated
have recently been summarized to describe the OPSCCs, episome-derived PCR products were
genetic landscape of HPV-associated HNSCC, only detected for more than 60% of samples
including structural alterations, mutation sig- (70). Also, HNSCC cell line analysis indicated
natures, viral integration, and their relation to that viral oncogene expression was independent
cellular pathways (64). of viral copy number and the presence of viral
Although latest sequencing results are a integration. One of the studied cell lines did not
great progress for cancer research, one has to show HPV DNA integration at all, indicating
mention that total numbers of analyzed sam- that HPV DNA integration is not a necessary
ples are still small. For example, the aforemen- event in carcinogenesis (71). Very recently,
tioned mutation in KRAS was found in 5.8% of RNA-Seq and whole genome sequence data
HPV-positive tumors (3/51 patients) (62), and from TCGA HNSCC samples were analyzed for
this finding could not be validated in another the possible HPV genome states (episomal only,
study (65). integrated state, and a state in which the viral

’
genome exists as a hybrid episome with human MiRNAs are the best studied noncoding
DNA). All three states were split relatively RNAs involved in gene regulation since their
evenly and more strikingly, about three quarters discovery in 1993 (86). After their processing
of HPV16-positive HNSCC contain episomal from 60 to 70 nucleotide, long hairpin-like
viral genomes (72). precursors, miRNAs are incorporated together
with DICER1 and Argonaute (AGO) proteins
in the miRNA-induced silencing complex
EPIGENETICS AND miRNAS
(miRISC). This complex is guided by sequence
Epigenetic alterations, either DNA methyla- complementary of the miRNA to its target
tion or histone modifications of viral and host mRNAs, and causing gene suppression by tar-
genomes, are two important processes effecting geted mRNA degradation and translational
gene expression. Especially the role of DNA repression. Although altered miRNA expres-
methylation in HPV-positive OPSCC is well sion is known in various cancers and carcino-
established, and affects not only pathogenesis genic processes, invasion and metastasis, less
of OPSCC but also clinical behavior of tumors. is known in head and neck cancer. A definite
Gene promoter methylation often causes tran- conclusion from the large-scale profiling studies
scriptional silencing of tumor suppressor genes is hampered by the fact that miRNAs do not
involved in DNA damage repair, detoxifica- have “one” target and one function. Because
tion, cell cycle regulation, and apoptosis, and of their small size of about 22 bases, miRNA
may be as important as inactivation of genes by may bind to more or less conserved target
deletion or somatic mutation (73,74). sequences and target genes themselves can
Viral E2 protein expression and binding to have several binding sites for one or different
E2 binding sites (E2BSs) in the viral genome are miRNAs. This generates rather complex net-
important regulators of E6 and E7 expression works of molecular interactions regulated by
during the normal HPV life cycle. Loss of E2 miRNAs. Although only partially documented,
function during carcinogenesis is considered a most cellular pathways involved in carcinogen-
prerequisite for consistent activation of viral esis of head and neck cancers are influenced by
oncogene expression and malignant transfor- miRNA regulation.
mation (75). Methylation marks at E2BS in Several differentially expressed miRNAs
the upstream regulatory region of E6 and E7 have been described until now for HPV-negative
regulate transcription in the presence of intact and -positive HNSCC and with the technical
E2 expression, which is particularly import- progress, their number and reliability of data
ant in tumors with episomal (nonintegrated) will certainly rise. Hsa-miR-363 is among the
HPV (76,77). Distinct patterns of DNA meth- best known miRNAs found to be upregulated
ylation in the host genome are described for in HPV-positive compared to HPV-negative
viral driven cancers including HPV (78–80). HNSCCs (87–89). Among others, its pre-
Since DNA methylation profiles persist or even dicted target sequences are within CDKN1A
increase during disease progression, this is of (cyclin-dependent kinase inhibitor 1), CASP3
particular clinical relevance. A trend toward (Caspase-3), and CD274 (programmed cell
a higher level of gene promoter methylation death 1 ligand 1), indicating regulatory func-
in HPV-related as compared to HPV-negative tion in apoptosis, cell cycle, transcriptional
OPSCC was shown, which is most likely due to regulation, and immunity. Downregulation
accelerated expression and enzymatic activity in HPV-positive compared to HPV-negative
of DNA methyltransferases (DNMTs) (80–84). HNSCC was reported for hsa-miR-125a, -143,
In patients with HPV-associated SCCs distinct -145, -199a, -126, -181b, and -31 in at least
subgroups were identified based on viral DNA two studies each (87–91). The most prominent
integration and the E2BS methylation status, target genes are: CD34 (hematopoietic progeni-
causally linked with viral oncogene expression tor cell antigen CD34), CDKN1A, TP53 (p53),
(70,76,77). Recently, a methylation signature ERBB2 (receptor tyrosine-protein kinase erbB-
for HPV-related cancers was determined based 2), KRAS (GTPase KRas), SOX2 (transcrip-
on quantitative evaluation of differentially tion factor SOX-2), MET (hepatocyte growth
methylated regions in the proximal promoter factor receptor), MTOR (serine/threonine-pro-
of five host genes (ALDH1A2, OSR2, IRX4, tein kinase mTOR), HIF1A (hypoxia-inducible
GRIA4, and GATA4), predicting the clinical factor 1-alpha), VEGFA (vascular endothelial
outcome of HNSCC patients, including HPV- growth factor A), PIK3R2 (phosphatidylinosi-
related OPSCC (78,85). tol 3-kinase regulatory subunit beta), TERT

’
(telomerase reverse transcriptase), BCL2 (apop- tissue and impact of environmental factors
tosis regulator Bcl-2), and FOXP3 (forkhead (chemicals, radiation, or carcinogenic viruses),
box protein P3). Other miRNAs reported in at a basic set of pathways seems comparable for
least two studies are hsa-miR-26b, -29a, -155, most cancers. Generally, proliferation and cel-
and -222 (87–91). Predicted target sequences lular survival are increased, while cell cycle
are within genes already mentioned or with control is changed, and DNA-repair and linked
similar important functions. However, expres- apoptotic programs are suppressed (Figure
sion data are conflicting for these miRNAs 3.1). This is achieved by the action of the major
indicating the need for further investigations in HPV oncoproteins E6 and E7 in HPV-induced
this field of gene regulation. Although miRNA carcinogenesis, and is independent from inac-
regulation is highly complex, miRNAs may tivation of anticancer sentinels like p53 on
serve as diagnostic and prognostic markers and the genetic level. Further steps involve dedif-
miRNA-mediated gene regulation could be the ferentiation of tumor cells and activation of
target of future therapy concepts. immune escape mechanisms. Downregulation
of HLA-A and –B alleles has been reported for
HPV-driven cancers in 1995 (92) and recent
sequencing data point to enrichment of muta-
HPV-NEGATIVE AND HPV- tions in HLA and beta-2-microglobulin genes
POSITIVE HNSCC: ALTERED in HPV-positive HNSCC (7). This is particu-
PATHWAYS larly interesting, since attraction and activa-
tion of CD56+ natural killer cells is expected by
For development and progression of every HLA I loss and higher numbers of CD56+ natu-
malignant disease, a critical set of cellular path- ral killer cells were reported in HPV-associated
ways has to be dysregulated. Although involved OPSCC recently, and correlate with improved
factors may differ depending on the originating survival independently from HPV status (93).
HPV
Altered pathways
16
in HPV+ve HNSCC
E7 E6
RB1 p53
surface molecules NFkB
HLA-A
HLA-B MYC E2F1
B2M immuno
-logy cell cycle control
apoptosis
senescence
membrane receptors
EGFR PI3K-
ERBB2 signaling inflammation
FGFR3 angiogenesis
NFkB migration
TNFR
LTBR
CYLD
TRAF3 p63
cellular
differentiation
NOTCH
100% 0% 100%
activation inactivation
FIGURE 3.1 Molecular pathways frequently altered in HPV-positive HNSCC.

HNSCC, head and neck squamous cell carcinoma.

’
Further, an increased disturbance in upstream growth factor receptors like Janus

NOTCH signaling was observed in both HPV- kinase (JAK) and EGFR and associated with
positive and HPV-negative HNSCC (7,59), oncogenic behavior and resistance to standard
indicating a certain need for dedifferentiation therapeutics in HNSCC (94).
in carcinogenesis for both entities. For develop- Options to interfere with dysregulated path-
ment of invasive properties, downregulation of ways in cancer are numerous and have been
cell surface adhesion molecules and activation recently summarized for HNSCC (95,96).
of extracellular matrix degrading enzymes have However, as HPV-negative HNSCC is mainly
to take place. Further, enhanced angiogenesis caused by tumor suppressor gene inactivation,
and adaptation of metabolic processes regard- synthetic lethal interactions with other genes
ing changing environmental conditions during need to be explored. Logical candidates might
tumor growth or migration of tumor cells, is be the remaining genes regulating the head
needed for tumor progression. and neck cancer cell cycle. In tumors the G1/S
The driving forces, details of the molecu- checkpoint is inactivated by the abrogation of
lar participants, and potentially the sequence pRb and p53 pathways, and molecules such as
of events differ between HPV-positive and Wee1 kinase that keep the cyclinB/CDK1 com-
HPV-negative HNSCC. Therefore, a detailed plex inactivated till cell division occurs, are now
knowledge of molecular processes is needed for becoming regulation nodes (97). Increasing
disease classification and development of more data of genetic alterations driving carcinogene-
specific and effective treatment concepts for sis, functional analysis of the cancer genes, and
distinct tumor types. future development of methods for their thera-
peutic targeting will provide further options for
IMPLICATIONS FOR the treatment of HNSCC. It remains to be seen
THERAPEUTIC TARGETING whether novel targeted treatment options have
Molecular and genetic classification of patients´ the power to complement or replace conven-
tumors will help to guide treatment decisions tional therapy, and the immunotherapies that
in the future. Further, the increasing knowledge are discussed in other chapters.
of altered pathways in HNSCC by investigat-
ing underlying genetic alterations will lead to
the prediction of novel therapeutic targets and SUMMARY
reevaluation of already known target/ther-
apy combinations, which in clinical trials with The genomic landscape of head and neck cancer is
genetically unselected patients, have not been known in greatest detail. The main classification
as successful as expected (e.g., EGFR-directed in our view at present is between HPV-positive
therapies). As a prerequisite, genetic profiling and HPV-negative tumors, certainly in the oro-
of patients has to become possible by routine, pharynx as these tumors differ enormously with
which can be assumed regarding developments respect to etiology, molecular changes, patient
in high-throughput sequencing technologies. characteristics, and most importantly, clinical
Generally, oncogenic alterations are more outcome. HPV-positive tumors are staged differ-
susceptible to pharmacologic inhibition than ently in TNM8 (12), and likely may be treated
changes in tumor suppressors or related path- differently in time. Within the oral cancers, there
ways. HPV-positive HNSCC might be more eligi- is also a subgroup of tumors that are devoid of
ble for therapeutic targeting than HPV-negative copy-number changes, and this group needs to
HNSCC, as they appear to be more homoge- be characterized in more detail.
neous regarding altered pathways and activa- The most important driver pathways in head
tion of cancer-associated pathways seems to be and neck cancer are p53-p21, p16-cyclinD1-Rb,
more frequent. To date, the most obvious candi- EGFR-PI3K-AKT, TGF-beta, and NOTCH1.
dates are PIK3CA and CDK4/CDK6 pathways, Many other genes have been found mutated in
due to high rates of PIK3CA mutations and much lower frequencies and are likely to play a
CCND1 amplifications. Furthermore, suitable role, but precisely how and in which pathways
therapeutics are already available for interfering remains to be investigated. Disappointingly,
with both pathways. STAT3 might be another the number of oncogenes involved in HNSCC
promising therapeutic target. Hyperactivation is very limited. EGFR and PIK3CA seem the
of the STAT3 transcription factor is a hallmark main oncogenes involved but only in subsets of
of HNSCC, although oncogenic mutations are tumors. Oncogenes are interesting targets for
not described. STAT3 activation is driven by therapy, but HNSCC seems more a disease of

’
inactivated tumor suppressor genes, which are 16. Walter V, Yin X, Wilkerson MD, et al. Molecular sub-
no direct targets, enforcing the exploration of types in head and neck cancer exhibit distinct patterns
other strategies. But new opportunities have of chromosomal gain and loss of canonical cancer
genes. PLOS ONE. 2013;8:e56823.
emerged. Head and neck cancers belong to the
17. Slebos RJ, Yi Y, Ely K, et al. Gene expression differ-
group of tumors with a relatively high muta- ences associated with human papillomavirus status in
tional load, which may make them susceptible head and neck squamous cell carcinoma. Clin Cancer
to immunotherapies. Thus far, treatment is Res. 2006;12:701–709.
still mainly based on stage and site, and not on 18. Hackett NR, Shaykhiev R, Walters MS, et al. The
genetic or other molecular classifications. This human airway epithelial basal cell transcriptome.
may change on short notice for the oropharyn- PLOS ONE. 2011;6:e18378.
geal tumors that are caused by HPV. 19. Wichmann G, Rosolowski M, Krohn K, et al. The
role of HPV RNA transcription, immune response-re-
lated gene expression and disruptive TP53 muta-
tions in diagnostic and prognostic profiling of head
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Evidence in Head and Neck Cancer

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HEAD AND NECK CANCERS

Head and Neck Cancers: Evidence-Based Treatment presents a practical, state-of-the-art

Argiris • Ferris • Rosenthal

An Imprint of Springer Publishing

© Springer Publishing Company

© Springer Publishing Company

Athanassios Argiris, MD, PhD, FACP

Robert L. Ferris, MD, PhD, FACS

David I. Rosenthal, MD, FACR, FASTRO

An Imprint of Springer Publishing

© Springer Publishing Company

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Names: Argiris, Athanassios, editor. | Ferris, Robert L., editor. |

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Contributors vii 7. Proton Therapy 109

3. The Genomic Landscape of 11. Targeting the Human Epidermal

4. HPV-Related Head and Neck 12. Therapies Targeting VEGF/

S E C TION II SEC TION III

Established and Emerging Site-Specific Management

© Springer Publishing Company

14. Non–HPV-Associated Oropharyngeal SEC TION IV

16. Nasopharyngeal Cancer 303 23. Recurrent or Metastatic HNSCC:

© Springer Publishing Company

David J. Adelstein, MD, Professor of Medicine, Cleveland Clinic Lerner College

Athanassios Argiris, MD, PhD, FACP, Professor, Department of Medical Oncology,

Shirin Attarian, MD, Fellow, Division of Oncology, Department of Medicine,

Julie E. Bauman, MD, MPH, Professor of Medicine, Chief, Division of Hematology

Jacques Bernier, MD, PhD, Department of Radiation Oncology, Oncology Institute

Pierre Blanchard, MD, PhD, Department of Radiation Oncology, The University of

Karim Boudadi, MD, Clinical Associate and Assistant Professor-Hematology/Medical

Barbara A. Burtness, MD, Professor of Medicine, Co-Director, Developmental

© Springer Publishing Company

Oscar S. H. Chan, FRCR, Honorary Associate Consultant, Department of Clinical

Anthony J. Cmelak, MD, Professor of Radiation Oncology, Senior Medical Director,

Yanqun Dong, MD, PhD, Radiation Oncology Resident, Department of Radiation

Avraham Eisbruch, MD, Professor of Radiation Oncology, Department of Radiation

Adel K. El-Naggar, MD, PhD, Professor, Department of Pathology, Kenneth D. Muller

Antoine Eskander, MD, ScM, FRCS(C), Assistant Professor, Department of

Carole Fakhry, MD, MPH, Associate Professor, Department of Otolaryngology-Head

Arlene A. Forastiere, MD, Professor of Oncology, Department of Oncology, Johns

Steven J. Frank, MD, Professor, Department of Radiation Oncology, The University

Thomas J. Galloway, MD, Associate Professor, Department of Radiation Oncology,

Adam S. Garden, MD, Professor, Department of Radiation Oncology, The University

Jessica L. Geiger, MD, Assistant Professor of Medicine, Cleveland Clinic Lerner

© Springer Publishing Company

G. Brandon Gunn, MD, Associate Professor, Department of Radiation Oncology, The

Patrick K. Ha, Professor, Department of Otolaryngology, University of California San

Robert I. Haddad, MD, Associate Professor of Medicine at Harvard Medical School,

Glenn J. Hanna, MD, Instructor of Medicine at Harvard Medical School, Department

Katherine A. Hutcheson, PhD, Associate Professor, Department of Head and Neck

Jennifer M. Johnson, MD, PhD, Assistant Professor, Department of Medical

Jens P. Klussmann, Dr. med., Professor and Chairman, Department of

Christien A. Kluwe, MD, Radiation Oncology Resident, Department of Radiation

Shlomo A. Koyfman, MD, Radiation Oncologist, Department of Radiation Oncology,

Ka On Lam, FRCR, Clinical Assistant Professor, Department of Clinical Oncology,

© Springer Publishing Company

Anne W. M. Lee, MD, Professor, Department of Clinical Oncology, The University of