Textbook of Oral Cancer: Prevention, Diagnosis and Management (Textbooks in Contemporary Dentistry) 3030323161, 9783030323165

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Textbooks in Contemporary Dentistry

Saman Warnakulasuriya John S. Greenspan   Editors

Textbook of Oral Cancer Prevention, Diagnosis and Management

Textbooks in Contemporary Dentistry

This textbook series presents the most recent advances in all fields of dentistry, with the aim of bridging the gap between basic science and clinical practice. It will equip readers with an excellent knowledge of how to provide optimal care reflecting current understanding and utilizing the latest materials and techniques. Each volume is written by internationally respected experts in the field who ensure that information is conveyed in a concise, consistent, and readily intelligible manner with the aid of a wealth of informative illustrations. Textbooks in Contemporary Dentistry will be especially valuable for advanced students, practitioners in the early stages of their career, and university instructors. More information about this series at http://www.­springer.­com/series/14362

Saman Warnakulasuriya John S. Greenspan Editors

Textbook of Oral Cancer Prevention, Diagnosis and Management

Editors Saman Warnakulasuriya Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London London, UK

John S. Greenspan Department of Orofacial Sciences Schools of Dentistry and Medicine, University of California San Francisco San Francisco, CA, USA

ISSN 2524-4612     ISSN 2524-4620 (electronic) Textbooks in Contemporary Dentistry ISBN 978-3-030-32315-8    ISBN 978-3-030-32316-5 (eBook) https://doi.org/10.1007/978-3-030-32316-5 © Springer Nature Switzerland AG 2020 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

V

We dedicate this book to our families, without whose sacrifices and support neither of us would be where we are. Saman and John

VII

Contents 1

Introduction – Cancers of the Mouth and Oropharynx . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   1 Saman Warnakulasuriya and John S. Greenspan

2

Epidemiology of Oral and Oropharyngeal Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   5 Saman Warnakulasuriya and John S. Greenspan

3

Risk Factors for Cancer of the Mouth: Tobacco, Betel Quid, and Alcohol . . . . . . . . . . . . . . . . .   23 Mia Hashibe

4

Human Papillomavirus Infection: A Risk Factor for Oral and Oropharyngeal Cancers . .   31 Giuseppina Campisi and Vera Panzarella

5

Clinical Presentation and Differential Diagnosis of Oral Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . .   47 Jose V. Bagan and Leticia Bagan-Debon

6

Staging of Oral Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   55 Ashley Hay and Jatin Shah

7

Pathology of Oral and Oropharyngeal Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   69 Saman Warnakulasuriya, Hatsuhiko Maeda, and John S. Greenspan

8

Oral Biopsy: Principles and Practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   81 Ranganathan Kannan

9

Diagnostic Adjuncts for Oral Cavity Squamous Cell Carcinoma and Oral Potentially Malignant Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   99 A. Ross Kerr

10

Detection Methods for Human Papillomavirus (HPV) in Head and Neck Cancers . . . . . . . . 119 Annemieke van Zante and Richard C. Jordan

11

Diagnostic Imaging of Oral Squamous Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 Michał Studniarek and Paulina Adamska

12

Potentially Malignant Disorders of the Oral Cavity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141 Saman Warnakulasuriya

13

Malignant Transformation of Oral Potentially Malignant Disorders . . . . . . . . . . . . . . . . . . . . . . 159 Anura Ariyawardana

14

Molecular and Signaling Pathways During Oral Carcinogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . 179 Luis Monteiro and Saman Warnakulasuriya

15

Early Diagnosis of Oral Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195 Andrei Barasch and Joel B. Epstein

16

Screening for Oral Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201 Paul M. Speight

17

Lifestyle Interventions for the Prevention of Oral Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215 Pankaj Chaturvedi, Swagnik Chakrabarti, and Arjun Gurmeet Singh

Contents VIII

18

Chemoprevention in Oral Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227 Holli A. Loomans-Kropp and Eva Szabo

19

General Workup Prior to the Treatment Phase of Oral Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239 Michael Awadallah, Ketan Patel, and Deepak Kademani

20

Basic Surgical Principles and Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253 Richard J. Shaw, John Edward O’Connell, and Mandeep Bajwa

21

Assessment of Surgical Margins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283 Ziv Gil and Shorook Na’ara

22

Chemoradiotherapy in Oral Cavity Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291 Bhartesh A. Shah, Sherry X. Yan, Catherine Concert, and Kenneth Hu

23

Deintensification of Treatment for HPV-Associated Cancers of the Oropharynx . . . . . . . . . 303 Susan Y. Wu and Sue S. Yom

24

Treatment of the Neck . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311 Robert M. Brody and Terry A. Day

25

Factors Affecting Survival for Oral Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327 Graham R. Ogden

26

Supportive and Palliative Care for Patients with Oral Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343 Pedro Diz Dios and Márcio Diniz Freitas

27

Molecular Targeted Therapy for Advanced Oral Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359 Toru Nagao

28

Immunotherapy-Based Approaches for Treatment of Oral and Oropharyngeal Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387 Barbara Wollenberg

29

Cancer Biology and Carcinogenesis: Fundamental Biological Processes and How They Are Deranged in Oral Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399 Newell W. Johnson

30

Cancer Stem Cells in Oral Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427 Miguel Ángel González-Moles, Lucía González-Ruiz, and Pablo Ramos-García

31

Controversial Factors on Causation of Oral Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439 Saman Warnakulasuriya

Supplementary Information Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449

IX

Contributors Paulina Adamska

Giuseppina Campisi

University Dental Centre, Medical University of Gdańsk Gdańsk, Poland [email protected]

Department of Surgical, Oncological and Oral Sciences (DICHIRONS), University of Palermo Palermo, Italy [email protected]

Anura Ariyawardana College of Medicine and Dentistry Cairns Campus, James Cook University Cairns, QLD, Australia Metro South Oral Health Wooloongabba, QLD, Australia [email protected]

Michael Awadallah Weill Cornell Medicine New York, USA [email protected]

Jose V. Bagan Oral Medicine and Service of Stomatology and Maxillofacial Surgery, University of Valencia and University General Hospital Valencia, Spain [email protected]

Swagnik Chakrabarti Department of Head and Neck Surgical Oncology Tata Memorial Hospital Mumbai, India

Pankaj Chaturvedi Department of Head and Neck Surgical Oncology Tata Memorial Hospital Mumbai, India

Catherine Concert Department of Radiation Oncology NYU Langone Health New York, NY, USA

Terry A. Day Department of Otolaryngology – Head & Neck Surgery Medical University of South Carolina Charleston, SC, USA [email protected]

Leticia Bagan-Debon Oral Medicine, University of Valencia Valencia, Spain [email protected]

Mandeep Bajwa Department of Molecular and Clinical Cancer Medicine University of Liverpool Liverpool, UK

Márcio Diniz Freitas Special Care Dentistry Unit, School of Medicine and Dentistry University of Santiago de Compostela Santiago de Compostela, Spain [email protected]

Pedro Diz Dios

Department of Maxillofacial/Head and Neck Surgery Aintree University Hospital Liverpool, UK [email protected]

Special Care Dentistry Unit, School of Medicine and Dentistry University of Santiago de Compostela Santiago de Compostela, Spain [email protected]

Andrei Barasch

Joel B. Epstein

Dental Clinics and Residency Program Cambridge Health Alliance Cambridge, MA, USA [email protected]

Cedars-Sinai Health System Los Angeles, CA, USA

Robert M. Brody Department of Otorhinolaryngology – Head & Neck Surgery, University of Pennsylvania Philadelphia, PA, USA [email protected]

City of Hope National Medical Center Duarte, CA, USA [email protected]

Contributors X

Ziv Gil

Richard C. Jordan

Otolaryngology, Head and Neck Surgery, The Head and Neck Center Rambam Healthcare Campus Haifa, Israel [email protected]

Departments of Orofacial Sciences, Pathology, and Radiation Oncology University of California San Francisco San Francisco, CA, USA [email protected]

Miguel Ángel González-Moles School of Dentistry, University of Granada Granada, Spain [email protected]

Lucía González-Ruiz Dermatology Service, Ciudad Real General University Hospital Ciudad Real, Spain

John S. Greenspan Department of Orofacial Sciences Schools of Dentistry and Medicine, University of California San Francisco San Francisco, CA, USA [email protected]

Mia Hashibe University of Utah School of Medicine Salt Lake City, UT, USA Huntsman Cancer Institute, University of Utah Salt Lake City, UT, USA [email protected]

Ashley Hay University of Edinburgh Edinburgh, Scotland, UK

Kenneth Hu Department of Radiation Oncology NYU Langone Health New York, NY, USA [email protected]

Newell W. Johnson Menzies Health Institute Queensland and School of Dentistry & Oral Health, Griffith University Gold Coast Campus, QLD, Australia Faculty of Dentistry, Oral and Craniofacial Sciences, King’s College London London, UK [email protected]

Deepak Kademani Oral and Maxillofacial Surgery and Head and Neck ­Oncologic and Reconstructive Surgery, North Memorial Medical Center Minneapolis, MN, USA [email protected]

A. Ross Kerr Department of Oral and Maxillofacial Pathology, Radiology and Medicine, New York University College of Dentistry New York, NY, USA [email protected]

Holli A. Loomans-Kropp Division of Cancer Prevention National Cancer Institute Rockville, MD, USA [email protected]

Hatsuhiko Maeda Department of Oral Pathology, School of Dentistry Aichi Gakuin University Nagoya, Japan [email protected]

Luis Monteiro Medicine and Oral Surgery Department Cancer Research Group – IINFACTS, Instituto ­Universitário de Ciências da Saúde (IUCS) – CESPU Gandra, Portugal

Shorook Na’ara Otolaryngology, Head and Neck Surgery, The Head and Neck Center, Rambam Healthcare Campus Haifa, Israel

Toru Nagao Department of Maxillofacial Surgery School of Dentistry, Aichi Gakuin University Nagoya, Japan [email protected]

John Edward O’Connell Department of Maxillofacial/Head and Neck Surgery, Aintree University Hospital Liverpool, UK

XI Contributors

Graham R. Ogden

Paul M. Speight

Oral & Maxillofacial Clinical Sciences, Dental Hospital & School, University of Dundee Dundee, Scotland, UK [email protected]

School of Clinical Dentistry, University of Sheffield Sheffield, UK [email protected]

Michał Studniarek Vera Panzarella Department of Surgical, Oncological and Oral Sciences (DICHIRONS) University of Palermo Palermo, Italy [email protected]

Ketan Patel Oral and Maxillofacial Surgery and Head and Neck Oncologic and Reconstructive Surgery, North Memorial Medical Center Minneapolis, MN, USA

Pablo Ramos-García School of Dentistry, University of Granada Granada, Spain [email protected]

Department of Radiology, Faculty of Medicine Medical University of Gdańsk Gdańsk, Poland [email protected]

Eva Szabo Division of Cancer Prevention National Cancer Institute Bethesda, MD, USA [email protected]

Annemieke van Zante Department of Pathology University of California San Francisco San Francisco, CA, USA [email protected]

Saman Warnakulasuriya Ranganathan Kannan Department of Oral Pathology Ragas Dental College and Hospital Chennai, India

Bhartesh A. Shah, MD Department of Radiation Oncology NYU Langone Health New York, NY, USA [email protected]

Jatin Shah Memorial Sloan Kettering Cancer Center New York, NY, USA [email protected]

Richard J. Shaw Department of Molecular and Clinical Cancer Medicine University of Liverpool Liverpool, UK Department of Maxillofacial/Head and Neck Surgery Aintree University Hospital Liverpool, UK [email protected]

Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London London, UK WHO Collaborating Centre for Oral Cancer King’s College London London, UK [email protected]

Barbara Wollenberg Clinic for Otorhinolaryngology, Head and Neck Surgery, MRI Klinikum rechts der Isar der Technischen Universität München Munich, Germany [email protected]

Susan Y. Wu Department of Radiation Oncology University of California – San Francisco San Francisco, CA, USA [email protected]

Sherry X. Yan Department of Radiation Oncology NYU Langone Health New York, NY, USA [email protected]

Arjun Gurmeet Singh Department of Head and Neck Surgical Oncology Tata Memorial Hospital Mumbai, India

Sue S. Yom Department of Radiation Oncology University of California – San Francisco San Francisco, CA, USA [email protected]

Acronyms AAO-HNS American Academy of Otolaryngol-

EPU

Epithelial Proliferation Unit

ogy-Head and Neck Surgery

ADC

Apparent Diffusion Coefficient

ADCC Antibody-Dependent Cellular

FDG-PET F-18-Fluorodeoxyglucose FEPE

Formalin-Fixed Paraffin-Embedded

Cytotoxicity

AJCC

FN

False Negatives

American Joint Committee on Cancer

ALT

FNA

Fine Needle Aspiration

Anterolateral Thigh Flap

ASR

FNAC

Fine Needle Aspiration Cytology

Age-Standardized Rates

ATC

FVL

Fluorescence Visualization Loss

Amplifying Transitory Cell

FVR

Fluorescence Visualization Retained Global Adult Tobacco Survey

ATP

Adenosine Triphosphate

ATR

Annual Transformation Rate

GATS

AUC

Area Under the Curve

GSH Glutathione

AUDIT Alcohol Use Disorders Identification Test BOTSCC Base of Tongue Squamous Cell Carcinomas

BTO

H&N

Head and Neck

HDR

High-Dose Rate

HNSCC Head and Neck Squamous Cell

Balloon Test Occlusion

13-cRA 13-cis-Retinoic Acid

Carcinoma

HPV

Human Papillomavirus

HR HPV

High-Risk HPV

CAF

Cancer-Associated Fibroblasts

CAMs

HR HPV DNA

High-Risk HPV DNA

Cell Adhesion Molecules

CAR

HRME

High-Resolution Microendoscopy

Chimeric Antigen Receptor

HSC

Haemopoietic Stem Cell

CASST Clinical Assessment Scoring System for Tracheostomy

CBCT

Cone Beam Computed Tomography

CCRT

Concurrent Chemoradiotherapy

CECT

Contrast-Enhanced CT

CSC

Cancer Stem Cell

CSS

Cause-Specific Survival

CT

Computed Tomography

CTCAE Common Terminology Criteria for Adverse Events

ct-DNA

Circulating Tumour DNA

CTP

Computed Tomography Perfusion

CTSc

Circulating Tumour Cells

DAMPs Damage-Associated Molecular Patterns

DCE

Dynamic Contrast-Enhanced MRI

DCIA Flap

Deep Circumflex Iliac Artery Flap

DFS

Disease-Free Survival

DOI

Depth of Invasion

DSS

Disease-Specific Survival

DWI-MRI

Diffusion-Weighted MRI

HSIL High-Grade Squamous Intraepithelial Lesions

IARC International Agency for Research on Cancer

ICD International Classification of Diseases

ICD-O International Classification of Diseases for Oncology

ICER

Incremental Cost-Effectiveness Ratio

IHC Immunohistochemistry IMRT Intensity Modulated Radiation Therapy

INHANCE International Head and Neck Cancer Epidemiology Consortium

INR

International Normalized Ratio

ISH

In Situ Hybridization

LCR

Long Control Region

LDR

Low-Dose Rate

LOH

Loss of Heterozygosity

LR HPV

Low-Risk HPV

LR

Likelihood Ratio

LSD

Late-Stage Disease

LVI

Lymphovascular Invasion

MCP-1

Monocyte Chemotactic Protein-1

E6 and E7

HPV Proteins

EBRT

External Beam Radiation Therapy

ECE

Extracapsular Extension

ECO

European Cancer Observatory

EMT

Epithelial to Mesenchymal Transition

ENE

Extranodal Extension

MDT

Multidisciplinary Team

EPOC

Erlotinib Prevention of Oral Cancer

MET

Mesenchymal to Epithelial Transition

MDCT Multi-detector Computed Tomography

XIII Acronyms

mi ENE

Microscopic Extranodal Extension

r TNM

TNM Staging for Recurrent Cancer

MRI

Magnetic Resonance Imaging

RAD

Radiation-Associated Dysphagia

MRONJ Medication-Related Osteonecrosis of

RANKL Receptor Activator of Nuclear Factor

the Jaw

Kappa-B Ligand

mT

Multiple Primary Tumours

RAVD Response-Adapted Volume

NBI

Narrow-Band Imaging

RBF

Regional Blood Flow

RBV

Regional Blood Volume

RFFF

Radial Forearm Free Flap

RFS

Recurrence-Free Survival

ROC

Receiver Operating Characteristic

SCC

Squamous Cell Carcinoma

Deescalation

NCCN National Comprehensive Cancer Network

NCDB

National Cancer Data Base

NPV

Negative Predictive Value

NSM

Necrotizing Sialometaplasia

NX Regional lymph nodes cannot be assessed by histopathology

OE

Oral Erythroplakia

OL

Oral Leukoplakia

OLL

Oral Lichenoid Lesions

OLP

Oral Lichen Planus

OPC

Oropharyngeal Cancer

SCM Sternocleidomastoid SEER Surveillance, Epidemiology, and End Results Program

SES

Socio-economic Status

SITEP Short-Term Intermittent Therapy to Eliminate Premalignancy

SLNB

Sentinel Lymph Node Biopsy

OPG Orthopantomogram

SMA

Smooth Muscle Actin

OPMD

SOP

Standard operating procedure

STI

Sexually Transmitted Infections

Oral Potentially Malignant Disorders

OPSCC Oropharyngeal Squamous Cell Carcinoma

ORF

Open Reading Frames

OS

Overall Survival

OSCC

Oral Squamous Cell Carcinoma

TAA

OTS

Oral Toxicity Scale

TAM

Tumour-Associated Macrophages

TCGA

The Cancer Genome Atlas

TGF-α

Transforming Growth Factor Alpha

Tis

Tumour In Situ

PAMPs Pathogen-Associated Molecular Patterns

PAP

Papanicolaou Smear

PATHOS Post-operative Adjuvant Treatment for HPV-Positive Tumours

PCR

Polymerase Chain Reaction

PD-1

Programmed Death Receptor-1

PD-L1 Programmed Death Receptor-1 Ligand

Tumour-Associated Antigens

TLM

Transoral Laser Microsurgery

TLR

Toll-Like Receptors

TME

Tumour Microenvironment

TN

True Negatives

TNM Tumour, Nodal, Metastasis classification Transoral Robotic Surgery

tomy

TPS

Tumour Proportion Score

Positron Emission Tomography

TSCC

Tonsillar Squamous Cell Carcinomas

TUGSE

Eosinophilic Granuloma

PPARγ Peroxisome Proliferator-Activated Receptor Gamma

PPV

tumour

TORS

PEG Percutaneous Endoscopic GastrosPET

T0 No pathological evidence of primary

TX Primary tumour cannot be assessed by histopathology

Positive Predictive Value

PRISMA Preferred Reporting Items for Systematic Review and Meta-analysis

PRO-CTCAE NCI Patient Reported Outcomes-

UADT

Upper Aerodigestive Tract

UICC Union for International Cancer Control

Common Terminology Criteria for Adverse Events

PSA

US Ultrasonography

Prostate-Specific Antigen

PVL

USgFNAC US-Guided Fine-Needle Aspiration

Proliferative Verrucous Leukoplakia

QALYs

Quality Adjusted Life Years

VEGF

qPCR

Quantitative PCR

WB-MRI

Whole Body MRI

qRT-PCR

Reverse Transcriptase PCR

WPS

Water Pipe Smoking

QUDAS-2 Quality Assessment of Diagnostic Accuracy Studies

Cytology Vascular Endothelial Growth Factor

1

Introduction – Cancers of the Mouth and Oropharynx Saman Warnakulasuriya and John S. Greenspan

© Springer Nature Switzerland AG 2020 S. Warnakulasuriya, J. S. Greenspan (eds.), Textbook of Oral Cancer, Textbooks in Contemporary Dentistry, https://doi.org/10.1007/978-3-030-32316-5_1

1

2

1

S. Warnakulasuriya and J. S. Greenspan

Recent decades have seen tremendous advances in our understanding of the etiology, biology, and molecular basis of oral cancer, as well as important clinical advances in the diagnosis and management of this disease. Our aim in launching this textbook is to present important achievements that have been made in these respective fields, to summarize the current evidence, and to identify future perspectives. In 2018, an estimated 354,864 people were diagnosed with oral cancer and 92,887 with oropharyngeal cancer, making this the eighth leading cause of cancer worldwide. Oral squamous cell carcinoma (OSCC) is the most frequent malignant tumor of the oral cavity, encompassing more than 90% of all oral malignancies. Though this book primarily deals with oral cancer in depth, we have devoted sections of some chapters to present some key information on oropharyngeal cancers. Since the 1970s, the incidence of oral cancer, particularly tongue cancer, has risen in many countries, and recent studies have also shown a steady rise in the oropharyngeal cancer trajectory in high-income countries, particularly in the USA. Despite the progress in therapy, the mortality and morbidity rates of patients with oral cancer have not improved except in a few countries with advanced cancer centers. In 7 Chapter 2, we present these global epidemiological data that are of particular interest to public health specialists. We draw the readers’ attention to the importance of considering various anatomical subsites of lip, oral cavity, and oropharynx as illustrated in . Figs. 1.1 and 1.2 and based on the ICD10 classification of diseases (. Table  1.1) (7 https://  

 

 

 

apps.­who.­int/classifications/apps/icd/icd10online2007/index.­ htm?kc00.­htm+) when reviewing the literature. As discussed ..      Fig. 1.1  Anatomy of the oral cavity. (Copyright license ©2012 Terese Winslow LLC, U.S. Govt. has certain rights). Note that the soft palate, uvula, and tonsil are parts of the oropharynx

Lip

in this chapter, it is clear that distinct differences exist in the epidemiology of the disease among the five continents. In 7 Chapters 3 and 4, we review the major risk factors of oral cancer, namely, tobacco, alcohol, and areca nut, and the role of human papillomavirus in the etiology of oropharyngeal cancers. There is an extensive literature on this topic, and we present the evidence in a summary form that we hope can be easily assimilated by our readers. The controversial aspects of the etiology are presented separately in a later chapter. In 7 Chapters 5, 6, and 7 we present the clinicopathological aspects of the disease. Correct staging of the tumor is important in making treatment decisions, and 7 Chapter 6 summarizes significant modifications for clinical and pathological staging of head and neck cancers extracted from the recently released eighth edition of the American Joint Committee on Cancer Staging Manual. In 7 Chapters 8, 9, 10, and 11, we summarize current knowledge on investigations to detect oral and oropharyngeal cancer helpful to clinicians and head and neck pathologists managing diagnostic services in secondary care facilities. Molecular aspects of oral cancer are discussed in 7 Chapter 14 to assist the reader in understanding new biomarkers that may in the future help in cancer diagnostics and directing therapy. The majority of oral cancers are still identified in late and in advanced clinical stages, and 7 Chapter 15 is devoted to advance the importance of the early detection of the disease. Since the publication of the World Health Organization classification of oral potentially malignant disorders (OPMDs) in 2007, there has been growth of research on this topic, with over 750 publications in the past decade. In 7 Chapters 12 and 13, we present knowledge from diagnosis  

 

 

 

 

 

 

Gingiva (gum)

Teeth Hard palate Soft palate

Uvula Tonsil

Retromolar trigone Buccal mucosa (lip and cheek lining) Tongue (front two-thirds) Floor of mouth

1

3 Introduction – Cancers of the Mouth and Oropharynx

..      Fig. 1.2  Anatomy of the pharynx. (Copyright license ©2012 Terese Winslow LLC, U.S. Govt. has certain rights)

Nasal cavity Nasopharynx Oral cavity Pharynx

Oropharynx

Hypopharynx

Hyoid bone Larynx

Esophagus Trachea

..      Table 1.1  ICD-10 Classification C00.3–C14.8: Cancers of lip, oral cavity, and oropharynx

..      Table 1.1 (continued) Lip and oral cavity

Lip and oral cavity

Oropharynx

C00.3 – Mucosa of upper lip

C01.9 – Base of tongue, NOS

C00.4 – Mucosa of lower lip

C02.4 – Lingual tonsil

C00.5 – Mucosa of lip, NOS

C05.1 – Soft palate, NOS

C00.6 – Commissure of lip

C05.2 – Uvula

C00.8 – Overlapping lesion of lip

C09.0 – Tonsillar fossa

C00.9 – Lip, NOS

C09.1 – Tonsillar pillar

C02.0 – Dorsal surface of tongue, NOS

C09.8 – Overlapping lesion of tonsil

C02.1 – Lateral border of tongue

C09.9 – Tonsil, NOS

C02.2 – Ventral surface of tongue, NOS

C10.2 – Lateral wall of oropharynx

C02.3 – Anterior 2/3 of tongue, NOS

C10.3 – Posterior wall of oropharynx

C02.8 – Overlapping lesion of tongue

C10.8 – Overlapping lesion of oropharynx

C02.9 – Tongue, NOS

C10.9 – Oropharynx, NOS

C03.0 – Upper gum

C03.1 – Lower gum C03.9 – Gum, NOS C04.0 – Anterior floor of the mouth C04.1 – Lateral floor of the mouth C04.8 – Overlapping lesion of the floor of the mouth C04.9 – Floor of the mouth, NOS C05.0 – Hard palate C05.8 – Overlapping lesion of palate C05.9 – Palate, NOS C06.0 – Cheek mucosa C06.1 – Vestibule of mouth C06.2 – Retromolar area C06.8 – Overlapping lesion of other and unspecified mouth C06.9 – Mouth, NOS C14.8 – Overlapping lesion of the lip, oral cavity, and pharynx

Oropharynx

4

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S. Warnakulasuriya and J. S. Greenspan

to the management of OPMDs and pertinent data from follow-­up studies examining the evidence on their malignant transformation. 7 Chapters 16, 17, and 18 deal with aspects of prevention of the disease and focus on controlling lifestyle risk factors and chemoprevention, including information on ongoing clinical trials and approaches to secondary prevention. The principles and application of screening to facilitate and improve early detection are covered in 7 Chapter 16. 7 Chapters 19, 20, 21, 22, 23, 24, and 25 are devoted to various primary treatment modalities and principles underlying surgical and radio-chemotherapy treatment and factors affecting survival. In 7 Chapter 23, the controversies on de-­ intensification of treatment for HPV-associated cancers of the oropharynx are discussed. 7 Chapters 27 and 28 focus on new advances in molecular therapies and immunotherapy and their role in the management of oral cancer through personalized medicine. After primary treatment, relapses or metastases are encountered often, and primary treatment can profoundly affect the functioning of the oral cavity complex.  

 

 

 

 

These aspects are less emphasized in standard textbooks, and 7 Chapter 26 deals with supportive and palliative care for patients with oral cancer. Cancer biology is comprehensively covered in 7 Chapter 29, and we hope this would be of interest to both clinicians and researchers to understand the evolution and clonal expansion of a malignant cell that leads to a squamous cell carcinoma. As a prelude to future perspectives, we have in 7 Chapter 30 included a critique on cancer stem cells to broaden the readership on this topic. The contributors to this textbook are well-known authorities in their respective fields, and this book has brought together their expertise to provide an all-encompassing synthesis of the current state of knowledge on oral cancer. The ultimate intent of the book is to have an appeal to a broad group of clinicians working in oral medicine, otolaryngology, oncology, maxillofacial pathology, and other aspects of head and neck cancer. We hope this textbook will particularly help surgical trainees, residents, and specialists to broaden their knowledge to comprehensively manage oral cancer patients that they encounter in routine practice.  

 

 

5

Epidemiology of Oral and Oropharyngeal Cancers Saman Warnakulasuriya and John S. Greenspan 2.1

Introduction – 6

2.2

Global Incidence and Mortality – 6

2.2.1 2.2.2

I ncidence – 6 Mortality – 8

2.3

Demography – 8

2.3.1 2.3.2 2.3.3

 ge and Sex – 8 A Socioeconomic Status – 8 Ethnicity – 8

2.4

Trends – 9

2.5

Survival – 10

2.6

World Regions – 12

2.6.1 2.6.2 2.6.3 2.6.4 2.6.5 2.6.6 2.6.7 2.6.8 2.6.9 2.6.10

 orth America – 12 N South America – 12 Europe – 14 Middle East and North Africa – 14 Sub-Saharan Africa – 14 South Asia – 14 Southeast Asia – 17 China – 17 Taiwan – 17 Oceania – 18

2.7

Young Persons – 18

2.8

Conclusions – 19

2.9

Acknowledgments – 19 References – 19

© Springer Nature Switzerland AG 2020 S. Warnakulasuriya, J. S. Greenspan (eds.), Textbook of Oral Cancer, Textbooks in Contemporary Dentistry, https://doi.org/10.1007/978-3-030-32316-5_2

2

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S. Warnakulasuriya and J. S. Greenspan

Core Message

2

With an estimated 500,000 new cases each year worldwide and rising trends reported in many countries, particularly among the young, focused public health measures are needed to reduce the incidence of and mortality from oral and oropharyngeal cancer. There is considerable variation in the global incidence patterns, reflecting population lifestyles in each country. The aim of this chapter collating global epidemiological evidence is to stimulate research and policy development and to highlight appropriate strategies to reduce the oral cancer burden worldwide.

2.1

Introduction

Cancer incidence in five continents [1], the GLOBOCAN (2018), and the Global Cancer Observatory (2018) of the International Agency for Research on Cancer (IARC) [2, 3] provide estimates of worldwide incidence for and mortality from oral and pharyngeal cancers. The GOBOCAN data source covers 184 countries worldwide and is the best source available for reporting global data. For US data, we consulted the National Cancer Institute’s (NCI’s) Surveillance, Epidemiology, and End Results (SEER) Program Statistics [4]. SEER data reports on incidence and mortality data, from all 18 SEER registries, covering 28% of the US population. Based on the SEER registry data on incidence and mortality, the stage distribution, the lifetime probability of developing cancer, and survival statistics for US population are estimated in the yearly reports on cancer statistics by Seigel, Miller, and Jemal et al. [5]. EUREG, operated by the European Cancer Observatory (ECO), informs us the geographical distribution and trends in incidence, mortality, and survival in European cancer registries for 35 major cancers from 100 registration zones [6]. Further sources of oral cancer data are several published recent reports following the presentations made at the Global Oral Cancer Forum (2016) [7]. For this chapter, under oral cancer, we include cancers of the lip, tongue, gum, floor of mouth, the palate, and rest of the mouth. In the International Classification of Diseases (ICD), 10th revision (ICD-10), these sites code for C00, C02, C03, C04, C05, and C06. In most epidemiological studies, the authors report data on oral cancer combined with the pharynx, for ICD-10 sites C01, C09–C10, and C12–C14. In general cancers involving the major salivary glands (C07– C08) are excluded. The oropharynx is of particular interest due to recent rising trends (see below), and this site includes cancers of the base of the tongue (C01); soft palate, uvula, and tonsil (C09); and lateral and posterior walls of the pharynx (C09–C10). When referring to oral and oropharyngeal sites, cancers of nasopharynx (C11) and hypopharynx are generally excluded as these anatomical locations have specific risk factors, different from those in the mouth. Correctly citing the topographical codes for oral cavity and pharyngeal cancers remains a complex task due to some anatomical sites such as the lingual tonsil (C02.4) and soft palate (C05.1) being included within C02–C06. Diagrammatic illustrations

of the oral cavity and pharyngeal sites are provided in 7 Chapter 1.  

2.2

Global Incidence and Mortality

2.2.1

Incidence

Oral Cancer  Global estimates indicate that oral cancer is one of the most common cancers in the world, falling within the top ten cancers in several countries and accounting for an estimated 354,864 new cases. When taken together with the oropharynx, these two sites account for an estimated 447,751 new cases and are together in the eighth position – corresponding to 2.5% of all cancer cases  – and 228,389 deaths annually in 2015 [2, 3]. The estimated ASR of oral cavity cancer was 5.8 in men and 2.3 in women per 100,000 in 2015. There are substantial regional differences also when examined by sex and age groups. Of the estimated global incidence, two-thirds of oral cancers occur in low-income countries, and half of those cases are in South Asia (. Fig. 2.1). India alone accounts for approximately 100,000 incident cases every year. There are considerable geographical variations in the incidence of this cancer, and the rates vary by more than 20-fold worldwide. Papua New Guinea is estimated to have the highest incidence rate of oral cancer in the world. Other regions reported to have high incidence rates for oral cancer (excluding lip) are found in South Asia (e.g., Maldives, Sri Lanka, India, and Pakistan), East Asia (e.g., Taiwan), parts of Western Europe (e.g., NW France and Portugal) and Eastern Europe (e.g., Hungary, Slovakia, and Slovenia), and parts of Latin America and the Caribbean (e.g., Brazil, Uruguay, and Puerto Rico). The five countries with the highest ASRs in the world (Papua New Guinea, Taiwan, Maldives, Sri Lanka, and Pakistan, in the order of frequency) were predominantly from the regions of the Oceania and Eastern and South Asia [2, 3, 8]. Age-adjusted rates for male populations in “high-­risk countries” in the world are shown in . Fig. 2.2.  

 

>>Important Geographical variations in oral cancer incidence within a country such as in Brazil, China, and Saudi Arabia should be borne in mind when interpreting the ASR assigned for any country. Oropharyngeal Cancer  Oropharyngeal cancer includes a

spectrum of anatomical sites. It occurs in four principal locations, which include the under surface of the soft palate, the base of the tongue, the tonsils, and walls of the pharynx as defined in 7 Chapter 4. Oropharyngeal cancer and oral cancer are two distinct diseases, although they have some risk factors in common, that is, tobacco and alcohol use. Close to 70% of oropharyngeal cancers are now considered to be caused by high risk types of human papillomavirus (HPV)  

2

7 Epidemiology of Oral and Oropharyngeal Cancers

..      Fig. 2.1  Map showing high incidence countries in the world

Country World Czech Republic Cambodia Brazil Spain USA Slovenia France (Metrapolitan) Croatia Germany Myanmar Australasia Madagascar Romania India Ukraine Pakistan Belarus Slovakia Portugal French – Guadeloupe Bangladesh French – la Reunion Maldives Sri Lanka Hungary Papua New Guinea Taiwan 0

5

10

15

20

25

30

35

Incidence (per 100,000) ..      Fig. 2.2  Age-standardized incidence rates of lip and oral cancer in men in selected high-risk countries. (Source Globocan, 2015 [3], Taiwan Cancer Registry [8])

8

S. Warnakulasuriya and J. S. Greenspan

(see 7 Chapter 4). It is estimated that around 130,300 new cases of pharyngeal cancers (excluding nasopharynx) are reported per year in the world, with an age-­adjusted incidence of 3.2 per 100,000.The incidence of oropharyngeal cancer is highest in France and increasing trends are reported from many countries. Rates are reported to be lower in most regions of Asia when compared with Europe, Australia and North America. Male to female excess of oropharyngeal cancer is observed consistently in both low and high incidence countries. In the USA, middle-aged white men (40–59 years old) have shown the highest increase in HPV-positive oropharyngeal cancers. An emergence of a modest rise in incidence in women has been noted. Cancers of the oropharynx, like oral cancer, are usually squamous cell carcinomas (SCCs) originating from epithelial cells that line the tonsillar crypt (specialized reticulated crypt epithelium) or middle part of the pharynx. In many centers across the globe nearly all patients with oropharyngeal cancers present with advanced tumors.  

2

Definition Anatomical subsites for oropharyngeal cancer need good definition and are discussed in 7 Chapter 4.  

Lip Cancer  The estimated global age-standardized rate (ASR) of cancers of lip in 2012 was 0.3 per 100,000 (0.4 in men and 0.2 in women), with marked differences in regional statistics. Lip cancer is common in Australia, Southern Spain, Greece, Israel, Serbia, and Ukraine and in some parts of Canada.

2.2.2

Mortality

Mortality rates are unacceptably high in most countries  – around 50%  – except in some outstanding centers in the world. This had not changed for many decades. Fortunately some reduction in mortality from oral cancer was noted in France and in the USA between 2002 and 2012, with an annual percentage decline of −1% in some cancer centers. The mortality rates have continued to rise in some Eastern European countries, including Hungary and Slovakia. Compared to deaths reported in GLOBOCAN 2012, the numbers have significantly risen by 2015.

as we refer to later. The differences by sex are clearly illustrated in the incidence rates reported in the world literature, and some examples are cited in 7 Section 2.6. The gender differences in incidence are due to tobacco and alcohol habits which are higher in men, and the ratio is falling in countries where women have taken up these ­habits. The incidence of oral cancer increases with age, and the majority of cases occur in people aged 50  years or over. . Figure 2.3 illustrates the age and sex distribution of persons diagnosed with oral cancer in South East England showing a higher incidence in men compared to women and a higher proportion of cases in the age group 50–75  years. In most published series, the average age at presentation is around 60–65 years (mean of 62 years). Toward the end of the last century, several reports did highlight a trend for oral cancer to affect younger individuals (under the age of 45 years) [9], and this trend is continuing (see 7 Section 2.7).  

 

 

2.3.2

Socioeconomic Status

Oral cancer is linked to socioeconomic status and deprivation, with the highest incidence rates occurring in the most disadvantaged groups of the population. As shown by Conway et al. [10] in a systematic review of 41 publications, the evidence for this is consistent whether measured by income, education, or employment and adjusted for other major risk factors (see 7 Chapter 29). This association is particularly strong for men. An exception is the young age group (under 45 years of age) in whom a quarter could be from professional classes. In the USA, being uninsured or receiving Medicaid raised the likelihood of presenting with more advanced stages of oropharyngeal cancer, thus decreasing the chances of survival [11].  

2.3.3

Ethnicity

There are some strong ancestral or ethnic variations in the incidence and mortality patterns of oral cancer, and these are largely explained by different cultural practices related to risk habits. For this reason, populations living in South and East Asia and Melanesia record high rates for oral cancer where betel quid chewing is prevalent. Even within a country, such differences are apparent: Indians living in Malaysia have higher incidence rates of oral cancer than Malays or Chinese [12]. In the Republic of South Africa, colourdes have higher rates of oral cancer than black Africans [13]. Comparative studies have shown that US black males have higher oral cancer rates compared with 2.3 Demography whites or Hispanic males [14]. The underlying reasons for these differences may be largely explained by social and 2.3.1 Age and Sex environmental factors. Racial disparities for oropharyngeal Several decades ago, the incidence rates for men were much cancer among black and white Americans have been noted, higher than in women (ratio of 7:1), but on average, the age-­ including advanced stage at presentation among blacks standardized rates for men are currently just twice as high as [15]. Migrant studies have shown that South Asians living the rates for women (in most countries in a ratio of 2:1). in the United Kingdom have significantly higher oral cancer There are some exceptions to this ratio in some populations rates compared with natives [16]. While most of these asso-

2

9 Epidemiology of Oral and Oropharyngeal Cancers

Oral cancer incidence by age and sex (SE England) 40 600

400 20

200

Rate per 100,000 population

Number of cases

30

10

85+

80–84

75–79

70–74

65–69

60–64

55–59

50–54

45–49

40–44

35–39

30–34

25–29

20–24

15–19

10–14

5–9

0 0–4

0

Age at diagnosis Mean Age ~ 62 years Male cases

Female cases

Male rates

Female rates

..      Fig. 2.3  Graph illustrating age and sex differences in numbers of new cases and age-specific incidence rates by sex in Southeast England in 2007

ciations reflect ethnicity, little is known about any racial differences. In Israel, the risk of developing oral cancer is twice as high in Ashkenazi Jews compared with Sephardi and Eastern Jewish ethnic groups [17]. 2.4

Trends

Lip cancer rates are reported to be declining in several countries that had earlier reported high incidences, for example, Australia [18], Madrid, Spain [19], and Israel (since 2000) [20]. Up to the twentieth century, oral cancer rates were rising; thereafter the rates stabilized and showed a decline in the post–Second World War years. Since the 1970s, data from several European countries showed evidence for rising incidence, with the initial reports coming from Scotland and Denmark [21–23]. It is estimated that by 2035, global oral

cancer incidence will rise by 62% to 856,000 new cases per year because of changes in demographics [24]. Rapidly increasing numbers of oral cancers and also incidence rates reported in the United Kingdom have been striking, with a 35% rise between 1995 and 2005, numbers going up from 3673 in 1995 to 4926 in 2005, and this increase happened at a faster rate in young adults. In Portugal, between 1998 and 2007, there was an increase in the age-standardized incidence of oral cancers of 1.96% per year for both sexes. This increase was higher in the female group being 4.34% per year [25]. Trends on the rising incidence of tongue cancer were reported in Nordic countries [26]. In the USA, overall age-adjusted rates for oral cancer among both white and black Americans have been declining [27], but there have been striking increases in incidence rates of tongue cancer in both men and women and oropharyngeal cancer in men between 1973 and 2012 [28] confirming earlier reports by Shiboski et al. [29, 30]. In the USA, the percent

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S. Warnakulasuriya and J. S. Greenspan

Age – adjusted SEER incidence rates by cancer site All ages, all races, both sexes 1975–2014 (SEER 9)

4.5

3.5

4.0

3.0 Rate per 100,000

3.5 Rate per 100,000

Age – adjusted SEER incidence rates by cancer site All ages, all races, both sexes 1975–2014 (SEER 9)

3.0 2.5 2.0 1.5

2.5 2.0 1.5 1.0

1.0

0.5

0.5 0.0 5 197

0.0 5 197

5 0 0 5 0 4 199 199 200 200 201 201 Year of Diagnosis Tongue Lip Floor of mouth Gum & other mouth

0 198

5 198

Cancer sites include invasive cases only unless otherwise noted. ..      Fig. 2.4  Graph illustrating trends for oral cancer in the USA (SEER regions) for all races, all ages, and both sexes combined over the period 1975–2014. Data for the lip, tongue, floor of mouth, gum, and other mouth are shown

annual increase in the incidence rates during the period 1973–2001 was 2.1% for the oral tongue, slightly lower for the base of the tongue (1.7%), and 3.9% for the tonsils [30]. US data for the period 1975–2014 (for all races, all ages, and both sexes combined) for oral sites and oropharyngeal sites are shown in . Figs. 2.4 and 2.5. The reasons for rising trends for tongue cancer remain unclear. In France (based on data from 11 registries covering 19% of the mainland French population), the incidence rates of lip and oral cavity cancers are decreasing considerably in men but showing an increase in women, especially for oropharyngeal and palatal cancers. The peak of high incidence in French men was around 1985. From1985 to 2005, the world-­ standardized incidence rates of lip and oral cavity cancers in French men decreased by 43%. Over this period, the mean annual decrease was −2.2%; however, this decrease accelerated over 2000–2005, at −5.0% per year. In women, the world-standardized incidence rates of these cancers rose by close to 50%. Women showed a 1.6% constant annual increase [31] (. Fig. 2.6). Japan also, which traditionally has had low incidence rates for oral cancer, has shown increases since the mid-­ 1970s in males and two decades later in females (. Fig. 2.7). There was a 3.5-fold increase in age-standardized rates for males and over twofold increase for females between 1975 and 2013 [32]. Fortunately, in India and Sri Lanka there has been a decline in incidence in recent times [33]. However, there  

 

 

0

198

5

198

0 5 0 200 199 199 Year of diagnosis

5

200

0 4 201 201

Oropharynx including tonsil Cancer siters include invasive cases only unless otherwise noted. ..      Fig. 2.5  Graph illustrating trends for cancers of the oropharynx in the USA (SEER regions) for all races, all ages, and both sexes combined over the period 1975–2014. Data for oropharynx inc. tonsil are shown

are pockets in India where rapid rises in incidence of oral cancer have occurred such as in Mumbai (2.7% annual increase among men during 1995 to 2009) [34] and in Ahmedabad City between 1985 and 1995 as shown by Gupta and co-­workers [35]. Crude incidence projections by GLOBOCAN [2, 3] demonstrate that new cases of oral cancer in India will rise to over 125,000 cases by 2030 in both sexes. 2.5

Survival

For lip cancers, the overall 5-year survival rate is around 85%. However, for oral cavity cancers, the situation is very different. In many world regions, there have been no marked improvements in the 5-year survival rates for intra-oral cancer, which remain at about 50%, despite advances in surgery and radiation treatment. In most South Asian countries, 5-year survival rates are below 50%. In the USA, during 2005 to 2011, relative 5-year survival for all races was recorded at 66% [5]. Five-year relative survival rates have gradually improved over the past period of 30 years and has shown a significant improvement by more than 11 percentage points between 1990 and 2006 [36]. An analysis of patients presenting with late-stage disease (LSD) showed an increase in 3-year overall survival from 18% to 34% over 1998–2006 [37]. The authors attributed this improvement in survival particularly to large percentage of

2

11 Epidemiology of Oral and Oropharyngeal Cancers

..      Fig. 2.6  Trends for lip and oral cavity cancers in adult French population in 1980–2005. Data for 2010 correspond to a projection based on the hypothesis that the past trend will continue. (Source: Figure drawn using data from Ligier et al., 2011- Ref 31 licence no 4543680567237)

Incidence rates for lip and oral cavity cancer in adult French population 1980–2010 45 40

39.4

38.2

37.8

Incidence per 100,000 persons

35

33.8

30

28.2

25 Men

21.8

20

Women 16.6

15 10 5

3.5

4

3.7

5.2

4.8

4

5.4

0 1980

1985

1990

1995

2000

2005

2010

16 14 12 10 8

6

4

2

0 75

19

80

19

85

19

95

90

19

19

Male

00

20

05

20

10

20

13

20

Female

..      Fig. 2.7  Age-standardized incidence rates for oral cavity and pharynx (C00–C14) in Japan (1975–2013). (Source: Cancer Statistics in Japan. National Cancer Center, Japan – reference 32)

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S. Warnakulasuriya and J. S. Greenspan

patients receiving treatment in high-volume centers in the later period of the study. An international collaborative study (Italy, Germany, the USA, Brazil, India, Taiwan, Australia) reported an 11–12% increase in 5-year survival in the period 2001–2011 compared to 1990–2000. [38]. As the stage at diagnosis had not shown any improvement, the reasons for these observations therefore remain unexplained, though likely factors are advances in imaging and therapeutic advances. Eyecatcher

Incidence data for the USA relate to 13 SEER information gathering sites covering 14% of the US population, and mortality data are from all 50 US states and therefore cover 100% of the US population. The five states with the highest number of estimated cases were California, Florida, Texas, New York, and Pennsylvania. The age-adjusted rate of oral and pharyngeal cancers was 11.2 per 100,000 (men and women combined) per year, while the number of deaths was 2.5 per 100,000 (men and women combined) per year. These figures are based on 2010–2014 cases and deaths [4]. The US trend can be extracted from the publicly available SEER data [4]. . Figures 2.4 and 2.5 refer to earlier illustrated long-term trends (1975–2014) in the combined incidence rates for oral (lip, tongue, gum, and other oral) and pharynx and tonsil for both sexes. . Figures  2.8, 2.9, 2.10, and 2.11 show these trends for US males and females separately. Since the year 2000, while tongue cancer incidence has gradually risen in men, there is a steady decline in the incidence of cancer in the lip and other oral sites (. Figs. 2.8 and 2.9) in both sexes. Since 2000, cancers of the oropharynx and tonsil have increased both in women and men (. Figs. 2.10 and 2.11). For oral and pharyngeal cancer combined, the mean 5-year survival rate (2007–2013) among all racial groups is 65%, and survival has improved since the mid-1970s. The proportion of cancers with regional or distant metastasis has not shown any changes. The lifetime probability of being diagnosed with oral and pharyngeal cancer during 2012–2014 was 1.1%, and the probability of dying from or with this cancer was 0.3%. Cancer occurrence and outcomes in the USA were reported to vary considerably between racial and ethnic groups [42]. Reported differences are highlighted by Siegel et al. [5] showing advanced stages in US blacks. These differences are largely due to differences in exposure to risk factors and because of inequalities in wealth that lead to barriers to cancer prevention, education, and access to care. However, some authors have suggested that these differences are now disappearing [43].  

For patients with late-stage disease, 3-year survival rate for oral cancer in the USA has risen from 17.9% to 33.9% over the period 1998–2006. This improvement correlates with the introduction of adjuvant chemoradiation and designating high-volume cancer centers for the management.

 

 

Reports from cancer registries in India indicate 5-year survival rates lower than 35 percent while in Pakistan, China, the Republic of Korea, Singapore, and Thailand it ranges between 32% and 54% [39]. On average, the 5-year survival rates for small and localized oral cancers are around 80%, and the 5-year survival falls close to 20% when the cancer has spread to regional lymph nodes (see 7 Chapter 25). The overall survival rates for patients treated for oral cancer relate not only to the tumor factors (i.e., staging) but also vary by patient factors such as age and comorbidities. Old age accounts for treatment-­related death, and comorbidities may compromise optimal therapies [40]. These modifying factors should be considered when describing the epidemiology data on survival. Survival in young people (age under 45 years) is significantly better than older patients [41], and this could be primarily due to differences in comorbidities in the two groups.  

2.6

World Regions

Based on the available information from the WHO country profiles and published literature, we highlight some noteworthy data for each region in the world. The anterior two-thirds of the tongue and floor of the mouth account for most oral cavity cancers in Americas and Europe and buccal mucosa in South Asian populations. 2.6.1

North America

zz United States of America

An estimated number of 51,540 oral and pharyngeal cancers and 10,030 deaths in 2018 have been predicted [5]. Oral and pharyngeal cancers account for about 4% of all cancers in men.

 

zz Canada

In Canada, as much as in the USA described above, the incidence of lip and oral cavity cancers (excluding tongue) among men has declined during 1990–2012. As in the USA, the incidence of tongue and oropharyngeal cancer has shown significant increases during 1990–2012 in Canadian men. 2.6.2

South America

The incidence of oral and oropharyngeal cancers in South America varies in different regions; highest rates are observed in Brazil, among males [44]. For the year 2018, the Brazilian National Institute of Cancer [45] estimated 11,200 new cases in men and 3500 in women totaling close to 15,000 cases in Brazil. The city of Sao Paulo has the highest oral cancer incidence in the country, with rates ranging from 10.4/100,000 in the period 1998–2002 to 9/100,000  in the period 2003–

2

13 Epidemiology of Oral and Oropharyngeal Cancers

7.0

Age – adjusted SEER incidence rates By cancer site All ages, all races, male 1975–2014 (SEER 9)

5.0

4.0

5.0

Rate per 100,000

Rate per 100,000

6.0

Age – adjusted SEER incidence rates By cancer site All ages, all races, male 1975–2014 (SEER 9)

4.0 3.0

3.0

2.0

2.0 1.0

1.0 0.0 5 197

0

198

Cancer sites include invasive cases only unless otherwise noted. ..      Fig. 2.8  US trends based on SEER data for individual oral cavity subsites in men (1975–2014)

2.5

0.0 5 197

0 0 0 4 5 5 199 200 201 201 199 200 Year of Diagnosis Lip Tongue Floor of mouth Gum & other mouth 5

198

5 0 5 0 199 200 200 199 Year of Diagnosis

0

201

4

201

Cancer sites include invasive cases only unless otherwise noted. ..      Fig. 2.10  US trends based on SEER data for oropharyngeal cancers in men (1975–2014)

Age – adjusted SEER incidence rates By cancer site All ages, all races, female 1975–2014 (SEER 9)

1.5

Age – adjusted SEER incidence rates By cancer site All ages, all races, female 1975–2014 (SEER 9)

1.3 Rate per 100,000

Rate per 100,000

5

198

Oropharynx inc. Tonsil

2.0

1.5

1.0

0.5

0.0 5 197

0

198

1.0 0.8 0.5 0.3

0

198

5

198

5 5 0 0 199 200 200 199 Year of Diagnosis

Lip Floor of mouth

4 0 201 201

Tongue Gum & other mouth

Cancer sites include invasive cases only unless otherwise noted. ..      Fig. 2.9  US trends based on SEER data for individual oral cavity subsites in women (1975–2014)

0.0 5 197

0

198

5

198

5 0 5 0 199 200 200 199 Year of Diagnosis

0

201

4

201

Oropharynx inc. Tonsil Cancer sites include invasive cases only unless otherwise noted. ..      Fig. 2.11  US trends based on SEER data for oropharyngeal cancers in women (1975–2014)

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2007 in men. Although the incidence rate of oral cancer in most South American countries has been decreasing since 1999, a significant increase is observed in Peru and women in Brazil [44]. Marked differences in oral cancer incidence and mortality are noted within Brazilian federative units. The estimates of the incidence and mortality rates for oral cancer (OC) from persons aged ≥40  years in the period 2005–2014 showed that the highest incidence was in the south and southeast region, followed by the northeast and midwest regions of Brazil [46] (. Fig. 2.12a, b).  

2.6.3

Europe

European data have been reviewed recently by Diz et al. [47]. Significant differences in the oral cancer burden are noted across the whole of Europe. These differences are marked particularly between Western and Eastern European countries (. Fig. 2.13). Eastern European countries rank among the highest age-standardized incidence rates of oral cancer worldwide. Among all European countries, Hungary recorded highest rates for both incidence and mortality. From the beginning of the last century up until now, France has had high incidence rates for oral cancer, particularly in the northwestern regions. Here oral cancer has been the most common cancer in men. Interestingly in the past one and a half decades, a decline in oral cancer incidence has been noted (. Fig. 2.6). However, among European citizens, French still record having the highest incidence rates of oropharyngeal cancer, one of the highest in the world. The incidence of lip and oral cavity cancers is also higher than in other Western European countries and North America. In French men, the geographical distribution of lip, oral cavity, and pharyngeal cancers shows unequal rates within the country. The northern, western, and eastern regions show a higher incidence than in the southern ones [31]. This north–south gradient probably relates to excessive alcohol consumption in the north compared southern France, special types of brandy consumed in northwest France (calvados) and to socioeconomic inequalities. Danish women record high rates of oral cancer (reasons unknown but smoking rates are generally high), while lip cancer incidence is high in Spain. High incidence of oral cancer in Portugal (both men and women) and rising trends were referred to earlier [25].  

two countries – use of toombak and qat, respectively [49, 50]. Jazan province in Saudi Arabia is reported to have high rates of oral cancer where shammah use is prevalent particularly among females [51, 52]. 2.6.5

Sub-Saharan Africa

Substantial regional variations are reported in the incidence and mortality rates of lip and of oral cancer in subSaharan Africa [53]. Among countries in sub-Saharan Africa, Kenya (7.3), Tanzania (6.8), Botswana (6.5), and South Africa (6.3 per 100,000) recorded high rates. During a 10-year period between 1992 and 2001, the overall incidence rates of oral and oropharyngeal cancer remained stable in South Africa. However, notable increases were reported among colored South Africans over this period; ASR is 10.8 compared with the white population (8.2) [13]. The male residents of the islands in the South Western Indian Ocean bordering Southern Africa account for much higher age-standardized incidence rates (Seychelles: 14.3/100,000; La Reunion, 13.7/100,000; Madagascar, 9.3/100,000; Comoros, 6.9/100,000) compared with the main African continent data [2, 3]. The HIV/AIDS pandemic does not yet appear to have had a spiking effect on oral squamous cell cancers in Africa. However since 1994, in Zimbabwe, oral Kaposi sarcoma has been the most common oral malignancy overtaking oral cancer [54].

 

2.6.4

Middle East and North Africa

Oral and oropharyngeal cancer for this region in the GLOBOCAN [2, 3] database shows low incidence probably due to underreporting. Age-standardized incidence rates for males and females were 2.6 and 1.8 per 100,000 per year, respectively [48]. Among the countries in the region, Sudan and Somalia have high rates reflecting cultural habits in these

2.6.6

South Asia

India has recorded highest rates for oral cancer since the inception of documenting cancer statistics. Oral cancer is one of the most common cancers in the country. The age-­ adjusted incidence rates of oral cancer in India are close to 20 per 100,000 population and account for over a third of all cancers in the country [55]. According to Cancer Incidence in V Continents – Vol. VIII [1], population-based cancer registry of Bhopal records the highest AAR of 10.9 of cancer of the tongue (C01–C02) and mouth (AAR 9.6) in the world. Bhopal consistently has shown high incidence rates since the inception of the registry. Several districts in the State of Gujarat also show high incidence rates of oral cancer, for example, Ahmedabad urban registry records a high ageadjusted incidence of 9.3/100,000, while other urban population-based cancer registries of India have recorded AARs between 3.4 and 6.0 [56]. Sri Lanka and Pakistan have also recorded high incidence rates in several reports from GLOBOCAN [2, 3]. Cancers of the gingivobuccal complex, which comprise the buccal mucosa, gingivobuccal sulcus, the lower gingiva, and the retromolar trigone, being sites that are relatively uncommon in the west, account for about 40% of oral cancers among the Indian patients and in the rest of Southeast Asia [57].

0

W

AC

600

S

N

1.200km

E

RO

AM

RR

MS

MT

RS

PA

PR

DF

TO

SC

SP

GO

AP

MG

MA

RJ

BA

PI

RN PB PE AL SE

[360.090 : 13538.221] (9)

[97.400 : 326.407] (9)

[35.820 : 91.579] (9)

Quantile: TxINC

ES

CE

b

W

0

AC

600

S

N

1.200km

E

RO

AM

RR

RS

MS

MT

SP

DF

TO

GO

SC

PR

PA

AP

PI

RJ

BA

MG

MA

ES

CE

[105 : 128] (9)

[75.9 : 98.7] (9)

[35.8 : 69.4] (9)

Quantile: TXMORT

SE

RN PB PE AL

..      Fig. 2.12  Maps of Brazil showing regional variations in a estimated incidence and b mortality rates for mouth cancer for the population of the age of 40 years or over per 100,000 inhabitants, in the Brazilian Federative Units, in the period from 2005 to 2014. (Figures Courtesy of Prof Gisele Pedroso Moi)

a

Epidemiology of Oral and Oropharyngeal Cancers 15

2

≥ 30

20 – 29.9

10 – 19.9

< 10

No data

b

≥8

6 – 7.9

4 – 5.9

1–4 years of quitting smoking, the risk of oral cavity cancer is reduced by 35% (OR  =  0.64; 95% CI: 0.52, 0.80 [8]. This pooled analysis included 3302 oral cavity cancer cases and 16,337 controls from 16 case-control studies. Increasing years since quitting tobacco smoking resulted in lower risk of oral cavity cancer (p for trend 15 years: OR = 1.06 (95% CI = 0.53, 2.11) p for trend = 0.78 Duration of IS at work 1–15 years: OR = 0.65 (95% CI = 0.28, 1.51) >15 years: OR = 1.31 (95% CI = 0.57, 3.00) p for trend = 0.75

Study center, age, sex, race/ethnicity, education and alcohol drinking (drink-years)

Lee [2]

Western Europe

111 oral cavity and oropharyngeal cancer cases, never tobacco users

706 hospital-­ based controls, never tobacco user

Ever IS at home only: OR = 1.72 (95% CI = 0.91–3.22) Ever IS at work only: OR = 2.46 (95% CI = 1.24–4.87) Ever IS at home & work: OR = 1.62 (95% CI = 0.84–3.14) Duration of IS at home 1–15 years: OR = 0.80 (95% CI = 0.40–1.62) >15 years: OR = 1.50 (95% CI = 0.89–2.53) p for trend = 0.133 Duration of IS at work 1–15 years: OR = 1.04 (95% CI = 0.56–1.93) >15 years: OR = 1.92 (95% CI = 1.12–3.28) p for trend = 0.025

Age, sex, education, study center, alcohol drinking intensity, alcohol drinking duration

Lee [15]

Pittsburgh, 2004–2010

132 oral cavity, other pharyngeal and laryngeal cancer, never smokers (not including oropharyngeal cancer cases)

415 hospital-­ based controls, never smokers

Ever IS in childhood: OR = 1.04 (95% CI = 0.68, 1.60)

Age, sex, race, recruitment period, drinking status, personal history of cancer, education

Troy [16]

China, 2010–2015

167 oral cavity cancer cases (some oropharyngeal cancer sites included), women only

390 hospital-­ based controls, women only

Ever IS in childhood: OR = 2.12 (95% CI = 1.11, 4.07) Ever IS as an adult: OR = 1.52 (95% CI = 1.01, 2.31) Hours per day in childhood: ≤2 hours/day: OR = 1.48 (95% CI = 0.60, 3.62) >2 hours/day: OR = 2.05 (95% CI = 1.26, 7.39) p for trend = 0.014 Years of IS in childhood: ≤10 years: OR = 0.93 (95% CI = 0.27, 3.22) >10 years: OR = 2.90 (95% CI = 1.37, 6.15) Hours per day as an adult: ≤2 hours/day: OR = 1.34 (95% CI = 0.82, 2.20) >2 hours/day: OR = 1.93 (95% CI = 1.06, 3.51) p for trend = 0.039 Years of IS as an adult: ≤10 years: OR = 1.41 (95% CI = 0.53, 3.86) >10 years: OR = 1.54 (95% CI = 1.01, 2.39)

Age, cooking fume exposure, occupation, education, body mass index, marital status, residence, tobacco smoking and alcohol drinking

He [17]

28

3

M. Hashibe

duration of exposure during childhood as well as adults [17]. Although the authors reported that the study included oral cavity cancer cases, they also included some oropharyngeal cancer subsites, specifically cancers of the base of the tongue. Additionally, the study was not restricted to never tobacco smokers, although there was adjustment of all estimates with tobacco smoking. In summary, the pooled analysis by Lee et al. was the only study that reported specifically on oral cavity cancer risk, and associations were not evident [14]. Three other studies reporting on increased cancer risks in a dose-dependent manner included oropharyngeal and/or laryngeal cancer sites in their case groups [13, 15, 17]. Two studies reported on childhood involuntary smoking exposure, with one reporting an association with dose-response relations [17] and the other reporting no association [16]. Additional studies are necessary before conclusions can be made on the potential association between involuntary smoking and oral cavity cancer risk. 3.2.6

 ther Smoking Habits (Waterpipes, O E-Cigarettes)

There do not appear to be any studies published on e-­cigarettes and the risk of oral cancer. For waterpipe smoking, there was a meta-analysis for “oral cancer” as an outcome, reporting a combined estimate of 4.17 (95% CI = 2.53, 6.89) across three studies [18]. However, the outcome was not oral cancer but histopathologic changes in the oral mucosa in the first study [19], the risk of referral in the second study [20], and white lesions in the third study [21]. Thus, the combined risk estimate for waterpipe smoking from this study was not for oral cancer [18]. Another metaanalysis study of waterpipe smoking and cancer reported that studies of oral cavity cancer were not identified [22]. Studies of oral cavity cancer for these forms of tobacco smoking would be of interest as a future direction of research. >>Important A dose-response relationship for tobacco smoking, alcohol use, and betel quid chewing has been confirmed.

3.3

Betel Quid

Betel quid contains a mixture of areca nut, catechu, and slaked lime wrapped in a Piper betle leaf [1]. The IARC monographs classified betel quid with and without tobacco as a human carcinogen for oral cavity cancers (Group 1) [1]. The summary estimate from a meta-analysis of 25 studies in India on betel quid with tobacco was 8.47 (95% CI: 6.49, 11.05) for oral cavity cancers [23]. For betel quid without tobacco in India, the summary estimate from 13 studies was 2.41 (95% CI: 1.82, 3.19) for the risk of oral cavity cancer

[23]. For betel quid chewing in Taiwan, 13 studies were identified for a pooled risk estimate of 10.98 (95% CI: 4.86, 24.84) [23]. In Taiwan, betel quid is chewed without tobacco. 3.4

Alcohol

Alcoholic drinking includes consumption of alcoholic beverages such as beer, wine, liquor, and local alcohol products. Alcohol is an established carcinogen specifically for oral cavity cancer, as reported by the IARC monographs in the 1988 (volume 44), 2010 (volume 96), and 2012 meeting meeting (volume 100 E) [1, 24, 25]. In the INHANCE pooled analysis of 383 oral cavity cancer cases and 5775 controls who were never tobacco users, alcohol drinking increased the risk of oral cavity cancer, with dose-response trends for both the frequency (drinks per day; p for trend  =  0.032) and duration (years) of alcohol drinking (p for trend 15 beers/week) [28]. From the same analysis, the ORs for liquor-only drinkers were 1.7 (95% CI: 0.9, 3.3) for ≤15 liquor drinks/week and 3.2 (95% CI: 1.6, 6.4) for >15 liquor drinks/ week. For individuals who only drank wine only, the ORs were 1.3 (95% CI: 0.7, 2.2) for ≤15 wine glasses/week and 5.9 (95% CI: 2.3, 15.4) for >15 wine glasses/week. When the analysis was stratified by geographic regions (North America, South America, Europe), differences in head and neck cancer risk by alcoholic beverage types were not observed. Other large studies have also investigated the alcoholic beverage types. A multicenter study in Western Europe including 489 oral cavity cancer cases reported odds ratios for men of 2.59 (95% CI: 0.94, 7.17) for drinking only wine, 3.58 (95% CI: 1.33, 9.61) for drinking only beer, and 1.64 (95% CI: 0.34, 7.86) for drinking only liquor [29]. The ORs were adjusted for demographic variables, smoking, fruit and vegetable intake, as well as cumulative alcohol consumption, to estimate the role of the alcoholic beverage types on oral cavity cancer risk. Women did not appear to have increased risks although the sample sizes were much smaller, with ORs of 0.65 (95% CI: 0.30, 1.39) for drinking only wine, 0.85 (95% CI: 00.28, 2.59) for drinking only beer, and 0.77 (95% CI: 0.22, 2.70) for drinking only liquor. In the NIH-AARP cohort, drinking >3 beers was associated with an increased

3

29 Risk Factors for Cancer of the Mouth: Tobacco, Betel Quid, and Alcohol

risk of oral cavity cancer among men and women, and drinking >3 liquor drinks conferred an elevated risk among women, adjusting for other types of alcohol [27]. Cessation of alcohol drinking has been associated with decreased risks of oral cavity cancer after 10–19 years since cessation (OR = 0.66; 95% CI: 0.47, 0.92, p for trend = 0.05) [8]. This INHANCE pooled analysis included 2478 oral cavity cases and 12,033 controls from 13 case-control studies. The risk of oral cavity cancer was similar for individuals who had quit drinking for 10–19  years to those who had never had alcohol. Both case-control and cohort studies continue to support the independent effect of alcohol drinking on risk of oral cavity cancer, with strong dose-response relationships measured by frequency or duration of alcohol drinking. Cessation of alcohol drinking reduces risks, with risks returning to those of never drinkers after 10 years. All types of alcoholic beverages confer an excess risk. Eyecatcher

Three-way interactions have been noted for tobacco smoking, alcohol drinking, and betel quid chewing.

3.5

Interactions Between Tobacco and Alcohol

Interactions between tobacco and alcohol have been on the multiplicative scale reported for oral cavity cancer in a pooled analysis including 2992 cases and 16,152 controls, with a multiplicative interaction parameter of 3.09 (95% CI: 1.82, 5.23) [30]. A multiplicative interaction parameter greater than 1 with a confidence interval excluding the null value indicates an interaction on the multiplicative scale. The highest risk was reported for individuals who smoked >20 cigarettes per day and consumed 3 or more alcoholic drinks per day (OR = 15.49; 95% CI: 7.24, 33.14). According to a cohort study in the US population, the attributable fraction for tobacco and/or alcohol was 66.6% [30]. Three-way interactions have also been assessed for tobacco smoking, alcohol drinking, and betel quid chewing. A meta-analysis of 14 studies from Taiwan and India reported that the summary risk estimate for individuals who had all 3 habits was 40.09 (95% CI = 35.06, 45.83) [31]. For individuals who had two of the three habits, the summary risk estimates were 6.29 (95% CI-5.41, 7.32) for smoking and drinking, 16.01 (95% CI = 13.67, 18.75) for smoking and chewing, and 10.44 (95% CI = 8.02, 13.60) for drinking and chewing. 3.6

Summary

Although tobacco smoking, betel quid chewing, and alcohol drinking are established risk factors for oral cavity cancer, additional studies are indicated to clarify the role of involun-

tary smoking, e-cigarettes, and waterpipe smoking for oral cavity cancer risk. Evidence for HPV is given in 7 Chapter 4, and controversies related to factors that have limited evidence are discussed in 7 Chapter 31.  

 

References 1. IARC. Personal habits and indoor combustions, Volume 100E. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. 2012. 2. World Health Organization. WHO global report on trends in prevalence of tobacco smoking. 2015. 3. IARC. Tobacco smoking, Volume 38. IARC monographs on the evaluation of carcinogenic risks to humans. 1986. 4. IARC.  Tobacco smoke and involuntary smoking, Volume 83. IARC monographs on the evaluation of carcinogenic risks to humans. 2004. 5. Wyss A, Hashibe M, Chuang SC, et  al. Cigarette, cigar, and pipe smoking and the risk of head and neck cancers: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. Am J Epidemiol. 2013;178(5):679–90. 6. Freedman ND, Abnet CC, Caporaso NE, et al. Impact of changing US cigarette smoking patterns on incident cancer: risks of 20 smokingrelated cancers among the women and men of the NIH-­AARP cohort. Int J Epidemiol. 2016;45(3):846–56. 7. Bagnardi V, Rota M, Botteri E, et al. Alcohol consumption and site-­ specific cancer risk: a comprehensive dose-response meta-­analysis. Br J Cancer. 2015;112(3):580–93. 8. Marron M, Boffetta P, Zhang ZF, et al. Cessation of alcohol drinking, tobacco smoking and the reversal of head and neck cancer risk. Int J Epidemiol. 2010;39(1):182–96. 9. Freedman ND, Abnet CC, Leitzmann MF, et al. Prospective investigation of the cigarette smoking-head and neck cancer association by sex. Cancer. 2007;110(7):1593–601. 10. Rahman M, Sakamoto J, Fukui T.  Bidi smoking and oral cancer: a meta-analysis. Int J Cancer. 2003;106(4):600–4. 11. IARC. Smokeless tobacco and some tobaccospecific N-­nitrosamines, Volume 89. IARC monographs on the evaluation of carcinogenic risks to humans. 2007. 12. Wyss AB, Hashibe M, Lee YA, et al. Smokeless tobacco use and the risk of head and neck cancer: pooled analysis of US studies in the INHANCE consortium. Am J Epidemiol. 2016;184(10):703–16. 13. Zhang ZF, Morgenstern H, Spitz MR, et  al. Environmental tobacco smoking, mutagen sensitivity, and head and neck squamous cell carcinoma. Cancer Epidemiol Biomark Prev. 1999;9(10):1043–9. 14. Lee YC, Boffetta P, Sturgis EM, et al. Involuntary smoking and head and neck cancer risk: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. Cancer Epidemiol Biomark Prev. 2008;17(8):1974–81. 15. Lee YC, Marron M, Benhamou S, et  al. Active and involuntary tobacco smoking and upper aerodigestive tract cancer risks in a multicenter case-control study. Cancer Epidemiol Biomark Prev. 2009;18(12):3353–61. 16. Troy JD, Grandis JR, Youk AO, et al. Childhood passive smoke exposure is associated with adult head and neck cancer. Cancer Epidemiol. 2013;37(4):417–23. 17. He B, Chen F, Yan L, et al. Independent and joint exposure to passive smoking and cooking oil fumes on oral cancer in Chinese women: a hospital-based case-control study. Acta Otolaryngol. 2016;136(10): 1074–8. 18. Waziry R, Jawad M, Ballout RA, et  al. The effects of waterpipe tobacco smoking on health outcomes: an updated systematic review and meta-analysis. Int J Epidemiol. 2017;46(1):32–43. 19. Ali AA. Histopathologic changes in oral mucosa of Yemenis addicted to water-pipe and cigarette smoking in addition to takhzeen al-qat. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007;103(3):e55–9.

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20. Dangi J, Kinnunen TH, Zavras AI. Challenges in global improvement of oral cancer outcomes: findings from rural Northern India. Tob Induc Dis. 2012;10:5. 21. Schmidt-Westhausen AM, Al Sanabani J, Al-Sharabi AK. Prevalence of oral white lesions due to qat chewing among women in Yemen. Oral Dis. 2014;20(7):675–81. 22. Awan KH, Siddiqi K, Patil S, et al. Assessing the effect of waterpipe smoking on cancer outcome  - a systematic review of current evidence. Asian Pac J Cancer Prev. 2017;18(2):495–502. 23. Guha N, Warnakulasuriya S, Vlaanderen J, et al. Betel quid chewing and the risk of oral and oropharyngeal cancers: a meta-analysis with implications for cancer control. Int J Cancer. 2014;135(6): 1433–43. 24. IARC. Alcohol consumption and ethyl carbamate, Volume 96. IARC monographs on the evaluation of carcinogenic risks to humans. 2010. 25. IARC. Alcohol drinking, Volume 44. IARC monographs on the evaluation of carcinogenic risks to humans. 1988. 26. Hashibe M, Brennan P, Benhamou S, et al. Alcohol drinking in never users of tobacco, cigarette smoking in never drinkers, and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. J Natl Cancer Inst. 2007;99(10):777–89.

27. Freedman ND, Schatzkin A, Leitzmann MF, et al. Alcohol and head and neck cancer risk in a prospective study. Br J Cancer. 2007;96(9):1469–74. 28. Purdue MP, Hashibe M, Berthiller J, et al. Type of alcoholic beverage and risk of head and neck cancer  – a pooled analysis within the INHANCE Consortium. Am J Epidemiol. 2009;169(2):132–42. 29. Marron M, Boffetta P, Moller H, et  al. Risk of upper aerodigestive tract cancer and type of alcoholic beverage: a European multicenter case-control study. Eur J Epidemiol. 2012;27(7):499–517. 30. Hashibe M, Brennan P, Chuang SC, et  al. Interaction between tobacco and alcohol use and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. Cancer Epidemiol Biomark Prev. 2009;18(2):541–50. 31. Petti S, Masood M, Scully C. The magnitude of tobacco smoking-­ betel quid chewing-alcohol drinking interaction effect on oral cancer in South-East Asia. A meta-analysis of observational studies. PLoS One. 2013;8(11):e78999. 32. Sinha DN, Abdulkader RS, Gupta PC. Smokeless tobacco-associated cancers: A systematic review and meta-analysis of Indian studies. Int J Cancer. 2016;138(6):1368–79. https://doi.org/10.1002/ ijc.29884.

31

Human Papillomavirus Infection: A Risk Factor for Oral and Oropharyngeal Cancers Giuseppina Campisi and Vera Panzarella 4.1

Introduction – 32

4.2

 uman Papillomavirus: Classification, Structural H Characteristics, and Natural History of Infection – 32

4.2.1 4.2.2

 apillomavirus Classification – 32 P Structural Characteristics of HPV Genome and Natural Viral Life Cycles – 33

4.3

Molecular and Oncologic Aspects of HR-HPVs – 35

4.4

 pidemiological Trends of Human Papillomavirus Infection E in Head and Neck Carcinogenesis – 37

4.5

HR-HPV Infection and Oropharyngeal Carcinogenesis – 39

4.5.1 4.5.2

 urden of Anatomic Site of OPSCC – 40 B Burden of Diagnostic Methods of HPVs in OPSCC – 40

4.6

HR-HPV Infection and Oral Carcinogenesis – 41

4.6.1 4.6.2

 revalence of Oral HPV Infection – 41 P HPV Oral Status and Its Real Oncogenic Potential Role – 43

4.7

 ontroversies Related to Oral Carcinogenesis C and HPV Infection – 43

4.8

Conclusions – 44 References – 44

© Springer Nature Switzerland AG 2020 S. Warnakulasuriya, J. S. Greenspan (eds.), Textbook of Oral Cancer, Textbooks in Contemporary Dentistry, https://doi.org/10.1007/978-3-030-32316-5_4

4

32

G. Campisi and V. Panzarella

Core Message

4

A wide range of human papillomavirus (HPV) prevalence data is now available for head and neck squamous cell carcinomas (HNSCCs), especially for those cancers originating from the epithelial lining of the upper aero-digestive tract (UADT) (i.e., the pharynx, the larynx, and the oral cavity). There is strong evidence that supports HPV as an etiological cause of head and neck carcinogenesis particularly for distinct oropharyngeal subsites. A specific molecular, histopathological, clinical, and prognostic profile is intimately connected with HPV infection. While the role of HPV in oropharyngeal carcinogenesis is firmly acknowledged, its role in oral cancer is currently being debated. Several recent studies suggest the importance of correctly distinguishing HNSCCs by subsites, and utilizing more sensitive HPV-DNA detection techniques, in designing future studies. Defining the HPV status of the tumor aids in the correct management of patients with oropharyngeal cancers.

4.1

betel-quid chewing remain the major risk factors for OSCC (see 7 Chapter 3). The recent review of the World Health Organization (WHO) classification of tumors of the H&N and the new staging proposed in the 8th edition of the American Joint Committee on Cancer (AJCC) are based on the new emerging evidence on the role of HPV in H&N tumors [3, 4]. According to these new guidelines, oropharyngeal squamous cell carcinoma (OPSCC) is recognized as a different entity from OSCC, where HPV infection plays a crucial role in relation to the specific clinical characteristics (site specificity and scant local aggressiveness) and prognosis (better response to treatment and survival outcomes) [4]. In this chapter, the molecular and oncological aspect of HPV infection will be discussed, together with its role in oropharyngeal and oral carcinogenesis. The methods of ­ detection of HPV in tumors are discussed in 7 Chapter 10.  

 

Definition Among the HR-αHPVs, HPV16 is responsible for most cervical cancers, followed by HPV18. In the head and neck region, HPV16 represents the primary viral cause of squamous cancers and has been identified in at least 87% of HPV-positive OPSCC.

Introduction

The role of human papillomavirus (HPV) has been examined extensively as an etiological factor for high-grade cervical squamous dysplasia, as well as for anal and penile cancers. HPV has also been implicated in the development of high-­ grade squamous intraepithelial lesions (HSIL) in several other anatomic zones, such as head and neck (H&N) including the oropharynx, larynx, and oral cavity [1]. Genital HPV infection is regarded as one of the most common sexually transmitted infections (STIs) in the world: in the United States, it has been estimated that the prevalence of HPV infection in women aged between 19 and 54 years is approximately 40%, strongly associated with practices related to sexual behaviors; in European populations, the prevalence of cervical HPV infection with high oncological risk is 3–15% in women aged 20 to 60  years; the reported  risk in young women (20–24 years) are significantly higher (29–45%) [2]. In light of recent changes of sexual habits in the general population (e.g., lower age of onset of sexual activity, a higher number of sexual partners, and orogenital sexual practices), the demographic characteristics of the infection have changed, with increasing exposure to the infection of individuals at an earlier age. This phenomenon explains the growing frequency of HPV-related cancers in the target organs including the H&N. The increasing evidence for HPV carcinogenicity has attracted attention within H&N oncology communities, creating much debate and several, often unclear, studies on the true extent of HPV carcinogenesis in these regions. Interestingly, during the last three decades, there has been an inversion of thought regarding the involvement of HPV, in the face of an ever stronger evidence for a viral role in oncogenesis in specific H&N sites, particularly the oropharynx. It appears that HPV may be responsible for only a small subset (1–10%) of all oral squamous cell carcinomas (OSCCs). In general, tobacco use, alcohol consumption, and

4.2

 uman Papillomavirus: Classification, H Structural Characteristics, and Natural History of Infection

4.2.1

Papillomavirus Classification

Papillomaviruses are small viruses with specific tropism for cutaneous and mucosal squamous epithelia. In nature, they are discovered in several species of vertebrates: to date, the family Papillomaviridae contains 49 genera, and more than 300 papillomaviruses are completely identified and sequenced (7 https://pave.­niaid.­nih.­gov/#home). Among these, over 200 types involve humans and are classified as defined human papillomaviruses (HPVs). Currently, HPVs are categorized into five evolutionary phylogenetic genera named alpha, beta, gamma, mu, and nu (α, β, γ, μ, and ν). To be classified as distinct genotypes, HPVs must show at least 10% divergence from each other in their L1 nucleotide sequence, containing hypervariable loops that are exposed on the virion surface [5]. The main distinctive characteristic of HPVs is the preference for particular anatomical sites, where they cause several distinct clinical diseases, from benign hyper-proliferative lesions to invasive malignant cancers. This property is based in part on the ability of the virus to generate a persistent infection and to evade the host’s immune system. The largest genotype group is the α group, containing about 64 HPVs that mainly infect mucosal and cutaneous sites. α-HPVs are able to induce a prominent and persistent epithelial infection. Of these, the majority infect the skin and  

33 Human Papillomavirus Infection: A Risk Factor for Oral and Oropharyngeal Cancers

the anogenital tract; only one-third involve mucosal epithelia of the H&N regions (e.g., oral cavity, oropharynx, larynx, and pharynx). On the basis of the oncogenetic potential, α-HPVs are classically divided into two groups: HPVs considered as “high risk” [high-risk (HR) HPVs: 16-18-31-33-35-39-45-­ 51-­ 56-58-59-68-73-82)], associated with potentially and overtly malignant disorders (e.g., cervical and anogenital cancers, giant condyloma of Buschke–Löwenstein) and HPVs considered “low risk” [low-risk (LR) HPV, 2-4-6-1113-­32)], more commonly associated with benign disorders (e.g., common wart, condyloma, focal epithelial hyperplasia, squamous cell papilloma, Bowen’s papillomatosis) [5]. Among the HR-αHPVs, HPV16 is responsible for most cervical cancers, followed by HPV18. At least ten of the oncogenic HR-HPVs (16-18-31-33-45-51-52-56-58 and 59), as well as six LR-HPVs (11-32-44-53-57 and 81), have been isolated from HNSCCs. Also in the H&N region, HPV16 is proven as the primary viral cause of tumors and has been identified in around 90% of HPV-positive OPSCC [6]. The next largest group of HPVs is the β-group that mainly infects cutaneous sites. In immunocompetent population, β-HPV infection is generally asymptomatic and results in long-term virion production and scanty genetic viral expression (persistent sub-clinical infections above all in children and in young people). However, in susceptible individuals (e.g., patient exposed to known risk factors for skin cancer such as UV irradiation), the viral infection can be associated with tumors, especially nonmelanoma squamous cell carcinoma. The remaining HPV groups (γ, μ, and ν) generally are involved in isolated cutaneous benign diseases and/or asymptomatic persistent sub-clinical infections [5]. The availability of increasingly sophisticated techniques based on molecular and genetic studies has made it possible to deepen the knowledge on viral tropism, pathogenicity, and biological processes that govern the different modes of HPV infection. 4.2.2

 tructural Characteristics of HPV S Genome and Natural Viral Life Cycles

As mentioned above, HPVs infect several different anatomical locations, including the skin, genital tract, and the oropharyngeal sites, but they do not always result in clinical lesions. Instead, the virus sometimes persists in the epithelium, leading to asymptomatic latent infection and at other times inducing epithelial transformation to produce benign or malignant lesions. In order to understand these different outcomes, it is necessary to know the basic structure of the HPV genome and the expression patterns of the viral gene products in relation to the viral life cycle in the epithelium and associated viral infections. Human papillomavirus has a small diameter (50 μM) and a circular double-stranded DNA episome of around 6900–

8607 base pairs enclosed by an iso-exahedric capsid with no envelope and formed by 72 capsomeres [7]. Despite the small size of the genome, the molecular biology of HPV is complex. Transcription occurs unidirectionally, and generally only one of the two strands contains the coding sequences or “open reading frames” (ORF) which are designated early (E) or late (L) in reference to their sequence of expression during the viral life cycle. Gene analysis has revealed the presence of three functionally distinct regions [7]: 1. The first region, named “long control region” (LCR, 10% of the nucleotide sequence), does not encode for any protein but contains binding sites for many repressors and viral and cellular transcriptional activators. It plays a regulatory role in the transcription and replication of the viral genome under the control of the host cell. 2. The second region, called “early” (E, 45% of the nucleotide sequence), contains the ORFs codifying for six early functional proteins (E1, E2, E4, E5, E6, and E7) expressed in the initial phases of the viral replicative cycle and involved in the regulation of DNA duplication, in the persistence of the genome and in HPV-induced cellular oncogenesis. These genes are the only ones expressed in cells with a non-productive infection of the basal layer of the epithelium. Some have oncogenic action, as they can interfere with the regulation of cell cycle and apoptosis and deregulate the infected keratinocytes. E1 is a virus-specific DNA helicase and E2 DNA-binding protein that directly mediates early viral genome transcription and replication. The remaining early gene products (E4, E5, E6, and E7) are considered “accessory” and are implicated in viral genome amplification and virulence in stratified epithelium. It is believed that a major determinant of virus tropism and virulence may lie in the functions related to these accessory genes. 3. The third region, labeled “late” (L, 45% of the nucleotide sequence), contains two gene sequences, L1 and L2, coding for two late-structural proteins (L1 and L2) expressed during the final phases of the replicative cycle in the differentiated squamous cells of the superficial layers of the epithelium. L1 encodes major capsid proteins necessary for virion assembly, while L2 encodes minor capsid proteins implicated in genome encapsidation. Episome of HPV16 with gene sequences, protein products, and their functions are illustrated in . Fig. 4.1. The life cycle of HPV, primarily the synthesis of viral DNA and the expression of viral genes, is connected to the differentiation program of the infected epithelial host cells. The production of mature virion particles takes place at the differentiated supra-basal cells. The replication cycle of the virus is a highly regulated process, determined by some viral proteins codified by the viral genome and the stage of differentiation of the infected keratinocyte. The dynamic changes of keratinocytes, from the basal or progenitor layer up to the  

4

34

G. Campisi and V. Panzarella

E2

E2

E1

SP1

E2

E2

TATA TSS0

Protein

Function

pE1

ATP-dependent helicase; together with pE2 starts viral replication and maintains the viral episomic status

pE2

It is considered the main factor of intra-genomic regulation; directs the replication and transcription of viral DNA, in particular of the ORFs E6-E7

pE4

It is expressed in the late phases of the replicative cycle. It promotes, through the arrest of the cytoskeletal organization, the fragility of the infected host cells and the release of the mature virions. It can induce the cell cycle arrest in G2-phase, promoting viral genome amplification

pE5

It is capable of interacting with cell membrane proteins altering the cellular morphology. In this way, helps the virus to evade the immune response by modification of MHC (Major Histocompatibility Complex) presentation of viral peptides moreover, by stabilization of EGFR (Epidermal Growth Factor Receptor) and stimulation of MAPK (Mitogen-Activated Protein Kinase), it can control the cells division

pE6

It realizes the binding and the degradation of the p53 (with loss of functions performed by it: cycle control, promotion of damaged DNA repair e induction of apoptosis of mutated/damaged cells) and actives telomerase. It also involved in viral immune evasion

pE7

It makes the link with the Rb protein, antioncogenic factor involved in the regutation of the cell growth. The interaction between pE7 and pRB favors the chromosomal instability and uncontrolled replication of cellular DNA

pL1

Major capisd protein: self-assembles late-structural proteins into pentameric capsomeres

pL2

Minor capsid protein: determines the endocapsidation of viral DNA and its entry into the nucleus

LCR E6

92

723

69

3

E7

1

L1 S TS

4775

HPV16 7906 bp

E1

89

47

19

L2

29

4

E5

E4 E2

..      Fig. 4.1  The HPV16 genome and functions of early and late protein products

surface, create a suitable micro-environment for the productive replication of the virus particles, responsible for the malignant transformation of the keratinocyte into a permissive cell [7]. It is widely accepted that, in normal stratified squamous epithelia, HPV infection usually occurs once virus accesses the basal keratinocyte stem cells that are continuously dividing and providing a reservoir of cells for the supra-basal regions to form terminally differentiated keratinocytes. While inside the undifferentiated basal cells, HPVs find a cellular DNA replication machinery necessary for the E and L protein expression and for the mature virion production, finally taking advantage of keratinocyte proliferation pathways and their differentiation to favor viral reproduction and completion of the viral life cycle. This necessary condition is the reason why some anatomical sites, such as the squamo-columnar junction of the endocervix or Waldeyer’s tonsillar mucosa, naturally containing fenestration/interruption of the epithelial barrier, are more susceptible and frequently infected by HPV [8]. In the basal epithelium, HPV benefits from availability of specific host cellular receptors able to bind the viral capsid and “activate” the infection. These are in order of involvement: (i)  heparin sulfate proteoglycans (HSPGs) that are considered receptors for initial viral binding to the host cell wall and (ii) epidermal growth factor (EGF) receptors (EGFRs), integrins (α6 integrin), tetraspanin-enriched membrane microdomains, laminins, syndecan-1, annexin-A2 heterotetramer, and vimentin that are instead considered to be involved in primary viral capsid disassembling and cellular entrance. Approximately 24 hours following cellular inoculation, the viral episomal genome gains access to cellular nucleus following breakdown of the nuclear membrane during mitosis. While in the nucleus, the replication of the viral genome begins with the production of approximately 50–100 episomal copies per cell [8].

This initial phase, with low viral expression, accounts for the latent status of the infection, and it is considered as one important mechanism to avoid the local immune response. This type of HPV infection is typical for the silent presence of the viral genome in the basal cells of the inoculation site in the absence of clinical, histological, and cellular changes. It can be diagnosed only through the application of specific molecular biology techniques, to identify viral DNA in cells and can be induced by both LR-HPV and HR-­ HPV.  The HPV episomal DNA is a kind of reservoir of infected cells, morphologically indistinguishable from those that are not infected. The promoters of this early phase of the viral replication cycle are E1/E2 complexes that activate viral replication and limit viral genome amplification. In this way, HPVs are capable of maintaining infection of the epithelial cell for a long time. There follows a latency phase, characterized by the maintenance of the viral genome in the basal and parabasal cells in division. At this stage, the viral expression is limited to other genes in the E regions, such as E4, E5, E6, and E7. Specifically, E6 and E7 have an essential role in episomal genome maintenance, probably by their capacity to interfere with normal epithelial cell differentiation, thus promoting the quantity of mitotic cells potentially to be infected. The expression of E5 can result in permanent alterations of cell growth and morphology. The expression of E6 and E7 genes mediates the blockade of cell differentiation and subsequent cell immortalization, respectively. These genes codify for oncoproteins pE6 and pE7 able to form complexes with the two anti-oncogene products p105Rb and p53 and stop them functioning as down-regulators in cellular replication. The final step of viral infection is complete viral gene expression during the process of differentiation of the squamous epithelium, starting from basal and para-basal cell layers, where E portions of the viral genome are further expressed and activated and maturing to intermediate and

35 Human Papillomavirus Infection: A Risk Factor for Oral and Oropharyngeal Cancers

superficial epithelial layers along with the L region expression and the formation of the complete virions considered as the infecting viral particles [7–9]. This latest process characterizes the phase of the viral ­replication cycle and distinguishes the so-called productive infection by HPV. Normally, this is a transient infection and can be associated with benign lesions, e.g., wart, condyloma, focal epithelial hyperplasia, squamous papilloma, or Bowen’s papillomatosis. The process is characterized by the complete viral DNA codification resulting in the assemblage of several infecting virions (. Fig. 4.2). The mature virions are expelled from the cells of the superficial layer by the desquamation process. The presence of the virions at the surface permits transition mainly by direct horizontal contact during sexual intercourse through genital and/or oral contact against the mucous membranes of an infected individual. Transmission can also happen by indirect contact (e.g., through unsterilized medical instruments, contaminated utensils or linen); in both situations, the transmission can only occur through micro-cracks of the epithelium which favor the entry of the virus particles into the deeper layers of the epithelium, i.e., receptive basal cells. HPV infection is considered mostly sexually transmitted, but vertical spread (e.g., prenatal trans-placental route, during birth or postnatal) and self-inoculation have been also reported. HPV anogenital infections mainly happen by transmission from an infected partner. The risk of contracting the infection is closely related to sexual activity and increased by predisposing factors related to STIs (e.g., high number of sexual partners, early onset of sexual activity). Condom use does not appear to protect adequately from coming in contact with the virus, since it can be transmitted through contact with any other infected site not protected by condoms [10]. Oropharyngeal transmission of the virus remains unclear; it is plausible that orogenital sex may result in the spread of the infection from the genital mucosa to the oral cavity. The likelihood of transmission by autoinoculation, rather common among children, is poorly investigated [10, 11].  

>>Important HPV is known to cause several distinct clinical diseases, from benign hyper-proliferative lesions to invasive malignant cancers. This last property is fundamentally based on the ability of the virus to generate a persistent infection and to evade the host immune system.

Histologically, productive HPV infection may manifest as acanthosis, dyskeratosis, and multinucleation of keratinocytes and koilocytosis; the latter, although not pathognomonic, is regarded as the evident microscopic expression of a viral cytopathy: the koilocytotic cell contains a thicker layer of cytoplasm at the level of the cell’s internal membrane wall

and an atypical nucleus that appears morphologically collapsed (stellate) [12] (. Fig. 4.3). The immune response of an individual plays a vital role in the susceptibility to HPV infection. It is known, for instance, that in immunocompetent subjects, skin warts may often regress spontaneously, while immunodeficiency, either congenital or acquired (e.g., transplanted subjects or with HIV/AIDS), may favor a higher incidence and persistence of skin and mucosal warts induced by low-risk HPV types. Nevertheless, in HPV-related diseases, immune responses (both the adaptive and innate) to the virus are generally poorly expressed compared to other viral infections. This could be due to the fact that life cycle of the virions is being totally intracellular without viremia, cell lysis, or inflammation. Moreover, since the viral replication cycle takes place inside maturing keratinocytes able to continuously remove mature virions, the result is that, during latent infection, local or systemic viral antigen presentation to the functioning immune system is limited and the infection generally runs for long periods [8]. This condition is considered to be determinant for the oncogenic expression of HR-HPV, as will be detailed in the next section.  

4.3

 olecular and Oncologic Aspects M of HR-HPVs

An alternative to the mechanism of a productive HPV cycle is a persistent infection, mainly associated with HR-HPVs. If persistent infection is not detected and cleared by the immune system, there is a possibility of its progression to cancer. This is a rare event favoring prolongation of viral genome replication in the undifferentiated epithelial infected cells and consequently increased levels of viral oncoproteins E5, E6, and E7 in dividing cells and progressive accumulation of genetic aberrations favoring tumor progression [5] (. Fig. 4.4). Although persistent infection over a period of several years is a necessary event, this may not be sufficient to drive full tumorigenesis. Currently two different mechanisms are considered plausible to explain HPV oncological potential in persistent infection. The most validated model (estimated to occur in between 70% and 85% of cases) is represented by the entry of viral DNA into the cellular genome. It is not considered a part of the normal HPV replication cycle, being an “abortive” event for the virus, without any productive advantage. Viral HPV-­ DNA integration is non-random but occurs through the viral episomal DNA rupture in correspondence with E2 and E1 ORFs. As a consequence of this integration, the viral cycle gets terminated. This results in large portions of the viral genome being disrupted with preservation of E6 and E7 segments contributing to their overexpression. Increased E6 and E7 transcripts’ activity arising from HPV-integrated DNA is generally more stable compared to those synthesized from episomal HPV genomes, being transcribed as a part of a  

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a

b

4

c

d

..      Fig. 4.2  Schematic and clinical images of productive transient infection of HPV: a viral access to the basal layer; b viral production and life cycle completion using the normal differentiated keratinocyte

process; c squamous papilloma of the tongue; d condyloma of the soft palate. Histology of c and d are also illustrated here

4

37 Human Papillomavirus Infection: A Risk Factor for Oral and Oropharyngeal Cancers

a

b koilocyte

..      Fig. 4.3  Images of an intra-oral lesion (proliferative verrucous leukoplakia) associated with HPV productive infection a and its corresponding tissue section b. The characteristic koilocytotic cells are indicated by the arrow

cellular ORF. E6/E7 overexpression potentially induces many host cellular and genomic changes related to carcinogenesis [5, 6, 8, 9]. Two types of integration are recognized: type 1 when only one copy of the viral DNA gets integrated into the host cell and type 2, when many concatamerized full-length copies of viral DNA undergo integration. It is believed that type 1 integrants contribute to active expression of E6 and E7 oncogenes via more stable viral-host transcript relationship and by the disruption of the E2-ORF [13]. Beyond the integration of the viral genome, another mechanism related to oncogenic expression of HPV, recently highlighted and supported by several studies, has been proposed. This consists of increased expression of E6 and E7 oncogenes carried forward to the episomal HPV genome, possibly through epigenetic and/or chromatin conformation changes around the P97/E2 promoter. Some cervical and oropharyngeal cancers could develop uniquely in this manner [8]. The differences in the patterns of integration of the two most common HR HPV16 and HPV18 are of interest. The former (HPV16) is more likely to remain in the episomal form during the entire viral life cycle, while the latter (HPV18) will customarily integrate to the host genome [8, 9]. HPV persistence (with or without integration) contributes to a plethora of epigenetic regulations, such as changes in both viral and host cellular DNA methylation, chromatin remodeling, histone modifications, and up-/downregulations of micro-RNAs promoting carcinogenesis [13, 14]. The features of the two different types of HPV infections are listed on (7 Box 4.1).  

!!Warning HPV status in oral cancer and OPSCC presents several controversial ambiguities supporting a substantial heterogeneity in HPV prevalence among studies and clinical reports.

Box 4.1  Features of Transient and Persistent Infection

Features of productive-transient infection: 1. Maintenance of the keratinocyte differentiation 2. Association with clinical benign lesions (e.g., papilloma, condyloma) 3. Complete viral DNA codification and assemblage of virions 4. Low level expression of E6 and E7 Features of productive-persistent infection: 5. Abrogation of the keratinocyte differentiation 6. Altered organization of the epithelial layers 7. Altered cellular/viral gene expression 8. Viral DNA integration or epigenetic changes 9. High level expression of E5, E6, and E7 10. Cellular insult and progressive genetic aberrations favoring tumor progression

4.4

Epidemiological Trends of Human Papillomavirus Infection in Head and Neck Carcinogenesis

Head and neck squamous cell carcinoma (HNSCC), accounting for 932,000 new cases and 379,000 deaths reported annually, represents the sixth most common malignancy worldwide [15]. Head and neck cancer defines a heterogeneous group of neoplasms involving mostly the non-­ keratinizing epithelium covering different anatomical subsites (oral cavity, oropharynx, hypopharynx, and larynx) with a similar multi-phasic and multi-factorial pathogenesis. The nasopharynx is the exception with a different etipathogenesis. In the last five decades, two main demographics and epidemiological trends were recorded in relation to HNSCC: (i) a declining trend in the overall incidence of HNSCC in the last four decades, thanks to awareness campaigns against the abuse of tobacco and alcohol, considered the main etiological risk factors and (ii) the increased incidence of a specific sub-

38

G. Campisi and V. Panzarella

a

b

4

c

..      Fig. 4.4  Schematic and clinical images of productive-persistent infection of HPV: a viral access to the basal layer; b maintenance of viral replication – with or without genoma integration – in the undifferentiated epithelial infected cell and probably progressive accumulation of

genetic aberrations favoring tumor progression; c erythroleukoplakia of the tongue and its corresponding tissue section

set of HNSCC, i.e., the oropharyngeal squamous cell carcinoma (OPSCC) and/or tongue squamous cell carcinoma (TSCC), mostly due to the greater exposure to HPV infection by a rise high risk sexual practices [16]. Moreover, several studies have been undertaken on molecular mechanisms related to carcinogenesis of the H&N (particularly in oropharyngeal specific subsite), contributing to suggest the theory, now widely accepted, of the existence of two different H&N carcinogenic pathways [10, 12, 14, 16]: 1. The canonical (traditional) H&N carcinogenic pathway, associated with known risk factors (i.e., tobacco and alcohol), occurring mainly in older men (>60 years) and affecting any H&N subsites. HNSCC supported by this model shows a decreasing epidemiological trend, although without substantial reduction of mortality related to its aggressiveness and unfavorable prognosis.

2. The new H&N carcinogenic pathway that occurs mainly in young subjects (>Important Oral cancer has multiple forms of presentation, and this sometimes makes the disease difficult to recognize, especially in its early stages.

5.3

 arly Stages of Oral Squamous Cell E Carcinoma

OSCCs initially manifest as localized and usually well-­ delimited erythroleukoplastic areas. Apart from their red or combined white-red color, the only salient feature of these lesions is their hardened texture, resulting from partial loss of mucosal elasticity. The early lesions of OSCC are usually non-ulcerated, though over time one or more ulcerated zones appear on the erythroleukoplastic plaques (. Fig.  5.1), characterized by somewhat irregular margins, a gradual increase in depth, elevated margins, and especially the earlier mentioned loss of elasticity. By the time the lesions suffer ulceration (. Fig. 5.2), evident hardening is noted in response to clinical exploration. Some months can elapse between the initial manifestation of the erythroleukoplastic plaques and appearance of ulceration. In the pre-ulcerative stage, the lesions are usually painless and may cause only some nonspecific discomfort. However, persistent pain irradiating to adjacent regions develops once the ulcerations appear. The pain gradually increases as the ulcerated surface increases. The above-described characteristics, when the lesions measure less than 2 cm in maximum diameter, are considered to correspond to very-early-stage OSCC. Apart from the  

 

Definition Oral squamous cell carcinoma is a malignant neoplasm arising from the lining oral epithelium and could present in any part of the oral cavity.

5.2

Clinical Presentation

In Europe and North America, over 50% of OSCCs are located on the lateral margins of the tongue and the floor of the mouth, while in the Indian subcontinent, most OSCCs are found in the gingivobuccal complex [3]. However, OSCCs can also be found in any other location of the oral cavity such as the palate, retromolar trigone, and lip mucosa. Oral squamous cell carcinoma can be broadly divided into initial or early stages and late or advanced stages of the disease based on the size and extent of the tumor at presentation [4].

..      Fig. 5.1  Early-stage oral squamous cell carcinoma in the form of erythroleukoplastic and small tumor lesions in the retrocommissural area

49 Clinical Presentation and Differential Diagnosis of Oral Cancer

5.3.1 

 ifferential Diagnosis of the Early D Stages of Oral Squamous Cell Carcinoma

As commented above, these early stages are characterized by erythroleukoplastic lesions, exophytic tumors, or small ulcerations, and the differential diagnosis is established with the following disease conditions that may mimic a squamous cell carcinoma in its clinical appearance. 5.3.2 

..      Fig. 5.2  Early-stage oral squamous cell carcinoma in the form of a small ulcer on the lateral margin of the tongue

..      Fig. 5.3  Oral squamous cell carcinoma in the form of an ulceration of the buccal mucosa

erythroleukoplastic areas and ulcerations, these initial lesions may also exhibit early exophytic tumor growth, with poorly defined margins. All these clinical features, i.e., erythema, ulceration, and a new growth, may coexist in the early stages of OSCC. The presence of rolled margins and induration are the most significant features of malignancy. The lesions become increasingly larger over time, and in a few months grow from less than 2 cm in size to the limit of what is regarded as early stage OSCC, i.e., stage T2 tumors or lesions measuring under 4 cm in size (. Fig. 5.3). At this point, and with the described lesion dimensions, the patient presents with clear ulcerations, accompanied by a greater exophytic tumor component and especially intense pain. The latter is now constant and radiates to more distant zones such as the external ear  – especially in the case of tumors located on the tongue.  

!!Warning The presence of rolled margins and induration are the most significant features of malignancy.

Traumatic Ulcerations

On establishing the differential diagnosis of early-stage OSCC, we first must consider traumatic lesions caused by mechanical factors such as ill-fitting dentures, chronic friction from sharp/broken cusps of teeth or dental malpositioning, as well as accidental biting or trauma. In all these cases, the lesions are usually short lasting, and a causal traumatic event can be clearly identified. The oral lesions in such situations usually consist of painful and well-­ delineated, non-elevated ulcerations with a clean base. The most important distinguishing feature is the absence of the induration that characterizes OSCC.  Nevertheless, in some cases, these traumatic ulcerations may persist over time, and this can complicate the differential diagnosis. The most significant feature is the fact that once the trauma-causing factor is removed, the ulcerations heal. In the case of such chronic traumatic ulcerations, it is always advisable to obtain a biopsy if healing is not observed within 14 days after elimination of the causal factor. The biopsy leading to histopathological study contributes to establish the definitive diagnosis with OSCC. The presence of invasion of underlying connective tissue by carcinomatous epithelial islands is a pathognomonic feature in a biopsy from an OSCC. 5.3.3 

Erythroleukoplakia

Erythroleukoplakia is characterized by red or white-red maculae or plaques that cannot be removed by scraping. It is very difficult to distinguish between erythroleukoplakia and early OSCC on the basis of the clinical features alone. In effect, erythroleukoplakia is very similar to early-stage OSCC, and perhaps the only distinguishing feature is that the latter is characterized by induration with a loss of mucosal flexibility. Nevertheless, it must be underscored that these lesions should not be assessed based only on the clinical features, and that a biopsy is always required, since the risk of diagnostic error is very high even among expert clinicians. The histological study allows us to establish a firm diagnosis in all cases. 5.3.4 

Median Rhomboid Glossitis

Median rhomboid glossitis has sometimes been confused with OSCC. However, it is a candidal infection of the dorsal

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J. V. Bagan and L. Bagan-Debon

region of the tongue that resolves with antifungal treatment. Nevertheless, it sometimes manifests in the form of rhomboid bulges on the dorsal region of the tongue that can be misdiagnosed as OSCC. 5.3.5 

5

Eosinophilic Granuloma (TUGSE)

Eosinophilic ulcer is an uncommon self-limiting chronic benign ulcerative lesion of the oral mucosa that it is similar to oral squamous cell carcinoma in its early stages. It is believed that trauma can cause TUGSE.  Shen et  al. [5] reported 34 oral TUGSE lesions in Taiwanese patients. The most frequent location was found to be the tongue, mainly on the dorsal area and tip. Although this is a self-limiting lesion, a biopsy is required to distinguish it from OSCC.  However, once the diagnosis has been established, no further treatment is needed. 5.3.6 

Keratoacanthoma (KA)

Keratoacanthoma of the lip is a relatively common low-grade tumor originating in the pilosebaceous glands and closely resembling OSCC. In fact, strong arguments support classifying keratoacanthoma as a variant of invasive SCC. 5.3.7 

Necrotizing Sialometaplasia (NSM)

Necrotizing sialometaplasia is a rare condition that mimics OSCC, which is characterized by salivary gland metaplasia, necrosis, and ulceration. NSM commonly occurs in a minor salivary gland of the palate and appears as a painful, necrotic ulcer with irregular margins. Perilesional erythema may be present. NSM is a reactive benign lesion caused by the infarction of the minor salivary gland due to localized ischemia. Histopathology could be challenging due to squamous metaplasia of the acini tissue. 5.3.8 

lomas are clearly associated to some local infectious factor such as dental plaque  – particularly when they affect the gingiva or are located in proximity to sharp tooth fragments causing chronic infectious processes. In comparison, squamous cell carcinomas usually present with a shorter evolution, with no cause-effect association to local infectious processes. On the other hand, OSCC should not be confused with hemangiomas or lymphangiomas, where vascular component and prolonged evolution of the lesions (often from childhood) are evident which allow clear differentiation between these benign processes and malignant disease. Lipomas are likewise long-evolving, soft submucosal tumors with a transparent yellowish appearance. All of these features distinguish them from malignant lesions. Lastly, benign tumors of neurological origin such as schwannomas, neurofibromas, or granular cell tumors are long-evolving submucosal lesions presenting with no alteration of the morphology of overlying oral mucosa.

Benign Tumors

Benign tumors of the oral mucosa are characterized by well-­ delimited margins and are sometimes pediculate, though without the hardness and infiltration seen in OSCC. With the exception of vascular lesions such as pyogenic granulomas or peripheral giant cell granulomas, benign tumors of the oral mucosa usually exhibit no surface ulceration, in contrast to what is often seen in OSCC.  Disorders where differentiation versus OSCC may be considered include fibromas and papillomas, though, as commented above, these are well-­circumscribed and welldelimited lesions, without the ulceration or clinical induration characterizing oral cancer. In addition to a tendency to bleed, pyogenic granulomas or peripheral giant cell granu-

5.3.9 

Infectious Processes

The infectious processes that may be considered in the differential diagnosis of early-stage OSCC include oral tuberculosis, primary syphilis, and deep fungal infections. In the case of tuberculosis, the most frequent presentation is the presence of secondary forms of the disease in the oral cavity, arising from primary foci in the lungs. It is also possible to detect primary tuberculosis in the oral cavity, though in this case the patients are usually children – a fact that suffices to distinguish the condition from oral cancer, which usually manifests in individuals over 40–50 years of age. Secondary forms of tuberculosis can be clinically confused with OSCC, since they are characterized by irregular ulcerations with an anfractuous base and an evolution of several months. While these features can be mistaken for early ulcerated OSCC, in the case of tuberculosis, the ulceration typically exhibits peripheral inflammation and is normally painful and of soft consistency (though cases of peripheral induration have been described). Apart from the characteristics that can give rise to confusion with early ulcerated OSCC, in the latter case the lesions are indurated and exhibit in-depth infiltration, in contrast to the situation usually observed in patients with tuberculosis. Nevertheless, in many cases it is difficult to establish a clinical differential diagnosis, and a biopsy is needed to confirm the diagnosis. Syphilis is associated to a primary oral lesion with very typical characteristics called syphilitic chancre. This lesion usually appears 1 month after sexual contact involving Treponema pallidum infection. The chancre is typically located on the lower lip and consists of a single hard and painless nodule that undergoes erosion and has well-delimited but non-­elevated and sometimes whitish margins. The base of the lesion is flat and clean. Chancre heals spontane-

51 Clinical Presentation and Differential Diagnosis of Oral Cancer

ously within approximately 5 weeks and is accompanied by multiple asymptomatic neck adenopathies that can persist even longer than the primary oral chancre. In contrast, OSCC is characterized by pain, with comparatively larger lesion induration and infiltration. On the other hand, chancre develops rapidly over a few days, while oral cancer takes a number of months to reach the same size. Lastly, the spontaneous resolution of oral chancre is not seen in OSCC; indeed, the latter grows in size over time. The definitive diagnosis is of course established by serological tests such as the rapid plasma reagin (RPR), venereal disease research laboratory (VDRL) test, or fluorescent treponemal antibody absorption (FTA-ABS) tests. In the case of deep fungal infections, mention must be made of two conditions that can be clinically confused with OSCC: histoplasmosis and paracoccidioidomycosis. The former is caused by Histoplasma capsulatum which is endemic in certain Latin American countries, and the oral lesions can affect any part of the oral mucosa – though with a clear predilection for the palate and tongue. The oral findings comprise single or multiple ulcerations, with extensive indurated papulonodular lesions composed of ulcerated granular masses and wide tissue destruction and even bone erosion. The symptoms are important and range from pain and dysphagia to weight loss and the presence of neck adenopathies. The differential diagnosis with OSCC is sometimes difficult to establish, and a histological study with the use of appropriate stains, culture, and serological testing are required in all cases. Paracoccidioidomycosis is a chronic granulomatous disease initially and primarily located in the lungs, though multiple typically ulcerated and painful granulomatous lesions can subsequently appear in the oral and nasal mucosa, as well as in other organs. The skin is usually also affected, along with the lymph node chains of the neck. The oral ulcerations are long-evolving and chronic and are typically located in the gingiva, palate, and other areas of the oral cavity. Here again a biopsy and histological study, as well as microbiological culture, are required in all cases. 5.3.10 

5.4

 dvanced Stages of Oral Squamous Cell A Carcinoma

Advanced-stage OSCC is defined by the presence of tumors measuring over 4 cm in size or infiltrating neighboring structures. These stages of the disease manifest as extensive ulcerated zones with important in-depth infiltration or as exophytic growths with a notorious verrucous component (. Figs. 5.4, 5.5, and 5.6). It is common to observe combined clinical presentations characterized by ulceration and exophytic tumors within the same lesion (i.e., mixed lesions). Advanced-stage OSCC is associated with constant pain, with the need for frequent doses of analgesic medication. Narcotic agents are commonly required to control the pain, which irradiates toward neighboring structures such as the parietal zone, the ear, or in-depth areas. In addition to pain, advanced-stage OSCC can be associated with mobility of teeth, bleeding, and paresthesias, among other manifestations. Dental mobility usually mani 

..      Fig. 5.4  Oral squamous cell carcinoma. A large tumor on the lateral margin of the tongue

Immune-Mediated Disorders

Atypical forms of major aphthous ulcers can have clinical features similar to those of the ulcerations seen in patients with early OSCC. These major aphthae measure over 1 cm in size and cause intense pain. The differential diagnosis with OSCC is based on the fact that major aphthae develop in under 1 month, and other simultaneous ulcerations are usually also present in other locations of the oral mucosa. Major aphthae moreover manifest in the form of recurrent flare-­ ups. The lesions resolve (even spontaneously) within 1–1.5 months maximum. In some cases, major aphthae are associated with genital lesions and ulcerations affecting other mucous membranes, as in Behcet syndrome. The abovementioned characteristics suffice to clinically distinguish major aphthous ulcerations from OSCC.

..      Fig. 5.5  Oral squamous cell carcinoma. A large tumor on the lower gingiva

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Table 5.1  Robbins’ classification of the neck lymph nodes [6, 7] 55 55 55 55 55 55 55 55 55

5

Ia. Submental group Ib. Submandibular group II. Upper jugular group IIa. Anterior-inferior to spinal accessory IIb. Posterior-superior to spinal accessory III. Middle 1/3 of internal jugular vein group IV. Lower 1/3 of internal jugular vein group V a, b. Posterior triangle group VI. Anterior central compartment group

..      Fig. 5.6  Oral squamous cell carcinoma. A large tumor on the floor of the oral cavity

IIB

IB

fests when the tumor infiltrates the periodontal tissues and jaw bone. In the case of teeth not affected by periodontal disease secondary to dental plaque, spontaneous dental mobility manifesting in a short period of time should cause us to suspect underlying malignancy  – particularly when the patient moreover presents with a tumor enveloping the tooth. In the absence of antecedents of trauma (e.g., tooth extraction, dental surgery, or injury), the presence of paresthesias in an area such as the chin is always suggestive of a malignant lesion – whether clinically manifest or otherwise. A very important aspect in carcinomas of head and neck is neoplastic cell-mediated degradation of the basal membrane, with consequent connective tissue invasion. The tumor cells spread through the blood vessels, lymphatics, and nervous tissue, and such metastases initially to the neck are associated to a poorer patient prognosis [6]. 5.4.1 

Neck Metastasis

The Committee for Head and Neck Surgery and Oncology of the American Academy for Otolaryngology–Head and Neck Surgery classified the neck into six anatomical levels, with eight groups of lymph nodes (. Table 5.1) (. Fig. 5.7) [7]. It is known that tumors of the base of the tongue, floor of the mouth, and mandibular gingival tissue have a greater tendency to produce regional lymphatic metastases than tumors of the palate or maxillary gingiva. The lymph of the maxillary gingiva drains toward the lymph nodes of the submandibular region, while the lymph of the hard palatal region drains directly toward the deep cervical lymph nodes through the parapharyngeal or retropharyngeal lymphatic system [8]. In principle, OSCCs of the tongue, floor of the mouth, and mandibular gingiva are more likely to metastasize to cervical lymph node levels I to III. Tumor locations in oral posterior sectors have a greater probability of metastatic spread,  

 

IIA

IA

III

VA

VI

IV

VB

..      Fig. 5.7  Diagrammatic representation of lymph node levels in the neck

and tumors of the mandibular gingiva are more likely to metastasize than tumors located in the maxillary region [9]. However, according to some authors, the risk of neck metastasis in OSCC of the maxilla and hard palate may be greater than expected, depending on the size of the tumor and other histological characteristics of the primary lesion, such as lymphatic or vascular invasion [9]. The risk of regional lymph node metastasis in head and neck cancer is directly conditioned by the location of the primary tumor, its size and depth, and, of course, other histological features of the primary lesion such as lymphatic, vascular, or neurological tissue invasion, in addition to the presence of high-grade dysplasia at the surgical resection margins [10]. As mentioned above, OSCC of the tongue, floor of the mouth, and mandibular gingiva has a strong tendency to produce neck metastases. Indeed, the metastatic risk is far higher than might be expected; elective neck dissection surgery is therefore recommended in many cases.

53 Clinical Presentation and Differential Diagnosis of Oral Cancer

Neck metastases are therefore typical manifestations of intraoral lesion spread and can have a negative impact upon the prognosis [9, 10]. In general terms, neck metastases are detected in 33% of all elective radical neck dissections (RNDs) and in 82% of all therapeutic RNDs. The greater or lesser risk of neck metastatic spread in OSCC is particularly dependent upon the location of the primary tumor. In this regard, hypopharyngeal tumors are classically considered to be more likely to produce metastasis (in 70% of the cases). Cancers of the oral cavity usually drain to the upper lymph node levels I, II, and III, while laryngeal tumors fundamentally metastasize to levels II and III and to a lesser extent to lymph node level IV. The presence of contralateral metastases is infrequent, except when the lesion is located on the midline and in those cases where lymphatic drainage is bilateral. Metastatic spread to lymph node level V is quite infrequent [11]. 5.5

Other OSCC Subtypes

Different OSCC forms or subtypes have been established, including basaloid squamous cell carcinoma (SCC), spindle cell SCC, adenosquamous carcinoma, carcinoma cuniculatum, verrucous SCC, lymphoepithelial carcinoma, papillary SCC, and acantholytic SCC [12]. A description of these histological variants is given in 7 Chapter 7 in this volume.  

5.6

Classification by TNM System

The TNM classification of tumor stages considers tumor size (T), the presence of affected regional lymph nodes (N), and the existence of distant metastatic spread (M). The first edition of the TNM classification was published by the Union for International Cancer Control (UICC) in 1968 and was followed by a number of subsequent editions. The current version is the eighth edition [13, 14]. Huang and Sullivan have described the changes introduced in relation to previous editions. In the case of oral squamous cell carcinoma, category T of the classification has been modified according to the “depth of invasion (DOI)” [13, 14]. The staging of oral cancer is addressed in 7 Chapter 6. The differential diagnosis of advanced OSCC is made with other malignant tumors arising in the oral cavity and confirmed by pathology.  

Eyecatcher

The histological study allows us to establish a firm diagnosis in all cases.

..      Fig. 5.8  Verrucous carcinoma on the lower gingiva

5.7

 ther Malignant Tumors of the Oral O Epithelium

5.7.1 

Ackerman’s Verrucous Carcinoma

This malignant tumor of epithelial origin is not as aggressive as OSCC and typically manifests as a proliferative and verrucous exophytic mass. This variant is more often encountered in smokeless tobacco users. It is usually well delimited and may be pediculated to an extent (. Fig.  5.8). These tumors are not ulcerated, cause no pain, and are usually not characterized by lymphatic neck metastases. Growth progresses superficially and hence is exophytic with no in-depth invasion or infiltration of the underlying bone. Some bone resorption is possible, however. Ackerman’s verrucous carcinoma grows so slowly that there have been reports of cases evolving over almost 20 years. Nevertheless, special caution is required with these tumors, since some lesions that totally mimic verrucous carcinoma may transform over time into invasive carcinoma at the base of the lesion. Thus, a very deep and not simply superficial biopsy is required in all patients presenting what clinically appears to be a verrucous carcinoma. Following resection of the lesion, the entire specimen must be carefully examined to discard possible initial neoplastic connective tissue invasion, since in such cases the management strategy is no longer that used in patients with typical verrucous carcinoma, and subsequent follow-up and control also differ. Verrucous carcinoma is most often located in the buccal mucosa, tongue, lip, gingiva, alveolar ridge, and floor of the mouth. It is more frequent in elderly people and particularly in males over 60 years of age. The favorable prognosis of these tumors is related to their slow and rather localized growth and their absent tendency to produce metastasis [15].  

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5.7.2 

Melanoma

Malignant melanoma typically manifests as intensely pigmented blackish ulcerated tumors in the oral cavity. However, early-stage melanoma of the oral cavity is characterized by pigmented maculae that progressively grow in size until the typical black ulcerated tumor appearance is reached. Pain is intense in advanced stage disease, and satellite lesions in the oral cavity are common as a consequence of hematogenous spread from the primary lesion. This intense blackish pigmentation is the distinguishing feature with respect to OSCC. Primary melanoma of the oral cavity is a very aggressive neoplasm. In the same way as in cutaneous melanoma, a first radial growth phase is observed, followed by vertical in-­ depth growth associated to deep invasion of the connective tissue. Despite recommended treatment, the prognosis of melanoma of the oral cavity is very poor. An early diagnosis is essential, with very radical treatment accompanied by oncological adjuvant therapy [16].

5.8

Conclusions

Oral squamous cell carcinoma (OSCC) is the most frequent type of oral cancer, accounting for about 90% of all oral malignancies. We highlight the clinical presentation of OSCC, explaining the main aspects of early-stage OSCC with typical erythroleukoplastic areas and describing the morphological features in this early stage. A differential diagnosis of these early stages is made with traumatic ulcerations, erythroleukoplakia, eosinophilic granuloma, benign tumors, infectious processes, and immune-mediated disorders. In comparison to the early-stage OSCC, we present the clinical characteristics of advanced-stage OSCC, with ulceration, exophytic tumors, the presence of pain in all advanced stages, and other less common symptoms such as tooth mobility, trismus, or paresthesia. The presence of neck metastases as regional progression of OSSC is described, as well as the other less frequent forms of OSSC. Lastly, a brief description is provided of other malignant tumors of the epithelium such as Ackerman’s verrucous carcinoma and oral melanoma.

References 1. Shield KD, Ferlay J, Jemal A, Sankaranarayanan R, Chaturvedi AK, Bray F, Soerjomataram I. The global incidence of lip, oral cavity, and pharyngeal cancers by subsite in 2012. CA Cancer J Clin. 2017;67: 51–64. 2. Bagan J, Sarrion G, Jimenez Y. Oral cancer: clinical features. Oral Oncol. 2010;46:414–7. 3. Walvekar RR, Chaukar DA, Deshpande MS, Pai PS, Chaturvedi P, Kakade AC, D’Cruz AK. Prognostic factors for loco-regional failure in early stage (I and II) squamous cell carcinoma of the gingivobuccal complex. Eur Arch Otorhinolaryngol. 2010;267:1135–40. 4. Bagan J, Scully C. Oral cancer: comprehending the condition, causes, controversies, control and consequences. 5. Clinical features and diagnosis of cancer. Dent Update. 2011;38:209–11. 5. Shen WR, Chang JY, Wu YC, Cheng SJ, Chen HM, Wang YP. Oral traumatic ulcerative granuloma with stromal eosinophilia: a clinicopathological study of 34 cases. J Formos Med Assoc. 2015; 114:881–5. 6. Inglehart RC, Scanlon CS, D’Silva NJ. Reviewing and reconsidering invasion assays in head and neck cancer. Oral Oncol. 2014;50: 1137–43. 7. Robbins KT, Medina JE, Wolfe GT, Levine PA, Sessions RB, Pruet CW. Standardizing neck dissection terminology. Official report of the Academy’s Committee for Head and Neck Surgery and oncology. Arch Otolaryngol Head Neck Surg. 1991;117:601–5. 8. Beltramini GA, Massarelli O, Demarchi M, Copelli C, Cassoni A, Valentini V, Tullio A, Giannì AB, Sesenna E, Baj A. Is neck dissection needed in squamous-cell carcinoma of the maxillary gingiva, alveolus, and hard palate? A multicentre Italian study of 65 cases and literature review. Oral Oncol. 2012;48:97–101. 9. Zhang WB, Peng X. Cervical metastases of oral maxillary squamous cell carcinoma: a systematic review and meta-analysis. Head Neck. 2016;38(Suppl 1):E2335–42. 10. Nibu KI, Hayashi R, Asakage T, Ojiri H, Kimata Y, Kodaira T, et al. Japanese clinical practice guideline for head and neck cancer. Auris Nasus Larynx. 2017;44:375–80. 11. Hamoir M, Schmitz S, Gregoire V. The role of neck dissection in squamous cell carcinoma of the head and neck. Curr Treat Options in Oncol. 2014;15:611–24. 12. El-Naggar AK, Chan JKC, Grandis JR, Takata T, Slootweg PJ. WHO classification of head and neck tumours. WHO classification of tumours, vol. 9. 4th ed. Lyon: International Agency for Research on Cancer (IARC); 2017. 13. Huang SH, O’Sullivan B. Overview of the 8th edition TNM classification for head and neck cancer. Curr Treat Options in Oncol. 2017;18(7):40. 14. Brierley J, Gospodarowicz M, Wittekind C. UICC TNM classification of malignant tumours. 8th ed. Chichester: Wiley; 2017. 15. Peng Q, Wang Y, Quan H, Li Y, Tang Z. Oral verrucous carcinoma: from multifactorial etiology to diverse treatment regimens (review). Int J Oncol. 2016;49:59–73. 16. Chatzistefanou I, Kolokythas A, Vahtsevanos K, Antoniades K. Primary mucosal melanoma of the oral cavity: current therapy and future directions. Oral Surg Oral Med Oral Pathol Oral Radiol. 2016;122:17–2.

55

Staging of Oral Cancer Ashley Hay and Jatin Shah 6.1

Introduction – 56

6.2

Principles and Purpose of Cancer Staging – 56

6.2.1 6.2.2

T he History of the TNM Staging System – 56 The Functions of a Cancer Staging System – 56

6.3

Rules of the TNM System – 56

6.3.1 6.3.2 6.3.3 6.3.4

T NM System – 56 Applying the Rules – 57 Sentinel Node Nomenclature – 57 Residual Tumor Nomenclature – 57

6.4

Staging and Prognostic Groups – 57

6.5

Anatomy for TNM Staging of the Lips and Oral Cavity – 58

6.5.1 6.5.2 6.5.3 6.5.4 6.5.5

L ips – 59 Oral Cavity – 59 Tongue – 59 Floor of the Mouth – 59 Neck – 59

6.6

 JCC Staging for the Cancers of the Oral A Cavity 8th Edition – 60

6.6.1 6.6.2 6.6.3 6.6.4 6.6.5

T Staging for Oral Cavity – 60 N Staging for Oral Cavity – 60 Pathological N Staging – 61 M Staging for Oral Cavity – 62 Stage Groupings – 62

6.7

 hanges Between AJCC 7th Edition and C AJCC 8th Edition – 62

6.7.1 6.7.2 6.7.3

T Staging for Oral Cavity – 62 Staging for Oral Cavity – 64 Introduction of Different Clinical and Pathological Neck Staging – 64

6.8

Outcomes for AJCC Staging System – 65

6.9

External Validation of the 8th Edition Staging System – 65

6.10

Conclusion – 66 References – 66

© Springer Nature Switzerland AG 2020 S. Warnakulasuriya, J. S. Greenspan (eds.), Textbook of Oral Cancer, Textbooks in Contemporary Dentistry, https://doi.org/10.1007/978-3-030-32316-5_6

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Core Message Cancer staging is an integral part of cancer care, from selection of therapy to reporting outcomes. The TNM staging system first introduced in 1958 is accepted by AJCC and UICC. The 8th edition of the AJCC/UICC staging manual introduces major changes to how oral cavity cancers are staged. Two significant changes were the introduction of depth of invasion (DOI) in determining the T stage of primary tumors and extra-­ nodal extension (ENE).

6.1 

6

Introduction

There were 410,000 new cases of oral cavity cancers in 2015 worldwide [1]. Oral cavity cancer represents a large heath problem in both developed countries and developing countries. For the assessment and treatments of these conditions, as with all cancers, staging is important. Staging is required to assess the tumor, document the extent of disease, and allow for the formation of a treatment plan. In this chapter, we describe the TNM (tumor, node, metastasis) staging system for oral cavity cancer. The recent changes with the latest recommendations are discussed. The purposes for the changes are explained, and evidence in support of these changes is also presented. 6.2 

 rinciples and Purpose of Cancer P Staging

6.2.1

The History of the TNM Staging System

The TNM (tumor, node, metastasis) system was initially developed between 1943 and 1952 by Dr. Pierre Denoix working at the Institut Gustave Roussy in France for the classification of malignant tumors. The Union for International Cancer Control (UICC) established a special committee on clinical stage classification under his leadership. In 1958, the initial recommendations for the clinical classification of breast and larynx cancer were published by the UICC [2]. The next publication was the pocket book, Livre de Poche, which was first published in 1968 [3].The first recommendations for the staging of oral cavity cancer were included in this edition as part of 23 cancer sites. The American Joint Committee on Cancer staging (AJCC) published their first cancer staging manual in 1977 [4]. The UICC and AJCC classifications were unified in 1987. They are periodically updated to reflect the improvements in understanding of cancer, advances in diagnosis, and changes in cancer epidemiology. There has been increasing emphasis on incorporating changes in the staging system, whenever it is supported by data and clinical evidence, with each successive editions of the staging manual. The current publication (AJCC Staging Manual, 8th edition) has revisions in the staging system of several tumors which went into effect in clinical practice on January 1, 2018 [5]. There are important differences between the UICC and AJCC 7th edition [6, 7] and 8th edition [5, 8] for oral cavity cancer, and these will be addressed in this chapter.

6.2.2

 he Functions of a Cancer Staging T System

A cancer staging system enables us to perform a number of different functions. Cancer staging is essential for selecting treatment options for patients, for undertaking clinical and scientific investigation, and for reporting of outcomes for improvement in cancer control. It has to aid the clinician in making treatment decisions. It should convey prognostic information specific to the cancer. It should also allow for the assessment and evaluation of treatment outcomes. It must also provide a terminology and language for the communication of cancer-specific information. It should also facilitate the investigation into human cancers and provide opportunities to support cancer control activities. Some essential functions of a staging system have overlapping requirements, but some objectives have competing requirements. The need to aid the surgeon and incorporate the latest prognostic information may affect the ability of the system to provide robust longitudinal information if the system is changed radically, too frequently, or is not stable over time. To address these needs and by international agreement, cancer staging is primarily based on a classification method of anatomical extent of cancer, and this is what the TNM or tumor, mode, metastasis system addresses. There are some important features of a staging system that were described by Groome et al. [9]. The stratification of patients should lead to similar (uniform) survival for each patient allocated to the subgroup, termed hazard consistency. Survival rates in each assigned group should be different from other; this is called hazard discrimination. There should be uniform distribution of patients within subgroups. The assigned stage should provide a good approximation of survival that could be relayed to an individual patient. The assigned group should have a high predictive ability to help describe the prognosis for an individual. 6.3 

Rules of the TNM System

6.3.1

TNM System

To correctly understand and apply the staging system for oral cavity cancer, the general rules of the TNM system must be followed. TNM is comprised of three anatomically based elements that describe the extent of the disease. The combination of these components indicates the extent of spread of the malignant disease process. T or tumor denotes the extent of the primary tumor. The T category includes T1, T2, T3, and T4 categories indicating advancing disease. N or node describes the absence or presence of nodal metastases and then the extent of regional lymph node metastasis. The N category includes N0, N1, N2, and N3 which again indicates increasing extent or volume of nodal disease. The M or metastasis category indicates the absence of distant metastasis (M0) or the presence of distant metastatic disease (M1).

57 Staging of Oral Cancer

6.3.2

Applying the Rules

The following rules are applicable when using the TNM system: (i) The diagnosis of malignancy for all tumors should be confirmed microscopically. (ii) Clinical classification or the cTNM is based on pretreatment information and guides the use and selection of therapy. The pathological classification or pTNM uses information from surgery and pathological examination and can guide the need for adjuvant treatments and provides further prognostic information. (a) After the assignment of the cTNM or pTNM categories, patients may be grouped into oncology or prognostic groups. This information, obtained at initial diagnosis, remains unchanged. (b) If there is doubt regarding a category, the lower, less advanced should be allocated. (iii) If multiple primaries that vary in size are identified at one site, the tumor which is largest in size and falling to the highest T category should be used to classify the T stage, and the multiplicity must be documented. (iv) The TNM categories can be telescoped or expanded for research or clinical needs if the basic definitions should be adhered to. (v) Additional general definitions and descriptors that are part of the TNM system that may be useful are: (a)   TX   Primary tumor cannot be assessed by histopathology (b)   T0   There is no pathological evidence of primary tumor (this category has been removed from oral cavity staging in the 8th edition) (c)   Tis    Carcinoma in situ (d)   mT   Multiple primary tumors (e)   NX   Regional lymph nodes cannot be assessed by histopathology (f)   N0    No regional lymph nodes histopathology (g)   “U”   Used in N category (for upper neck) to indicate metastasis above lower border of cricoid (h)   “L”   Used in N category (for lower neck) to indicate metastasis below lower border of cricoid (i)   ENE(−)  Absence of extra-nodal extension (j)   ENE(+)  Presence of extra-nodal extension (k)   miENE  Microscopic extra-nodal extension (l)   maENE  Macroscopic extra-nodal extension (m) rTNM   TNM staging for recurrent cancer There are other important rules and procedures when applying the TNM classification. When the primary tumor has direct extension into lymph nodes, this should be classified as lymph node metastasis. When tumor deposits or satellites are detected in the lymphatic drainage basin of the primary carcinoma and the deposit is smooth lined and felt by the histopathologist to represent a totally replaced lymph node, each

individual lymph nodule should be counted for the pN determination. For pN classification, it is the size of the metastasis in the lymph node, not the lymph node size, that is used for classification. A metastasis in a lymph node that is not a lymph node in the regional drainage basin should be classified as a distant metastasis. A micrometastasis is classified as a metastasis of less than 0.2 cm in size. When the only metastasis present is micrometastasis (less than 0.2 cm in size), this is recorded with the addition of the suffix (mi) to the node category. Isolated tumor cells (ITC) are either single or clusters of cell detected on routine hematoxylin and eosin stained sections and are smaller than 0.2 mm. These are not counted toward the node category because they typically do not show metastatic activity. The exception to this however is in cutaneous melanoma and Merkel cell tumors where ITC are counted as metastatic nodes in the nodal category determination. 6.3.3

Sentinel Node Nomenclature

Sentinel lymph node mapping has been used in oral cavity cancers. The sentinel lymph node is the first lymph node to receive lymphatic drainage from the primary tumor. The following designations can be applied for sentinel node assessment: 55 (p)NX(sn)  Sentinel lymph node could not be assessed 55 (p)N0(sn)  No sentinel lymph node metastasis 55 (p)N1(sn)  Sentinel lymph node metastasis 6.3.4

Residual Tumor Nomenclature

Residual tumor (R) classification is a further additional classification group that is commonly used. The R classification is seen as supplemental information describing the tumor status after treatment. The R categories are: 55 RX  Presence of residual tumor cannot be assessed 55 R0  No residual tumor 55 R1  Microscopic residual tumor 55 R2  Macroscopic residual tumor 6.4 

Staging and Prognostic Groups

The TNM classification uses a system to describe the anatomical extent of disease. These categories can be condensed into groups (stage grouping) for analysis and comparison. In general, and for consistency, the following rules are applied. Carcinoma in situ is categorized as stage 0. For oral cancer, tumors localized to the organ or site of origin are classified in stages I and II. Local extension of the primary tumor or spread, to region lymph nodes, upstages the cancer to stage III or IV. When distant metastases are present, it is stage IV. The purpose of this grouping is to allow each group within distinctive cancer sites to have comparable survivals. For example, a patient with stage IV will have a worse prognosis than stage II across all cancer types.

6

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The TNM system based on anatomical extent is a powerful predicative indicator across all cancer types. However, other factors also have a significant impact on predicting outcomes in some cancer types. The prognostic grouping allows for the incorporation of nonanatomical data for a few cancer types where this is most relevant. Age is incorporated into prognostic grouping in thyroid cancer, and in the AJCC 8th edition, human papillomavirus status has been included for oropharyngeal squamous cell cancer. The 8th edition introduces important definitions that are to be used for staging and to form prognostic groups. The term “stage” is used to define the extent and spread of the disease to the anatomical locations whether it is the primary, regional, or distant sites. “Prognostic group” is the term for describing the reorganization that incorporates other factors in addition to TNM. Traditionally, we combine the stage in differentiated thyroid cancer and grade in soft tissue sarcoma with anatomical extent of disease and included in the stage and the prognostic group. 6.5 

 natomy for TNM Staging of the Lips A and Oral Cavity

To accurately assign a T stage to primary tumors of the oral cavity, a concise understanding of the anatomy is required. The oral cavity is divided into several anatomical sites and subsites, and these are used to assign the extent of disease. The lips are divided into two areas by the line of contact with the opposing lip. The separation creates the “dry vera

..      Fig. 6.1  The lips are divided into two areas by the line of contact with the opposing lip, called the red line. a and b show this separation, creating the “dry vermilion” and the “wet vermilion.” The dry vermilion

milion” and the “wet vermilion” (. Fig.  6.1). The dry vermilion is that part of the visible area of upper lip, covered by keratinizing squamous lining. This part of the lip is now grouped with and staged as cutaneous squamous carcinoma of the skin of the face. On the other hand, the wet vermilion is that part of the lip, covered by a smooth glistening mucosa, posterior to the line of contact with the opposing lip. This part of the lip is grouped with oral cancer primary sites. Clinical examination and radiological imaging are used to assess the oral cavity for disease extent. This TNM classification of oral cavity applies to carcinomas of the mucosal lip and the carcinomas of the oral cavity, including minor salivary gland carcinomas. Lesions of dentoalveolar origin are a rare and unique group of cysts and neoplasms that can be benign or malignant. These are excluded from the TNM staging system for oral cancer and are primarily categorized using the World Health Organization classification [10], based on histopathological examination. The anterior border of the oral cavity is the mucosal lip. The dorsal posterior border is taken as the junction of the hard and soft palates, for the tongue the circumvallate papillae, and for lateral borders the anterior tonsillar pillars. The oral cavity can be broadly divided into the oral cavity proper and the vestibule. The oral cavity proper consists of all the structures within the upper and lower alveolar arches. The vestibule is the slit-like opening of the mouth and the area between the lips and the dentoalveolar structures (. Fig. 6.2). The various sites within the oral cavity that are listed in the AJCC 8th edition manual include the following.  

 

b

is that part of the visible area of upper lip and part of the skin cancer staging. The wet vermilion is part of the oral cavity cancer staging. Source: Richard et al. [25]

59 Staging of Oral Cancer

Mucosal lip (upper and lower) Tongue (anterior 2/3rds) Floor of mouth Gingiva (upper and lower) Buccal mucosa Retromolar trigone Hard palate

..      Fig. 6.2  Anatomical diagram showing the different sites in the oral cavity. Source: Richard et al. [25]

6.5.1

Lips

The lip subsite for oral cavity includes the mucosal parts of the lip. This includes: (i) Upper lip (ii) Lower lip (iii) Commissures 6.5.2

Oral Cavity

The oral cavity includes the mucosal structures inside the mouth and also the number of complex areas associated with the dentoalveolar and bony structures of the face. These include: (i) Mucosa of the upper and lower lips (ii) Mucosa covering the cheeks (iii) Retromolar areas (iv) Buccoalveolar sulci, upper and lower (vestibule of the mouth) (v) Upper alveolus and gingiva (upper gum) (vi) Lower alveolus and gingiva (lower gum) (vii) Hard palate 6.5.3

Tongue

The oral tongue is defined as the mobile part of the tongue which is the anterior two thirds of the tongue from the tip

anteriorly to the V-shaped sulcus terminalis, a shallow transverse depression found posteriorly, demarcated by the circumvallate papillae. It includes the anterior two thirds of the tongue, the dorsal surface of the tongue and lateral borders up to circumvallate papillae. The oral tongue has the following subsites: (i) Inferior (ventral) surface (ii) Superior (doral) surface (iii) Ventral surface 6.5.4

Floor of the Mouth

This is the mucosa covering the floor of mouth, generally covered by the tongue and visible on lifting the tongue. 6.5.5

Neck

A system for the anatomical description of regional lymph nodes of the neck to which lymph drains from the oral cavity and in which lymph node metastasis can be found was initially described by the head and neck service at Memorial Sloan Kettering cancer center, New York [11]. It divided the lateral neck nodes into five levels. Level 1 is nodes in the submandibular triangle. Levels 2, 3, and 4 are upper, middle, and deep jugular lymph nodes. Lymph nodes in the posterior triangle of the neck are designated as level 5. These definitions of the neck levels have been modified by

6

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the American Academy of Otolaryngology-Head and Neck Surgery (. Fig. 6.3). Level 1 is divided into 1a and 1b. Level 1a is the fibrofatty tissue containing lymph nodes found between the anterior bellies of the two digastric muscles in the midline. Level 1b is the area bounded by the anterior and posterior belly of the digastric muscle with the lower edge of the mandible bone superiorly. Levels 2, 3, and 4 encompass the fibro-fatty tissue and lymph nodes found under the sternocleidomastoid muscle. Laterally, these levels are defined by the posterior border of the sternocleidomastoid muscle and medially by the lateral edge of the strap muscles. Level 2 extends from the skull base superiorly down to the hyoid bone. It is divided into 2a (inferior) and 2b (superior) by the spinal accessory nerve. Level 3 extends from the hyoid bone superiorly to the level of the cricoid cartilage inferiorly. Level 4 extends superiorly from the level of the cricoid superiorly to the superior border of the clavicle. Level 5 is the fibro-fatty tissue containing lymphatic structures lateral to the posterior border of the sternocleidomastoid muscle and anterior to the anterior border of the trapezius muscle. Superiorly the area starts where these two muscles meet, and inferiorly it extends to the clavicle. It is divided into 5a superiorly and 5b inferiorly by the spinal accessory nerve.  

6

IIB

IB IIA

IA

III VI

IV

VA

VB

>>Important Summary of changes between 7th and 8th editions of AJCC cancer staging in oral cavity 55 Introduction depth of invasion (DOI) as a criterion in the T category. 55 T0 category has been removed. 55 Invasion into the extrinsic tongue muscles as a criterion for upstaging tumors has been removed. 55 Cutaneous lip malignancies have been removed from staging of oral cavity and moved into the staging system for cutaneous cancers. 55 Introduction of separate neck clinical and pathological staging systems. 55 The neck staging now includes extra-nodal extension (ENE) as a criterion for upstaging disease.

6.6 

 JCC Staging for the Cancers of the Oral A Cavity 8th Edition

The staging criteria published in the UICC and AJCC 8th editions are described below. 6.6.1

T Staging for Oral Cavity

55 T1 - T  umor 2 cm or less in greatest dimension and 5 mm or less depth invasion 55 T2 - T  umor 2 cm or less in greatest dimension and more than 5 mm but no more than 10 mm depth of invasion or tumor more than 2 cm but not more than 4 cm in greatest dimension and depth of invasion no more than 10 mm 55 T3 - T  umor more than 4 cm in greatest dimension or any tumor with depth of invasion more than 10 mm 55 T4 - T  4a (lip): Tumor invades through cortical bone, inferior alveolar nerve, floor of the mouth, or skin (chin or nose) T4a: (oral cavity): Tumor invades through cortical bone of mandible or maxillary sinus or invades the skin of the face T4b (lip and oral cavity): Tumor invades masticator space, pterygoid plates, or skull base or encases the internal carotid artery (Superficial erosion alone of bone/tooth socket by gingival primary is not sufficient to classify as T4a.) 6.6.2

N Staging for Oral Cavity

Clinical N Staging (. Fig. 6.4) 55 NX   Regional lymph nodes cannot be assessed 55 N0   No regional lymph node metastasis 55 N1  Metastasis in a single ipsilateral node, 3 cm or less and without extra-nodal extension (ENE)  

..      Fig. 6.3  Anatomical diagram of the neck levels from the American Academy of Head and Neck Surgery. Source: Richard et al. [25]

61 Staging of Oral Cancer

N0

N1

N2A

N2C

N3A

N3B

N2B

6 cms ENEAny size ENE+

..      Fig. 6.4  The new 8th edition neck staging system for clinical N staging of oral cavity cancer. Source: Richard et al. [25]

55 N2  Metastasis in a single ipsilateral node larger than 3 cm but not larger than 6 cm in greatest dimension and without (ENE), or metastases in multiple ipsilateral lymph nodes, not larger than 6 cm in greatest dimension and without ENE or bilateral or contralateral lymph nodes, not larger than 6 cm in greatest dimension and without ENE.

(Involvement of the skin overlying the nodes or soft tissue invasion around the nodes with deep fixation/ tethering or clinical signs of nerve invasion is classified as positive extra-­ nodal extension.)

Metastasis are subdivided into the following categories: (i)   N2a Metastasis in a single ipsilateral lymph node more than3 cm but less than 6 cm in greatest dimension and without extra-nodal extension (ii)   N2b Metastasis in multiple ipsilateral nodes, not more than 6 cm in greatest dimension and without extra-nodal extension (iii) N2c Metastasis in contralateral or bilateral lymph nodes not more than 6 cm in greatest dimension and without extra-nodal extension

Histopathological examination of surgical neck dissection specimen allows for the determination of pN stage. In a primary selective neck dissection, there will typically be 10 or more nodes, and in radical or modified radical neck dissection specimens, there will be 15 or more nodes. Extra-nodal extension is defined histologically as an extension of metastatic carcinoma from within a lymph node bursting through the fibrous capsule of the node and spilling out to the adjacent connective tissue, regardless of the presence of stromal reaction. Metastatic carcinoma that stretches the capsule but does not breach it and is contained within the node does not constitute extra-nodal extension [12]. 55 pNX Regional lymph nodes cannot be assessed 55 pN0  No regional lymph node metastasis 55 pN1 Metastasis in a single ipsilateral node, 3 cm or less and without extra-nodal extension 55 pN2 Metastasis in a single ipsilateral lymph node, 3 cm or smaller and with extra capsular extension (ENE) or larger than 3 cm but not larger than 6 cm in greatest dimension and without ENE, or metasta-

55 N3   M  etastasis in a lymph node larger than 6 cm in greatest dimension and without ENE or metastasis in any node(s) and clinically overt ENE Metastasis are subdivided into the following categories: (i) N3a Metastasis in a single node more than 6 cm in greatest dimension without extra-nodal extension (ii) N3b Metastasis in a single or multiple lymph nodes of any size and with clinical extra-nodal extension (ENE)

6.6.3

Pathological N Staging

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A. Hay and J. Shah

ses in multiple ipsilateral lymph nodes, not larger than 6 cm in greatest dimension and without ENE or bilateral or

6

Metastasis are subdivided into the following categories: (i)   pN2a Metastasis in a single ipsilateral lymph node or contralateral node 3 cm or smaller with ENE or a single ipsilateral node larger than 3 cm but larger than 6 cm in greatest dimension and without extra-nodal extension (ii)   pN2b Metastasis in multiple ipsilateral nodes, not more than 6 cm in greatest dimension and without extra-nodal extension (iii) pN2c Metastasis in contralateral or bilateral lymph nodes not more than 6 cm in greatest dimension and without extra-nodal extension 55 pN3 Metastasis in a lymph node larger than 6 cm in greatest dimension and without ENE or a single ipsilateral node larger than 3 cm greatest dimension with ENE or multiple ipsilateral, contralateral, or bilateral nodes with any having ENE Metastasis are subdivided into the following categories: (i)  pN3a Metastasis in a lymph node more than 6 cm in greatest dimension without extra-nodal extension (ii)  pN3b Metastasis in a single ipsilateral node larger than 3 cm in greatest dimension and with ENE or multiple ipsilateral, contralateral, or bilateral nodes any with ENE 6.6.4

M Staging for Oral Cavity

The classification of metastasis is: 55 M0 No distant metastasis 55 M1 Distant metastasis Routine assessment of patients with a risk for distant metastasis will usually include imaging the chest and the liver. However, as PET (positron emission tomography) becomes more available, this is frequently used to assess for distant disease. 6.6.5

Stage Groupings

The 8th edition prognostic stage groupings are shown in . Table 6.1. These are the same stage groupings found in the 7th edition.  

6.7 

 hanges Between AJCC 7th Edition C and AJCC 8th Edition

6.7.1

T Staging for Oral Cavity

zz Depth of Invasion (DOI)

DOI has been included as a modification to the T classification for oral cavity tumors in the 8th edition of oral cavity cancer staging. It incorporates the relationship of tumor infil-

..      Table 6.1  Prognostic stage groupings in the 8th edition AJCC staging system. These are the same stage groupings found in the 7th edition Stage

T Category

N Category

M Category

0

Tis

N0

M0

I

T1

N0

M0

II

T2

N0

M0

III

T3 T1, T2, T3

N0 N1

M0 M0

IVA

T4a T1, T2, T3, T4a

N0, N1 N2

M0 M0

IVB

Any T T4b

N3 Any N

M0 M0

IVC

Any T

Any N

M1

tration with outcome into the staging system. Spiro et al. recognized that tumor thickness is an important predictive factor in oral cavity cancers in 1986 [13]. Superficial lesions have been shown to have less aggressive biological behavior than thicker lesions. This has now been shown in multiple studies and in multiple datasets [14]. The previous staging system took into account only the two-dimensional size of the tumor, not allowing for an assessment of tumor infiltration (. Fig. 6.5). The 7th edition T classification instead had a category for the invasion of the deep extrinsic muscles of the tongue, such as the styloglossus muscle complex. This has been replaced by the introduction of a system that recognizes the important third dimension of the tumor, the depth of the tumor. Using physical examination by an experienced clinician (. Fig.  6.6), tumors can be classified as of superficial depth (less and equal to 5 mm), moderate depth (more than 5 mm but less than 10 mm), and deep infiltration (more than 10 mm). The T category is increased in the first three T categories for every 5 mm increase in depth (. Fig. 6.7). The term “depth of invasion” or DOI is used because exophytic and ulcerative tumors can create inconsistencies in the histopathological determination of thickness. An exophytic tumor may appear thick but may have minimal invasion and exposure to the underlying lymphovascular networks. An ulcerative lesion may have been in contact with deep lymphovascular channels but as a measure of thickness would not show this. DOI assesses the invasiveness of the tumor and has been shown to be a more reliable predictive parameter [15]. DOI has also been shown in a large multicenter trial to have significant differences in the outcome for T1 tumors with more than 5 mm DOI and for T2, T3, and T4 tumors with greater than 10 mm DOI. It is measured by first finding the horizon (the level) of the basement membrane of the adjacent squamous epithelium [8]. A perpendicular “plumb line” from the horizon is drawn to the deepest point of the tumor. This is measured in mm and represents the depth of invasion (. Fig. 6.8).  

 

 

 

63 Staging of Oral Cancer

..      Fig. 6.6  Clinical examination of a tongue cancer to determine an estimation of thickness. Source: Richard et al. [25]

T1 = 4 cm

zz Removal of T0 Stage

The T0 category, which represents the unknown primary, has been removed from all sites because assigning a primary site is not possible. The carcinoma of unknown primary in the head and neck has a new chapter in the 8th edition staging system dedicated to this entity. The only exception to this is for the virally related HPV-positive oropharynx site staging system and for the EBV-related nasopharynx site staging system. This is because lymph nodes with these characteristics, such as staining positively for EBV, HPV, or P16, indicate a virally related carcinoma is consistent with virally driven head and neck malignancies.

T1 = 10 mm

T3

zz Removal of Extrinsic Tongue Muscle Invasion

The use of extrinsic tongue muscle invasion as part of the T staging category has been removed and has been superseded by DOI.  The assessment of extrinsic tongue muscle invasion by clinical examination and on pathological examination is difficult. It also can be difficult on radiological imaging and can lead to some superficial tumors being

..      Fig. 6.7  Summary of 8th edition T staging showing the impact of depth of invasion on T stage. Source: Richard et al. [25]

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A. Hay and J. Shah

a

b

“Plumb line”

6

“Plumb line”

6 mm

9 mm

..      Fig. 6.8  Examples of the determination of depth of invasion (DOI) . To measure depth of invasion, establish the horizon that is at the level of the basement membrane relative to the closest intact squamous

mucosa. The greatest invasion is measured by dropping a “plumb line” from the horizon. (Lydiatt et al. [24], 7 http://onlinelibrary.­wiley.­com/ doi/10.­3322/caac.­21389/abstract. License number- 4286471216108)

moved into more advanced T stage categories [16]. This is called stage migration and was a limitation in the previous system. Using DOI, for T stage categories, achieves better hazard consistency [16, 17].

6.7.2

zz Removal of Cutaneous Malignancies of the Vermillion

Cutaneous malignancies of the vermillion (dry vermilion) have been removed from the oral cavity section and moved to a new chapter in cutaneous malignancies of the head and neck. Cutaneous malignancies have different and separate adverse prognostic features, and these are now applied to the cutaneous vermillion. Definitions 55 Depth of invasion (DOI): Finding the horizon of the basement membrane of the adjacent squamous mucosa, drop a perpendicular “plumb line” to the deepest point of the tumor. This is measured in mm and represents the depth of invasion. 55 Clinical ENE: Skin involvement or soft tissue invasion with deep fixation/tethering or clinical signs of nerve invasion. 55 Pathological ENE: 55 Minor ENE (ENEmi) is defined as extension 2 mm from the capsule. 55 Major ENE (ENEma) ȤȤ Either extension apparent to the pathologist’s naked eye and palpation when the surgical specimen is examined or >2 mm beyond the lymph node capsule microscopically. ȤȤ Deposits of carcinoma in the soft tissue are regarded as major ENE.

 

Staging for Oral Cavity

zz Extra-Nodal Extension (ENE)

ENE has been shown to be an important predictor of prognosis in all tumors except those associated with HPV [18]. ENE is a very reliable adverse prognostic factor [19, 20] and has therefore been incorporated into the new staging system. The data supporting this change was derived from National Cancer Database (NCDB) in which head and neck squamous carcinoma with HPV-related oropharynx and nasopharynx carcinoma were excluded. The new N categories were then externally validated on a large collaborative dataset from Memorial Sloan Kettering Cancer Center in New York and the Princess Margaret Hospital in Toronto. However, the inclusion of nonsurgically treated cervical neck metastasis is problematic because there is not an accurate method for the detection of ENE except for surgical removal and histopathological examination. Therefore, the dataset included a majority of oral cavity cancer with full histopathological assessment. This was the basis for the introduction of a clinical and pathological neck staging system. 6.7.3

I ntroduction of Different Clinical and Pathological Neck Staging

The importance of staging the regional cervical lymph nodes for a head and neck cancer is paramount because they have prognostic significance. In addition to the number, size, and laterality of the involved regional lymph nodes, ENE has been added to the N stage category. The prognostic value of ENE has been known for a number of years [21, 22]. Data supporting the use of ENE is from pathological examination, in which microscopic and macroscopic ENE can be determined. However, when the primary

6

65 Staging of Oral Cancer

Overall survival - 8th edition T-stage 1.0

0.8

Cum survival

modality of treatment is not surgery, the pathological details of ENE cannot be determined. Therefore, a universal system that allowed for staging in both situations of the primary treatment modality being either surgery for radiotherapy was needed. Therefore, a separate clinical and pathological N stage has been introduced. Current methods of assessment of clinical ENE, such as clinical examination and radiological imaging, are less accurate than pathological examination. Radiological examination lacks sensitivity and specificity in the detection of early or minor ENE [23]. Therefore, only unquestionable ENE (gross ENE) should be classified as clinical ENE. This includes matted nodes, invasion of the skin, infiltration of muscle, and tethering to cranial nerves, branchial plexus, and other nerve such as the phrenic nerve. Only the more extreme examples of ENE can be reliably determined by clinical and radiological assessment. Therefore, different criteria are applied in the clinical and pathological N groupings. When clinical ENE is present, a cN3b in the clinical N category is allocated. With more detailed analysis of the surgically treated neck disease, histopathology can confirm ENE in more subtle situations. In a single ipsilateral or contralateral lymph node which is less than 3 cm, the presence of ENE upstages the N category to N2a. Other examples of ENE affecting all other nodes are categorized as pN3b. Although not mandatory for the staging of patients in the current system, ENE will be collected as an additional feature as part of the cancer database registry. ENE is confirmed on pathological examination. ENE can be described as either minor (mi) or major (ma). Pathologically, minor ENE (ENEmi) is defined as extension of up to 2 mm from the capsule. Major ENE (ENEma) is defined as either tumor extension apparent to the pathologist’s naked eye and palpation when the surgical specimen is examined or >2 mm beyond the lymph node capsule microscopically. Deposits of carcinoma in the soft tissue are regarded as major ENE.

0.6

0.4 T1 T2 T3 T4

0.2

0.0

0

10

20

30

40

60

50

Time (months) ..      Fig. 6.9  Kaplan-Meier estimates of overall survival based on new tumor (T) criteria incorporating the influence of depth of invasion in oral cavity cancer (Memorial Sloan Kettering Cancer Center and Princess Margaret Hospital institutional data). (Lydiatt et al. [24], 7 http://onlinelibrary.­wiley.­com/doi/10.­3322/caac.­21389/abstract. License number- 4286471216108)  

6.8 

Outcomes for AJCC Staging System

The 8th edition T staging criteria was validated on oral cavity datasets from the Memorial Sloan Kettering Cancer Center in New York and the Princess Margaret Hospital in Toronto. The overall survival by T category is shown in . Fig. 6.9. The new N category using ENE as an important prognostic factor was also validated on a dataset from Memorial Sloan Kettering Cancer Center and the Princess Margaret Hospital. The overall survival by N category is shown in . Fig.  6.10. The survival outcome by clinical stage groupings using the new T and N categories is shown in . Fig. 6.11.  

 

Eyecatcher

 

Applying depth of invasion (DOI) 55 In addition to the surface measurements of a tumor, the depth is now an important part of the T staging. 55 The clinical T stage can be estimated by clinical examination using palpation. 55 A tumor less than 2 cm in greatest surface dimension and less than 5 mm in depth is a T1 lesion. 55 As depth of the tumor increases, so does the T stage. 55 The T stage is upstaged in increments of depth of 5 mm. 55 T1, 10 mm.

6.9 

 xternal Validation of the 8th Edition E Staging System

Since the publication of 8th edition staging system, further external validation studies have been published. In a study of 298 surgically treated oral cavity cancers in Brazil, the new system allowed for better stratification of patients. Patients with deep tumors and the presence of extra-nodal extension were corrected and moved into higher groups with a worse corresponding disease free and overall survival [17].

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A. Hay and J. Shah

6.10 

Overall survival - 8th edition N-stage 1.0

Cum survival

0.8

0.6

0.4

6

N0 N1 N2a N2b N2c N3b

0.2

0.0 0

12

24

36

48

60

Time (months) ..      Fig. 6.10  Kaplan-Meier estimates of overall survival based on new node (N) criteria incorporating the influence extra-nodal extension in oral cavity cancer (Memorial Sloan Kettering Cancer Center and Princess Margaret Hospital institutional data). (Lydiatt et al. [24], 7 http://onlinelibrary.­wiley.­com/doi/10.­3322/caac.­21389/abstract. License number- 4286471216108)

Conclusion

In this chapter, the TNM system for cancer staging was reviewed. A cancer staging system needs to be able to stratify patients into groups, termed “hazard consistency,” and each group should have a different survival, called “hazard discrimination.” There also should be relatively equal numbers of patients in each group, and the assigned group should have a high predictive ability to help describe the prognosis for an individual. The TNM rules and criteria were described, and the relation to oral cavity was explained. The important changes between the previous 7th AJCC edition and the current 8th edition AJCC staging system for oral cavity are also highlighted. These include the inclusion of depth of invasion (DOI) as a criterion in the T category, the removal of the T0 category, the removal of invasion of extrinsic tongue muscles as a criterion for upstaging, the removal of cutaneous lip malignancies from the staging of oral cavity, and the changed neck staging which now includes a clinical and pathological system and with the addition of extra-nodal extension (ENE) which leads to upstaging. The new system has been shown to perform well in institutional and multi institutional datasets.

References

 

1.0

Cum survival

0.8

0.6

0.4 Stage I Stage II Stage III Stage IVA Stage IVB

0.2

0.0

0

12

24

36

48

60

Time (months) ..      Fig. 6.11  Kaplan-Meier estimates of overall survival based on new AJCC prognostic groupings incorporating the influence of depth of invasion and extra-nodal extension in oral cavity cancer (Memorial Sloan Kettering Cancer Center and Princess Margaret Hospital institutional data). (Lydiatt et al. [24], 7 http://onlinelibrary.­wiley.­com/ doi/10.­3322/caac.­21389/abstract. License number- 4286471216108)  

1. Global Burden of Disease Cancer C, Fitzmaurice C, Allen C, Barber RM, Barregard L, Bhutta ZA, et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 Cancer Groups, 1990 to 2015: a systematic analysis for the Global Burden of Disease Study. JAMA Oncol. 2017;3(4):524–48. 2. International Union Against Cancer (UICC) Committee on Clinical Stage Classification and Applied Statistics. Clinical stage classification and presentation of results, maligant tumours of the breast and larynx. Paris; 1958. 3. International Union Against Cancer (UICC). TNM classification of malignant tumours. Geneva; 1968. 4. American Joint Committee on Cancer Staging End Results Reporting American Cancer Society National Cancer Institute. Manual for staging of cancer 1977. Chicago: American Joint Committee for Cancer Staging and End-Results Reporting American Joint Committee for Cancer Staging and End-Results Reporting; 1977. 183 p. ill.; 28 cm. p. 5. Amin MB, American Joint Committee on Cancer. AJCC cancer staging manual. 8th ed. Chicago: American Joint Committee on Cancer/ Springer; 2017. 6. Edge SB, American Joint Committee on C, American Cancer S. AJCC cancer staging handbook : from the AJCC cancer staging manual. 7th ed. New  York: Springer; 2010. xix, 718 p. : ill. (some col.); 21 cm. p. 7. Sobin LH, Sobin LH, Gospodarowicz MK, Wittekind C, International Union against C. TNM classification of malignant tumours. 7th ed. Chichester/West Sussex/Hoboken: Wiley-Blackwell; 2010. xx, 309 pages ; 18 cm. p. 8. Brierley J, Gospodarowicz MK, Wittekind C.  TNM classification of malignant tumours. 8th ed. Oxford: Wiley-Blackwell; 2017. 9. Groome PA, Schulze K, Boysen M, Hall SF, Mackillop WJ. A comparison of published head and neck stage groupings in carcinomas of the oral cavity. Head Neck. 2001;23(8):613–24.

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10. Barnes L, Universitèats-Spital Zurich. Dept P, International Academy of P, World Health O, International Agency for Research on C.  Pathology and genetics of head and neck tumours. Lyon: IARC Press; 2005. 430 p: ill. (some col.) ; 27 cm. p. 11. Spiro RH, Strong EW, Shah JP. Classification of neck dissection: variations on a new theme. Am J Surg. 1994;168(5):415–8. 12. Liu J, Ebrahimi A, Low TH, Gao K, Palme CE, Sydney C, et al. Predictive value of the 8th edition American Joint Commission Cancer (AJCC) nodal staging system for patients with cutaneous squamous cell carcinoma of the head and neck. J Surg Oncol. 2017;117:765. 13. Spiro RH, Huvos AG, Wong GY, Spiro JD, Gnecco CA, Strong EW.  Predictive value of tumor thickness in squamous carcinoma confined to the tongue and floor of the mouth. Am J Surg. 1986;152(4):345–50. 14. Pentenero M, Gandolfo S, Carrozzo M. Importance of tumor thickness and depth of invasion in nodal involvement and prognosis of oral squamous cell carcinoma: a review of the literature. Head Neck. 2005;27(12):1080–91. 15. Shim SJ, Cha J, Koom WS, Kim GE, Lee CG, Choi EC, et  al. Clinical outcomes for T1-2N0-1 oral tongue cancer patients underwent surgery with and without postoperative radiotherapy. Radiat Oncol. 2010;5:43. 16. Murthy SP, Thankappan K, Jayasankaran SC, Milind K, Prasad C, Balasubramanian D, et al. “Deep extrinsic muscle involvement” is a fallacy in the American Joint Committee on Cancer’s seventh edition of tumor staging of oral cavity cancers. J Oral Maxillofac Surg. 2018;76(1):206–12. 17. Matos LL, Dedivitis RA, Kulcsar MAV, de Mello ES, Alves VAF, Cernea CR. External validation of the AJCC Cancer staging manual, 8th edition, in an independent cohort of oral cancer patients. Oral Oncol. 2017;71:47–53.

18. International Consortium for Outcome Research in H, Neck C, Ebrahimi A, Gil Z, Amit M, Yen TC, et al. Primary tumor staging for oral cancer and a proposed modification incorporating depth of invasion: an international multicenter retrospective study. JAMA Otolaryngol Head Neck Surg. 2014;140(12):1138–48. 19. Patel SG, Amit M, Yen TC, Liao CT, Chaturvedi P, Agarwal JP, et  al. Lymph node density in oral cavity cancer: results of the International Consortium for Outcomes Research. Br J Cancer. 2013;109(8): 2087–95. 20. Shaw RJ, Lowe D, Woolgar JA, Brown JS, Vaughan ED, Evans C, et al. Extracapsular spread in oral squamous cell carcinoma. Head Neck. 2010;32(6):714–22. 21. Wreesmann VB, Katabi N, Palmer FL, Montero PH, Migliacci JC, Gonen M, et al. Influence of extracapsular nodal spread extent on prognosis of oral squamous cell carcinoma. Head Neck. 2016;38(Suppl 1):E1192–9. 22. Myers JN, Greenberg JS, Mo V, Roberts D.  Extracapsular spread. A significant predictor of treatment failure in patients with squamous cell carcinoma of the tongue. Cancer. 2001;92(12):3030–6. 23. Prabhu RS, Magliocca KR, Hanasoge S, Aiken AH, Hudgins PA, Hall WA, et al. Accuracy of computed tomography for predicting pathologic nodal extracapsular extension in patients with head-­and-­neck cancer undergoing initial surgical resection. Int J Radiat Oncol Biol Phys. 2014;88(1):122–9. 24. Lydiatt WM, Patel SG, O’Sullivan B, Brandwein MS, Ridge JA, Migliacci JC, Loomis AM, Shah JP.  Head and neck cancers—major changes in the American Joint Committee on cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67:122–37. 25. Richard et al. Jatin Shah’s head and neck surgery and oncology. 5th ed. Elsevier; 2020.

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69

Pathology of Oral and Oropharyngeal Cancers Saman Warnakulasuriya, Hatsuhiko Maeda, and John S. Greenspan 7.1

Introduction – 70

7.2

Essential Pathology – 70

7.3

Histological Types – 70

7.4

The Grade – 71

7.5

Pattern of Invasion – 73

7.6

Malignancy Grading Systems – 73

7.7

Tumour Thickness – 74

7.8

Depth of Invasion – 74

7.9

Lymphovascular Invasion – 74

7.10

Perineural Invasion – 75

7.11

Bone Invasion – 75

7.12

Stromal Response – 76

7.13

Metastasis – 76

7.14

Variants of Squamous Cell Carcinoma – 77

7.15

Conclusion – 79 References – 79

© Springer Nature Switzerland AG 2020 S. Warnakulasuriya, J. S. Greenspan (eds.), Textbook of Oral Cancer, Textbooks in Contemporary Dentistry, https://doi.org/10.1007/978-3-030-32316-5_7

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Core Message

7.2 

Over 90% of oral cancers are squamous cell carcinomas. The WHO grading system, based on cellular differentiation, is used in routine pathology reporting and may assist in treatment planning. Several histologic parameters guide us determination of the aggressive nature of the tumour. Understanding the pathology of oral cancer helps the pathologist in running a diagnostic service and the researcher regarding the biological aspects of this tumour.

7.1 

7

Introduction

As defined by R.A. Willis: “A neoplasm is an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissues, and persists in the same excessive manner after cessation of the stimulus which evoked the change”. In the oral cavity, one encounters both benign and malignant neoplasms; benign neoplasms are far more common. The term “oral cancer” refers to malignant neoplasms of the oral cavity and Willis’ definition accurately fits the description of their biological nature. Of the cancers encountered in the cavity, over 95% are squamous cell carcinomas arising from the epithelium of the lining mucous membrane. The rest arise from salivary glands, lymphoid tissue, the odontogenic apparatus or bone or are metastatic tumours to the oral cavity and not commonly considered under the term “oral cancer”. As mentioned in 7 Chapter 1, we therefore here primarily focus on “squamous cell carcinomas” and to be comprehensive include a few variants of epithelial origin. Oral squamous cell carcinomas are a heterogenous group of tumours as they may arise from any anatomical site in the oral cavity. For practical reasons when describing their pathology, they are considered together in a generic fashion. Where specific characteristics arise, such as in their spread, these features are highlighted by sub-site. The pathology of oral cancer merits discussion under several subheadings relating to the histological elements often encountered in routine pathology reporting so that the reader is familiarised with the surgical pathology of the disease. These include the histologic type, the tumour grade, tumour thickness, depth of invasion, perineural spread, lymphovascular invasion, bone invasion, stromal response and nodal involvement. Under histologic type, the variants of squamous cell carcinomas are considered separately at the end this chapter. Pathology related to surgical margins is presented in 7 Chapter 21.  

Essential Pathology

Over 90% of malignant neoplasms of the oral cavity are squamous cell carcinomas. Well-differentiated squamous cell carcinomas resemble the tissue of their origin, i.e. parent tissue, the maturation compartment of the epithelium showing morphological transitions from basaloid-type cells, through a stratum spinosum, and as they mature contain increasing amounts of keratin. The presence of keratin pearls is a typical feature of well-differentiated SCC.  The tumour may expand outwards resulting in an exophytic growth or expand inwards—the process known as infiltration. The key histological feature that enables confirmation of a squamous cell carcinoma is this process of invasion of the deeper tissues. SCC can be microinvasive (. Fig. 7.1) or superficially invasive when it involves subepithelial connective tissue or the lamina propria only or frankly invasive when invading deep submucosal tissue, muscle and fat. Tumour invasion may extend to different depths and anatomic levels. Tumour budding is thought to be a microscopic indicator of tumour invasiveness. As stated earlier, there is marked heterogeneity in the microscopic appearance of these tumours, and invariably there is a host response of lymphocytes and plasma cells in the stroma, which sometimes is dense.  

7.3 

Histological Types

When a lump or a persisting ulcer of the oral mucosa has been subjected to a diagnostic biopsy, of prime importance is knowing the tumour type from histology before planning treatment. This chapter deals with conventional oral squamous cell carcinoma. Subtypes of squamous carcinoma, such as papillary, verrucous, basaloid, adenosquamous, acantholytic, spindle cell carcinoma and basaloid squamous cell carcinoma, are presented later in 7 Section 7.14. HPV-positive tumours are discussed in 7 Chapter 10.  

 

 

Definition Oral squamous cell carcinomas are malignant neoplasms arising from the lining squamous epithelium of the oral cavity.

..      Fig. 7.1  SCC microinvasive: a squamous cell carcinoma shows microinvasion of the tumour superficially into the connective tissue (arrows)

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7.4 

The Grade

The reporting pathologist signs out the surgical pathology report identifying the grade of the tumour. The grade is often considered to be associated with prognosis (see later) and can help the surgeon and other clinicians to plan appropriate management. Based on Broders’ original classification [1], the histopathological grading of conventional OSCC falls into three categories: well (pG1), moderately (pG2) or poorly differentiated (pG3) (. Fig. 7.2). This system is routinely used because it is simple and practical to apply during reporting and is recommended by the World Health Organisation for uniform reporting [2, 3]. In fact, assigned grade is often referred to as the WHO grade by head and neck pathologists. When the  

pG1 Well-differentiated

number of carcinoma islands invading the submucosa is small, it is sometimes difficult to accurately grade the cancer. The grade is determined based on the resemblance of tumour tissue to the normal oral epithelium from which the cancer has arisen. The degree of “differentiation” (resemblance to normal oral epithelium) is subjectively assessed in terms of keratinisation, nuclear and cellular pleomorphism, mitotic activity and nuclear aberrations. A well-differentiated tumour shows a considerable amount of keratin production, forming pools of keratin in the centre of tumour islands referred to as “keratin pearls” (. Fig.  7.3). Furthermore, stratification of epithelial cell layers is retained, and the tumour islands are lined by a well-formed basal cell layer (or layers). Moderately differentiate tumours may show

pG2 Moderately differentiated

 

pG3 Poorly differentiated

High malignancy poor prognosis ..      Fig. 7.2  Histopathological grading of conventional OSCC falls into three categories: well (pG1), moderately (pG2) or poorly differentiated (pG3)

..      Fig. 7.3  A well-differentiated tumour shows a considerable amount of keratin production, forming pools of keratin in the centre of tumour islands referred to as “keratin pearls” (arrows)

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7 ..      Fig. 7.4  Moderately differentiated OSCC (pG2). Some keratin formation (arrows) is shown

..      Fig. 7.6  Poorly differentiated tumours (pG3): Bizarre mitotic figures are shown (arrows)

..      Fig. 7.5  Poorly differentiated tumours (pG3): Keratinisation is inconspicuous; cellular and nuclear pleomorphism are marked with large hyperchromatic nuclei

..      Fig. 7.7  Undifferentiated carcinomas: This tumour has no resemblance at all to the parent tissue

some keratin formation, and the epithelial islands show some cellular atypia (. Fig.  7.4). In poorly differentiated tumours, keratinisation is unremarkable, and cellular and nuclear polymorphism is marked—cells and nuclei assume different forms or shapes—with large hyperchromatic nuclei and bizarre mitotic figures (. Figs.  7.5 and 7.6). Some poorly differentiated carcinomas have a predominantly basaloid appearance, or it may be difficult to recognise that the tumour has arisen from epithelial origin. At the extreme end are tumours that have no resemblance at all to the parent tissue, referred to as undifferentiated carcinomas or anaplastic tumours (. Fig. 7.7). It is usually the practice that the deeper aspect of the tumour is used for grading and the highest grade is documented in reporting. A comment on the predominant pattern may also be added in the pathology report. In most centres, over 60% of oral SCCs are moderately differentiated, about one third being well differentiated and

less than 10% being poorly differentiated. This distribution, with predominance of moderately differentiated tumours, contributes to poor discrimination of tumours by this grading system. On the whole, well-differentiated squamous cell carcinomas are considered to be less aggressive than poorly differentiated or undifferentiated carcinomas. The latter types infiltrate more rapidly and more widely and metastasise earlier than well-differentiated neoplasms, with consequent implications for patient survival. Several studies reported in the 1990s indeed showed a significant association between tumour differentiation (i.e. histologic grading) and nodal metastasis [4] as well as prognosis [5]. In addition to being predictive for prognosis, the grade may also have a bearing on responsiveness to chemoradiotherapy (see 7 Chapter 22) However, currently there is a lack of consensus whether the pathology grading based on tumour differentiation helps in

 

 

 

 

73 Pathology of Oral and Oropharyngeal Cancers

predicting the prognosis of a tumour. As a result, other grading systems which can to quantify the aggressiveness of a tumour have been proposed. >>Important 1 Histological grade is important for prognostication and prediction of response to adjuvant radiation and/ or chemotherapy.

7.5 

Pattern of Invasion

The pattern of invasion or, generally speaking, the shape of the tumour front is recognised as an important predictor of prognosis. Tumours with pushing borders and a cohesive pattern of growth are recognised to be more indolent than tumours showing small foci of cells at some distance away from the bulk of the tumour. Four patterns or modes of invasion have been described: type I pattern is cohesive in the form of a pushing border with bulbous rete pegs which tend to infiltrate at the same level (. Fig.  7.8). Type II pattern shows infiltrating cords, strands or large islands which tend to be branching and continuous with the main tumour mass (. Fig. 7.9). Type III pattern shows small islands and cords which are separated from the main tumour (. Fig. 7.10), and type IV pattern is characterised by widely infiltrating small islands and single cells (. Fig. 7.11). Based on the above four distinct patterns, grading of oral squamous cell carcinomas can be simplified into two histologic types: cohesive (types I and II, broad cohesive sheets of cells or strands of cells >15) and non-cohesive (types III and IV, carcinomas composed of narrow strands, non-­ cohesive small groups or single cells).The Royal College of Pathologists (UK) recommends including the pattern of invasion using the above binary system [6]. A fifth pattern was added by Brandwein-Gensler’s Group for cases with tumour satellites >1 mm away from the tumour perimeter [7]. The significance of a growth pattern of small cell islands or satellites at invasive margins of small T1 tumours being indicative of high risk was confirmed in a multicentre study [8]. In several independent studies, the pattern of invasion has been shown to be an important predictor of oral ­squamous cell carcinoma behaviour [9–11]. The Japanese pathologists use the Yamamoto-Kohama mode of invasion (YK classification), to determine the degree of malignancy of oral squamous cell carcinoma [12, 13].

..      Fig. 7.8  Type I pattern: The form of a pushing border with bulbous rete pegs which tend to infiltrate at the same level is present (arrows)

 

 

 

 

7.6 

..      Fig. 7.9  Type II pattern: Large islands which tend to be branching and continuous with the main tumour mass are seen (arrows)

Malignancy Grading Systems

Several deficiencies are associated with the grading of oral squamous cell carcinomas based on their differentiation pattern. To overcome these deficiencies, new histologic grading systems have been proposed by several authors. These were built on the pattern of invasion described above but include other histologic parameters, mostly assessed at the infiltrat-

..      Fig. 7.10  Type III pattern: Small islands and cords which are separated from the main tumour are present

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7.7 

Tumour Thickness

Tumour thickness represents the maximum vertical dimension between the surface of the tumour and the deepest point of invasion. A meta-analysis on T1-2 tongue cancers has shown that intraoral ultrasonography and histopathology have a high correlation in measuring tumour thickness [24]. Tumour thickness tends to overestimate the malignant potential of exophytic tumours and underestimates ulcerated tumours. For these reasons, the depth of invasion of a tumour (7 Section 7.8) is the preferred variable to study the aggressiveness of a tumour.  

7

7.8  ..      Fig. 7.11  Type IV pattern: Widely infiltrating small islands are seen (arrows)

ing margin (depth) of the tumour. The histologic parameters evaluated in these new systems as originally proposed by Jakobson et al., Anneroth et al. and Bryne et al. [14–16] were the pattern of invasion, nuclear pleomorphism, differentiation/keratinisation, mitotic activity and lymphoid response. Each parameter was given a score of 1–4, giving, for example, in the Bryne’s1992 system [17], a final total score ranging from 4 to 16. The model allows a calculation of the total risk score and an outcome stratification (better or worse). In a comparative study that examined four histopathologic grading systems of oral squamous cell carcinoma (OSCC), namely, the WHO differentiation grade [2], Anneroth’s Multiparameter Grading System [15] and Bryne’s two different malignancy grading systems [16, 17], the authors found Bryne’s (1992) grading system [17] to be more effective in predicting survival in OSCC [18]. In 2005, malignancy grading was further refined by Matinez-­Gimeno and Brandwein-Genslerby [19, 20] who developed a “histologic risk assessment” by adding perinueral invasion, lymphovascular invasion and tumour thickness which are also independent predictors of risk. Lindenblatt et  al. [21] compared three of the earlier mentioned grading systems against the “histologic risk assessment” and found the latter provided the strongest association with overall, cancer-specific and disease-free survival. In a more recent assessment, “tumour budding” has been added as a prognostic indicator, particularly for early-stage tongue lesions [22]. A meta-analysis based on 16 publications examined the utility of tumour budding as a prognostic indicator. The authors reported a positive sevenfold association between tumour budding and regional lymph node metastasis and a twofold association with disease-free survival and overall survival [23]. There is no agreement yet as to the optimal histologic grading system that discriminates indolent from aggressive cancers, and further multicentre research is needed to assess their utility in routine reporting.

Depth of Invasion

Depth of invasion (DOI) is measured in mm from a line through the surface of (adjacent) normal mucosa to the deepest point of the tumour. In the case of ulcerated SCCs, this is achieved by drawing a reconstructed line establishing the horizon that is at the level of the basement membrane relative to the closest intact squamous mucosa [25]. In practice, DOI measurement is carried out with a ruler by dropping a “plumb line” to the deepest point of the invasive tumour from the level of the basement membrane of the normal mucosa adjacent to the invasive tumour (see . Fig.  6.8 in 7 Chapter 6). The cut-off point for DOI has been a point of debate. From many studies, a DOI of 4 mm is considered the threshold that best predicts cervical node metastasis [26, 27]. A positive deep margin in a resection specimen may stand in the way of DOI measurement particularly in an early SCC [28]. The 8th edition of the American Joint Committee on Cancer (AJCC 8th) staging manual [29] has now included depth of invasion (DOI) for staging of oral cavity cancer (pT). The manual specifies 5 mm and 10 mm as the cut-off values for staging of tumours (T1 being less than 5 mm and T3 greater than 10 mm). In many case studies, DOI is positively associated with nodal metastasis, particularly for early T1/T2 carcinomas of the oral cavity and tongue.  

 

>>Important 2 There is good evidence for the prognostic value of depth of invasion and perineural invasion in oral cavity carcinomas.

7.9 

Lymphovascular Invasion

The observation of carcinomatous cells within an endothelial-­ lined space histologically represents lymphovascular invasion (LVI) (. Fig.  7.12). Usually no distinction is made whether LVI is in a lymph vessel or in a vein. LVI should be distinguished from a retraction artefact due to tumour cells getting dislodged into a vascular space during the operative technique. LVI is considered to be significantly correlated with lymph node metastases leading to poor prognosis. In a  

75 Pathology of Oral and Oropharyngeal Cancers

..      Fig. 7.12  Lymphovascular invasion (arrows)

..      Fig. 7.13  Neural extension of an SCC (arrows)

UK study, 87% of the patients that had nodal metastasis were correctly identified when classified by presence or absence vascular invasion [9]. However, LVI is not included in many of the histological grading systems discussed above, except by Jacobsson et al. and Martinez-Gimeno [14, 19].

The prevalence of PNI in oral SCCs is reported to range from 6% to 82% [32], and this variability probably reflects variations in reporting criteria. Initially, PNI is asymptomatic but in later stages could lead to pain and paraesthesia. PNI represents a risk factor for local failure, regional spread and tumour spread along nerve pathways to the skull base. Large nerve involvement, intraneural or multifocal PNI may be considered indications for adjuvant therapy (see 7 Chapter 22). Neural extension of SCC can be demonstrated through a thorough histopathological examination (. Fig.  7.13) and perineural spread by MRI or CT. There is a marked variation in reporting of PNI by pathologists, and under-reporting could be frequent. Some laboratories use S100, GAP43 or Tuj1 antibodies that can enhance the detection of PNI with immunohistochemical staining.

7.10 

Perineural Invasion

 

Spread of the tumour by perineural invasion (PNI) is observed in some oral SCCs, and this feature is known to contribute to an aggressive behaviour. PNI is an independent factor predictive of neck metastasis, local recurrence and decreased survival [20, 30]. PNI contributes to metastatic spread similar to but distinct from vascular or lymphatic invasion. Distant tumour spread through PNI may extend to sites well beyond the extent of any local invasion, and, in some tumours, PNI may be the sole route of metastatic spread. There is lack of consensus on the exact criteria for reporting of PNI. PNI is considered positive on finding the tumour cuffing at least one-third of the circumference of the nerve or deposits of tumour cells inside any of the three layers of the nerve sheath (epi-, peri- and endoneurium) [31]. It is also possible to find penetration of tumour cells within the nerve itself—referred to as intraneural spread. Recent work by D’Silva’s group has further clarified the criteria for microscopic evaluation of PNI in oral cancers [32, 33]. The invasion of large diameter nerves has been found to be more significant than small nerves. The pathological mechanism of PNI has not been well examined. It has been hypothesised that SCC cells exhibit neurotropic behaviour. The perineural space facilitates the growth of SCC cells by providing a microenvironment that is rich in cellular and growth factors that allows their growth along the nerves. One proposed theory is that galanin, a neuropeptide secreted by both nerves and tumour tissue, induces galanin receptor 2 on SCC cells, to promote the release of cytokines [34]. In turn, the cytokines promote tumour invasion and development of neurones (neuritogenesis).

 

!!Warning Perinueral extension is often under-reported in routine pathology reporting.

7.11 

Bone Invasion

For tumours invading jaw bones, two distinct invasive patterns are recognised: an infiltrative (. Fig. 7.14a) and an erosive pattern (. Fig. 7.14b). The infiltrative pattern demonstrates little osteoclastic activity. SCC cells enter into cancellous spaces in the cortical bone in small clusters or chords through available portals of entry. The presence of fenestrations on the alveolar ridge, a recent extraction socket, promote the infiltration of the tumour or perhaps tumour tissue may infiltrate through the periodontal ligament. In the erosive pattern, the osteoclasts are activated, and the neoplastic cells advance as a broad front, enter the cancellous bone and lie in the intervening connective tissue layer. Several signal pathways altered in malignant cells can affect osteoclast activity. The proteases that participate in bone invasion of OSCC include matrix metalloproteinases and cathepsins. Experimental studies have shown that among matrix  

 

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a

b

* * 7

*

..      Fig. 7.14  Two patterns of jaw bone invasion: An infiltrative a and an erosive form b are present. ∗: bone tissue

metalloproteinases (MMPs), specifically MMP-2 and MMP-9 were expressed by invading malignant keratinocytes and in osteoclasts of clinical samples [35]. Neural spread through the inferior alveolar canal could also contribute to bone metastasis. 7.12 

Stromal Response

Oral squamous cell carcinomas evoke a wide variation of inflammatory responses. These range from a dense lymphocyte/plasma cell/ macrophage infiltrate to a limited infiltration of chronic inflammatory cells surrounding the advancing front of the carcinoma. Some malignancy grading systems referred to above, e.g. Bryne et al. [17], include the chronic inflammatory cell response scored at the tumour interphase (a score of 1–4) for their grading. It is clearly of great interest to know whether these immune-effector cells are actually controlling the progression of the lesion [36]. Lundqvist et al., in their Swedish series (n = 94), reported that a dense lymphocytic infiltrate favoured a favourable response to radiotherapy. No recurrences were noted in 63% of their patients with a good host response [37]. However, other authors have noted that cytokines generated by inflammatory cells found in tumours contribute to proliferation of neoplastic cells, progression of the tumour and immunosuppression and are unlikely to mount an effective host antitumour response [38]. The immune cells, mostly lymphocytes, resident fibroblasts and angiogenic vascular cells contribute to the tumour microenvironment (TME) that may control the growth, invasion and spread of the cancer cells [39]. Through epithelial-­mesenchymal interactions, the resident fibroblast population may contribute to the genesis of cancer-­associated fibroblasts (CAF). CAF have properties leading to tumour promotion, invasion and migration. Constituently they closely resemble myofibroblasts and can be detected by immunohistochemical staining for smooth muscle actin (SMA). Finding of SMA-positive CAF within the stromal tissues has been linked to an increase in aggressiveness of the tumour leading to invasion and spread to deeper tissues [40].

*

..      Fig. 7.15  Lymphovascular invasion: Tumour emboli (∗) are seen in endothelial-lined lymphatic channel

7.13 

Metastasis

The earliest stage of pathological metastasis is lymphovascular invasion (. Fig.  7.15), mostly within endothelial lined lymphatic channels referred to as tumour emboli. These emboli have the tendency to travel to the lymph nodes, the first echelon draining the primary tumour site. These tumour emboli may enter the lymph node via the afferent lymphatic channels and then traverse the capsular sinuses and get deposited in the medullary sinuses. Some of these may remain dormant or may die due to host-defence systems. Some cancer cells survive and form established metastases and expand within the node. Micrometastasis refers to single or multiple deposits of tumour cells confined within the lymph node measuring not more than 2 mm in their greatest diameter. Any metastatic deposit greater than 2  mm is considered as conventional metastasis (. Figs. 7.16a, b). The anatomical description of regional lymph nodes of the neck (levels 1–4) in which lymph node metastasis can be found is described in 7 Chapter 5. The initial spread is nor 

 

 

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77 Pathology of Oral and Oropharyngeal Cancers

a

b

*

*

..      Fig. 7.16  Conventional lymph node metastasis: Low magnification a, high magnification b. ∗: tumour metastasis

mally to levels l and 2, but skip metastases have been described. In a study of 277 tongue carcinomas, Byers et al. [41] reported 15.8% had either level 4 neck metastasis as the primary presentation of the disease in the neck, or the level 3 node was the only node present without disease in levels 1–2. Left untreated, nodal metastasis will invade the node capsule, leading to extracapsular spread, (ECS) also now referred to as extra-nodal extension (ENE). ENE is defined as an extension of tumour cells through the nodal capsule, with the tumour found deposited in the adjacent tissues. The presence of ECS/ENE is now considered in the UICC/TNM classification of head and neck tumours, and the extent of spread is important in selecting post-resection management and in the prediction of prognosis (see 7 Chapter 25). Lymphovascular invasion by gingival cancers enters the mucoperiosteum covering the jaws and may lead to bone invasion. Furthermore, PNI may contribute to mandibular bone involvement due to spread through the alveolar nerve and alveolar canal spread. Distant metastases arising from oral SCCs are rare. Some authors have reported metastases in 2–9% of cases. Metastatic disease is often associated with extracapsular spread in lymph nodes, level 4 nodes or bilateral neck nodes. The most common distant metastases are to the lung, bones or liver. Liquid biopsy is an emerging technique (see 7 Chapter 8) to detect circulating tumour DNA (ctDNA) that helps to confirm disseminated disease.  

 

small proportion of anaplastic tumours. Other histological subtypes are encountered. Most variants are uncommon, except verrucous carcinoma which is particularly common among tobacco chewers in Asia. These subtypes are described below: Verrucous carcinoma  This variant favours older individuals, particularly tobacco chewers and cigar/bedi smokers. It has a predilection for lip, buccal and commissural mucosa. In one Indian series of oral cavity cancers, close to 16% were of verrucous type [42]. An exophytic or papillary appearance (rather than infiltrative) should raise the possibility of verrucous carcinoma. It is a slow growing tumour spreading laterally, is more indolent than conventional SCC and lacks cellular atypia. The epithelium is highly acanthotic, with extensive keratinisation and with finger-like projections forming an exophytic tumour. Verrucous carcinoma characteristically has broad, bulbous or club-shaped rete ridges, with a pushing margin (. Figs. 7.17a, b) rather than an infiltrative cords or islands. The host response is dense, and the tumour remains superficial without extending to muscle. Nodal metastasis is rare but may recur locally after incomplete excision [43].  

Carcinoma cuniculatum  The variant often involves gingival

tissues and appears as a warty mass, often loosening teeth. Deep keratin-filled crypts are found on the superficial margins, and the tumour invades on a broad pushing front and forms histologically characteristic tube-like columns (. Fig. 7.18).  

Eyecatcher

Clinicians may occasionally find a variant of “squamous carcinoma” reported by the pathologist following microscopy.

7.14 

Variants of Squamous Cell Carcinoma

As mentioned in 7 Section 7.2, over 90% of oral carcinomas are conventional squamous type and resemble the squamous epithelium from which the carcinoma has arisen, except in a

Papillary squamous cell carcinoma  This is a rare variant, with an exophytic and papillary architecture, often seen in the elderly and thought to be HPV positive. A papillary growth pattern is seen on histological examination, and the tumour retains squamous differentiation. 70% of the tumour is expected to show papillary growth to be labelled as a papillary squamous cell carcinoma. The tumour shows minimal or no invasion. These tumours are often p53 positive.

 

Adenosquamous carcinoma  Glandular structures, either

duct-like or acinar structures, are seen with the squamous

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b

a

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..      Fig. 7.17  Verrucous carcinoma: Low magnification a, high magnification b

*

* *

..      Fig. 7.18  Carcinoma cuniculatum: Deep keratin-filled crypts are found on the superficial margins, and the tumour invades on a broad pushing

tumour. Two distinct components are found, with a superficial keratinising squamous cell carcinoma and a glandular component on the deeper aspect of the tumour (. Fig.  7.19). The lesion is largely aneuploid and known to metastasise early. The prognosis is worse than that of conventional squamous cell carcinoma.  

Basaloid squamous cell carcinoma  It is a rare tumour in the

oral cavity. Those that arise in the posterior part of the oral cavity should be distinguished from HPV-positive oropharyngeal cancers. This is a poorly differentiated tumour with large lobules of basaloid areas, packed with tumour cells with a high nuclear to cytoplasmic ratio (. Fig. 7.20a, b).  

Spindle cell carcinoma  This appears clinically as an exophytic, ulcerative or polypoid lesion and is an unusual variant of SCC that frequently recurs and metastasises. These neoplasms occur most frequently on the lower lip, tongue and alveolar ridge. Mean survival time is short—often under

..      Fig. 7.19  Adenosquamous carcinoma: Glandular structures (∗) are seen with the squamous tumour

2 years. Histopathologic features include foci of SCC or severe epithelial dysplasia and malignant dysplastic spindle cells (. Fig.  7.21) while cellular atypia is marked. Transition between these cell compartments may be found, with prominent intercellular spaces, atypical tumour giant cells, abundant mitotic figures and necrosis. These tumour cells stain positive with anti-pan cytokeratins (AE1/AE3) and are negative for mesenchymal markers. The mesenchymal component is clonally derived from the squamous epithelium but histologically appears sarcomatoid [44].  

Giant cell carcinoma  This is infrequently observed, though laryngeal giant cell carcinomas have been reported. The pathological features include numerous focal, bizarre giant cells, with multiple nuclei and prominent nucleoli interspersed within SCC. There can be associated neutrophils and cellular debris. Immunohistochemistry with cytokeratins helps in the characterisation of the epithelial origin of these tumours. The clinical significance of various types is not fully established

79 Pathology of Oral and Oropharyngeal Cancers

b

a

..      Fig. 7.20  Basaloid squamous cell carcinoma: Large lobules of basaloid areas, packed with tumour cells with a high nuclear to cytoplasmic ratio, are found. Low magnification a, high magnification b

References

..      Fig. 7.21  Spindle cell carcinoma: Histopathologic features include foci of SCC or severe epithelial dysplasia, and malignant dysplastic spindle cells and cellular atypia are marked

except that verrucous and papillary carcinoma may pose a better prognosis and basaloid and adenosquamous types have a poorer prognosis than conventional SCC. 7.15 

Conclusion

Pathology is the cornerstone for diagnosing and confirming malignant neoplasms of the oral cavity, of which over 90% are squamous cell carcinomas. Some heterogeneity is noted in the appearance and even within an individual tumour. The WHO grading system based on tumour differentiation is used in routine reporting and to plan treatment, but other additional histologic parameters can help in determining prognosis. Of these, determining the pattern of invasion and extracapsular spread in lymph nodes are now mandatory and is an important component of the clinicopathological grading of oral carcinomas.

1. Broders AC. The microscopic grading of cancer. Surg Clin North Am. 1941;21:947–62. 2. Barnes L, Eveson JW, Reichert P, et al. World Health Organization Classification of Head and Neck Tumors. Lyon: IARC Press; 2005. p. 166–75 3. Sloan P, Gale N, Hunter K, et al. Malignant surface epithelial tumours. In: El-Naggar AK, Chan JKC, Grandis JR, Takata T, Sootweg P, editors. WHO Classification of Head and Neck Tumours. 4th ed. Lyon: IARC; 2017. p. 109–11. 4. Umeda M, Yokoo S, Take Y, Omori A, Nakanishi K, Shimada K. Lymph node metastasis in squamous cell carcinoma of the oral cavity: correlation between histologic features and the prevalence of metastasis. Head Neck. 1992;14(4):263–72. 5. Rogers SN, Brown JS, Lowe D, et al. Survival following primary surgery for oral cancer: a regional unit’s experience in the UK.  Oral Oncol. 2008;45:201–11. 6. The Royal College of Pathologists (UK): https://www.­rcpath.­org/ uploads/assets/uploaded/e485236e-6d2a-4109-­96fe1da9d5e140f9.­ pdf. p. 27 Accessed 7 Feb 2019. 7. Li Y, Bai S, Carroll W, Dayan D, Dort JC, Heller K, Jour G, Lau H, Penner C, Prystowsky M, Rosenthal E, Schlecht NF, Smith RV, Urken M, Vered M, Wang B, Wenig B, Negassa A, Brandwein-Gensler M. Validation of the risk model: high-risk classification and tumor pattern of invasion predict outcome for patients with low-stage oral cavity squamous cell carcinoma. Head Neck Pathol. 2013;7(3):211–23. 8. Almangush A, Bello IO, Coletta RD, Mäkitie AA, Mäkinen LK, Kauppila JH, Pukkila M, Hagström J, Laranne J, Soini Y, Kosma VM, Koivunen P, Kelner N, Kowalski LP, Grénman R, Leivo I, Läärä E, Salo T. For early-stage oral tongue cancer, depth of invasion and worst pattern of invasion are the strongest pathological predictors for locoregional recurrence and mortality. Virchows Arch. 2015;467(1):39–46. 9. Woolgar JA, Scott J. Prediction of cervical lymph node metastases in squamous cell carcinoma of the tongue/floor of mouth. Head Neck. 1995;17:463–72. 10. Larsen SR, Johansen J, Sørensen JA, Krogdahl A. The prognostic significance of histological features in oral squamous cell carcinoma. J Oral Pathol Med. 2009;38(8):657–62. 11. Odell EW, Jani P, Sherriff M, et al. The prognostic value of individual grading parameters in small lingual squamous cell carcinomas. The importance of the pattern of invasion. Cancer. 1994;74:789–94. 12. Yamamoto E, Miyakawa A, Kohama G. Mode of invasion and lymph node metastasis in squamous cell carcinoma of the oral cavity. Head Neck Surg. 1984;6(5):938–47.

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13. Izumo T, Yagishita H, Yagihara K. Yamamoto-Kohama classification for the clinical classification of oral cancer. J Japanese Soc Oral Oncol. 2012;24(3):64–76. 14. Jakobsson PA, Eneroth CM, Killander D, Moberger G, Mårtensson B. Histologic classification and grading of malignancy in carcinoma of the larynx. Acta Radiol Ther Phys Biol. 1973;12(1):1–8. 15. Anneroth G, Hansen LS, Silverman S Jr. Malignancy grading in oral squamous cell carcinoma. I. Squamous cell carcinoma of the tongue and floor of mouth: histologic grading in the clinical evaluation. J Oral Pathol. 1986;15(3):162–8. 16. Bryne M, Koppang HS, Lilleng R, Stene T, Bang G, Dabelsteen E. New malignancy grading is a better prognostic indicator than Broders’ grading in oral squamous cell carcinomas. J Oral Pathol Med. 1989;18(8):432–7. 17. Bryne M, Koppang HS, Lilleng R, Kjaerheim A. Malignancy grading of the deep invasive margins of oral squamous cell carcinomas has high prognostic value. J Pathol. 1992;166:375–81. 18. Wagner VP, Webber LP, Curra M, Klein IP, Meurer L, Carrad VC, Martins MD. Bryne’s grading system predicts poor disease-specific survival of oral squamous cell carcinoma: a comparative study among different histologic grading systems. Oral Surg Oral Med Oral Pathol Oral Radiol. 2017;123(6):688–96. 19. Martínez-Gimeno C, Molinero AP, Castro V, Sastre MJ, Castro EE, Aguirre-Jaime A.  Prospective validation of the Martinez-Gimeno clinicopathologic scoring system (MGSS) for evaluating risk of cervical lymph node metastases of squamous cell carcinoma of the oral cavity. Head Neck. 2005;27(4):320–5. 20. Brandwein-Gensler M, Teixeira MS, Lewis CM, Lee B, Rolnitzky L, Hille JJ, Genden E, Urken ML, Wang BY.  Oral squamous cell carcinoma: histologic risk assessment, but not margin status, is strongly predictive of local disease-free and overall survival. Am J Surg Pathol. 2005;29(2):167–78. 21. Lindenblatt RC, Martinez GL, Silva LE, Faria PS, Camisasca DR, LourençoSde Q.  Oral squamous cell carcinoma grading systems– analysis of the best survival predictor. J Oral Pathol Med. 2012;41(1):34–9. 22. Almangush A, Bello IO, Keski-Säntti H, Mäkinen LK, Kauppila JH, Pukkila M, Hagström J, Laranne J, Tommola S, Nieminen O, Soini Y, Kosma VM, Koivunen P, Grénman R, Leivo I, Salo T. Depth of invasion, tumor budding, and worst pattern of invasion: prognostic indicators in early-stage oral tongue cancer. Head Neck. 2014;36(6):811–8. 23. Almangush A, Pirinen M, Heikkinen I, Mäkitie AA, Salo T, Leivo I.  Tumour budding in oral squamous cell carcinoma: a meta-­ analysis. Br J Cancer. 2018;118(4):577–86. 24. Klein Nulent TJW, Noorlag R, Van Cann EM, Pameijer FA, Willems SM, Yesuratnam A, Rosenberg AJWP, de Bree R, van Es RJJ.  Intraoral ultrasonography to measure tumor thickness of oral cancer: a systematic review and meta-analysis. Oral Oncol. 2018;77:29–36. 25. Lydiatt WM, Patel SG, O’Sullivan B, Brandwein MS, Ridge JA, Migliacc JC, Loomis AM, Shah JP. Head and neck cancers—major changes in the American Joint Committee on cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67:122–37. 26. Woolgar JA. Histopathological prognosticators in oral and oropharyngeal squamous cell carcinoma. Oral Oncol. 2006;42:229–39. 27. Huang SH, Hwang D, Lockwood G, Goldstein DP, O’Sullivan B.  Predictive value of tumor thickness for cervical lymph-node involvement in squamous cell carcinoma of the oral cavity: a metaanalysis of reported studies. Cancer. 2009;115:1489–97.

28. Berdugo J, Thompson LDR, Purgina B, Sturgis CD, Tuluc M, Seethala R, Chiosea SI. Measuring depth of invasion in early squamous cell carcinoma of the oral tongue: positive deep margin, extratumoral perineural invasion, and other challenges. Head Neck Pathol. 2018; https://doi.org/10.1007/s12105-018-0925-3. 29. Amin MB, American Joint Committee on Cancer. AJCC Cancer staging manual. 8th ed. Chicago: American Joint Committee on Cancer/ Springer; 2017. 30. Rahima B, Shingaki S, Nagata M, Saito C. Prognostic significance of perineural invasion in oral carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2004;97(4):423–31. 31. Liebig C, Ayala G, Wilks JA, Berger DH, Albo D. Perineural invasion in cancer: a review of the literature. Cancer. 2009;115(15):3379–91. 32. Schmitd LB, Beesley LJ, Russo N, Bellile EL, Inglehart RC, Liu M, Romanowicz G, Wolf GT, Taylor JMG, D’Silva NJ. Redefining perineural invasion: integration of biology with clinical outcome. Neoplasia. 2018;20(7):657–67. 33. Schmitd LB, Scanlon CS, D’Silva NJ. Perineural invasion in head and neck cancer. J Dent Res. 2018;97(7):742–50. 34. Scanlon CS, Banerjee R, Inglehart RC, Liu M, Russo N, Hariharan A, van Tubergen EA, Corson SL, Asangani IA, Mistretta CM, et  al. Galanin modulates the neural niche to favour perineural invasion in head and neck cancer. Nat Commun. 2015;6:6885. 35. Quan J, Zhou C, Johnson NW, Francis G, Dahlstrom JE, Gao J.  Molecular pathways involved in crosstalk between cancer cells, osteoblasts and osteoclasts in the invasion of bone by oral squamous cell carcinoma. Pathology. 2012;44(3):221–7. 36. Johnson NW. The role of histopathology in diagnosis and prognosis of oral squamous cell carcinoma. Proc R Soc Med. 1976;69(10): 740–7. 37. Lundqvist L, Stenlund H, Laurell G, Nylander K. The importance of stromal inflammation in squamous cell carcinoma of the tongue. J Oral Pathol Med. 2012;41(5):379–83. 38. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2001;357:539–45. 39. Salo T, Vered M, Bello IO, Nyberg P, Bitu CC, ZlotogorskiHurvitz A, Dayan D. Insights into the role of components of the tumor microenvironment in oral carcinoma call for new therapeutic approaches. Exp Cell Res. 2014;325(2):58–64. 40. Dourado MR, Guerra ENS, Salo T, Lambert DW, Coletta RD. Prognostic value of the immunohistochemical detection of cancer-­associated fibroblasts in oral cancer: a systematic review and meta-analysis. J Oral Pathol Med. 2018;47:443–53. 41. Byers RM, Weber RS, Andrews T, McGill D, Kare R, Wolf P. Frequency and therapeutic implications of ‘skip metastases’ in the neck from squamous carcinoma of the oral tongue. Head Neck. 1997;19(1): 14–9. 42. Rekha KP, Angadi PV. Verrucous carcinoma of the oral cavity: a clinico-pathologic appraisal of 133 cases in Indians. Verrucous carcinoma of the oral cavity: a clinico-pathologic appraisal of 133cases in Indians. Oral Maxillofac Surg. 2010;14(4):211–8. 43. Oliveira DT, de Moraes RV, Fiamengui Filho JF, FantonNeto J, Landman G, Kowalski LP. Oral verrucous carcinoma: a retrospective study in São Paulo Region, Brazil. Clin Oral Investig. 2006;10(3): 205–9. 44. Choi HR, Sturgis EM, Rosenthal DI, Luna MA, Batsakis JG, El-Naggar AK.  Sarcomatoid carcinoma of the head and neck: molecular evidence for evolution and progression from conventional squamous cell carcinomas. Am J Surg Pathol. 2003;27(9):1216–20.

81

Oral Biopsy: Principles and Practice Ranganathan Kannan 8.1

Introduction – 82

8.2

Types of Biopsy – 82

8.3

Clinical Assessment for Biopsy – 82

8.3.1 8.3.2 8.3.3

L ocal Examination – 82 Patient Assessment – 84 Adjunctive Diagnostic Aids – 85

8.4

Cytology/Cytopathology – 86

8.4.1 8.4.2 8.4.3

E xfoliative Cytology – 86 Transepithelial Brush Biopsy – 87 Fine Needle Aspiration Cytology (FNAC) – 89

8.5

Tissue Biopsy – 89

8.5.1 8.5.2

 unch Biopsy – 89 P Incisional and Excisional Biopsies – 92

8.6

Biopsy Submission for Histopathology – 94

8.6.1 8.6.2

F ixation – 94 Biopsy Requisition Form – 95

8.7

The Biopsy Report – 95

8.8

Emerging Techniques – 96

8.9

Medicolegal Issues – 97

8.10

Conclusions – 97 References – 97

© Springer Nature Switzerland AG 2020 S. Warnakulasuriya, J. S. Greenspan (eds.), Textbook of Oral Cancer, Textbooks in Contemporary Dentistry, https://doi.org/10.1007/978-3-030-32316-5_8

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Core Message Biopsy plays a key role in the investigation of malignant disorders and is the cornerstone of diagnosis and management of oral cancer and oral potentially malignant disorders (OPMDs). Histological examination of the tissue from the biopsy is the initial step in confirmation or refutation of clinical diagnoses and assists in the development of a treatment protocol for patients with oral cancer or OPMDs. In addition to this important pretreatment role, biopsies done during and after treatment are critical to establish a successful treatment outcome or to identify failures and to detect recurrences. A thorough understanding of the biopsy principles, procedures, and medicolegal issues associated with the process is imperative for the practitioner and a foundation for good clinical practice.

8.1 

8

Introduction

The French dermatologist Ernest Besnier coined the term biopsy in 1879 [1]. The term is derived from Greek  – bios meaning “life” and opsis meaning “sight.” Biopsy is defined as a surgical procedure to obtain tissue from a living organism for its microscopical examination, usually to perform a diagnosis. The tissue removed from the representative area is sent in a suitable medium, called the fixative, to the pathologist for processing and microscopic interpretation. Of all the investigations, biopsy is the gold standard for rendering a definitive diagnosis, particularly when investigating a suspected malignancy. A thorough understanding of the method and process involved is important for the clinician. There are different types of biopsy, each with its own advantages and limitations. The need to perform a biopsy and the appropriate method is decided upon based on the site of the oral lesions and the provisional diagnosis. Definition Biopsy procedures can be classified based on the features of the condition that is being investigated (direct or indirect), the tissue needing investigation (soft, bone, or blood), and the timing of the biopsy (pre-, intra-, postoperative).

8.2 

Types of Biopsy

Biopsy procedures can be classified based on [2, 3]: I. Features of the condition that is being investigated II. Tissue needing investigation and surgical removal III. Timing of the biopsy I. Features of the condition 55 Direct biopsy: A mucosal lesion apparent at the surface of the mucosa and can be accessed from the surface. 55 Indirect biopsy: An abnormality deep in the tissue and covered by normal-appearing mucosa.

II. Tissue needing surgical removal Soft tissue: 55 Punch biopsy 55 Incisional biopsy 55 Excisional biopsy Blood: 55 Liquid biopsy Hard tissue: 55 Needle core 55 Trephine 55 Curettage/enucleation III. Timing of the biopsy 55 Preoperative 55 Intraoperative 55 Postoperative (during follow-up or surveillance) Keeping in mind the focus of this chapter, we present only soft tissue biopsy here. A brief description of the important steps in the systematic approach to taking a biopsy and the techniques are discussed in this chapter.

8.3 

Clinical Assessment for Biopsy

8.3.1

Local Examination

When a patient presents with an oral mucosal alteration or if one is detected during routine screening [4–6], the clinician may decide to perform a biopsy based on the scheme illustrated in . Fig. 8.1. The clinical criteria include: 55 A definitive clinical diagnosis cannot be made 55 It was thought to be an inflammatory condition but has not responded to treatment 55 It has persisted for more than 2 weeks 55 It is a new growth, an ulcer, or a pigmentation that has been progressively increasing in size 55 It is a white or red patch that requires pathology confirmation 55 It is any soft tissue or hard tissue alteration associated with paresthesia or anesthesia 55 It is any mucosal disorder suspected to be cancer or a potentially malignant disorder 55 It has radiolucent or radiopaque changes, found in a jaw radiograph.  

Clinical situations where biopsy is not indicated include the following: 55 Variations from normal such as Fordyce spots or granules 55 Inflammatory conditions, that respond to treatment, such as pericoronitis 55 Reactive or trauma-induced mucosal disorder that responds to removal of local irritants such as a sharp tooth or prosthesis

83 Oral Biopsy: Principles and Practice

Patient presenting with a mucosal abnormality

Clinical, systemic and local examination and history recording

• Diagnostic label of a benign condition • Less than two weeks duration • No suspicion of malignancy

• More than two weeks duration • Suspicion of malignancy

Treat appropriately

Patient disease-free

Disease persistent

Biopsy

Treat appropriately

Appropriate Follow up

..      Fig. 8.1  Decision algorithm for biopsy

55 Other known benign disorders that have pathognomonic clinical presentations, e.g., geographic tongue and leukoedema Soft tissue abnormalities of the oral cavity may arise due to pathology of the surface epithelium, the associated ­connective tissue, or both. Alterations noted on the surface epithelium may be white (hyperkeratosis, chemical burn, candidiasis), red (atrophy, erosion, ulcer), pigmented (melanotic macule), fluid-filled elevations (vesiculo-bullous lesions, viral infection), ulcer (traumatic, aphthous, squamous cell carcinoma), or a growth (papilloma, carcinoma). Abnormalities of the underlying connective tissue may arise from the nerves, fibrous tissue, muscle, fat, or structures such as the salivary gland and bone. They usually present as superficial nodular or deep-seated swellings. The abnormality is assessed visually, by palpation, and if needed by auscultation (bruit in vascular anomalies). The following findings are documented: location (mucosal, submucosal, intraosseous), color, number, duration, size, shape, borders, precipitating factors if any, prior therapy details, surface texture, consistency on palpation, and visible or palpable vascular pulsation.

In mucosal abnormalities that are vascular or close to neurovascular bundles and carry a risk of bleeding or numbness, or in difficult-to-access regions such as the posterior one-third of the tongue, the biopsy may have to be done in a hospital setting with access to emergency care, or referral to a specialist may be necessary. Radiographs and further imaging are necessary for disorders involving the jawbones. For intraosseous conditions the following are recorded: radiolucent/radiopaque/mixed and pattern if any, the borders, the size, the nature of involvement of roots, cortical involvement, degree of expansion of jawbones, involvement of adjacent anatomic structures, and pathological fracture, if any (see 7 Chapter 11 for more information). The visual and tactile examination of the mucosal abnormality and surrounding tissues will help in deciding the type of biopsy to be taken, based on the location and presentation. Surface alterations of the mucosa as in candidiasis are best studied by smears and OPMDs such as leukoplakia by incision or excision biopsy depending on their size and location, while deep-seated swellings such as those involving the salivary gland or lymph nodes are better investigated with fine needle aspiration cytology, to reduce the morbidity associ 

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a

Table 8.1  Features that raise the suspicion of malignancy 55 55 55 55 55 55 55 55 55

Persistent red/white patch Non-healing ulcer Sudden onset tooth mobility without apparent cause Any lesion with induration on palpation Sudden onset paresthesia of the lip or tongue Dysphagia Chronic ear ache Trismus of unknown cause Persistent cervical lymphadenopathy

b

ated with incisional biopsies. Each of these procedures differs in the depth of tissue sampled and the extent to which the tissue architecture can be assessed (. Fig.  8.2). A detailed description of these procedures is discussed below. One of the important reasons to biopsy is to diagnose or rule out malignancy. Oral squamous cell carcinoma (OSCC) has protean clinical manifestations. It can present as a plaque (leukoplakia, erythroplakia), an endophytic or exophytic growth, an ulcer, or an ulcero-proliferative growth (see 7 Chapter 5). Also, cancers are preceded by or associated with alterations of the mucosa called OPMD. OPMDs include leukoplakia, erythroplakia, erosive lichen planus, actinic cheilitis, and oral submucous fibrosis (see 7 Chapter 12). Features that may require a biopsy are listed in . Table 8.1.  

8 c

 

 

 

>> Important One of the important reasons to biopsy is to diagnose or rule out malignancy. d

e

..      Fig. 8.2  This figure depicts the tissue samples obtained by the different biopsy techniques. a Exfoliative cytology, b brush biopsy, c fine needle aspiration cytology, d punch biopsy, e incisional biopsy

8.3.2

Patient Assessment

Following the clinical examination, an assessment of the various organ systems is carried out by taking a thorough history in preparation for biopsy. History of allergies, recent surgical procedures, and medications being taken are recorded. If necessary, relevant hematological investigations are done. Some of the common health issues of concern to the clinician undertaking a biopsy include uncontrolled diabetes mellitus or a recent history (>Important Questions to ponder related to diagnostic adjuncts

Table 9.1  Ideal attributes of a diagnostic adjunct 55 Improve current clinical paradigms of care 55 High test performance linked to important patient measures 55 Widely available 55 Easily and consistently used by experts or nonexperts 55 Noninvasive with high patient acceptance 55 Point of care, generating results in real time 55 Inexpensive/covered by insurance or healthcare system 55 Separates high- vs low-risk OPMDs/patients 55 Helps move patients into higher care settings

Is it available for use? Resource rich vs poor settings? How easy is it to use chairside? Patient vs clinician? How quickly do you get results? Point of care vs lab? What’s the cost and who pays? Healthcare system? Can it help lesion/patient risk stratification? High vs low? Can it help predict malignant transformation? Yes vs no? Can it help in patient referral/management? 10 to 20or 20 to 30care? What’s the evidence base? Accuracy measures?

9.1.2 

 efinitions of Diagnostic Adjunct and D Predictive Marker

The term diagnostic adjunct is defined here as a technique or test that is applied to an “identified” abnormal oral lesion which aids in the lesion’s clinical assessment and diagnosis. A diagnostic adjunct is not the same as a “screening” adjunct, and the distinction is important. A “screening” adjunct would be applied to all apparently healthy patients undergoing an opportunistic visual and tactile examination during a routine visit, irrespective of the presence of OPMDs. Furthermore, diagnostic adjuncts could be applied in a baseline setting (i.e., used by primary care clinicians or experts to clinically assess or characterize a lesion in order to make diagnostic decisions), in a treatment setting (i.e., used by experts as an aide to map or assess the margins of disease), or in a surveillance setting (i.e., used by expert clinicians to monitor high-risk patients). A predictive marker (which may be employed within an adjunctive technique) is defined as marker, which, if present, correlates with a risk for malignant transformation of a nonmalignant OPMD. 9.1.3 

I deal Attributes of Diagnostic Adjuncts

It is important to consider the many “ideal” attributes of diagnostic adjuncts in the context of different clinical (i.e., primary, secondary, or tertiary care) and resource settings (i.e., low versus high resource) (. Table 9.1). First and foremost, diagnostic adjuncts must improve the current paradigm of care across these different settings.  

In a primary care setting, a diagnostic adjunct would ideally be employed in the risk assessment of an OPMD (i.e., as a “triage” test) to help make a decision about whether a patient requires referral for further diagnostic testing. Compared to the gold standard biopsy/histopathology, such an adjunct should have high test performance (i.e., accuracy), be less invasive, be simple to perform from the perspective of both the clinician and patient, offer a more cost-effective alternative, reduce the unnecessary referral of patients with lesions that have no malignant potential (or, in low-resource settings, those deemed at low risk for malignant potential), and most importantly allow the identification and prompt referral of those patients with OPMDs that have OSCC, or who are at the highest risk for malignant transformation (i.e., helps move patients to a higher care setting). In a secondary or tertiary care setting, diagnostic adjuncts might be utilized to allow a more detailed characterization or mapping of disease in patients with OPMDs (particularly those with large non-homogeneous lesions with variable pathology or multifocal lesions). This might facilitate incisional biopsy site selection both at baseline and in a surveillance setting or reduce the propensity for positive margins following the excision of OSCC or OED. In a surveillance setting, such adjuncts could also aid in the decision to escalate or de-escalate the need for further diagnostic steps (i.e., biopsy now versus a wait and see approach). In high-resource settings, healthcare infrastructure typically includes established pathways for the detection, biopsy, and management (including long-term surveillance) of all patients with OSCC and OED. Yet even in this setting, with soaring healthcare costs, the use of adjuncts is likely unsustainable unless they are shown to be cost-effective. New technologies and strategies which can better differentiate the high-risk from low-risk lesions (or patients) and resolve them into the general population (i.e., return to a primary care setting) are needed. In low-resource settings in which the individual may only be seen once and the treatment options are limited, the detection of lower risk lesions (or patients) for which there are little to no resources to treat, or are not likely to be followed up, is not of high value. This leaves the minimal resources to detect, diagnose, and treat the higher-risk lesions (or patients). Other important considerations for diagnostic adjuncts include the capital cost, consumable costs, amount of user training required versus

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acceptable levels of performance, integration of the procedure into the workflow, patient acceptance, technical support and maintenance, and access to parts and supplies [7, 8]. In low-resource settings, the challenges associated with consumable costs, technical support, and maintenance can be especially significant barriers to successful implementation. Finally, even the simplest technologies require continuous, ongoing user training and effective quality control procedures. Yet the current paradigm for the diagnosis and treatment of OPMDs based on biopsy and histopathology has limitations. The “diagnostic threshold” that is used to classify an “at-risk” population is predicated on the histopathologic diagnosis (see 7 Chapter 12). There are established evidence-­ based treatments for patients diagnosed with OSCC or with high-grade dysplasia. However, this population comprises the minority of OPMDs, and the majority of OPMDs are diagnosed with lower-grade OED. The diagnosis of lower-­ grade OED is fraught with a high degree of both intra- and inter-pathologist diagnostic variability [9, 10]), there is a low propensity for malignant transformation, and treatment decisions are less clear-cut and not based on interventional studies linked to important patient-related endpoints (such as propensity for malignant transformation, mortality, or morbidity). Therefore, it would seem preferable, especially at this lower end of the diagnostic spectrum, if the outcomes of an adjunct were linked to such important patient-related endpoints. A predictive marker that could improve the ability of histopathology to help stratify higher-risk patients (i.e., those nonmalignant OPMDs with a high risk for malignant transformation) from lower-risk patients (i.e., those with OPMDs that have a lower risk of malignant transformation) would improve the current paradigm of care. With all the new technological advances in medicine, one might hypothesize that a predictive marker might one day replace the current gold standard.  

9

9.1.4 

 ypes of Diagnostic Adjuncts and T Predictive Markers

Some diagnostic adjuncts are “point-of-care” techniques providing real-time results (e.g., visualization adjuncts), while for others, the results require the time taken for a clinical sample to be analyzed by an outside laboratory (e.g., cytology). Adjuncts may provide “macroscopic” or wide-field information about a lesion (or lesions), while others provide “microscopic” or narrow-field information at the cellular or even molecular level. Visualization-based or “optical” adjuncts include devices or machines which expose tissues, in vivo, to various wavelengths of light, generating (in real time) various optical signals depending on interactions of light with tissue. “Vital” dyes or markers may be directly applied to a lesion in vivo to provide real-time macroscopic information. Technologies based on the collection of tissue noninvasively (i.e., cytology) or biofluid samples (i.e., salivary or serum samples) may be

processed and analyzed in various ways (i.e., to assess cellular morphology or the presence of various biomarkers). Finally, some adjuncts employ biomarkers that could help improve the ability to predict risk for malignant transformation in patients with OPMDs (i.e., predictive markers). Such markers might be incorporated into the current clinical paradigm, either as an additional marker detected by further “analysis” of an archived tissue specimen (or cytopathologic or other biofluid specimen) by a pathology laboratory or conceivably within a point-of-care technology (i.e., a cytopathologic or saliva-based test processed chairside with real-time results). Some diagnostic adjuncts have received regulatory approval for clinical use (. Table 9.2 and . Fig. 9.1), while others are in various stages of preclinical or clinical study. A discussion of the commercialization of diagnostic adjuncts/ predictive markers and regulatory issues is beyond the scope of this chapter, although a recent review covers this well [11].  

9.1.5 

 

 erformance Measures Used in P Research Studies

Before embarking on a more detailed analysis of the various diagnostic adjuncts and predictive markers, it is important to be able to evaluate their performance across different clinical and resource settings. This requires an understanding about how to critically interpret research studies. In this field, where tissue biopsy and histopathologic endpoints remain immutably anchored as the gold standard, and where current treatment algorithms are already predicated on such histopathologic endpoints, the almost exclusive design of research studies exploring the performance of new diagnostic adjuncts has been the “accuracy study.” These studies do not require long-term follow-up and may be conducted relatively quickly, limited only by the accrual rate of patients with OPMDs [12].Because of the relative ease and low cost of performing accuracy studies, this methodology has been popularized for the evaluation of “triage”-type diagnostic adjuncts where the intent of the adjunct is not to replace the gold standard “reference” test, and where the adjunctive test and reference test can be performed consecutively on the same lesion. Such a design has the ability not only to measure test accuracy but also other outcomes (i.e., the ease of performing and interpreting the test from both the clinician and patient perspective and other metrics such as the time taken to receive the results and cost-effectiveness). However, accuracy studies have significant methodological flaws. They are linked to histopathologic endpoints (which are imperfect) and not to important patient-related outcomes (such as malignant transformation, morbidity or mortality, survival, or other factors). The evidence for the performance of adjuncts employing predictive markers is largely based on retrospective studies linked to longitudinal data (i.e., from cancer registries) comparing rates of malignant transformation (or other important patient-related outcomes) in patients with nonmalignant OPMDs (i.e., typically those harboring OED) testing positive

103 Diagnostic Adjuncts for Oral Cavity Squamous Cell Carcinoma and Oral Potentially Malignant Disorders

..      Table 9.2 Adjuncts approved for use in the United States marketplace Visualization adjuncts VELscope Vx

LED Apteryx, White Rock, BC, Canada

Autofluorescence

Oral ID

Forward Science, Houston, TX, USA

Autofluorescence

BioScreen

AdDent Inc., Danbury, CT, USA

Autofluorescence

Vizilite Pro

DenMat Holdings Inc., Lompoc, CA, USA

Autofluorescence

Goccles

Pierrel s.p.A, Capua, Italy

Autofluorescence

DOE SE Kit

DentLight Inc., Plano, TX

Autofluorescence

Identafi

DentalEZ, Malvern, PA, USA

Autofluorescence + reflectance

Microlux DL

AdDent Inc., Danbury, CT, USA

Reflectance

Orascoptic DK

Kerr Corp. Middleton, WI, USA

Reflectance

Vizilite Tblue

DenMat Holdings Inc., Lompoc, CA, USA

Reflectance + toluidine blue

OraBlu

AdDent Inc., Danbury, CT, USA

Toluidine blue

Vizilite Tblue

DenMat Holdings Inc., Lompoc, CA, USA

Reflectance + toluidine blue

Oral CDx Brush Test

CDx Diagnostics, Sufferin, NY, USA

Cytopathology

Cyte ID

Forward Science, Houston, TX, USA

Cytopathology

Salimark OSCC

PeriRx, Broomall, PA, USA

DUSP1, SAT, OAZ1

OraMark

Vigilant Biosciences, Fort Lauderdale, FL, USA

CD44, total protein

OraRisk HPV

OralDNA Labs, Eden Prairie, MN, USA

HPV subtypes

Vital staining adjuncts

Cytopathological adjuncts

Salivary testing

for the marker versus those testing negative for the marker. The results of such studies should be interpreted with caution because they are based on retrospective data and may be confounded by the impact of various uncontrolled interventions such as surgery and other methodological biases. Few of these studies have been independently validated, and most are expensive assays which have not been commercialized. In an accuracy study, the diagnostic adjunct is first tested on a target population of patients with OPMDs, yielding test results (typically a dichotomized positive versus negative result). This is followed by the reference test (biopsy and histopathology) also typically yielding a dichotomized test result (i.e., positive is mild dysplasia or worse, negative is no dysplasia). The diagnostic adjunct test performance is compared to the reference standard initially by constructing a 2 × 2 tabulation showing the number of true-positive (TP), true-­ negative (TN), false-positive (FP), and false-negative (FN) outcomes, and then various parameters may be calculated such as sensitivity, specificity, positive and negative predictive values, likelihood ratios, diagnostic odd ratios, receiver operating characteristic (ROC), and area under the curve (AUC) [13] (. Fig. 9.2). In order to understand the meaning of test accuracy in the context of interpreting a single accuracy study or a meta-­  

analysis of multiple studies, it is important for the reader to understand whether and how these measures and parameters are clinically meaningful. A true-positive test result indicates that an adjunct correctly helped identify a patient as “having the disease” resulting in a timely referral to a specialist for biopsy. It is important to note that “having the disease” in such accuracy studies means that the reference positive test (i.e., histopathologic diagnosis) outcome is typically commensurate with any grade of OED, carcinoma in situ, or OSCC. A true-negative test result indicates that an adjunct correctly helped identify a patient as not having the disease (i.e., a benign diagnosis) and the patient will receive reassurance that he or she is healthy. A false-negative test result indicates that an adjunct incorrectly helped identify a patient as not having the disease, and therefore the true diagnosis would be missed, potentially worsening the prognosis of the disease. A false-positive test result indicates that an adjunct incorrectly helped identify a patient as having the disease, and therefore the patient would undergo additional unnecessary testing and biopsy, not to mention the psychological stress. Sensitivity is the proportion of patients who have the disease, correctly classified by the adjunct test as such, and specificity is the proportion of patients who do not have the

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9

..      Fig. 9.1  Various approved diagnostic adjuncts currently marketed to frontline healthcare providers in the United States

disease, correctly classified as such. Sensitivity and specificity are related to each other and are not intrinsic test characteristics. The false-negative rate is 1-sensitivity, and the false-­ positive rate is 1-specificity. The positive predictive value (PPV) is the proportion of those who test positive and have the disease, and the negative predictive value (NPV) is the proportion of those who test negative and do not have the disease. The PPV and NPV are linked to the prevalence of the disease. The likelihood ratio (LR) is the ability for a test to move us from a pretest probability to a posttest probability. Pretest probability is the proportion of people in the ­population at risk who have the disease at a specific time or

time interval (i.e., the point prevalence or the period prevalence of the disease). In other words, it is the probability, before the diagnostic test is performed, that a patient has the disease. Clinicians can estimate pretest probabilities from routine data, practice data, or clinical judgment. Posttest probability is the proportion of patients testing positive who truly have the disease. It is similar to the PPV, but apart from the test performance, it also includes a patient-based probability of having the disease. A LR+ indicates how much more likely a positive test result is in patients with the disease versus in patients without the disease. A LR- indicates the probability of a patient without the disease having a negative test

105 Diagnostic Adjuncts for Oral Cavity Squamous Cell Carcinoma and Oral Potentially Malignant Disorders

Test negative

# patients

Test positive

Disease(+)

Disease(–) TN

TP

FN

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Sensitivity = TP /TP+ FN Specificity = TN/TN+ F P PPV = TP/TP+FP NPV = TN/TN+FN LR+= TP/TP+FN FP/TN+FP LR– = FN/TP+FN TN/TN+FP DOR= TP*TN FP*FN

..      Fig. 9.2  Performance of a given test (such as diagnostic adjunct for OPMDs) across two populations of patients, one population without the disease and one population with the disease. Note that the test performance falls into four distinct groups (true positives (TP), true

negatives (TN), false positives (FP), and false negatives (FN)). The numbers of patients within each group allow calculations of test performance (sensitivity, specificity, positive and negative predictive values, likelihood ratio +/−, and diagnostic odds ratios)

result. The further away the LRs are from 1, the better the diagnostic test. The diagnostic odds ratio (DOR) is a good measure to represent both sensitivity and specificity. It can be used to compare across tests for the same disease and patients and represent the odds of positivity in the patient with the disease relative to the odds of positivity in patients without the disease. The ROC is essentially a plot of true-negative rate (x axis) by true-positive rate (y axis). The closer the curve is to the upper left corner and away from the “line of random chance,” the greater the sensitivity and specificity. The AUC of an ROC curve equates with the ability to discriminate between two outcomes [14]. No diagnostic adjunct is perfect, and in the context of accuracy studies, important questions are: What thresholds of test accuracy are considered acceptable? Would a patient be more upset by a false-negative or false-positive test result? One has to consider these test results in the context of the disease and the prevalence in the population. Typically tests with high sensitivity, specificity, PPV, and NPV (>90%) are acceptable. An AUC = 1 is a perfect test, and tests generating an AUC of 0.99–0.90, 0.89–0.80, 0.79–0.70, and 10 and LR- 1000).

There are a number of other important considerations in the interpretation of accuracy studies as there are many methodological limitations related to their design and conduct. A number of quality assessment tools area available for accuracy studies, such as QUADAS-2, which assess bias and issues of test applicability [15], and are particularly useful in systematic reviews. Some of the key domains include the selection of the patient population, a description of the diagnostic adjunct and how it is performed and interpreted, a description of the reference test and how it is performed and interpreted, and a description of the flow and timing of the tests. Furthermore, there is significant heterogeneity across accuracy studies in the definition of OPMDs and in the inclusion and exclusion criteria defining the accrued patient population. This creates a wide range in the prevalence of OED or OSCC within the study population. Coupled with the fact that most of the accuracy studies are not performed by frontline clinicians but rather by experts in secondary or tertiary care settings, these two factors introduce bias and suggest limitations in applicability to a general population. Specific and detailed descriptions about how the diagnostic adjuncts are performed and interpreted are also quite variable and lead to issues of bias and applicability. The most

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important element associated with the interpretation of a test result is a clear-cut description of the objective criteria that differentiate between a positive or negative test outcome (chairside or laboratory). Similarly, a detailed description of how the reference test is performed (i.e., biopsy) and interpreted (i.e., histopathology) is critical. Finally, the relationship in the flow and timing of the two tests being compared must be clearly defined. Two issues are of principal importance, namely, that the biopsy is performed during the same visit and at the identical lesion site as the diagnostic adjunct (i.e., allowing direct comparison) and that the tissue sample is interpreted by one or more pathologists who are blinded to all other study data. If more than one pathologist is employed, given the variability in inter- and intra-rater agreement, there should be considerations about a methodologic plan for calibration and adjudication [16]. The interpretation of retrospective studies to assess the performance of predictive biomarkers is by comparing cohorts of patients that test positive versus negative for the marker at baseline and report Kaplan-Meier curves and or hazard ratios to report differences in malignant transformation rates. It seems important for the future development of diagnostic or predictive adjuncts to design prospective randomized clinical trials that are directly linked to interventions with important patient-related outcomes. There is a paucity of such studies because the measurement of such endpoints requires long-term follow-up which adds additional complexity and expense. 9.2

Visualization Adjuncts/Optical Biopsy

A variety of imaging devices and techniques are now available to aid the clinician in visualizing and characterizing OPMDs in real time at the point of care [17–19]. These devices detect changes in optical properties (absorption, reflection, refraction, fluorescence, and scattering) associated with carcinogenesis in oral tissues [20–22]. In particular, recent technological advances in optical and electronic components (high-power LED illumination sources, cameras, tablet computers, other consumer electronics) have led to the development of a generation of low-cost, portable visualization methodologies which can be used as adjuncts during an evaluation of OPMDs. Evaluation of the utility of these visualization-based adjuncts must take into account the type of adjunct, the clinician users and their experience with these technologies, the settings in which they would be used, and the patient populations in which they are to be employed. Some adjuncts are designed to crudely image larger areas of tissue, referred to here as “wide-field” visualization adjuncts, while others image small areas of tissue, referred to here as “narrow-field” visualization adjuncts. Different wide-field adjuncts interrogate different tissue properties (e.g., some are better at detecting vascular changes, while others detect variations in the distribution of fluorophores). Some of the narrow-field

devices are considered a rudimentary “in vivo biopsy” or “optical biopsy,” and although unlikely to replace the conventional biopsy and histopathology anytime soon, these adjuncts may play an increasingly important role in diagnosis [23]. To take advantage of the different tissue properties, two or more wide-field (or narrow-field) techniques may be combined to improve accuracy (e.g., multispectral imaging) [24]. Alternatively, wide- and narrow-field subcategories may be combined, allowing a clinician to localize the region of interest and then zoom in for more detail [25]. Visualization adjuncts are also well suited to take advantage of continuing advances in molecular-specific contrast agents (i.e., “molecular paints”) [26]. Wide-field visualization adjuncts are designed to be used as either a “screening” adjunct to scan the entire oral cavity or as a diagnostic adjunct to further evaluate OPMDs following their detection. The intent is to help differentiate between “normal” and “abnormal,” further characterize or delineate the extent of OPMDs, or to map out high-risk areas. There are three subcategories of visualization diagnostic adjunct that provide wide-field visualization: direct viewing enhanced by illumination and/or acetic acid (i.e., tissue reflectance or chemiluminescence), autofluorescence, and narrow-band imaging. These methods are generally preferentially designed to trade increased sensitivity at the expense of some specificity loss. Narrow-field visualization adjuncts are designed to interrogate specific sites at a “microscopic” level with high spatial resolution (in vivo microscopy), high spectral resolution (spectroscopy), or tomography and include confocal microscopy, high-resolution microendoscopy, elastic-scattering spectroscopy, differential path-length spectroscopy, diffuse reflectance spectroscopy, Ramen spectroscopy, time-resolved autofluorescence spectroscopy, and optical coherence tomography, These devices, often implemented in a point probe format, are typically used to characterize lesions after they have been mapped out with wide-field devices (and therefore could be used in tandem) and as such have a tendency to be biased toward increased specificity relative to the wide-field diagnostic adjuncts. In vivo microscopy or optical biopsy allows real-time imaging of subcellular features that can otherwise only be seen via biopsy and histopathologic examination and has the potential to drive immediate treatment decisions [23, 27]. Spectroscopy does not generate images showing tissue architecture but rather shows spectral plots that equate to structural or molecular changes in the tissue. Cost is a significant issue with most of these technologies, and their application would be in the purview of experts (such as surgeons in conjunction with pathologists) for mapping and surgical treatment of patients with OPMDs. 9.2.1 

Tissue Reflectance

This subcategory of diagnostic adjunct was developed first as an adjunct for the evaluation of cervical neoplasia and then adapted for use in the oral cavity [28]. As a diagnostic adjunct,

107 Diagnostic Adjuncts for Oral Cavity Squamous Cell Carcinoma and Oral Potentially Malignant Disorders

the evaluation of OPMDs is performed in two steps: topical application of acetic acid followed by the direct illumination using of a low (blue-white)-light source. The light source in some of these platforms is generated by a chemical reaction, hence the term “chemiluminescence,” whereas others are generated by LED. The proposed basis for the use of this adjunct is that OMPDs harboring OSCC or OED have a differential tissue reflectance compared to normal mucosa. Accuracy studies have been performed [29–36], and a recent meta-analysis of five of these studies yielded pooled sensitivity and specificity compared histopathological outcomes of 72% (95% CI: 62–81%) and 31% (95% CI: 25–36%), respectively [37], poor outcomes indeed. However, this technology is not currently marketed for stand-alone use but rather in combination with toluidine blue vital staining, and in four studies, the combined use of these two adjuncts led to improvements in the pooled sensitivity and specificity to 81% (95% CI: 71–89%) and 69% (95% CI: 63–75%), respectively. Nevertheless, these outcomes along with a low-quality level of evidence due to “serious issues of bias and indirectness” were strong grounds for the expert panel to recommend against the use of tissue reflectance devices by frontline clinicians. 9.2.2 

Autofluorescence

Tissue autofluorescence devices are hand-held and generate a blue-violet light (in the 400–450 nm range) that excites naturally occurring tissue fluorophores (i.e., molecules such as FAD and NADH in the epithelium and collagen or elastin cross-links in the submucosa) revealing a visible fluorescence emission, thus enabling clinicians to visually scan the mucosa in a darkened environment for abnormal disruptions in natural tissue autofluorescence [38]. Two early case series of OPMDs harboring carcinoma or high-grade dysplasia demonstrated that such lesions exhibited a characteristic “loss of fluorescence visualization” (FVL) (in contrast to normal tissue which exhibits “retained fluorescence visualization” (FVR)), suggesting a role as a diagnostic adjunct [39, 40] (. Fig. 9.3). However, given the relatively low prevalence of such lesions in the general population, clinicians using these devices must be able to distinguish them from “false-­ positive” common FVL benign lesions (known as “confounder” lesions), predominantly inflammatory lesions (such as oral lichen planus or erythematous candidiasis), non-­inflammatory vascular changes, or pigmented lesions, all of which absorb blue light (. Fig. 9.4). This issue of suboptimal specificity has been borne out in numerous accuracy studies [41–47], and a recent meta-analysis of these studies yielded pooled sensitivity and specificity compared histopathological outcomes of 90% (95% CI: 76–100%) and 72% (95% CI: 35–100%), respectively, leading the expert panel to recommend against the use of tissue autofluorescence devices as diagnostic adjuncts for OPMDs by frontline clinicians [37]. It is important to note that these studies were performed largely in secondary care settings by experts with  

 

..      Fig. 9.3  Images from a 64-year-old female presenting with an OMPD involving the right lateral/ventral surface of the tongue. A clinician’s eye is immediately drawn to the two white plaques, the larger is superior and the smaller inferior and posterior. A granular lesion just posterior to the larger white plaque is less obvious and easily overlooked. An autofluorescence device reveals FVL in the granular area yet not in the white plaque (FVR). The granular area harbored a microinvasive OSCC. The white plaque revealed mild dysplasia. Inferiorly a second less distinct FVL area posterior to the smaller white plaque revealed moderate dysplasia. The FVL areas represent true-positive outcomes for this visualization adjunct. The FVR areas are false negatives because mild dysplasia is a positive disease outcome

greater experience in the clinical diagnosis of mucosal disease and that these results are not generalizable to frontline clinicians. However, studies support that specificity may be bolstered in primary care settings (such as general dental practice) through adequate training and/or by reappointing patients with FVL lesions later to rule out benign inflammatory lesions [48, 49]. Occult lesions (i.e., lesions not detected by a standard visual and tactile oral examination) have been detected, a small fraction of which showed OED [50]. One issue that deserves consideration is the effect of different habits/risk factor exposures on the use of autofluorescence devices. While alcohol and tobacco use are the predominant risk factors in the West, areca nut chewing habits (often used in combination with smokeless tobacco) predominate in Asia (i.e., Southeast Asia, Taiwan, and China). Areca nut chewing can affect the performance of autofluorescence devices and other visualization adjuncts due to the effect of surface debris on the mucosa (i.e., betel chewer’s

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bands of light, one in the blue/green spectrum (400–430 nm) which helps delineate superficial vasculature (blood vessels appear brown) and the other in the green spectrum (525–555 nm) which delineates thicker vessels in the submucosa (they appear cyan). Compared to healthy tissues, OSCC and OED may exhibit abnormal neovascular/angiogenic patterns, hence the premise for NBI’s utility [54]. Two studies met the criteria for inclusion in a systematic review [55] of accuracy studies to determine NBI’s use as a diagnostic adjunct for OSCC or OPMDs, and in both studies, against histopathologic endpoints, NBI was significantly more accurate than white light evaluation alone [56, 57]. The studies were of low quality, and more studies are needed. An NBI unit is a sophisticated and an expensive piece of equipment, unlikely to be used by frontline clinicians or in low-resource settings. However, similar to autofluorescence in the hands of trained experts, NBI has been demonstrated to facilitate the mapping and surgical excision of OSCC [58, 59], and in a single-center study, patients undergoing NBI-­ guided resections had a reduction in recurrence rates and improved survival compared to traditional resection [60]. Further prospective multicenter trials are needed to confirm these findings.

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9.2.4 

Confocal Microscopy

Confocal microscopes can image superficial tissues up to depths of 200–300 μm, such as oral epithelium [61]. Confocal reflectance microscopes utilize the interaction of a white ..      Fig. 9.4  Images from a 42-year-old asthmatic female smoker presenting with an erythematous area involving the hard palate. An light source with the tissue (similar to conventional microsautofluorescence device reveals impressive FVL on the palate. The copy), whereas confocal fluorescence microscopes utilize erythematous area was an erythematous candidiasis which responded light sources to detect autofluorescence or employ fluoresto an antifungal regimen. The FVL areas represent a false-positive cent stains (e.g., topical acriflavine or intravenous fluoresoutcome for this visualization adjunct, a “confounder lesion” cein) to improve cellular detail and offer the potential to explore not only morphology but may also be linked to mucosa) or altered collagen deposition (i.e., oral submucous molecular markers (e.g., EGFR). Yet, cost aside, this technolfibrosis) [51]. Mucosal changes in patients who have received ogy has a number of limitations, including inability to image radiation treatment to the oral cavity or undergone surgical subepithelial tissues due to depth restrictions and therefore procedures (i.e., scarring, grafts, or free flaps) may also affect increasing the risk of missing tumor invasion, difficulty performance of tissue autofluorescence devices (personal imaging lesions with hyperkeratotic surfaces due to the high communication). refractive index of keratin, and, in the case of fluorescent There is evidence based on a retrospective study to sup- microscopes, the limited penetration of topically applied port the use of tissue autofluorescence devices to guide the fluorescent agents [62]. One small preliminary accuracy surgical excision of both early OSCC and OPMDs with high-­ study of 21 patients with head and neck lesions (>75% were grade OED [52], leading to a significant reduction in recur- OSCCs and OPMDs with and without OED) reported high rence rates, and has the potential to spare more normal tissue accuracy comparing fluorescence confocal microscopy with at the surgical margin [53]. Prospective studies are needed to matched histopathology [63], and the same investigators confirm this indication for autofluorescence devices. subsequently reported good interobserver agreement of the interpretation of the images generated by the confocal ­microscope [64]. Further studies are needed. 9.2.3 

Narrow-Band Imaging

Narrow-band imaging (NBI) is an endoscopic diagnostic adjunct used in a number of aerodigestive tract mucosal tissues to evaluate the surface texture and patterns of vasculature. NBI units simultaneously emit two distinct narrow

9.2.5 

High-Resolution Microendoscopy

High-resolution microendoscopy (HRME) was developed as a cost-effective alternative to confocal microscopy. It

109 Diagnostic Adjuncts for Oral Cavity Squamous Cell Carcinoma and Oral Potentially Malignant Disorders

uses a light-emitting diode connected to a fiber-optic probe placed in contact with the tissue and detects the fluorescence of cells stained by the topical application of a fluorescent dye (proflavine), images of which are sent to a camera and may be viewed on a chairside laptop. A preliminary accuracy study demonstrated good sensitivity and specificity for the expert to interpret the HRME images compared to histopathology [65]. Limitations include the small probe size, and similar to confocal microscopy, there are issues related to imaging lesions with surface hyperkeratosis. The use of an automated algorithm for selecting and interpreting diagnostic images from video capture imaging may abrogate the need for experts and therefore suggests possible applicability in low-­resource settings [66]. This technology has also been studied for its utility in the determination of surgical margins, and while not linked to prognostic endpoints, a single preliminary study demonstrated that HRME compared to histopathological endpoints was able to accurately differentiate neoplastic versus normal mucosa (sensitivity and specificity were 95% and 96%, respectively) [67]. 9.2.6 

Elastic Scattering Spectroscopy

Light scatters as it passes through tissues and is reflected back creating measureable signature spectra from different depths (i.e., within the epithelium and underlying connective tissue) commensurate with the cellular and subcellular structures present. There are a number of elastic scattering spectroscopy (ESS) systems which employ different broad-spectrum light sources. Preliminary studies have demonstrated the potential utility of ESS to determine the presences of OED and/or OSCC in OPMDs [68] and to facilitate margin evaluation during resection of OSCC [69]. 9.2.7 

Differential Path-Length Spectroscopy

Differential path-length spectroscopy utilizing a white light source allows interrogation of small and superficial areas for microvascular changes and a single preliminary in vivo study suggests that dysplastic and non-dysplastic OMPDs can be accurately differentiated [70]. 9.2.8 

Diffuse Reflectance Spectroscopy

Diffuse reflectance spectroscopy can detect the concentration of hemoglobin and oxygen saturation along with changes in light scattering. Preliminary in vivo studies using diffuse reflectance spectroscopy alone [71] and in conjunction with narrow-field autofluorescence [72] demonstrate its potential utility in discriminating normal tissue and benign lesions from OSCC and OED.

9.2.9 

Time-Resolved Autofluorescence Spectroscopy

The decay time following the excitation of natural tissue fluorophores by may be measured using time-resolved spectroscopy, and preliminary in vivo studies have demonstrated a difference in decay times in OMPDs [73]. 9.2.10 

I nelastic Light-Scattering (Raman) Spectroscopy

Raman spectroscopy (RS) is based on the detection of inelastic scattering of light (i.e., the Raman effect) from a monochromatic laser light source hitting tissue which generates signature spectra equating with the molecular composition of cellular/subcellular structures [74]. This technique may be used in vivo or on tissue samples (ex vivo), such as biopsy/ resected tissue, cytological specimens, serum, or even urine. Two preliminary studies in patients with OPMDs/oral carcinoma demonstrated the feasibility of RS to discriminate, in vivo, between normal tissue, “premalignant lesions” and OSCC [75, 76]. A number of the studies have explored the utility of RS to determine the presence of OSCC at the margins following resection (i.e., as an alternative to standard “frozen sections”). Ex vivo accuracy studies have demonstrated that RS in conjunction with automated tissue classification modeling can accurately discriminate between OSCC and “non-tumor” tissue [77, 78].More studies are needed. 9.2.11 

Optical Coherence Tomography

Optical coherence tomography (OCT) is the light-based equivalent to ultrasound and works by the “interferometric” depth resolved detection of “elastic” light scattering. It can image tissues several millimeters deep (2 mm is optimal) and has a high resolution of approximately 1–2 μm (close to that of microscopy). A flexible probe connected to a light source in the near infrared spectrum is used to illuminate tissues, and the light refraction will vary depending on the cell types. Malignant tissues have a higher refractive index compared to normal tissue, hence the basis for use in OSCC or OPMDs [79]. There are a number of different systems in use, including time-domain OCT (TD-OCT), spectral-domain OCT (SD-OCT), and swept source OCT (SS-OCT) which is a combination of TD-OCT and SD-OCT principally used for the viewing of blood vessels. There are two low-quality accuracy studies comparing in vivo OCT with histopathologic endpoints to diagnose OSCC or OED in OPMDs [80, 81], and while both suggest high sensitivity and specificity, there is a need for larger studies to confirm these findings. An ex vivo study has shown that OCT can be used to accurately assess margins following the resection of early stage OSCC [82]. Recently, a promising

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new wide-field OCT system has been developed to allow screening of larger areas of tissue, suggesting that OCT might have utility in biopsy site selection [83]. 9.3

Vital Staining

Vital staining involves the topical application of a dye to an OPMD to help characterize the lesion and facilitate lesion biopsy, mapping for purposes of surgical excision, and surveillance of high-risk patients. 9.3.1 

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Toluidine Blue

Toluidine blue (TB) vital staining as a diagnostic adjunctive technique for assessing OPMDs was first reported by Neibel et al. more than half a century ago [84]. The mechanism by which it works remains somewhat of a mystery, but it is likely related to the affinity for nuclear material in the context of increased permeability in squamous cell carcinoma and high-grade dysplasia. It may be prepared as a 1% or 2% solution or is available commercially in preprepared packages, and its application is used in conjunction with a 1% acetic acid solution (acetic acid is applied first, followed by toluidine blue, and then acetic acid). As a diagnostic adjunct, a recent meta-analysis of 16 vital staining accuracy studies [85], predominantly using toluidine blue as a single stain, revealed a sensitivity and specificity of 87% (95% CI: 80–94%) and a specificity of 71% (95% CI: 61–0.82%) compared to histopathologic endpoints (i.e., any grade of dysplasia or carcinoma) [86–100]. There was broad heterogeneity in accuracy values which may be attributed to several factors including the population of OPMDs tested (i.e., a higher percentage of high-grade dysplasias/carcinoma in situ/carcinoma will lead to higher sensitivity) [36], variability in the testing protocols, and in the interpretation of cases of light or equivocal staining patterns (some authors assigned a light blue stained lesion as positive and others as negative). The potential for both false positives and false negatives and clinician experience is critical. False-positive result may occur in benign inflammatory, ulcerative, and regenerating tissues (. Fig. 9.5). In addition, the dye is mechanically retained in the crevices of rough/fissured lesions and the filiform papillae. False negatives can occur and may be due to the inability of the dye to penetrate through thick hyperkeratotic lesions (i.e., leukoplakias). Given that frontline clinicians will encounter of blend of lesions reflective of the general population (i.e., more likely to be traumatic and inflammatory and less likely to be high risk OPMDs), higher false-positive and false-negative rates may be anticipated. A follow-up visit for repeated staining may improve specificity. Collectively, these findings led an expert panel to recommend against the use of vital staining as a diagnostic adjunct for OPMDs by frontline clinicians [37]. In a secondary or tertiary care settings, expert clinicians may use toluidine blue in a number of ways: to help guide  

..      Fig. 9.5  Images from a 51-year-old male presenting with an oral ulceration with faint lichenoid striae at the periphery. The ulcer bed stains positive with toluidine blue (TB+). However, the ulcer was a component of a lichenoid mucositis secondary to a medication he had been prescribed (i.e., there was no evidence of OED or OSCC). The fibrin pseudomembrane covering such an ulcer will stain TB+, and this is a false-positive outcome. Also note that the filiform papillae (arrow) retain the toluidine blue staining

biopsy site selection at baseline (in an attempt to reduce sampling error), particularly in nonhomogeneous/mixed OPMDs or patients with multifocal OMPDs where variable histopathology can exist within a lesion or across multiple lesions (. Fig. 9.6); to help identify/map high-risk disease prior to surgical excision; and to incorporate toluidine blue staining into the long-term surveillance of high-risk patients with a past history of carcinoma or dysplasia to facilitate the identification of new or evolving disease, thereby minimizing the need for serial biopsies. In a study testing toluidine blue rinse in a high-risk surveillance cohort, TB was more sensitive at detecting OED or OSCC compared to standard clinical examination [101].  

9.3.2 

Lugol’s Iodine

Lugol’s iodine, named after the French physician Jean Lugol, stains for glycogen content, and normal nonkeratinized oral

111 Diagnostic Adjuncts for Oral Cavity Squamous Cell Carcinoma and Oral Potentially Malignant Disorders

Eyecatcher

Some diagnostic adjuncts are “point-of-care” techniques providing real-time results.

9.4

..      Fig. 9.6  Images from a 64-year-old female presenting with an OMPD involving the right lateral/ventral surface of the tongue. A clinician’s eye is immediately drawn to the two white plaques, the larger is superior and the smaller inferior and posterior. A granular lesion just posterior to the larger white plaque is less obvious and easily overlooked. Toluidine blue (TB) staining is retentive (i.e., positive) in three small spots within the granular area and in one small spot inferiorly. Neither of the white plaques retained the toluidine blue (i.e., negative) (FVR). The most posterior TB+ spot on the granular area was a microinvasive OSCC (the other spots were severe dysplasia). The white plaque revealed mild dysplasia yet was TB-. Inferiorly a second less distinct TB+ area posterior to the smaller white plaque revealed moderate dysplasia. The TB+ areas represent true-positive outcomes for this vital stain. The TB- white plaques represent false-negative outcomes because mild dysplasia is a positive disease outcome

mucosa will preferentially retain the stain. Given the contrasting staining effects of Lugol’s iodine and toluidine blue, the two agents have been tested in combination and can bolster the specificity of toluidine blue staining [94, 99]. There is limited evidence suggesting that this inexpensive vital stain may reduce the propensity for positive surgical margins following resection of oral carcinoma, although there is no data to suggest that this is commensurate with improved patient outcomes such as recurrence rate or survival [102]. 9.3.3 

Other Vital Stains

Methylene blue and rose bengal have a similar staining profile and performance as toluidine blue [91, 92].

Oral Cytology

An important diagnostic adjunct is oral cytology which has traditionally been defined as microscopic examination of surface epithelial cells which have been harvested via noninvasive methods (such as brush, spatula, or curette) and historically referred to as exfoliative cytology. The concept of using cytology to diagnose cancer was based on the work of Papanicolaou and Traut, who developed this idea as an adjunct for the diagnosis of cervical neoplasia and cancer [103]. Using exfoliative cytology to diagnose oral cancer and OPMDs was proposed back in the 1950s [104]; however, it fell out of favor for four decades until the publication of an accuracy study based on a computer-assisted cytological platform which demonstrated high sensitivity and specificity for detecting OSCC or OED [105]. Since then, there have been numerous cytology studies, conducted in both highand low-resource countries, incorporating various different methods for sample collection, processing, and analysis. Of these, 15 accuracy studies [98, 105–118] have met the criteria for inclusion in a recent meta-analysis [85]. Interestingly, despite methodological differences in the various platforms studied, the accuracy of cytology compared to histopathologic endpoints across these different platforms is uniformly high, and pooled sensitivity and specificity were calculated to be 96% (95% CI: 81–100%) and 90% (95% CI: 79–97%), respectively. In general, an algorithm for cytology includes the sample collection from an OPMD with a brush, the placement and fixation of the sample directly onto glass slides, and staining/analysis of the slides by an outside laboratory. Across the accuracy studies, most samples were typically collected using specialized brushes, although even a toothbrush may be employed [109], suggesting a lower cost option for low-­ resource settings. Two studies employed a liquid-based collection, where samples were not immediately plated/fixed on glass slides but instead placed into a liquid preservative and then transported to the lab where the cells were spun down by centrifuge and evenly dispersed onto a glass slide as a monolayer before processing [111, 113]. Most laboratories use conventional cytopathologic stains (e.g., modified Papanicolaou stain), and cytopathologists render results based upon cellular morphology. The samples in five studies were analyzed using a highly efficient proprietary computer-­ assisted neural network software system [105–107, 111, 114], although the processing costs of this platform may be prohibitive in low-resource settings. Beyond the standard staining and morphometric analysis of cytological samples, laboratory processing to detect the presence of alternative or additional molecular markers is feasible. Two of the accuracy studies employed a quite differ-

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ent approach, taking advantage of the finding that there are often alterations in the amount of DNA in nuclei found in OSCC and OED, known as aneuploidy. In these studies, the samples underwent Feulgen staining and DNA image cytometry to analyze changes in nuclear DNA content [113, 116]. A nano-engineered microfluidic chip employing morphometrics in conjunction with multiple molecular markers has been tested in a recent accuracy study, yielding AUCs of 0.88 and 0.84 for training and validation models and with the potential for point-of-care use (i.e., “lab-on-a-chip”) [119]. Despite cytology’s accuracy coupled with its ease of use and noninvasiveness, it would be controversial to suggest that cytology be considered as a possible replacement to the current gold standard, as current platforms do not provide a tissue diagnosis that enables a pathologist to distinguish OSCC from OED (or between grades of OED), and therefore patients with a “positive” cytological test result must still be referred for tissue biopsy and histopathology to inform treatment decisions. As such, the ADA expert panel only recommended the use of cytology by frontline clinicians if the patient is unwilling or unable to undergo tissue biopsy [37]. Such recommendations apply to frontline clinicians in settings where expert referral is commonplace; however, in low-­ resource settings where referral to experts for tissue biopsy is limited, cytology may be a good first-line option to “triage” patients with OPMDs. The application of cytology might also have a place in the surveillance setting. The noninvasive serial sampling of patients or lesions might reduce the morbidity of serial tissue samples, particularly in patients who have undergone multiple biopsies or surgical excisions over many years. One study, using 12 microsatellite markers for loss of heterozygosity (LOH) at 4 chromosomes (3p, 9p, 11q, 17p), suggests that cytology in conjunction with a marker deemed predictive for malignant transformation might be useful in a surveillance setting [120]. 9.5

Salivary Adjuncts

Saliva is an ideal diagnostic fluid because it is so simple to collect. There are number of different analytes that may be detected in the saliva including hormones, endogenous steroids (e.g., estrogen and testosterone), antibodies, cytokines and chemokines, human and microbial nucleic acids (DNA, RNA, microRNA), growth factors, a myriad of proteins, and drugs (e.g., drugs of abuse and therapeutic drugs) [121]. Depending on the analyte(s) under investigation, it is feasible for patients to perform self-testing (and send/take the sample to a laboratory), for a sample to be collected and analyzed chairside by a clinician (point of care), or to be collected and sent to a laboratory for analysis. Research on salivary diagnostics for oral cavity and oropharyngeal SCC has identified a number of putative biomarkers revealed from studies comparing cohorts of cancer patients with various control groups (healthy patients or patients with benign mucosal condi-

tions) which have been recently reviewed in detail by others [122–125]. The process for the commercialization of salivary diagnostics for potential use in dental offices has been reviewed by Jacobson [126]. From a diagnostic standpoint, there are a number of research questions: (a) Can saliva be used to screen a population and identify “at-risk” patients (i.e., those with clinically detectable disease versus those with clinically undetectable “occult” disease)? (b) Can saliva be used to determine the significance of an oral lesion (or lesions) that has (or have) been detected by a frontline examiner? (c) Can saliva be used to serially monitor “high-risk” patients (i.e., those that have a history of OSCC or OED)? There are a number of salivary diagnostic platforms, some indicated as screening adjuncts and others as diagnostic adjuncts; however, none of them have been sufficiently validated as yet by rigorous accuracy trials on patients with OMPDs to warrant their use by clinicians. Two platforms currently available for use in selected countries are based on methodologically weak studies, one using CD44 and “total protein” levels as a screening adjunct [127] and the other using a panel of mRNA biomarkers (DUSP1/SAT/OAZ1) as a diagnostic adjunct [128]. !!Warning No diagnostic adjunct is perfect. In the studies reported so far, there are many methodological limitations related to their design and conduct.

9.6

 redictive Markers for Malignant P Transformation

Predictive marker research is a growing area in the field of oncology. Prospective randomized studies, ideally linked to interventions and appropriately powered to capture important patient-related endpoints, are considered the gold standard to assess such predictive markers. A “model” prospective study is the Erlotinib Prevention of Oral Cancer (EPOC) trial [129]. This chemoprevention trial explored the efficacy of erlotinib as a chemoprevention agent, and, despite being a negative trial, it validated a previous prospective longitudinal study [130], confirming the utility of microsatellite analysis for loss of heterozygosity (LOH) at various chromosomal sites (3p14 and/or 9p21 plus other sites (17p, 8p, 11p, 4q, 13q) from tissue biopsies), as a predictive marker for malignant transformation in patients with OPMDs. Importantly, LOH is a marker that can help stratify the risk of malignant transformation in patients with low-grade OED [131]. The evidence for most predictive markers comes largely from a number of lower-quality retrospective studies with longitudinal data (i.e., from cancer registries) linked to malignant transformation. Such markers are typically detected in paraffin-embedded biopsy tissue from OMPDs (by immunohistochemistry, quantitative real-time PCR, fluorescence in situ hybridization (FISH), or quantitative DNA cytometry) and include cyclin D1 genotype [132], podo-

113 Diagnostic Adjuncts for Oral Cavity Squamous Cell Carcinoma and Oral Potentially Malignant Disorders

planin [133, 134], HuR and podoplanin [135], aldehyde dehydrogenase 1 and podoplanin [134], aneuploidy [136– 140], gene expression profiling [141], ATP-binding cassette G2 subfamily or BMI-1 [142], copy number alterations of selected genes (amplification of BTBD7, KHDRBS1, PARP1, and RAB1A) [143], gain of the human telomerase RNA component (hTERC) gene [144], promoter methylation of AGTR1, FOXI2, and PENK, and global DNA hypomethylation [145], a panel of microRNAs (208b-3p, 204-5p, 129-2-­ 3p, and 3065-5p) [146], microRNA 31 [147], microRNA 375 [148], a combination of markers (age, dysplasia, p53/CA9 immunohistochemistry) [149], Snail and Axin2 protein expression [150], and S100A7 [151]. 9.7

Summary

None of the numerous diagnostic adjuncts (or predictive markers) meet all criteria for an ideal test. Furthermore, our understanding of the natural history of carcinogenesis has not been sufficiently elucidated through longitudinal studies which makes it challenging to appreciate the significance of an OPMD detected at a single point in time along its evolution. We must find better ways to assess which lesions or patients have a higher propensity for malignant transformation. Point-of-care diagnostics seem more imperative in low-­ resource settings where patient follow-up is challenging. Their ability to identify high-risk patients and prompt their referral to higher care settings is critical. The use of telemedicine and mobile technology to facilitate the dissemination of information from the field to experts in such higher care setting is attractive, and it is expected that this mode of communication will evolve as the world becomes increasingly more connected. In higher care settings, particularly in high-resource settings, it is expected that optical techniques will be increasingly employed to better assess and inform treatment of high risk OPMDs or patients. Multicenter collaborations are needed to accrue OPMD patient populations with the power to run studies using these technologies and linked to intervention trials where possible. The question is: Will conventional tissue biopsies and histopathology become obsolete? Will they be replaced by optical biopsies, surveillance using predictive biomarkers, and nanotechnology used to localize and treat disease? The technological and information age has provided opportunities to both deepen our understanding about oral carcinogenesis and to generate exciting new diagnostics and therapeutics. Yet, embracing these new technologies without careful consideration about their utility across different settings and in the context of escalating healthcare costs, we must rely on the results of meticulous research studies with rigorous inclusion criteria and validated endpoints and an endeavor not to oversell their benefits.

References 1. Warnakulasuriya S, Johnson NW, van der Waal I. Nomenclature and classification of potentially malignant disorders of the oral mucosa. J Oral Pathol Med. 2007;36:575–80. 2. Petti S. Pooled estimate of world leukoplakia prevalence: a systematic review. Oral Oncol. 2003;39:770–80. 3. Warnakulasuriya S, Ariyawardana A. Malignant transformation of oral leukoplakia: a systematic review of observational studies. J Oral Pathol Med. 2016;45(3):155–66. 4. Lee JJ, Hong WK, Hittelman WN, Mao L, Lotan R, Shin DM, et al. Predicting cancer development in oral leukoplakia: ten years of translational research. Clin Cancer Res. 2000;6:1702–10. 5. Holmstrup P, Vedtofte P, Reibel J, Stoltze K. Long-term treatment outcome of oral premalignant lesions. Oral Oncol. 2006;42: 461–74. 6. Walsh T, Liu JL, Brocklehurst P, Glenny AM, Lingen M, Kerr AR, et al. Clinical assessment to screen for the detection of oral cavity cancer and potentially malignant disorders in apparently healthy adults. Cochrane Database Syst Rev. 2013;11:CD010173. 7. Sinha SR, Barry M. Health technologies and innovation in the global health arena. NEJM. 2011;365:779–82. 8. Boppart SA, Richards-Kortum R. Point-of-care and point-of-­ procedure optical imaging technologies for primary care and global health. Sci Transl Med. 2014;6:253rv2. 9. Abbey LM, Kaugars GE, Gunsolley JC, Burns JC, Page DG, Svirsky JA, et al. Intraexaminer and interexaminer reliability in the diagnosis of oral epithelial dysplasia. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1995;80:188–91. 10. Fischer DJ, Epstein JB, Morton TH, Schwartz SM. Interobserver reliability in the histopathologic diagnosis of oral pre-malignant and malignant lesions. J Oral Pathol Med. 2004;33:65–70. 11. Huber MA. Adjunctive diagnostic techniques for oral and oropharyngeal cancer discovery. Dent Clin N Am. 2018;62:59–75. 12. Brozek JL, Akl EA, Jaeschke R, Lang DM, Bossuyt P, Glasziou P, et al. Grading quality of evidence and strength of recommendations in clinical practice guidelines: Part 2 of 3. The GRADE approach to grading quality of evidence about diagnostic tests and strategies. Allergy. 2009;64:1109–16. 13. Macey R, Walsh T, Brocklehurst P, Kerr AR, Liu JL, Lingen MW, et al. Diagnostic tests for oral cancer and potentially malignant disorders in patients presenting with clinically evident lesions. Cochrane Database Syst Rev. 2015;5:CD010276. 14. Carter JV, Pan J, Rai SN, Galandiuk S. ROC-ing along: Evaluation and interpretation of receiver operating characteristic curves. Surgery. 2016;159:1638–45. 15. Whiting PF, Rutjes AW, Westwood ME, Mallett S, Deeks JJ, Reitsma JB, et al. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med. 2011;155:529–36. 16. Speight PM, Abram TJ, Floriano PN, James R, Vick J, Thornhill MH, et al. Interobserver agreement in dysplasia grading: toward an enhanced gold standard for clinical pathology trials. Oral Surg Oral Med Oral Pathol Oral Radiol. 2015;120:474–82.e2. 17. Rashid A, Warnakulasuriya S. The use of light-based (optical) detection systems as adjuncts in the detection of oral cancer and oral potentially malignant disorders: a systematic review. J Oral Pathol Med. 2015;44:307–28. 18. Laronde DM, Corbett KK. Adjunctive screening devices for oral lesions: their use by Canadian Dental Hygienists and the need for knowledge translation. Int J Dent Hyg. 2017;15(3):187–94. 19. Fedele S. Diagnostic aids in the screening of oral cancer. Head Neck Oncol. 2009;1(5):1–6. 20. Gillenwater A, Papadimitrakopoulou V, Richards-Kortum R. Oral premalignancy: new methods of detection and treatment. Curr Oncol Rep. 2006;8:146–54.

9

114

9

A. Ross Kerr

21. Rosenthal EL. Optical imaging of head and neck cancer: opportunities and challenges. JAMA Otolaryngol Head Neck Surg. 2014;140:93–4. 22. Jacques SL. Optical properties of biological tissues: a review. Phys Med Biol. 2013;58:R37–61. 23. Hariri LP. In vivo microscopy: will the microscope move from our desk into the patient? Arch Pathol Lab Med. 2015;139:719–20. 24. Roblyer D, Kurachi C, Stepanek V, Schwarz RA, Williams MD, El-­ Naggar AK, et al. Comparison of multispectral wide-field optical imaging modalities to maximize image contrast for objective discrimination of oral neoplasia. J Biomed Opt. 2010;15:066017. 25. Pierce MC, Schwarz RA, Bhattar VS, Mondrik S, Williams MD, Lee JJ, et al. Accuracy of in vivo multimodal optical imaging for detection of oral neoplasia. Cancer Prev Res. 2012;5:801–9. 26. Rosbach KJ, Williams MD, Gillenwater AM, Richards-Kortum RR. Optical molecular imaging of multiple biomarkers of epithelial neoplasia: epidermal growth factor receptor expression and metabolic activity in oral mucosa. Transl Oncol. 2012;5:160–71. 27. Liu JT, Loewke NO, Mandella MJ, Leigh SY, Levenson RM, Crawford JM, et al. Real-time pathology through in vivo microscopy. Stud Health Technol Inform. 2013;185:235–64. 28. Kerr AR, Sirois DA, Epstein JB. Clinical evaluation of chemiluminescent lighting: an adjunct for oral mucosal examinations. J Clin Dent. 2006;17:59–63. 29. Farah CS, McCullough MJ. A pilot case control study on the efficacy of acetic acid wash and chemiluminescent illumination (ViziLite) in the visualisation of oral mucosal white lesions. Oral Oncol. 2007;43:820–4. 30. McIntosh L, McCullough MJ, Farah CS. The assessment of diffused light illumination and acetic acid rinse (Microlux/DL) in the visualisation of oral mucosal lesions. Oral Oncol. 2009;45:e227–31. 31. Awan KH, Morgan PR, Warnakulasuriya S. Utility of chemiluminescence (ViziLite) in the detection of oral potentially malignant disorders and benign keratoses. J Oral Pathol Med. 2011;40:541–4. 32. Ujaoney S, Motwani MB, Degwekar S, Wadhwan V, Zade P, Chaudhary M, et al. Evaluation of chemiluminescence, toluidine blue and histopathology for detection of high risk oral precancerous lesions: a cross-sectional study. BMC Clin Pathol. 2012;12:6. 33. Mehrotra R, Singh M, Thomas S, Nair P, Pandya S, Nigam NS, et al. A cross-sectional study evaluating chemiluminescence and autofluorescence in the detection of clinically innocuous precancerous and cancerous oral lesions. JADA. 2010;141:151–6. 34. Chaudhry A, Manjunath M, Ashwatappa D, Krishna S, Krishna AG. Comparison of chemiluminescence and toluidine blue in the diagnosis of dysplasia in leukoplakia: a cross-sectional study. J Investig Clin Dent. 2016;7(2):132–40. 35. Awan KH, Morgan PR, Warnakulasuriya S. Assessing the accuracy of autofluorescence, chemiluminescence and toluidine blue as diagnostic tools for oral potentially malignant disorders-a clinicopathological evaluation. Clin Oral Investig. 2015;19:2267–72. 36. Chainani-Wu N, Madden E, Cox D, Sroussi H, Epstein J, Silverman S Jr. Toluidine blue aids in detection of dysplasia and carcinoma in suspicious oral lesions. Oral Dis. 2015;21:879–85. 37. Lingen MW, Abt E, Agrawal N, Chaturvedi AK, Cohen E, D'Souza G, et al. Evidence-based clinical practice guideline for the evaluation of potentially malignant disorders in the oral cavity: a report of the American Dental Association. JADA. 2017;148:712–27.e10. 38. Poh CF, Lane P, MacAulay C, Zhang L, Rosin MP. The application of tissue autofluorescence in detection and management of oral cancer and premalignant lesions. In: Rosenthal E, Zinn KR, editors. Optical imaging of cancer. New York/Dordrecht/Heidelberg/ London: Springer; 2010. p. 110–8. 39. Lane PM, Gilhuly T, Whitehead P, Zeng H, Poh CF, Ng S, et al. Simple device for the direct visualization of oral-cavity tissue fluorescence. J Biomed Opt. 2006;11:024006. 40. Poh CF, Ng SP, Williams PM, Zhang L, Laronde DM, Lane P, et al. Direct fluorescence visualization of clinically occult high-risk oral

premalignant disease using a simple hand-held device. Head Neck. 2007;29:71–6. 41. Onizawa K, Saginoya H, Furuya Y, Yoshida H, Fukuda H. Usefulness of fluorescence photography for diagnosis of oral cancer. Int J Oral Maxillofac Surg. 1999;28:206–10. 42. Awan KH, Morgan PR, Warnakulasuriya S. Evaluation of an autofluorescence based imaging system (VELscope) in the detection of oral potentially malignant disorders and benign keratoses. Oral Oncol. 2011;47:274–7. 43. Koch FP, Kaemmerer PW, Biesterfeld S, Kunkel M, Wagner W. Effectiveness of autofluorescence to identify suspicious oral lesions–a prospective, blinded clinical trial. Clin Oral Investig. 2011;15:975–82. 44. Scheer M, Neugebauer J, Derman A, Fuss J, Drebber U, Zoeller JE. Autofluorescence imaging of potentially malignant mucosa lesions. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2011;111:568–77. 45. Farah CS, McIntosh L, Georgiou A, McCullough MJ. Efficacy of tissue autofluorescence imaging (VELScope) in the visualization of oral mucosal lesions. Head Neck. 2012;34:856–62. 46. Hanken H, Kraatz J, Smeets R, Heiland M, Assaf AT, Blessmann M, et al. The detection of oral pre- malignant lesions with an autofluorescence based imaging system (VELscope) – a single blinded clinical evaluation. Head Face Med. 2013;9:23. 47. Petruzzi M, Lucchese A, Nardi GM, Lauritano D, Favia G, Serpico R, et al. Evaluation of autofluorescence and toluidine blue in the differentiation of oral dysplastic and neoplastic lesions from non dysplastic and neoplastic lesions: a cross-sectional study. J Biomed Opt. 2014;19:76003. 48. Laronde DM, Williams PM, Hislop TG, Poh C, Ng S, Bajdik C, et al. Influence of fluorescence on screening decisions for oral mucosal lesions in community dental practices. J Oral Pathol Med. 2014;43:7–13. 49. Bhatia N, Matias MA, Farah CS. Assessment of a decision making protocol to improve the efficacy of VELscope in general dental practice: a prospective evaluation. Oral Oncol. 2014;50:1012–9. 50. Truelove EL, Dean D, Maltby S, Griffith M, Huggins K, Griffith M, et al. Narrow band (light) imaging of oral mucosa in routine dental patients. Part I: assessment of value in detection of mucosal changes. Gen Dent. 2011;59:281–9; quiz 90–1, 319–20. 51. Chiu CJ, Chang ML, Chiang CP, Hahn LJ, Hsieh LL, Chen CJ. Interaction of collagen-related genes and susceptibility to betel quid-­induced oral submucous fibrosis. Cancer Epidemiol Biomark Prev. 2002;11:646–53. 52. Poh CF, Anderson DW, Durham JS, Chen J, Berean KW, MacAulay CE, et al. Fluorescence visualization-guided surgery for early-stage oral cancer. JAMA Otolaryngol Head Neck Surg. 2016;142(3):209–16. 53. Guillaud M, MacAulay CE, Berean KW, Bullock M, Guggisberg K, Klieb H, et al. Using quantitative tissue phenotype to assess the margins of surgical samples from a pan-Canadian surgery study. Head Neck. 2018;40(6):1263–70. (epub ahead of print). 54. Vu A, Farah CS. Narrow band imaging: clinical applications in oral and oropharyngeal cancer. Oral Dis. 2016;22:383–90. 55. Vu AN, Farah CS. Efficacy of narrow band imaging for detection and surveillance of potentially malignant and malignant lesions in the oral cavity and oropharynx: a systematic review. Oral Oncol. 2014;50:413–20. 56. Piazza C, Cocco D, Del Bon F, Mangili S, Nicolai P, Majorana A, et al. Narrow band imaging and high definition television in evaluation of oral and oropharyngeal squamous cell cancer: a prospective study. Oral Oncol. 2010;46:307–10. 57. Yang SW, Lee YS, Chang LC, Chien HP, Chen TA. Light sources used in evaluating oral leukoplakia: broadband white light versus narrowband imaging. Int J Oral Maxillofac Surg. 2013;42:693–701. 58. Farah CS, Dalley AJ, Nguyen P, Batstone M, Kordbacheh F, Perry-­ Keene J, et al. Improved surgical margin definition by narrow band imaging for resection of oral squamous cell carcinoma: a prospective gene expression profiling study. Head Neck. 2016;38:832–9.

115 Diagnostic Adjuncts for Oral Cavity Squamous Cell Carcinoma and Oral Potentially Malignant Disorders

59. Tirelli G, Piovesana M, Marcuzzo AV, Gatto A, Biasotto M, Bussani R, et al. Tailored resections in oral and oropharyngeal cancer using narrow band imaging. Am J Otolaryngol. 2018;39(2):197–203. 60. Farah CS. Narrow Band Imaging-guided resection of oral cavity cancer decreases local recurrence and increases survival. Oral Dis. 2018;24:89–97. 61. Maher NG, Collgros H, Uribe P, Ch'ng S, Rajadhyaksha M, Guitera P. In vivo confocal microscopy for the oral cavity: current state of the field and future potential. Oral Oncol. 2016;54:28–35. 62. Abbaci M, Breuskin I, Casiraghi O, De Leeuw F, Ferchiou M, Temam S, et al. Confocal laser endomicroscopy for non-invasive head and neck cancer imaging: a comprehensive review. Oral Oncol. 2014;50:711–6. 63. Nathan CA, Kaskas NM, Ma X, Chaudhery S, Lian T, Moore-Medlin T, et al. Confocal laser endomicroscopy in the detection of head and neck precancerous lesions. Otolaryngol Head Neck Surg. 2014;151:73–80. 64. Moore C, Mehta V, Ma X, Chaudhery S, Shi R, Moore-Medlin T, et al. Interobserver agreement of confocal laser endomicroscopy for detection of head and neck neoplasia. Laryngoscope. 2016;126: 632–7. 65. Muldoon TJ, Roblyer D, Williams MD, Stepanek VM, Richards-Kortum R, Gillenwater AM. Noninvasive imaging of oral neoplasia with a high-resolution fiber-optic microendoscope. Head Neck. 2012;34:305–12. 66. Ishijima A, Schwarz RA, Shin D, Mondrik S, Vigneswaran N, Gillenwater AM, et al. Automated frame selection process for highresolution microendoscopy. J Biomed Opt. 2015;20:46014. 67. Miles BA, Patsias A, Quang T, Polydorides AD, Richards-Kortum R, Sikora AG. Operative margin control with high-resolution optical microendoscopy for head and neck squamous cell carcinoma. Laryngoscope. 2015;125:2308–16. 68. Sharwani A, Jerjes W, Salih V, Swinson B, Bigio IJ, El-Maaytah M, et al. Assessment of oral premalignancy using elastic scattering spectroscopy. Oral Oncol. 2006;42:343–9. 69. Grillone GA, Wang Z, Krisciunas GP, Tsai AC, Kannabiran VR, Pistey RW, et al. The color of cancer: margin guidance for oral cancer resection using elastic scattering spectroscopy. Laryngoscope. 2017;127(Suppl 4):S1–s9. 70. Amelink A, Sterenborg HJ, Roodenburg JL, Witjes MJ. Non-invasive measurement of the microvascular properties of non-dysplastic and dysplastic oral leukoplakias by use of optical spectroscopy. Oral Oncol. 2011;47:1165–70. 71. Hu F, Vishwanath K, Beumer HW, Puscas L, Afshari HR, Esclamado RM, et al. Assessment of the sensitivity and specificity of tissue-­ specific-­based and anatomical-based optical biomarkers for rapid detection of human head and neck squamous cell carcinoma. Oral Oncol. 2014;50:848–56. 72. Schwarz RA, Gao W, Redden Weber C, Kurachi C, Lee JJ, El-Naggar AK, et al. Noninvasive evaluation of oral lesions using depth-­ sensitive optical spectroscopy. Cancer. 2009;115:1669–79. 73. Chen HM, Chiang CP, You C, Hsiao TC, Wang CY. Time-resolved autofluorescence spectroscopy for classifying normal and premalignant oral tissues. Lasers Surg Med. 2005;37:37–45. 74. Sahu A, Krishna CM. Optical diagnostics in oral cancer: an update on Raman spectroscopic applications. J Cancer Res Ther. 2017;13: 908–15. 75. Singh SP, Deshmukh A, Chaturvedi P, Murali Krishna C. In vivo Raman spectroscopic identification of premalignant lesions in oral buccal mucosa. J Biomed Opt. 2012;17:105002. 76. Guze K, Pawluk HC, Short M, Zeng H, Lorch J, Norris C, et al. Pilot study: Raman spectroscopy in differentiating premalignant and malignant oral lesions from normal mucosa and benign lesions in humans. Head Neck. 2015;37:511–7. 77. Knipfer C, Johanna M, Werner A, Kathrin B, Tesfay GM, Robert H, et al. Raman difference spectroscopy: a non-invasive method for identification of oral squamous cell carcinoma. Biomed Opt Express. 2014;5:3252–65.

78. Cals FL, Koljenovic S, Hardillo JA, Baatenburg de Jong RJ, Bakker Schut TC, Puppels GJ. Development and validation of Raman spectroscopic classification models to discriminate tongue squamous cell carcinoma from non-tumorous tissue. Oral Oncol. 2016;60: 41–7. 79. Wessels R, De Bruin DM, Faber DJ, Van Leeuwen TG, Van Beurden M, Ruers TJ. Optical biopsy of epithelial cancers by optical coherence tomography (OCT). Lasers Med Sci. 2014;29:1297–305. 80. Tsai MT, Lee HC, Lee CK, Yu CH, Chen HM, Chiang CP, et al. Effective indicators for diagnosis of oral cancer using optical coherence tomography. Opt Express. 2008;16:15847–62. 81. Wilder-Smith P, Lee K, Guo S, Zhang J, Osann K, Chen Z, et al. In vivo diagnosis of oral dysplasia and malignancy using optical coherence tomography: preliminary studies in 50 patients. Lasers Surg Med. 2009;41:353–7. 82. Hamdoon Z, Jerjes W, Upile T, McKenzie G, Jay A, Hopper C. Optical coherence tomography in the assessment of suspicious oral lesions: an immediate ex vivo study. Photodiagn Photodyn Ther. 2013;10:17–27. 83. Lee AM, Cahill L, Liu K, MacAulay C, Poh C, Lane P. Wide-field in vivo oral OCT imaging. Biomed Opt Express. 2015;6:2664–74. 84. Niebel HH, Chomet B. In vivo staining test for delineation of oral intraepithelial neoplastic change: preliminary report. JADA. 1964;68:801–6. 85. Lingen MW, Tampi MP, Urquhart O, Abt E, Agrawal N, Chaturvedi AK, et al. Adjuncts for the evaluation of potentially malignant disorders in the oral cavity: diagnostic test accuracy systematic review and meta-analysis-a report of the American Dental Association. JADA. 2017;148:797–813.e52. 86. Mashberg A. Reevaluation of toluidine blue application as a diagnostic adjunct in the detection of asymptomatic oral squamous carcinoma: a continuing prospective study of oral cancer III. Cancer. 1980;46:758–63. 87. Silverman S Jr, Migliorati C, Barbosa J. Toluidine blue staining in the detection of oral precancerous and malignant lesions. Oral Surg Oral Med Oral Pathol. 1984;57:379–82. 88. Warnakulasuriya KA, Johnson NW. Sensitivity and specificity of OraScan (R) toluidine blue mouthrinse in the detection of oral cancer and precancer. J Oral Pathol Med. 1996;25:97–103. 89. Onofre MA, Sposto MR, Navarro CM. Reliability of toluidine blue application in the detection of oral epithelial dysplasia and in situ and invasive squamous cell carcinomas. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2001;91:535–40. 90. Cheng B, Yang L. The clinical evaluation of Oratest in detecting oral mucosal lesions. West China J Stomatol. 2003;21:124–6. 91. Chen YW, Lin JS, Fong JH, Wang IK, Chou SJ, Wu CH, et al. Use of methylene blue as a diagnostic aid in early detection of oral cancer and precancerous lesions. Br J Oral Maxillofac Surg. 2007;45: 590–1. 92. Du GF, Li CZ, Chen HZ, Chen XM, Xiao Q, Cao ZG, et al. Rose bengal staining in detection of oral precancerous and malignant lesions with colorimetric evaluation: a pilot study. Int J Cancer. 2007;120:1958–63. 93. Allegra E, Lombardo N, Puzzo L, Garozzo A. The usefulness of toluidine staining as a diagnostic tool for precancerous and cancerous oropharyngeal and oral cavity lesions. Acta Otorhinolaryngol Ital. 2009;29:187–90. 94. Nagaraju K, Prasad S, Ashok L. Diagnostic efficiency of toluidine blue with Lugol’s iodine in oral premalignant and malignant lesions. Indian J Dent Res. 2010;21:218–23. 95. Cancela-Rodriguez P, Cerero-Lapiedra R, Esparza-Gomez G, Llamas-­ Martinez S, Warnakulasuriya S. The use of toluidine blue in the detection of pre-malignant and malignant oral lesions. J Oral Pathol Med. 2011;40:300–4. 96. Upadhyay J, Rao NN, Upadhyay RB, Agarwal P. Reliability of toluidine blue vital staining in detection of potentially malignant oral lesions–time to reconsider. Asian Pac J Cancer Prev. 2011;12: 1757–60.

9

116

9

A. Ross Kerr

97. Awan K, Yang Y, Morgan P, Warnakulasuriya S. Utility of toluidine blue as a diagnostic adjunct in the detection of potentially malignant disorders of the oral cavity–a clinical and histological assessment. Oral Dis. 2012;18:728–33. 98. Rahman F, Tippu SR, Khandelwal S, Girish KL, Manjunath BC, Bhargava A. A study to evaluate the efficacy of toluidine blue and cytology in detecting oral cancer and dysplastic lesions. Quintessence Int. 2012;43:51–9. 99. Chaudhari A, Hegde-Shetiya S, Shirahatti R, Agrawal D. Comparison of different screening methods in estimating the prevalence of precancer and cancer amongst male inmates of a jail in maharashtra, India. Asian Pac J Cancer Prev. 2013;14:859–64. 100. Singh D, Shukla RK. Utility of toluidine blue test in accessing and detecting intra-oral malignancies. Indian J Otolaryngol Head Neck Surg. 2015;67:47–50. 101. Epstein JB, Feldman R, Dolor RJ, Porter SR. The utility of tolonium chloride rinse in the diagnosis of recurrent or second primary cancers in patients with prior upper aerodigestive tract cancer. Head Neck. 2003;25:911–21. 102. McMahon J, Devine JC, McCaul JA, McLellan DR, Farrow A. Use of Lugol’s iodine in the resection of oral and oropharyngeal squamous cell carcinoma. Br J Oral Maxillofac Surg. 2010;48:84–7. 103. Papanicolaou GN, Traut HF. The diagnostic value of vaginal smears in carcinoma of the uterus. 1941. Arch Pathol Lab Med. 1997;121:211–24. 104. Silverman S Jr. Intraoral exfoliative cytology. CA Cancer J Clin. 1959;9:125–8. 105. Sciubba JJ. Improving detection of precancerous and cancerous oral lesions. Computer-assisted analysis of the oral brush biopsy. U.S. Collaborative OralCDx Study Group. JADA. 1999;130:1445–57. 106. Svirsky JA, Burns JC, Carpenter WM, Cohen DM, Bhattacharyya I, Fantasia JE, et al. Comparison of computer-assisted brush biopsy results with follow up scalpel biopsy and histology. Gen Dent. 2002;50:500–3. 107. Scheifele C, Schmidt-Westhausen AM, Dietrich T, Reichart PA. The sensitivity and specificity of the OralCDx technique: evaluation of 103 cases. Oral Oncol. 2004;40:824–8. 108. Navone R, Marsico A, Reale I, Pich A, Broccoletti R, Pentenero M, et al. Usefulness of oral exfoliative cytology for the diagnosis of oral squamous dysplasia and carcinoma. Minerva Stomatol. 2004;53:77–86. 109. Mehrotra R, Singh MK, Pandya S, Singh M. The use of an oral brush biopsy without computer-assisted analysis in the evaluation of oral lesions: a study of 94 patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2008;106:246–53. 110. Navone R, Pentenero M, Rostan I, Burlo P, Marsico A, Broccoletti R, et al. Oral potentially malignant lesions: first-level micro-­ histological diagnosis from tissue fragments sampled in liquidbased diagnostic cytology. J Oral Pathol Med. 2008;37: 358–63. 111. Delavarian Z, Mohtasham N, Mosannen-Mozafari P, Pakfetrat A, Shakeri MT, Ghafoorian-Maddah R. Evaluation of the diagnostic value of a Modified Liquid-Based Cytology using OralCDx Brush in early detection of oral potentially malignant lesions and oral cancer. Med Oral Patol Oral Cir Bucal. 2010;15:e671–6. 112. Koch FP, Kunkel M, Biesterfeld S, Wagner W. Diagnostic efficiency of differentiating small cancerous and precancerous lesions using mucosal brush smears of the oral cavity–a prospective and blinded study. Clin Oral Investig. 2011;15:763–9. 113. Ng SP, Mann IS, Zed C, Doudkine A, Matisic J. The use of quantitative cytology in identifying high-risk oral lesions in community practice. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;114: 358–64. 114. Seijas-Naya F, Garcia-Carnicero T, Gandara-Vila P, Couso-­Folgueiras E, Perez-Sayans M, Gandara-Vila R, et al. Applications of OralCDx(R) methodology in the diagnosis of oral leukoplakia. Med Oral Patol Oral Cir Bucal. 2012;17:e5–9.

115. Fontes KB, Cunha KS, Rodrigues FR, Silva LE, Dias EP. Concordance between cytopathology and incisional biopsy in the d ­ iagnosis of oral squamous cell carcinoma. Braz Oral Res. 2013;27:122–7. 116. Kammerer PW, Koch FP, Santoro M, Babaryka G, Biesterfeld S, Brieger J, et al. Prospective, blinded comparison of cytology and DNA-image cytometry of brush biopsies for early detection of oral malignancy. Oral Oncol. 2013;49:420–6. 117. Trakroo A, Sunil MK, Trivedi A, Garg R, Kulkarni A, Arora S. Efficacy of oral brush biopsy without computer-assisted analysis in oral premalignant and malignant lesions: a study. J Int Oral Health. 2015;7:33–8. 118. Nanayakkara PG, Dissanayaka WL, Nanayakkara BG, Amaratunga EA, Tilakaratne WM. Comparison of spatula and cytobrush cytological techniques in early detection of oral malignant and premalignant lesions: a prospective and blinded study. J Oral Pathol Med. 2016;45:268–74. 119. Abram TJ, Floriano PN, Christodoulides N, James R, Kerr AR, Thornhill MH, et al. ‘Cytology-on-a-chip’ based sensors for monitoring of potentially malignant oral lesions. Oral Oncol. 2016;60:103–11. 120. Bremmer JF, Graveland AP, Brink A, Braakhuis BJ, Kuik DJ, Leemans CR, et al. Screening for oral precancer with noninvasive genetic cytology. Cancer Prev Res. 2009;2:128–33. 121. Malamud D. Saliva as a diagnostic fluid. Dent Clin N Am. 2011;55:159–78. 122. Cheng YS, Rees T, Wright J. A review of research on salivary biomarkers for oral cancer detection. Clin Transl Med. 2014;3:3. 123. Yakob M, Fuentes L, Wang MB, Abemayor E, Wong DT. Salivary biomarkers for detection of oral squamous cell carcinoma – current state and recent advances. Curr Oral Health Rep. 2014;1:133–41. 124. Tian X, Chen Z, Shi S, Wang X, Wang W, Li N, et al. Clinical diagnostic implications of body fluid MiRNA in oral squamous cell carcinoma: a meta-analysis. Medicine. 2015;94:e1324. 125. Gualtero DF, Suarez Castillo A. Biomarkers in saliva for the detection of oral squamous cell carcinoma and their potential use for early diagnosis: a systematic review. Acta Odontol Scand. 2016;74:170–7. 126. Jacobson JJ. Is dentistry going to get into the salivary diagnostics game or watch from the sidelines? J Calif Dent Assoc. 2013;41: 125–31. 127. Franzmann EJ, Reategui EP, Pereira LH, Pedroso F, Joseph D, Allen GO, et al. Salivary protein and solCD44 levels as a potential screening tool for early detection of head and neck squamous cell carcinoma. Head Neck. 2012;34:687–95. 128. Martin JL, Gottehrer N, Zalesin H, Hoff PT, Shaw M, Clarkson JH, et al. Evaluation of salivary transcriptome markers for the early detection of oral squamous cell cancer in a prospective blinded trial. Compend Contin Educ Dent. 2015;36:365–73. 129. William WN Jr, Papadimitrakopoulou V, Lee JJ, Mao L, Cohen EE, Lin HY, et al. Erlotinib and the risk of oral cancer: the Erlotinib Prevention of Oral Cancer (EPOC) randomized clinical trial. JAMA Oncol. 2016;2:209–16. 130. Zhang L, Poh CF, Williams M, Laronde DM, Berean K, Gardner PJ, et al. Loss of heterozygosity (LOH) profiles–validated risk predictors for progression to oral cancer. Cancer Prev Res (Philadelphia, PA). 2012;5:1081–9. 131. Lingen MW, Szabo E. Validation of LOH profiles for assessing oral cancer risk. Cancer Prev Res (Philadelphia, PA). 2012;5:1075–7. 132. Izzo JG, Papadimitrakopoulou VA, Liu DD, den Hollander PL, Babenko IM, Keck J, et al. Cyclin D1 genotype, response to biochemoprevention, and progression rate to upper aerodigestive tract cancer. J Natl Cancer Inst. 2003;95:198–205. 133. Kawaguchi H, El-Naggar AK, Papadimitrakopoulou V, Ren H, Fan YH, Feng L, et al. Podoplanin: a novel marker for oral cancer risk in patients with oral premalignancy. J Clin Oncol. 2008;26:354–60. 134. Habiba U, Hida K, Kitamura T, Matsuda AY, Higashino F, Ito YM, et al. ALDH1 and podoplanin expression patterns predict the risk of

117 Diagnostic Adjuncts for Oral Cavity Squamous Cell Carcinoma and Oral Potentially Malignant Disorders

malignant transformation in oral leukoplakia. Oncol Lett. 2017;13:321–8. 135. Habiba U, Kitamura T, Yanagawa-Matsuda A, Higashino F, Hida K, Totsuka Y, et al. HuR and podoplanin expression is associated with a high risk of malignant transformation in patients with oral preneoplastic lesions. Oncol Lett. 2016;12:3199–207. 136. Torres-Rendon A, Stewart R, Craig GT, Wells M, Speight PM. DNA ploidy analysis by image cytometry helps to identify oral epithelial dysplasias with a high risk of malignant progression. Oral Oncol. 2009;45:468–73. 137. Bradley G, Odell EW, Raphael S, Ho J, Le LW, Benchimol S, et al. Abnormal DNA content in oral epithelial dysplasia is associated with increased risk of progression to carcinoma. Br J Cancer. 2010;103:1432–42. 138. Bremmer JF, Brakenhoff RH, Broeckaert MA, Belien JA, Leemans CR, Bloemena E, et al. Prognostic value of DNA ploidy status in patients with oral leukoplakia. Oral Oncol. 2011;47:956–60. 139. Sperandio M, Brown AL, Lock C, Morgan PR, Coupland VH, Madden PB, et al. Predictive value of dysplasia grading and DNA ploidy in malignant transformation of oral potentially malignant disorders. Cancer Prev Res (Philadelphia, PA). 2013;6:822–31. 140. Siebers TJ, Bergshoeff VE, Otte-Holler I, Kremer B, Speel EJ, van der Laak JA, et al. Chromosome instability predicts the progression of premalignant oral lesions. Oral Oncol. 2013;49:1121–8. 141. Saintigny P, Zhang L, Fan YH, El-Naggar AK, Papadimitrakopoulou VA, Feng L, et al. Gene expression profiling predicts the development of oral cancer. Cancer Prev Res (Philadelphia, PA). 2011;4: 218–29. 142. Liu W, Feng JQ, Shen XM, Wang HY, Liu Y, Zhou ZT. Two stem cell markers, ATP-binding cassette, G2 subfamily (ABCG2) and BMI-­1, predict the transformation of oral leukoplakia to cancer: a long-­ term follow-up study. Cancer. 2012;118:1693–700.

143. Cervigne NK, Machado J, Goswami RS, Sadikovic B, Bradley G, Perez-Ordonez B, et al. Recurrent genomic alterations in sequential progressive leukoplakia and oral cancer: drivers of oral tumorigenesis? Hum Mol Genet. 2014;23:2618–28. 144. Dorji T, Monti V, Fellegara G, Gabba S, Grazioli V, Repetti E, et al. Gain of hTERC: a genetic marker of malignancy in oral potentially malignant lesions. Hum Pathol. 2015;46:1275–81. 145. Foy JP, Pickering CR, Papadimitrakopoulou VA, Jelinek J, Lin SH, William WN Jr, et al. New DNA methylation markers and global DNA hypomethylation are associated with oral cancer development. Cancer Prev Res. 2015;8:1027–35. 146. Philipone E, Yoon AJ, Wang S, Shen J, Ko YC, Sink JM, et al. MicroRNAs-208b-3p, 204-5p, 129-2-3p and 3065-5p as predictive markers of oral leukoplakia that progress to cancer. Am J Cancer Res. 2016;6:1537–46. 147. Hung KF, Liu CJ, Chiu PC, Lin JS, Chang KW, Shih WY, et al. MicroRNA-31 upregulation predicts increased risk of progression of oral potentially malignant disorder. Oral Oncol. 2016;53:42–7. 148. Harrandah AM, Fitzpatrick SG, Smith MH, Wang D, Cohen DM, Chan EK. MicroRNA-375 as a biomarker for malignant transformation in oral lesions. Oral Surg Oral Med Oral Pathol Oral Radiol. 2016;122:743–52.e1. 149. Zhang X, Kim KY, Zheng Z, Bazarsad S, Kim J. Nomogram for risk prediction of malignant transformation in oral leukoplakia patients using combined biomarkers. Oral Oncol. 2017;72:132–9. 150. Zhang X, Kim KY, Zheng Z, Kim HS, Cha IH, Yook JI. Snail and Axin2 expression predict the malignant transformation of oral leukoplakia. Oral Oncol. 2017;73:48–55. 151. Hwang JT, Gu YR, Shen M, Ralhan R, Walfish PG, Pritzker KP, et al. Individualized five-year risk assessment for oral premalignant lesion progression to cancer. Oral Surg Oral Med Oral Pathol Oral Radiol. 2017;123:374–81.

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119

Detection Methods for Human Papillomavirus (HPV) in Head and Neck Cancers Annemieke van Zante and Richard C. Jordan 10.1

Introduction – 120

10.2

Biology of HPV – 120

10.3

HPV and Carcinogenesis – 120

10.4

Pathology – 120

10.5

Determining HPV Status – 122

10.5.1 10.5.2 10.5.3

 CR-Based Techniques – 122 P In Situ Hybridization (ISH) – 122 p16 Immunohistochemistry – 122

10.6

Fine-Needle Aspiration (FNA) for HPV Testing – 123

10.7

Testing Saliva for HPV Infection – 123

10.8

Conclusions – 124 References – 125

© Springer Nature Switzerland AG 2020 S. Warnakulasuriya, J. S. Greenspan (eds.), Textbook of Oral Cancer, Textbooks in Contemporary Dentistry, https://doi.org/10.1007/978-3-030-32316-5_10

10

120

Core Message

Definition

The escalating incidence of squamous cell carcinoma of the oropharynx and base of the tongue (OPC) is associated with remote exposure to hrHPV and thereby indicates that the increasing numbers of these cancers will be seen in the clinical setting. HPV status in OPC impacts a range of clinical factors including primary site determination, extent of surgery, adjuvant treatment, and prognosis. Thus, accurate and reproducible methods to determine HPV status will be needed for an increasing volume of patients. For OPC, p16 is now considered to be a reliable surrogate for detection of hrHPV, but its use will likely wane as molecular testing such as in situ hybridization becomes more widespread and laboratories become more comfortable with application and interpretation of these methodologies.

HPV16 is responsible for the vast majority of oropharyngeal cancers, with only a minority associated with other high-risk subtypes such as HPV18.

10.1 

10

A. van Zante and R. C. Jordan

Introduction

Traditional risk factors for head and neck squamous cell carcinoma (HNSCC) include tobacco and alcohol use. These factors acting synergistically increase the risk of cancer development by 26-fold [1].Since the 1980s, there has been a relatively modest decrease in the incidence of HNSCC that has generally paralleled the decrease in use of tobacco [2]. By contrast, over the past two decades, the emergence of a form of squamous cell carcinoma that occurs primarily in the oropharynx and base of tongue (OPC) has been noted that is linked biologically and epidemiologically to oncogenic forms of the human papillomavirus (HPV) [3]. While tobacco- and alcohol-linked HNSCC continues to be more common in older men, OPC is now seen in a group of younger men whose principal risk factor is sexual behaviors that facilitate the transmission of HPV.  In this group, the greatest risk is associated with a high number of sex partners, a history of oral-genital and oral-anal sex, and marijuana use [4]. While tobacco use is not clearly linked to the causation of this form of cancer, its concurrent or former use is strongly linked to worsened response to therapy and 5-year survival [5]. 10.2 

Biology of HPV

HPV is a family of DNA viruses whose only known host is humans. There are over 130 unique subtypes of HPV that can infect the skin and mucosa. An important biological distinction is between the oncogenic or “high-risk” forms of HPV (subtypes 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 73, 82) and the non-oncogenic (“low-risk”) forms (6, 11, 13, 32, etc.) [6]. High-risk HPV (hrHPV) is causative in sexually transmitted high-grade squamous intraepithelial lesions and the vast majority of anogenital malignancies in the USA and in most parts of Europe (cervical, vaginal, vulvar, and anal carcinoma). In contrast, low-risk HPV is associated with anogenital condyloma acuminatum and benign oral lesions including squamous papilloma, oral warts, and focal epithelial hyperplasia (Heck’s disease) [7].

The circular HPV genome encodes DNA sequences for six early (E) proteins associated with viral gene regulation and cell transformation, two late (L) proteins which form the shell of the virus, and one region of regulatory DNA. In the pathogenesis of virally induced malignant disease, continued expression of E6 and E7 proteins is required to sustain a malignant phenotype. When the HPV genome is integrated into the host nuclear DNA, the E2 regulatory region is disrupted, leaving the expression of viral proteins E6 and E7 unregulated. In a normal cell, the wild-type p53 protein negatively regulates cell growth limiting cell cycle transition from G0/G1 to S phase and functioning as a tumor suppressor protein. Viral E6 specifically binds to p53, resulting in its degradation. Similarly, the Rb protein normally inhibits the cell cycle through interaction with the E2F transcription factor. In response to DNA damage, Rb typically binds and inactivates E2F halting replication or inducing apoptosis. Viral E7 inhibits the function of Rb protein by disrupting the E2F/Rb protein complex allowing uncontrolled cell proliferation [8].

10.3 

HPV and Carcinogenesis

HPV-associated malignancies within the anogenital tract have clinically and histologically recognized dysplastic precursor lesions with a well-understood risk of progression to invasive carcinoma. In contrast within the head and neck, and particularly within the base of tongue and oropharynx, there are few recognized precursor lesions associated with oncogenic HPV infection. An exception appears to be the recently described form of oral epithelial dysplasia associated with HPV16 [9]. Sometimes reported using the terms koilocytic dysplasia or HPV-associated oral intraepithelial neoplasia, the natural history of this form of dysplasia is not fully defined although a proportion have been reported to progress to oral squamous cell carcinoma [10]. Over 75% of oropharyngeal carcinomas (OPC) are linked to hrHPV. HPV16 is responsible for the vast majority of these tumors; a minority is associated with other high-risk subtypes such as HPV18.

10.4 

Pathology

HPV-associated oropharyngeal cancers have distinct phenotypic and molecular features [11]. Pathologically, hrHPV+ OPC are presumed to arise from the tonsillar crypts without evidence of a noninvasive precursor lesion analogous to epithelial dysplasia for traditional SCC.  The majority of the HPV-related tumors have a characteristic lobular or nested

121 Detection Methods for Human Papillomavirus (HPV) in Head and Neck Cancers

a

b

c

d

..      Fig. 10.1 Panel a: An example of a hrHPV+ SCC from the oropharynx showing the characteristic lobular or nested growth pattern intimately permeated by lymphocytes (H&E 20×). Panel b: An example of a hrHPV+ SCC with papillary architecture and keratinization (H&E 40×). Panel c: RNA in situ hybridization using probes to detect E6 and

E7 mRNA of hrHPV showing punctate positive signals (H&E 40×). Panel d: An example of a p16-positive SCC from the oropharynx showing greater than 70% of tumor cells with nuclear and cytoplasmic staining

growth pattern with central necrosis and are intimately permeated by lymphocytes (. Fig. 10.1 panel a). The cytomorphology of hrHPV+ OPC is typically basaloid with limited keratinization, resembling the reticulated epithelium of the tonsillar crypt [12]. The nomenclature of the hrHPV+ tumors has evolved with several names having been proposed including “poorly differentiated,” “nonkeratinizing,” and “basaloid” squamous cell carcinoma. The term “basaloid” is particularly problematic since there is a histologically similar entity, “basaloid squamous cell carcinoma,” that can arise in the oropharynx [13]. Basaloid squamous cell carcinoma has long been recognized as a poorly differentiated tumor mainly caused by smoking and alcohol, the traditional risk factors for squamous cell carcinoma, and, unlike the HPV-­associated tumors, has a poor prognosis [14].Given the prognostic significance of HPV status in the oropharynx, and the potential for confusion arising from histologic

descriptors, the current WHO Classification advocates the term “squamous cell carcinoma” for OPC with a modifier indicating the HPV status. Given the disconnect between the apparent lack of differentiation of the HPV-associated tumors and the relatively good prognosis, histologic grading for hrHPV+ squamous cell carcinoma arising in the oropharynx is discouraged [15].

 

>>Important The cytomorphology of high-risk HPV-positive OPC is typically basaloid with limited keratinization, resembling the reticulated epithelium of the tonsillar crypt.

A small percentage of hrHPV+ squamous cell carcinomas show divergent histology. This group includes keratinizing tumors with papillary architecture (. Fig. 10.1 panel b) and hrHPV+ high-grade neuroendocrine/small cell carcinoma.  

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Occasionally hrHPV+ tumors with histomorphology similar to the typical oropharyngeal type can occur in the nasopharynx. These HPV+ nasopharynx tumors show overlapping features with the typical EBV-associated nasopharyngeal carcinoma but are more frequent in white men, unlike EBV+ nasopharyngeal carcinoma that is most common in people of Chinese descent [16]. 10.5 

10

Determining HPV Status

Determining and reporting of HPV status for OPC are now considered the standard of care, with the majority of head and neck pathologists recognizing the significance of evaluating all tumors [17]. HPV status is proven to be a strong, independent prognostic factor for OPC [18] predicting responsiveness to induction chemotherapy with cisplatin [19] and radiotherapy [20]. HPV status can also aid in the confirmation of the diagnosis of cystic neck lesions [21] and locating a clinically occult primary tumor since an HPV-­ positive tumor in cervical levels 2 and 3 of the neck is likely to have arisen from an oropharyngeal primary [21]. An increasing number of organizations now recommend HPV testing and the determination of HPV status including the National Comprehensive Cancer Network (NCCN) [22], the College of American Pathologists, and the Collaborative Stage Data Collection System, utilized by several US groups including the American Joint Committee on Cancer and the Surveillance Epidemiology and End Results (SEER) program. Outside the USA, the Royal College of Pathologists (UK) and the Australasian College of Pathologists also recommend the determination of HPV status for OPC.  The problem remains that there is no uniform standard for validation or interpretation of HPV detection assays, although a consensus statement for reporting HPV status was issued by the College of American Pathologists in an attempt to standardize the application and interpretation of hrHPV testing [23]. The ideal test for hrHPV is technically reliable, reproducible, and easily interpreted. For histologic specimens, the test should ideally localize hrHPV within tumor cells. Currently used methodologies include PCR, HPV16 DNA in situ hybridization (ISH), hrHPV E6/E7 mRNA ISH, and p16 immunohistochemistry (IHC). 10.5.1 

PCR-Based Techniques

PCR-based testing for HPV is problematic because it fails to identify transcriptionally active virus within tumor cells. This is particularly an issue for DNA based testing; some studies have reported that close to 50% of OPC positive for hrHPV DNA by PCR are negative for E6/E7 mRNA expression [24]. In a comprehensive analysis of different methodologies Jordan et  al. reported 14% of hrHPV DNA-positive OPCs were negative for hrHPV E6/E7 mRNA expression and had very low HPV DNA viral load, concluding that PCR may detect “bystander” virus and arguing against the application

of PCR alone for classifying HPV status [25]. Sample contamination, especially in DNA-based testing protocols, is a well-known limitation of PCR. !!Warning Use of PCR technique alone is not recommended for classification of HPV status of tumors due to low specificity of the technique.

10.5.2 

In Situ Hybridization (ISH)

Type-specific HPV probes or “cocktails” can be applied on formalin-fixed, paraffin-embedded tissues for in situ hybridization (ISH), and the method allows localization ­topographically in tumor cells. Although the HPV16 DNA ISH assay can detect single-copy HPV with good sensitivity and high performance in comparison to hrHPV E6/E7 mRNA expression, it is type-specific, nonautomated, technically demanding to perform and has limited commercial availability. As reported by Schlecht et  al., commercially distributed assays by Ventana (INFORM HPV-III Fam16B) and Dako (HPV16/18) have lower test performance standards in comparison to analysis of HPV16 E6/E7 mRNA expression (AUC 0.48–0.69) [26]. The test that may well become the standard for hrHPV detection is hrHPV E6/E7 mRNA ISH that is commercially available and can be performed on the automated platforms utilized for routine immunohistochemistry. One currently marketed kit (Advanced Cell Diagnostics) detects E6 and E7 mRNA of 18 hrHPV subtypes and has excellent performance showing punctate signal (. Fig. 10.1 panel c) [27].  

10.5.3 

p16 Immunohistochemistry

Immunohistochemistry for the endogenous cell cycle protein p16 has proven a simple and practical surrogate marker for hrHPV in the setting of OPC. P16 is overexpressed in tumor tissue with transcriptionally active hrHPV. Therefore, detection of p16 protein by immunohistochemistry (IHC) is an acceptable and a satisfactory alternative to HPV ISH [26]. In HPV-induced cancers, overexpression of p16 is due to inactivation of pRB by the hrHPV E7 oncoprotein. During the natural history of cervical cancer, p16 expression progressively increases with the severity of dysplasia and is commonly used for triage of low-grade vs. high-grade dysplasia [28]. Standardization of testing methods and interpretation of positive/negative status of p16 IHC has recently been achieved for HPV-associated squamous intraepithelial lesions and superficially invasive anogenital squamous carcinomas [29]. >>Important p16 staining must be both nuclear and cytoplasmic to be considered positive in reporting HPV status of an oropharyngeal carcinoma.

The p16 immunohistochemical staining protocol has been standardized with a single monoclonal antibody (E6H4,

10

123 Detection Methods for Human Papillomavirus (HPV) in Head and Neck Cancers

MTM Labs) used in the vast majority of laboratories. High inter-rater agreement has been reported [30], confirming the competency of pathologists in interpretation and reporting of IHC assays. In tissue biopsies from the oropharynx, p16 IHC is interpreted as positive when there is moderate to strong staining in at least 70% of tumor cells. Both nuclear and cytoplasmic staining should be present to be considered positive for HPV (. Fig.  10.1 panel D). When interpreted correctly, the statistical correlation between p16 IHC status and HPV-specific tests such as hrHPVE6/E7 mRNA ISH is very high [31]. A reproducible and validated H-score has also been described and used in large clinical trials for p16 scoring [25]. The H-score is the cross product of staining intensity (0, 1, 2, or 3) and the percentage positive cells that show that intensity. On a scale of 0–300, an optimal cut-off point has been set at 60. This score contributes to an average sensitivity of 91.6% and specificity of 90.4% for hrHPV oncogene expression. P16 IHC is likely the most practical test for resource-poor settings, although the specificity of this marker as a surrogate for hrHPV drops precipitously when applied to tumors arising outside of the oropharynx. This is reflected in current testing guidelines published by the College of American Pathologists that discourages p16 testing for carcinomas outside of the oropharynx [23]. A comparison of the performance characteristics of the different methods described here is shown in . Table 10.1.  

 

10.6 

 ine-Needle Aspiration (FNA) for HPV F Testing

HPV-associated squamous cell carcinomas frequently present as an enlarged cervical lymph node with a small, clinically occult primary tumor within the palatine tonsils or base of the tongue. As many hrHPV+ OPC initially present

..      Table 10.1  Performance of individual tests compared to hrHPV qPCR [33] Assay method

Sensitivity %

Specificity %

PPV %

NPV %

p16 IHC

97

82

80

97

hrHPV DNA ISH

94

91

89

95

DNA qPCR

91

87

83

93

hrHPV RNA ISH

97

93

91

98

Abbreviations: hrHPV DNA ISH high-risk HPV DNA in situ hybridization, IHC immunohistochemistry, ISH in situ hybridization, NPV negative predictive value, PPV positive predictive value, qPCR quantitative PCR

with an enlarged upper cervical lymph node, HPV testing of fine-­needle aspirate (FNA) specimens obtained from a cervical metastasis is of considerable clinical value as it may direct the clinician to perform close examination of the oropharynx. The presence of hrHPV is so specific for oropharyngeal origin that a diagnostic tonsillectomy and base of the tongue resection may be performed in order to identify a microscopic primary tumor. Prior to recognizing the frequency of occult oropharyngeal primary tumors, pathologists previously rendered a diagnosis of “squamous carcinoma arising in a branchial cleft cyst” for those cases where a primary tumor was not clinically evident. HPV testing of unknown primary SCCs has proven that the majority of these represent HPV-driven malignancies, likely of oropharyngeal origin. [32] OPC characteristically metastasizes to the upper and mid jugular chain (cervical levels 2 and 3). Aspiration of these enlarged nodes can be performed with a narrowgauge needle (23 or 25 gauge, . Fig. 10.2 panel a), allowing for i­mmediate diagnosis of malignancy. Specimens can be preserved in alcohol-based preservative solutions (. Fig. 10.2 panel b) and/or formalin for hrHPV testing, in addition to traditional cytologic preparations (. Fig.  10.2 panel c).The cytomorphology of the hrHPV+ squamous cell carcinoma recapitulates the histomorphology of these tumors. Aspirate smears contain cohesive clusters of hyperchromatic, “basaloid” epithelium and scattered keratinizing cells (. Fig.  10.2 panel d). While incisional biopsy of the primary tumor or metastasis can yield tissue for HPV testing, testing of FNA specimens has the advantage of not contaminating the neck or disrupting the surgical field within the oropharynx. Furthermore, highly sensitive and specific hrHPV testing platforms developed for cervical cancer screening are available in most clinical laboratories and can be utilized in testing of FNA samples held in the appropriate liquid preservative.  

 

 

 

Eyecatcher

HPV-associated squamous cell carcinoma of the oropharynx may frequently first present as an enlarged cervical lymph node.

10.7 

Testing Saliva for HPV Infection

Salivary tests for HPV in asymptomatic patients are commercially available but have several significant limitations including high false positives, low specificity, and inability to differentiate persistent from transient infection. Most importantly, the action prompted by a positive result is unclear since a clinically visible precancerous lesion is usually not present. Because of these important limitations, their incorporation into clinical practice is currently not recommended.

124

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A. van Zante and R. C. Jordan

a

b

c

d

..      Fig. 10.2 Panel a: Percutaneous aspiration of an enlarged node is performed with a narrow-gauge needle attached to a syringe and an aspirator. Panel b: FNA samples can be held in alcohol-based preservative solutions and/or fixed in formalin for hrHPV testing. Panel c: Conventional cytologic smears and cell block stained prior to

10.8 

Conclusions

The escalating incidence of OPC associated with remote exposure to hrHPV means that increasing numbers of these cancers will be seen in the clinical setting. HPV status in OPC impacts a range of clinical factors including primary site determination, extent of surgery, adjuvant treatment, and

microscopic examination. Panel d: Cytologic preparation from a hrHPV+ squamous cell carcinoma containing cohesive clusters of hyperchromatic, “basaloid” epithelium, and scattered keratinizing cells

prognosis. Thus, accurate and reproducible methods to determine HPV status will be needed for an increasing volume of patients. Although p16 has proven to be a reliable surrogate for detection of hrHPV, its use will likely wane as molecular testing such as in situ hybridization becomes more widespread and laboratories become more comfortable with the application and interpretation of these methodologies.

125 Detection Methods for Human Papillomavirus (HPV) in Head and Neck Cancers

References

squamous cell carcinoma of the head and neck in UK head and neck multidisciplinary teams. Br J Oral Maxillofac Surg [Internet] 2011; Available from: http://www.­ncbi.­nlm.­nih.­gov/entrez/query.­fcgi?cmd 1. Castellsagué X, Quintana MJ, Martínez MC, et al. The role of type of =Retrieve&db=PubMed&dopt=Citation&list_uids=21450378. tobacco and type of alcoholic beverage in oral carcinogenesis. Int J 18. Ang KK.  Larynx preservation clinical trial design: summary of Cancer. 2004;108(5):741–9. key recommendations of a consensus panel. Oncologist. 2. Elashoff D, Zhou H, Reiss J, et al. Prevalidation of salivary biomarkers 2010;15(Suppl 3):25–9. for oral cancer detection. Cancer Epidemiol Biomarkers Prev. 19. Fakhry C, Westra WH, Li S, et al. Improved survival of patients with 2012;21(4):664–72. human papillomavirus-positive head and neck squamous cell carci 3. Gillison ML, Shah KV.  Human papillomavirus-associated head and noma in a prospective clinical trial. J Natl Cancer Inst. neck squamous cell carcinoma: mounting evidence for an etiologic 2008;100(4):261–9. role for human papillomavirus in a subset of head and neck cancers. 20. Cantley RL, Gabrielli E, Montebelli F, Cimbaluk D, Gattuso P, Curr Opin Oncol. 2001;13(3):183–8. Petruzzelli G. Ancillary studies in determining human papillomavi 4. D’Souza G, Gross ND, Pai SI, et al. Oral Human Papillomavirus (HPV) rus status of squamous cell carcinoma of the oropharynx: a review. infection in HPV-positive patients with oropharyngeal cancer and Pathol Res Int. 2011;2011:138469. their partners. J Clin Oncol. 2014;32(23):2408–15. 21. Cao D, Begum S, Ali SZ, Westra WH. Expression of p16 in benign and 5. Ang KK, Harris J, Wheeler R, et  al. Human papillomavirus and surmalignant cystic squamous lesions of the neck. Hum Pathol. vival of patients with oropharyngeal cancer. N Engl J Med. 2010;41(4):535–9. 2010;363(1):24–35. 22. Pfister DG, Ang KK, Brizel DM, et al. Head and neck cancers. J Natl 6. Guo M, Lin CY, Gong Y, et al. Human papillomavirus genotyping for Compr Cancer Netw. 2011;9(6):596–650. the eight oncogenic types can improve specificity of HPV testing in 23. Lewis JS, Beadle B, Bishop JA, et al. Human papillomavirus testing in women with mildly abnormal Pap results. Mod Pathol. 2008; head and neck carcinomas: guideline from the College of American 21(8):1037–43. Pathologists. Arch Pathol Lab Med. 2017; 7. Praetorius F. HPV-associated diseases of oral mucosa. Clin Dermatol. 24. Weinberger PM, Yu Z, Haffty BG, et al. Molecular classification iden1997;15(3):399–413. tifies a subset of human papillomavirus–associated oropharyngeal 8. Delius H, Saegling B, Bergmann K, Shamanin V, de Villiers EM. The cancers with favorable prognosis. J Clin Oncol. 2006;24(5):736–47. genomes of three of four novel HPV types, defined by differences of 25. Jordan RC, Lingen MW, Perez-Ordonez B, et al. Validation of meththeir L1 genes, show high conservation of the E7 gene and the ods for oropharyngeal cancer HPV status determination in US coopURR. Virology. 1998;240(2):359–65. erative group trials. Am J Surg Pathol. 2012;36(7):945–54. 9. Woo S-B, Cashman EC, Lerman MA.  Human papillomavirus-­ 26. Schlecht NF, Brandwein-Gensler M, Nuovo GJ, et al. A comparison of associated oral intraepithelial neoplasia. Mod Pathol. 2013; clinically utilized human papillomavirus detection methods in head 26(10):1288–97. and neck cancer. Mod Pathol. 2011;24(10):1295–305. 10. Lerman MA, Almazrooa S, Lindeman N, Hall D, Villa A, Woo S-B. HPV 27. Mirghani H, Casiraghi O, Amen F, et  al. Diagnosis of HPV-driven 16  in a distinct subset of oral epithelial dysplasia. Mod Pathol. head and neck cancer with a single test in routine clinical practice. 2017;30(12):1646–54. Mod Pathol. 2015;28(12):1518–27. 11. Shi W, Kato H, Perez-Ordonez B, et al. Comparative prognostic value of 28. Klaes R, Friedrich T, Spitkovsky D, et al. Overexpression of p16(INK4A) HPV16 E6 mRNA compared with in situ hybridization for human oroas a specific marker for dysplastic and neoplastic epithelial cells of pharyngeal squamous carcinoma. J Clin Oncol. 2009;27(36):6213–21. the cervix uteri. Int J Cancer. 2001;92(2):276–84. 12. Westra WH. The changing face of head and neck cancer in the 21st 29. Darragh TM, Colgan TJ, Cox JT, et al. The lower anogenital squamous century: the impact of HPV on the epidemiology and pathology of terminology standardization project for HPV-associated lesions: oral cancer. Head Neck Pathol. 2009;3(1):78–81. background and consensus recommendations from the College of 13. Wain SL, Kier R, Vollmer RT, Bossen EH.  Basaloid-squamous carciAmerican Pathologists and the American Society for Colposcopy noma of the tongue, hypopharynx, and larynx: report of 10 cases. and Cervical Pathology. Arch Pathol Lab Med. 2012;136(10): Hum Pathol. 1986;17(11):1158–66. 1266–97. 14. Begum S, Westra WH.  Basaloid squamous cell carcinoma of the 30. Thavaraj S, Stokes A, Guerra E, et al. Evaluation of human papillomahead and neck is a mixed variant that can be further resolved by virus testing for squamous cell carcinoma of the tonsil in clinical HPV status. Am J Surg Pathol. 2008;32(7):1044–50. practice. J Clin Pathol. 2011;64(4):308–12. 5. El-Naggar AK, Chan JKC, Takata T, Grandis JR, Slootweg PJ.  The 1 31. Begum S, Gillison ML, Ansari-Lari MA, Shah K, Westra WH. Detection fourth edition of the head and neck World Health Organization blue of human papillomavirus in cervical lymph nodes: a highly effective book: editors’ perspectives. Hum Pathol. 2017;66:10–2. strategy for localizing site of tumor origin. Clin Cancer Res. 16. Punwaney R, Brandwein MS, Zhang DY, et al. Human papillomavirus 2003;9(17):6469–75. may be common within nasopharyngeal carcinoma of Caucasian 32. Zengel P, Assmann G, Mollenhauer M, et al. Cancer of unknown priAmericans: investigation of Epstein-Barr virus and human papillomary originating from oropharyngeal carcinomas are strongly cormavirus in eastern and western nasopharyngeal carcinoma using related to HPV positivity. Virchows Arch. 2012;461(3):283–90. ligation-dependent polymerase chain reaction. Head Neck. 33. Schache AG, Liloglou T, Risk JM, et al. Validation of a novel diagnos1999;21(1):21–9. tic standard in HPV-positive oropharyngeal squamous cell carci 17. Ahmed A, Cascarini L, Sandison A, Clarke P. Survey of the use of tests noma. Br J Cancer. 2013;108(6):1332–9. for human papilloma virus and epidermal growth factor receptor for

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127

Diagnostic Imaging of Oral Squamous Cell Carcinoma Michał Studniarek and Paulina Adamska 11.1

The Detection of Oral Squamous Cell Carcinoma – 128

11.2

Primary Tumour – 128

11.3

Metastases in Regional Lymph Nodes – 133

11.3.1

Sentinel Lymph Node Biopsy – 135

11.4

Distant Metastases – 136

11.5

I maging Methods Used to Assess the Response to Chemoand Radiotherapy – 136

11.5.1 11.5.2

 ECIST – 136 R PERCIST – 136

11.6

Conclusions – 138 References – 138

© Springer Nature Switzerland AG 2020 S. Warnakulasuriya, J. S. Greenspan (eds.), Textbook of Oral Cancer, Textbooks in Contemporary Dentistry, https://doi.org/10.1007/978-3-030-32316-5_11

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Core Message

11.2 

Contemporary oncology diagnostics cannot succeed without imaging examinations. Diagnostic imaging techniques have a huge impact on detecting, planning and monitoring the treatment of patients with oral squamous cell carcinoma (OSCC). Imaging studies are performed to detect malignancies, assess staging (primary tumour size and localisation) metastases in regional lymph nodes and distant metastases, response to radiotherapy or chemotherapy and detect recurrence and disease dissemination. The methods which play a crucial role in the diagnosis of a tumour are plain radiography (e.g. dental X-ray, orthopantomography), ultrasonography (US), cone beam computed tomography (CBCT) and a wide variety of advanced techniques, e.g. multi-detector computed tomography (MDCT), computed tomography perfusion (CTP), diffusion-weighted MRI (DWI MRI) , dynamic contrast-enhanced MRI (DCE), wholebody MRI (WB-MRI), positron emission tomography (PET) and hybrid methods. The images are evaluated along with clinical and histopathological data. CT and MRI are referred to as the “gold standard” for imaging OSCC. An optimal combination of preoperative examination methods to predict bone invasion is necessary for the planning of definitive therapy for OSCC patients.

11

In order to determine the size of the primary lesion (T-stage), it is “gold standard” to perform computed tomography (CT) or magnetic resonance imaging (MRI). Other tools, including cone beam computed tomography (CBCT), plain radiography, ultrasonography or hybrid methods, are mostly additional techniques available for the radiologist when indicated. The size of the primary lesion and its relationship to adjacent structures  – particularly invasion of muscle and bone tissue – can be assessed by computed tomography. With the refinement of CT technology, multi-detector slice computed tomography (MDCT) with thin collimation is now widely used. The advantages of this kind of study include imaging in various cross sections with high spatial resolution, high availability and shorter examination time compared to, e.g. MRI. The disadvantages of CT are exposure to ionising radiation, the formation of quite strong artefacts from metal restorations and relatively low tissue contrast [2]. Dental restoration artefacts are common. What is needed in such cases is to repeat the scan with imaging along the line of the mandible – parallel to the plane containing the metal structures [3]. The CT protocol used in our centre is described in . Table 11.1. Dynamic MDCT with a contrast agent may increase the likelihood of detecting malignant lesions and improving the accuracy of staging, provide information about perfusion within the tumour tissue, which is a marker of angiogenesis, and enable monitoring of response to the treatment. Changes with a high degree of differentiation (low grade of malignancy) in CT studies include relatively weakly enhancement after administration of the contrast agent. Poorly differentiated cancers (high-grade tumours) with a high degree of malignancy are usually visible in a CT. The enhanced lesion is hyperdense in relation to the unaltered tissues. In a CT image, there is a clear border between tumour mass and healthy tissue [1]. Computed tomography enables the detection of neoplastic lesions with a sensitivity of 41–82% and specificity of 82–100%.The accuracy of the assessment of bone infiltration in the CT examination depends on the thickness of the imaged layer. The smaller the degree of osteolysis, the more false-negative results can occur [4]. Computed tomography with perfusion measurement provides information on microvasculature in neoplastic tissues. This method is routinely performed by our unit and is economical. Furthermore, it also allows data standardisation. Studies show higher sensitivity and specificity in the detection of neoplastic lesions compared with CT examination carried out without perfusion. The disadvantage of this in comparison with CT examination is higher dose of X-rays. Perfusion CT scan defines regional blood flow (RBF) in the tumour, regional blood volume (RBV), mean transit time  

11.1 

 he Detection of Oral Squamous Cell T Carcinoma

The basis of oral squamous cell carcinoma detection is a history and physical examination with histopathological studies. Diagnostic imaging methods are rarely used to detect a primary tumour arising from soft tissue. Most patients that are already diagnosed with a OSCC are referred to radiology departments for imaging to stage the cancer. Malignant lesions are sometimes found incidentally when radiology examinations are performed for investigation of other diseases of the orofacial region. For example, radiolucent lesions are sometimes noted on dental radiographs, orthopantomography and in cone beam computed tomography images. Ultrasonography to investigate a neck lump may reveal a metastatic node of an unknown primary, particularly arising from the oropharynx. In 12–56% of cases, OSCC may spread to and involve bones of the maxilla or mandible. Therefore, diagnostic imaging methods are used to assess the stage of neoplastic lesions (particularly when the tumour is located close to jaw bones) and contribute to staging by the TNM classification (see 7 Chapter 6). Positron emission tomography (PET) imaging with F-18-fluorodeoxyglucose (FDG-PET), when indicated, may further improve staging by facilitating detection of metastatic disease. TNM with clinical data analysis affects the treatment choice for patients with OSCC [1] (. Figs. 11.1 and 11.2).  

 

Primary Tumour

129 Diagnostic Imaging of Oral Squamous Cell Carcinoma

a

b

c

d

..      Fig. 11.1  a, b: Contrast-enhanced computed tomography. There is a tumour in the tongue (1 cm in diameter) on the left side (T1 stadium). On histopathological examination, it was diagnosed as a highly differentiated oral squamous cell carcinoma (G1). a Axial view, b sagittal view. c, d: Computed tomography without contrast administra-

tion. There is a tumour in the tongue (3.55 × 1.31 cm in diameter) on the right side (T2b stadium). On histopathological examination, it was diagnosed as an oral squamous spindle cell cancer. c Axial view, d sagittal view

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a

b

c

d

e

f

11

..      Fig. 11.2  a, b: Computed tomography (CT) without contrast administration showing a tumour in the tongue (3.55 × 1.31 cm in diameter) on the right side (T4a stadium) with pathological fracture. On histopathological examination, this was diagnosed as a highly differentiated oral squamous cell carcinoma (G1). a Coronal view, b 3D

reconstruction. c–f: Magnetic resonance imaging showing a tumour in the tongue (5.73 × 2.43 × 5.17 cm) on the right side (T4a stadium). c T1 post-contrast sequence in axial view, d T2 sequence, coronal view, e DWI, f ADC map, axial view (mean value of 983.64 × 10−6 mm2/s)

131 Diagnostic Imaging of Oral Squamous Cell Carcinoma

Currently, imaging of advanced cancers of the tongue is not performed, except in patients selected for radiotherapy. Some authors recommend radiotherapy for neoplastic lesions Patient placed Head first supine placed on the tongue using the “tongue out” technique. There in position is no information to support the use of this technique in Contrast 100 ml of 350 mg/ml (or equivalent) of diagnostics. medium (CM) iodine contrast medium administered at CT fluoroscopy is a real-time imaging method which can 3–4 ml/s be used for directing biopsies of OSCC.  It has not been Baseline Inferior orbital ridge described so far in a clinical setting. The MDCT also shows the highest specificity for bone Scan range From pituitary fossa to aortic arch lysis. The accuracy of the method in detecting involvement of Scan type Spiral the lower alveolar nerve is approximately 100%. These earlier Delay 45–60 s observations were confirmed by Vidiri et al. [11, 12] Osteolysis may be assessed on CT, plain radiography and Quality ref. mAs 150–280a cone beam computed tomography images. The accuracy of Quality ref. kV 80–140a bone infiltration on the CT depends on the thickness of the imaged layer. Osteolysis is detected in CT axial view, panSlice collimation 1–1.5 mm oramic imaging and cross-sectional images. There are four Feed rotation 10–40 mma degrees of osteolysis: class I is no bone invasion, class II is Voice instruction “Breathe gently and do not swallow” invasion confined to the alveolar part of mandible, class III is invasion extending between the alveolar part of mandible aIn relation to the number of rows in detector and the mandibular canal and class IV is invasion beyond/ crossing the mandibular canal. A lower degree of osteolysis may cause greater presence of false-negative results. Ogura (MTT), fraction of extraction (transfer of contrast agent et al. showed that analysis of mandibular bone invasion in a from intravascular space to extravascular and extracellular CT scan is useful as a prognostic indicator of cervical lymph EES) and permeability surface area product (PS) [1, 5–9]. nodes metastasis [4, 13]. The CT protocol enables acquisition of dynamic images Osteolytic changes in routine plain radiographs are visiat the rate of one per second for a period of 40–60 s after the ble when the neoplastic lesion is significantly advanced (stage injection of 40–50 ml of the contrast medium given at a rate T4) and the tumour infiltrates bone tissue. Bone involvement of 4–7  ml/s. This dynamic phase is followed by a second is noticeable when the loss of tissue is greater than 30%. The phase in which images are acquired at the rate of one every radiographic examination can show osteolytic defects, atro10  s for 2  min. The dynamic data is used to calculate the phy of cortical lamina, irregular shape of the cavity and loss blood volume and flow, while the second phase provides data of bone support for standing teeth in the jaw. Plain radioon vascular permeability. graphs do not allow the assessment of soft tissue involvement Oral cancer is characterised by increased parameters of by the cancer. perfusion, especially surface permeability × total surface Panoramic radiographs are used in the initial evaluation area, blood volume (BV) and blood flow (BF) in contrast to of the dentition and for any essential dental treatment healthy tissue. It is noticed that there is a low value of mean ­planning to remove foci of infection before surgical treattransit time (MTT = BV/BF). The relationship between histo- ment and radio/chemotherapy. The orthopantomography pathological changes and CTP parameters has been described. has shown bone infiltration with a sensitivity of 75% and a There can be an observed correlation with necrosis and tissue specificity of 100%, respectively [14]. Plain and panoramic hypoxia. The results show that perfusion of the tumour is sig- methods are now mostly of historical value in OSCC staging. nificantly different in comparison with the surrounding soft Cone beam computed tomography (CBCT) is an increastissue. This difference is significantly different in advanced ingly used tool in dental and maxillofacial surgery. The tumours (T3/T4) but not in small tumours (T1/T2) [1, 5–9]. advantages of this technique are as follows: the availability, MDCT allows an accurate determination of the bound- higher spatial resolution, lower or similar intensification of ary between tumour tissue and healthy tissue. The puffed-­ artefacts induced by metal restorations, lower cost and lower cheek method (Valsalva manoeuvre) in MDCT is used in the dose of ionising radiation. The main disadvantage of the diagnosis of retromolar triangle and gingivobuccal cancers study is very poor assessment of soft tissue image resolution (2.5 mm scan thickness, transverse plane; 0.625 mm, trans- which is in the range 0.12–0.4 mm and absorbed dose lower verse; frontal and sagittal reconstructions) and shows a than 0.1 mSv. sensitivity of 83–94% and specificity of 90–92% in the assessDetection of bone infiltration in the assessment of oral ment of bone infiltration of the mandible and bone marrow. cancer is of great prognostic value. CBCT is important in The puffed-cheek method enables a detailed assessment of assessing bone osteolysis (sensitivity 89–95%, specificity the mucous membrane of the oral cavity in relation to stan- 60–100%). CBCT has similar accuracy in the assessment of dard CT scans [10]. bone invasion to MRI, CT and bone scintigraphy, and it is a ..      Table 11.1  CT protocol

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much more accurate method than orthopantomographic examination [10]. False positives occur in the presence of inflammatory bone lesions [4, 15–19]. CBCT examination can be used to assess the accuracy of prefabricated surgical templates. Surgical templates are more accurate in relation to the virtual operation plan [20]. Magnetic resonance imaging (MRI) is characterised by high spatial and contrast resolution as well as a lack of exposure to ionising radiation. Imaging methods are divided into T1 and T2 dependent, STIR (short tau inversion recovery), DWI (diffusion-weighted imaging) and perfusion with and without the administration of a contrast agent. T1-weighted images have a very good spatial resolution, T2 images show better oedema, and STIR scans show suppression of fat signal. On T1 scans, lesions have intermediate to low signal and on T2 images intermediate to high signal [2]. An MRI protocol published in earlier studies is described in . Table 11.2 [3, 21]. Patients with cardiac pacemakers, neurostimulators and other electrical devices as well as after neurosurgical surgery for clipping an aneurysm (when the clip is not approved) cannot be examined by MRI. Ferromagnetic materials in the craniofacial region may lead to artefacts that may hinder or prevent proper diagnosis of malignant lesions. Moreover, artefacts can be caused by amalgam fillings, permanent prosthetic restorations (crowns, bridges, implants) or steel screws after osteosynthesis [22, 23]. Diagnostics using MRI enable to visualise the location and extent of OSCC in the soft tissues, including the detection of very small tumours, and the extent and infiltration of adjacent structures by the tumour. This enables the surgeon in surgery planning, evaluation of surgery and reconstruction methods to visualise possible complications that may occur during and after the procedure. It also allows the assessment of earlier reconstructive procedures and any recurrences within postoperative scars. In addition to that, it helps to determine the infiltration of soft tissues, bone marrow and bone with a sensitivity of 82% and specificity of 66.7%, as well as infiltration of vessels and nerves [1, 24, 25]. Dynamic MRI with the application of contrast agent provides information about perfusion within the tumour, and thus increases the detection of malignant lesions and the accuracy of anatomical spread of disease (staging). Imaging of the hard palate and nerve infiltration is better seen in the MRI study after administration of a contrast agent. MRI has comparable sensitivity and specificity to CT and CBCT in the assessment of bones, but it has a higher sensitivity in the soft tissue analysis [11, 26]. Diffusion-weighted (DW) imaging is a non-invasive imaging tool, potentially able to provide information about microstructural tumour characteristics. It uses the measurement of movements of extracellular water molecules (diffusion speed of water molecules). It is characterised by low spatial and high contrast resolution. It can indicate tumour cellularity. In MR, DW imaging areas with lower (reduced, restricted) diffusion are hyperintensive in relation to the surrounding tissue [27, 28]. DWI MRI has an 80% sensitivity and 82% specificity in residual OSCC detection [29].  

11

..      Table 11.2  MRI protocol Patient placed in position

Head first supine (the prone position for patients suffering from claustrophobia)

Contrast agent

Gadopentetate dimeglumine (gadolinium-­DTPA)

Baseline

Inferior orbital ridge

Scan range

From pituitary fossa to aortic arch

Scan type

Head coil or superficial coil

Sequences

Slices thick/gap

Field of view (FOV)

T1-weighted (T1W), axial

3.0 mm/0.3 mm

180 mm

T1-weighted (T1W), coronal

3.0 mm/0.3 mm

180 mm

Selective saturation pulse or STIR, coronal T2-weighted (T2W) fatsat, axial

3.0 mm/0.3 mm

180 mm

Post injection of gadolinium-based CM (recommended dose for the most of CM is 0.1 mmol/kg) T1W fatsat, axial with CM

3.0 mm/0.3 mm

180 mm

T1W fatsat, coronal with CM

3.0 mm/0.3 mm

180 mm

T1W fatsat, sagittal with CM

3.0 mm/0.3 mm

180 mm

Diffusion-weighted imaging (DWI), axial b = 500

4.0/1.0 mm

240 mm

Voice instruction

“Breathe gently, do not swallow, and do not move”

Apparent diffusion coefficient (ADC) allows quantitative analysis of diffusion of water molecules. The ADC obtained by DW MRI is a marker of cell density and potentially may distinguish malignant from benign lesions. In ADC images, impaired diffusion is seen as hypointensive change. Malignant lesions can show low ADC values 0.93 [0.18] × 10−3 mm2/s. Values below 1.25 × 10−3 mm2/s are characteristic for cancers with an accuracy of 92.8% [30]. Carcinomas with low degree of differentiation (G3/4) have more cells, nuclei are larger and more angulated, and there is less extracellular space than moderate to highly differentiated cancers (except necrosis). Based on ADC maps, the sensitivity is 94% and specificity is 91%, respectively. Necrotic lesions are hyperintensive and have liquid-like values 2.11 [+/−0.58]∗10−3 mm2/s. The surgeon must avoid these areas when performing a biopsy [28–32]. Dynamic MRI after contrast administration is characterised by high spatial and contrast resolution. DCE MRI is used to detect malignant lesions and in the analysis of perfu-

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133 Diagnostic Imaging of Oral Squamous Cell Carcinoma

sion in preoperative extranodal dissemination and allows to evaluate the response to treatment. The sensitivity is 96%, and the specificity is 100%. Perfusion measurements can be also performed without the use of a contrast agent [1, 33–35]. Ultrasonography is a non-invasive diagnostic tool that is used to assess superficial lesions. The result of the test depends upon the experience of the physician performing examination [36]. !!Warning Any neoplastic invasion at the deeper aspect of the tumour cannot be assessed precisely by ultrasonography.

I-shaped, hockey sticks or endocavitary probes (during operation) are used for the examination. The probes used intraorally are placed directly adjacent to the lesion. They are held by the tip of the fingers (fingertip probes). For superficial structures, higher ultrasound beam frequencies are used, which allows a higher image resolution. Images with a resolution of 0.5 mm are obtained. Intraoral colour Doppler sonography is used to assess the size of the primary focus and relation of the lesion to adjacent structures. An increased flow can be demonstrated, which indicates a greater vascularisation of the lesion [37–39]. Any neoplastic invasion at the deeper aspect of the tumour cannot be assessed precisely. Single-photon emission tomography (SPECT) provides information about anatomy, physiology and biology of the tumour and enables the creation of an image of tissue metabolic activity using gamma radiation. Radiopharmaceuticals such as 99mTc-2,3-dicarboxypropane-1,1-diphosphonate (99mTcDPD SPECT) and 99mTc-2-methoxyisobutylisonitrile (MIBI) SPECT are used for this technique [15]. 99mTcDPD SPECT examination demonstrates bone tissue involvement with a sensitivity of 100% and specificity of 14.3% [14, 40, 41]. Positron emission tomography (PET) is a cross-sectional and functional imaging technique that is performed in conjunction with CT (PET/CT) and MRI (PET/MRI) examinations. PET quantifies the metabolic activity of any neoplastic lesion. Unfortunately, PET scanning is characterised by worse spatial resolution in comparison with computed tomography and magnetic resonance imaging. A wide range of PET tracers, which reflect metabolism, proliferation or hypoxia, or binding to specific receptors are available. Radiopharmaceuticals used in the study are 2-deoxy-2[18F] fluoro-­D-­glucose (18F-FDG), 3-deoxy-3[18F] fluorothymidine (18F-FLT), L-3[18F] fluoro-alpha-methyl tyrosine (18F-FAMT) and/or 18F-fluoromisonidazole (18F-FMISO). The spatial distribution of the radioisotope in a given organ can be visualised in PET scans [1, 41–45]. PET/CT with the 18F-FAMT can be used to evaluate the tumour proliferation activity but should not be used to determine the infiltration of bone tissue or to assess the extent of the neoplastic lesion. Bone marrow involvement may also be determined using 18F-FAMT. PET/MRI is characterised by a higher sensitivity compared to MRI in the assessment of soft tissue involvement [1, 40, 42–45].

11.3 

Metastases in Regional Lymph Nodes

The evaluation of cervical lymph nodes invasion (. Fig. 11.3) can be assessed by computer tomography, magnetic resonance imaging and ultrasonography. Hybrid methods can be performed in addition to the above methods. A meta-analysis has shown that imaging techniques described below, e.g. CT, MRI, US and particularly US-­ guided fine-needle aspiration cytology (USgFNAC), are more reliable than neck palpation for the detection of lymph node metastasis [46]. CT scans with any contrast agent fairly accurately detect metastases to lymph nodes and distinguish cervical vessels. Mancuso et al. defined the criteria for involved or suspicious lymph nodes in CT and MRI studies. Features of the metastatic lymph nodes are an oval shape or round shape, a node over 10  mm in the transverse diameter (for group I over 15  mm), presence of necrosis, dense centre, topography of node distribution, creation of clusters, changes in perinodal tissues and obliteration of the capsule. The assessment of lymph nodes may be underestimated because lymph nodes may contain micrometastases. Such micrometastases are detected by histopathological examination and not by imaging [47, 48]. Detection of lymph nodes with and without metastases has a sensitivity of 31–85% and specificity of 74–94%. Detection of small lymph nodes (less than 10  mm in the transverse diameter) has a lower sensitivity of 71.4%. The ­contrast-­enhanced CT (CECT) study shows higher sensitivity and specificity in detecting nodal deposits in groups IB and II compared to ultrasound and PET/CT [47, 49]. MRI is used to assess lymph node metastases. The sensitivity and specificity of detecting of lymph node metastases are 51–74% and 95–100%, respectively. MRI may give false-­ negative results of micrometastases in regional lymph nodes. This problem may affect up to 20% of patients. In these cases, the valuable tools are DWI MRI or hybrid methods [50]. Diffusion-weighted (DW) MRI is used to measure differences in tissue microstructural changes that are based on random displacement of water molecules. The DW MRI examination enables the assessment of structures affected by the tumour, and it may be useful in distinguishing inflammatory changes from metastatic deposits in lymph nodes. Detection of cervical lymph nodes with metastases has a sensitivity of 94% and specificity of 88%, respectively. Lymph nodes with metastatic cells are characterised by larger cells and more frequent divisions (mitosis). There is a restriction of water molecule movement, which in the DWI MRI scans is seen as a hyperintensive image. DW MRI examination has a higher sensitivity than MRI in the assessment of a lymph node involvement smaller than 1 cm [30].  

>>Important Diffusion-weighted (DW) MRI uses the apparent diffusion coefficient (ADC) as a marker of cell density, and the values are higher in benign lymphadenopathy and lower in metastatic lymph nodes.

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a

b

c

d

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..      Fig. 11.3  a, b: Contrast-enhanced computed tomography. This is a lymph node package with necrosis in the left submandibular space (T4aN2cMx stadium). On histopathological examination, it was diagnosed as a moderate/poorly differentiated oral squamous cell carcinoma (G2/3). a Axial view, b sagittal view. c, d: Magnetic resonance

imaging. There is a metastases to lymph node on the right side (T3N2cMx). On histopathological examination, it was diagnosed as a poorly differentiated oral squamous cell carcinoma (G3). c T1 sequence sagittal view, d T2 sequence coronal view

Metastatic lymph nodes have higher cellularity, so there is less movement of water molecules, and ADC values are lower (0.59–1.09  ×  10−3  mm2/s) than that of benign (1.21– 1.64 × 10−3 mm2/s) cervical lymph nodes. While distinguishing between malignant and benign cervical lymph nodes, the threshold is at ADC value of 1.22 × 10−3 mm2/s. The accuracy, sensitivity and specificity in detecting lesions are 86%, 84% and 91%, respectively. Inflammation can reduce the

value of the ADC. It is always a good practice to compare the appearance of nodes with ADC values and clinical symptoms. Sarcoid and tuberculous nodes may also record decreased ADC values [30]. Ultrasound is a non-invasive tool often used to assess cervical nodes although is not useful for evaluating retropharyngeal and superior mediastinal nodes. When assessing cervical lymph nodes, attention should be paid to the num-

135 Diagnostic Imaging of Oral Squamous Cell Carcinoma

ber, size and presence of clustered nodes. Metastatic nodes are enlarged (in the transverse diameter must be at least 10  mm), solid and hypoechoic and have circular or oval shape, with contour that maybe obscured and with necrosis suggested by anechoic areas. Rollon-Mayordomo et  al. described the ultrasound criteria for metastatic nodes: enlarged nodes at multiple levels, measuring in transverse diameter more than 6.5  mm and presenting longitudinal/ transverse ratio below 1.3  in lymph nodes of level II and medium/low differentiation OSCC [51]. Doppler ultrasound allows the assessment of vascularity and flow in the regional lymph nodes. The metastatic node is characterised by a lack of hilar flow/perfusion and increased peripheral flow, in contrast to inflamed lymph nodes where increased flow is seen in the hilum. The sensitivity, specificity and accuracy of US were 47–78.9%, 68.7–93% and 73.2– 100%, respectively [47, 52]. Contrast-enhanced ultrasound (CEUS) mapping of lymph nodes is used to detect sentinel lymph nodes. The method uses contrast agents in the form of microbubbles (e.g. SonovueTM). The contrast medium is administrated peritumourally. In this examination the transit time from the injection site to the node can be recorded, and it is also possible to determine the lymph node-filing pattern, whether uniform or not. In one study, sentinel nodes were detected in 91.7% [52]. This technique can be considered as a potentially useful lymph node mapping tool. Ultrasound enables precise fine-needle aspiration (USgFNA) biopsy, providing material for cytological examination. The test is used where there is suspicion of nodal metastasis. Ultrasound-guided biopsy is used for the evaluation of tongue base and floor of mouth cancers. Performing only an ultrasound examination is insufficient to assess cervical nodes when nodal metastases are suspected (sensitivity of 79%, specificity of 69%) [47, 53]. Sentinel lymph node biopsy is a sensitive method in the detection of neck metastases in cT1/T2 N0 OSCC [54, 55]. 11.3.1 

Sentinel Lymph Node Biopsy

Sentinel lymph node biopsy (SLNB) is of value in the investigation of early stage cancers. It is performed to determine whether to remove the nodes of the neck. The study locates lymph nodes, which are the first to become involved. If the sentinel lymph node is not involved, metastasis to regional lymph nodes can be excluded. For the detection of sentinel nodes, the technique used includes the following steps: preoperative lymphoscintigraphy and SPECT/CT. The shine-through phenomenon may occur when lymph nodes are clustered and isotope has been administered. The shine-through phenomenon means an activity at the site of radioisotope injection. Freehand SPECT (fhSPECT) is characterised by a higher accuracy. Three gamma probes are used. Biopsy is performed during surgery. Two probes are placed above the patient, and the third is held by the operator – the gamma probe. The third probe can be freely set in the

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operating field. The fhSPECT study allows determination of the location of a suspicious sentinel node in relation to the skin and adjacent structures. The operator in real time precisely marks the sentinel nodes and can selectively remove those nodes for microscopic investigation. fhSPECT, in combination with UsgFNA, increases the sensitivity of UsgFNA [56–63]. Preoperative SPECT/CT in sentinel node biopsies increases the detection of such nodes [64]. Fewer false-negative results occur in the shorter period between marker administration, imaging and surgery. Detection of nodal metastases is more accurate in lymph node I and level II studies (96% of metastases are nodes I and II level for oral cancer) [65]. In floor of the mouth lesions, the examination should be performed on both sides. A handheld intraoperative probe and a portable or a handheld gamma camera contribute to accurate surgical planning and procedure [66]. PET examination can be used to assess metastatic lymph nodes with sensitivity of 33–96% and specificity of 76–100%, especially for N0 neck. It is useful to detect the presence of excessive activity of small lymph nodes in which there was no visible focus of central necrosis in CT and MRI studies. PET/CT imaging may not be sufficient in the study of nodal metastases in the presence of granulomatous disease. Therefore, PET/CECT should be used. 18F-FDG PET/CT study is more effective in detecting metastases located in the lymph nodes than CT/MRI.  Metabolic tumour volumes (MTV) by 18F-FDG PET/CT correlate with occult metastasis in tongue carcinoma [67]. Diagnosis using 18F-FDG PET/ MRI imaging does not improve the assessment of lymph node metastases in comparison with independent MRI and 18F-FDG PET [17]. Inflammatory lesions, cN0 nodes and metastatic nodes smaller than 3 mm in the 18F-FDG PET/ CT study may give false-negative results. On FMISO, PET examination can indicate higher tumour/muscle ratio (TMR), and maximum standard uptake value (SUVmax) values were higher in OSCC patients with higher Ki-67 scores and positive hypoxia-­inducible factor-1α (HIF-1α) [45, 47, 52]. FDG-PET has an important role in the detection of occult primary tumours in patients with cervical lymph node metastasis of the neck. In a meta-analysis of 16 studies that analysed 302 patients with no palpable lymph nodes and where conventional workup was negative, addition of FDG-­ PET to the in 74 patients (24.5%) [68]. Eyecatcher

Patients with cardiac pacemakers, neurostimulators and other electrical devices as well as after neurosurgical surgery for clipping an aneurysm (when the clip is not approved) cannot be examined by MRI. Ferromagnetic materials in the craniofacial region may lead to artefacts that may hinder or prevent proper diagnosis of malignant lesions. Moreover, artefacts can be caused by amalgam fillings, permanent prosthetic restorations (crowns, bridges, implants) or steel screws after osteosynthesis [22, 23].

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11.4 

Distant Metastases

Distant metastases are observed commonly in the lungs, mediastinal lymph nodes, bones, liver, pleura, muscle or brain. Metastases are rare in the bladder, cervix and kidney. Studies that can be used to detect distant metastases include computed tomography, magnetic resonance imaging, ultrasonography and PET/CT [69]. Low-dose computed tomography (LDCT) should be a standard in the detection of pulmonary metastases. Even the presence of one nodule is considered to be a distant metastasis. However, calcifications of subpleural nodules are not considered as metastatic disease. MRI and PET/CT can also be of value in the search for synchronous and metachronous lesions in the lungs [2, 69]. Diagnosis using PET/CT is a very effective method for locating distant metastases and synchronous cancers in comparison to chest radiographs, chest CT or MRI. Synchronous neoplasms involve primarily head and neck, lungs and malignant lymphoma. Suspicious lesions have an abnormal focally enhanced tracer uptake, which cannot be attributed to normal physiological uptake [69]. Xu GZ et al. showed similar sensitivity and specificity for distant metastases staging of head and neck cancer by whole-­ body MRI (WB-MRI) and 18FDG-PET/CT [70]. Bone metastases can present as osteolytic or osteosclerotic lesions. Bones are assessed by CT scans and bone scintigraphy [69, 71]. The basic method for liver metastases detection is abdominal ultrasound that should be repeated according to the follow-up scheme. Computed tomography and magnetic resonance imaging can be valuable tools in the assessment of liver metastases. In the detection of distant metastases, whole-body MRI (WB-MRI) can be used. Sequences T1, T2, TSE-T2, STIR, DWI and DCE are used. Low signal of T1 is considered as suspicious for metastasis [1, 24, 71]. In CT, the liver should be evaluated in the liver window. Metastatic lesions are hypodense. The rim and necrotic tissue should be included in measuring metastases [72]. Computed tomography, magnetic resonance imaging and angiography can be valuable tools in the evaluation of brain metastases [69, 71]. Mediastinal lymph nodes are evaluated according to the following criteria: enlarged and round lymph nodes, dense centre with necrosis, absence of fatty hilum, topography of node distribution and 18F-FDG avidity for PET [69, 70]. Lesions located in muscles cause a change in the shape and the development foci of increased uptake of 18F-FDG [69, 71]. 11.5 

I maging Methods Used to Assess the Response to Chemoand Radiotherapy

Diagnostic methods, which can be used to assess the response to radiotherapy and chemotherapy, are as follows:

55 CT with perfusion CT 55 MRI with diffusion and perfusion 55 PET 55 Ultrasound In order to detect recurrence, there are three methods that can be used: perfusion CT, MRI (DWI, DCE, whole-­body MRI) and hybrid method. Hybrid method, magnetic resonance imaging and ultrasonography are used to detect the reaction of the tumour. The response to applied treatment is evaluated by the following imaging modalities: 11.5.1 

RECIST

Response Evaluation Criteria in Solid Tumours: This is a set of rules and criteria introduced in 2000 and updated in 2009 that were provided to evaluate the quantitative response to any applied treatment. To apply this method, it is necessary to find at minimum one measurable lesion, i.e. larger than 10 mm (target lesion), maximum less than 4 weeks before the beginning of treatment. Complete response (CR) means that the target lesion has disappeared in the control study. Partial response (PR) means that target lesion decreased in size by at least 30%. Progressive disease (PD) means an increase in the size at least 20%. Stable disease (SD) means the same size in control study than in baseline one (not smaller than 30% and not larger than 20% of basic size). All these measurements can be applied in any imaging modality [72].

11.5.2 

PERCIST

Positron Emission Tomography (PET) Response Criteria in Solid Tumours: Measurements of target lesion size used in RECIST criteria are not sensitive enough, and there are many responders with the SD or even PD in the first control study, having positive reactions to applied treatment. Using PET, the quantitative 18F-FDG target lesion uptake is measured. If such uptake is not seen, it can be concluded that there are no new lesions and complete resolution is noted. Diminution by at least 30% of basic uptake is interpreted as partial resolution. Growth of at least 30% uptake is interpreted as PD. The size of the target lesion is less significant in the decision [73]. There are some other methods and specific applications used to assess the tumour response to treatment. Using CT, it is not possible to distinguish between postoperative scars and radiotherapy changes due to tumour recurrence. The RECIST criteria are useful in the quantitative or qualitative evaluation of perfusion parameters in the response assessment. Sensitivity and specificity in the tumour relapse and reaction to treatment are reported at 50% and 88%, respectively [1, 4–9, 14, 47]. The DCE MDCT can be used also to predict a future reaction to chemotherapy. Popovic et al. found that higher perfusion of the cancer indicates better results of cisplatin treatment [7].

137 Diagnostic Imaging of Oral Squamous Cell Carcinoma

CT perfusion has predictive value as a marker of tumour response to chemotherapy and radiotherapy. If there are more necrotic changes, there is a worse response to radiotherapy. Popovic et  al. showed that patients responding to treatment with cisplatin have significantly higher baseline volumes and blood flows. This relationship is still under investigation. The CT perfusion test shows superiority to CT examination in detecting cancer recurrence in the postoperative scar [1, 5–9].

MRI examination can be used to evaluate patient’s response to treatment. It is a better diagnostic tool in the detection of recurrence in surgical scars compared to computed tomography. It can also be used to assess the spread of neoplastic lesions. DCE MRI is a good tool for monitoring response to treatment [1] as well as ADC measurements [74]. DWI MRI imaging may be useful for monitoring and for early assessment of tumour tissue response to chemoradiotherapy (one to two cycles) [30]. The ADC maps can be used

a

b

c

d

..      Fig. 11.4  a, b: This is a lymph node in the left submandibular space (T4aN1Mx stadium; lymph node 1.57 cm). On histopathological examination, it was diagnosed as a poorly differentiated oral squamous

cell carcinoma (G3). a CT axial view, b PET/CT axial view. c, d: The same patient. c PET/CT axial view, d whole-body PET coronal view (in the left cubitus, the injection site is seen)

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to assess the response to radiotherapy and chemotherapy. As a result, they become useful as predictive indicators [50]. Ultrasound-guided fine-needle aspiration is used to verify the presence of cancer cells in any suspected region after oncology treatment. Calcifications are more frequent in lymph nodes after radiotherapy, compared to non-irradiated nodes. Radiation therapy affects the image of the lymph nodes and should be noted when reporting [53]. Share wave elastography can be useful in the monitoring of tumour stiffness during and after therapy [75]. 18F-FDG PET/CT is the main radiopharmaceutical used to assess the tumour response to applied therapy. PET is used when planning neoadjuvant treatment and predicting survival without recurrence. As a marker of metabolic activity, it is a well-known way of evaluating cancer vitality (. Fig. 11.4). Some drugs act mostly on cell division, so a different marker should be used (18F-FLT or 11C-acetate) [1, 45, 76, 77]. Subclinical relapse of OSCC is a diagnostic challenge, where PET/CT seems to have advantages over MDCT or MRI [1, 15, 40–42]. Multivariate logistic regression analysis showed that FMISO uptake was an independent, significant predictive indicator of response to preoperative chemotherapy. PET is recommended in advanced clinical OSCC (stage IV) and allows to carry out more accurate TNM assessment [15, 40–42, 78].  

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11.6 

Conclusions

Radiographic imaging of oral cancer can be complex. In order to assess the extent of any neoplastic lesion, CT and MRI examinations are performed. The assessment of cervical lymph nodes should be supplemented with ultrasonography, MRI, CT or PET. Currently, there is a tendency to use hybrid methods in combination with PET, which enables accurate assessment of distant metastases. In summary, each method of diagnostic imaging has advantages and limitations. It is necessary to select the appropriate technique suitable to current needs, which has an impact on the diagnosis, treatment selection and survival of the patient.

References 1. Blatt S, Ziebart T, Krüger M, Pabst AM.  Diagnosing oral squamous cell carcinoma: how much imaging do we really need? A review of the current literature. J Craniomaxillofac Surg. 2016;44(5): 538–49. 2. Lewis-Jones H, Colley S, Gibson D. Imaging in head and neck cancer: United Kingdom National Multidisciplinary Guidelines. J Laryngol Otol. 2016;130:S28–31. 3. Law CP, Chandra RV, Hoang JK, Phal PM. Imaging the oral cavity: key concepts for the radiologist. Br J Radiol. 2011;84(1006):944–57. 4. Linz C, Müller-Richter UD, Buck AK, Mottok A, Ritter C, Schneider P, et  al. Performance of cone beam computed tomography in comparison to conventional imaging techniques for the detection of bone invasion in oral cancer. Int J Oral Maxillofac Surg. 2015;44: 8–15.

5. Trojanowska A. Squamous cell carcinoma of the head and neck— The role of diffusion and perfusion imaging in tumor recurrence and follow-up. Rep Pract Oncol Radiother. 2011;16(6):207–12. 6. Trojanowska A, Grzycka-Kowalczyk L, Trojanowski P, Klatka J, Drop A. Computed tomography perfusion examination is helpful in evaluating the extent of oropharyngeal and oral cancer. Pol J Radiol. 2011;76(1):14–9. 7. Popovic KS, Lukic S, Popovic P. Pretreatment perfusion CT and CT volumetry in squamous cell carcinoma of the head and neck region. J BUON. 2014;19(4):937–43. 8. Nesteruk M, Lang S, Veit-Haibach P, Studer G, Stieb S, Glatz S, et al. Tumor stage, tumor site and HPV dependent correlation of perfusion CT parameters and [18F]-FDG uptake in head and neck squamous cell carcinoma. Radiother Oncol. 2015;117(1):125–31. 9. Bisdas S, Nguyen SA, Anand SK, Glavina G, Day T, Rumboldt Z. Outcome prediction after surgery and chemoradiation of squamous cell carcinoma in the oral cavity, oropharynx, and hypopharynx: use of baseline perfusion CT microcirculatory parameters vs. tumor volume. Int J Radiat Oncol Biol Phys. 2009;73(5):1313–8. 10. Weissman JL, Carrau RL. “Puffed-cheek” CT improves evaluation of the oral cavity. AJNR Am J Neuroradiol. 2001;22(4):741–4. 11. Arya S, Rane P, Sable N, Juvekar S, Bal M, Chaukar D. Retromolar trigone squamous cell cancers: a reappraisal of 16 section MDCT for assessing mandibular invasion. Clin Radiol. 2013;68(12):680–8. 12. Vidiri A, Guerrisi A, Pellini R, Manciocco V, Covello R, Mattioni O, et al. Multi-detector row computed tomography (MDCT) and magnetic resonance imaging (MRI) in the evaluation of the mandibular invasion by squamous cell carcinomas (SCC) of the oral cavity. Correlation with pathological data. J ExpClin Cancer Res. 2010;29:73. 13. Ogura I, Kurabayashi T, Amagasa T, Okada N, Sasaki T. Mandibular bone invasion by gingival carcinoma on dental CT images as an indicator of cervical lymph node metastasis. Dentomaxillofac Radiol. 2002;31:339–43. 14. Kushraj T, Chatra L, Shenai P, Rao PK. Bone invasion in oral cancer patients: a comparison between orthopantamograph, conventional computed tomography, and single positron emission computed tomography. J Cancer Res Ther. 2011;7(4):438–41. 15. Uribe S, Rojas LA, Rosas CF. Accuracy of imaging methods for detection of bone tissue invasion in patients with oral squamous cell carcinoma. Dentomaxillofac Radiol. 2013;42(6):20120346. 16. Hendrikx AW, Maal T, Dieleman F, Van Cann EM, Merkx MA. Cone-­ beam CT in the assessment of mandibular invasion by oral squamous cell carcinoma: results of the preliminary study. Int J Oral Maxillofac Surg. 2010;39(5):436–9. 17. Dreiseidler T, Alarabi N, Ritter L, Rothamel D, Scheer M, Zöller JE, et al. A comparison of multislice computerized tomography, conebeam computerized tomography, and single photon emission computerized tomography for the assessment of bone invasion by oral malignancies. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2011;112:367–74. 18. Momin MA, Okochi K, Watanabe H, Imaizumi A, Omura K, Amagasa T, et al. Diagnostic accuracy of cone-beam CT in the assessment of mandibular invasion of lower gingival carcinoma: comparison with conventional panoramic radiography. Eur J Radiol. 2009;72:75–81. 19. Hakim SG, Wieker H, Trenkle T, Sieg P, Konitzer J, Holl-Ulrich K, et al. Imaging of mandible invasion by oral squamous cell carcinoma using computed tomography, cone-beam computed tomography and bone scintigraphy with SPECT. Clin Oral Investig. 2014;18:961– 7. 20. Weijs WL, Coppen C, Schreurs R, Vreeken RD, Verhulst AC, Merkx MA, et al. Accuracy of virtually 3D planned resection templates in mandibular reconstruction. J Craniomaxillofac Surg. 2016;44(11): 1828–32. 21. Olliff J, Richards P, Connor S, Wong WL, Beale T, Madani G. Head and neck cancers. In: Nicholson T, editor. Recommendations for crosssectional imaging in cancer management. 2nd ed. London: The Royal College of Radiologists; 2014. p. 3–19.

139 Diagnostic Imaging of Oral Squamous Cell Carcinoma

22. Bovenschulte H, Schlüter-Brust K, Liebig T, Erdmann E, Eysel P, Zobel C. MRI in patients with pacemakers: overview and procedural management. Dtsch Arztebl Int. 2012;109(15):270–5. 23. Pałasz P, Adamski Ł, Chrząstek-Górska M, Starzyńska A, Studniarek M. Contemporary diagnostic imaging for the oral squamous cell carcinoma – a review of the literature. Pol J Radiol. 2017;82:193–202. 24. Sarrión Pérez MG, Bagán JV, Jiménez Y, Margaix M, Marzal C. Utility of imaging techniques in the diagnosis of oral cancer. J Craniomaxillofac Surg. 2015;43(9):1880–94. 25. Kim M, Higuchi T, Arisaka Y, Achmad A, Tokue A, Tominaga H, et al. Clinical significance of 18F-a-methyl tyrosine PET/CT for the detection of bone marrow invasion in patients with oral squamous cell carcinoma: comparison with 18F-FDG PET/CT and MRI.  Ann Nucl Med. 2013;27:423–30. 26. Souren C, Kloss-Brandstätter A, Stadler A, Kross K, Yamauchi K, Ketelsen D, et  al. Ultrasound-guided fine-needle aspiration cytology as a diagnostic tool in comparison to ultrasound and MRI for staging in oral- and oropharyngeal squamous cell tumors. J Craniomaxillofac Surg. 2016;44(2):197–201. 27. Rosenberger R, Wojtek P, Konopka M, Pieniążek P, Bogusz I, Sąsiadek M. Clinical application of perfusion imaging computed tomography and diffusion and perfusion magnetic resonance imaging in detecting early changes in ischemic stroke. Via Medica Udar Mozgu. 2004;6(2):71–8. 28. Hejduk B, Bobek-Billewicz B, Jedrzejewska M.  Application of MRI imaging DWI-evaluation of lymph nodes in patients with head and neck cancer – a preliminary report. Pol J Radiol. 2007;72(1):207–8. 29. Noij DP, Jagesar VA, de Graaf P, de Jong MC, Hoekstra OS, de Bree R, et al. Detection of residual head and neck squamous cell carcinoma after (chemo)radiotherapy: a pilot study assessing the value of diffusion-weighted magnetic resonance imaging as an adjunct to PET-CT using 18F-FDG. Oral Surg Oral Med Oral Pathol Oral Radiol. 2017;124(3):296–305. 30. Khalek AA, Razek A. Diffusion-weighted magnetic resonance imaging of head and neck. J Comput Assist Tomogr. 2010;34:808–15. 31. Bobek-Billewicz B. Diffusion-weighted MRI (DWI-MR) – oncological applications. Pol J Radiol. 2010;75(1):53. 32. Thoeny HC, De Keyzer F, King AD. Diffusion-weighted MR imaging in the head and neck. Radiology. 2012;263(1):19–32. 33. Jansen JFA, Schoder H, Lee NY, Stambuk HE, Wang Y, Fury MG, et al. Tumor metabolism and perfusion in head and neck squamous cell carcinoma: pretreatment multimodality imaging with 1H magnetic resonance spectroscopy, dynamic contrast-­enhanced MRI, and [18F] FDG-PET. Int J Radiat Oncol Biol Phys. 2012;82(1):299–307. 34. Chikui T, Kitamoto E, Kami Y, Kawano S, Kobayashi K, Kamitani T, et al. Dynamic contrast-enhanced MRI of oral squamous cell carcinoma: a preliminary study of the correlations between quantitative parameters and the clinical stage. Br J Radiol. 2015;88(1050):20140814. 35. Bernstein JM, Homer JJ, West CM.  Dynamic contrast-enhanced magnetic resonance imaging biomarkers in head and neck cancer: potential to guide treatment? A systematic review. Oral Oncol. 2014;50(10):963–70. 36. Takano JH, Yakushiji T, Kamiyama I, Nomura T, Katakura A, Takano N, et  al. Detecting early oral cancer: narrowband imaging system observation of the oral mucosa microvasculature. Int J Oral Maxillofac Surg. 2010;39:208–13. 37. Klein Nulent TJW, Noorlag R, Van Cann EM, Pameijer FA, Willems SM, Yesuratnam A, et  al. Intraoral ultrasonography to measure tumor thickness of oral cancer: a systematic review and meta-­analysis. Oral Oncol. 2018;77:29–36. 38. Ariji Y, Goto M, Fukano H. Role of intraoral color Doppler sonography in predicting delayed cervical lymph node metastasis in patients with early-stage tongue cancer: a pilot study. Oral Surg Oral Med Oral Pathol Oral Radiol. 2015;119(2):246–53. 39. Eshghyar N, Mohammadi N, Rahrotaban S, Motahhary P, VahediVaez SM. Endoglin (CD105) positive microvessel density and its relation-

11

ship with lymph node metastasis in squamous cell carcinoma of the tongue. Arch Iran Med. 2011;14:276–80. 40. Schimming R, Juengling FD, Lauer G, Altehöfer C, Schmelzeisen R. Computer-aided 3-D 99mTc-DPD-SPECT reconstruction to assess mandibular invasion by intraoral squamous cell carcinoma: diagnostic improvement or not? J Craniomaxillofac Surg. 2000; 28(6):325–30. 41. Leitha T, Glaser C, Pruckmayer M.  Technetium-99-MIBI in primary and recurrent head and neck tumours: contribution of bone SPECT image fusion. J Nucl Med. 1998;39:1166–71. 42. Kyzas PA, Evangelou E, Denaxa-Kyza D, Ioannidis JP. 18F-fluorodeoxyglucose positron emission tomography to evaluate cervical node metastases in patients with head and neck squamous cell carcinoma: a meta-analysis. J Natl Cancer Inst. 2008;100(10):712–20. 43. Krabbe CA, Balink H, Roodenburg JL, Dol J, de Visscher JG. Performance of 18F-FDG PET/contrast-enhanced CT in the staging of squamous cell carcinoma of the oral cavity and oropharynx. Int J Oral Maxillofac Surg. 2011;40(11):1263–70. 44. Krabbe CA, van der Werff-Regelink G, Pruim J, van der Wal JE, Roodenburg JNL.  Detection of cervical metastases with (11) C-tyrosine PET in patients with squamous cell carcinoma of the oral cavity or oropharynx: a comparison with (18)F-FDG PET. Head Neck. 2010;32(3):368–74. 45. Sato J, Kitagawa Y, Watanabe S, Asaka T, Ohga N, Hirata K, et  al. 18F-Fluoromisonidazole positron emission tomography (FMISO-­ PET) may reflect hypoxia and cell proliferation activity in oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol. 2017;124(3):261–70. 46. de Bondt RBJ, Nelemans PJ, Hofman PAM, Cassleman JW, Kremer B, Engelshoven JM, et al. Detection of lymph node metastasis in head and neck cancer; a meta-analysis comparing US, USgFNAC, CT and MRI imaging. Eur J Radiol. 2007;64:266–72. 47. Chaukar D, Dandekar M, Kane S, Arya S, Purandare N, Rangarajan V, et  al. Relative value of ultrasound, computed tomography and positron emission tomography imaging in the clinically node-­ negative neck in oral cancer. Asia Pac J Clin Oncol. 2016;12(2): 332–8. 48. Mancuso AA, Maceri D, Rice D, Hanafee W.  CT of cervical lymph node cancer. AJR Am J Roentgenol. 1981;136(2):381–5. 49. Pandeshwar P, Jayanthi K, Raghuram P.  Pre-operative contrast enhanced computer tomographic evaluation of cervical nodal metastatic disease in oral squamous cell carcinoma. Indian J Cancer. 2013;50:310–5. 50. Kim JW, Roh JL, Kim JS, Lee JH, Cho KJ, Choi SH, et al. Evaluation of 18F-FDG PET/CT and CT/MRI with histopathologic correlation in patients undergoing central compartment neck dissection for squamous cell carcinoma of the larynx, hypopharynx, and esophagus. Oral Oncol. 2013;49(5):449–53. 51. Rollon-Mayordomo A, Creo-Martinez T, Marin-Lapeira Y, Rodriguez-­ Ruiz JA, Infante-Cossio P. Preoperative ultrasonography for evaluation of clinically N0 neck in oral cavity carcinoma. J Craniomaxillofac Surg. 2017;45(3):420–6. 52. Gvetadze SR, Xiong P, Lv M, Li J, Hu J, Ilkaev KD, et  al. Contrast-­ enhanced ultrasound mapping of sentinel lymph nodes in oral tongue cancer  – a pilot study. Dentomaxillofac Radiol. 2017;46(3):20160345. 53. Wagner JM, Conrad RD, Cannon TY, Alleman AM.  Ultrasound-­ guided transcutaneous needle biopsy of the base of the tongue and floor of the mouth from a submental approach. J Ultrasound Med. 2016;35(5):1009–13. 54. Govers TM, Hannink G, Merkx MA, Takes RP, Rovers MM.  Sentinel node biopsy for squamous cell carcinoma of the oral cavity and oropharynx: a diagnostic meta-analysis. Oral Oncol. 2013;49(8):726–32. 55. Lo WC, Cheng PW, Wang CT.  The effect of radiotherapy on ultrasound guided fine needle aspiration biopsy and the ultrasound characteristics of neck lymph nodes in oral cancer patients after primary treatment. PLoS One. 2016;11(3):e0149346.

140

11

M. Studniarek and P. Adamska

56. Heuveling DA, van Weert S, Karagozoglu KH, de Bree R. Evaluation of the use of freehand SPECT for sentinel node biopsy in early stage oral carcinoma. Oral Oncol. 2015;51(3):287–90. 57. Alkureishi LW, Burak Z, Alvarez JA, Ballinger J, Bilde A, Britten AJ, European Association of Nuclear Medicine Oncology Committee; European Sentinel Node Biopsy Trial Committee, et al. Joint practice guidelines for radionuclide lymphoscintigraphy for sentinel node localization in oral/oropharyngeal squamous cell carcinoma. Ann Surg Oncol. 2009;16:3190–210. 58. Bluemel C, Herrmann K, Müller-Richter U. Freehand SPECT-guided sentinel lymph node biopsy in early oral squamous cell carcinoma. Head Neck. 2014;36(11):E112–6. 59. Mihaljevic AL, Rieger A, Belloni B, Hein R, Okur A, Scheidhauer K, et  al. Transferring innovative freehand SPECT to the operating room: first experiences with sentinel lymph node biopsy in malignant melanoma. Eur J Surg Oncol. 2014;40(1):42–8. 60. de Bree R, Pouw B, Heuveling DA, Castelijns JA. Fusion of freehand SPECT and ultrasound to perform ultrasound-guided fine-needle aspiration cytology of sentinel nodes in head and neck cancer. AJNR Am J Neuroradiol. 2015;36(11):2153–8. 61. Chand M, Keller DS, Devoto L, McGurk M.  Furthering precision in sentinel node navigational surgery for oral cancer: a novel triple targeting system. J Fluoresc. 2018;28(2):483–6. 62. Sieira-Gil R, Paredes P, Martí-Pagés C, Ferrer-Fuertes A, García-Díez E, Cho-Lee GY, et al. SPECT-CT and intraoperative portable gammacamera detection protocol for sentinel lymph node biopsy in oral cavity squamous cell carcinoma. J Craniomaxillofac Surg. 2015;43(10):2205–13. 63. Christensen A, Juhl K, Charabi B, Mortensen J, Kiss K, Kjær A, et al. Feasibility of real-time near-infrared fluorescence tracer imaging in sentinel node biopsy for oral cavity cancer patients. Ann Surg Oncol. 2016;23(2):565–72. 64. Chandra P, Dhake S, Shah S, Agrawal A, Purandare N, Rangarajan V. Comparison of SPECT/CT and planar lympho-scintigraphy in sentinel node biopsies of oral cavity squamous cell carcinomas. Indian J Nucl Med. 2017;32(2):98–102. 65. Tartaglione G, Stoeckli SJ, de Bree R, Schilling C, Flach GB, et  al. Sentinel node in oral cancer: the nuclear medicine aspects. A survey from the sentinel European node trial. Clin Nucl Med. 2016;41(7):534–42. 66. Stoeckli SJ, Huebner T, Huber GF, Broglie MA. Technique for reliable sentinel node biopsy in squamous cell carcinomas of the floor of mouth. Head Neck. 2016;38(9):1367–72. 67. Chung MK, Jeong HS, Son YI, So YK, Park GY, Choi JY, et al. Metabolic tumor volumes by [18F]-fluorodeoxyglucose PET/CT correlate with

occult metastasis in oral squamous cell carcinoma of the tongue. Ann Surg Oncol. 2009;16:3111–7. 68. Rusthoven KE, Koshy M, Paulino AC. The role of fuorodexyglucose positron emission tomography in cervical lymph node metastases from unknown primary tumor. Cancer. 2004;101:2642–9. 69. Rohde M, Nielsen AL, Johansen J, Sørensen JA, Nguyen N, Diaz A, et al. Head-to-head comparison of chest x-ray/head and neck MRI, chest CT/head and neck MRI, and 18 F-FDG-PET/CT for detection of distant metastases and synchronous cancer in oral, pharyngeal, and laryngeal Cancer. J Nucl Med. 2017;58(12):1919–24. 70. Xu GZ, Guan DJ, He ZY. (18)FDG-PET/CT for detecting distant metastases and second primary cancers in patients with head and neck cancer. A meta-analysis. Oral Oncol. 2011;47(7):560–5. 71. Wallowy P, Diener J, Grünwald F, Kovács AF. 18F-FDG PET for detecting metastases and synchronous primary malignancies in patients with oral and oropharyngeal cancer. Nuklearmedizin. 2009; 48(5):192–9. 72. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47. 73. O JH, Lodge MA, Wahl RL.  Practical PERCIST: a simplified guide to PET response criteria in solid tumors 1.0. Radiology. 2016;280(2):576–84. 74. Padhani AR, Liu G, Mu-Koh D, Chenevert TL, Thoeny HC, Takahara T, et al. Diffusion-weighted magnetic resonance imaging as a cancer biomarker: consensus and recommendations. Neoplasia. 2009;11(2):102–25. 75. Ingle A, Varghese T.  Three dimensional shear wave elastographic reconstruction of ablations. Conf Proc IEEE Eng Med Biol Soc. 2014;2014:2857–60. 76. Sato J, Kitagawa Y, Yamazaki Y, Hata H, Okamoto S, Shiga T, et  al. 18F-fluoromisonidazole PET uptake is correlated with hypoxia-­ inducible factor-1α expression in oral squamous cell carcinoma. J Nucl Med. 2013;54(7):1060–5. 77. Shimomura H, Sasahira T, Yamanaka Y, Kurihara M, Imai Y, Tamaki S, et  al. [18F]fluoro-2-deoxyglucose-positron emission tomography for the assessment of histopathological response after preoperative chemoradiotherapy in advanced oral squamous cell carcinoma. Int J Clin Oncol. 2015;20(2):308–16. 78. Haerle SK, Fischer DR, Schmid DT, Ahmad N, Huber GF, Buck A. 18FFET PET/CT in advanced head and neck squamous cell carcinoma: an intra-individual comparison with 18F-FDG PET/CT. Mol Imaging Biol. 2011;13(5):1036–42.

141

Potentially Malignant Disorders of the Oral Cavity Saman Warnakulasuriya 12.1

Introduction – 142

12.2

Definition and Nomenclature – 142

12.3

Prevalence – 142

12.4

Clinical Conditions – 142

12.4.1 12.4.2 12.4.3 12.4.4 12.4.5 12.4.6 12.4.7 12.4.8 12.4.9 12.4.10 12.4.11 12.4.12 12.4.13 12.4.14 12.4.15

L eukoplakia – 142 Proliferative Verrucous Leukoplakia – 143 Chronic Hyperplastic Candidosis – 144 Erythroplakia – 146 Erythroleukoplakia – 146 Oral Lichen Planus – 146 Oral Lichenoid Lesions – 147 Graft Versus Host Disease (cGVHD) – 147 Lupus Erythematosus – 148 Oral Submucous Fibrosis – 148 Exophytic Verrucous Hyperplasia – 148 Palatal Changes of Reverse Smokers – 149 Epidermolysis Bullosa – 149 Dyskeratosis Congenita – 149 Actinic Cheilitis – 149

12.5

Pathology – 150

12.5.1 12.5.2 12.5.3

 ral Epithelial Dysplasia – 150 O Historical Perspectives and Recent Advances in Grading – 152 Pathology of Submucous Fibrosis – 152

12.6

Risk Stratification – 153

12.7

Management – 154

12.8

Conclusion – 155 References – 155

© Springer Nature Switzerland AG 2020 S. Warnakulasuriya, J. S. Greenspan (eds.), Textbook of Oral Cancer, Textbooks in Contemporary Dentistry, https://doi.org/10.1007/978-3-030-32316-5_12

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Core Message

12.2 

A proportion of oral cancers stem from preexisting oral potentially malignant disorders. These are a group of disorders whose natural history is not clearly characterized but there is sufficient evidence that some may transform to cancer. The most common oral potentially malignant disorder is oral leukoplakia. Most of these conditions are asymptomatic and may be detected during a screening examination by a health professional. The clinical features vary and a diagnostic biopsy is performed to assess the grade of dysplasia. Several factors should be considered for stratification of their risk. The management includes interventions on risky life styles, surveillance of low risk lesions, and excision of lesions demonstrating higher grades of dysplasia.

12.1 

12

Introduction

Oral potentially malignant disorders, herein abbreviated to OPMD, are recognized to have an increased risk of malignancy. These conditions often precede the development of cancers of the lip and oral cavity. Their taxonomy was described in a seminal paper following an expert meeting of the WHO Collaborating Centre for Oral Cancer in 2005 [1]. Prior to 2005, the literature classified these conditions under various terms: “pre-cancer,” “precancerous/premalignant lesions and conditions,” and “intra epithelial neoplasia.” An unambiguous term – “potentially malignant disorders” – was adopted by the WHO Collaborating Centre as not all precancerous lesions and conditions will develop into oral cancer during the lifetime of a patient. The WHO expert group included several oral mucosal disorders under the umbrella term OPMD. The term embraces both precancerous lesions and conditions that were named in an earlier WHO classification [2]. Primarily, these disorders are asymptomatic in the early stages of their development. During evolution they become clinically visible and may be detected by oral health professionals on routine oral examinations or during an oral mucosal screening program (see 7 Chapter 16).

Definition and Nomenclature

The conditions that have an increased risk of developing into a malignancy and included under the term OPMD are oral leukoplakia (OL), erythroplakia, erythroleukoplakia, proliferative verrucous leukoplakia, oral submucous fibrosis (OSF), palatal lesions in reverse smokers, oral lichen planus, lupus erythematosus, and some hereditary conditions such as dyskeratosis congenita and epidermolysis bullosa. Actinic cheilitis of the lower lip is also associated with an increased risk of lip cancer. Since the publication characterizing oral potentially malignant disorders in 2007 in the past decade, new evidence has emerged that supports the inclusion of chronic hyperplastic candidosis, oral lichenoid lesions, exophytic verrucous hyperplasia, and oral lesions of graft vs host disease as potentially malignant disorders. It is proposed to reach a consensus for classifying these under OPMDs at an expert workshop of the WHO Collaborating Centre that will be held in March 2020. 12.3 

Prevalence

Based on 22 population surveys, a recent meta-analysis by Mello et al. [6] reported that the prevalence of OPMD worldwide was 4.47% (95% CI  =  2.43–7.08). The prevalence of OPMD differs between populations and males are more frequently affected by these disorders. Among the reported OPMDs the prevalence of OL was 4.11% (95% CI  =  1.98– 6.97). An earlier review reported an estimated prevalence of OL was 2.6% (95% CI 1.72–2.74%) [7]. Asian populations had a higher reported prevalence of OPMDs of 10.54% (95% CI = 4.60–18.55) and among Asians the most prevalent OPMD was oral submucous fibrosis (OSF) (4.96%; 95% CI = 2.28–8.62) [6]. 12.4 

Clinical Conditions

 

Definition Potentially malignant disorders may precede the development of a squamous cell carcinoma of the oral cavity

A description of clinical aspects of these conditions was published recently [3]. This chapter considers both clinical aspects and the pathological basis of these disorders essential to make a diagnosis of OPMDs. We provide a schematic guideline adapted from Speight et al. [4] to assess the risk of three of the commonly encountered OPMDs and then briefly outline their management. Malignant potential of these disorders were addressed in a recent review [5] and are considered in detail in 7 Chapter 13.  

12.4.1 

Leukoplakia

OL is the most common potentially malignant disorder affecting the oral cavity (. Fig. 12.1). Several definitions have been given to OL over the past few decades. The 2007 definition adopted by the WHO Collaborating Centre [1] refers to leukoplakia as “predominantly white plaques of questionable risk having excluded (other) known diseases or disorders that carry no increased risk for cancer.” Customarily the term leukoplakia was used as a clinical term to refer to any adherent white patch or a plaque (keratosis). There is now consensus that all white patches appearing in the oral cavity should not be labelled as OL.  Following the first international workshop on OL held in Malmo, Sweden, in 1983, other white patches associated with any chemical or physical causative agents are excluded under this term, allowing any arising due to  

143 Potentially Malignant Disorders of the Oral Cavity

..      Table 12.1  Clinical features of oral leukoplakia Oral features Oral leukoplakia

Clinical presentation

Persistent white patch that cannot be rubbed off Small and circumscribed area or may be an extensive lesion

Common sites

Lateral margin of the tongue or the floor of mouth In betel quid chewers: Buccal mucosa, lower retromolar region, and lower buccal grooves Gingival leukoplakia is rare but reported in the Japanese [9]

Clinical typesa

..      Fig. 12.1  An adherent white patch on the lateral margin of the tongue: homogeneous leukoplakia

Homogeneous leukoplakia

Uniformly white, flat, and thin, have a smooth surface, and may exhibit shallow cracks

Erythroleukoplakia

Mixed, white, and red (speckled) but retaining predominantly white character

Nodular leukoplakia

Small polypoid or rounded outgrowths, red or white excrescences

Verrucous leukoplakia

The surface is raised, exophytic, wrinkled, or corrugated

Symptoms

Generally asymptomatic Nonhomogeneous speckled variety: Discomfort, tingling, and sensitivity to touch, hot beverages, or spicy foods

tobacco, alcohol, or betel quid use or those that have no known cause (idiopathic) to be included under the term oral leukoplakia [8]. OL may be asymptomatic and just discovered during a visit to a dentist. Many are diagnosed around the fourth decade of life. They are more common in males [6], among the elderly [6] and are six times more common among tobacco-users than among non-users. Smoking, chewing tobacco, betel quid use, and alcohol are considered the major risk factors. The cause for some leukoplakias may remain unknown and are therefore considered idiopathic. The term leukoplakia is a provisional clinical diagnosis for a white patch having excluded any traumatic cause, having worked-out that the patch cannot be scrapped off (using the dental mirror head) and that the white color does not fade-off on stretching the tissues. Clinical features of leukoplakia are listed in . Table  12.1. There are several clinical types that could be distinguished based on the color and surface appearance (. Fig. 12.2 and 12.3). Two broad types are homogeneous and non-­homogeneous. The non-homogeneous varieties have a mixed white/red appearance, a nodular, or a corrugated surface (. Table 12.1). It is important to exclude other conditions (. Fig. 12.4 a–c) that may clinically mimic leukoplakia. Following are examples of some of the common conditions that a clinician should exclude in order to decide that a white patch could be labelled as an OL: frictional keratosis (cheek biting), linea alba buccalis, alveolar ridge keratosis, candidiasis, leukoedema, and white sponge nevus. In . Table 12.2 the complete list of conditions that should be excluded are listed with their presenting features including any investigations needed to exclude these conditions. . Figure 12.5 illustrates acute pseudomonas candidiasis that is often mistaken for OL.

..      Fig. 12.2  White and red patch on the buccal mucosa - erythroleukoplakia. (Note: lichen planus should be excluded by biopsy)

!!Warning

12.4.2 

aThe

distinction is based on surface color and morphological (thickness and texture) characteristics

 

 

 

 

 

 

Misclassification of leukoplakia and erythroplakia has contributed to a wide range of prevalence figures and transformation rates of these conditions found in the literature

Proliferative Verrucous Leukoplakia

Proliferative verrucous leukoplakia (PVL) is a distinct entity that may affect more than one site of the oral cavity. The surface characteristics have a warty, exophytic appearance (. Fig. 12.6) and  

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the condition tends to be widespread over a period of time and has a propensity to recur after excision. Gingiva, alveolar mucosa, or palate are often affected but may spread to the tongue and buccal mucosa. A set of diagnostic criteria were established by Bagan’s group. The major clinical criteria they cite include: “(A) leukoplakia lesions in more than two different oral sites, most

frequently found on the gingiva, alveolar processes and palate (B) the existence of a verrucous area (C) that the lesions have spread or engrossed during development of the disease and (D) that there had been a recurrence in a previously treated area” [10]. Following the observation that not all PVLs have a verrucous appearance, an alternative term “proliferative multifocal leukoplakia” has also been proposed for this condition [11, 12]. 12.4.3 

Chronic Hyperplastic Candidosis

Some candidal species have the ability to penetrate and colonize host tissues and Candida may preferentially infect areas of keratosis. Smoking, the main etiological factor for OL is seen to have a significant association with candida infection [13]. In the published scientific literature, candidal infection in OL lesions (referred to as candidal leukoplakia) was considered synonymous with chronic hyperplastic candidiasis (CHC). However, these two conditions are now considered histologically distinct [14–16]. CHC is therefore regarded as a separate clinical entity (. Fig. 12.7) that is caused primarily by candidal infection. In Candida-infected OL, the OL must exist as the primary lesion which is secondarily infected with Candida  

..      Fig. 12.3  Verrucous leukoplakia on the lateral margin of the tongue involving the floor of mouth

a

b

12

c

..      Fig. 12.4  Examples of conditions to exclude when diagnosing leukoplakia a frictional keratosis b linea alba buccalis c leukoedema

145 Potentially Malignant Disorders of the Oral Cavity

..      Table 12.2  Other white lesions to be excluded before considering a clinical diagnosis of oral leukoplakia Disorder

Diagnostic features

Biopsy

White sponge nevus

Noted in early life, family history, large areas involved, genital mucosa may be affected

Should not be undertaken

Frictional keratosis

History of trauma, mostly along the occlusal plane, an etiological cause apparent, mostly reversible on removing the cause

Biopsy if persistent after elimination of cause

Biting lip-commissure

Habitual cheek – Lip biting known, irregular whitish flakes with jagged out line

Biopsy not indicated

Chemical injury

Known history of a caustic damage, site of lesion corresponds to chemical injury, painful, resolves rapidly

Not indicated

Acute pseudomembranous candidiasis

The membrane can be scraped off leaving an erythematous/raw surface. Systemic disease may be found

Swab for culture Biopsy not indicated

Leukoedema

Bilateral on buccal mucosa, could be made to disappear on stretching (retracting), racial

Not indicated

Fordyce’s spots/ condition

Small, elevated, circular buff colored spots/ papules distinctly demarcated from the normal surrounding mucosa

Not indicated

Skin graft

Known history

Not indicated

Hairy leukoplakia

Bilateral tongue keratosis Positive history of HIV disease

Biopsy indicated Specific histopathology with koilocytosis; EBV demonstrable on ISH

Leukokeratosis nicotina palate (smokers’ palate)

Smoking history, grayish white palate with red spots (inflamed mucous glands)

Not indicated

EBV Epstein Barr Virus, ISH in situ hybridization

particularly in the presence of local or systemic immunosuppression. In a recent systematic review on candida infection in OL, the incidence of infection ranged between 6.8% and 100% [16]. Three of 16 studies included in this systematic review that reported malignant transformation rates of 2.5%, 6.5%, and

..      Fig. 12.5  Acute pseudomembranous candidiasis

..      Fig. 12.6  Widespread white patches on dorsal tongue: proliferative verrucous leukoplakia

28.7% of OL lesions associated with candida infection. However, the authors were of the of the view that these studies did not represent the clinical entity of chronic hyperplastic candidosis and further research is needed by careful follow up to investigate it’s malignant potential.

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..      Fig. 12.8  Erythroplakia on the posterior buccal mucosa

..      Table 12.3  Clinical features of oral erythroplakia Oral Features Oral erythroplakia

12

Clinical presentation

Persistent red patch with a bright red velvety surface Well-defined margin Surface could be granular

Common sites

Soft palate and floor of mouth

Clinical conditions to exclude [17, 18]

Erythematous candidiasis (denture-associated stomatitis) Erythema migrans Erosive and inflammatory/ infective disorders Desquamative gingivitis Discoid lupus erythematosus Erosive lichen planus Pemphigoid

Symptoms

Discomfort, pain, and sensitivity to touch, hot beverages or spicy foods.

..      Fig. 12.7  Chronic hyperplastic candidosis on dorsal tongue

Erythroplakia

12.4.4 

Erythroplakia is defined as ‘a fiery red patch that cannot be characterized clinically or pathologically as any other definable disease’ (. Fig. 12.8). Clinical presentation is outlined in . Table 12.3. Other clinically appearing red patches should be excluded to make this diagnosis [17]. A well-demarcated, solitary red patch raises the clinical suspicion of erythroplakia as other red lesions affecting the oral cavity are often more widespread [18].  

12.4.5 

 

Erythroleukoplakia

White and red lesions earlier classified as speckled leukoplakia are now referred to as erythroleukoplakia [1]. Both speckling and atrophy are characteristic features and the lining epithelium is often thinner than adjacent normal mucosa (. Fig.  12.2). The presence of an irregular margin makes it difficult to assess the extent (size) of this lesion [19]. Due to speckling and atrophy (thinning) of the epithelium, the patient may experience soreness. Erythroleukoplakia may affect buccal commissures in betel-quid chewers and some lesions could be infected with candidal hyphae.  

12.4.6 

Oral Lichen Planus

Oral lichen planus affects multiple oral sites and have a symmetrical distribution [20]. Concurrent presence of papular and itchy skin patches or a history of cutaneous lichen planus may help in the identification of a patient presenting with oral lichen planus. Several clinical sub-types have been described and the reticular form is the most commonly encountered clinical presentation (. Fig. 12.9). In . Table 12.4 the main clinical features are h ­ ighlighted. Plaque type may resemble OL but white striae may be found elsewhere in the mouth. The keratotic types of oral lichen planus are generally asymptomatic: their presence may be unknown to the patient and are often discovered at a dental examination. Ulcerative lichen planus results in oral soreness and the patients are unable to tolerate any hot or spicy food.  

 

147 Potentially Malignant Disorders of the Oral Cavity

..      Fig. 12.9  Reticular oral lichen planus on buccal mucosa

..      Fig. 12.10  Oral lichenoid lesions adjacent to amalgam restorations

12.4.7  ..      Table 12.4  Clinical features of oral lichen planus Oral features Oral lichen planus

Clinical presentation

Lace-like network of white striae Bilateral More than one clinical subtype may be present The presentation may vary from one person to another

Common sites

Buccal mucosa and lateral margins of the tongue. Rare in palate and floor of mouth.

Clinical types

Reticular, linear, annular, papular, plaque-type, atrophic, and ulcerative. Bullous lichen planus is rare. In dark skinned people, associated with pigmentation

Symptoms

Generally asymptomatic. Atrophic and ulcerative lichen planus are symptomatic and painful

Desquamative gingivitis – a form of lichen planus – presenting with red and atrophic gums affecting several sextants of gingivae should be differentiated from pemphigus or mucous membrane pemphigoid. Vulvo-vaginal gingival (VVG) variant of lichen planus [21] affects gingivae and genitalia. Based on its bilateral distribution and in the presence of the classical reticular/lace-like white striae, it is credible to make a chair-side diagnosis. In the presence of erythematous/ulcerative patches, oral lichen planus should be distinguished from lichenoid lesions, lichen sclerosus, lupus erythematosus, chronic ulcerative stomatitis, or when plaque like from OL. Oral lichen planus is a chronic disease that may last for several years to decades, with periods of remission.

Oral Lichenoid Lesions

Oral lichenoid lesions (OLL) are white and red lesions often with reticular striae sharing similar clinical features as oral lichen planus (OLP), also referred to as oral lichenoid reactions (OLR) or oral lichenoid contact lesions (OLCL). OLL/ OLR are classified into three clinical types: (1) those in close relationship to a dental restoration [22], often amalgam, (2) drug-induced lichenoid reactions, and (3) as a part of chronic graft versus host disease (cGVHD) [20]. OLL lesions are difficult to differentiate from lichen planus based on their clinical presentation alone but may have a mixed red/white appearance or white plaque-like patches [23]. OLL/OLR due to hypersensitivity would show a topographical relationship to a dental restoration (. Fig. 12.10), while oral lichen planus has a bilateral and widespread presentation. van der Meij et al. [24] followed up a case-series of OLL that were identified on specified criteria and proposed for the first time that OLL (contact reactions) may have a premalignant character. The clinical diagnosis of OLP/OLL/OLR is largely based on the synthesis between clinical history, noting the presence of a dental restoration, and performing a skin patch test when indicated [25]. It is often difficult to distinguish between OLL/ OLR and OLP and following a biopsy as the microscopic criteria to distinguish these two entities are not clear cut [26]. The evidence for the potential for malignant changes of both oral lichen planus and oral lichenoid lesions is presented in a systematic review by Fitzpatrick et al. [27]  

12.4.8 

Graft Versus Host Disease (cGVHD)

The recipients of allogenic hematopoietic stem cells or bone marrow transplantation may subsequently present with symptoms affecting many organs collectively known as GVHD. Oral lesions of GVHD are often the first presentation and a high prevalence of this manifestation is noted in the oral cavity. Many of the signs and symptoms that are found in

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oral GVHD – keratotic striations, white plaques, or erosive and ulcerative areas  – have a close clinical resemblance to oral lichen planus [28]. Recent evidence suggests that cGVHD may have premalignant potential [29]. 12.4.9 

Lupus Erythematosus

This chronic autoimmune disease has a wide spectrum of manifestations and could present as a systemic condition, as a discoid type (DLE) mainly affecting the skin or be drug induced. It is the skin type (DLE) with a typical butterfly rash across the nasal bridge that may also involve the lips and the oral cavity, but around 20% patients with systemic lupus may also manifest with oral lesions. As DLE lesions in the mouth are difficult to differentiate from oral lichen planus (. Fig. 12.11), the lupus band test  – subepithelial immunoglobulin and complement deposition – helps to confirm the condition [30]. Diffuse post inflammatory pigmentation is often encountered in DLE and could be a sign of resolution. Malignant transformation in DLE-affected subjects commonly involves the lower lip [31, 32].  

12

12.4.10 

Oral Submucous Fibrosis

Oral submucous fibrosis (OSF) is a chronic, insidious disease that affects the lamina propria of the oral mucosa by excess deposition of collagen resulting in loss of fibroelasticity. Patients with OSF primarily present with some limitation of mouth opening and the social history will reveal betel quid chewing and areca nut use that should arouse suspicion of this condition. The presence of palpable fibrous bands on the lips, buccal mucosa, and soft palate are the hallmark features of the disease (. Fig. 12.12 a,b). The early and late features were discussed in two workshop reports focused on this topic [33, 34] and are outlined in . Table 12.5. The disease severity is assessed objectively by measuring the inter-incisal opening [35]. In advanced stages due to deterioration of the oral health the quality of life is affected [36]. Most parts of the oral cavity (both the lining epithelium and the underlying mucosa) are involved in the fibrotic process and a high proportion of subjects with OSF develop oral squamous cell carcinomas.  

 

12.4.11 

Exophytic Verrucous Hyperplasia

Oral verrucous hyperplasia (OVH) was recently described among betel quid users, and in a small proportion of cases with OSF. Follow-up studies of a case series have indicated some malignant potential of this variant of OVH [37]. In a workshop report, a panel of South Asian pathologists [38] discussed this “mass type” lesion with an exophytic and verrucous phenotype originally observed in Taiwanese betel quid chewers. Further studies from India have complemented their findings [39]. Based on the clinical and histological features, the workshop report introduced a new term for this specific entity as called “exophytic oral verrucous hyperplasia.” The presence or absence of dysplasia (see 7 Section 12.5.1) in OVH was debated. However, the presence of verrucous architecture could be regarded as a dysplastic feature and these verrucous and papillary lesions should be labelled as having at least  

..      Fig. 12.11  Discoid lupus erythematosus

a

b

..      Fig 12.12  Oral submucous fibrosis. a Buccal mucosa showing blanching, pigmentation, and vertical fibrous bands in an early case b affecting the soft palate and the uvula

149 Potentially Malignant Disorders of the Oral Cavity

..      Table 12.5  Clinical features of oral submucous fibrosis Oral features Oral submucous fibrosis

Clinical presentation

Burning sensation to spicy food Loss of pigmentation Marked loss of tongue papillae Leathery mucosa Fibrous bands Limited mobility of tongue (rigidity) Shrunken or deformed uvula Limitation of mouth opening Sunken cheeks

Common sites

Whole of the oral cavity could be affected

Symptoms

Initially asymptomatic Burning sensation Oral dryness Restricted mouth opening

mild dysplasia. Whether exophytic OVH is just hyperplastic or should be considered as a dysplastic condition requires clarification and further research is needed on this entity to fully characterize its potentially malignant nature. 12.4.12 

Palatal Changes of Reverse Smokers

A 10-year follow-up study at the Tata Institute of Fundamental Research (TIFR), India, by Gupta et  al. [40] first described palatal changes in reverse smokers in several Indian cohorts. The mucosal changes described by the TIFR group included, “thickened leukoplakic plaques of palate, mucosal nodularity, excrescences around orifices of palatal (minor)mucosal glands, yellowish brown staining, erythema and ulceration” [40]. This habit is also prevalent among the people in the Caribbean Islands, in Latin America (Colombia, Panama, Venezuela), Sardinia, and among some Pacific islanders, for example, the Philippines. Reports on palatal lesions of reverse smokers similar to the Indian study are also described among elderly Filipino women [41] and from several regions in Colombia among persons with similar smoking habits [42]. Compared with leukoplakia, palatal changes in reverse smokers have a higher hazard ratio to develop malignancies.

12

subtypes may affect the oral cavity and present with intraoral and perioral bullae formation leading to secondary ulceration. The healing process may lead to severe scaring and obliteration of the oral vestibule manifesting as microstomia [43]. Over 90% of EB-affected individuals are reported to have a life-time risk of developing squamous skin cancers. In a national study conducted in the USA, 2.6% of patients diagnosed with EB developed skin cancers and one non-­ cutaneous SCC was reported on the tongue [44]. Among the different subgroups, multiple SCCs were found in recessive dystrophic EB (RDEB). A seminal review of oral squamous cell carcinomas in patients with RDEB [45] confirms the potentially malignant nature of this rare condition. However, the specific clinical presentation of an oral premalignant lesion associated with EB is not well described, suggesting chronic ulceration may lead to an increased risk of oral squamous cell carcinoma in EB. 12.4.14 

Dyskeratosis Congenita

Dyskeratosis congenita (DC) is a rare syndromic condition primarily with bone marrow failure and an increased risk of oral malignancy is reported. OL can be found in 65–80% of patients diagnosed with DC [46]. The classical triad of features of the syndrome includes leukoplakia of the dorsal tongue [47], reticular hyperpigmentation of the skin, and dystrophic nails. Being an inherited disorder, tongue leukoplakia could be detected at a young age and case reports in children under the age of 15 years and in adolescents can be found in the published literature [48]. An early description of a case report of OL was in a 10-year-old boy diagnosed with DC by Ogden [49]. DC is caused primarily by certain mutations of the DKC1 gene encoding dyskerin responsible for the function of maintaining telomeres [50]. Follow-up studies on patients diagnosed with DC have shown clear evidence of malignant transformation in these leukoplakic patches with a high frequency. 12.4.15 

Actinic Cheilitis

Actinic cheilitis (AC) is caused by excessive exposure of lips to solar ultraviolet (UV) radiation, the lower lip being more prone for solar damage. The demographic risk factors are being white male, and working in out-door occupations or leisure activities with regular exposure to solar radiation [51, 52]. AC in a chronic inflammatory condition that has a wide range of clinical features: keratosis with crusting and flaking and dry skin with a mottled appearance [53]. The area may 12.4.13  Epidermolysis Bullosa get ulcerated leading to the loss of the surface epithelium. Squamous cell carcinoma of the lip may develop in an existEpidermolysis bullosa (EB) is a blistering skin disease with ing patch of actinic cheilitis. However, evolution of SCC from an underlying epithelial fragility manifesting with vesicular-­ AC has not been studied in detail by follow-up studies except by bullous eruptions and superficial erosions of the oral mucosa. Markopoulos et al. [54] who reported 65 Greek patients with Thirty-two different subtypes of the disease are described. All AC. Close to 17% of this series developed lip cancer.

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The available evidence for the malignant transformation of actinic cheilitis is discussed in a recent systematic review [55]. Protection from direct solar radiation has shown to minimize the risk. 12.5 

Pathology

 

Leukoplakia and erythroplakia are just clinical terms and are not used as pathological diagnoses. However, having examined a biopsy taken from any of these OPMDs, the pathologist in the process of issuing their report would consider whether the histopathological features observed are compatible with a clinical diagnosis of leukoplakia or erythroplakia. Leukoplakia being a white patch will demonstrate a surface layer of keratin referred to as keratosis (if the affected site is a nonkeratinized mucosa) or hyperkeratosis (if the affected site is a keratinized mucosa) (. Fig. 12.13 and 12.14). The keratin will be of orthokeratin or parakeratin or of mixed ortho/para keratin. The hyperkeratosis that leads to this clinical manifestation is a biochemical process, and the association between this process in oral epithelium and the potential for carcinogenesis remains unknown. The presence or absence of surface keratinization, the type of keratin observed (ortho or para keratin), and the thickness of keratin are of little importance. Homogeneous leukoplakia may have an increased thickness due to the surface keratin layer and other nonhomogeneous clinical varieties will show varying degrees of increased thickness of the proliferative or surface compartments of the epithelium referred to as acanthosis. An erythroplakia generally would not show any keratosis.  

12

12.5.1 

ticularly leukoplakia or erythroplakia), it is customary to check for the presence or absence of epithelial dysplasia. This remains the gold standard in diagnostic pathology as these microscopic features observed in the epithelium offer clues as to the degree of risk. The microscopic features used for assessing and grading oral epithelial dysplasia [56–58] are listed in . Table 12.6. As a rule they could be categorized as changes to the architecture (strata) of the epithelium and cellular abnormalities that manifest as cellular atypia. There are the degrees of epithelial dysplasia that can be seen and to some extent quantified. The more prominent or numerous they are, the more severe the grade of dysplasia. Dysplasia may take a uniform pattern, show a focal distribution, or form complex discontinuous patterns. There is great variability among observers in their interpretation of the presence and the degree of severity of dysplasia. There is lack of consensus among the experts on the significance of these individual criteria. In the initial stages of development, a white patch may demonstrate simple keratosis without any dysplastic features (. Fig. 12.13). When only squamous hyperplasia or acanthosis are noted, the lesion is still considered nondysplastic (. Fig. 12.14). While the WHO grading system is used extensively in routine pathology practice, the precise combination that defines severity and weightage given to each architectural and cytologic feature for each grade is not precisely defined and to some extent is subjective. The WHO classification system of dysplasia is a three-tier grading as mild, moderate, and severe. During grading a pathologist would primarily consider the architectural features and then the cytological abnormalities (atypia). The three grades of oral epithelial dysplasia are briefly described below.

Oral Epithelial Dysplasia

During microscopic evaluation of a biopsy taken from a representative area of an oral potentially malignant disorder (par-

 

 

zz Mild Dysplasia

A grade of mild dysplasia is considered when the architectural disturbance is limited to the lower third of the epithelium, and when accompanied by minimal cytological atypia limited to mostly two such features (. Fig. 12.15).  

..      Fig. 12.13  A strip of mucosa showing simple orthokeratosis with no architectural disturbance or cellular atypia. The appearance is consistent with oral leukoplakia with no dysplasia and no inflammation is noted in the lamina propria

..      Fig. 12.14  This epithelium demonstrates acanthosis and orthokeratosis without any dysplastic features. Minimal inflammation is present

12

151 Potentially Malignant Disorders of the Oral Cavity

..      Table 12.6  Cytologic and architectural diagnostic criteria of oral epithelial dysplasia Architecture

Cytology

Irregular epithelial stratification Loss of polarity of basal cells Drop-shaped rete ridges Increased number of mitotic figures Abnormally superficial mitotic figures Premature keratinization in single cells Keratin pearls within rete ridges Loss of epithelial cell cohesion Basal cell hyperplasia∗

Abnormal variation in nuclear size (anisonucleosis) Abnormal variation in nuclear shape (nuclear pleomorphism) Abnormal variation in cell size (anisocytosis) Abnormal variation in cell shape (cellular pleomorphism) Increased nuclear-cytoplasmic ratio Atypical mitotic figures Increased number and size of nucleoli Hyperchromasia

..      Fig. 12.16  A biopsy of a red patch found on the floor of mouth showing architectural changes with bulbous rounded rete processes and mild anisonucleosis and hyperchromatism extending up to the middle third of the epithelium, consistent with moderate dysplasia

* Adapted from WHO [56], Warnakulasuriya et al. [57], Reibel et al. [58]

..      Fig. 12.15  This strip of epithelium shows normal mucosa to the right and the adjacent area to the left shows a thickly parakeratinized epithelium. Compared with the normal epithelium, the keratinized zone shows basal compartment expansion in the lower third of the epithelium and some nuclear hyperchromatism consistent with mild dysplasia. Dysplastic lesions are clonal and often have a sharply defined lateral limit as illustrated here

zz Moderate Dysplasia

The first and foremost criterion for recognizing this category would be when any architectural disturbance extends to the middle third of the epithelium (. Fig. 12.16). The pathologist would then give consideration to the degree of cytological atypia. The presence of marked atypia would favor a decision to categorize this as severe dysplasia despite not extending into the upper third of the epithelium. On the other hand. an epithelium with mild atypical features but extending to the middle third of the epithelium may qualify being graded as mild dysplasia.  

..      Fig. 12.17  An epithelium showing both architectural disturbance and marked cellular atypia extending to the upper third of the epithelium. Atypical features include marked suprapapillary atrophy, hyperchromatism, cellular and nuclear pleomorphism, and lack of intercellular cohesion. There is a marked host response with chronic inflammatory cells in the lamina propria. The features are consistent with severe epithelial dysplasia

zz Severe Dysplasia

The key feature of severe dysplasia could be regarded as any architectural disturbance extending beyond the lower two-­ thirds of the epithelium with some associated cytologic atypia. However, as noted in the previous paragraph, architectural disturbance limited to the middle third of the epithelium but with extensive cytologic atypia is upgraded from moderate to severe dysplasia (. Fig. 12.17). The microscopic changes seen in mild and moderate dysplasia would also be present in severe dysplasia but in addition there is marked pleomorphism often with abnormally large nuclei with prominent or even multiple nucleoli. Suprabasal mitoses are usually evident (. Fig. 12.18) and abnormal tripolar or star-­shaped forms may be seen. Architectural changes are severe, often with a complete loss of  

 

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>>Important Minimizing the subjectivity of grading dysplasia by at least two pathologists agreeing on the severity would help in the management of leukoplakia and erythroplakia

 istorical Perspectives and Recent H Advances in Grading

12.5.2 

..      Fig. 12.18  A high power view of a lesion with severe dysplasia showing basaloid compartment expansion, suprabasal mitosis and spontaneous apoptosis, and reduced cohesion

12

Grading of dysplasia is the most widely accepted predictor of cancer development in these lesions. Oral epithelial dysplasia can be assessed by using various systems. Smith and Pindborg [60] reported on a grading system that required evaluation of 36 histological features illustrated with photographic standards published by them. A more widely used system was adapted by the WHO in 2005 [56] and as described above uses both cytological and architectural changes in the epithelium (. Table 12.6). Based on these features, the lining epithelium of a mucosal biopsy can be classified into mild/ moderate/severe dysplasia. These grading systems have limitations due to high inter and intra observer variability that amount to low reproducibility [57]. To overcome these difficulties, a new binary diagnostic system was proposed by Kujan et al. [61]. This system used the same microscopic criteria as given in the WHO classification 2005 [56] but instead of the three dysplasia grades lesions were classified as lowrisk oral leukoplakia (no dysplasia and mild dysplasia) or as high risk oral leukoplakia (moderate/ severe dysplasia) (. Table 12.7). Those graded as high-risk lesions would show at least four architectural features and five cytologic features (. Table 12.2), whereas low-risk lesions show fewer microscopic changes in either category. According to these authors, the binary system classified a dysplastic lesion as a “highrisk” lesion that has a significantly higher chance of transformation to malignancy. The authors graded 68 leukoplakia lesions as “high risk” or “low risk” based on a protocol that combined both architectural and cytologic features shown in . Table 12.6. Of 35 lesions graded as high risk, 28 (80%) progressed to cancer, compared with 5 of 33 low-risk lesions (15%) indicating that the binary system has a good discriminatory value in predicting cancer-risk. Histological grading of epithelial dysplasia using the binary system is reproducible and also complements the WHO system. However, the moderate dysplasia grade is problematic (. Table 12.7) as these lesions may be designated under either low-risk and high-risk lesions. The recent WHO guidance recommends the use of both systems to enable future auditing of the two systems.  

 

 

..      Fig. 12.19  An epithelium with severe dysplasia showing abnormal shaped rete pegs, with subdividing and branching morphology. Supra-basal mitosis in a case of severe dysplasia

stratification and with deep abnormal keratinization. Abnormal forms of rete pegs are common and bulbous rete pegs are particularly significant in the diagnosis of severe dysplasia. Abnormally shaped rete pegs may present with lateral extensions, small branches, or budding (. Fig.  12.19) very similar to what may be seen in the earliest signs of invasion. Dysplastic changes remain somewhat controversial as to predicting transformation to carcinoma and therefore raises the question whether we should utilize the dysplasia grade as the sole evidence for effective management. But the grade of epithelial dysplasia (non, mild, moderate, severe) remains our best available cell/tissue marker at this time in assessing risks for transformation. In a recent study, by multivariate analysis of several demographic, clinical, and pathology factors, we have found that the severity of dysplasia has a significant prognostic value, for malignant transformation of OPMDs, as well as time to transformation [59].  

 

 

12.5.3 

Pathology of Submucous Fibrosis

The pathognomonic features of oral submucous fibrosis are thickening of subepithelial connective tissue, hyalinization, and deposition of collagen in the submucosa leading to avascularization of tissue (. Fig. 12.20). The epithelium becomes  

12

153 Potentially Malignant Disorders of the Oral Cavity

..      Table 12.7  Two-tier grading system compared with the WHO three-tier grading system

..      Table 12.8  Potential risk of clinical conditions included under the term OPMD

Three-tier grading

Two-tier grading

OPMD

◻ Mild dysplasia

◻ Low risk

Low risk

Leukoplakia (homogenous)

●

◻ Moderate dysplasia ◻ Severe dysplasia

◻ High risk

Erythroplakia

●

Proliferative verrucous leukoplakia

● ● ●

Oral lichen planus Oral lichenoid lesions

●

Oral submucous fibrosis

●

Discoid lupus erythematosus (DLE)

●

Epidermolysis bullosa

● ●

Dyskeratosis congenita

atrophic and in some cases may show cellular atypia. In advanced cases, the fibrosis may extend deeper to involve the muscle fibers. Infiltration by modest numbers of chronic inflammatory cells is found. 12.6 

Risk Stratification

Risk assessment is the foundation stone for the management of OPMDS, employing the latest evidence to identify those patients who have a higher likelihood of developing cancer. Risk assessment of OPMDs is complex based on lifestyle exposures to carcinogenic substances, clinical presentation, and pathology. Based on the evidence from follow-up studies and the author’s clinical experience, the grade of risk of different OPMDs is outlined in . Table 12.8. In the author’s experience malignant transformation of OPMDs is largely preventable and it is important to identify high-risk individuals and high-risk lesions. Unfortunately individual clinician’s assessment of risk is highly variable and there are no validated systems yet to predict the risk of oral cancer. The demographic and clinical variables that need consideration include age, gender, site, duration of the lesion, clinical appearance (white or red), size (greater than 200 mm2), and etiology (idiopathic or tobacco-associated) and are discussed in the next chapter. OLs that are infected with Candida  

High

●

Erythroleukoplakia (speckled leukoplakia)

Palatal lesion of reverse smokers

..      Fig. 12.20  A strip of atrophic epithelium showing orthokeratosis with no epithelial dysplasia. The underlying connective tissue shows dense deposition of collagen extending to underneath striated muscle pathognomanic of oral submucous fibrosis. The connective tissue is mildly inflamed with some narrowing of the microvasculature

Moderate

demonstrate more severe dysplastic changes, placing them at higher risk of progressing to malignancy. For lip cancer fair-skinned people who reside in tropical regions, who have had excessive and direct exposure to UV radiation, older aged males and smokers are at increased risk [55]. Adjunctive techniques that are commercially available for chair-side use (discussed in 7 Chapter 9) though are able to detect OPMDs with good accuracy [62, 63] have so far not reached sufficient sensitivity to be able to discriminate high-­ risk lesions or sufficient specificity to differentiate OPMDs from benign mucosal disorders [64–66]. Following pioneering work by Speight’s group [67] and Odell’s group [68], there is new evidence that ploidy analysis may assist in risk stratification. A ploidy analysis measures the amount of DNA present in cells harvested from a biopsy. Tissues with abnormal DNA content are termed DNA aneuploid while those with DNA content equal to normal cells are termed DNA diploid. A meta-analysis of five studies demonstrated that the presence of aneuploidy is a useful marker of malignant transformation in OPMD [69]. Ploidy analysis was also helpful to stratify the risk patients diagnosed with oral lichen planus [70]. In 2000, Rosin’s group proposed that loss of heterozygosity (LOH) may assist in developing a risk model for OL. In their retrospective and prospective studies they validated that leukoplakia lesions with 3p and/or 9p LOH had a 22.6-­fold increase in risk (P = 0.002) compared with low-risk lesions that had 3p and 9p retention. The addition of two extra LOH markers (loci on 4q/17p) further improved the risk prediction [71]. Biomarkers (presented in 7 Chapter 14) and those specifically associated with OPMDs [72], other new technolo 

 

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..      Fig. 12.21  A schematic diagram showing a guide for risk stratification for a patient diagnosed with oral leukoplakia. (Reproduced from Speight et al., with permission)

12

gies, such as genome-wide high-throughput array platforms, next generation sequencing, microendoscopy, and “Cytologyon-­a-chip” based sensors developed in a Canadian Laboratory [73] have intensified the scope for risk assessment of OPMDs and have the potential of further boosting our ability to identify high-risk lesions when applied either alone or in combination. These being mostly in the development phase have so far not reached the level of acceptance to be introduced to the routine practice. Eyecatcher

Determination of ploidy status and assessing of loss of heterozygosity in important genetic loci help in risk assessment in addition to dysplasia grading

Speight et al. [4] have graphically presented the features to be considered at each stage of evaluation that may be associated with risk. At the outset it is important to identify a patient at risk and then consider during the clinical evaluation the presenting features of a suspicious lesion, that is, leukoplakia, erythroleukoplakia, or an erythroplakia lesion. At the third level the biopsy report is taken into account to stratify risk. In . Fig. 12.21 (reproduced with permission), the factors noted at each level of assessment are given a risk profile: green, amber, or red, indicating low, medium, or high risk, respectively. Such a combined approach is essential to achieve optimal outcomes in the risk assessment of OPMDs.  

12.7 

Management

The management of any OPMD is based on eliciting a complete social history, accurate chair-side assessment of the condition, appropriate sampling of the lesion, and obtaining

a reliable pathology diagnosis. Of the OPMDs a large bulk of literature refers to the management of OL and erythroplakia. A protocol for the diagnosis and management of OL and erythroplakia is available from the European Association of Oral Medicine [74]. If OL and erythroplakia can be effectively recognized, diagnosed, and appropriately treated, a proportion of oral and oropharyngeal cancers could be prevented. The main challenge encountered in the management of OPMDs is that the natural history of these lesions remains unclear [75]. While some may remain stable for many years or even regress, few may transform to cancer. The presence of oral dysplasia significantly increases the rate of transformation to cancer and this may increase with the grade. It is therefore argued that treatment of dysplastic lesions may prevent cancer development in high-risk persons with OL.  A recent meta-analysis has provided evidence that surgical treatment of OL may reduce the risk of transformation but does not completely eliminate this risk [76]. Whether we can prevent malignancy by treating precursor lesions by surgery or chemoprevention remains a complex issue. It is one of the most important problems in oral medicine and needs further research. Currently, there is neither consistency nor standardized policy for the clinical management of OPMDs. The decision whether to treat or not to treat OPMDs with OED is best guided by evidence-based protocols available at the treating center and the experience of the clinician. Management depends upon the extent of the lesion, clinician experience, the dysplasia grading, and patient wishes/ compliance. If removing an identified life-style factor that evoked the disorder will reverse a lesion, that is considered optimal treatment. Discontinuing tobacco habits and other agents (e.g., betel quid) or moderating alcohol use are essential to achieve optimal outcomes. The managing clinician should adopt suitable protocols for treating tobacco dependence such as the 5A scheme and cross refer to counselling services in addition to the use of pharmacotherapy to help in cessation [77]. “At risk” alcohol drinkers could be identified using several questionnaires available for clinic use. These include, the Alcohol Use Disorders Identification Test (AUDIT), Alcohol Problems Questionnaire, and the Severity of Alcohol Dependence Questionnaire, and laboratory blood tests (gamma glutamyl transferase, mean cell volume) that are surrogate markers for heavy alcohol use. Counselling, the use of self-diaries, or a mobile phone app (Drinksmeter) may help in reducing the quantity and frequency of alcohol use. Leukoplakias that are reported to demonstrate candidal infection need to be treated with antifungals to clear the infection. In the author’s experience, topical application of antifungals (e.g., miconazole) is ineffective for this purpose. A systemic course of antifungal therapy (e.g., fluconazole 50 mg once daily) for a week to be repeated thrice for 3 months (a week in each month) is recommended. Patients with OPMDs may benefit by improving their diet and should be advised to take 5-a-day portions of fruits, fruit juices, and fresh yellow, green, and red vegetables.

155 Potentially Malignant Disorders of the Oral Cavity

For a persistent leukoplakia that has been already diagnosed/evaluated, management considerations include often monitoring milder cases of OED and actively treating through surgical excision those deemed to be severe. If a follow-up protocol is instituted, regular surveillance incorporating adjunctive techniques (see 7 Chapter 9) for re-­ examination may help the clinician. Timely re-biopsy is recommended if any changes are noted in the signs and symptoms. Photographic records at the first visit and during follow-up assist in surveillance. Definitive treatment for high-risk lesions is by surgical removal. As mentioned earlier, a recent systematic review concluded that surgical excision reduces malignant transformation but does not totally eliminate the risk [76]. The use of laser has been effective, but any means of removal that works for the operator is in order. The problem is one of including adequate margins to minimize chances for recurrence. The benefits of laser surgery in OL is that recurrences following treatment are far fewer compared with knife excision [78]. Extensive excisions are sometimes difficult in trying to attain biologically clear margins, as well as maintaining optimal comfort and function for the patient. While the use of adjunctive techniques to assist and identify “safe” margins may be helpful, they are not evidence-based or reliable. Their utility is based upon the reports of experienced clinicians. Medical management would be a better option for treating OL due to field changes observed beyond the margins of these lesions. However, no medical therapies have been found to be effective for treatment [79] . Although there have been extensive studies utilizing chemoprevention (see 7 Chapter 18), none have shown any clinical utility. First tried were vitamin A and retinoids (retinoic acid); the treatments have not been effective. Though there is evidence showing regression most recur after discontinuation of therapy and the trials have not been run for sufficiently long periods to assess the effects on cancer prevention. Moreover, high dosages must be used resulting in adverse side effects in most patients, such as dry skin, pruritus, rash, angular cheilitis, and an increase of serum triglycerides. The other chemotherapeutic agent that has undergone a prospective randomized trial is lycopene. Lycopene is a carotenoid, a cyclic isomer of beta-carotene and is a natural pigment synthesized by plants, predominantly accumulated in tomatoes. A Japanese group has shown that serum levels of lycopene among men with OL was significantly lower than controls [80]. A clinical trial on 58 subjects with leukoplakia when given 8 mg or 4 mg lycopene per day for 3 months showed clinical responses of 80% and 66%, respectively [81]. This study however, did not follow consort guidelines and the follow-up period was far too short. More recently, NSAIDs and molecular targets have drawn the most attention as chemoprevention agents. The ideal chemopreventive agent remains to be discovered. Oral submucous fibrosis (OSF) is a poorly understood condition and its treatment is largely empirical for early stages of the disease, without any evidence base [82], with  

 

surgery remaining the mainstay treatment for advanced cases. A scoring index based on signs and symptoms recommended at the World Workshop of Oral Medicine V may help to guide the choice of therapy [33]. Advice and support to quit betel quid (areca nut) chewing habit should be instituted at every opportunity. Many OSF patients are anemic and undernourished and multivitamin supplementation has helped to improve the mucosal health [83]. Historically, intralesional steroid injections have been tried though the method has not been tested scientifically. The basis of therapeutic intervention in OSF is to imrove the mouth opening, reducing burning symptoms and halting transformation to cancer. Zinc mouthwash (150  mg solvazinc dissolved in 10  ml of water) used once daily has been tried with some success to improve symptoms. As for OL, rigorous follow-up is needed to detect any early stages of cancer if OSF were to transform to cancer. Some attempts at chemoprevention have been reported, particularly with the use of curcumin [84], but results to date have not been confirmed by sufficiently powered Phase 3 trials [33]. Surgical excision of the fibrous bands, reconstruction with a suitable flap such as the nasolabial flap [85], and physical therapy for maintenance of elasticity following surgery have been employed for advanced disease. 12.8 

Conclusion

Since the introduction of the new nomenclature and classification of OPMDs in 2005, the concept is now well established and firmly supported by the scientific literature in the past decade. Some modifications by inclusion of new entities and updating is recommended in view of the emerging scientific evidence. The clinical characterization of each disorder is presented here to assist clinicians in accurately diagnosing these conditions. Due to a lack of sufficient follow-up studies, the natural history of OPMDs still remains unclear. New research is needed to improve the evidence-based management of OPMDs through prospective studies utilizing randomized control trials. Acknowledgement  . Figure  12.21 is reproduced with permis 

sion from Speight et  al. [4]. Elsevier license number 443270125426. I wish to thank Professor Edward Odell for kindly providing me with photomicrographs for . Figures 12.13– 12.20 for this publication and Professor Paul Speight for providing the original copy of . Figure 12.21.  

 

References 1. Warnakulasuriya S, Johnson NW, van der Waal I. Nomenclature and classification of potentially malignant disorders of the oral mucosa. J Oral Pathol Med. 2007;36:575–80. 2. WHO Collaborating Centre for Oral Precancerous Lesions. Definition of leukoplakia and related lesions: an aid to studies on oral precancer. Oral Surg Oral Med Oral Pathol. 1978;46:518–39.

12

156

12

S. Warnakulasuriya

3. Warnakulasuriya S. Clinical features and presentation of oral potentially malignant disorders. Oral Surg Oral Med Oral Pathol Oral Radiol. 2018;125(6):582–90. 4. Speight PM, Khurram SA, Kujan O. Oral potentially malignant disorders: risk of progression to malignancy. Oral Surg Oral Med Oral Pathol Oral Radiol. 2018;125(6):612–27. 5. Warnakulasuriya S, Ariyawardena A.  Malignant transformation of oral leukoplakia  – a systematic review. J Oral Pathol Med. 2016;45(3):155–66. 6. Mello FW, Miguel AFP, Dutra KL, Porporatti AL, Warnakulasuriya S, Guerra ENS, Rivero ERC.  Prevalence of oral potentially malignant disorders: a systematic review and meta-analysis. J Oral Pathol Med. 2018;47(7):633–40. 7. Petti S. Pooled estimate of world leukoplakia prevalence: a systematic review. Oral Oncol. 2003;39(8):770–80. 8. Axéll T, Pindborg JJ, Smith CJ, van der Waal I. Oral white lesions with special reference to precancerous and tobacco- related lesions: conclusions of an international symposium held in Uppsala, Sweden, May 18–21 1994. International Collaborative Group on Oral White Lesions. J Oral Pathol Med. 1996;25(2):49–54. 9. Nagao T, Warnakulasuriya S, Hasegawa S, et al. Elucidating risk factors for oral leukoplakia affecting gingivae in Japanese subjects. Transl Res Oral Oncol. 2016;1:1. 10. Cerero-Lapiedra R, Baladé-Martínez D, Moreno-López LA, Esparza-­ Gómez G, Bagán JV. Proliferative verrucous leukoplakia: a proposal for diagnostic criteria. Med Oral Patol Oral Cir Bucal. 2010;15(6): e839–45. 11. Villa A, Menon RS, Kerr AR, De Abreu Alves F, Guollo A, Ojeda D, Woo SB. Proliferative leukoplakia: proposed new clinical diagnostic criteria. Oral Dis. 2018; https://doi.org/10.1111/odi.12830. 12. Aguirre-Urizar JM. Proliferative multifocal leukoplakia better name that proliferative verrucous leukoplakia. World J Surg Oncol. 2011;9:122. 13. Dilhari A, Weerasekera MM, Siriwardhana A, et al. Candida infection in oral leukoplakia: an unperceived public health problem. Acta Odontol Scand. 2016;74(7):565–9. 14. Scardina GA, Fuca G, Ruggieri A, et  al. Oral candidiasis and oral hyperplastic candidiasis. Res J Biol Sci. 2007;2(4):408–12. 15. Shah N, Ray J, Kundu S, et  al. Surgical management of chronic hyperplastic candidiasis refractory to systemic antifungal treatment. J Lab Physicians. 2017;9(2):136–9. 16. Khilan Shukla, Ida Vun, Ivan Lov, George Laparidis, Caitlin McCamley, Anura Ariyawardana. Role of Candida infection in the malignant transformation of oral leukoplakia - A systematic review of observational studies. Translational Research in Oral Oncology. 2019; 4:1–10. 17. Reichart PA, Philipsen HP. Oral erythroplakia – a review. Oral Oncol. 2005;41:551–61. 18. Boy SC. Leukoplakia and erythroplakia of the oral mucosa – a brief overview. SADJ. 2012;67:558–60. 19. Suter VG, Morger R, Altermatt HJ, et al. Oral erythroplakia and erythroleukoplakia: red and red-white dysplastic lesions of the oral mucosa–Part 1: epidemiology, etiology, histopathology and differential diagnosis. Schweiz Monatsschr Zahnmed. 2008;118(5): 390–7. 20. Al-Hashimi I, Schifter M, Lockhart PB, et al. Oral lichen planus and oral lichenoid lesions: diagnostic and therapeutic considerations. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007;103(Suppl):S25.e1–12. 21. Pelisse M. The vulvo-vaginal-gingival syndrome. A new form of erosive lichen planus. Int J Dermatol. 1989;28(6):381–4. 22. McParland H, Warnakulasuriya S. Oral lichenoid contact lesions to mercury and dental amalgam–a review. J Biomed Biotechnol. 2012.; ID:589569; https://doi.org/10.1155/2012/589569. 23. Van der Waal I. Oral lichen planus and oral lichenoid lesions; a critical appraisal with emphasis on the diagnostic aspects. Med Oral Patol Oral Cir Bucal. 2009;14:E310–4.

24. van der Meij EH, Mast H, van der Waal I. The possible premalignant character of oral lichen planus and oral lichenoid lesions: a prospective five-year follow-up study of 192 patients. Oral Oncol. 2007;43:742–8. 25. Suter VG, Warnakulasuriya S. The role of patch testing in the management of oral lichenoid reactions. J Oral Pathol Med. 2016;45(1):48–57. 26. Thornhill MH, Sankar V, Xu XJ, Barrett AW, High AS, Odell EW, Speight PM, Farthing PM. The role of histopathological characteristics in distinguishing amalgam-associated oral lichenoid reactions and oral lichen planus. J Oral Pathol Med. 2006;35(4):233–40. 27. Fitzpatrick SG, Hirsch SA, Gordon SC. The malignant transformation of oral lichen planus and oral lichenoid lesions: a systematic review. J Am Dent Assoc. 2014;145:45–56. 28. Schubert MM, Correa ME. Oral graft-versus-host disease. Dent Clin N Am. 2008;52(1):79–109.. viii–ix 29. Mawardi H, Elad S, Correa ME, et  al. Oral epithelial dysplasia and squamous cell carcinoma following allogeneic hematopoietic stem cell transplantation: clinical presentation and treatment outcomes. Bone Marrow Transplant. 2011;46:884–91. 30. Burge SM, Frith PA, Millard PR, Wojnarowska F. The lupus band test in oral mucosa, conjunctiva and skin. Br J Dermatol. 1989;121(6): 743–52. 31. Arvanitidou IE, Nikitakis NG, Georgaki M, Papadogeorgakis N, Tzioufas A, Sklavounou A. Multiple primary squamous cell carcinomas of the lower lip and tongue arising in discoid lupus erythematosus: a case report. Oral Surg Oral Med Oral Pathol Oral Radiol. 2018;125(2):e22–30. 32. Millard LG, Barker DJ. Development of squamous cell carcinoma in chronic discoid lupus erythematosus. Clin Exp Dermatol. 1978;3(2):161–6. 33. Kerr AR, Warnakulasuriya S, Mighell AJ, Dietrich T, Nasser M, Rimal J, et al. A systematic review of medical interventions for oral submucous fibrosis and future research opportunities. Oral Dis. 2011;17(Suppl 1):42–57. 34. Zain RB, Ikeda N, Gupta PC, et  al. Oral mucosal lesions associated with betel quid, areca nut and tobacco chewing habits: consensus from a workshop held in Kuala Lumpur, Malaysia, November 25–27, 1996. J Oral Pathol Med. 1999;28(1):1–4. 35. Warnakulasuriya S.  Semi-quantitative clinical description of oral submucous fibrosis. Ann Dent. 1987;46:18–21. 36. Tadakamadla J, Kumar S, Lalloo R, et al. Impact of oral potentially malignant disorders on quality of life. J Oral Pathol Med. 2018;47(1):60–5. 37. Wu MH, Luo JD, Wang WC, Chang TH, Hwang WL, Lee KH, et al. Risk analysis of malignant potential of oral verrucous hyperplasia: a follow-up study of 269 patients and copy number variation analysis. Head Neck. 2018; https://doi.org/10.1002/hed.25076. [Epub ahead of print]. 38. Zain RB, Thomas GK, Ramanathan A, Jin K, Tillakaratne WM, Tanaaka T, Warnakulasuriya S, et al. Exophytic verrucous hyperplasia of the oral cavity – application of standardized criteria for diagnosis from a consensus report. Asian Pac J Cancer Prev. 2016;17(9):4491. 39. Patil S, Warnakulasuriya S, Raj T, Sanketh DS, Rao RS. Exophytic oral verrucous hyperplasia: a new entity. J Investig Clin Dent. 2016;7(4):417–23. 40. Gupta PC, Mehta FS, Daftary DK, Pindborg JJ, Bhonsle RB, Jalanwalla PN, et al. Incidence rates of oral cancer and natural history of oral precancerous lesions in a 10-year follow-up study of Indian villagers. Com Dent Oral Epidemiol. 1980;8:287–333. 41. Mercado-Ortiz G, Wilson D, Jiang DJ. Reverse smoking and palatal mucosal changes in Filipino women. Epidemiological features. Aust Dent J. 1996;41(5):300–3. 42. Gómez AGJ, Martínez AE, Gómez JR, Mosquera Silva Y, Núñez GAM, Agudelo GA, et al. Reverse smokers’s and changes in oral mucosa. Department of Sucre, Colombia. Med Oral Patol Oral Cir Bucal. 2008;13(1):E1–8.

157 Potentially Malignant Disorders of the Oral Cavity

43. Feijoo JF, Bugallo J, Limeres J, Peñarrocha D, Peñarrocha M, Diz P. Inherited epidermolysis bullosa: an update and suggested dental care considerations. J Am Dent Assoc. 2011;142(9):1017–25. 44. Fine JD, Johnson LB, Weiner M, Li KP, Suchindran C. Epidermolysis bullosa and the risk of life-threatening cancers: the National EB Registry experience, 1986–2006. J Am Acad Dermatol. 2009;60(2):203–11. 45. Wright JT.  Oral manifestations in the epidermolysis bullosa spectrum. Dermatol Clin. 2010;28(1):159–64. 46. Bongiorno M, Rivard S, Hammer D, Kentosh J.  Malignant transformation of oral leukoplakia in a patient with dyskeratosis congenita. Oral Surg Oral Med Oral Pathol Oral Radiol. 2017;124(4):e239–42. 47. Handley TP, Ogden GR. Dyskeratosis congenita: oral hyperkeratosis in association with lichenoid reaction. J Oral Pathol Med. 2006;35(8):508–12. 48. Noto Z, Tomihara K, Furukawa K, Noguchi M. Dyskeratosis congenita associated with leukoplakia of the tongue. Int J Oral Maxillofac Surg. 2016;45(6):760–3. 49. Ogden GR, Connor E, Chisholm DM. Dyskeratosis congenita: report of a case and review of the literature. Oral Surg Oral Med Oral Pathol. 1988;65(5):586–91. 50. Abdel-Karim A, Frezzini C, Viggor S, Davidson LE, Thornhill MH, Yeoman CM. Dyskeratosis congenita: a case report. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009;108(2):e20–4. 51. Wood NH, Khammissa R, Meyerov R, Lemmer J, Feller L. Actinic cheilitis: a case report and a review of the literature. Eur J Dent. 2011;5(1):101–6. 52. de Oliveira Ribeiro A, da Silva LC, Martins-Filho PR.  Prevalence of and risk factors for actinic cheilitis in Brazilian fishermen and women. Int J Dermatol. 2014;53(11):1370–6. 53. Jadotte YT, Schwartz RA. Solar cheilosis: an ominous precursor: Part I. Diagnostic insights. J Am Acad Dermatol. 2012;66(2):173–84. 54. Markopoulos A, Albanidou-Farmaki E, Kayavis I.  Actinic cheilitis: clinical and pathologic characteristics in 65 cases. Oral Dis. 2004;10(4):212–6. 55. Dancyger A, Heard V, Huang B, Suley C, Tang D, Ariyawardana A. Malignant transformation of actinic cheilitis: a systematic review of observational studies. J Investig Clin Dent. 2018;9(4):e12343. 56. Gale N, Pilch BZ, Sidransky D, et al. Epithelial precursor lesions. In: Barnes L, Eveson JW, Reichart PP, Sidransky D, editors. World Health Organization classification of tumours: pathology and genetics of head and neck tumours, vol. 2005. Lyon: IARC Press; 2005. p. 132. 57. Warnakulasuriya S, Reibel J, Bouquot J, Dabelsteen E. Oral epithelial dysplasia classification systems: predictive value, utility, weaknesses and scope for improvement. J Oral Pathol Med. 2008;3: 127–33. 58. Reibel J, Gale N, Hille J, et al. Oral potentially malignant disorders and oral epithelial dysplasia. In: El-Naggar AK, Chan JKC, Grandis JR, Takata T, Slootweg PPJ, editors. WHO classification of head and neck tumours. 4th ed. Lyon: IARC; 2017. p. 112–5. 59. Warnakulasuriya S, Kovacevic T, Madden P, Coupland VH, Sperandio M, Odell E, Møller H. Factors predicting malignant transformation in oral potentially malignant disorders among patients accrued over a 10-year period in South East England. J Oral Pathol Med. 2011;40(9):677–83. 60. Smith CJ, Pindborg JJ. Histological grading of oral epithelial atypia by the use ofphotographic standards. C. Hamburgers Bogtrykkeri: Copenhagen; 1969. 61. Kujan O, Oliver RJ, Khattab A, Roberts SA, Thakker N, Sloan PP. Evaluation of a new binary system of grading oral epithelial dysplasia for prediction of malignant transformation. Oral Oncol. 2006;42:987–93. 62. Rashid A, Warnakulasuriya S. The use of light-based (optical) detection systems as adjuncts in the detection of oral cancer and oral potentially malignant disorders: a systematic review. J Oral Pathol Med. 2015;44(5):307–28.

63. Awan KH, Morgan PR, Warnakulasuriya S. Assessing the accuracy of autofluorescence, chemiluminescence and toluidine blue as diagnostic tools for oral potentially malignant disorders–aclinicopathological evaluation. Clin Oral Investig. 2015;19(9):2267–72. 64. Macey R, Walsh T, Brocklehurst P, Kerr AR, Liu JL, Lingen MW, Ogden GR, Warnakulasuriya S, Scully C. Diagnostic tests for oral cancer and potentially malignant disorders in patients presenting with clinically evident lesions. Cochrane Database Syst Rev. 2015;5:CD010276. 65. Lingen MW, Tampi MP, Urquhart O, et al. Adjuncts for the evaluation of potentially malignant disorders of the oral cavity: diagnostic test accuracy systematic review and meta-analysis-a report of the American Dental Association. J Am Dent Assoc. 2017;148: 797–813. 66. Warnakulasuriya S. Diagnostic adjuncts on oral cancer and precancer: an update for practitioners. Br Dent J. 2017;223(9):663–6. 67. Torres-Rendon A, Stewart R, Craig GT, Wells M, Speight PM.  DNA ploidy analysis by image cytometry helps to identify oral epithelial dysplasias with a high risk of malignant progression. Oral Oncol. 2009;45:468–73. 68. Sperandio M, Brown AL, Lock C, Morgan PR, Coupland VH, Madden PB, Warnakulasuriya S, Møller H, Odell EW. Predictive value of dysplasia grading and DNA ploidy in malignant transformation of oral potentially malignant disorders. Cancer Prev Res (Phila). 2013;6(8):822–31. 69. Alaizari NA, Sperandio M, Odell EW, Peruzzo D, Al-Maweri SA. Metaanalysis of the predictive value of DNA aneuploidy in malignant transformation of oral potentially malignant disorders. J Oral Pathol Med. 2018;47(2):97–103. 70. Sperandio M, Klinikowski M, Brown AL, Shirlaw PJ, Challacombe SJ, Morgan PR, Warnakulasuriya S, Odell EW.  Image-based DNA ploidy analysis aids prediction of malignant transformation in oral lichen planus. Oral Surg Oral Med Oral Pathol Oral Radiol. 2016;121(6):643–50. 71. Zhang L, Poh CF, Williams M, Laronde DM, Berean K, Gardner PJ, Jiang H, Wu L, Lee JJ, Rosin MP. Loss of heterozygosity (LOH) profiles–validated risk predictors for progression to oral cancer. Cancer Prev Res (Phila). 2012;5(9):1081–9. 72. Nikitakis NG, Pentenero M, Georgaki M, Poh CF, Peterson DE, Edwards P, Lingen MSauk JJ.  Molecular markers associated with development and progression of potentially premalignant oral epithelial lesions: Current knowledge and future implications. Oral Surg Oral Med Oral Pathol Oral Radiol. 2018;125(6):650–69. 73. Abram TJ, Floriano PN, Christodoulides N, James R, Kerr AR, Thornhill MH, et  al. ‘Cytology-on-a-chip’ based sensors for monitoring of potentially malignant oral lesions. Oral Oncol. 2016;60:103–11. 74. Diz P, Gorsky M, Johnson NW, et al. Oral leukoplakia and erythroplakia: a protocol for diagnosis and management. https://www.­kcl.ac.­ uk/dentistry/about/acad/oral-leukoplakia-and-­erythroplakia.­pdf. 75. Napier SS, Speight PM. Natural history of potentially malignant oral lesions and conditions: an overview of the literature. J Oral Pathol Med. 2008;1:1–10. 76. Mehanna HM, Rattay T, Smith J, McConkey CC. Treatment and follow-­up of oral dysplasia—a systematic review and metaanalysis. Head Neck. 2009;31:1600–9. 77. Warnakulasuriya S, Sutherland G, Scully C. Tobacco, oral cancer, and treatment of dependence. Oral Oncol. 2005;41(3):244–60. 78. Monteiro L, Barbieri C, Warnakulasuriya S, Martins M, Salazar F, Pacheco JJ, Vescovi P, Meleti M.  Type of surgical treatment and recurrence of oral leukoplakia: a retrospective clinical study. Med Oral Patol Oral Cir Bucal. 2017;22(5):e520–6. 79. Lodi G, Franchini R, Warnakulasuriya S, Varoni EM, Sardella A, Kerr AR, Carrassi A, MacDonald LC, Worthington HV.  Interventions for treating oral leukoplakia to prevent oral cancer. Cochrane Database Syst Rev. 2016;7:CD001829. 80. Nagao T, Ikeda N, Warnakulasuriya S, Fukano H, Yuasa H, Yano M, Miyazaki H, Ito Y. Serum antioxidant micronutrients and the risk of oral leukoplakia among Japanese. Oral Oncol. 2000;36(5): 466–70.

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81. Singh M, Krishanappa R, Bagewadi A, Keluskar V.  Efficacy of oral lycopene in the treatment of oral leukoplakia. Oral Oncol. 2004;40(6):591–6. 82. Warnakulasuriya S, Kerr AR. Oral submucous fibrosis: a review of the current management and possible directions for novel therapies. Oral Surg Oral Med Oral Pathol Oral Radiol. 2016;122(2):232–41. 83. Maher R, Aga P, Johnson NW, Sankaranarayanan R, Warnakulasuriya S.  Evaluation of multiple micronutrient supplementation in the management of oral submucous fibrosis in Karachi, Pakistan. Nutr Cancer. 1997;27(1):41–7.

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84. Hazarey VK, Sakrikar AR, Ganvir SM.  Efficacy of curcumin in the treatment for oral submucous fibrosis – a randomized clinical trial. J Oral Maxillofac Pathol. 2015;19(2):145–52. 85. Borle RM, Nimonkar PV, Rajan R.  Extended nasolabial flaps in the management of oral submucous fibrosis. Br J Oral Maxillofac Surg. 2009;47(5):382–5.

159

Malignant Transformation of Oral Potentially Malignant Disorders Anura Ariyawardana 13.1

Introduction – 160

13.2

Leukoplakia – 160

13.2.1 13.2.2

 revalence of Malignant Transformation – 160 P Clinical Determinants of Malignant Transformation – 164

13.3

Proliferative Verrucous Leukoplakia – 169

13.4

Erythroplakia – 169

13.4.1

Prevalence of Malignant Transformation – 169

13.5

Oral Submucous Fibrosis – 169

13.5.1 13.5.2

 revalence of Malignant Transformation – 170 P Factors Affecting Malignant Transformation of OSF – 170

13.6

Oral Lichen Planus – 170

13.6.1 13.6.2

 revalence of Malignant Transformation – 171 P Factors Affecting Malignant Transformation – 173

13.7

Actinic Keratosis (Actinic Cheilitis) – 173

13.7.1 13.7.2

 revalence of Malignant Transformation – 173 P Factors Affecting Malignant Transformation – 173

13.8

Palatal Keratosis Associated with Reverse Smoking – 174

13.8.1

Prevalence of Malignant Transformation – 174

13.9

Discoid Lupus Erythematosus – 174

13.9.1

Prevalence of Malignant Transformation – 174

13.10 R  are Inherited Disorder Affecting Oral Mucosa (Dyskeratosis Congenita) – 174 13.10.1 Prevalence of Malignant Transformation – 174

13.11 Summary – 175 References – 175

© Springer Nature Switzerland AG 2020 S. Warnakulasuriya, J. S. Greenspan (eds.), Textbook of Oral Cancer, Textbooks in Contemporary Dentistry, https://doi.org/10.1007/978-3-030-32316-5_13

13

160

A. Ariyawardana

Core Message Prior to noticing any signs and symptoms of an oral squamous cell carcinoma, certain changes may be visible on the oral mucosa that are grouped under the term oral potentially malignant disorders. This concept is based on follow-up studies that have described the natural history of the disease. We present here the evidence that indicates the potentially malignant nature of these disorders.

13.1 

13

Introduction

The malignant potential of certain oral mucosal disorders has been the focus in many scientific forums. The WHO Collaborating Centre for Oral Cancer and Precancer in the UK recommended the term “Oral Potentially Malignant Disorders” (OPMD) in 2005 after considering the pitfalls of the previous terms “Oral Precancer” and “Oral Premalignancy” [1]. This new terminology denotes that not all disorders (previously referred to as lesions and conditions) that are encompassed under this common term transform into oral cancer. OPMDs include a group of heterogeneous disorders affecting oral mucosa, namely, leukoplakia, erythroplakia, erythroleukoplakia, oral submucous fibrosis, lichen planus, actinic cheilitis, palatal keratosis associated with reverse smoking, discoid lupus erythematosus, dyskeratosis congenita, and epidermolysis bullosa [1]. Although oral cancer does occur on apparently normal oral mucosa, a large proportion of oral squamous cell carcinomas do arise from potentially malignant disorders [2]. The risk (or hazard ratio) of malignant transformation may vary based on the type of OPMD [3–6], and the characteristics of the lesion including, color, location, size, gender, and presence and grade of dysplasia [7].The reported malignant transformation rates also depend upon the study population and the methodology used in those studies. Moreover, the malignant transformation rates are not reported for all the types of OPMDs, perhaps due to the rarity of some types. This chapter describes the malignant transformation of OPMDs based on the available evidence to date. 13.2 

Leukoplakia

Among several OPMDs, leukoplakia is the most common condition that we come across in clinical as well as in community settings [8, 9, 10]. Over the years, various definitions have been put forward to characterize oral leukoplakia [11– 13] and the latest states “white plaques of questionable risk having excluded (other) known diseases or disorders that carry no increased risk for cancer” [1]. Clinical characteristics of leukoplakia are well described (see 7 Chapter 12 for further details) [14]. Leukoplakia can present at any oral mucosal site and their topography is generally related to the afflicting risk factor [14]. Betel quid, areca nut, or tobacco chewers tend to develop the lesions in the gingivobuccal  

sulcus, while tobacco smokers develop lesions on the tongue, floor of the mouth, or at the commissure [15, 16]. Eyecatcher

Leukoplakia is the most common OPMD which carries varying malignant transformation rates of 0.13–34%.

Despite numerous observational studies, the natural history and prediction of malignant transformation still remain dilemmas [15, 17]. Most leukoplakias follow a benign course or regress if the risk factors are removed [17, 18]. A small proportion of lesions may undergo molecular and cellular dysplastic changes leading to oral cancer over time [17, 19]. Literature indicates an enormous variation of malignant transformation rates among various anatomical sites within the oral cavity, population to population, and from study to study. Heterogeneity of methodology used in the follow-up studies reporting malignant transformation, especially in case selection, definition, and follow-up period, has a significant impact on reported data. A recent systematic review of observational studies revealed an average malignant transformation rate of 3.5% with a wide range between 0.13% and 34.0% [6]. The rate of annual transformation is reported to be between 0.3% and 6.9% (mean 3.8% per annum) with a variable follow-up period from 2.4 to 11 years [6]. 13.2.1 

Prevalence of Malignant Transformation

Since the early 1960s, several population- and clinic-based studies were reported to document the malignant transformation rates of oral leukoplakia (. Table 13.1). Varying definitions and classification systems have been used in the studies conducted over the three decades since 1960. However, the majority of the studies conducted in the late 1990s onward have used the 1977 WHO definition and clearly defined criteria for case selection.  

!!Warning Regardless of the type of OPMD, the reported malignant transformation rates are largely depended upon the study population and the definition and the methodology used for case selection.

The following section provides evidence of malignant transformation based on follow-up studies as reported from different parts of the world. zz Sweden

The first comprehensive report on malignant transformation of oral leukoplakia was from Sweden, published in 1967. Between 1920 and 1960, Einhorn and Wersall [20] followed up 782 clinic attendees by examination or regular correspondence with patients’ physicians, who conducted oral examinations over a period of 1–44 years (mean 11.7 years). During

13

161 Malignant Transformation of Oral Potentially Malignant Disorders

..      Table 13.1  Summary data on malignant transformation of oral leukoplakia Author, country

Definition of leukoplakia used

Number of cases/ lesions followed-­up Number transformed in parenthesis

Follow-up duration – median years (range)

Annual transformation rate (ATR)

Overall malignant transformation %

Einhorn and Wersall, 1967 Stockholm, Sweden [20]

Author definition

782 (12)

11.7 (1–44)

0.3%

1.5% (in 3 years) 2.4% (in 10 years) 4.0% (in 20 years)

Pindborg et al., 1968 Copenhagen, Denmark [21]

WHO 1967

214 (8)

3.7 (0.25–9)

NA

3.73%

Roed-Petersen, 1971 Copenhagen, Denmark [22]

Not given

331 (9)

4.3

NA

2.71%

Gangadharan and Paymaster, 1971 Bombay, India [24]

WHO 1967

1411 (63)

NA

NA

4.5%

Silverman et al., 1976 Gujarat, India [25]

Not given

4762 (6)

2

NA

0.13%

Banoczy, 1977 Budapest, Hungary [39]

Author definition

670 (40)

9.8 (1–30)

NA

5.97%

Kramer et al., 1978 London, UK [34]

WHO 1978

29 (7)

4.2 (1–19)

NA

24.1%

Pogrel, 1979 Wales, UK [35]

Not given

19 (3)

9.5 (4–15)

NA

15.8%

Gupta et al., 1980 Ernakulam, India [26]

Not given

410 (9)

7 (1–10)

NA

2.19%

Gupta et al., 1980 Srikakulam, India [6]

Not given

302 (1)

7 (1–10)

NA

0.30%

Roch-berry, 1981 Cheltenham, UK [36]

Not given

117 (20)

NA

NA

17.0%

Silverman et al., 1984 California, USA [31]

Author definition

257 (45)

8.1 (0.5–39)

NA

17.5%

Lind, 1987 Oslo, Norway [39]

Axell, 1984

157 (14)

9.3

NA

8.91%

Hogewind et al., 1989 Amsterdam, the Netherlands [40]

Axell, 1984

46 (3)

2.5 (1–8)

NA

6.52%

Schepman et al., 1998 Amsterdam, the Netherlands [41]

Axell, 1984

166 (20)

2.4 (0.5–17)

2.9%

12.4%

Saito et al., 1999 Hokkaido, Japan [27]

WHO, 1978

111 (8)

4 (0.6–16)

6.9%

7.2%

Napier et al., 2003 Belfast, UK [32]

No

50 (17)

6 (1.8–13)

NA

34.0%

Holmstrup et al., 2006a Copenhagen, Denmark [23]

No

147 (7) (number of lesions =169)

5.5 (1.1–20.2)

NA

4.0%

Hsue et al., 2007 Kaohsiung, Taiwan [28]

No

423 (15)

3.5

NA

3.6%

Yen et al., 2008 Taipei, Taiwan [29]

No

615

20

NA

42.2%b (continued)

162

A. Ariyawardana

..      Table 13.1 (continued) Author, country

Definition of leukoplakia used

Number of cases/ lesions followed-­up Number transformed in parenthesis

Follow-up duration – median years (range)

Annual transformation rate (ATR)

Overall malignant transformation %

Arduino et al., 2009 Turin, Italy [43]

No

207 (15)

4.5 (1–16)

NA

7.24%

Warnakulasuriya et al., 2011 London, UK [32]

Axell, 1984 & Warnakulasuriya et al., 2007

335 (23)

9.04

NA

6.9%

Brzak et al., 2012 Zagreb, Croatia [44]

WHO, 1978; Axell, 1996

157

10

NA

0.63% (1/157)

Liu et al., 2012 Shanghai, China [30]

Warnakulasuriya et al., 2007

320

5.1 (1–20)

NA

17.8% (57/320)

Ho et al., 2012 Liverpool, UK [37]

Not given

65

5

NA

3% at two years 15% at 5 years

Adapted from Warnakulasuriya and Ariyawardana [6] cases, NA Not available bCumulative risk aNon-interventional

13

the first 3 years of follow-up, 1.3% developed carcinoma and 2.4% and 4% after 10 and 20 years, respectively. The authors were able to calculate the annual incidence of carcinoma in this group and compare with cancer rates in the general population. The annual incidence (0.3%) of oral cancer in the leukoplakia group was 50–100 times greater than the population incidence in Sweden. zz Denmark

A follow-up study in Denmark with a median follow-up period of 3.7 years reported that 8 (5 males and 3 females) out of 214 developed oral carcinoma giving a malignant transformation rate of 3.7% [21]. Of these, patients who ­presented with cancer in the first year of follow-up, all had speckled leukoplakia. In 1971, Roed-Petersen reported results of another follow-up study based on a Danish population with a median period of follow-up of 4.3  years. Nine carcinomas arose from pre-existing leukoplakias with a transformation rate at 2.7% [22]. In a further retrospective study conducted by Holmstrup and colleagues among Danish patients reported that seven lesions out of 169 leukoplakia lesions (4%) developed cancer over a mean observation period of 6.6 years (range: 1.0–17.2 years) [23].

zz India

A follow-up study was conducted at the Tata Memorial Hospital, Bombay, India, from 1941 to 1969. Sixty-three carcinomas were found in 1411 patients during the followup period amounting to a malignant transformation rate of 4.46% [24]. Silverman et al. [25] followed up 6718 industrial workers with leukoplakia in Gujarat, India. The study continued from 1967 to 1971 and 4762 (71%) were recalled after 2 years of the initial examination. The original biopsy

revealed 35 OL lesions (>Important The risk of malignant transformation varies depending on the type of OPMD, and the characteristics of the lesion including color, location, size, gender, and presence and grade of dysplasia.

13.2.2 

While there is no substantial explanation there is clear evidence that OL among older people are more likely to develop oral squamous cell carcinomas compared with younger people (. Table 13.2). This may be attributable to the duration of the lesion that has been present in the oral cavity and it can be assumed that older people have had the lesions for a longer period. Similarly it can also be argued that older people, as a result of immune dysfunction and longer exposure to related risk factors, may be more susceptible to develop cancer [46]. The cohort of leukoplakia patients followed up at a Swedish cancer hospital reported the highest incidence of malignant transformation in those aged between 70 and 89 years, with a malignant transformation rate at 6.4% (7/109 patients). In contrast, malignant transformation rate among those between the ages of 20 and 69 was less than 1% (5/673) [20]. A Hungarian study that followed up 670 patients with leukoplakia reported that the incidence of malignant transformation increases with age and the peak incidence was reported to be between 61 and 70 years [38]. A retrospective hospital-based study in the Netherlands reported on 84 patients diagnosed with oral leukoplakia followed up for a period of 1–8 years. Of the 84 patients only 46 patients were followed for 8 years due to attrition in the initial phases of the study. Three cases of malignant transformation were found and all of them were above the age of 60 years [40]. Another study in the Netherlands reported that patients with longer follow-up periods had higher rates of malignant transformation. Out of 166 patients with oral leukoplakia, an estimated 50% developed a carcinoma within 200 months [41]. These estimates should be viewed with some caution as malignant transformation is more likely to occur in the earlier years of follow-up and the rates may not always be linear.

 linical Determinants of Malignant C Transformation

Recent review papers [6, 15, 45] critically examining the natural history of OL remarked on the following key determinants of malignant transformation among affected individuals. They include age and gender, lesion location, clinical

zz Gender

Several studies have noted unequal sex distribution of malignant transformation of leukoplakia with female preponderance [22, 25, 26, 30, 31, 39, 40, 41, 43]. Contrary to this, few studies reported male predominance [35, 43] or equal distribution [21]. When collating these studies it is evident that females are at a significantly higher risk of malignant transformation of leukoplakia lesions (. Table 13.3). However, to date it is not very clear why females are more vulnerable for transformation of their leukoplakia lesions. It is important to ascertain whether this distribution is because females are followed up for more years compared to males or males may die due to various other comorbidities afflicted to tobacco habits. Further studies are required to clarify this finding.  

zz Site

Studies have shown that the anatomical sub-site affecting OL has a significant effect on malignant transformation

165 Malignant Transformation of Oral Potentially Malignant Disorders

..      Table 13.3  Malignant transformation of leukoplakia - Subgroup analysis of transformation by gender Author (year)

Follow-­up period

Malignant transformation n (%)a No

Yes

M

F

M

F

Pindborg et al., 1968 Copenhagen, Denmark [21]

3.7 (0.25–9)

128 (96.2)

78 (96.3)

5 (3.8)

3(3.7)

Roed-­Petersen, 1971 Copenhagen, Denmark [22]

4.3

188 (97.9)

131 (94.2)

4(2.1)

8 (5.8)

Silverman et al., 1976 Gujarat, India [25]

2

4682 (99.8)

65 (86.6)

5 (0.1)

10 (13.3)

Banoczy, 1977 Hungary [38]

9.8 (1–30)

484 (94.9)

146 (91.3)

26 (5.1)

14 (8.7)

Pogrel, 1979 UK [35]

9.5 (4–15)

5 (71.4)

11 (91.7)

2 (28.6)

1 (8.3)

Silverman et al., 1984 California, USA [31]

8.1 (0.5–39)

106 (84.8)

106 (80.3)

19 (15.2)

26 (19.7)

Lind,1987 Oslo, Norway [39]

9.3

94 (92.2)

49 (90.7)

8 (7.8)

6 (9.3)

Hogewind et al., 1989 Amsterdam, the Netherlands [40]

2.5 (1–8)

50 (100)

31 (91.2)

0 (0)

3 (8.8)

Schepman et al., 1998 Amsterdam, the Netherlands [41]

2.4 (0.5–17)

72 (94.7)

74 (82.2)

4 (5.3)

16 (17.7)

Napier et al., 2003 North Ireland [32]

6 (1.8–13)

14 (77.7)

19 (59.4)

4 (22.3)

13 (40.6)

Arduino, 2009 Italy [43]

4.5 (1–16)

98 (91.6)

94 (94.0)

9 (8.4)

6 (6.0)

Liu et al., 2012, Shanghai, China [30]

5.1 (1–20)

125 (86.2)

138 (78.9)

20 (13.8)

37 (21.1)

6046 (98.3)

942 (86.8)

106 (1.7)

143 (13.1)

All casesa

Adapted from Warnakulasuriya and Ariyawardana [6] Chi-Square = 364.395, p Important A biomarker may be a molecule secreted by a tumor or a specific response of the body to the presence of cancer.

181 Molecular and Signaling Pathways During Oral Carcinogenesis

14

E6 E7

Invasive carcinoma

Normal

Hyperplasia

Mild dysplasia

Moderate dysplasia

PDPN Cyclin D1 c-Fos / c-Jun p27 PCNA CENP-F LAMC2

Ki-67 Cyclin E p16 pRb ∆Np63 COX-2 HIF-1alpha

EGFR TGF-a p53 Mcm-2 p73 EZH2 hTERT

EGFR Ki-67 p53 Cathepsin L MAGE-A CD133

miR-21 DNA ploidy

miR-181b

miR-345

miR-31 miR-181b DNA ploidy LOH 3p, 9p, 8p, 11q, 13q, 17p

Correlated with dysplasia

MMP-1 / 9 Cyclin D p16 S100A7 EZH2 ALDH1

Severe dysplasia Carcinoma in situ FGFR-2 / FGF-2 pRb ∆Np63 Mcm-2 LAMC2 CD-3

c-Met PDPN Survivin SMAD4 GRP78 ABCG2

miR-345

miR-21

Correlated with malignant transformation Oral carcinogenesis

..      Fig. 14.1  An integrative oral carcinogenesis model depicting changes from a normal cell to a transformed cell indicating possible alterations in clinical, histological, and molecular changes. Several

genes/proteins could be important for the oral carcinogenesis development

14.2.1  Evading Growth Suppressors

cycle arrest at the G1 phase checkpoint, by inhibition of the complex CDK4/6  – cyclin D1. At this time, non-­ phosphorylated pRB binds and inhibits E2F family preventing the transcription of factors required for the cell cycle and for other cyclins such as cyclin E and cyclin A to act in consort [14]. This cell cycle arrest allows DNA repair mainly by the activation of the GADD45 family of genes in association with PCNA, p48/DDB2, ERCC2, and ERC3. Nevertheless, if the DNA injury is too severe, or if p53 DNA repair is not possible, apoptosis occurs. P53 is capable of inducing pro-­ apoptotic genes such as BAX, PUMA, PIG3, NOXA, TRAIL, or  PTEN and can inactivate anti-apoptotic genes such as BCL2 or SURVIVIN. In the case of successful DNA repair, the now active MDM2 promotes P53 degradation and the break

55 P53 P53, a phosphoprotein of 53 kD, is a transcription factor present in most cells with several significant functions: the regulation of gene transcription, regulation of DNA synthesis, and repair and apoptosis. It is encoded by TP53, an oncosuppressor gene located on chromosome 17 (17p13.1) [13]. In the presence of cellular stress (including DNA errors, hypoxia, oxidative damage, or exposure to radiation), P53  levels increase dramatically, initiating a cell protective response. Briefly, an increase in P53 induces transcription of CDKN1A gene encoding the P21 protein, responsible for cell

182

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of the cell cycle [14]. Hence, this protein could be considered as a guardian of the genome [13]. Alterations in P53 protein occurs in several types of tumors and in half of them by mutations in TP53. Most of the mutations are located in the DNA binding domain, impairing the P53 binding to target genes [15]. Interestingly, many of the TP53 mutations observed in head and neck carcinomas affect guanine nucleotide (G) and are caused by tobacco carcinogens [14]. Loss of P53 function can occur by other mechanisms even without any mutations of TP53 and in the presence of the normal protein, such as its upregulation by amplification or due to polymorphisms of the MDM2, leading to P53 degradation by the ubiquitin proteasome system. Infection of cells with high risk types of human papillomavirus (HPV) can also lead to P53 degradation, brought about by viral E6 protein which binds to P53 leading to ubiquitin proteasome degradation. Somatic mutations in TP53 gene with consequent and frequent P53 overexpression represent one of the most reported changes in squamous cell carcinomas of the oral cavity and found in more than 50% of cases and correspond to an early event already present in potentially malignant disorders [16–19]. Overexpression of P53 is associated with poor survival of oral squamous cell carcinomas [15, 19–21]. In addition to TP53 mutations, other early events in oral carcinogenesis include the loss of chromosome 9p, which is the locus for this gene [22]. CDKN2A is a gene located on chromosome 9p21 and encodes P16, a tumor suppressor protein that promotes cycle arrest in G1/S check-point, by binding to the complex cyclin D1/CDK4, which inactivates pRb. Loss or inactivation of this gene is frequent (by mutations, methylation, chromosome loss, or homozygous deletion) in early oral carcinogenesis. Many oral carcinomas have reduced expression of P16 and this has been correlated with a poor prognosis [22]. 55 pRb pRb protein is encoded by the RB1 gene (3q14.1-q14.2) and the loss of both alleles of this gene leads to retinoblastoma. In the normal cell, pRb is in a hypo-phosphorylated state. When a mitogenic stimulus is transmitted, the transcription of cyclins A, D, E increase dramatically leading to the phosphorylation of pRb. Now, the phosphorylated form of pRb becomes permissive with the transcription of genes involved in DNA replication and cell cycle progression [1]. RB1mutations in oral cancer are rare, but pRB protein could be inactivated by other forms such as the action by E7 from HPV [22]. 14.2.2  Enabling Replicative Immortality zz Telomerase and TERT Proteins

Other mechanisms of cell cycle persistency would involve other genes, such as telomerase and TERT proteins. Although the data on these proteins for oral cancer are not obvious yet,

the altered malignant cells could undergo alternative lengthening of telomeres (ALT), a related TERT process of telomere lengthening [22]. Tumor cells could gain the capacity to sustain proliferative signaling using mitogenic signaling pathways by producing growth factors themselves in an autocrine proliferative manner, to induce stromal tumor cells to produce mitogenic factors for tumor cells, or simply by constitutive activation of components of mitogenic pathways. In oral cancer, the most commonly affected pathways includes EGFR pathway, MAP kinases or PI3K/AKT/mTOR pathways, or even the endpoint of mitotic pathways in the nucleus as cyclins and kinases. 14.2.3  Sustaining Proliferative Signaling

55 EGFR The epidermal growth factor receptor (EGFR) is a transmembrane receptor encoded by the c-erbB proto-oncogene (located at 7p12). This glycoprotein is composed of an extracellular ligand-binding part, an intermediate trans­ membrane region, and an intracellular domain with tyrosine kinase capacity (. Fig. 14.2). When a ligand such as epidermal growth factor (EGF), transforming growth factor alpha (TGF-α), epiregulin (ER), or amphiregulin (RA) binds to EGFR, a homo- or heterodimer is formed with one or more members of the ErbB family (such as ErbB2/HER-2, ErbB3/ HER-3, or ErbB4/HER-4) leading to the phosphorylation of cytoplasmic tyrosine residues mainly at positions 992, 1068, 1086, 1148, or 1173 [23]. The activated tyrosine kinase domain induces the transduction of mitogenic and survival signals by mitogen-activated protein kinase (MAPK) pathway, phosphatidylinositol 3-kinase (PI3K)/Akt pathway, or phospholipase Cγ (PLCγ1) [24]. EGFR is involved in cell proliferation and survival not only in a normal cell but also promotes tumor growth and resistance to apoptosis, promotion of cell motility, alteration and reduction of adhesion molecules such as E-cadherin, stimulating metalloproteinases (MMP-9), or even in the process of angiogenesis by regulating VEGF [24]. EGFR overexpression has been reported in several cancers and interestingly in more than 90% of head and neck squamous cell carcinomas (HNSCC) and has been associated with aggressive disease and poor prognosis [7, 25–27]. Some studies have shown that both membranous and cytoplasmic expression of EGFR could have an adverse influence in the overall survival of patients with oral squamous cell carcinoma [28]. EGFR overexpression can be caused by several mechanisms. EGFR gene amplification has been reported in 10–30% of head and neck cancers [24]. EGFR mutations have been described with a fewer frequency (1–7%) and could include point mutations (e.g., exon 21 (L858R)), deletions in exons 2–7 that result in the EGFRv III variant, lacking the extracellular binding domain but with active constituent [29–33] and  

183 Molecular and Signaling Pathways During Oral Carcinogenesis

..      Fig. 14.2  A schematic resume of EGFR pathway is shown including the dimerization and phosphorylation of the tyrosine kinase receptor EGFR and subsequent activation of several pathways resulting in cell growth, proliferation, and survival

EGF

P

EGFR

14

Plasma membrane

P

RAS

PI3K

RAF

Akt

MAPK

mTOR

PLC

PKC

CAMK

Cell growth Survival Angiogenesis Proliferation Metabolism

by other mechanisms such as an autocrine expression with EGF and TGF-α, albeit unusual in head and neck cancers [34]. EGFR is one of the popular molecular targets for therapeutic agents against head and neck cancers due to the high overexpression rate of this receptor found in these cancers. The inhibition of this receptor can be achieved using monoclonal antibodies, tyrosine kinase inhibitors (TKIs), ligand-­ toxin conjugates, or immunoconjugates [35]. Monoclonal antibodies, such as Cetuximab, block the binding of the growth factor to the external domain of EGFR impairing the activation of the receptor. This anti-EGFR drug has shown to increase the overall survival of HNSCC patients presenting in advanced stages as part of combination therapies with radiation and chemotherapy [36]. EGFR can be inactivated also using tyrosine kinase inhibitors, small molecules which inhibit the tyrosine kinase activity of this receptor. TKIs include gefitinib, erlotinib, and lapatinib [37] (see for details 7 Chapter 27).  

Nucleus

55 c-MET Another tyrosine-protein kinase receptor that has been shown to be involved in oral cancer is the mesenchymal-­ epithelial transition factor (c-MET), a receptor for the hepatocyte growth factor (HGF) encoded by the proto-oncogene MET [38]. Mutations and gene amplifications of MET have been found in several cancers, including oral cancers [22]. c-MET has been found overexpressed in tumor cells and also in carcinoma-associated fibroblasts (CAFs) promoting cell growth, motility, and lymphangiogenesis in oral squamous cell carcinomas (OSCC) via PI3K/AKT, ERK1/2, and NF-κB pathways [38, 39]. 55 TGFβ/SMAD Pathway Signaling through TGFβ/SMAD pathway can be involved in oral tumorigenesis [40]. Transforming growth factor-β

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(TGF-β) is a receptor with inhibitory growth control regulation function [39]. This receptor can phosphorylate SMAD2 and SMAD3 proteins, and then together they can activate SMAD4 protein that will regulate the expression of target genes such as p15, p21, or p57 [22]. Interestingly, mutations have been found on SMAD2, SMAD3, and SMAD4 proteins in OSCC [22, 41]. Numerous studies showed that TGF-β/ SMAD signaling pathway is associated with tumor progression and worsening of prognosis of OSCC [41, 42]. 55 PI3K /AKT and mTOR Pathways

14

encodes a protein phosphatase with lipid and protein phosphatase activity. The AKT activation is normally turned off by PTEN gene that promotes the switch of phosphatidylinositol (3,4,5)-triphosphate (PIP-3) to PIP2. Loss of the PTEN function is reported in ~10% of head and neck cancers. This may lead to increasing levels of PIP-3, resulting in a hyperactivation of AKT and unrestricted activity of mTOR [46]. 55 RAS and MAPK Pathway

The classical cellular signal transducers include a family of proteins with ~21 kda protein with guanosine triphosPI3K/AKT/PTEN/mTOR has become a recognized impor- phate (GTP) activity known as RAS  proteins. They were tant dysregulated signaling pathway in head and neck cancer. named because they were discovered from the genome of This multiple role pathway can influence proliferation and murine leukemia virus (rat sarcoma virus) in rodent sarcocellular survival, as well as cell motility, migration, and glu- mas. Currently, three genes characterize the RAS gene famcose metabolism [43]. Several genes and proteins are involved ily: HRAS (Harvey sarcoma virus–associated oncogene), in this pathway, such as PI3K proteins, mTOR complex, AKT KRAS (Kirsten sarcoma virus), and NRAS (neuroblastoma-­ protein, and PTEN. derived sarcoma virus) [49]. The phosphatidyl inositol 3-Kinase (PI3K) is composed RAS becomes active after the phosphorylation of a tyroof the subunits p100 and p87 which works as a heterodimer sine kinases receptor (rtks) thought to result in Grb2–SOS coupled to tyrosine kinase receptors such as EGFR.  When complexes and G proteins (guanine nucleotide-binding prothe receptor is activated, p100 promotes the phosphorylation teins). Active RAS leads to the stimulation of several pathof PIP2 into PIP3. This attracts the PDK1 and phosphorylates ways, including mitogen-activated protein kinase (MAPK) by the AKT protein a serine/threonine kinase, which in turn RAF1 kinase, of both MEK1/2 or the phosphatidylinositol-­3-­ stimulates several proto-oncogenes and suppresses other kinase (RAS)/AKT, resulting in cell growth and differentiatumor oncosuppressor genes, resulting in cell proliferation tion [49]. and inhibition of apoptosis [22]. The p110 subunit is encoded RAS is commonly mutated in several cancers including by PIK3CA, on locus 3q26. Interestingly, this locus or the oral cancer, especially as point mutations. Some mutations gene have been found to be amplified or to have activating occur in codons 12, 13, or 61, and the RAS protein becomes mutations, in some head and neck cancers. AKT can also be permanently activated with a continuous cell growth. phosphorylated by activation of the mTOR complex [22]. Although mutations can appear in all three isoforms of the One of the main targets of the PI3K/AKT signaling path- RAS gene, most of them appear in HRAS (0–55%) especially way is the mammalian target of rapamycin (mTOR), a serine-­ in South Asian populations [49, 50]. Other mechanisms of threonine protein kinase that makes part of two different RAS overexpression can be related to gene amplification. protein complexes – mTOR complex 1 (rapamycin sensitive) and mTOR complex 2 with multiple actions, including cell 55 Cyclins and Mitotic Checkpoint proliferation and survival, cell motility, protein synthesis, or insulin receptors regulation (. Fig. 14.3). In the presence of Cyclins correspond to several forms of proteins divided into nutrient or oxygen stimuli or other factors such as insulin, two groups based on their function: the G1 cyclins (C, D, E), growth factors, ATP, or toxins of tobacco, mTOR becomes regulating the passage of cells through the G1 phase and their phosphorylated and activates the eukaryotic translation fac- entry into the S phase, and the mitotic cyclins (A, B) [2, 51]. tor 4E (eIF4E), the p70 ribosomal S6 kinase (p70S6 kinase), Cyclins have no phosphorylation capacity, so they work and elongation factor 2 (eEF2) that will modulate protein together with several kinases (CDK) during the passage of biosynthesis. pS6 protein is one of the targets of mTORC1 the cell cycle. The cyclin D1, encoded by CCND1 proto-­ and is inhibited by rapamycin and is used as a marker for the oncogene (11q13), is the great opener or activator of the cell mTORC1 pathway [44]. cycle. After activation, by second messengers such as proteins mTOR has been found to be overexpressed and is related from MAPK the pathway, this cyclin binds and activates prowith poor overall survival in several cancers including oral teins CDK4 and CDK6, leading to phosphorylation of pRb, cancer [45, 46]. Importantly, mTOR has been used as a driving the cell cycle from the G1 to the S-phase. Other molecular target for anticancer therapy including everoli- cyclins conduct the completion of the rest of the phases of mus, temsirolimus, and ridaforolimus [47]. Interestingly, cell cycle. Cyclin A (CCNA2 gene 4q25-q31) is required for some authors have reported on the anti-cancer effect of met- DNA synthesis during the S phase and progression through formin by inhibition of mTOR activity [48]. the G2/M transition. Cyclin E (CCNE1 gene in 19q12) is Another protein involved in this pathway is PTEN. PTEN expressed in the middle of G1 and ends at the beginning of gene (phosphatase and tensin homolog deleted on chromo- the S phase, and cyclin B1 (CCNB1 gene in 5q12) is crucial to some TEN) is a tumor suppressor gene, located at 10q23.3, that drive cells into mitosis phase.  

185 Molecular and Signaling Pathways During Oral Carcinogenesis

Growth-factor receptor

PTEN

Plasma membrane

PI3K

OH

308 H2N

P

OH

473 H2N

COOH

P

rictor

COOH

mTORC2

Akt

GβL

2481 OH H2N

P

COOH

Rapa mycin

2448

OH

H 2N

COOH

P

DEPTOR

mTORC1 GβL

DEPTOR raptor

P70S6K

mRNA translation elF4E

4EBP1

Proliferation

Cell growth ..      Fig. 14.3  Representation of the AKT/mTOR pathway from a membrane receptor activation to cell growth and proliferation. The inhibition effect of rapamycin is illustrated

CCND1 amplification and Cyclin D1 overexpression have been reported to be a frequent event in several tumors, including head and neck cancers, and are related to poor survival [20, 52–55]. Cyclin E and cyclin B1 overexpression may lead to accelerated G1/S transition or even to premature entry into mitosis, contributing to increased chromosomal instability [56] and abnormal cell proliferation. Cyclin A, E, or B1 overexpression have been found to be adverse prognostic factors in oral potentially malignant disorders and oral malignancies [51, 56–60]. Genetic instability is one of the hallmarks of cancer and is a known process for tumor development. Spindle assembly checkpoint (SAC) is one of the most important checkpoints that controls cell division and prevents genetic instability. During this phase, when errors in the attachment of chromosomes are detected, there is formation of an

inhibitory complex, called mitotic checkpoint complex (MCC), composed by mitotic checkpoint proteins such as Mad2, Bub3, or BubR1 [61]. This complex prevents the function of other proteins such as CDC20 that normally lead to activation of the anaphase-promoting complex/ cyclosome (APC/C), and the 26S proteasome degradation of securin and cyclin B, preventing premature anaphase and aneuploidy due to deregulation of chromosomal alignment and separation (. Fig.  14.4, adapted from Teixeira et  al. 2014) [61]. After normal sister chromatid separation and anaphase onset, the destruction of securin and cyclin B promotes the exit from mitosis and the beginning of interphase [61–63]. Among the proteins mentioned, CDC20 and BubR1 have been found overexpressed and related to reduced survival rates in OSCC [64, 65].  

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..      Fig. 14.4  Signaling pathway of the spindle assembly checkpoint (SAC). An inappropriate attached kinetochore activates the spindle assembly checkpoint via an association of Mad2, Bub3, BubR1, and Cdc20 [61]

55 Wingless-Related Integration Site (WNT)

14

WNT signaling pathway is an important signaling pathway composed of several proteins including WNT ligands, the protein AXIN, and APC.  During an non-activated phase a complex including AXIN, APC, and glycogen synthase kinase 3b sequesters β-catenin leading to their proteasomal degradation. By contrast, in the presence of a WNT ligand this complex is attached to the cell membrane leaving β-catenin free into cytoplasm and nucleus with the activation of several Wnt target genes, resulting in cell proliferation, tumor growth, and a stem cell phenotype [66]. Deregulation of the Wnt/β-catenin pathway lead to the carcinogenesis of many types of human cancers. Recently, other proteins were associated with this pathway including the Fat1 protein, a cadherin-like protein, and the NOCTH, a tumor suppressor gene, in oral cancer. FAT1 mutations in multiple cancer types suggests that FAT1 is a major cause of Wnt pathway activation in several human cancers. The inactivation of FAT1 by mutation has been reported to increase the Wnt signaling and tumor progression carrying an adverse prognosis in patients with head and neck cancers) [67]. 55 NOTCH NOTCH signaling is an evolutionarily conserved pathway already present in unicellular eukaryotic cells and in multicellular organisms, regulating cell proliferation, apoptosis, and differentiation. In humans, the NOTCH family is composed of four receptors (NOTCH1–4) and five ligands (JAGGED1 and 2, and DLL1, 3, and 4) [68]. The binding of the ligand to NOTCH receptor leads to the proteolytic release of the NOTCH intracellular domain (NIC) by secretases and

its translocation to the nucleus, starting the transcription of the NOTCH target genes [69]. Dysregulation of NOTCH pathway has been reported in several cancers, including non-small cell lung cancer, ovarian carcinomas, colon cancer, pancreatic cancer, osteosarcoma, T-cell acute lymphoblastic leukemia, and head and neck carcinoma [70, 71]. NOTCH-1 has been reported as the second most frequently mutated gene in head and neck carcinoma after TP53 [72]. This was reported especially in a Chinese population and was related to the use of high alcohol-­ containing beverages in China [70]. NOTCH-1 mutations were also found in oral potentially malignant disorders, suggesting a role for NOTCH  receptor in early stages of oral carcinogenesis and OSCC progression [73, 74]. Molecular therapies directed to NOTCH pathway could be interesting, such as the γ-secretase inhibitor (GSI), a pharmacological agent, which is capable of blocking NOTCH activation, preventing the in vitro growth of OSCC cells and resulting in the delay of tumorigenesis [75]. 14.2.4  Invasion and Angiogenesis

Many oral cancers show an invasive phenotype and are capable of metastasis, especially to the regional lymph nodes. Regional spread occurs in more than one-third of the cases [76]. Invasion and metastatic dissemination are sequential processes in which, with acquired capacities, tumor cells escape from their tissue of origin, enter the stroma, and travel to distant sites. As part of such acquired capabilities, tumor cells must lose their surface adhesion molecules, which bind them to their own tissue, must be capable of migrating into and through the connective tissue and must be capable of

187 Molecular and Signaling Pathways During Oral Carcinogenesis

VEGF Endothelial cell MMPs 1,2,3,9 EMMPRIN

Fibroblast

Tumour cell

Tumor cell Invasion

..      Fig. 14.5  The stimulation effect of EMMPRIN on fibroblast and endothelial cells resulting in MMP or VEGF production promoting tumor cell invasion

entering lymphatic or vascular channels to escape to other locations. A group of molecules play a key role in intercellular adhesion of keratinocytes in the oral epithelium. 55 Cadherins, Claudins, and Occludins Cadherins are a family of junctional cell-surface glycoproteins commonly represented by E-cadherin, a 120-kDa transmembrane glycoprotein encoded by the CDH1 gene located on chromosome 16q22.1. E-cadherin is also involved in the transduction of signals controlling various cellular events, including polarity, differentiation, cell growth, and cell migration [77]. Reduced expression of E-Cadherin has been found in oral cancers and was related to tumor progression, dissemination, and poor prognosis [77]. Another group of adhesion molecules belongs to tight junctions. These form intercellular junctional complexes located at the apical side of the lateral membranous surface cells and are important in maintaining cell polarity. This group of proteins includes claudins and occludins. Their deregulation has been reported in a variety of cancers, including oral squamous cell carcinomas, and is related with poor survival rates [78, 79].

Tumor cells and specially tumor microenvironment (TME) cells, such as tumor-associated fibroblasts, can produce factors that stimulate the production of collagenases such as matrix metalloproteinase (MMPs). There are several types of MMPs and related proteins such as extracellular matrix metalloproteinase inducer (EMMPRIN), which increase their expression and function or decreases such as TIMPs. EMMPRIN and MMP-9 have been related to tumor progression and invasion in oral cancers [80, 81]. 55 EMMPRIN and MMP-9 One of these molecules is the EMMPRIN, also known as CD147. It is a highly glycosylated transmembrane protein that has shown a strong capacity to induce the expression of matrix metalloproteinases. EMMPRIN also contributes to cell adhesion modulation, tumor growth, invasion, and angiogenesis. Overexpression of EMMPRIN was found in OSCC, with an autocrine and paracrine positive effect for MMP production enhancing tumor invasion and dissemination [80] (. Fig. 14.5). Matrix metalloproteinase 9 (MMP-9), also known as gelatinase-B or type IV collagenase, is a 92-kDa zinc-­dependent endopeptidase, involved in the degradation of the extracel 

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lular matrix. Overexpression of MMP-9 could promote the degradation of the basement membrane and the extracellular matrix, in particular collagen IV, contributing to tumor invasion. Overexpression of MMP-9 has been associated with the lymph node and distant metastasis in oral squamous cell carcinomas and is related to adverse overall survival [81]. Neoangiogenesis has been considered an important hallmark of tumorigenesis and tumor dissemination. Since the work of Folkman, it is well known that solid tumors cannot exceed 1–2 mm3 without the existence of a new blood supply formed from the adjacent connective tissue vessels [80, 82]. Several molecules participate in this angiogenic process, ­including vascular endothelial growth factor (VEGF) and its receptors VEGFRs [83]. 55 VEGF and VEGFRs

14

VEGF is a heparin glycoprotein produced by tumor cells, and also by peritumoral endothelial cells and inflammatory cells such as macrophages in the presence of hypoxic-­inducing factors (HIF). VEGF can increase vascular permeability, stimulate production of proteases, migration, proliferation, and differentiation of endothelial cells and capillary tube formation, increasing vascular support within tumor cells [83, 84]. The majority of solid cancers overexpress this factor and this is associated with a higher risk of recurrence, metastasis, and poor survival [83]. VEGF effects are mediated by vascular endothelial growth factor receptors (VEGFR) composed of 3 tyrosine kinase receptors including VEGFR-1 (Flt-1), VEGFR-2 (KDR / flk-­1), and VEGFR-3 (flt-4) [83–85]. VEGFR-1 and VEGFR-2 are located on the vascular endothelial cells and macrophages, while VEGFR-3 is found mostly in the endothelium of lymphatic vessels. Interestingly, all can be found in the cells of several tumors, including head and neck cancers. Each receptor could contribute differently to tumorigenesis. VEGFR-1 has been related to the infiltration of macrophages and increases in MMP-9 in lung tissues before the appearance of lung metastasis. VEGFR-2 has been related to the recruitment of hematopoietic and endothelial precursor cells from bone marrow, while VEGFR-3 is mostly involved in tumoral lymphangiogenesis, contributing to its metastatic effect [83–86]. Targeting tumoral angiogenesis is an attractive therapeutic approach. Several antibodies and selective inhibitors have been studied and validated and some are already in clinical use. Bevacizumab is a VEGF antibody approved for anti-­ angiogenic therapy for several types of cancers, while vandetanib, sorafenib, and sunitinib are tyrosine kinase inhibitors [85, 87] (see 7 Chapter 27).  

55 Podoplanin Podoplanin is a transmembrane glycoprotein encoded by the PDPN gene and was named after its discovery in kidney podocytes [88, 89]. It is a classic marker of lymphatic endothelium but not blood vessel endothelium. Some recent

reports gave visibility to this protein as a predictive marker of malignant transformation in oral leukoplakia. Podoplanin is normally not expressed in normal oral epithelium and when expressed, sometimes in cluster points, it indicates that it could be a stem cell marker, or even in a diffuse pattern it may represent a sign of an increased risk of malignant transformation. Moreover, podoplanin could promote cell motility and migration of tumor cells to the invasive front of the tumors, many times working along with metalloproteins such as MMP-9 [90–92]. As a lymphatic endothelium marker, podoplanin has been related with lymph node metastasis [93, 94]. Overexpression of podoplanin has been reported in cancers of the lung, breast, skin, larynx, uterine cervix, esophagus, germ cell tumors, as well as head and neck cancers including oral cancers and is related with poor prognosis [81, 95–98]. Interestingly, molecular therapies against PDPN have been evaluated, including antibodies against PDPN with promising results in preclinical studies [99]. Eyecatcher

Podoplanin has been recently reported to have both prognostic significance in oral cancer and heightened malignant transformation of oral leukoplakia.

14.2.5  Reprograming Cellular Energetics

and Evading Immune Destruction

Malignant cells can recruit and corrupt adjacent non-­ transformed cells and become involved in interactions that create the tumor microenvironment (TME). Such interactions modify the tumor stroma and, ultimately, promote regulation of energy availability, angiogenesis, and tumor metastasis [6, 100, 101]. Moreover, in addition to the fibroblasts, cells of tumor vasculature and lymphatics, the non-­ transformed cells include cells of the immune system, suggesting a relation between tumor cells and the immune system [6]. Proliferative tumors have also developed energy pathways responsible for sustained tumor growth and survival in adverse conditions. This is obtained essentially by glycolysis, even in an aerobic environment, a condition known as “Warburg effect” that results in lactic acid secretion in the stroma [101, 102]. To compensate the missing energetic efficiency of aerobic energy, tumor cells use glucose transporters such as GLUT1, which increase glucose transportation to the cytoplasm. In the presence of hypoxia, HIF1 and HIF2 also upregulate glycolysis. As a consequence, high concentration of lactic acid is produced, which is exported out of the cells by monocarboxylate transporters (MCTs). Deregulated expression of MCT1 and MCT4 has been reported in many cancers including oral cancers and has been correlated with poor prognosis [6, 103]. For many years there have been reports of infiltration of immune cells in the tumor microenvironment but without

189 Molecular and Signaling Pathways During Oral Carcinogenesis

any known significance. Nowadays, it is believed that cancers, such oral cancer, can avoid their identification by immune cells, escaping any host defense mechanisms. A hypothesis for this could be the related remodulation of tumor cells in order to eliminate some high immunogenic clones, a process called immunoediting. Deficiencies in the CD8+ and CD4+ T lymphocytes and NK cells had been related with increased tumor incidence [6]. Other explanations could include the capacity of tumor cells to produce immunosuppressive factors. In particular, special attention has been put on some molecules that can control the function of T-cells, programmed death protein one (PD-1) and its ligands, programmed death ligand one and two (PD-L1, PD-­L2). PD-1 and PD-L1 are immune-checkpoint proteins that primarily function to limit the effector function of T-cells in peripheral tissues during inflammatory responses and limit autoimmunity. These are considered as one of the immune evasion mechanisms for cancer. Recently, strategies to help improve the efficacy of the immune system against cancer represent an important breakthrough in cancer treatment. In humans, clinical trials with anti-programmed death (PD)-1/PD-ligand 1 (L1) monoclonal antibodies have shown objective clinical activity of these agents (e.g., nivolumab, pembrolizumab) in several malignancies, including melanoma, non-small-cell lung cancer, bladder cancer, and squamous cell head and neck cancer [104–106]. Other immune cells that could be of importance in tumor microenvironment (TME) are the tumor-associated macrophages (TAMs). In this context, macrophages contribute to tumor progression through wound-healing and tissue-repair mechanisms that allow cancerous tissues to repair damages caused by low oxygen tension and acidic pH that result from metabolic reprogramming of tumor cells and vascular abnormalities of the tumor. TAMs belong to the monocyte-­ macrophage lineage and, according to the stimulus, there are two main phenotypes of macrophages: the pro-inflammatory (anti-tumoral) M1 and the immunosuppressive (pro-­ tumoral) M2 macrophages [107]. Soluble tumor-derived factors initiate the polarization of macrophages into M2 macrophages, leading to the expression of molecules that support angiogenesis, immunosuppression, tumor growth, and metastasis. M2 macrophage phenotypes have been identified in oral cancer and were related with more aggressive tumors [108].

the high-risk HPVs. HPV-16 type is the most common genotype found in these tumors. The virus contains a circular double-stranded DNA with several areas such E6 and E7 oncogenes. These proteins, E6 and E7 can bind and inhibit two proteins p53 and pRb. In these HPV + ve tumors no mutations are found on these tumor suppressor genes, but their function is inhibited by E6 and E7 viral proteins which represent an early event in oral carcinogenesis [6]. The same is observed in the CDKN2A, the gene encoding p16, without mutations or deletions on HPV + ve cancer but overexpressed in these tumors. In the view of this, p16 overexpression in a surrogate marker of HPV-16 infection of tumor cells in oral cancers. Interestingly, genetic studies have shown that PI3K pathway genes are commonly altered in HPV + ve cancers with mutations or amplifications of the gene PIK3CA [10, 109]. Knowledge of these molecular characteristics is important in the selection of a treatment plan for patients with HPV + ve tumors as they have a more favorable prognosis than tumors that harbor TP53 mutations or p16 loss, generally HPV -ve tumors. Recent genomic analysis has identified two subgroups of HPV + ve tumors – one having a mesenchymal and immunological signature (HPV-IMU), and the other having a keratinocyte differentiation and oxidative stress genes signature (HPV-KRT) [110]. !!Warning Some of the biomarkers published in the literature are neither necessary nor sufficient for the evolution of a cancer.

14.4  Prognostic Biomarkers

The genes and proteins involved in the multiple pathways most often disrupted in oral cancer permit the possible use of such alterations as biomarkers of prognosis. We present in . Table 14.1 several genes or proteins that have been reported as usefulness prognostic biomarkers in oral cancers [108, 109, 111–115].  

14.5  Conclusion

Oral carcinogenesis is a multistep process where many biological pathways could be affected. These pathways are not always similar or common to all patients. Subgroups of head 14.3  HPV+ve Pathways for Oral Cancer and neck cancers have been identified, including patients with HPV infection (HPV + ve), tumors with aneuploidy staA new group of head and neck cancers, referred to as HPV + tus, tumors with few copy number alterations, and some ve cancers, are now identified and related with the identifica- pathways have been linked to some subclasses of tumors. tion of human papillomavirus in tumor cells. They are pres- This highlights the importance of the molecular knowledge ent in cancers located mainly in the oropharynx, especially of the biological tumoral phenotype for each patient and they in the tonsillar crypt epithelium (47%). By contrast, HPV-­ could function as biomarkers of disease, not only for early related SCC in oral cavity correspond only to 3.9% of all diagnosis but also for predicting prognosis as presented in tumors [109]. There are more than 200 genotypes of HPV, this chapter. The significant markers include p53, EGFR, p16, and some are related with tumor carcinogenesis – these are cyclin A, or Akt/mTOR pathways.

14

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L. Monteiro and S. Warnakulasuriya

..      Table 14.1  Most common protein markers reported as prognostic markers in oral cancer

14

Marker

Gene

Most important function

EGFR

EGFR

Positive regulation of cell proliferation

Ki-67

MKI67

Cell cycle, cell proliferation

Cyclin D1

CCND1

Cell cycle, cell division

Cyclin A

CCNA2

Cell cycle, cell division

Ras

RAS

Signal transduction of cell proliferation

p-mTOR

MTOR

Signal transduction of cell proliferation

Myc

MYC

Positive regulation of cell proliferation

BubR1

BUBR1

Cell cycle, cell proliferation

Cdc 20

CDC20

Cell cycle, positive regulation of cell proliferation

p53

TP53

Cell cycle, cell cycle arrest

p16

CDKN2A

Cell cycle, cell cycle arrest

p21

CDKN1A

Cell cycle, cell cycle arrest

pRB

RB1

Cell cycle, cell cycle arrest

p63

TP63

Stem cell and positive regulation of cell proliferation

CD44

CD44

Cell adhesion and stem cell marker

Cd147

BSG

Metalloproteinase inducer

E-cadherin

CDH1

Cell adhesion

β-catenin

CTNNB1

Cell adhesion

Mucin-4

MUC4

Cell adhesion

Versican

VCAN

Cell adhesion

Cortactin

CTTN

Cell motility and focal adhesion assembly

MMP-11

MMP1

Proteolysis

MMP-2

MMP2

Angiogenesis, response to hypoxia and proteolysis

MMP-9

MMP9

Proteolysis

Podoplanin

PDPN

Lymphangiogenesis

VEGF

VEGF

Angiogenesis

CD34

CD34

Angiogenesis

CD31

CD31

Angiogenesis

HMOX1

HMOX1

Angiogenesis

PTK2

PTK2

Angiogenesis

CXCL8

CXCL8

Angiogenesis, movement of cell or subcellular component

HIF-1 α

HIF1A

Angiogenesis, response to hypoxia

LSD1

LSD1

Cell differentiation and stem cell maintenance

GLUT-1

GLUT-1

Metabolism marker

SLC2A1

SLC2A1

Glucose transport

STAT3

STAT3

Transcription factor of cell proliferation

Snail

SNAI1

Transcription factor of epithelial-mesenchymal transition

Bcl-2

BCL-2

Apoptotic process

191 Molecular and Signaling Pathways During Oral Carcinogenesis

..      Table 14.1 (continued) Marker

Gene

Most important function

Bax

BAX

Apoptotic process

MAP1LC3A

MAP1LC3A

Microtubule-associated protein; autophagy

FAS

FAS

Apoptotic process

FASLG

FASLG

Apoptotic process

Aldehyde dehydrogenase 1 A1

ALDH1A1

Ethanol oxidation

S100-A2

S100-A2

S100 calcium binding protein A2; endothelial cell migration

References 1. Khan Z, Bisen PS. Oncoapoptoticsignaling and deregulated target genes in cancers: special reference to oral cancer. Biochim Biophys Acta. 2013;1836(1):123–45. 2. Hahn WC, Weinberg RA.  Rules for making human tumors cells. N Engl J Med. 2002;347:1593–603. 3. Ha PK, Benoit NE, Yochem R, Sciubba J, Zahurak M, Sidransky D, Pevsner J, Westra WH, Califano J.  A transcriptional progression model for head and neck cancer. Clin Cancer Res. 2003;9:3058–64. 4. Hanahan D, Weinberg RA.  The hallmarks of cancer. Cell. 2000;100(1):57–70. 5. Bernstein JM, Bernstein CR, West CM, Homer JJ. Molecular and celular processes underlying the hallmarks of head and neck cancer. Eur Arch Otorhinolaryngol. 2013;270(10):2585–93. 6. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74. 7. Chung CH, Parker JS, Karaca G, Wu J, Funkhouser WK, Moore D, Butterfoss D, Xiang D, Zanation A, Yin X, Shockley WW, Weissler MC, Dressler LG, Shores CG, Yarbrough WG, Perou CM. Molecular classification of head and neck squamous cell carcinomas using patterns of gene expression. Cancer Cell. 2004;5(5):489–500. 8. Smeets SJ, Brakenhoff RH, Ylstra B, van Wieringen WN, van de Wiel MA, Leemans CR, Braakhuis BJ.  Genetic classification of oral and oropharyngeal carcinomas identifies subgroups with a different prognosis. Cell Oncol. 2009;31(4):291–300. 9. Slebos RJ, Jehmlich N, Brown B, Yin Z, Chung CH, Yarbrough WG, Liebler DC.  Proteomic analysis of oropharyngeal carcinomas reveals novel HPV-associated biological pathways. Int J Cancer. 2013;132(3):568–79. 10. Cancer Genome Atlas Network. Comprehensive genomic char acterization of head and neck squamous cell carcinomas. Nature. 2015;517(7536):576–82. 11. Hermsen M, Guervós MA, Meijer G, Baak J, van Diest P, Marcos CA, Sampedro A.  New chromosomal regions with high-level amplifications in squamous cell carcinomas of the larynx and pharynx, identified by comparative genomic hybridization. J Pathol. 2001;194(2):177–82. 12. Sinevici N, O'sullivan J. Oral cancer: deregulated molecular events and their use as biomarkers. Oral Oncol. 2016;61:12–8. 13. Lane DP.  Cancer. P53, guardian of the genome. Nature. 1992;358: 15–6. 14. Partridge M, Costea DE, Huang X. The changing face of p53 in head and neck cancer. Int J Oral Maxillofac Surg. 2007;36(12):1123–38. 15. Li VD, Li KH, Li JT. TP53 mutations as potential prognostic markers for specific cancers: analysis of data from The Cancer Genome Atlas and the International Agency for Research on Cancer TP53 database. J Cancer Res Clin Oncol. 2019;145(3):625–36. 16. Oliveira LR, Ribeiro-Silva A, Costa JP, Simões AL, Matteo MA, Zucoloto S. Prognostic factors and survival analysis in a sample of oral

squamous cell carcinoma patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2008;106(5):685–95. 17. Poeta ML, Manola J, Goldwasser MA, Forastiere A, Benoit N, Califano JA, Ridge JA, Goodwin J, Kenady D, Saunders J, Westra W, Sidransky D, Koch WM. Tp53 mutations and survival in squamous-cell carcinoma of the head and neck. N Engl J Med. 2007;357:2552–61. 18. van Houten VM, Tabor MP, van den Brekel MW, Kummer JA, Denkers F, Dijkstra J, Leemans R, van der Waal I, Snow GB, Brakenhoff RH. Mutated p53 as a molecular marker for the diagnosis of head and neck cancer. J Pathol. 2002;198:476–86. 19. Warnakulasuriya S. Lack of molecular markers to predict malignant potential of oral precancer. J Pathol. 2000;190(4):407–9. 20. Lu XJD, Liu KYP, Soares RC, Thomson T, Prisman E, Wu J, Poh CF. Potential clinical implications of HPV status and expressions of p53 and cyclin D1 among oropharyngeal cancer patients. J Oral Pathol Med. 2018;47(10):945–53. 21. Monteiro LS, Diniz-Freitas M, Warnakulasuriya S, Garcia-Caballero T, Forteza J, Fraga M.  An immunohistochemical score to predict the outcome for oral squamous cell carcinoma. J Oral Pathol Med. 2018;47(4):375–81. 22. Leemans CR, Braakhuis BJ, Brakenhoff RH. The molecular biology of head and neck cancer. Nat Rev Cancer. 2011;11(1):9–22. 23. Monteiro L, Ricardo S, Delgado M, Garcez F, do Amaral B, Lopes C. Phosphorylated EGFR at tyrosine 1173 correlates with poor prognosis in oral squamous cell carcinomas. Oral Dis. 2014;20(2):178–85. 24. O-charoenrat P, Rhys-Evans PH, Archer DJ, Eccles SA. C-erbB receptors in squamous cell carcinomas of the head and neck: clinical significance and correlation with matrix metalloproteinases and vascular endothelial growth factors. Oral Oncol. 2002;38:73–80. 25. Mao L, Hong WK, Papadimitrakopoulou VA. Focus on head and neck cancer. Cancer Cell. 2004;5(4):311–6. 26. Forastiere A, Koch W, Trotti A, Sidransky D. Head and neck cancer. N Engl J Med. 2001;345(26):1890–900. 27. Grandis JR, Melhem MF, Gooding WE, Day R, Holst VA, Wagener MM, Drenning SD, Tweardy DJ. Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival. J Natl Cancer Inst. 1998;90(11):824–32. 28. Monteiro LS, Diniz-Freitas M, Garcia-Caballero T, Warnakulasuriya S, Forteza J, Fraga M.  Combined cytoplasmic and membranous EGFR and p53 overexpression is a poor prognostic marker in early stage oral squamous cell carcinoma. J Oral Pathol Med. 2012;41(7): 559–67. 29. 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;53:3579–84. 30. Loeffler-Ragg J, Witsch-Baumgartner M, Tzankov A, Hilbe W, Schwentner I, Sprinzl GM, Utermann G, Zwierzina H. Low incidence of mutations in EGFR kinase domain in Caucasian patients with head and neck squamous cell carcinoma. Eur J Cancer. 2006;42:109–11.

14

192

14

L. Monteiro and S. Warnakulasuriya

31. Temam S, Kawaguchi H, El-Naggar AK, Jelinek J, Tang H, Liu DD, Lang W, Issa JP, Lee JJ, Mao L.  Epidermal growth factor receptor copy number alterations correlate with poor clinical outcome in patients with head and neck squamous cancer. J Clin Oncol. 2007;25:2164–70. 32. Sok JC, Coppelli FM, Thomas SM, Lango MN, Xi S, Hunt JL, Freilino ML, Graner MW, Wikstrand CJ, Bigner DD, Gooding WE, Furnari FB, Grandis JR.  Mutant epidermal growth factor receptor (EGFRvIII) contributes to head and neck cancer growth and resistance to EGFR targeting. Clin Cancer Res. 2006;12:5064–73. 33. Sauer T, Guren MG, Noren T, Dueland S.  Demonstration of EGFR gene copy loss in colorectal carcinomas by fluorescence in situ hybridization (FISH): a surrogate marker for sensitivity to specific anti-EGFR therapy? Histopathology. 2005;47:560–4. 34. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2(2):127–37. 35. Sacco AG, Worden FP.  Molecularly targeted therapy for the treatment of head and neck cancer: a review of the ErbB family inhibitors. Onco Targets Ther. 2016;9:1927–43. 36. Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, Jones CU, Sur R, Raben D, Jassem J, Ove R, Kies MS, Baselga J, Youssoufian H, Amellal N, Rowinsky EK, Ang KK.  Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354:567–78. 37. Venook AP.  Epidermal growth factor receptor-targeted treatment for advanced colorectal carcinoma. Cancer. 2005;103:2435–46. 38. Gao P, Li C, Chang Z, Wang X, Xuan M. Carcinoma associated fibroblasts derived from oral squamous cell carcinoma promote lymphangiogenesis via c-Met/PI3K/AKT in vitro. Oncol Lett. 2018;15(1):331–7. 39. Sun Z, Liu Q, Ye D, Ye K, Yang Z, Li D. Role of c-Met in the progression of human oral squamous cell carcinoma and its potential as a therapeutic target. Oncol Rep. 2018;39(1):209–16. 40. Cheng CM, Shiah SG, Huang CC, Hsiao JR, Chang JY. Up-regulation of miR-455-5p by the TGF-β-SMAD signalling axis promotes the proliferation of oral squamous cancer cells by targeting UBE2B.  J Pathol. 2016;240(1):38–49. 41. Sivadas VP, George NA, Kattoor J, Kannan S.  Novel mutations and expression alterations in SMAD3/TGFBR2 genes in oral carcinoma correlate with poor prognosis. Genes Chromosomes Cancer. 2013;52(11):1042–52. 42. Hwang YS, Park KK, Chung WY. Stromal transforming growth factor-­ beta 1 is crucial for reinforcing the invasive potential of low invasive cancer. Arch Oral Biol. 2014;59(7):687–94. 43. Molinolo AA, Amornphimoltham P, Squarize CH, Castilho RM, Patel V, Gutkind JS. Dysregulated molecular networks in head and neck carcinogenesis. Oral Oncol. 2009;45(4–5):324–34. 44. Xu K, Liu P, Wei W. mTORsignaling in tumorigenesis. Biochim Biophys Acta. 2014;1846(2):638–54. 45. Marques AE, Elias ST, Porporatti AL, Castilho RM, Squarize CH, De Luca Canto G, Guerra EN. mTOR pathway protein immunoexpression as a prognostic factor for survival in head and neck cancer patients: a systematic review and meta-analysis. J Oral Pathol Med. 2016;45(5):319–28. 46. Monteiro LS, Delgado ML, Ricardo S, Garcez F, do Amaral B, Warnakulasuriya S, Lopes C.  Phosphorylated mammalian target of rapamycin is associated with na adverse outcome in oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol. 2013;115(5):638–45. 47. Simpson DR, Mell LK, Cohen EE. Targeting the PI3K/AKT/mTOR pathway in squamous cell carcinoma of the head and neck. Oral Oncol. 2015;51(4):291–8. 48. Vitale-Cross L, Molinolo AA, Martin D, Younis RH, Maruyama T, Patel V, Chen W, Schneider A, Gutkind JS. Metformin prevents the development of oral squamous cell carcinomas from carcinogen-induced premalignant lesions. Cancer Prev Res (Phila). 2012;5(4):562–73. 49. Murugan AK, Munirajan AK, Tsuchida N. Ras oncogenes in oral cancer: the past 20 years. Oral Oncol. 2012;48(5):383–92.

50. Saranath D, Chang SE, Bhoite LT, Panchal RG, Kerr IB, Mehta AR, Johnson NW, Deo MG. High frequency mutation in codons 12 and 61 of H-ras oncogene in chewingtobacco-related human oral carcinoma in India. Br J Cancer. 1991;63(4):573–8. 51. Saarilahti K, Kajanti M, Kouri M, Aaltonen LM, Franssila K, Joensuu H.  Cyclin A and Ki-67 expression as predictors for locoregional recurrence and outcome in laryngeal cancer patients treated with surgery and postoperative radiotherapy. Int J Radiat Oncol Biol Phys. 2003;57(4):986–95. 52. Hanken H, Gröbe A, Cachovan G, Smeets R, Simon R, Sauter G, Heiland M, Blessmann M.  CCND1 amplification and cyclin D1 immunohistochemical expression in head and neck squamous cell carcinomas. Clin Oral Investig. 2014;18(1):269–76. 53. Huang SF, Cheng SD, Chuang WY, Chen IH, Liao CT, Wang HM, Hsieh LL.  Cyclin D1 overexpression and poor clinical outcomes in Taiwanese oral cavity squamous cell carcinoma. World J Surg Oncol. 2012;10:40. 54. Noorlag R, van Kempen PM, Stegeman I, Koole R, van Es RJ, Willems SM. The diagnostic value of 11q13 amplification and protein expression in the detection of nodal metastasis from oral squamous cell carcinoma: a systematic review and meta-analysis. Virchows Arch. 2015;466(4):363–73. 55. Zhao Y, Yu D, Li H, Nie P, Zhu Y, Liu S, Zhu M, Fang B. Cyclin D1 overexpression is associated with poor clinicopathological outcome and survival in oral squamous cell carcinoma in Asian populations: insights from a meta-analysis. PLoS One. 2014;9(3):e93210. 56. Fraczek M, Wozniak Z, Ramsey D, Zatonski T, Krecicki T.  Clinicopathologic significance and prognostic role of cyclin E and cyclin A expression in laryngeal epithelial lesions. Acta Otolaryngol. 2008;128(3):329–34. 57. Chen HM, Yen-Ping Kuo M, Lin KH, Lin CY, Chiang CP. Expression of cyclin A is related to progression of oral squamous cell carcinoma in Taiwan. Oral Oncol. 2003;39(5):476–82. 58. Tandon R, Cunningham LL, White DK, Herford AS, Cicciu M. Overexpression of cyclin A in oral dysplasia: an international comparison and literature review. Indian J Cancer. 2014;51(4):502–5. 59. Ko MT, Su CY, Huang SC, Chen CH, Hwang CF.  Overexpression of cyclin E messenger ribonucleic acid in nasopharyngeal carcinoma correlates with poor prognosis. J Laryngol Otol. 2009;123(9):1021–6. 60. Hoffmann TK, Trellakis S, Okulicz K, Schuler P, Greve J, Arnolds J, Bergmann C, Bas M, Lang S, Lehnerdt G, Brandau S, Mattheis S, Scheckenbach K, Finn OJ, Whiteside TL, Sonkoly E. Cyclin B1 expression and p53 status in squamous cell carcinomas of the head and neck. Anticancer Res. 2011;31(10):3151–7. 61. Teixeira JH, Silva PM, Reis RM, Moura IM, Marques S, Fonseca J, Monteiro LS, Bousbaa H.  An overview of the spindle assembly checkpoint status in oral cancer. Biomed Res Int. 2014;2014:145289. 62. Musacchio A, Salmon ED.  The spindle-assembly checkpoint in space and time. Nat Rev Mol Cell Biol. 2007;8:379–93. 63. Kops GJ, Weaver BA, Cleveland DW. On the road to cancer: aneuploidy and the mitotic checkpoint. Nat Rev Cancer. 2005;5:773–85. 64. Moura IM, Delgado ML, Silva PM, Lopes CA, do Amaral JB, Monteiro LS, Bousbaa H.  High CDC20 expression is associated with poor prognosis in oral squamous cell carcinoma. J Oral Pathol Med. 2014;43(3):225–31. 65. Teixeira JH, Silva P, Faria J, Ferreira I, Duarte P, Delgado ML, Queirós O, Moreira R, Barbosa J, Lopes CA, do Amaral JB, Monteiro LS, Bousbaa H.  Clinicopathologicsignificanceof BubR1 and Mad2 overexpression in oral cancer. Oral Dis. 2015;21(6):713–20. 66. Shiah SG, Shieh YS, Chang JY. The role of WntSignaling in squamous cell carcinoma. J Dent Res. 2016;95(2):129–34. 67. Morris LG, Kaufman AM, Gong Y, Ramaswami D, Walsh LA, Turcan Ş, Eng S, Kannan K, Zou Y, Peng L, Banuchi VE, Paty P, Zeng Z, Vakiani E, Solit D, Singh B, Ganly I, Liau L, Cloughesy TC, Mischel PS, Mellinghoff IK, Chan TA.  Recurrent somatic mutation of FAT1  in multiple human cancers leads to aberrant Wnt activation. Nat Genet. 2013;45(3):253–61.

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68. Kayamori K, Katsube K, Sakamoto K, Ohyama Y, Hirai H, Yukimori A, Ohata Y, Akashi T, Saitoh M, Harada K, Harada H, Yamaguchi A.  NOTCH3 is induced in cancer-associated fibroblasts and promotes angiogenesis in oral squamous cell carcinoma. PLoS One. 2016;11(4):e0154112. 69. Hijioka H, Setoguchi T, Miyawaki A, Gao H, Ishida T, Komiya S, Nakamura N.  Upregulation of Notch pathway molecules in oral squamous cell carcinoma. Int J Oncol. 2010;36(4):817–22. 70. Yap LF, Lee D, Khairuddin A, Pairan MF, Puspita B, Siar CH, Paterson IC. The opposing roles of NOTCH signalling in head and neck cancer: a mini review. Oral Dis. 2015;21(7):850–7. 71. Song X, Xia R, Li J, Long Z, Ren H, Chen W, Mao L. Common and complex Notch1 mutations in Chinese oral squamous cell carcinoma. Clin Cancer Res. 2014;20:701–10. 72. Agrawal N, Frederick MJ, Pickering CR, Bettegowda C, Chang K, Li RJ, Fakhry C, Xie TX, Zhang J, Wang J, Zhang N, El-Naggar AK, Jasser SA, Weinstein JN, Treviño L, Drummond JA, Muzny DM, Wu Y, Wood LD, Hruban RH, Westra WH, Koch WM, Califano JA, Gibbs RA, Sidransky D, Vogelstein B, Velculescu VE, Papadopoulos N, Wheeler DA, Kinzler KW, Myers JN. Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science. 2011;333(6046):1154–7. 73. Izumchenko E, Sun K, Jones S, Brait M, Agrawal N, Koch W, McCord CL, Riley DR, Angiuoli SV, Velculescu VE, Jiang WW, Sidransky D. Notch1 mutations are drivers of oral tumorigenesis. Cancer Prev Res (Phila). 2015;8:277–86. 74. Yoshida R, Nagata M, Nakayama H, Niimori-Kita K, Hassan W, Tanaka T, Shinohara M, Ito T. The pathological significance of Notch1 in oral squamous cell carcinoma. Lab Investig. 2013;93(10):1068–81. 75. Zhang JP, Qin HY, Wang L, Liang L, Zhao XC, Cai WX, Wei YN, Wang CM, Han H. Overexpression of Notch ligand Dll1 in B16 melanoma cells leads to reduced tumor growth due to attenuated vascularization. Cancer Lett. 2011;309:220–7. 76. Monteiro LS, Amaral JB, Vizcaíno JR, Lopes CA, Torres FO. A clinical-­ pathological and survival study of oral squamous cell carcinomas from a population of the North of Portugal. Med Oral Patol Oral Cir Bucal. 2014;19(2):e120–6. 77. Diniz-Freitas M, García-Caballero T, Antúnez-López J, Gándara-Rey JM, García-García A. Reduced E-cadherin expression is an indicator of unfavourable prognosis in oral squamous cell carcinoma. Oral Oncol. 2006;42(2):190–200. 78. DE Vicente JC, Fernández-Valle Á, Vivanco-Allende B, Santamarta TR, Lequerica-Fernández P, Hernández-Vallejo G, Allonca-Campa E. The prognostic role of claudins −1 and −4 in oral squamous cell carcinoma. Anticancer Res. 2015;35(5):2949–59. 79. Lourenço SV, Coutinho-Camillo CM, Buim ME, Pereira CM, Carvalho AL, Kowalski LP, Soares FA. Oral squamous cell carcinoma: status of tight junction claudins in the different histopathological patterns and relationship with clinical parameters. A tissue-microarray-­ based study of 136 cases. J Clin Pathol. 2010;63(7):609–14. 80. Monteiro LS, Delgado ML, Ricardo S, Garcez F, do Amaral B, Pacheco JJ, Lopes C, Bousbaa H. EMMPRIN expression in oral squamous cell carcinomas: correlation with tumor proliferation and patient survival. Biomed Res Int. 2014;2014:905680. 81. Monteiro LS, Delgado ML, Ricardo S, do Amaral B, Salazar F, Pacheco JJ, Lopes CA, Bousbaa H, Warnakulasuryia S. Prognostic significance of CD44v6, p63, podoplanin and MMP-9 in oral squamous cell carcinomas. Oral Dis. 2016;22(4):303–12. 82. Folkman J. Tumor angiogenesis. Therapeutic implications. N Engl J Med. 1971;285:1182–6. 83. Zang J, Li C, Zhao LN, Shi M, Zhou YC, Wang JH, Li X.  Prognostic value of vascular endothelial growth factor in patients with head and neck cancer: a meta-analysis. Head Neck. 2013;35(10):1507–14. 84. Neuchrist C, Erovic BM, Handisurya A, Steiner GE, Rockwell P, Gedlicka C, Burian M. Vascular endothelial growth factor receptor 2 (VEGFR2) expression in squamous cell carcinomas of the head and neck. Laryngoscope. 2001;111(10):1834–41.

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85. Vassilakopoulou M, Psyrri A, Argiris A.  Targeting angiogenesis in head and neck cancer. Oral Oncol. 2015;51(5):409–15. 86. Hiratsuka S, Nakamura K, Iwai S, Murakami M, Itoh T, Kijima H, Shipley JM, Senior RM, Shibuya M.  MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. Cancer Cell. 2002;2(4):289–300. 87. Hsu HW, Wall NR, Hsueh CT, Kim S, Ferris RL, Chen CS, Mirshahidi S. Combination antiangiogenic therapy and radiation in head and neck cancers. Oral Oncol. 2014;50(1):19–26. 88. Preuss SF, Anagiotos A, Seuthe IM, Drebber U, Wedemeyer I, Kreppel M, Semrau R, Eslick GD, Klussmann JP, Huebbers CU. Expression of podoplanin and prognosis in oropharyngeal cancer. Eur Arch Otorhinolaryngol. 2015;272(7):1749–54. 89. Kahn HJ, Marks A.  A new monoclonal antibody, D2-40, for detection of lymphatic invasion in primary tumors. Lab Investig. 2002;82(9):1255–7. 90. Ochoa-Alvarez JA, Krishnan H, Pastorino JG, Nevel E, Kephart D, Lee JJ, Retzbach EP, Shen Y, Fatahzadeh M, Baredes S, Kalyoussef E, Honma M, Adelson ME, Kaneko MK, Kato Y, Young MA, Deluca-­ Rapone L, Shienbaum AJ, Yin K, Jensen LD, Goldberg GS. Antibody and lectin target podoplanin to inhibit oral squamous carcinoma cell migration and viability by distinct mechanisms. Oncotarget. 2015;6(11):9045–60. 91. Li YY, Zhou CX, Gao Y.  Podoplanin promotes the invasion of oral squamous cell carcinoma in coordination with MT1-MMP and Rho GTPases. Am J Cancer Res. 2015;5(2):514–29. 92. Inoue H, Miyazaki Y, Kikuchi K, Yoshida N, Ide F, Ohmori Y, Tomomura A, Sakashita H, Kusama K. Podoplanin promotes cell migration via the EGF-Src-Cas pathway in oral squamous cell carcinoma cell lines. J Oral Sci. 2012;54(3):241–50. 93. Huber GF, Fritzsche FR, Züllig L, Storz M, Graf N, Haerle SK, Jochum W, Stoeckli SJ, Moch H.  Podoplanin expression correlates with sentinel lymph node metastasis in early squamous cell carcinomas of the oral cavity and oropharynx. Int J Cancer. 2011;129(6): 1404–9. 94. Cueni LN, Hegyi I, Shin JW, Albinger-Hegyi A, Gruber S, Kunstfeld R, Moch H, Detmar M. Tumorlymphangiogenesis and metastasis to lymph nodes induced by cancer cell expression of podoplanin. Am J Pathol. 2010;177(2):1004–16. 95. Swain N, Kumar SV, Routray S, Pathak J, Patel S.  Podoplanin-a novel marker in oral carcinogenesis. Tumour Biol. 2014;35(9): 8407–13. 96. Yuan P, Temam S, El-Naggar A, Zhou X, Liu DD, Lee JJ, Mao L. Overexpression of podoplanin in oral cancer and its association with poor clinical outcome. Cancer. 2006;107(3):563–9. 97. Vormittag L, Thurnher D, Geleff S, Pammer J, Heiduschka G, Brunner M, Grasl MC, Erovic BM.  Co-expression of Bmi-1 and podoplanin predicts overall survival in patients with squamous cell carcinoma of the head and neck treated with radio(chemo)therapy. Int J Radiat Oncol Biol Phys. 2009;73(3):913–8. 98. Kreppel M, Drebber U, Wedemeyer I, Eich HT, Backhaus T, Zöller JE, Scheer M.  Podoplanin expression predicts prognosis in patients with oral squamous cell carcinoma treated with neoadjuvantradiochemotherapy. Oral Oncol. 2011;47(9):873–8. 99. Retzbach EP, Sheehan SA, Nevel EM, Batra A, Phi T, Nguyen ATP, Kato Y, Baredes S, Fatahzadeh M, Shienbaum AJ, Goldberg GS.  Podoplanin emerges as a functionally relevant oral cancer biomarker and therapeutic target. Oral Oncol. 2018;78:126–36. 100. Joyce JA, Pollard JW. Microenvironmental regulation of metastasis. Nat Rev Cancer. 2009;9:239–52. 101. Yu M, Chen S, Hong W, Gu Y, Huang B, Lin Y, Zhou Y, Jin H, Deng Y, Tu L, Hou B, Jian Z.  Prognostic role of glycolysis for cancer outcome: evidence from 86 studies. J Cancer Res Clin Oncol. 2019;145(4):967–99. 102. Vander Heiden M, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324(5930):1029–33.

194

L. Monteiro and S. Warnakulasuriya

103. Romero-Garcia S, Moreno-Altamirano M, Prado-Garcia H, Sánchez-García F.  Lactate contribution to the tumor microenvironment: mechanisms, effects on immune cells and therapeutic relevance. Front Immunol. 2016;7:52. 104. Festino L, Botti G, Lorigan P, Masucci GV, Hipp JD, Horak CE, Ascierto PA. Cancer treatment with anti-PD-1/PD-L1 agents: is PD-L1 expression a biomarker for patient selection? Drugs. 2016;76(9):925–45. 105. Pai SI, Zandberg DP, Strome SE. The role of antagonists of the PD1:PD-L1/PD-L2 axis in head and neck cancer treatment. Oral Oncol. 2016;61:152–8. 106. Zandberg DP, Strome SE. The role of the PD-L1:PD-1 pathway in squamous cell carcinoma of the head and neck. Oral Oncol. 2014;50(7):627–32. 107. Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004;25(12):677–86. 108. Mori K, Hiroi M, Shimada J, Ohmori Y.  Infiltration of m2 tumor-­ associated macrophages in oral squamous cell carcinoma correlates with tumor malignancy. Cancers (Basel). 2011;3(4):3726–39. 109. Castellsagué X, Alemany L, Quer M, Halec G, Quirós B, Tous S, Clavero O, Alòs L, Biegner T, Szafarowski T, Alejo M, Holzinger D, Cadena E, Claros E, Hall G, Laco J, Poljak M, Benevolo M, Kasamatsu E, Mehanna H, Ndiaye C, Guimerà N, Lloveras B, León X, Ruiz-­Cabezas JC, Alvarado-Cabrero I, Kang CS, Oh JK, Garcia-Rojo M, Iljazovic E, Ajayi OF, Duarte F, Nessa A, Tinoco L, Duran-Padilla MA, Pirog EC, Viarheichyk H, Morales H, Costes V, Félix A, Germar MJ, Mena M, Ruacan A, Jain A, Mehrotra R, Goodman MT, Lombardi LE, Ferrera A, Malami S, Albanesi EI, Dabed P, Molina C, López-Revilla R, Mandys V, González ME, Velasco J, Bravo IG, Quint

14

110.

111.

112.

113.

114.

115.

W, Pawlita M, Muñoz N, de Sanjosé S, Xavier Bosch F, ICO International HPV in Head and Neck Cancer Study Group. HPV involvement in head and neck cancers: comprehensive assessment of biomarkers in 3680 patients. J Natl Cancer Inst. 2016;108(6):djv403. Zhang Y, Koneva LA, Virani S, Arthur AE, Virani A, Hall PB, Warden CD, Carey TE, Chepeha DB, Prince ME, McHugh JB, Wolf GT, Rozek LS, Sartor MA.  Subtypes of HPV-positive head and neck cancers are associated with HPV characteristics, copy number alterations, PIK3CA mutation, and pathway signatures. Clin Cancer Res. 2016;22(18):4735–45. Rivera C, Oliveira AK, Costa RAP, De Rossi T, PaesLeme AF. Prognostic biomarkers in oral squamous cell carcinoma: a systematic review. Oral Oncol. 2017;72:38–47. Almangush A, Heikkinen I, Mäkitie AA, Coletta RD, Läärä E, Leivo I, Salo T. Prognostic biomarkers for oral tongue squamous cell carcinoma: a systematic review and meta-analysis. Br J Cancer. 2017;117(6):856–66. Lakshminarayana S, Augustine D, Rao RS, Patil S, Awan KH, Venkatesiah SS, Haragannavar VC, Nambiar S, Prasad K. Molecular pathways of oral cancer that predict prognosis and survival: a systematic review. J Carcinog. 2018;17:7. Peterle GT, Maia LL, Trivilin LO, de Oliveira MM, Dos Santos JG, Mendes SO, Stur E, Agostini LP, Rocha LA, Moysés RA, Cury PM, Nunes FD, Louro ID, Dos Santos M, da Silva AMÁ. PAI-1, CAIX, and VEGFA expressions as prognosis markers in oral squamous cell carcinoma. J Oral Pathol Med. 2018;47(6):566–74. Götz C, Bissinger O, Nobis C, Wolff KD, Drecoll E, Kolk A. ALDH1 as a prognostic marker for lymph node metastasis in OSCC. Biomed Rep. 2018;9(4):284–90.

195

Early Diagnosis of Oral Cancer Andrei Barasch and Joel B. Epstein 15.1

Introduction – 196

15.2

Diagnostic Delays – 196

15.2.1

The Oral Cavity – 196

15.3

The Patient Interval – 197

15.4

The Primary Care Interval – 198

15.5

The Diagnostic Interval – 198

15.6

The Pretreatment Interval – 199

15.7

Medicolegal Aspects of Diagnostic Delay – 199

15.8

Conclusion – 199 References – 199

© Springer Nature Switzerland AG 2020 S. Warnakulasuriya, J. S. Greenspan (eds.), Textbook of Oral Cancer, Textbooks in Contemporary Dentistry, https://doi.org/10.1007/978-3-030-32316-5_15

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Core Message The subject of detection and diagnosis timing for oral cancer has not been adequately studied and no robust conclusions can be reached with the current evidence. A majority of oral cancers are diagnosed in advanced stages (3 and 4) and have relatively poor prognosis. The reasons for this are not always clear but appear to be associated with low education levels about the disease in both populations at risk and primary care practitioners. Sets of heterogeneous data indicate that early diagnosis followed by swift implementation of therapy has superior outcomes and lower morbidity. Improved educational models may benefit future patients as well as the society at large.

15.1 

Introduction

Despite increased governmental and educational efforts aimed at early diagnosis, oral cancer continues to be identified in advanced stages in a majority of the afflicted populations. The extant literature on reasons for this delayed diagnosis remains fragmented, and firm conclusions remain elusive. The consequences of this delay are also inconclusive, although in general, prognosis appears to be more guarded in patients with late-stage disease as compared to those diagnosed early. In this chapter, we will review the pertinent available information and propose avenues for the reduction of late diagnosis of oral cancer. 15.2 

15

Diagnostic Delays

and metastatic spread is not predicted solely on anatomic criteria. Molecular study holds the promise to improve our ability to predict the future behavior of cancer and to assist in selecting specific therapies. Definition Diagnostic delay is the time lapse between patient arrival at different healthcare providers and the time lapse during healthcare utilization by the patients before a cancer diagnosis is made.

15.2.1 

The Oral Cavity

The oral cavity is easily accessible for examination that can be completed in mere minutes. Nevertheless, more than half of oral malignancies are diagnosed in late stages [5]. To further complicate the discussion, tumor doubling time is highly variable, and that is not reflected in anatomical staging systems. We will discuss in this chapter the causes and consequences of late diagnosis together with some possible solutions. Oral cancer is an umbrella word that encompasses several types of malignant diseases. Practically all tissues of the oral cavity (save the teeth) may undergo malignant transformation, and a number of malignant diseases from distant sites can metastasize to the mouth. Hence, a number of cancers have been diagnosed in the region: various sarcomas (e.g., osteo- and chondrosarcoma, Ewing’s and Kaposi’s sarcoma), lymphoma, leukemia, multiple myeloma, salivary gland cancers (e.g., mucoepidermoid, adenoid cystic), and basal cell carcinoma. However, by far the most common oral malignancy is squamous cell carcinoma (SCC), which accounts for over 90% of all diagnosed oral cancers. As all other entities are relatively rare, most reports on oral cancer in the literature concentrate on SCC, which is also the focus of this chapter. The oral cavity is easily accessible to direct vision and palpation, which makes delays in diagnosing malignancy at the site somewhat puzzling. However, the oral cavity has complex and differing mucosal surfaces including keratinized and nonkeratinized mucosa, oropharyngeal lymphoid tissues, areas challenging to visualize in the posterior oral cavity, and oropharynx. Oral cancers have variable presentation from leukoerythroplakia, erythroplakia, leukoplakia, and homogeneous and non-homogeneous ulcerative lesions and masses, and presentations that can mimic much more common inflammatory and reactive oral conditions. Furthermore, many oral lesions with cancer risk or frank cancer are associated with minimal or no symptoms, thus limiting detection.

It has been generally accepted that the diagnosis of disease at an earlier stage is associated with better chances for cure or amelioration, with less complex and less costly treatment. It makes teleological sense that a treatment applied prior to a disease producing extensive damage has a better chance of being successful and has less morbidity. This theory may hold true for malignant diseases based upon staging of disease designed to reflect outcome of therapy/prognosis [1, 2]. The quest for early detection has led to implementation of screening programs, of which some have reported success while others remain controversial. Notable in the former categories, screening for colorectal, skin, cervical, and breast cancers has resulted in significant decreases in morbidity and mortality from the respective diseases [3]. However, there is growing concern that overdiagnosis and overtreatment have been occurring, with potential associated morbidity and increasing cost of care, which may be reflected in current reported outcomes [4]. Additionally, simplistic anatomical staging does not account for differences in biology of the >>Important tumor, tumor heterogeneity, and rate of progression of indiEarly detection is a goal of oral evaluation vidual cases. An advanced-stage tumor could represent a Early detection may affect treatment required and preminimally symptomatic and slow-growing lesion or a recent-­ dict outcome of treatment onset lesion with rapid progression. Further, tumor behavior Staging of cancer is designed to reflect outcomes of of regional spread (bone invasion, lymph node involvement) stages of cancer

197 Early Diagnosis of Oral Cancer

Staging of cancer is used to assist in selection of cancer therapy Potentially malignant lesions may mimic benign conditions and may be asymptomatic/minimally symptomatic

A number of researchers have studied this issue over the past few decades, yet the problem appears to persist. Initial efforts were hampered by heterogeneous definitions of delay and criteria for assessing timing of various steps in the diagnosing process. In response to these problems, an international panel of scientists has issued the Aarhus guidelines [6], in which standards for time intervals were proposed (. Table 15.1). The framework thus created allowed for more consistency among studies and easier determination of specific barriers and consequences of delay. These studies then were able to show a clear association of late diagnosis/treatment of oral cancer with worse outcomes. [7]  

15.3 

..      Fig. 15.1  Lateral tongue stage 1 SCC presenting as an ulcer on erythroleukoplakia. This lesion was asymptomatic and treated initially as a traumatic ulcer

The Patient Interval

The length of the patient interval and its exact causes have had limited evaluation. It appears that patient delay is on average 5–6 months [5] and is related to the lack of awareness of oral cancer in the general population and particularly among populations at high risk. This may certainly reflect the minimally symptomatic or asymptomatic nature of SCC, until advanced (. Fig. 15.1). Even when noted, patients may assume the lesion would heal with time or attempt nonmedical treatment (. Fig.  15.2). It is important to note that patients who have knowledge of oral cancer are more likely to seek medical evaluation [5, 7, 8]. A meta-analysis on this topic [9] included 16 pertinent publications. The populations, methodologies, and location of the studies were heterogeneous, which makes any firm conclusions difficult. The author concludes that sociodemographic variables were not associated with delay, as were the presence of oral habits such as smoking, quid or betel nut chewing, and alcohol consumption. A third category of reasons, the psychosocial factors, was too amorphous and inconsistent to permit any conclusions. A recent study of Indian patients reported a median  

 

..      Table 15.1  Time intervals according to the Aarhus guidelines Interval

Definition

Patient interval

First symptom to first presentation to a health professional (HCP)

Primary care interval

First presentation to HCP to first referral to secondary care level

Diagnostic interval

First presentation to HCP to diagnosis

Pretreatment interval

Diagnosis to start of treatment

..      Fig. 15.2  Stage 3 SCC on lateral border of the tongue. The patient waited for 6 months for the lesion to heal

patient interval of 30 days (range 4–365); lack of awareness and hope of spontaneous healing were the main reasons for delay in this population as well [10]. A similar study of 52 Bulgarian patients concluded with similar results, in terms of both duration and reasons for delay. In this latter study, an additional cause for diagnostic delay was the oral location of the tumor [11]. A typical initial presentation complaint is either an enlarging lump/swelling persistent ulcer or pain/ other neurologic symptom. [12] It remains unclear whether demographic factors play a role in the patient interval [5], although it appears that being female or married was associated with earlier diagnosis, whereas being non-white was associated with later diagnosis [13]. In particular, AfricanAmerican populations in the USA, with low education levels, have significantly less knowledge of oral cancer and its risk factors [14]. Additionally, there are large differences in access to and utilization of medical and dental care between rural and urban populations, ethnic minority and majority populations, and poorly educated and college degree populations

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[15]. Where and to whom patients present may be a significant factor in dental providers identifying earlier-stage cancers identified on oral examination or with oral symptoms and physicians’ diagnosis of advanced-stage disease associated with symptoms such as weight loss, sore throat, and blood in sputum [16]. A study of a younger group (age  >Key Features of a Cancer Screening Program 55 Early detection of disease in people who are otherwise asymptomatic. 55 Uses a test to detect early stages of cancer or changes of precancer. 55 The test identifies those who probably have the disease, to distinguish them from those who probably do not. 55 The screening test is not diagnostic. Those screened positive are referred for more specific diagnostic tests. 55 Screening is an ongoing process repeated at intervals and includes protocols for managing people who screen positive and must include effective treatment of screen-detected disease. 55 The outcome must be a reduction in mortality in the whole population offered screening. If the screening test also aims to detect precancer, then a further expected outcome will be reduced incidence of invasive cancer.

16.2 

Evaluation of Screening

16.2.1 

Evaluation of a Screening Test

The validity or accuracy of a test is determined by the proportion of the results that are confirmed as truly positive or negative by an acceptable diagnostic procedure  – often referred to as the “gold-standard” diagnosis. An ideal screening test would correctly identify all individuals in the screened population with the disease as positive and all individuals without the disease as negative. However, this never happens and, therefore, there must be a balance between how well the screening test correctly classifies people with the disease (sensitivity) and how well it classifies people without the disease (specificity). The possible outcomes of a test are illustrated in . Fig. 16.1, and definitions of these and the metrics used to evaluate a test are shown in . Tables 16.3 and 16.4. The most widely used metrics are the sensitivity and specificity, and in general the calculation of these parameters is regarded as essential in the evaluation of a test. However, obtaining the data to do this can be very difficult because it is necessary to determine the number of true (TN) and false  

 

Gold standard diagnosis Disease present

Disease absent

True positive (TP)

False positive (FP)

False negative (FN)

True negative (TN)

Test result

..      Table 16.2  Potential advantages and disadvantages of a screening program Advantages

Disadvantages

Reduced mortality

Detection of cases already incurable may increase morbidity for some patients

Reduced morbidity

Unnecessary treatment for lesions which may not have progressed

Reduced incidence of invasive cancers

Psychological trauma for those with a false-positive screen

..      Table 16.3  The four possible outcomes of a screening test

Improved prognosis for individual patients

False reassurance for those with a false-negative screen

True positive (TP)

The test correctly classifies an individual with the disease as positive

Identification of high-risk groups and opportunities for primary intervention

Reinforcement of bad habits among those screened negative

False positive (FP)

The test incorrectly classifies an individual without the disease as positive

Reassurance for those screened negative

Excessive costs

True negative (TN)

The test correctly classifies an individual without the disease as negative

False negative (FN)

The test incorrectly classifies an individual with the disease as negative

Cost savings

..      Fig. 16.1  The four possible outcomes of a screening test. The gold-standard diagnosis determines the true presence of disease in the population. In a perfect test, all subject will fall into the TP box, but this never happens (see text)

Definition

16

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P. M. Speight

..      Table 16.4  Metrics used to evaluate the accuracy of a screening test Calculation

16

Definition

Survival

Sensitivity

TP TP + FN

The ability of the test to correctly classify people with the disease as positive

Specificity

TN FP + TN

The ability of the test to correctly classify people without the disease as negative

Positive predictive value (PPV)

TP TP + FP

The proportion of people with the disease among those who test positive

Negative predictive value (NPV)

TN FN + TN

The proportion of people with the disease among those who test positive

(FN) negatives. This means that all individuals subjected to the screening test who are negative must also be subjected to the gold-standard diagnostic test to prove they are truly negative. In large studies, where a disease may be of low prevalence, this can be a difficult or impossible undertaking and may be too expensive to justify funding. In this case, the PPV may be used as an acceptable substitute. There is no agreed definition for what constitutes an acceptable test, and there must always be a “trade-off ” between sensitivity and specificity. While it is important that the test records a low number of false positives (FP), to prevent unnecessary overdiagnosis and anxiety, it is also important that the number of false negatives (FN) is kept as low as possible so that disease is not missed. Acceptable tests generally have a sensitivity and specificity of 0.8 or more, but in order to capture and treat as many cancers as possible, a higher sensitivity is preferable – but this will result in more false positives and may come at extra cost. 16.2.2 

Apparent increase in survival

Birth

Death Positive screen

Symptoms and clinical presentation

..      Fig. 16.2  An illustration of lead-time bias. The screening test detects the presence of cancer, but the disease is already incurable and life is not prolonged (see text for explanations)

Survival

a

Birth Symptoms and clinical presentation

True increase in survival Survival

b

Birth

Death

Positive Treatment screen ..      Fig. 16.3  An illustration of an effective screening program. The screening test detects disease at an early stage when treatment is effective, and life is prolonged (see text for explanations)

Lead-Time Bias

A major unintentional consequence of early detection of cancer is that it may result in overdiagnosis of disease and cause many people to receive unnecessary treatment. This is called lead-time bias and refers to a situation where a screening test detects disease which may be asymptomatic but is already so far advanced that treatment is not effective and will not prolong life (. Fig. 16.2). For example, screening tests for lung cancer proved ineffective, because when disease was detected, even in asymptomatic patients, it was already advanced and treatment would not prolong life [8]. . Figure  16.2 shows that the earlier diagnosis due to a positive screen results in an apparent increase in survival, but in reality, life is not prolonged and the patient dies at the same age. The outcome for the patient does not change, but they are subjected to unnecessary treatment after the screen and to the psychological trauma of living with cancer for a longer period than is  

 

necessary. . Figure 16.3 illustrates an effective screening program, such as cervical cancer screening. In this case, subject (b) benefits from a positive screen early in life, and effective treatment results in a prolongation of life and a true increase in survival compared to subject (a), whose cancer presents late with symptoms and dies soon after. A phenomenon similar to lead-time bias is referred to as length-time bias. In this situation, a sensitive screening test detects small slow-growing cancers, which may be less aggressive and may not have killed the patient or even become clinically apparent within their natural lifetime. In this case, the screening results in unnecessary treatment as well as the psychological trauma of being diagnosed with a disease that, in the absence of the screen, the patient may never have known about. This scenario applies to prostate  

205 Screening for Oral Cancer

cancer where the PSA test (for prostate-specific antigen) may be too sensitive and may also lack specificity. 16.2.3 

Evaluation of a Screening Program

Although a test may have adequate sensitivity and specificity, it must also be demonstrated that it is able to detect relevant lesions in the context of a screening program and that the program achieves the desired objectives for successful implementation (. Table 16.1) [3, 4]. In particular, it is expected that a screening program for cancer will reduce mortality and morbidity, and ideally this should be tested in a prospective randomized controlled trial (RCT). In such a project, populations are randomized to a screened and non-screened group and the mortality is compared [9]. The primary outcome is a significant reduction in mortality in the whole population that was offered screening. In reality, RCTs of this scale are very difficult to carry out, since they must often involve hundreds of thousands of subjects with follow-up long enough to determine mortality  – usually for about 10  years. The number of participants needed is greater for cancers with a low prevalence such as oral cancer. Few RCTs of this nature have been undertaken, but one, in the context of oral cancer, will be discussed in a subsequent section. Alternative research methods include retrospective cohort studies, where the incidence of disease and mortality in a population that has been offered screening are compared to a population that has not been screened. A similar study design may compare the same population before and after the implementation of the screening program. Cervical cancer is of relatively low incidence, and the effectiveness of screening programs has mostly been determined in retrospective cohort studies. Breast and bowel cancer screening however have been evaluated in RCTs, since the diseases have high incidence and the number of subjects required may be less than 100,000 [10]. RCTs for prostate cancer screening are currently ongoing [11]. Once a screening program has been introduced, or is under evaluation, a number of interim or surrogate measures can be applied that can suggest whether or not the program is likely to bring about a satisfactory outcome [9, 12] (. Table 16.5).  

 

16.3 

Screening for Oral Cancer

16.3.1 

I s Oral Cancer an Important Health Problem?

Worldwide, there are an estimated 300,000 new cases of oral cancer per annum and145,400 deaths, making it one of the most common cancers [13, 14]. Although there are wide variations in incidence, overall about two-thirds of cases occur in the developing world [14]. There is also good evidence that oral cancer is increasing in incidence throughout the world [13] with significant increases in younger people. In

..      Table 16.5  Interim or surrogate measures that can be used to monitor the success and progress of a screening program Measure

Description

Yield of disease

The number of cases of cancer detected when a population is first screened should exceed the expected incidence. This is because the screening test should detect cancers and precancers in a pool of undetected cases

Disease stage (stage shift)

The screen-detected cancers should have a higher proportion of early-stage lesions than normally seen in the unscreened population (a shift to lower stage). Over time, the incidence of advanced cancers in the population should fall – an early indicator of a reduction in mortality

Participation rate (compliance)

This measures the proportion of the population who take up the offer of screening. If compliance is low, then the screening program is unlikely to demonstrate any benefit

Sensitivity and specificity of the test

This determines if the test is likely to detect cancer with an adequate degree of accuracy. During a screening program, the sensitivity of the test is continually monitored and the number of false negatives includes cases of cancer which present symptomatically after a negative test (interval cases). If this causes a reduction in sensitivity, the program may not achieve its aims

Effective follow­up and treatment

The screening program cannot reduce mortality if the treatment for detected lesions is inadequate. This is not usually a problem in programs designed to only detect early cancers but is a particular problem when the program is also designed to detect premalignant lesions, the management of which may be uncertain

recent decades, there have been some major advances in treatment, but despite this, the 5-year survival rate has not improved and remains at about 50%. The most important reason for this, even in developed countries, is diagnostic delay, with more than 60% of patients presenting with late-­stage disease (stages III/IV) [15], when complex multimodality therapy may be needed. Cancers detected when they are small or at an early stage however can be treated by simple surgery, with a good chance of cure. For example, in a UK study, the 5-year survival for stage I oral cancer was 96%, while patients presenting at stage IV had only 57% survival [16]. The majority of oral cancers are preceded by a clinically detectable potentially malignant lesion, the most common of which is a white patch or leukoplakia [17]. This suggests that a screening program to detect preinvasive disease may also be feasible and may reduce the incidence of established lesions of oral cancer.

16

206

P. M. Speight

Taken together, these data show that oral cancer is a significant health problem and that screening is feasible since there is good evidence for a detectable premalignant lesion and early detection of established cancers should result in improved survival. The disease appears to meet the first four principles suggested by Wilson and Jungner (. Table 16.1) [3].  

16.3.2 

Evaluation of a Screening Test for Oral Cancer

 

The efficacy of a screening test is ideally determined by measures of sensitivity and specificity, as discussed in 7 Section 16.2.1. The most widely studied test for oral cancer screening has been a conventional oral examination. However, only nine studies have been reported that have properly determined the sensitivity and specificity by retesting negative cases against the gold-standard diagnosis [18–26]. These are summarized in . Table 16.6. In all studies, the criterion for a positive screen was the finding of a persistent red or white lesion or ulcer, which encompassed a range of lesions regarded as potentially malignant, including leukoplakia, erythroplakia, lichen planus, and submucous fibrosis. However, other nonrelevant lesions, for example, benign hyperkeratotic lesions, may have been regarded as positive. In most studies, the screen was carried out by a dental professional, but some used trained nonmedical or non-dental healthcare workers [23–25], with similar results. Walsh et al. [27] undertook a Cochrane systematic review of test accuracy that reviewed a number of these studies [18–25] and found a variable degree of sensitivity (0.50 to 0.99) but a consistently high value for specificity (greater than 0.80). They also examined vital staining, light-based detection (including fluorescence), biomarkers, and mouth self-examination as potential screening tests but found insufficient evidence to determine their test accuracy. A meta 

 

16

analysis of some of these studies [28] found pooled values of sensitivity of 0.85 (95%CI; 0.73–0.92) and specificity of 0.97 (95%CI; 0.93–0.98). These analyses have shown that an oral examination can correctly identify oral lesions with a sensitivity and specificity of 0.8 or greater, which is regarded as acceptable and is similar to the test performance in established screening programs [9]. These data further support the view that oral cancer screening may be feasible and that both dentists and trained healthcare workers can accurately detect oral lesions (. Table 16.6). 16.3.3 

 pplication of an Oral Examination A as a Screening Test

Although an oral examination may show a satisfactory degree of accuracy and reproducibility, the use of this as a test in a real-world screening scenario is controversial. As discussed above, most research studies have reported using the presence of an oral potentially malignant disorder or early oral cancer as the criteria for a positive screen. The lesion most often detected in screening studies is a white patch or leukoplakia, which is a common lesion with an estimated global prevalence of 2.6% [17, 29], but its natural history is not fully understood since progression to cancer is not predictable and it is almost impossible to clearly categorize which lesions will transform to cancer [30]. In addition, the overall malignant transformation rate is estimated to be less than 5% [31]. Lesions at the highest risk may have a nonhomogeneous surface and show evidence of epithelial dysplasia on biopsy [31–33], but these features may not be evident on screening and may not be suitable for a screening test. In real terms, up to 95% of the lesions detected by oral examination may not progress to malignancy and a white patch cannot therefore be used as the criteria for a positive test that should only detect lesions with the highest probability of progressing to cancer. It is not economically fea-

..      Table 16.6  Published evaluations of an oral examination as a screening test Country

n

Sensitivity

Specificity

PPV

NPV

Taiwan

13,606

2.1

0.99

0.99

0.62

0.99

Chang et al. [18]

United Kingdom

309

5.5

0.71

0.99

0.86

0.98

Downer et al. [19]

Japan

154

9.7

0.60

0.94

0.67

0.96

Ikeda et al. [20]

United Kingdom

2027

2.7

0.74

0.99

0.67

0.99

Jullien et al. [21]

India

2069

10.3

0.94

0.98

0.87

0.99

Mathew et al. [22]

India

1921

1.4

0.59

0.98

0.31

0.99

Mehta et al. [23]

Sri Lanka

1872

4.2

0.95

0.81

0.58

0.98

Warnakulasuriya et al. [24]

Portugal

727

3.4

0.96

0.98

0.96

0.98

Monteiro et al. [25]

Japan

137a

0.92

0.64

0.78

0.86

Nagao et al. [26]

aTotal

%positive

68

screened was 19,065, but calculations are based only on subjects who attended for a second examination

207 Screening for Oral Cancer

sible to treat all screen-detected white patches in the hope that the less than 5% that may have progressed will be included. This is a major barrier for the implementation of an oral cancer screening program, since principle 7 (. Table 16.1) is not met and therefore principles 4 and 5 are also in doubt. There is therefore an urgent need to find a new test for oral cancer screening that will detect only lesions that are most likely to progress to cancer. At the present time, no biomarkers have been shown to accurately predict which oral potentially malignant lesions may progress to cancer, and none have been found suitable for a screening test [32–34]. There are many recent studies that have described a number of new tests or adjunctive techniques designed to assist clinical diagnosis, including vital staining (toluidine blue), light-based techniques (usually using fluorescence), mouth self-examination, and some cytological methods. However, most have been used as diagnostic aids in secondary care environments, but none have been evaluated for use in subjects who are otherwise asymptomatic or evaluated in the context of oral cancer screening [35]. A Cochrane systematic review found that none of the adjunctive tests were suitable for use as a screening test or can be used as a substitute for the current diagnostic standard of a biopsy and histological examination [36]. Lingen et  al. [37] have updated this Cochrane review on behalf of the American Dental Association. They undertook a detailed review and metaanalysis of 46 studies that evaluated the diagnostic test accuracy of more than ten different adjunctive methods for use in primary care settings. They found that, with the exception of cytological studies, adjunctive tests showed pooled sensitivities of 0.00 to 0.90 and specificities of 0.31 to 0.76. The authors concluded that the overall low specificities and high rate of false positives raised doubts about the potential benefits of adjunctive tests. They did however suggest that cytology had potential as a test for both innocuous and suspicious lesions with pooled sensitivities of 0.95 (CI: 0.86–0.99) and 0.90 (CI: 0.86–0.98), respectively. Corresponding specificities were 0.90 (CI: 0.79–0.97) and 0.94 (CI: 0.88–0.99). However, the quality of the evidence was low, and it should be noted that none of the methods were evaluated as potential screening tests for use on otherwise symptomless individuals. These date show that none of these adjuncts have been found to have adequate diagnostic test accuracy for the routine evaluation of oral potentially malignant lesions, and they have not been recommended for use in routine clinical practice [38] or for screening [39]. At the present time therefore, although it is possible to accurately detect oral lesions, the criteria for a positive oral examination are not suitable to detect those lesions with the highest probability of progressing to malignancy. A major research priority is to further understand the natural history of the progression of oral lesions to cancer and to find biomarkers or clinical tests that can be used to identify truly premalignant oral lesions. A further challenge will be to find a test that can be applied to apparently clinically normal subjects for the detection of potentially malignant lesions or occult oral cancers.  

16.3.4 

Screening Programs for Oral Cancer

Screening programs for oral cancer have been the subject of a number of research projects, but only two countries, Taiwan and Cuba, have implemented any sort of formally organized oral cancer control programs. Cuba recognizes that oral cancer screening may not reduce mortality [40] but nevertheless have introduced a national oral cancer case-finding program [41]. The strategy involves an annual oral examination and teaching oral self-examination for the whole population and opportunistic case-finding for highrisk individuals over 35 years [40]. Originally, the program recruited all individuals over age 15  years, but there have been no published evaluations since 1997 [41, 42]. Between 1982 and 1990, over ten million people were examined and 30,478 (0.3%) were referred with an oral abnormality. Only 27% (8259) complied, but the yield of lesions included 481 squamous cell carcinomas and 127 other oral malignancies. There were also 3220 oral potentially malignant lesions including 2367 leukoplakias. The only reported outcome measure was a stage shift (. Table 16.5) with the proportion of lesions detected at stage I increasing from 22.8% in 1982 to 48.2% in 1988 [41]. Although this suggests a successful program, the improvement in stage was only analyzed in the cases detected from within the program, and not for the population as a whole. Others have noted [42] that the program only actually identified 16% of the incident oral cancers over the period and that there was no overall change in mortality or morbidity in Cuba. No data has been published since 1997, and it is not possible to assess the ongoing status of the program [40]. Taiwan has a very high prevalence of oral potentially malignant disorders, in particular oral submucous fibrosis, as a result of the common habit of chewing betel quid (areca nut) [43]. Over a 3-year period, 1999–2001, a large project evaluated a multiple disease screening program in Keelung County, Taiwan, which included an oral examination for oral submucous fibrosis or leukoplakia [44]. About 10,500 subjects who used betel quid, tobacco, or alcohol received an oral examination, and in 285 (2.7%), a lesion was detected. After referral, a total of 116 lesions (1.08%) were diagnosed, including 2 cases of oral cancer, 23 oral submucous fibrosis, and 86 leukoplakias. Following this trial, national screening programs for cervical, breast, oral, and colorectal cancer were introduced and are ongoing [45]. A fuller evaluation of the oral cancer screening outcomes was reported in 2016 and will be discussed in the following section.  

16.3.5 

 valuation of Oral Cancer Screening E Programs

The ideal test of the effectiveness of a screening program is a randomized controlled trial with a primary outcome measure of reduced mortality. In a Cochrane systematic review, Brocklehurst et al. [46] found 30 potentially eligible studies investigating oral cancer screening, but only one of these was

16

208

16

P. M. Speight

a controlled trial that met the inclusion criteria. All other studies were uncontrolled, were observational only, or were reviews. Thus, to date, there has only ever been one properly conducted randomized controlled trial to evaluate the effectiveness of an oral cancer screening program. This oral cancer screening trial was undertaken in Kerala, India, and has been reported in a series of papers [47–51]. From 1994 to 2009, the investigators carried out four rounds of screening in a community-based trial where 13 municipalities were randomized to give an intervention (screened) population and a control (not screened) population, each of almost 100,000 subjects. Healthy residents 35 years of age or over were examined by trained nonmedical university graduates who carried out a visual oral examination of each subject. The criteria for a positive screen were the presence of a potentially malignant disorder (including white/red lesions, oral submucous fibrosis, and lichen planus) or of an ulcer suspected to be malignant. After three rounds of screening, it was reported that 87,655 (91%) subjects in the intervention group were screened at least once and 6.55% were found to be positive [48]. Overall 205 oral cancers were diagnosed in the intervention group (131 screen-detected, 59 interval cancers, and 15 nonparticipants), compared to 158 in the control group. They found that 5-year survival was significantly different between the two groups with 50% in the intervention arm and 34% in the control arm. They also found evidence of a significant stage shift, with 42% of cases in the intervention arm diagnosed early (in stages I and II), compared to only 23% in the control arm. However, there was no significant reduction in mortality in the population as a whole. Deaths from oral cancer were 37.6% in the intervention arm (77 individuals) and 55% (87 individuals) in the control arm, but this difference was not significant. The authors further analyzed their data to determine the outcome if only high-risk groups had been screened. They found a significant reduction in mortality, from 42.9% to 24.6%, in males who used tobacco and/or alcohol. Among females there was no significant reduction in mortality. After four rounds of screening, completed in 2009 [50], there was a significant improvement in 5- and 10-year survival rates and in early detection (stage shift). However, there was still no significant reduction in death rates or reduced mortality in the population. This suggests that the improvements in survival were due to lead-time bias (see 7 Section 16.2.2) and that the overall screening program had not been effective. However, the authors did find a significant reduction in mortality among those subjects who had attended all four cycles of screening. The death rate in the intervention arm was 17.1 per 100,000 and reduced to 3.0 per 100,000 in the control arm. In the high-risk group, the corresponding rates were 39 per 100,000 and 7.1 per 100,000. The authors suggested that targeted or opportunistic screening of high-­ risk groups may be effective. However, the fact that only 19,288 subjects (20%) completed all four cycles of the program means that the effect  

on oral cancer incidence or mortality on the population as a whole was slight. The authors of the Kerala study concluded that opportunistic screening of high-risk groups should be considered as an effective intervention to reduce incidence and mortality of oral cancer [50, 51]. The Cochrane review [46] acknowledged the significant findings of the Kerala study but, on critical examination, found a number of methodological weaknesses that reduced the validity of the findings. They concluded that there was insufficient evidence to recommend population-­ based screening programs for oral cancer. Alternatives to a full randomized controlled trial include retrospective analyses or evaluation of demonstration studies (7 Section 16.2.3). Following the implementation of screening in Taiwan (7 Section 16.3.4 [44, 45]), the program was evaluated by comparing the outcomes in the population cohort who attended for screening with those who did not attend [52]. Between 2004 and 2009, a total of more than 4.2 million individuals aged 18 years or over, who were smokers and/or betel quid users, were invited for a biennial oral examination by a trained dentist or physician. Fiftyfive percent (2,334,299 individuals) attended for screening, and 18,116 (0.8%) were found to have a positive lesion including 4110 oral cancers at the first screen. The main outcome measures relevant to a screening program were yield of lesions, incidence of invasive cancers, stage shift, and mortality. In the screened group (“attendees”; n  =  2,334,299), the yield of lesions was directly observed, but other parameters, including incidence of interval cancers, stage at presentation, and survival, were obtained from the national registries of cancer or deaths, with a median follow-up period of 4.5  years. The non-screened group comprised those individuals who had not accepted the invitation to be examined (“non-attendees”; n  =  1,900,094). However, because information was not available to confirm the high-risk habits of this group, the expected incidence of disease, stage of presentation, and mortality rates were calculated from cancer registry data, based on an estimate that 90% of oral cancers arose in those who smoked or chewed betel quid. The effectiveness of the program was then estimated using the observed values in the screened group and the expected values of the non-screened group. Overall, the data showed good evidence that the screening program was effective. The total number of oral cancers in the screened group, including cases detected at subsequent screens and interval cases, was 8033 with an annual incidence of 133.4 per 100,000. This was significantly lower than the incidence in the non-screened group (190.9 per 100,000). There was evidence of a significant stage shift, with 46.5% of cases presenting in stages I and II in the screened group compared to 39.6% in the non-screened group. The study also showed a 26% reduction in mortality in the screened group (RR vs. non-screened: 0.74; CI, 0.72–0.77). The results of this Taiwan study support the findings from the Kerala project and provide further evidence that screening may reduce mortality from oral cancer among high-risk  

 

209 Screening for Oral Cancer

groups. The study also presents important new data showing that the screened population had a reduced incidence of invasive oral cancers after only 5 years. This suggests that the early detection and treatment of potentially malignant lesions may prevent malignant transformation. The potentially malignant lesions included as positive were leukoplakia, erythroleukoplakia, erythroplakia, oral submucous fibrosis, and verrucous hyperplasia, but the authors do not indicate how the lesions were treated. Neither study was able to show that a national screening program is able to reduce mortally from oral cancer in the population as a whole. Further RCTs may be needed to provide more robust evidence to support oral cancer screening, but as can be seen from these studies and from the previous discussion (7 Section 16.2.3), this is a major undertaking requiring significant resource and large numbers of subjects followed over a long period. Few funding bodies or governments are likely to support a project of the standard and scale of the Kerala study.  

16.4 

Cost-Effectiveness of Cancer Screening

16.4.1 

Principles of Cost-Effectiveness Analysis and Thresholds

When considering the implementation of a screening program, a major consideration (principle 9 in . Table 16.1) is that it should be cost-effective. The most common method used to determine the value of a new healthcare intervention is to undertake a cost-effectiveness analysis. This assesses if the health benefits obtained from the intervention are sufficient to justify the costs. When evaluating a cancer screening program, the benefits are measured in the number of lives saved, but in order to be able to give a reproducible and comparable measure, the lives saved are expressed in the number of years adjusted using a measure of perceived quality of life (health-state utilities [53]) and are expressed as quality-­adjusted life years (QALYs) [54]. In a screened population, the total number of additional QALYs gained as a result of early detection can be compared to the number of QALYs in the non-screened population and can be costed. The resulting measure is called the incremental cost-effectiveness ratio (ICER) and represents the additional cost for each QALY saved in the population. There is no expectation that the ICER will be zero or negative, but it is expected that the cost of saving lives through screening will be within the resources available and will have a beneficial effect on the health system as a whole. Thus, a government may set a cost-effectiveness threshold on what they (or the taxpayer) are prepared to spend on a new healthcare intervention [55]. This threshold is likely to be lower in low- and middle-income countries than in high-income countries [55]. In the United Kingdom and the United States, the thresholds are set at about £20,000 to £30,000 and $50,000, respectively [56, 57].  

16.4.2 

16

 ost-Effectiveness of Oral Cancer C Screening Programs

In the Kerala screening study, the research group undertook a detailed analysis of the costs of the program and was able to calculate the ICER [51]. They showed that the screening program produced a benefit of 270 life years saved per 100,000 for the whole population and 1438 life years for the high-risk groups. The incremental cost per life-year saved was US$835 for the whole screened population, but it decreased to US$156 for the high-risk group only. This cost is within the range considered acceptable in a low-middle-income country and suggests that opportunistic screening of high-risk groups may be feasible and cost-effective [50, 51]. However, it must be noted that there has not been an RCT or formal cost-effectiveness analysis in any high-income country or low-prevalence population. An alternative to a fully costed clinical trial is to simulate a screening program using computer modeling. Speight et al. [58] used simulation modeling to evaluate the outcome of screening on a population of 100,000 people over the age of 40 years. The model was a decision tree analysis informed by published NHS costs and using data on disease prevalence, malignant transformation, and test performance from previously published research. The modeling showed that whole-­ population screening was unlikely to be cost-effective but that targeting high-risk groups for opportunistic screening in medical or dental primary care may be cost-effective. They found that the ICER for an opportunistic high-risk screen was £22,850 by primary care dentist and £23,728 by a general medical practitioner. These costs assumed that detection and treatment of potentially malignant lesions would have no effect on disease progression. If the model assumed malignant transformation was reduced by 10% or 20%, the ICERs for opportunistic screening by a dentist were reduced to £18,919 and £15,790, respectively. These costs are below the cost-effectiveness threshold set by the United Kingdom and the United States [56, 57] and suggest that opportunistic high-risk screening in primary dental or medical care settings may be a cost-effective strategy. However, the simulation model assumed that detection of potentially malignant lesions may prevent further disease progression and reduce the incidence of invasive cancers. In their literature reviews, Speight et  al. [58] found little evidence that this is the case and undertook a value of information analysis, which estimates the value of future research that could be undertaken to reduce the uncertainty in the data. The analysis showed that the most valuable research should be directed at studies of the natural history of the oral cancer  – in particular to determine the exact malignant transformation rates of individual potentially malignant disorders and the rate of disease progression of established lesions of oral cancer. Further research was also needed on cancer referral pathways from primary to secondary care and the identification of sources of delay and how to prevent them.

210

P. M. Speight

16.4.3 

 pportunistic Screening for Oral O Cancer

The evidence discussed in 7 Sections 16.3.5 and 16.4.2 suggests that opportunistic screening of the oral cavity by visual examination in high-risk groups may be cost-effective and may provide an effective strategy for oral cancer screening. However, there are few studies on the ideal environment for undertaking opportunistic screening. In their simulation modeling, Speight et  al. [58] suggested that patients attending either a medical or dental practitioner could be effectively screened, but these estimates were based on attendance rates and disease prevalence. They did not account for the additional training that would be necessary to enable medical practitioners to examine the oral cavity. Since dentists are already trained, it seems intuitive that opportunistic screening in dental primary care, when a patient attends for a routine “checkup,” would be the most effective strategy. However, there is evidence that those thought to be at the highest risk of oral cancer, especially males over 40 who smoke and/or drink, are the least likely to attend for regular dental checkups [59]. Yusof et al. [60] analyzed patterns of attendance for regular dental checkups over a 10-year period and found that males over 40 years, who belonged to lower socioeconomic groups, and who were heavy smokers were less likely to attend than females, younger people, nonsmokers, and those from a higher socioeconomic class. These studies concluded that opportunistic screening is unlikely to be an effective strategy for early detection or prevention of oral cancer. Further research is needed to more fully understand the patient pathway to secondary care and to establish the frequency and nature of contacts that patients with oral cancer have had with a full range of healthcare professionals. This may identify more ideal sites for opportunistic screening by a wider range of healthcare workers. Integration of oral cancer screening with general health screening or with other cancer screening programs was found to be effective in Taiwan [44, 45, 52], but when trialed in a Japanese population, it was associated with low compliance among the elderly and a low yield of lesions, and regular smokers were less likely to attend for rescreening [26, 61, 62]. The Japanese screening program did however find that annual screening could detect new oral potentially malignant lesions in the screened population. Poor attendance for screening or regular checkups may also be related to a lack of awareness of the signs of oral cancer and its causes, meaning that individuals may not be aware that they are at high risk [63] and may not appreciate the importance of regular attendance. Research on attendance patterns may be helpful, but more health education on risk factors and the importance of oral health is needed. There is good evidence that health promotion aimed at smoking cessation may be effective in reducing the incidence of oral cancer [64] but also that regular dental attendance is associated with diagnosis of oral cancer at an earlier stage [65].  

16

16.5 

Conclusion and Future Perspectives

Overall, it appears clear that oral cancer is a significant health problem and that screening for oral cancer and for potentially malignant lesions is feasible. However, there are considerable barriers to the implementation of any sort of formal screening program. Although principle 1 suggested by Wilson and Jungner (. Table 16.1) [3] is met, the evidence for the other key principles is lacking or inconclusive. The main barriers and potential solutions and research priorities are summarized in . Table 16.7.  

 

Eyecatcher

Criteria for implementing screening for a disease require that the benefits and advantages of screening outweigh the disadvantages and any potential physical or psychological harm to subjects.

16.5.1 

 he Natural History of Oral Cancer T and Precancer

Although there is good evidence that an oral examination can detect potentially malignant lesions with a sensitivity and specificity sufficient to justify it as a screening test, the currently used criteria for a positive test are not sufficiently specific to identify only those lesions that have the highest probability of progression to cancer, since only about 5% of the most commonly detected lesions (leukoplakia) are expected to transform [30–32]. Even for those that will progress, studies have shown that the main source of uncertainty in determining the outcomes of an oral cancer screening program was a lack of knowledge of malignant transformation rates and disease progression [58].Currently, there are no biomarkers or accurate indicators of which lesions are most likely to progress (7 Section 16.3.3). Further research is needed on the natural history of oral cancer, the development of biomarkers, and the feasibility of commercially available clinical tests and adjunctive aids, all of which will help to inform the development of more accurate tests.  

16.5.2 

 he Management of Screen-Detected T Lesions

A further consideration is principle 2 (. Table  16.1). Although there are well established protocols for the management of oral cancer, the treatment for potentially malignant disorders remains controversial. Holmstrup et  al. [66, 67] showed that surgical removal of potentially malignant lesions did not prevent the development of oral cancer and suggested that this was because the clinically detectable lesion only represents one small part of a whole field of altered oral mucosa, any area of which could progress to  

211 Screening for Oral Cancer

..      Table 16.7  Barriers to the implementation of a screening program for oral cancer, with possible solutions and suggested areas of research Barrier

Possible solutions

Research priorities

Need more accurate tests that will detect those lesions that are most likely to be malignant or potentially malignant

Studies of malignant transformation rates Development and testing of adjunctive clinical tests and molecular biomarkers which identify the high-risk lesions

Establish clear, globally agreed protocols for the diagnosis and management of leukoplakia and other potentially malignant lesions

Prospective randomized controlled trials are needed

Methods for identifying and targeting high-risk groups may not be effective

Provide health education and resources for high-risk individuals to self-identify and attend for screening

Evaluate education programs and artificial intelligence as ways of supporting people to understand the risks

Opportunistic screening may work, but the best environment for this is not agreed. Regulatory bodies may restrict what type of healthcare workers are permitted to examine the mouth

Provide screening in a variety of environments also utilizing nonmedical or dental healthcare workers Utilize mHealth to support clinical decision-making and facilitate screening programs

Clinical trials to evaluate the effectiveness of screening by different types of healthcare practitioners workings in populations with low and high disease prevalence Evaluate mHealth systems to support screening programs

Screening programmes may not work, and there appears to be a high risk of lead-time bias

Solutions relate to the accuracy of the test and criteria for a positive result.

Programs need to be tested, ideally in randomized controlled trials. But demonstration studies and simulation modeling may also be informative

The natural history of oral cancer and precancer Only about 5% of screen-detected lesions may progress to cancer. The natural history of lesions is poorly understood The management of screen-detected lesions Lack of agreement on the effectiveness of treatment for potentially malignant lesions

Identification and targeting of high-risk groups

would be effective in a primary care setting. To make opportunistic screening more effective, methods are needed for the easy identification of high-risk groups so that dentists can appropriately target those most likely to have lesions. Apart from issues of health education [63, 64], this could be done using a simple patient checklist that enquires about tobacco and alcohol habits [72, 73]. Lim et al. [73] conducted a demonstration project of opportunistic screening in a group of selected general dental practices and used a patient checklist, which showed a strong correlation between self-reported habits of tobacco and alcohol use and the presence of oral potentially malignant lesions. Another effective way of identifying high-risk individuals may be to use artificial intelligence (AI) systems. These have been developed to support oral cancer screening and have been shown to be effective in identifying those at the 16.5.3  Identification of High-Risk Groups highest risk of having lesions [74, 75]. An advantage of and the Potential of mHealth using AI is that it can be embedded into a standard computerized system for medical history taking and internal algoIt also remains to be determined who should be screened and rithms can accurately flag patients at different levels of risk where. The evidence discussed in 7 Section 16.4.3 suggests [75]. Such a system could also be used in any setting (e.g., in that opportunistic screening of high-risk groups may be cost-­ a pharmacy or any waiting area) or be made available as a effective and may provide an effective strategy for oral cancer smartphone app, allowing patients to anonymously selfscreening, but it is not certain that opportunistic screening identify as high risk and seek advice. The use of mobile malignancy. A systematic review of interventions for treating leukoplakia [68] found few randomized controlled trials and a lack of evidence that any treatment options, including surgical intervention and preventive chemotherapy, are effective in reducing progression to oral cancer. A further systematic review on the surgical management of lesions shown to be dysplastic found evidence that surgery reduces malignant transformation rates [69], but the authors could not find any properly conducted trials. Holmstrup [70, 71] has highlighted this lack of evidence for the effectiveness of surgery for the treatment of oral precancer and has drawn attention to the urgent need for randomized controlled trials with long-term follow-up to establish optimal treatment protocols.

 

16

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P. M. Speight

phones (“mHealth”) is providing many new opportunities in the delivery of healthcare, especially in low- and middleincome countries and “last-mile” rural communities [76]. It is estimated that 97% of the world’s population live within reach of a mobile phone signal and mobile phones are increasingly being used to support cancer control programs by improving communications, enhancing attendance and compliance, and facilitating data collection and decision support [76]. Birur et  al. [77] have described a mobile phone-based oral cancer detection program using a hub and node model based on Bangalore, India. The mHealth system enabled remote dentists and frontline healthcare workers to input demographic and risk factor data and clinical photographs into a mobile phone app, linked directly to oral cancer specialist at a cancer center. Built-in algorithms identified high-­ risk patients for targeted examinations and follow-up, and any lesions detected were photographed and uploaded for interpretation by the center specialists. If a lesion met the criteria for a potentially malignant or malignant lesion, the specialist sent instructions for referral and follow-up. Two thousand patients were targeted for examination by healthcare workers, and 1440 were examined opportunistically by dentists, with a yield of 130 (6.5%) and 106 (7.36%) lesions in each group, respectively. The remote diagnosis was confirmed by the oral cancer specialist in 45% of cases photographed by the healthcare workers and in 100% of cases photographed by the dentists. However, of a total of 129 patients referred for biopsy and histological evaluation, only 62 attended: 1 (4%) from the targeted population and 61 (57%) referred by the dentists. Of the 61 lesions referred by the dentists, there was a high rate of true positives, with 49 shown to be dysplastic and 5 proving to be squamous cell carcinomas. A similar study in Malaysia [78] evaluated mobile phone imaging for early detection of oral cancer in 16 individuals. Lesions and normal areas of mucosa were photographed, and diagnoses on the images were compared to a gold-standard clinical examination by a specialist. Sensitivity exceeded 70% and specificity was 100%. Together, these studies show the potential of mHealth systems to support cancer screening and to improve the efficiency of early detection of oral potentially malignant or malignant lesions. 16.6 

Conclusion

This chapter reviews the principles of cancer screening and discusses the currently available evidence for the effectiveness of oral cancer screening programs. It is noted that no oral cancer screening program has yet been shown to be effective and no country has formally introduced a national program. Much work, however, has been done and there is evidence that screening is feasible. More research is needed to refine screening tests and to determine the optimal screening environment and ways to target appropriate population groups.

References 1. World Health Organization. National cancer control programmes: policies and managerial guidelines. 2nd ed. WHO; 2002. www.­who.­ int/cancer/media/en/408.­pdf. 2. Petersen PE. Oral cancer prevention and control – the approach of the World Health Organization. Oral Oncol. 2009;45:454–60. 3. Wilson JMG, Jungner G. Principles and practice of screening for disease. Geneva: WHO; 1968. 4. UK National Screening Committee. Criteria for appraising the viability, effectiveness and appropriateness of a screening programme. London, UK: National Screening Committee, 2003. Updated 2015: https://www.­gov.­uk/government/publications/evidence-reviewcriteria-national-screening-programmes. 5. Oral cancer Screening. National Cancer Institute: U.S. National Institutes of Health. http://www.­cancer.­gov/cancertopics/pdq/screening/oral/healthprofessional. 6. U.S. Preventive Services Task Force: Screening for Oral Cancer: Recommendation Statement. Rockville: U.S.  Preventive Services Task Force, 2004. http://www.­uspreventiveservicestaskforce.­org/Page/ Document/UpdateSummaryFinal/oral-cancer-screening1. 7. Speight PM, Epstein J, Kujan O, Lingen MW, Nagao T, Ranganathan K, Vargas P.  Screening for oral cancer  – a perspective from the Global Oral Cancer Forum. Oral Surg Oral Med Oral Pathol Oral Radiol. 2016;123:680–7. 8. Parkin DM, Moss SM. Lung cancer screening: improved survival but no reduction in deaths–the role of “overdiagnosis”. Cancer. 2000;89(11 Suppl):2369–76. 9. Chamberlain J, Moss S, editors. Evaluation of cancer screening. London: Springer; 1996. 10. Vermeer NC, Snijders HS, Holman FA, Liefers GJ, Bastiaannet E, van de Velde CJ, Peeters KC.  Colorectal cancer screening: systematic review of screen-related morbidity and mortality. Cancer Treat Rev. 2017;54:87–98. 11. de Koning HJ, Gulati R, Moss SM, Hugosson J, Pinsky PF, Berg CD, Auvinen A, Andriole GL, Roobol MJ, Crawford ED, Nelen V, Kwiatkowski M, Zappa M, Luján M, Villers A, de Carvalho TM, Feuer EJ, Tsodikov A, Mariotto AB, Heijnsdijk EAM, Etzioni R. The efficacy of prostate-specific antigen screening: impact of key components in the ERSPC and PLCO trials. Cancer. 2018;124:1197–206. 12. Chamberlain J. Evaluation of screening for cancer. Community Dent Health. 1993;10(Suppl 1):5–11. 13. Warnakulasuriya S. Global epidemiology of oral and oropharyngeal cancer. Oral Oncol. 2009;45:309–16. 14. Ferlay J, Soerjomataram I, Dikshit R, et  al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359–86. 15. Seoane J, Alvarez-Novoa P, Gomez I, et al. Early oral cancer diagnosis: The Aarhus statement perspective. A systematic review and meta-analysis. Head Neck. 2016;38(Suppl 1):E2182–9. 16. Rogers SN, Brown JS, Woolgar JA, et al. Survival following primary surgery for oral cancer. Oral Oncol. 2009;45:201–11. 17. Warnakulasuriya S, Johnson NW, van der Waal I. Nomenclature and classification of potentially malignant disorders of the oral mucosa. J Oral Pathol Med. 2007;36(10):575–80. 18. Chang IH, Jiang RS, Wong YK, Wu SH, Chen FJ, Liu SA. Visual screening of oral cavity cancer in a male population: experience from a medical center. J Chin Med Assoc. 2011;74:561–6. 19. Downer MC, Evans AW, Hughes Hallett CM, Jullien JA, Speight PM, Zakrzewska JM. Evaluation of screening for oral cancer and precancer in a company headquarters. Community Dent Oral Epidemiol. 1995;23:84–8. 20. Ikeda N, Downer MC, Ishii T, Fukano H, Nagao T, Inoue K.  Annual screening for oral cancer and precancer by invitation to 60 year-­old residents of a city in Japan. Community Dent Health. 1995;12: 133–7.

213 Screening for Oral Cancer

21. Jullien JA, Downer MC, Zakrzewska JM, Speight PM. Evaluation of a screening test for the early detection of oral cancer and precancer. Community Dent Health. 1995;12:3–7. 22. Mathew B, Sankaranarayanan R, Sunilkumar KB, Kuruvila B, Pisani P, Nair MK.  Reproducibility and validity of oral visual inspection by trained health workers in the detection of oral precancer and cancer. Brit J Cancer. 1997;76:390–4. 23. Mehta FS, Gupta PC, Bhonsle RB, et  al. Detection of oral cancer using basic health workers in an area of high oral cancer incidence in India. Cancer Detect Prev. 1986;9:219–25. 24. Warnakulasuriya S, Pindborg JJ. Reliability of oral precancer screening by primary health care workers in Sri Lanka. Community Dent Health. 1990;7:73–9. 25. Monteiro LS, Salazar F, Pacheco JJ, Martins M, Warnakulasuriya S. Outcomes of invitational and opportunistic oral cancer screening initiatives in Oporto, Portugal. J Oral Pathol Med. 2015 Feb;44: 145–52. 26. Nagao T, Ikeda N, Fukano H, Miyazaki H, Yano M, Warnakulasuriya S. Outcome following a population screening programme for oral cancer and precancer in Japan. Oral Oncol. 2000 Jul;36:340–6. 27. Walsh T, Liu JL, Brocklehurst P, Glenny AM, Lingen M, Kerr AR, et al. Clinical assessment to screen for the detection of oral cavity cancer and potentially malignant disorders in apparently healthy adults. Cochrane Database Syst Rev. 2013;11:CD010173. 28. Downer MC, Moles DR, Palmer S, Speight PM. A systematic review of test performance in screening for oral cancer and precancer. Oral Oncol. 2004;40:264–73. 29. Petti S. Pooled estimate of world leukoplakia prevalence: a systematic review. Oral Oncol. 2003;39:770–80. 30. Napier SS, Speight PM. Natural history of potentially malignant oral lesions and conditions: an overview of the literature. J Oral Pathol Med. 2008;37:1–10. 31. Warnakulasuriya S, Ariyawardana A.  Malignant transformation of oral leukoplakia: a systematic review of observational studies. J Oral Pathol Med. 2016;45:155–66. 32. Speight PM, Khurram SA, Kujan O. Oral potentially malignant disorders: risk of progression to malignancy. Oral Surg Oral Med Oral Pathol Oral Radiol. 2017;. pii: S2212-4403(17)31248-8. 33. Warnakulasuriya S, Reibel J, Bouquot J, Dabelsteen E. Oral epithelial dysplasia classification systems: predictive value, utility, weaknesses and scope for improvement. J Oral Pathol Med. 2008;3: 127–33. 34. Warnakulasuriya S. Lack of molecular markers to predict malignant potential of oral precancer. J Pathol. 2000;190:407–9. 35. Lingen MW, Kalmar JR, Karrison T, Speight PM. Critical evaluation of diagnostic aids for the detection of oral cancer. Oral Oncol. 2008;44:10–22. 36. Macey R, Walsh T, Brocklehurst P, Kerr AR, Liu JL, Lingen MW, et al. Diagnostic tests for oral cancer and potentially malignant disorders in patients presenting with clinically evident lesions. Cochrane Database Syst Rev. 2015;5:CD010276. 37. Lingen MW, Tampi MP, Urquhart O, Abt E, Agrawal N, Chaturvedi AK, Cohen E, D'Souza G, Gurenlian J, Kalmar JR, Kerr AR, Lambert PM, Patton LL, Sollecito TP, Truelove E, Banfield L, Carrasco-Labra A. Adjuncts for the evaluation of potentially malignant disorders in the oral cavity: diagnostic test accuracy systematic review and meta-analysis-a report of the American Dental Association. J Am Dent Assoc. 2017;148:797–813. 38. Lingen MW, Abt E, Agrawal N, Chaturvedi AK, Cohen E, D'Souza G, Gurenlian J, Kalmar JR, Kerr AR, Lambert PM, Patton LL, Sollecito TP, Truelove E, Tampi MP, Urquhart O, Banfield L, Carrasco-Labra A. Evidence-based clinical practice guideline for the evaluation of potentially malignant disorders in the oral cavity: a report of the American Dental Association. J Am Dent Assoc. 2017;148:712–27. 39. Rethman MP, Carpenter W, Cohen EE, Epstein J, Evans CA, Flaitz CM, et al. Evidence-based clinical recommendations regarding screening for oral squamous cell carcinomas. J Am Dent Assoc. 2010;141:509–20.

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40. González RS. Cancer screening: global debates and Cuban experience. MEDICC Rev. 2014;16:73–7. 41. Santana JC, Delgado L, Miranda J, Sánchez M.  Oral Cancer Case Finding Program (OCCFP). Oral Oncol. 1997;33:10–2. 42. Frenández Garrote L, Sankaranarayanan R, Lence Anta JJ, Rodriguez Salvá A, Maxwell Parkin D. An evaluation of the oral cancer control program in Cuba. Epidemiology. 1995;6:428–31. 43. Yen AM, Chen SC, Chen TH.  Dose-response relationships of oral habits associated with the risk of oral pre-malignant lesions among men who chew betel quid. Oral Oncol. 2007;43:634–8. 44. Chen TH, Chiu YH, Luh DL, et al. Community-based multiple screening model: design, implementation, and analysis of 42,387 participants. Cancer. 2004;100:1734–43. 45. Taiwan Breast cancer, Oral cancer and Colorectal cancer Screening Programs. Taiwan Ministry of Health and Welfare. https://www.­hpa.­ gov.­tw/EngPages/Detail.­aspx?nodeid=1051&pid=5957. Accessed May 2018. 46. Brocklehurst P, Kujan O, O’Malley LA, Ogden G, Shepherd S, Glenny AM. Screening programmes for the early detection and prevention of oral cancer. Cochrane Database Syst Rev. 2013;11:CD004150. 47. Sankaranarayanan R, Mathew B, Jacob BJ, Thomas G, Somanathan T, Pisani P, Pandey M, Ramadas K, Najeeb K, Abraham E. Early findings from a community-based, cluster-randomized, controlled oral cancer screening trial in Kerala, India. The Trivandrum Oral Cancer Screening Study Group. Cancer. 2000;88:664–73. 48. Ramadas K, Sankaranarayanan R, Jacob BJ, Thomas G, Somanathan T, Mahe C, Pandey M, Abraham E, Najeeb S, Mathew B, Parkin DM, Nair MK. Interim results from a cluster randomized controlled oral cancer screening trial in Kerala, India. Oral Oncol. 2003;39:580–8. 49. Sankaranarayanan R, Ramadas K, Thomas G, Muwonge R, Thara S, Mathew B, Rajan B, Trivandrum Oral Cancer Screening Study Group. Effect of screening on oral cancer mortality in Kerala, India: a cluster-randomised controlled trial. Lancet. 2005;365:1927–33. 50. Sankaranarayanan R, Ramadas K, Thara S, Muwonge R, Thomas G, Anju G, Mathew B. Long term effect of visual screening on oral cancer incidence and mortality in a randomized trial in Kerala, India. Oral Oncol. 2013;49:314–21. 51. Subramanian S, Sankaranarayanan R, Bapat B, Somanathan T, Thomas G, Mathew B, Vinoda J, Ramadas K.  Cost-effectiveness of oral cancer screening: results from a cluster randomized controlled trial in India. Bull World Health Organ. 2009;87:200–6. 52. Chuang SL, Su WW, Chen SL, Yen AM, Wang CP, Fann JC, Chiu SY, Lee YC, Chiu HM, Chang DC, Jou YY, Wu CY, Chen HH, Chen MK, Chiou ST.  Population-based screening program for reducing oral cancer mortality in 2,334,299 Taiwanese cigarette smokers and/or betel quid chewers. Cancer. 2017;123:1597–609. 53. Downer MC, Jullien JA, Speight PM.  An interim determination of health gain from oral cancer and precancer screening: 1. Obtaining health state utilities. Community Dent Health. 1997;14:139–42. 54. Downer MC, Jullien JA, Speight PM.  An interim determination of health gain from oral cancer and precancer screening: 2. Developing a model of population screening. Community Dent Health. 1997;14:227–32. 55. Woods B, Revill P, Sculpher M, Claxton K.  Country-level cost-­ effectiveness thresholds: initial estimates and the need for further research. Value Health. 2016;19:929–35. 56. National Institute for Health and Care Excellence (NICE). Carrying NICE over the threshold. https://www.­nice.­org.­uk/news/blog/ carrying-­nice-over-the-threshold. Accessed May 2018. 57. Neumann PJ, Cohen JT, Weinstein MC.  Updating cost-­ effectiveness—the curious resilience of the $50,000-per-QALY threshold. N Engl J Med. 2014;371:796–7. 58. Speight PM, Palmer S, Moles DR, Downer MC, Smith DH, Henriksson M, Augustovski F. The cost-effectiveness of screening for oral cancer in primary care. Health Technol Assess. 2006;10:1–144. 59. Netuveli G, Sheiham A, Watt RG.  Does the ‘inverse screening law’ apply to oral cancer screening and regular dental check-ups? J Med Screen. 2006;13:47–50.

214

P. M. Speight

60. Yusof ZY, Netuveli G, Ramli AS, Sheiham A. Is opportunistic oral cancer screening by dentists feasible? An analysis of the patterns of dental attendance of a nationally representative sample over 10 years. Oral Health Prev Dent. 2006;4:165–71. 61. Nagao T, Warnakulasuriya S, Ikeda N, Fukano H, Fujiwara K, Miyazaki H.  Oral cancer screening as an integral part of general health screening in Tokoname City, Japan. J Med Screen. 2000;7:203–8. 62. Nagao T, Warnakulasuriya S. Annual screening for oral cancer detection. Cancer Detect Prev. 2003;27:333–7. 63. Warnakulasuriya KA, Harris CK, Scarrott DM, Watt R, Gelbier S, Peters TJ, Johnson NW. An alarming lack of public awareness towards oral cancer. Br Dent J. 1999;187:319–22. 64. van der Waal I. Are we able to reduce the mortality and morbidity of oral cancer; some considerations. Med Oral Patol Oral Cir Bucal. 2013;18:e33–7. 65. Langevin SM, Michaud DS, Eliot M, Peters ES, McClean MD, Kelsey KT. Regular dental visits are associated with earlier stage at diagnosis for oral and pharyngeal cancer. Cancer Causes Control. 2012;23:1821–9. 66. Holmstrup P, Vedtofte P, Reibel J, Stoltze K.  Long-term treatment outcome of oral premalignant lesions. Oral Oncol. 2006;42:461–74. 67. Holmstrup P, Vedtofte P, Reibel J, Stoltze K.  Oral premalignant lesions: is a biopsy reliable? J Oral Pathol Med. 2007;36:262–6. 68. Lodi G, Franchini R, Warnakulasuriya S, et al. Interventions for treating oral leukoplakia to prevent oral cancer. Cochrane Database Syst Rev. 2016;7:CD001829. 69. Mehanna HM, Rattay T, Smith J, McConkey CC. Treatment and follow-­up of oral dysplasia  – a systematic review and meta-analysis. Head Neck. 2009;31:1600–9.

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70. Holmstrup P. Can we prevent malignancy by treating premalignant lesions? Oral Oncol. 2009;45:549–50. 71. Holmstrup P, Dabelsteen E. Oral leukoplakia-to treat or not to treat. Oral Dis. 2016;22:494–7. 72. McGurk M, Scott SE. The reality of identifying early oral cancer in the general dental practice. Br Dent J. 2010;208:347–51. 73. Lim K, Moles DR, Downer MC, Speight PM. Opportunistic screening for oral cancer and precancer in general dental practice: results of a demonstration study. Br Dent J. 2003;194:497–502. 74. Speight PM, Elliott AE, Jullien JA, Downer MC, Zakzrewska JM. The use of artificial intelligence to identify people at risk of oral cancer and precancer. Br Dent J. 1995;179:382–7. 75. Speight PM, Hammond P. The use of machine learning in screening for oral cancer. In: Naguib RNG, Sherbet GV, editors. Artificial neural networks in cancer diagnosis, prognosis, and patient management. Boca Raton: CRC Press; 2001. 76. Bhatt S, Evans J.  Mobile healthcare for cancer care and control in low- and middle-income countries. In: Finkel ML, editor. Cancer screening in the developing world. New England: Dartmouth College Press; 2018. 77. Birur PN, Sunny SP, Jena S, Kandasarma U, Raghavan S, Ramaswamy B, Shanmugam SP, Patrick S, Kuriakose R, Mallaiah J, Suresh A, Chigurupati R, Desai R, Kuriakose MA. Mobile health application for remote oral cancer surveillance. J Am Dent Assoc. 2015;146:886–94. 78. Haron N, Zain RB, Nabillah WM, Saleh A, Kallarakkal TG, Ramanathan A, Sinon SH, Razak IA, Cheong SC.  Mobile phone imaging in low resource settings for early detection of oral cancer and concordance with clinical oral examination. Telemed J E Health. 2017;23:192–9.

215

Lifestyle Interventions for the Prevention of Oral Cancer Pankaj Chaturvedi, Swagnik Chakrabarti, and Arjun Gurmeet Singh

17.1

Introduction – 216

17.2

Lifestyle and Oral Cancer – 216

17.3

Tobacco – 216

17.3.1

Oral Cancer Risk among ex-Smokers – 217

17.4

Tobacco Cessation – 217

17.4.1

Ways to Reduce Tobacco Use – 218

17.5

Alcohol and Oral Cancer – 219

17.5.1

Ways to Reduce Alcohol Use – 220

17.6

Areca Nut – 220

17.6.1

Effect of Cessation – 220

17.7

Dietary Habits and Oral Cancer – 220

17.8

Other Emerging Lifestyle Risk Factors and Oral Cancer – 220

17.8.1 17.8.2 17.8.3

 oor Oral Hygiene and Oral Cancer – 220 P Maté Drinking – 221 Human Papillomavirus (HPV) – 221

17.9

Modified Lifestyles of Cancer Survivors – 221

17.10 Some Successful Oral Cancer Awareness Programs – 221 17.11 Conclusion – 222 References – 223

© Springer Nature Switzerland AG 2020 S. Warnakulasuriya, J. S. Greenspan (eds.), Textbook of Oral Cancer, Textbooks in Contemporary Dentistry, https://doi.org/10.1007/978-3-030-32316-5_17

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Core Message Lifestyle-related risk factors contribute significantly to the etiology of oral cancer. These include tobacco and alcohol use and areca nut chewing, while emerging factors include poor oral hygiene, microbes, maté consumption, and HPV infection. Tobacco use has decreased in high-income countries in the past few decades, but heavy use still continues in middle- and low-income countries. Primary prevention in the form of appropriate health education aiming at modifying lifestyles is the key to prevention of oral cancer.

17.1 

17

Introduction

Even after major developments in the fields of public awareness, health education, and treatment facilities over the past decade, the incidence of and mortality from cancer have not decreased; instead both are on the rise [1]. Cancer is known to occur in those who are exposed to certain risk factors, many having innate susceptibility to its development. Major factors cited relate to lifestyle [2]. These behavioral and environmental lifestyle factors include addictive substance use, reproductive practices, diets, physical inactivity, and exposure to polluted air [3]. About 35% of the attributable fraction of cancer cases is due to the joint effect of these lifestyle factors [3]. Such exposure can be reduced by modifying lifestyle which could eventually have a sizable impact on the overall incidence of cancer. The etiology of various cancers differs across geographical and socioeconomic backgrounds. Colorectal cancer being predominantly caused by an unhealthy diet and obesity is more prevalent in developed countries like Australia, Europe, and North America, while smoking-associated lung cancer is common in Eastern Asia, Europe, and North America. Stomach cancer, most often associated with Helicobacter pylori infection and dietary habits, is rampant in the endemic regions like Eastern Asia (particularly in Japan, Korea, Mongolia, and China). Cervical cancers, having known risk factors like HPV, poor genital hygiene, early age of pregnancy, and multiple pregnancies, predominantly occur in the less-­developed countries [4]. Thus, this diversity in risk factors for various cancers reflects a strong association with varied lifestyles across the globe. 17.2 

Lifestyle and Oral Cancer

Like many other cancers, oral cancer is predominantly associated with lifestyle risk factors. Traditional risk factors for the development of oral cancer (presented in 7 Chapter 3) include the use of tobacco and alcohol and areca nut chewing, while others include hot maté drinking, poor oral hygiene, and dietary deficiencies [5–7]. The geographical heterogeneity of the incidence of oral cancer (discussed in 7 Chapter 2) is fairly consistent with the global distribution of these associated habits. For example, oral cancer continues  

 

to be of high incidence in middle- and low-income countries where there is heavy use of the key risk factors, such as cigarette smoking, tobacco and areca nut chewing, and alcohol abuse. In high-income countries like the United States, Canada, and parts of Western and Southern Europe, there is significant decline in the prevalence of tobacco-related oral cancer consistent with the decrease in cigarette smoking over the past four decades [8]. On the other hand, several authors have found an increase in the overall number of oral and oropharyngeal cancer patients in the West, especially among younger men [9–11]. One study found this increase to be significant at younger ages (Important Addressing lifestyle issues by deploying proactive 7.6% over a period of 17 years [64]. nationwide public health measures specifically Areca nut is commonly chewed with tobacco. However, stressing educating and altering these practices is the the detrimental effects of chewing areca nut alone and its key to reduce the burden of oral cancer worldwide relative contribution in the causation of oral cancer are well especially in less developed countries. established, especially among Taiwanese. One study evaluated the effect of tobacco-free areca nut chewing on head and neck cancer in the Taiwanese population. They recruited 487 men newly diagnosed with head and neck cancer and 617 17.8  Other Emerging Lifestyle Risk Factors male controls who were age-matched to the cases. A nonlinand Oral Cancer ear positive association between areca nut chewing and head and neck cancer was found with the highest risk for the first 17.8.1  Poor Oral Hygiene and Oral Cancer 5 pack-years [65]. A meta-analysis of 50 published studies assessing the Poor oral hygiene has been a considered as a risk factor relationship between oral and oropharyngeal cancers and with limited evidence, but few studies have found this to be betel quid chewing, with or without added tobacco, showed an independent risk factor persisting after adjustment for that the risk increased in a dose-dependent manner, inde- confounders [70–73]. A recent study found that three spependent of tobacco or alcohol use. For the group using betel cies of periodontopathogenic bacteria, Prevotellatannerae, quid without tobacco, among Indian or Pakistani subjects, ­Fusobacterium nucleatum, and Prevotella intermedia, were the risk was 2.56 (95%CI, 2.00–3.28; 15 studies), and in associated with an increased oral cancer risk [74]. The use

221 Lifestyle Interventions for the Prevention of Oral Cancer

of alcohol, betel quid, and cigarettes and poor oral hygiene were associated with an abundance of oral periodontopathogenic bacteria. Poor dental health can result in inflammatory changes and higher levels of inflammatory cytokines, which eventually might lead to facilitation of carcinogenesis and malignant transformation in high-risk individuals. Another mechanism suggested is an association with alcoholism and the role of biofilms and microbes facilitating the metabolism of ethanol to acetaldehyde (a class 1 carcinogen) [75]. Improving oral hygiene may reduce oral cancer risk. Maintenance of good oral hygiene, brushing of teeth, and regular dental checkups are simple but important lifestyle modifications in preventing oral cancer and should be included as a part of public health campaigns to control oral cancer. 17.8.2 

Maté Drinking

Yerba maté is a beverage made from fermented leaves and stems of Ilex paraguariensis, majorly consumed in Latin American countries like Argentina, Uruguay, Paraguay, and Southern Brazil (Chimarrão). Initially it was found that maté drinkers have a threefold increase in laryngeal cancers [76]. A meta-analysis based on four studies estimated an increased risk (OR of 2.11; 95% CI: 1.39, 3.19) of developing oral cancer in maté users [77]. Its use has also been linked with esophageal cancers. Maté when consumed hot had a threefold increase risk than cold maté. It is important to realize this emerging possibly lifestyle risk factor and take action to reduce its consumption early, as a study has shown an astonishingly high annual consumption of 6–8 kg per person of maté in Uruguay [78]. A recent IARC monograph reevaluated the latest evidence of its carcinogenic effects and concluded that very hot maté (>65 °C) still remains a probable carcinogen to humans (Group 2A), while maté that is not very hot is not considered carcinogenic to humans (Group 3) [79]. A recent meta-analysis based on 15 reported studies, however, reported that both hot and cold maté could cause cancer in the mouth, pharynx, larynx, and esophagus [80]. There are no reports on interventions on maté drinking from Latin American countries. 17.8.3 

Human Papillomavirus (HPV)

There is sufficient evidence, particularly from Western countries, suggesting an association between HPV and head and neck cancer, independent of tobacco and alcohol use [81]. This is especially true for the oropharynx but substantially affects the oral cavity as well. A recent systematic review gathered the evidence associating the role of different sexual behaviors in the causation of oral and oropharyngeal cancers. The results indicated a significantly increased risk of developing oral cancer with a high number of lifetime sexual partners (nine studies), practice of oral sex (five studies), and homosexual relations (two cohort studies). The results for other sexual behaviors were inconsistent and limited [82].

The incidence of oral cancer is rising, affecting youth, especially those reporting no major risk habits such as smoking and alcohol consumption, suggesting a clear change in sexual behaviors that is linked to sexual transmission of HPV [83]. This requires a conscious change in lifestyle to reduce the number of HPV-associated oral cancers. Sex education at an early age and gender-neutral HPV vaccination should be considered at policy levels. !!Warning Much of the Western literature has shifted its focus on the changing trends in etiology of oral and oropharyngeal cancer, from tobacco to HPV, with special pertinence to the emerging lifestyle changes like modern sexual practices.

17.9 

Modified Lifestyles of Cancer Survivors

Studies of cancer survivors give an indication of the importance attributable to modification of lifestyles and behaviors in the hope of preventing recurrences [84, 85]. Several surveys give examples of changes to lifestyles in about 50–80% of the clinic populations attending follow-up following cancer therapy [86, 87]. In these cases, the dramatic effects of the disease may create an opportune time for health modifications. Cancer survivors thus can set an excellent example of lifestyle modifications and act as well-informed nuclei for society, helpful in propagating health education to the population at risk of developing oral cancer. Eyecatcher

Lifestyle-related modifications to major risk factors can be an effective method in the primary prevention of this consuming disease.

17.10 

 ome Successful Oral Cancer S Awareness Programs

With the help of the World Health Organization (WHO) in the recent decades, many countries have initiated National Cancer Control Programmes (NCCP). Targeted oral cancer awareness programs have been included in these measures since its inception in the Western countries, while it is quite nascent in the developing world. Some examples of these are as follows: 55 The National Oral Cancer Awareness Program, USA, empowers nurses who play a significant role in patient health education and therefore became a part of this cooperative effort [88]. 55 West of Scotland Cancer Awareness Programme (WoSCAP), Scotland. The chief intention of this ­campaign was to mobilize people to visit their health practitioners for regular checkups and seek advice regarding anything suspicious. Their slogan was “if in

17

222

P. Chaturvedi et al.

TTobacco obacc cco o

In Inc Incentive centive programs p rog grams

G Group rou oup p or or IIndividual ndi d vid di duall

D eadict ctiion Deadiction programs p ro ograamss

Com Co mbi bin natio ion n Combination ttherapy herrapy he ((medication me edi d cat atiion + psyc ps ycho yc ho osocia iall) psychosocial)

Publ Pu blic bl ic aawarness warn rne es s Public

W hatt can ha can a What healthcare he ealthccare work wo rker ker do?? do?? o??? worker

Alcohol A lcohol

D Deadiction eadict ctiion programs p rog grams

Arecaa n Arec ut Areca nut

Cesation C esa sati tio on programs p rog grams

Dietary D ietary h habits abi bitts

Poor P oorr oral oo oral hyygien ene e and and hygiene Chr Ch ronic trauma trau aum ma Chronic

Com Combination C ombin binati attion ttherapy her erap ap py (medica cattion + (medication psych hosociiall) psychosocial)

V Vegetables egeta tabl ble es and and fruits fru fr uits

IIncrease ncre reaase in in citrus ci itruss ffruits ruit its

Pr Pro ocessed d meat me at Processed

R educe rred ed Reduce me att iintake nttake k meat

R Regular egular Dental Dent ntaal ccheckups hec eckkups HPV H PV

EEmerging mergi ging habits habits its

SSex ex education ed ducattion HPV Vaccination HPV Va Vacc ccin inat atio ion n

M até drinking drink inking ing Maté SSecond econd d h and/Passive hand/Passive smo sm oking smoking

..      Fig. 17.1  Action needed to improve lifestyles for combating oral cancer

17

doubt, get it checked out” and was broadcasted in the form of reports on the local news, television commercials (40 seconds), and the radio. The result was that nearly all dentists (92.4%) in the region had heard about this campaign and about 40% indicated an increase in referrals [89]. 55 Oral, Head, and Neck Cancer Awareness Week (OHANCAW), USA. The Head and Neck Cancer Alliance promotes this week every year. The goal of this initiative is to encourage people to take advantage of free screening available all across the United States and abroad during this week, involving both health practitioners and patients [90]. 55 British Oral Health Foundation Mouth Cancer Action Month, UK. The foundation runs a month-long campaign in November to increase the awareness of mouth cancer. They often have a theme to the month and urge all dental professionals to wear blue ribbons to show their support [91]. Mass media are encouraged to write

feature articles in press or TV channels to promote education on risk factors and improve awareness on symptoms of the disease. 55 Let’s Talk About Mouth Cancer is a Scottish Charitable Incorporated Organisation that promotes improvements in oral health including mouth self-examination. 55 National Cancer Screening Program, India. The Indian government launched a nationwide screening program in 2016 to screen for oral, breast, and cervical cancers, which will be mandatory for individuals over 30 years of age. It initially started in 100 districts before it expands to the rest of the country [92]. 17.11 

Conclusion

Lifestyle-related modifications to major risk factors can be an effective method in primary prevention of this consuming disease. Although there has been increased public awareness

223 Lifestyle Interventions for the Prevention of Oral Cancer

in the more developed countries, tobacco and alcohol abuse is still rampant in less developed nations, resulting in high incidence of oral cancer. Proactive awareness programs stressing on lifestyle modifications one are key to reducing the burden of oral cancer worldwide, especially in less developed countries (. Fig. 17.1).  

References 1. You W, Henneberg M. Cancer incidence increasing globally: the role of relaxed natural selection. Evol Appl. 2018;11(2):140–52. https:// doi.org/10.1111/eva.12523. 2. Anand P, Kunnumakara AB, Sundaram C, et al. Cancer is a preventable disease that requires major lifestyle changes. Pharm Res. 2008;25(9):2097–116. https://doi.org/10.1007/s11095-008-­9661-­9. 3. Weiderpass E. Lifestyle and cancer risk. J Prev Med Public Health. 2010;43(6):459–71. https://doi.org/10.3961/jpmph.2010.43.6.459. 4. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108. https:// doi.org/10.3322/caac.21262. Epub 2015 Feb 4 5. Sankaranarayanan R, Ramadas K, Amarasinghe H, et al. Oral cancer: prevention, early detection, and treatment. In: Gelband H, Jha P, Sankaranarayanan R, et al., editors. Cancer: disease control priorities, vol. 3. 3rd ed. Washington (DC): The International Bank for Reconstruction and Development / The World Bank; 2015. Chapter 5. Available from: https://www.­ncbi.­nlm.­nih.­gov/books/ NBK343649/. https://doi.org/10.1596/978-1-4648-0349-9_ch5. 6. Hashibe M, Brennan P, Benhamou S, et al. Alcohol drinking in never users of tobacco, cigarette smoking in never drinkers, and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. J Natl Cancer Inst. 2007;99:777–89. 7. Johnson NW, Warnakulasuriya S, Gupta PC, et al. Global oral health inequalities in incidence and outcomes for oral cancer: causes and solutions. Adv Dent Res. 2011;23:237–46. 8. Cancer Incidence in Five Continents, Volumes I to IX (electronic version). Lyon: International Agency for research on Cancer. Available from: http://ci5.­iarc.­fr. Accessed [05/05/2018]. 9. Weatherspoon DJ, Chattopadhyay A, Boroumand S, Garcia AI. Oral cavity and oropharyngeal cancer incidence trends and disparities in the United States: 2000–2010. Cancer Epidemiol. 2015;39(4):497– 504. https://doi.org/10.1016/j.canep.2015.04.007. 10. Chaturvedi AK, Anderson WF, Lortet-Tieulent J, et al. Worldwide trends in incidence rates for oral cavity and oropharyngeal cancers. J Clin Oncol. 2013;31(36):4550–9. https://doi.org/10.1200/ JCO.2013.50.3870. Epub 2013 Nov 18 11. Warnakulasuriya S. Global epidemiology of oral and oropharyngeal cancer. Oral Oncol. 2009;45(4–5):309–16. https://doi.org/10.1016/j. oraloncology.2008.06.002. Epub 2008 Sep 18 12. Herrero R, Castellsagué X, Pawlita M, IARC Multicenter Oral Cancer Study Group, et al. Human papillomavirus and oral cancer: the International Agency for Research on Cancer multicenter study. J Natl Cancer Inst. 2003;95(23):1772–83. 13. Bedi R. Betel-quid and tobacco chewing among the United Kingdom’s Bangladeshi community. Br J Cancer Suppl. 1996;29: S73–7. 14. Llewellyn CD, Johnson N, Warnakulasuriya K. Risk factors for squamous cell carcinoma of the oral cavity in young people—a comprehensive literature review. Oral Oncol. 2001;37:401–18. 15. Al-Maweri SA, Tarakji B, Alsalhani AB, et al. Oral cancer awareness of the general public in Saudi Arabia. Asian Pac J Cancer Prev. 2015;16(8):3377–81. 16. WHO report on the global tobacco epidemic, 2017: monitoring tobacco use and prevention policies. Geneva: World Health Organization; 2017. Licence: CC BY-NC-SA 3.0 IGO.

17

17. Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC Cancer Base no. 11 [Internet]. International Agency for Research on Cancer: Lyon; 2013. 18. Niaz K, Maqbool F, Khan F, Bahadar H, Ismail HF, Abdollahi M. Smokeless tobacco (paan and gutkha) consumption, prevalence, and contribution to oral cancer. Epidemiol Health. 2017; 39:e2017009. https://doi.org/10.4178/epih.e2017009. 19. Sinha DN, Suliankatchi RA, Gupta PC, et al. Global burden of all-­ cause and cause-specific mortality due to smokeless tobacco use: systematic review and meta-analysis. Tob Control. 2018;27(1):35– 42. https://doi.org/10.1136/tobaccocontrol-2016-053302. Epub 2016 Nov 30 20. Sadri G, Mahjub H. Tobacco smoking and oral cancer: a meta-­ analysis. J Res Health Sci. 2007;7(1):18–23. 21. Awan KH, Patil S. Association of smokeless tobacco with oral cancer- evidence from the South Asian Studies: a systematic review. J Coll Physicians Surg Pak. 2016;26(9):775–80. 22. Sinha DN, Abdulkader RS, Gupta PC. Smokeless tobacco-­associated cancers: a systematic review and meta-analysis of Indian studies. Int J Cancer. 2016;138(6):1368–79. https://doi.org/10.1002/ijc.29884. Epub 2015 Oct 27 23. La Vecchia C, Franceschi S, Bosetti C, Levi F, Talamini R, Negri E. Time since stopping smoking and the risk of oral and pharyngeal cancers. J Natl Cancer Inst. 1999;91(8):726–8. 24. Sweeney B, Grayling M. Smoking and anaesthesia: the pharmacological implications. Anaesthesia. 2009;64(2):179–86. Available from: http://www3.­interscience.­wiley.­com/journal/121575043/ abstract. 25. Australian and New Zealand College of Anaesthetists. Statement on smoking as related to the perioperative period. Review PS12 (2007). Melbourne: Australian and New Zealand College of Anaesthetists, 2007. 26. Wong J, Lam DP, Abrishami A, Chan MT, Chung F. Short-term preoperative smoking cessation and postoperative complications: a systematic review and meta-analysis. Can J Anaesth. 2012;59(3):268–79. https://doi.org/10.1007/s12630-011-9652-x. Epub 2011 Dec 21 27. Hatcher JL, Sterba KR, Tooze JA, et al. Tobacco use and surgical outcomes in head and neck cancer patients. Head Neck. 2016;38(5):700– 6. https://doi.org/10.1002/hed.23944. 28. Browman GP, Wong G, Hodson I, et al. Influence of cigarette smoking on the efficacy of radiation therapy in head and neck cancer. N Engl J Med. 1993;328(3):159–63. 29. Koshiaris C, Aveyard P, Oke J, et al. Smoking cessation and survival in lung, upper aero-digestive tract and bladder cancer: cohortstudy. Br J Cancer. 2017;117(8):1224–32. https://doi.org/10.1038/ bjc.2017.179. Epub 2017 Sep 12 30. Overgaard J, Nielsen JE, Grau C. Effect of carboxyhemoglobin on tumor oxygen unloading capacity in patients with squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys. 1992;22(3):407–10. 31. Gupta PC, Murti PR, Bhonsle RB, Mehta FS, Pindborg JJ. Effect of cessation of tobacco use on the incidence of oral mucosal lesions in a 10-yr follow-up study of 12,212 users. Oral Dis. 1995;1(1):54–8. 32. Fijuth J, Mazeron JJ, Le Péchoux C, et al. Second head and neck cancers following radiation therapy of T1 and T2 cancers of the oral cavity and oropharynx. Int J Radiat Oncol Biol Phys. 1992;24:59. 33. Warren S, Gates DC. Multiple primary malignant tumors: a survey of the literature. Am J Cancer. 1932;16:1358. 34. Hong WK, Lippman SM, Itri LM, et al. Prevention of second primary tumors with isotretinoin in squamous cell carcinoma of the head and neck. N Engl J Med. 1990;323:795. 35. Gluckman JL, Crissman JD, Donegan DO. Multicentric squamous-­ cell carcinoma of the upper aerodigestive tract. Head Neck Surg. 1980;3:90. 36. Haughey BH, Gates GA, Arfken CL, Harvey J. Meta-analysis of second malignant tumors in head and head cancer: the case for an endoscopic screening protocol. Ann Otol Rhinol Laryngol. 1992;101:105.

224

17

P. Chaturvedi et al.

37. Schwartz LH, Ozsahin M, Zhang GN, et al. Synchronous and metachronous head and neck carcinomas. Cancer. 1994;74:1933. 38. Day GL, Blot WJ, Shore RE, et al. Second cancers following oral and pharyngeal cancers: role of tobacco and alcohol. J Natl Cancer Inst. 1994;86(2):131–7. 39. Jha P, MacLennan M, Chaloupka FJ, et al. Global hazards of tobacco and the benefits of smoking cessation and tobacco taxes. In: Gelband H, Jha P, Sankaranarayanan R, et al., editors. Cancer: disease control priorities, third edition (volume 3). Washington, DC: The International Bank for Reconstruction and Development / The World Bank; 2015. Chapter 10. Available from: https://www.­ncbi.­nlm.­nih.­gov/books/ NBK343639/. https://doi.org/10.1596/978-1-­4648-0349-9_ch10. 40. Jha P, Ramasundarahettige C, Landsman V, et al. 21st-century hazards of smoking and benefits of cessation in the United States. N Engl J Med. 2013;368(4):341–50. https://doi.org/10.1056/ NEJMsa1211128. 41. Chaloupka F, Yurekli A, Fong GT. Tobacco taxes as a tobacco control strategy. Tob Control. 2012;21(2):172–80. 42. Jha P, Chaloupka FJ. Curbing the epidemic: governments and the economics of tobacco. Washington, DC: The World Bank; 1999. 43. Global Adult Tobacco Survey. Fact sheet China 2010. Available at: http://www.­w ho.­i nt/tobacco/surveillance/en_tfi_china_gats_ factsheet_2010.­pdf. Accessed 3/5/18. 44. Raute LJ, Pednekar MS, Gupta PC. Pictorial health warnings on cigarette packs: a population based study findings from India. Tobacco Use Insights. 2009;2:11–6. 45. Federal Trade Commission. Federal Trade Commission Cigarette Report for 2015. Available at: https://www.­ftc.­gov/system/files/ documents/reports/federal-trade-commission-cigarette-report-­ 2015-federal-trade-commission-smokeless-tobacco-­report/2015_ cigarette_report.­pdf. Accessed 3/5/18. 46. Volpp KG, Troxel AB, Pauly MV, et al. A randomized, controlled trial of financial incentives for smoking cessation. N Engl J Med. 2009 Feb 12;360(7):699–709. https://doi.org/10.1056/NEJMsa0806819. 47. Farsalinos K. Electronic cigarettes: an aid in smoking cessation, or a new health hazard? Ther Adv Respir Dis. 2018;12: 1753465817744960. https://doi.org/10.1177/1753465817744960. Epub 2017 Dec 7 48. Omaña-Cepeda C, Jané-Salas E, Estrugo-Devesa A, Chimenos-­ Küstner E, López-López J. Effectiveness of dentist’s intervention in smoking cessation: a review. J Clin Exp Dent. 2016;8(1):e78–83. https://doi.org/10.4317/jced.52693. 49. Keat R, Fricain JC, Catros S, et al. The Dentist’s role in smoking cessation management – a literature review and recommendations: Part 2. Dent Update. 2018;45:298–309. 50. Yoon YH, Chen CM. Surveillance report #105: liver cirrhosis mortality in the United States: national, state, and regional trends, 2000– 2013. Bethesda, MD: National Institute on Alcohol Abuse and Alcoholism (NIAAA); 2016. Available at: http://pubs.­niaaa.­nih.­gov/ publications/Surveillance105/Cirr13.­pdf. Accessed 8/5/18. 51. World Health Organization (WHO). Global Status Report on Alcohol and Health. p. XIV. 2014 ed. Available at: http://www.­who.­int/substance_abuse/publications/global_alcohol_repor t/msb_ gsr_2014_1.­pdf?ua=1(linkisexternal). Accessed 8/5/18. 52. Sacks JJ, Gonzales KR, Bouchery EE, Tomedi LE, Brewer RD. 2010 national and state costs of excessive alcohol consumption. Am J Prev Med. 2015;49(5):e73–9. https://doi.org/10.1016/j.amepre.2015. 05.031. Epub 2015 Oct 1 53. Fioretti F, Bosetti C, Tavani A, Franceschi S, La Vecchia C. Risk factors for oral and pharyngealcancer in never smokers. Oral Oncol. 1999;35(4):375–8. 54. Goldstein BY, Chang SC, Hashibe M, Vecchia CL, Zhang ZF. Alcohol consumption and cancer of the oral cavity and pharynx from 1988 to 2009: an update. Eur J Cancer Prev. 2010;19(6):431–65. https:// doi.org/10.1097/CEJ.0b013e32833d936d.

55. Altieri A, Bosetti C, Gallus S, et al. Wine, beer and spirits and risk of oral and pharyngeal cancer: a case-control study from Italy and Switzerland. Oral Oncol. 2004;40:904–9. 56. Schildt EB, Eriksson M, Hardell L, Magnuson A. Oral snuff, smoking habits and alcohol consumption in relation to oral cancer in a Swedish case-control study. Int J Cancer. 1998;77:341–6. 57. Garrote LF, Herrero R, Reyes RM, et al. Risk factors for cancer of the oral cavity and oro-pharynx in Cuba. Br J Cancer. 2001;85:46–54. 58. Schlecht NF, Pintos J, Kowalski LP, Franco EL. Effect of type of alcoholic beverage on the risks of upper aerodigestive tract cancers in Brazil. Cancer Causes Control. 2001;12:579–87. 59. Znaor A, Brennan P, Gajalakshmi V, et al. Independent and combined effects of tobacco smoking, chewing and alcohol drinking on the risk of oral, pharyngeal and esophageal cancers in Indian men. Int J Cancer. 2003;105:681–6. 60. Deleyiannis FW, Thomas DB, Vaughan TL, Davis S. Alcoholism: independentpredictor of survival in patients with head and neck cancer. J Natl Cancer Inst. 1996;88(8):542–9. 61. Jhanjee S. Evidence based psychosocial interventions in substance use. Indian J Psychol Med. 2014;36(2):112–8. https://doi. org/10.4103/0253-7176.130960. 62. Latt NC, Jurd S, Houseman J, Wutzke SE. Naltrexone in alcohol dependence: a randomised controlled trial of effectiveness in a standard clinical setting. Med J Aust. 2002;176(11):530–4. 63. Yoshimura A, Kimura M, Nakayama H, et al. Efficacy of disulfiram for the treatment of alcohol dependence assessed with a multicenter randomized controlled trial. Alcohol Clin Exp Res. 2014;38(2):572–8. https://doi.org/10.1111/acer.12278. Epub 2013 Oct 11 64. Tilakaratne WM, Klinikowski MF, Saku T, Peters TJ, Warnakulasuriya S. Oral submucous fibrosis. Review on aetiology and pathogenesis. Oral Oncol. 2006;42(6):561–8. Epub 2005 Nov 28. Review. PMID:16311067 65. Wu YH, Yen CJ, Hsiao JR, et al. A comprehensive analysis on the association between tobacco-free betel quid and risk of head and neck cancer in Taiwanese men. PLoS One. 2016;11(10):e0164937. https:// doi.org/10.1371/journal.pone.0164937. eCollection 2016 66. Guha N, Warnakulasuriya S, Vlaanderen J, Straif K. Betel quid chewing and the risk of oral and oropharyngeal cancers: a meta-­analysis with implications for cancer control. Int J Cancer. 2014;135(6):1433– 43. https://doi.org/10.1002/ijc.28643. Epub 2014 May 14 67. Garavello W, Lucenteforte E, Bosetti C, La Vecchia C. The role of foods and nutrients on oral and pharyngeal cancer risk. Minerva Stomatol. 2009;58(1–2):25–34. Review. PMID:19234434 68. Lucenteforte E, Garavello W, Bosetti C, La Vecchia C. Dietary factors and oral and pharyngeal cancer risk. Oral Oncol. 2009;45(6):461–7. https://doi.org/10.1016/j.oraloncology.2008.09.002. Epub 2008 Nov 5. Review. PMID:18990606 69. Pavia M, Pileggi C, Nobile CG, Angelillo IF. Association between fruit and vegetable consumption and oral cancer: a meta-analysis of observational studies. Am J Clin Nutr. 2006;83(5):1126–34. 70. Oji C, Chukwuneke F. Poor oral hygiene may be the sole cause of oral cancer. J Maxillofac Oral Surg. 2012;11(4):379–83. 71. Maier H, Zoller J, Herrman A, Kriess M, Heller WD. Dental status and oral hygiene in patients with head and neck cancer. Otolaryngol Head Neck Surg. 1993;108:655–61. 72. Velley AM, Franco EL, Schlecht N, et al. Relationship between dental factors and risk of upper aerodigestive tract cancer. Oral Oncol. 1998;34:284–91. 73. Zheng T, Boyle P, Hu HF, et al. Dentition, oral hygiene, and risk of oral cancer: a case study in Beijing, People’s Republic of China. Cancer Causes Control. 1990;1:235–41. 74. Hsiao JR, Chang CC, Lee WT, et al. The interplay between oral microbiome, lifestyle factors and genetic polymorphisms in the risk of oral squamous cell carcinoma. Carcinogenesis. 2018;39(6): 778–87.

225 Lifestyle Interventions for the Prevention of Oral Cancer

75. Warnakulasuriya S. Causes of oral cancer–an appraisal of controversies. Br Dent J. 2009;207(10):471–5. https://doi.org/10.1038/sj. bdj.2009.1009. 76. De Stefani E, Correa P, Oreggia F, et al. Risk factors for laryngeal cancer. Cancer. 1987;60(12):3087–91. 77. Dasanayake AP, Silverman AJ, Warnakulasuriya S. Maté drinking and oral and oro-pharyngeal cancer: a systematic review and meta-analysis. Oral Oncol. 2010;46(2):82–6. https://doi. org/10.1016/j.oraloncology.2009.07.006. Epub 2009 Dec 29 78. Vázquez A, Moyna P. Studies on mate drinking. J Ethnopharmacol. 1986 Dec;18(3):267–72. 79. Loomis D, Guyton KZ, Grosse Y, et al. Carcinogenicity of drinking coffee, matmaté, and very hot beverages. Lancet Oncol. 2016;17(7):877–8. https://doi.org/10.1016/S1470-2045(16)30239-­X. Epub 2016 Jun 15 80. Fernanda WM, Fernanda MS, Gilberto M, et al. Maté consumption association with upper aerodigestive tract cancers: a systematic review and meta-analysis. Oral Oncol. 2018;82:37–47. 81. Furniss CS, McClean MD, Smith JF, et al. Human papillomavirus 6 seropositivity is associated with risk of head and neck squamous cell carcinoma, independent of tobacco and alcohol use. Ann Oncol. 2009;20:534–41. 82. Chancellor JA, Ioannides SJ, Elwood JM. Oral and oropharyngeal cancer and the role of sexual behaviour: a systematic review. Community Dent Oral Epidemiol. 2016;45:20. https://doi. org/10.1111/cdoe.12255. 83. Martín-Hernán F, Sánchez-Hernández JG, Cano J, Campo J, del Romero J. Oral cancer, HPV infection and evidence of sexual trans-

mission. Medicina Oral, Patología Oral y Cirugía Bucal. 2013;18(3):e439–44. https://doi.org/10.4317/medoral.18419. 84. Stewart DE, Cheung AM, Duff S, et al. Attributions of cause and recurrence in long-term breast cancer survivors. Psychooncology. 2001;10(2):179–83. 85. Linn MW, Linn BS, Stein SR. Beliefs about causes of cancer in cancer patients. Soc Sci Med. 1982;16(7):835–9. 86. Demark-Wahnefried W, Peterson B, McBride C, Lipkus I, Clipp E. Current health behaviors and readiness to pursue life-style changes among men and women diagnosed with early stage prostate and breast carcinomas. Cancer. 2000;88(3):674–84. 87. van Weert E, Hoekstra-Weebers J, Grol B, et al. A multidimensional cancer rehabilitation program for cancer survivors: effectiveness on health-related quality of life. J Psychosom Res. 2005;58(6):485–96. 88. Bonner P. The national oral cancer awareness program. ORL Head Neck Nurs. 1998;16(2):15–9. 89. Rodgers J, Macpherson LM. General dental practitioners’ perceptions of the West of Scotland Cancer Awareness Programme oral cancer campaign. Br Dent J. 2006;200(12):693–7. discussion 675 90. Head and Neck Cancer Alliance. About OHANCAW. 2017. https:// www.­headandneck.­org/ohancaw/. Accessed June 3, 2018. 91. Speight P, Warnakulasuriya S, Ogden G. Early detection and prevention of oral cancer: a management strategy for dental practice. BDA Occasional Paper, Issue 6, 2010. Accessed 3/06/2018. 92. Bagcchi S. India launches plan for national cancer screening programme. BMJ. 2016;355:i5574. https://doi.org/10.1136/bmj.i5574.

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227

Chemoprevention in Oral Cancer Holli A. Loomans-Kropp and Eva Szabo 18.1

Introduction: Definition of Chemoprevention – 228

18.2

Oral Cancer Prevention – 228

18.2.1

Chemoprevention of Oral Cancer: A Historical Perspective – 228

18.3

Considerations for Chemoprevention Clinical Trials – 229

18.3.1 18.3.2 18.3.3 18.3.4

T argets for Intervention – 229 High-Risk Cohorts – 230 Intermediate Endpoint Biomarkers – 230 Risk-Benefit in Cancer Prevention – 231

18.4

Ongoing Chemoprevention Trials – 231

18.5

Future Directions and Outlook – 235

18.5.1 18.5.2

F uture Directions – 235 Outlook – 236

References – 236

© Springer Nature Switzerland AG 2020 S. Warnakulasuriya, J. S. Greenspan (eds.), Textbook of Oral Cancer, Textbooks in Contemporary Dentistry, https://doi.org/10.1007/978-3-030-32316-5_18

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H. A. Loomans-Kropp and E. Szabo

Core Message Despite a new understanding of the molecular biology of oral cancer and the development of promising new approaches for the treatment of oral cancer, this disease remains a major source of morbidity and mortality worldwide. Prevention of oral cancer, using pharmacologic or immunologic approaches, is a promising strategy to combat the devastating effects associated with the diagnosis of invasive malignancy. An understanding of the early molecular events leading to the development of cancer is critical to the identification of appropriate targets for early intervention. Refinement of clinical trial methodologies to assess efficacy in early-phase cancer prevention clinical trials and appropriate identification of high-risk individuals who are most likely to benefit from interventions are key to making progress. This chapter summarizes the state of knowledge and ongoing efforts in oral cancer prevention.

18.1 

18

Introduction: Definition of Chemoprevention

The term “chemoprevention” was originally defined in reference to retinoids (vitamin A analogs) by Michael Sporn in 1976, when he suggested that there was “the possibility of active pharmacological intervention to arrest or reverse the process of carcinogenesis before invasion and metastasis occur” [1, 2]. The goal of chemoprevention is to intervene in or block the carcinogenic process, thus decreasing cancer incidence and cancer-related mortality [2–4]. This primarily involves the use of interventions with low toxicity in individuals at high risk for cancer development. To adequately balance the risks and benefits of chemopreventive efforts, the ideal target population, which consists of individuals who are asymptomatic but are at-risk for the development of a life-­ threatening cancer, must be properly identified [5]. Although chemoprevention initially specifically referred to pharmacological interventions, the realization that biologic or immunological interventions also have the potential to prevent cancer has broadened the scope of the chemopreventive (or cancer prevention) label and will also be referenced in this chapter. Definition Chemoprevention – intervention to arrest or reverse the process of carcinogenesis before invasion or metastasis occurs.

Initially, efforts in cancer prevention focused on agents such as dietary supplements, antioxidants, and nonsteroidal antiinflammatory drugs (NSAIDs). These classes of agents generally have acceptable safety profiles which may allow for long-term use with minimal toxicity and for broad use in the general population [1, 4]. However, the risk of cancer ranges substantially within the population, and it is unrealistic to

expect universal cancer prevention. Therefore, to efficiently deliver chemoprevention to those individuals who are most likely to benefit, it is necessary to accurately predict which individuals are at greatest risk for cancer, which cancer precursor lesions are likely to progress, and which early cancers are likely to recur, progress, or be associated with the development of second primary cancers [5]. However, the lack of understanding of the molecular pathways and targets that are directly involved in the progression of normal epithelium to preneoplastic lesions and malignancies is a current limitation to improving chemoprevention efforts. Therefore, current research and clinical efforts have increasingly focused on the identification and validation of molecular targets to intervene in pathways critical to carcinogenic progression, which should facilitate the development of novel agents to effectively prevent cancer [6, 7]. A key example of success of a preventive intervention is the development, implementation, and dissemination of human papilloma virus (HPV) vaccines for the prevention of cervical cancer, which have >90% efficacy in preventing HPV infections and precancerous lesions caused by the vaccine-­ targeted genotypes [6]. Unfortunately, the majority of cancers do not result from a singular cause, such as a viral infection like HPV, but rather through the accumulation of multiple abnormalities that culminate in an invasive and metastatic phenotype [7]. Given that cancer is a heterogeneous disease that occurs in individuals with diverse genetic profiles, it is crucial that chemoprevention efforts ultimately focus on the biology of the disease. In this chapter, we will specifically discuss chemoprevention efforts in oral cancer, with some broader examples from head and neck squamous cell carcinomas (HNSCC) arising in other anatomic sites to provide a comprehensive overview of the complexity of oral cancer and the efforts, both historical and ongoing, to prevent it. Definition Field carcinogenesis – the process by which an entire epithelial area that is exposed to carcinogens (e.g., tobacco smoke) has increased susceptibility to develop cancer.

18.2 

Oral Cancer Prevention

18.2.1 

 hemoprevention of Oral Cancer: C A Historical Perspective

In the early 1980s, multiple clinical studies investigated the association between retinoids and upper aerodigestive tract cancers [8]. Retinoic acids have an important role in maintaining cell growth and differentiation of hematopoietic and epithelial tissues through regulating the expression of several retinoic acid receptors, which are often downregulated during cancer progression [3, 9]. These observations, as well as data from in vivo models, spurred the first chemoprevention trials investigating the efficacy of such compounds in chemo-

229 Chemoprevention in Oral Cancer

prevention. The first trial tested the efficacy of 13-cis-retinoic acid (13-cRA) in preventing the progression of oral leukoplakia lesions to malignant oral cancer. In a 3-month placebo-­ controlled trial where the participants received daily either 13-cRA or placebo, 67% of the individuals who received 13-­ cRA had a complete or partial clinical response; dysplasia was reversed in 54% of cases [10]. Although this trial indicated retinoic acid could be tolerated in the short term and showed promise in the prevention of oral cancer, relapses and lesion recurrence upon discontinuation of treatment were noted in more than half of responders. A subsequent trial of 13-cRA for the prevention of HNSCC second primary tumors (SPTs) in 103 patients who were disease-free after curative therapy also showed a promising decrease in SPTs, although toxicity associated with high-dose 13-cRA treatment for 12  months (compared with 3  months in the oral leukoplakia trial) resulted in one-third of patients not finishing the required treatment course, despite dose modification [11]. The follow-up phase III trial of a tolerable, lower dose of 13-cRA failed to confirm any efficacy for 13-cRA treatment in SPT prevention in early-stage HNSCC [12]. These initial retinoic acid trials facilitated efforts exploring other vitamin A-related agents in oral cancer prevention. Several in  vivo studies indicated that the application of β-carotene, a pro-vitamin A carotenoid, inhibited the formation of carcinogen-induced malignant oral lesions [13, 14]. However, treatment with β-carotene had no additive effect in the prevention of oral cancer lesions compared to 13-cRA [15]. Additional early-phase clinical trials using other retinoids, such as the synthetic retinoid fenretinide, also failed to demonstrate sufficient activity to justify phase III trials, and thus strategies using retinoids for oral cancer prevention have largely been abandoned [16]. Nevertheless, the retinoid studies were particularly important because they established a methodology for testing chemopreventive efficacy that is still in use today. 18.3 

Considerations for Chemoprevention Clinical Trials

Fundamental to the concept of chemoprevention is the recognition that the development of oral cancer is a lengthy process that occurs over decades in response to carcinogeninduced epithelial cell damage and that the entire exposed epithelium is at-risk due to those exposures resulting in field carcinogenesis [17, 18]. However, multiple challenges are inherent to prevention research. These include the difficulty in accurately identifying individuals destined to develop oral cancer in a relatively short time frame such that risk-benefit can be optimized, difficulties in demonstrating preliminary efficacy in phase II trials where one cannot directly assess the effect of the intervention on cancer since the participants do not yet have cancer, an unclear link between regression of oral leukoplakia (as studied in the retinoid studies described above) and subsequent development of invasive cancer, and the eventual need for large and lengthy phase III trials to demonstrate definitive efficacy. Furthermore, the genomic

complexity of oral cancer, with both inter- and intra-tumoral heterogeneity, raises the possibility that different strategies may be needed for diverse molecular cancer subtypes [19, 20]. Thus, preventive strategies need to be broad and target processes deregulated across multiple cancer subtypes, rather than focusing on specific molecular abnormalities. Or, alternatively, identification of individuals at risk for particular molecular subtypes of oral cancer would allow the delivery of personalized interventions to the appropriate high-risk cohorts. 18.3.1 

Targets for Intervention

The appropriate selection of targets for preventive interventions requires a robust understanding of the efficacy profile as well as potential negative side effects of the putative agents. Evidence of efficacy comes from four main categories – knowledge of mechanism, in vitro and animal in vivo experimental data, epidemiologic studies, and secondary endpoint analyses from trials performed for other indications [21]. The more important a molecular abnormality or signaling pathway is for growth and survival, the more likely it will be that targeting that abnormality or pathway will be effective [22, 23]. Not only does the efficacy of an intervention depend on how important its target is to carcinogenesis, but it also depends on the ability to deliver the agent during the time that the target drives the carcinogenic process [24]. Given that epithelial carcinogenesis is a multiphase process, it is likely that the intermediate points in the development of a malignancy may be dependent on acquiring different molecular aberrations or signaling pathways. For instance, tobacco-­induced DNA damage is known to be critical to the development of oral and lung cancers [25, 26]. Preventing the damage is considerably easier and more effective during the early years of smoking, but once the damage is induced and DNA is adducted and cells have accumulated multiple genetic aberrations, blocking carcinogen-induced mutations is highly unlikely to be effective. This means that the Cancer Genome Atlas (TCGA)-type analysis of established tumors is insufficient to reveal the early events that occur during tumor development, creating a need for a systematic analysis of premalignant lesions from individuals at high risk for oral cancer [27]. As reported by Lee et al., such temporal considerations pose an additional and particularly daunting (although not insurmountable) challenge to the field of cancer prevention [28]. Eyecatcher

The PreCancer Atlas (PCA) is a new initiative which aims to provide insight into the molecular mechanisms responsible for cancer initiation and progression in a variety of premalignant conditions. An understanding of the molecular abnormalities in premalignant lesions is critical for identification of new targets for intervention in early oral cancer.

18

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H. A. Loomans-Kropp and E. Szabo

18.3.2 

High-Risk Cohorts

The selection of the appropriate cohort for clinical trials is of particular importance, since a higher-risk cohort will reduce the sample size, duration of the trial, and, ultimately, cost. As discussed above, the presence of premalignant lesions such as oral leukoplakia or erythroplakia identifies high-risk individuals, but the progression to cancer is highly variable and occurs over many years (see 7 Chapter 13). Furthermore, many lesions regress spontaneously, and most cancers occur in individuals without known prior premalignant lesions. Additional prognostic indicators are needed to identify the highest-­risk individuals with oral leukoplakia. Using data from a longitudinal population-based study of individuals with low-grade oral dysplasia, Rock et al. recently found that despite the majority of participants being smokers, nonsmokers had two-fold increase in progression to cancer, and in the case of lesions located in the floor of the mouth, nonsmokers had a 38-fold increase in cancer progression compared with smokers [29]. These data suggest that demographics can further identify higher-risk individuals and even though smoking is strongly associated with oral dysplasia, when dysplasia occurs in nonsmokers, it is more likely to progress to cancer. Loss of heterozygosity (LOH) at specific chromosomal loci is currently one of the best prognostic indicator of leukoplakia progression, although it is not a widely available test [30–32]. A recent clinical trial, Erlotinib Prevention of Oral Cancer (EPOC), took advantage of this information to test the EGFR inhibitor erlotinib for the prevention of cancer in a population of individuals with premalignant lesions with high-risk LOH profiles [33]. The focus on such a high-risk cohort allowed this phase III study to assess a cancer endpoint rather than rely on the effect of the intervention on oral leukoplakia. Even though the cancer-free survival was no different between erlotinib and placebo, the high progression rate to cancer imparted by the presence of high-risk LOH was confirmed and showed, for the first time, that a premalignant lesion-based clinical trial with a cancer endpoint was feasible. Nevertheless, much work needs to be done to better identify high-risk individuals who would benefit from specific preventive interventions.  

18

!!Attention/Warning Intermediate endpoints, such as precancerous lesion regression or modulation of a biomarker, are commonly used to identify efficacy in early-phase cancer prevention trials. Designing a prevention trial with cancer development as an endpoint requires substantial time and resources, and such phase III trials should only be performed when adequate efficacy and safety data are available.

18.3.3 

Intermediate Endpoint Biomarkers

Because the multistep process of carcinogenesis can take many years, assessment of clinical chemoprevention trials using cancer incidence as an endpoint requires a lengthy fol-

low-up and large sample sizes and thus only pertains to phase III definitive efficacy trials. The use of intermediate endpoints that are theoretically predictive of patient outcomes potentially circumvents these issues by evaluating a biologic event that occurs between a carcinogenic or external exposure and the subsequent development of cancer [23]. To be useful, the intermediate marker should be integrally involved in the process of carcinogenesis, such that its expression correlates with disease course. The expression of the marker should differ between normal and at-risk epithelium, it should be easily and reproducibly measurable in biospecimens that can be realistically obtained in clinical trials, and the expression should be able to be modulated only by effective interventions [21]. Validation in prospective clinical trials is required for a marker to become a validated surrogate endpoint, although no marker has achieved this status thus far [34]. In the setting of oral cancer chemoprevention clinical trials, premalignant lesions have been the most commonly used intermediate endpoint biomarkers, given their role in the development of invasive malignancy. The natural history of the various types of oral premalignant lesions is discussed in 7 Chapter 13. Given their slow and not inevitable rates of progression to cancer, it is recommended that trials using premalignant lesions as endpoints be placebo-controlled to ensure that spontaneous resolution is accounted for.  

>>Important Detection of biomarkers in biological specimens such as tissue or plasma can be an important method to monitor or detect changes in premalignant lesions or tumor initiation, progression, or regression.

Nevertheless, many other biomarkers could also be assessed as potential intermediate endpoints, especially to provide additional informative data to complement effects on premalignant lesions. These include the deregulated cellular processes that are the “hallmarks of cancer,” as described by Weinberg and Hanahan [35]. Classes of carcinogenesis biomarkers include measures of cellular proliferation such as Ki-67 and PCNA, mutated oncogenes and tumor suppressor genes, growth factors or their receptors, and molecules regulating cellular immortality, immune defense, and tumor-­associated angiogenesis (see 7 Chapter 14). In the arena of lung cancer prevention, abnormal gene expression profiles are described in the histologically normal-appearing aerodigestive epithelium of smokers and in lung cancer patients using global mRNA and microRNA techniques. A robust smoking-­related signature has been identified in the bronchial epithelium of smokers in which genes involved in the regulation of oxidant stress, xenobiotic metabolism, and oncogenesis are induced and genes involved in regulation of inflammation and tumor suppression are suppressed [36]. Of note, a smoking-­related gene expression signature has also been identified in the nasal and buccal epithelia, which can be repeatedly sampled in a relatively noninvasive fashion [37, 38]. This provides an opportunity to test whether chemopreventive interventions can affect  

231 Chemoprevention in Oral Cancer

the tobacco-induced gene expression changes, as has been tested in a recent clinical trial aimed at lung cancer prevention (NCT02123849). Circulating biomarkers are of major interest as their collection is undertaken in relatively noninvasive ways. Circulating levels of biomarkers of inflammation such as measures of oxidative stress or biomarkers of carcinogen detoxification may be measured in urine and have been assessed in oral cancer chemoprevention trials. Protein profiling (proteomics) in the blood and urine has also been performed. However, the more removed a biomarker is from the primary tissue of injury, the more potential there is for a less informative outcome, and therefore the emphasis thus far has been on biomarker assessments in the oral mucosal field. 18.3.4 

Risk-Benefit in Cancer Prevention

As with most medical interventions, risk-benefit analysis is cardinal to determining whether specific interventions can be studied in clinical trials and, even more important, whether strategies found to be effective can be adopted for general use. Efficacy needs to be balanced with safety to ensure that the overall outcome is of benefit. Since cancer prevention modalities may need to be administered over extended periods of time (e.g., tamoxifen was given for 5 years for breast cancer prevention), drugs need to be not just safe but also tolerable [39]. Common minor side effects (e.g., nausea) that do not significantly impact general health and are not considered serious by medical practitioners may nevertheless be bothersome enough to lead to noncompliance. Uncommon, but serious, side effects that impact on short- or long-term health may arise, adding another serious condition to a cancer patient. A particularly informative demonstration of this concept is the reporting of cardiotoxicity associated with rofecoxib use during a clinical trial designed for the prevention of colorectal adenoma recurrence. Although rofecoxib significantly reduced adenoma recurrence by 24%, this nonsteroidal anti-inflammatory drug (NSAID) led to an increase in the relative risk of thrombotic events to 1.92 (95% CI: 1.19–3.11; p = 0.008), attributable to cardiac events (hazard ratio (HR) = 2.80; 95% CI: 1.44–5.45) and cerebrovascular events (HR = 2.32; 95% CI: 0.89–6.74) [40, 41]. These unexpected findings led to the withdrawal of rofecoxib from the market; they underscore the importance of balancing the benefits with risks, especially when an intervention is aimed at prevention of cancer occurring in the future and with uncertain frequency. They also speak to the difficulties in drug development where drug approvals are based on relatively short duration of evaluation (as was the case of rofecoxib) even though the duration of use by individuals often far exceeds the duration of use in pivotal studies. The long careful follow-up in the rofecoxib cancer prevention trial uncovered a toxicity of major importance. Unfortunately, the issue of side effects of drug therapy has proven to be a major challenge in the development of cancer preventive drugs.

18

>>Important Because of the length of time needed for cancer prevention agents to be efficacious, understanding the risks and benefits of the agent is necessary. Long-term use of pharmacological interventions can have unknown or unforeseen side effects.

Approaches to shift the risk-benefit balance in patients’ favor include correctly selecting high-risk individuals who stand to gain the most from specific interventions. The EPOC trial is an excellent example of the focus on a very high-risk cohort with a significant short-term progression rate that enabled the use of a drug with significant side effects (erlotinib) [33]. Giving due consideration to the risk-benefit balance and trial team’s willingness to accept toxicities arising from interventions is substantially different in such high-risk groups compared with groups whose cancer risk is low. An alternative approach to shifting the risk-benefit balance is to lower the risk of the intervention, such as through local rather than systemic drug delivery, via combination therapy, or through intermittent dosing regimens. Local drug delivery through the oral mucosa is particularly suitable for the oral cavity, where agents that act locally and are not absorbed systemically can be utilized. However, regional drug delivery, such as through a mouthwash, would not reach deeper into the oropharynx or larynx, which means that areas at risk (due to field carcinogenesis) would remain undosed. Intermittent dosing regimens have been demonstrated to be effective in some animal models [42]. Short-­ term intermittent therapy to eliminate premalignancy (SITEP) has been proposed as a means of eliminating premalignant clones, through induction of apoptosis [43]. Focusing on identifying synthetic lethal interactions that lead to clonal elimination, the SITEP approach would cycle agents “on and off ” to allow for the eventual elimination of premalignant cells with long intervening periods of “no treatment,” perhaps even eventually leading to cure. Finally, pharmacogenomic evaluation to select responders or those likely to develop toxicities also offers potential avenues to shifting the risk-benefit equation in patients’ favor. Undoubtedly, agents that have beneficial effects in multiple chronic diseases (e.g., aspirin, antidiabetic agents) would be particularly attractive for cancer preventive development. 18.4 

Ongoing Chemoprevention Trials

Recent chemoprevention efforts have focused on a number of different agents, including inhibitors of cyclooxygenase-2 (COX-2), EGFR, signal transducers and activators of ­transcription (STAT), and vascular endothelial growth factor (VEGF), as well as the antidiabetic agents pioglitazone (an agonist of peroxisome proliferator-activator receptor gamma (PPARγ)) and metformin (. Table  18.1) [44]. None of the trials that have been completed thus far have identified sufficient chemopreventive activity to warrant phase III testing. Therefore, the following discussion will be limited to the tri 

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als that are currently recruiting participants (as listed at 7 clinicaltrials.­gov) and select others for which results have not been reported. Sulforaphane, a natural extract from cruciferous vegetables, such as broccoli, Brussel sprouts, and cabbage, has been under investigation for its efficacy in chemoprevention for several years. In vitro studies have indicated that sulforaphane leads to the activation of Nrf2 and reduces oxidative damage through cytochrome p450 [45, 46]. Topical application of sulforaphane in vivo reduced 4-nitroquinoline 1-oxide (4-NQO)induced carcinogenesis of the oral cavity [45]. Healthy volunteers participated in a pilot clinical trial to evaluate the bioavailability and pharmacodynamic activity of three different preparations of broccoli sprout extract as a source of sulforaphane, examining urinary sulforaphane metabolites and transcripts of NQ01, a NRF2 target gene, in buccal scrapings. Mucosal bioactivity was demonstrated in six of nine evaluable individuals ingesting one of the preparations, thereby providing a rationale for further clinical trials [47]. Ongoing studies are evaluating a new source of sulforaphane, Avmacol®, which is a commercially available supplement that contains glucoraphanin (a precursor of sulforaphane) and the active enzyme myrosinase (that hydrolyzes glucoraphane to produce sulforaphane) (. Table 18.1). Metformin is an oral biguanide that is the most widely used drug for the management of diabetes mellitus. Evidence from a variety of sources indicates that metformin treatment reduces tumor growth activity by reducing mTORC1 activity, which is hyperactivated in HNSCC [48, 49]. Animal carcinogenesis studies showed that metformin reduced the number of carcinogen-induced oral tumors and also reduced their size. Furthermore, the drug also prevented the spontaneous conversion of benign lesions to squamous cell carcinomas. Metformin also inhibited mTORC1 in the proliferating basal epithelial layers of oral premalignant lesions [50]. A number of epidemiologic studies have identified association between metformin use and overall cancer incidence, as well as incidence of specific cancer types, in individuals with diabetes [49]. A recent study extended this association to head and neck cancer [51]. A phase IIa trial of metformin (the M4OC trial) given for 3 months to individuals with oral leukoplakia and erythroplakia, but not diabetes, recently completed accrual, and final results are pending (NCT02581137). Whether the promising leads from epidemiologic studies, which were obtained in the setting of diabetes, can be translated to nondiabetic individuals who do not share the same metabolic abnormalities remains to be shown. The epidermal growth factor receptor (EGFR) has been implicated in head and neck carcinogenesis and is the target for the only US Food and Drug Administration (FDA)approved molecularly targeted agent, cetuximab [52]. EGFR expression has been shown to be elevated in oral potentially malignant disorders, and the use of EGFR inhibitors in rodent models of carcinogenesis demonstrates significant inhibition of tumor development [53]. Despite this strong rationale, the phase III EPOC trial discussed in 7 Section 18.3.2 failed to show any significant difference in  

 

18

 

cancer-free survival in high-risk individuals with oral leukoplakia when treated with erlotinib versus placebo for 12  months [33]. There remains one ongoing trial (NCT01414426) targeting both EGFR and the vascular endothelial growth factor receptor with vandetanib, a dual receptor blocker, in individuals with oral leukoplakia (. Table 18.1). Support for this trial comes from the 4-NQO mouse carcinogenesis model that demonstrated highly significant inhibition of dysplasia and oral squamous cell carcinoma by vandetanib compared to placebo (incidence of either lesion of 28% versus 96%, p ≤ 0.001, respectively) [54]. In the oncology community, the current excitement about immunotherapy for cancer treatment (see 7 Chapter 23) has yet to be translated to prevention. Inhibitors of the programmed death 1 (PD-1) pathway, which is implicated in tumor immune escape, have become important treatment modalities for a variety of tumors, including both squamous and adenocarcinoma types of non-small cell lung cancer. Pembrolizumab, an anti-PD-1 monoclonal antibody, was recently approved by the US FDA for the treatment of patients with recurrent or metastatic head and neck carcinoma with disease progression on or after platinum-based chemotherapy, adding head and neck cancer to a long list of regulatory approvals for this antibody. In the phase III KEYNOTE-040 study comparing pembrolizumab with standard treatments (methotrexate, docetaxel, or cetuximab) in the second- or third-line treatment of recurrent or metastatic head and neck cancer, Cohen et al. showed median overall survival of 8.4  months (95% CI: 6.4–9.4) with pembrolizumab and 6.9 months (95% CI: 5.9–8.0) with standard care (HR = 0.80; 95% CI: 0.65–0.98; p = 0.0161) [55]. However, PD-1 inhibitors have been associated with significant toxicities, even if these occur at lower incidence than those seen with standard chemotherapy. Thirteen percent of pembrolizumab-treated patients experienced grade 3 or worse adverse events in the KEYNOTE-040 trial, while 4 out of 247 patients died of treatment-related toxicities. The rationale for using pembrolizumab in oral premalignancy has not been published in the available literature. Knowledge on the immune microenvironment in human oral premalignant lesions is sparse, with no descriptive studies published to date. An ongoing clinical trial is evaluating four cycles of pembrolizumab in individuals with high-risk oral leukoplakia selected on the basis of LOH at high-risk loci (. Table 18.1). The limited duration of treatment, in comparison with the usual open-ended treatment in the setting of metastatic disease, may diminish the incidence of significant toxicity. With regard to other immunologic approaches, there have not been any vaccines against tumor-associated antigens relevant to oral cancer to date.  

 

 

Eyecatcher

In the absence of curative therapies for late-stage oral cancer, prevention using pharmacological or immune interventions is an appealing way to reduce mortality.

18

233 Chemoprevention in Oral Cancer

..      Table 18.1  Chemoprevention trials for oral squamous cell carcinoma in 7 ClinicalTrials.­gov  

Phase

Agent

Principle site

Study purpose

Lesion

Study goal

Study status

7 ClinicalTrials.­gov

0

Avmacol

University of Pittsburgh

Prevention

Head and neck squamous cell carcinoma

Evaluate systemic bioavailability and pharmacodynamics of Avmacol in the oral mucosa

Recruiting

NCT03268993

I

Avmacol

University of Arizona

Prevention

Oral premalignant lesion or cured head and neck squamous cell carcinoma

Examine the use of Avmacol in preventing second cancers in individuals with tobacco-­related head and neck squamous cell carcinoma

Recruiting

NCT03182959

II

Vandetanib

University of Chicago

Prevention

Oral premalignant lesion

Assess vandetanib in preventing head and neck cancer in individuals with oral premalignant lesions

Recruiting

NCT01414426

II

Pembrolizumab

M.D. Anderson Cancer Center

Prevention

Oral premalignant lesions, oral intraepithelial neoplasia

Compare pembrolizumab to standard of care in controlling premalignant lesions

Recruiting

NCT02882282

I

Black raspberry confection

Ohio State University Comprehensive Cancer Center

Prevention

None (healthy volunteers)

Prevent oral cancer in healthy volunteers

Active, not recruiting

NCT01961869

I

Lyophilized black raspberry

Ohio State University Comprehensive Cancer Center

Recurrence

Oral squamous cell carcinoma

Prevent recurrence of oral cancer in high-risk Appalachian patients previously treated with surgery

Active, not recruiting

NCT01504932

II

Thymoquinone

Cairo University

Prevention

Oral premalignant lesion

Clinically and immunohistochemically evaluate the chemopreventive effect of thymoquinone of oral premalignant lesions

Active, not recruiting

NCT03208790

IIa

Metformin hydrochloride

National Cancer Institute

Prevention

Oral premalignant lesions

Investigate the efficacy of metformin in regressing premalignant lesions

Active, not recruiting

NCT02581137

III

Erlotinib

M.D. Anderson Cancer Center

Prevention

Oral premalignant lesion

Assess the ability of erlotinib to reduce incidence of oral cancer in patients with oral leukoplakia with loss of heterozygosity and intraepithelial neoplasia

Completed

NCT00402779

I

Aspirin

Institute of Head and Neck Studies and Education, United Kingdom

Prevention

Oral leukoplakia

Study the side effects and dose of aspirin mouthwash in treating patients with oral leukoplakia

Completed

NCT01238185

 

(continued)

234

H. A. Loomans-Kropp and E. Szabo

..      Table 18.1 (continued) Phase

Agent

Principle site

Study purpose

Lesion

Study goal

Study status

7 ClinicalTrials.­gov

I/II

Phenethyl isothiocyanate

Georgetown University

Prevention

Oral neoplasms

Examine the effects of phenethyl isothiocyanate on oral cells with mutant p53

Completed

NCT01790204

I/II

Freeze-­dried black raspberry

Ohio State University

Prevention

Oral premalignant lesions

Evaluate the utility of freeze-dried black raspberry gels on oral cancer chemoprevention

Completed

NCT01192204

I/II

Adenovirus

National Cancer Institute

Prevention

Oral premalignant lesions

Determine toxicity and efficacy of the adenovirus Ad5CMVp53 (wild-type p53) in preventing oral squamous cell carcinoma

Completed

NCT00064103

II

Cetuximab

Sidney Kimmel Comprehensive Cancer Center

Prevention

Premalignant conditions of upper aerodigestive tract

Investigate the efficacy of cetuximab in treating patient with precancerous lesions of the upper aerodigestive tract

Completed

NCT00524017

II

Erlotinib

University of Alabama-­ Birmingham

Prevention

Recurrence or second primary squamous cell carcinoma

Assess erlotinib as adjuvant chemoprevention in high-risk head and neck cancers

Completed

NCT00570232

II

Celecoxib

Fox Chase Cancer Center

Prevention

Oral leukoplakia

Evaluate the clinical utility of celecoxib in preventing oral cancer and inducing oral leukoplakia regression

Completed

NCT00101335

II

Pioglitazone

National Cancer Institute

Prevention

Oral leukoplakia

Evaluate the clinical utility of pioglitazone in preventing oral cancer and inducing oral leukoplakia regression

Completed

NCT00099021

II

Bowman-­ Birk inhibitor

National Cancer Institute

Prevention

Oral leukoplakia

Evaluate utility of Bowman-Birk inhibitor in preventing oral cancer in oral leukoplakia patients

Completed

NCT003303382

II

Celecoxib

Memorial Sloan Kettering Cancer Center

Prevention

Oral premalignant lesions

Determine clinical response of oral premalignant lesions to treatment with celecoxib

Completed

NCT00014404

II

Fenretinide

University of Alabama-­ Birmingham

Prevention

Oral leukoplakia

Study the effectiveness of fenretinide in treating oral leukoplakia

Completed

NCT00004161

II

Rosiglitazone maleate

National Cancer Institute

Prevention

Oral leukoplakia

Study the effectiveness of rosiglitazone maleate in treating oral leukoplakia

Completed

NCT00369174

18

 

235 Chemoprevention in Oral Cancer

..      Table 18.1 (continued) Phase

Agent

Principle site

Study purpose

Lesion

Study goal

Study status

7 ClinicalTrials.­gov

I

Aminolevulinic acid

National Cancer Institute

Prevention

Oral leukoplakia

Study the side effects and dose of photodynamic therapy using aminolevulinic acid in treating patients with oral leukoplakia

Terminated

NCT00571558

II

Green tea lozenge

University of Medicine and Dentistry of New Jersey

Prevention

Oral leukoplakia

Assess effects of green tea lozenges in preventing oral cancer

Terminated

NCT00176566

IIb

Pioglitazone

National Cancer Institute

Prevention

Oral premalignant lesions

Determine clinical response of oral premalignant lesions to treatment with pioglitazone

Terminated

NCT00951379

II

Celecoxib

Dana-Farber Cancer Institute

Prevention

Oral leukoplakia, oral dysplasia

Determine clinical response of oral leukoplakia and dysplasia to treatment with celecoxib

Unknown

NCT00052611

18.5 

Future Directions and Outlook

18.5.1 

Future Directions

The field of cancer prevention is still relatively young and, as such, requires further developments in both the biologic underpinnings for intervention strategies (e.g., a complete understanding of the early events in carcinogenesis) and methodologies to efficiently test intervention strategies. Of particular importance is a better understanding of the mechanisms by which premalignant lesions progress, thereby allowing both the identification of targets for interventions to prevent progression and the delivery of interventions only to individuals who are highly likely to develop cancer over a short period of time. The collaborative PreCancer Atlas (PCA) is a new initiative which aims to provide insight into the molecular mechanisms responsible for cancer initiation and progression in a variety of premalignant conditions [56]. A comprehensive analysis of molecular abnormalities in oral premalignant lesions, both a cross-sectional analysis of lesions of different histologic grades and a longitudinal analysis following lesions over time, is a critical need for the identification of new targets for intervention. This analysis needs to incorporate robust studies of the immune microenvironment to determine if modulation of the immune system could have a role in the prevention of oral cancer. Although clinical trial strategies, such as targeting oral premalignancy to identify preliminary efficacy in phase II trials, have provided promising data on which to base phase

 

III definitive efficacy studies, the lack of validated intermediate endpoints has been a challenge for the entire field of chemoprevention. The need for multiple sequential biopsies during the course of clinical trials results in a need to limit the duration of interventions because biopsies can only be performed a finite number of times, both due to the ability of people to tolerate them and due to the eventual removal of the lesion of interest. Studies using cell-free DNA (cfDNA), which is found systemically in the blood and can be detected using highly sensitive assays that detect nanogram quantities of DNA, could theoretically improve longitudinal monitoring of at-risk individuals with premalignant lesions [57]. cfDNA could be detected to a lower limit of 0.01% for the selected mutations in one study of colorectal cancer patients [58]. The sensitivity of this type of assay could make earlier detection of cancer possible as well as potentially enable the diagnosis and monitoring of premalignancy [56]. Izumchenko et al. showed in a study of individuals with lung adenocarcinomas and premalignant lesions (atypical adenomatous hyperplasia, AAH) in the surrounding resected lung that a BRAF mutation that was present in the AAH but not invasive tumor was able to be detected in cfDNA analysis in the blood [59]. We need to investigate whether analysis of blood or saliva (a biofluid more proximal to oral tissue) could potentially differentiate premalignancy from nonmalignant tissue and allow longitudinal monitoring of high-risk individuals. This is, however, predicated on knowing which molecular abnormalities are important for cancer progression, again pointing to a strong need for understanding early carcinogenesis.

18

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Finally, a third area needing further investment is risk stratification to detect individuals at highest risk for progression to cancer within a short time frame. The EPOC trial was able to target individuals with oral premalignancy who were at high enough risk to progress to invasive cancer within the lifetime of a phase III trial. More robust markers that can be assessed in a standardized fashion across the medical community are needed to facilitate additional such trials. 18.5.2 

Outlook

Despite the challenges of developing effective chemopreventive interventions and delivering effective interventions to the populations most likely to benefit, immense progress has been made in recent years. Massive improvements in genomic technology have allowed for a better (albeit still very incomplete) understanding of the biology of early carcinogenesis and how genetic variants can contribute to premalignant-to-­ malignant progression. Multiple chemopreventive agents have been tested in clinical trials, and several models for phase II and phase III trials have been developed, providing a pathway for the development of future agents. The development of vaccines that target genetic drivers of malignancy, as well as new agents that modulate the immune system, offers exciting new avenues for research [60]. Personalized approaches to cancer prevention provide hope for improving outcomes for individuals at risk for oral cancer.

References

18

1. Hong WK, Sporn MB. Recent advances in chemprevention of cancer. Science. 1997;278:1073–7. 2. Sporn MB. Approaches to prevention of epithelial cancer during the preneoplastic period. Cancer Res. 1976;36:2699–702. 3. Hong WK, Lippman SM, Hittelman WN, Lotan R. Retinoid chemoprevention of aerodigestive cancer: from basic research to the clinic. Clin Cancer Res. 1995;1:677–86. 4. Maresso KC, Tsai KY, Brown PH, Szabo E, Lippman S, Hawk ET. Molecular cancer prevention: current status and future directions. CA Cancer J Clin. 2015;65(5):345–83. 5. Brahme NN, Szabo E.  Cancer prevention in the era of precision oncology. Clin Pharmacol Ther. 2017;101(5):575–7. 6. Castle PE, Maza M. Prophylactic HPV vaccination: past, present, and future. Epidemiol Infect. 2016;144(3):449–68. 7. Vineis P, Schatzkin A, Potter JD. Models of carcinogenesis: an overview. Carcinogenesis. 2010;31(10):1703–9. 8. Lippman SM, Benner SE, Hong WK. Retinoids in chemoprevention of heck and neck carcinogenesis. Prev Med. 1993;22:693–700. 9. Lotan R. Retinoids and chemoprevention of aerodigestive tract cancers. Cancer Metastasis Rev. 1997;16:349–56. 10. Hong WK, Endicott J, Itri LM, Doos W, Batsakis JG, Bell R, Fofonoff S, Byers R, Atkinson EN, Vaughan C, et  al. 13-cis-retinoic acid in the treatment of oral leukoplakia. NEJM. 1986;315(24):1501–5. 11. Hong WK, Lippman SM, Itri LM, Karp DD, Lee JS, Byers RM, Schantz SP, Kramer AM, Lotan R, Peters LJ, et  al. Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck. N Engl J Med. 1990;323(12):795–801. 12. Khuri FR, Lee JJ, Lippman SM, Kim ES, Cooper JS, Benner SE, Winn R, Pajak TF, Williams B, Shenouda G, et al. Randomized phase III trial of low-dose isotretinoin for prevention of second primary tumors in

stage I and II head and neck cancer patients. J Natl Cancer Inst. 2006;98(7):441–50. 13. Suda D, Schwartz J, Shklar G. Inhibiton of experimental oral carcinogenesis by topical beta carotene. Carcinogenesis. 1986;7(5):711–5. 14. Alam BS, Alam SQ.  The effect of different levels of dietary beta-­ carotene on DMBA-induced salivary gland tumors. Nutr Cancer. 1987;9(2–3):93–101. 15. Lippman S, Batsakis JG, Toth BB, Weber RS, Lee JJ, Martin JW, Hays GL, Goepfert H, Hong WK.  Comparison of low-dose isotretinoin with beta carotene to prevent oral carcinogenesis. NEJM. 1993;328(1):15–20. 16. William WN Jr, Lee JJ, Lippman SM, Martin JW, Chakravarti N, Tran HT, Sabichi AL, Kim ES, Feng L, Lotan R, et al. High-dose fenretinide in oral leukoplakia. Cancer Prev Res (Phila). 2009;2(1):22–6. 17. Phillips E, Wang TW, Husten CG, Corey CG, Apelberg BJ, Jamal A, Homa DM, King BA. Tobacco product use among adults  – United States, 2015. Morb Mortal Wkly Rep. 2017;66(44):1209–15. 18. Room R.  Smoking and drinking as complementary behaviours. Biomed Pharmacother. 2004;58(2):111–5. 19. Califano JA, van der Riet P, Westra W, Nawroz H, Clayman G, Piantadosi S, Corio R, Lee D, Greenberg B, Koch W, et al. Genetic progression model for head and neck cancer: implications for field cancerization. Cancer Res. 1996;56:2488–92. 20. Network TCGA.  Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015;517(7536): 576–82. 21. Szabo E.  Phase II cancer prevention clinical trials. Semin Oncol. 2010;37(4):359–66. 22. Ha PK, Chang SS, Glazer CA, Califano JA, Sidransky D.  Molecular techniques and genetic alterations in head and neck cancer. Oral Oncol. 2009;45(4–5):335–9. 23. Ausoni S, Boscolo-Rizzo P, Singh B, Da Mosto MC, Spinato G, Tirelli G, Spinato R, Azzarello G. Targeting cellular and molecular drivers of head and neck squamous cell carcinoma: current options and emerging perspectives. Cancer Metastasis Rev. 2016;35(3): 413–26. 24. Szabo E. Selecting targets for cancer prevention: where do we go from here? Nat Rev Cancer. 2006;6(11):867–74. 25. Alexandrov LB, Ju YS, Haase K, Van Loo P, Martincorena I, Nik-­Zainal S, Totoki Y, Fujimoto A, Nakagawa H, Shibata T, et al. Mutational signatures associated with tobacco smoking in human cancer. Science. 2016;354(6312):618–25. 26. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, Bignell GR, Bolli N, Borg A, Borresen-Dale AL, et  al. Signatures of mutational processes in human cancer. Nature. 2013;500(7463):415–21. 27. de Castro G Jr, Negrao MV.  The cancer genome atlas findings in head and neck cancer: a renewed hope. Curr Opin Oncol. 2014;26(3):245–6. 28. Lee JJ, Hong WK, Hittelman WN, Mao L, Lotan R, Shin DM, Benner SE, Xu X-C, Lee JS, Papadimitrakopoulou VM, et  al. Predicting cancer development in oral leukoplakia: ten years of translational research. Clin Cancer Res. 2000;6:1702–10. 29. Rock LD, Rosin MP, Zhang L, Chan B, Shariati B, Laronde DM.  Characterization of epithelial oral dysplasia in non-smokers: first steps towards precision medicine. Oral Oncol. 2018;78:119–25. 30. Zhang L, Poh CF, Williams M, Laronde DM, Berean K, Gardner PJ, Jiang H, Wu L, Lee JJ, Rosin MP. Loss of heterozygosity (LOH) profiles–validated risk predictors for progression to oral cancer. Cancer Prev Res (Phila). 2012;5(9):1081–9. 31. Rosin MP, Cheng X, Poh C, Lam WL, Huang Y, Lovas J, Berean K, Epstein JB, Priddy R, Le ND, et  al. Use of the allelic loss to predict malignant risk for low-grade oral epithelial dysplasia. Clin Cancer Res. 2000;6(2):357–62. 32. Lingen MW, Szabo E. Validation of LOH profiles for assessing oral cancer risk. Cancer Prev Res (Phila). 2012;5(9):1075–7. 33. William WN Jr, Papadimitrakopoulou V, Lee JJ, Mao L, Cohen EE, Lin HY, Gillenwater AM, Martin JW, Lingen MW, Boyle JO, et al. Erlotinib

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and the risk of oral cancer: the Erlotinib Prevention of Oral Cancer (EPOC) randomized clinical trial. JAMA Oncol. 2016;2(2):209–16. 34. Schatzkin A, Gail M. The promise and peril of surrogate end points in cancer research. Nat Rev Cancer. 2002;2(1):19–27. 35. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74. 36. Spira A, Beane J, Shah V, Liu G, Schembri F, Yang X, Palma J, Brody JS.  Effects of cigarette smoke on the human airway epithelial cell transcriptome. Proc Natl Acad Sci U S A. 2004;101(27):10143–8. 37. Sridhar S, Schembri F, Zeskind J, Shah V, Gustafson AM, Steiling K, Liu G, Dumas YM, Zhang X, Brody JS, et al. Smoking-induced gene expression changes in the bronchial airway are reflected in nasal and buccal epithelium. BMC Genomics. 2008;9:259. 38. Boyle JO, Gumus ZH, Kacker A, Choksi VL, Bocker JM, Zhou XK, Yantiss RK, Hughes DB, Du B, Judson BL, et  al. Effects of cigarette smoke on the human oral mucosal transcriptome. Cancer Prev Res (Phila). 2010;3(3):266–78. 39. Szabo E. Primer: first do no harm--when is it appropriate to plan a cancer prevention clinical trial? Nat Clin Pract Oncol. 2008;5(6): 348–56. 40. Baron JA, Sandler RS, Bresalier RS, Quan H, Riddell R, Lanas A, Bolognese JA, Oxenius B, Horgan K, Loftus S, et  al. A randomized trial of rofecoxib for the chemoprevention of colorectal adenomas. Gastroenterology. 2006;131(6):1674–82. 41. Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K, Lines C, Riddell R, Morton D, Lanas A, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med. 2005;352:1092–102. 42. Lubet RA, Scheiman JM, Bode A, White J, Minasian L, Juliana MM, Boring DL, Steele VE, Grubbs CJ. Prevention of chemically induced urinary bladder cancers by naproxen: protocols to reduce gastric toxicity in humans do not alter preventive efficacy. Cancer Prev Res (Phila). 2015;8(4):296–302. 43. Wu X, Lippman SM. An intermittent approach for cancer chemoprevention. Nat Rev Cancer. 2011;11(12):879–85. 44. Rahman MA, Amin AR, Shin DM.  Chemopreventive potential of natural compounds in head and neck cancer. Nutr Cancer. 2010;62(7):973–87. 45. Lan A, Li W, Liu Y, Xiong Z, Zhou S, Palko O, Chen H, Kapita M, Prigge JR, Schmidt EE, et al. Chemprevention of oxidative stress-­associated oral carcinogenesis by sulforaphane depends on NRF2 and the isothiocyanate moiety. Oncotarget. 2016;7:53502–14. 46. Chikara S, Nagaprashantha LD, Singhal J, Horne D, Awasthi S, Singhal SS. Oxidative stress and dietary phytochemicals: role in cancer chemoprevention and treatment. Cancer Lett. 2018;413:122–34. 47. Bauman JE, Zang Y, Sen M, Li C, Wang L, Egner PA, Fahey JW, Normolle DP, Grandis JR, Kensler TW, et al. Prevention of carcinogen-­ induced oral cancer by sulforaphane. Cancer Prev Res (Phila). 2016;9(7):547–57.

48. Pollak M. Metformin and other biguanides in oncology: advancing the research agenda. Cancer Prev Res (Phila). 2010;3(9):1060–5. 49. Heckman-Stoddard BM, Gandini S, Puntoni M, Dunn BK, DeCensi A, Szabo E.  Repurposing old drugs to chemoprevention: the case of metformin. Semin Oncol. 2016;43(1):123–33. 50. Vitale-Cross L, Molinolo AA, Martin D, Younis RH, Maruyama T, Patel V, Chen W, Schneider A, Gutkind JS. Metformin prevents the development of oral squamous cell carcinomas from carcinogen-­induced premalignant lesions. Cancer Prev Res (Phila). 2012;5(4):562–73. 51. Yen YC, Lin C, Lin SW, Lin YS, Weng SF. Effect of metformin on the incidence of head and neck cancer in diabetics. Head Neck. 2015;37(9):1268–73. 52. Mak MP, William WN Jr. Targeting the epidermal growth factor receptor for head and neck cancer chemoprevention. Oral Oncol. 2014;50(10):918–23. 53. Leeman-Neill RJ, Seethala RR, Singh SV, Freilino ML, Bednash JS, Thomas SM, Panahandeh MC, Gooding WE, Joyce SC, Lingen MW, et al. Inhibition of EGFR-STAT3 signaling with erlotinib prevents carcinogenesis in a chemically-induced mouse model of oral squamous cell carcinoma. Cancer Prev Res (Phila). 2011;4(2):230–7. 54. Zhou G, Hasina R, Wroblewski K, Mankame TP, Doci CL, Lingen MW. Dual inhibition of vascular endothelial growth factor receptor and epidermal growth factor receptor is an effective chemopreventive strategy in the mouse 4-NQO model of oral carcinogenesis. Cancer Prev Res (Phila). 2010;3(11):1493–502. 55. Cohen EEW, Soulieres D, LeTourneau C, Dinis J, Licitra L, Ahn M-J, Soria A, Machiels J-P, Mach N, Mehra R, et al. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet. 2018;393(10167): 156–67. 56. Spira A, Yurgelun MB, Alexandrov L, Rao A, Bejar R, Polyak K, Giannakis M, Shilatifard A, Finn OJ, Dhodapkar M, et al. Precancer atlas to drive precision prevention trials. Cancer Res. 2017;77(7):1510–41. 57. Volik S, Alcaide M, Morin RD, Collins C. Cell-free DNA (cfDNA): clinical significance and utility in cancer shaped by emerging technologies. Mol Cancer Res. 2016;14(10):898–908. 58. Mende M, Thiede C, Schuster C, Aust DE, Folprecht G. Detection of tumor progression via cell-free DNA (cfDNA) in patients with colorectal cancer. J Clin Oncol. 2015;33(3_suppl):598. 59. Izumchenko E, Chang X, Brait M, Fertig E, Kagohara LT, Bedi A, Marchionni L, Agrawal N, Ravi R, Jones S, et al. Targeted sequencing reveals clonal genetic changes in the progression of early lung neoplasms and paired circulating DNA. Nat Commun. 2015;6:8258. 60. Kensler TW, Spira A, Garber JE, Szabo E, Lee JJ, Dong Z, Dannenberg AJ, Hait WN, Blackburn E, Davidson NE, et al. Transforming cancer prevention through precision medicine and immune-­ oncology. Cancer Prev Res (Phila). 2016;9(1):2–10.

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239

General Workup Prior to the Treatment Phase of Oral Cancer Michael Awadallah, Ketan Patel, and Deepak Kademani 19.1

Introduction – 241

19.2

History and Physical Examination – 241

19.2.1 19.2.2

 ral Examination – 241 O Neck Examination – 243

19.3

 iopsy Techniques and Adjunctive Aids B in the Oral Cavity – 243

19.3.1 19.3.2 19.3.3

 rush Cytology – 243 B Fluorescent Markers – 244 Stains and Dyes – 245

19.4

Biopsy Techniques of Neck Masses – 245

19.4.1

Sentinel Lymph Node Biopsy (SLNB) – 245

19.5

Imaging – 245

19.5.1 19.5.2 19.5.3

 rthopantomography – 245 O Chest Radiographs – 245 Computed Tomography (CT) and Contrast-Enhanced CT (CECT) – 246 Magnetic Resonance Imaging (MRI) – 246 Positron Emission Tomography (PET) and Combined PET/CT – 246 PET/MRI – 246 Ultrasonography (US) – 247

19.5.4 19.5.5 19.5.6 19.5.7

19.6

 edical Workup, Optimization, and Impact M of Comorbidity – 247

19.6.1 19.6.2

 ptimization – 248 O Impact of Comorbidity – 248

19.7

Functional Status, Performance Status, and Frailty – 248

19.7.1 19.7.2 19.7.3

 ssessment of Functional Status and Performance Status – 248 A Frailty Index – 249 Nutritional Status and Optimization – 249

© Springer Nature Switzerland AG 2020 S. Warnakulasuriya, J. S. Greenspan (eds.), Textbook of Oral Cancer, Textbooks in Contemporary Dentistry, https://doi.org/10.1007/978-3-030-32316-5_19

19

19.7.4 19.7.5 19.7.6

 ssessment of Nutrition – 249 A Impact of Malnutrition – 249 Treatment of Malnutrition – 250

19.8

Presurgical Anesthesia Workup – 250

19.9

Dental Workup and Optimization – 250

19.9.1 19.9.2

 ental Therapy During Oral Cancer Treatment – 250 D Dental Therapy Post-oral Cancer Treatment – 251

19.10 Integration and Clinical Staging – 251 19.11 Conclusion – 251 References – 251

19

241 General Workup Prior to the Treatment Phase of Oral Cancer

Core Message The workup consists of taking a thorough history and physical examination which should include assessing the nutritional and functional status of the patient. Other inital assessments should include a thorough dental evaluation along with imaging modalities for staging. A thorough and preoperative medical, anesthetic, and surgical assessment is to be undertaken to identify pathophysiology and determine perioperative risk stratification, anesthetic management, medical management, surgical management, and medical optimization. Based on these assessments, the oncology team would determine if the patient is healthy enough to withstand treatment, and the decision is based on the interplay of existing comorbidities, patient age, functional status, performance status, and frailty. The eventual goal is to i­ntegrate all of this information and to clinically stage the patient and develop a treatment plan consistent with the patient’s treatment goals and tolerance for any side effects of treatment.

19.1 

Introduction

The workup of an oral cavity cancer patients is complex and should be approached with a comprehensive and global perspective. It should include clinical staging to direct therapy and to assess the patient for comorbidities to determine the efficacy and degree of morbidity these therapies will have on the patient. The general workup consists of taking a thorough history and physical examination which should include assessing the nutritional and functional status of the patient. Other inital assessments should include a thorough dental evaluation along with imaging modalities for staging. The eventual goal is to integrate all of this information for clinical staging and for developement of a treatment plan that is consistent with the patient’s goals of care (. Fig. 19.1). Clinical staging not only helps guide therapy but establishes extent of disease. Since 60–70% of patients with oral cancer usually present with later-stage tumors (stages 3 and 4), treatment is often multi-modal and requires a comprehensive medical assessment to ensure the patient will be able to tolerate treatment.  

19.2 

History and Physical Examination

Detailed history and physical examination are required for all patients diagnosed with head and neck cancer. This includes a detailed review of systems along with the patient’s past medical and surgical conditions, social and family history, medications, and allergies. If surgery is planned, all systems, especially the cardiac and pulmonary systems; are important to assess the risk of potential perioperative/treatment complications and morbidity. The functional status is mainly derived from the patient’s cardiopulmonary status. This can be fur-

History and physical

Biopsy

Imaging

Treatment

Clinical staging

Integration

Pathological staging

Adjunctive treatment if applicable

..      Fig. 19.1  Oral cancer workup flow

ther elucidated using adjunctive medical testing such as trans-­thoracic echocardiogram, pulmonary function testing, and stress testing if indicated. Additional coagulation, renal, and hepatic function studies are often indicated. The patient’s social history, with particular attention to alcohol and tobacco use, will aid in identifying etiologic agents that may increase the risk of perioperative/treatment comorbidities. Knowledge of risk factors along with patient counseling also helps to reduce any future risk of developing local, regional, or distant primaries and recurrences. 19.2.1 

Oral Examination

The clinical presentation of oral cancer is variable with a wide range of symptoms. Asymptomatic patients will usually present after an incidental finding on routine exam by a dental or medical practitioner. Symptomatic patients may present with pain, mobile teeth, ill-fitting dental prosthesis, odynophagia, and/or bleeding. A thorough head and neck examination is performed to determine the gross clinical size and depth of the lesion and to assess for any other synchronous primaries in the aerodigestive tract. Lesion-specific characteristics may include changes in color (white or red), exophytic growth, endophytic infiltration, and ulceration (see 7 Chapter 5). Photographic records are especially useful for case discussion. Assessment of maxillary and/or mandibular involvement should be performed to rule out gross bony infiltration. Mouth opening and tongue range of motion, along with assessing for dysphagia or odynophagia, are performed to rule out gross muscle invasion and extent of soft tissue infiltration. Neurosensory testing of the inferior alveolar and lingual nerves is performed for assessment of potential perineural invasion. Local invasion involving tissue beyond the mucosa including but not limited to nerve, bone, or muscle will aid the clinician in determining the duration, biologic  

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M. Awadallah et al.

behavior, and extent of infiltration; will directly impact the clinical staging of the lesion. Otalgia, trismus, dysphagia, odynophagia, tongue fixation or decreased tongue mobility, pathologic fracture, paresthesia, and pain are all likely signs of later-­stage lesions. A fiber-optic examination has limited

Box 19.1  Case Example

zz Patient History

19

55 CC: A 63-year-old Caucasian male presents to the clinic stating that “there is something wrong with my right cheek from the inside, and my dentist said I need to have it checked.” 55 HPI: The patient recently visited his general dentist for evaluation of his loosing lower dentures. Upon examination, a red and white fungating mass of the right posterior buccal mucosa was noted. The patient was otherwise asymptomatic and denies pain, bleeding, trismus, dysphagia, odynophagia, and neurosensory disturbances. The patient initially noticed this mass almost 8 months ago but it did not concern him to go see a dentist or physician because it was not painful. He did notice that the lesion did grow substantially in size over those 8 months. He endorses unintentional weight loss of around 15 kilograms over the last 4–5 months and currently weighs around 109 kilograms. 55 PMH: Hypertension, diabetes type 2, hyperlipidemia, gastroesophageal reflux disease, chronic obstructive pulmonary disease, coronary artery disease 55 MEDS: Metoprolol, lisinopril, metformin, Crestor, omeprazole, Advair, aspirin 55 PSH: Tonsillectomy, appendectomy, triple bypass surgery 55 ALL: NKDA 55 SH: The patient has a 47 pack-year history of tobacco use and drinks two to three beers daily. He is retired but has a wood shop at home, and he builds structures like tables, stands, small cabinets, and chest drawers for his family members. He cares for himself and for his wife who is quadriplegic from a severe car accident. 55 FH: Father passed away from lung cancer. Mum passed away from an MI.

use in the oral cancer patient since the area is amendable to direct visualization; this technique is usually reserved for oropharyngeal, hypopharyngeal, nasopharyngeal, and unknown primary tumors. There is a 2.4–4.5% incidence of synchronous primary tumors of the upper digestive tract [1].

zz Physical Exam

55 General: The patient is a well-developed and well-nourished overweight white man who appears older than his stated age, but no signs of cachexia, temporal muscle wasting, and buccal or ocular fat pad atrophy. 55 Maxillofacial: There is a 2 × 3.5 cm red and white/red fungating mass on the right posterior buccal mucosa without ulceration. There is no pain or bleeding noted on palpation of the lesion. Examination of the remaining oral cavity, including the left buccal mucosa, hard and soft palate, mandibular and maxillary alveolar gingiva, the ventral and dorsal tongue, and the retromolar trigones, revealed no other abnormalities. 55 Neck: Trachea midline, no gross masses visualized. During a firm and deep palpation of neck levels 1–6 bilaterally, an ipsilateral node in level 2a was detected. The node was non-tender, round, regular, but was fixed and firm on palpation. No erythema, edema, or ulceration was found bilaterally on the neck exam. 55 Heart and lungs: Normal s1, s2, no murmurs or gallops, chest rise equal and symmetric B/L, no rales, no wheezing, no rhonchi, hypoactive breath sounds bilaterally.

zz Interventions

Incisional Biopsy: A 5 mm punch biopsy was performed at the core of the lesion to the depth of the buccinators muscle under local anesthesia and sent off for histopathological examination in formalin. The histopathology report described a loss of normal maturation of the full-thickness epithelial layer with invasion of abnormal cells beyond the basement membrane into the underlying subcutaneous tissues and muscle layers (invasive tumor). The abnormal cells were pleomorphic with an increased nuclear-to-cytoplasmic ratio and abundant mitotic figures. The tumor was graded as a poorly differentiated invasive OSCC.

Imaging: A CT neck, maxillofacial, chest with contrast, and a head and neck carcinoma staging PET/CT were ordered. Results showed a local thickening of the right buccal mucosa on CT images with craniocaudal and AP extent of approximately 3 cm, with associated intense abnormal FDG uptake present nearby the anterior, superior angle of the right hemi-mandible, in association with obvious bone erosion here in keeping with known malignancy. There is right submandibular lymph node with intense FDG avid uptake that measures 1.8 cm in size. No evidence of distant metastasis within the chest, abdomen, pelvis, or bones.

zz Integration and Clinical Staging

This is a 53-year-old male with a biopsyproven oral squamous cell carcinoma of the right buccal mucosa. Physical exam is significant for a 3.5-cm-sized lesion in greatest dimension, large cortical and marrow erosion, and a prominent ipsilateral right submandibular lymph node. Imaging shows an FDG avid 3.3 cm right buccal mucosal lesion with mandibular cortical erosion and an ipsilateral submandibular lymph node also positive for FDG uptake. Because the lesion has frank cortical erosion, it would upstage the patient from a cT2 to a cT4a. There was one positive ipsilateral lymph node that is 50% of the time, performs light work at his wood shop, has multiple comorbidities, and has no clinical signs of malnourishment. He would be score a 1 and a 70–80 on the ECOG and Karnofsky performance status scores, respectively. Overall this patient is a good candidate for surgical a composite resection, right selective neck dissection levels 1–4, and reconstruction with a left composite free fibula to the right mandible.

243 General Workup Prior to the Treatment Phase of Oral Cancer

19.2.2 

Neck Examination

The clinician must palpate neck levels 1–6 (. Fig.  19.2) thoroughly to detect any gross lymphadenopathy and characterize it, and if present, size, side, tenderness, firmness, and mobility should all be noted (. Fig.  19.3). A benign neck (N0) on physical exam does not rule out regional metastasis; adjunctive imaging is mandatory for accurate and complete staging of the neck (see 7 Chapter 11). Neck lymphadenopathy is an ominous sign in patients above 40 years old and persisting greater than 2 weeks. A clinically positive neck in the presence of OSCC will decrease the 5-year survival rate by approximately half. Physical exami 

 

nation alone without any adjunctive imaging or techniques has a 74% sensitivity, an 81% specificity, and a 77% accuracy [2]. A differential diagnosis of a neck metastasis is based on the location of the lump in the neck and patient’s age and can include thyroglossal duct cyst, brachial cleft cyst, epidermoid and sebaceous cysts, salivary gland tumors, lymphoma, and metastatic or primary thyroid neoplasms (. Figs. 19.4 and 19.5).  

 

IB

IA

IIB

IIA

19.3 

 iopsy Techniques and Adjunctive Aids B in the Oral Cavity

Once a tumor has been identified in the oral cavity, confirmation of malignancy with histopathological examination is undertaken. An incisional biopsy is performed with either a soft tissue punch or blade incision. For an incisional biopsy, a core representative sample of the lesion with adequate depth preferably down to bone or muscle is undertaken to minimize sampling error and help the pathologist confirm a diagnosis. In general it is recommended to avoid excisional biopsy for small lesions that are clinically suspicious for malignancy as this may compromise the development of definitive surgical margins. More detailed information regarding biopsy techniques can be found in 7 Chapter 8.  

III

Definition Pathology diagnosis following a formal biopsy remains the gold standard to confirm a malignancy and to start the workup phase of a cancer patient.

VA VI

VB IV

19.3.1  ..      Fig. 19.2  Clinical neck levels. Copied from the AJCC 7th edition Cancer Staging Manual

Brush cytology is a minimally invasive technique compared with a knife biopsy and involves obtaining a transepithelial specimen. The cellular material is then transferred to a glass slide, fixed, and sent for microscopic examination by a cytopathologist or computer-assisted analysis. Sampling is limited to the basal, intermediate, and superficial layers of a lesion and not the submucosa; it cannot be used to differentiate carcinoma in situ vs invasive carcinoma. The sensitivity of the technique varies from 73% to 100% and specificity ranges from 32% to 94% [3, 4]. If cytopathological examination is negative for carcinoma and suspicion is high, repeat incisional knife biopsy is warranted. Histologic grading is routinely performed on all biopsies positive for squamous cell carcinoma (SCC) and is based on the WHO grading system taking into account the degree of differentiation of the tumor tissue: Grade 1 is well differentiated, grade 2 is moderately differentiated, and grade 3 is poorly differentiated. The prognostic value of pathological grading of OSCCs is discussed in 7 Chapters 7 and 25. Brush cytology is usually reserved for non-malignant lesions but is included here for completeness of discussion.  

..      Fig. 19.3  Lymphadenopathy of neck level 1B

Brush Cytology

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Age

< 40

Differential

1) Inflammatory

Location

Cental /Lateral Compartment

Central Compartments

Lateral Compartment

Central Compartment

Lateral Compartment

Common Lesions

Bacterial Lymphadenopathy

Epidermoid/dermoid cyst

Branchial Cleft Cyst

Thyroid neoplasm

Lymphoma

Viral Lymphadenopathy

Throglossal duct /thymic cyst

Lymphangioma

Lymphoma

Lymph node metastasis

Parasitic lymphadenopathy

Laryngocele

Vascular lesions

Laryngeal neoplasm

Salivary Gland Neoplasms

2) congenital

3) Malignant

..      Fig. 19.4  Algorithm of neck masses below the age of 40 years old

Age

Differential

> 40

1) Malignant tumors and Benign tumors

2) Inflammatory

3) congenital

Location

Central Compartment

Lateral Compartment

Central/Lateral Compartments

Central Compartment

Lateral Compartment

Common Lesions

Thyroid neoplasm

Lymph node Metastasis

Bacterial Lymphadenopathy

Epidermoid/dermoid cyst

Lymphangioma

Lymphoma

Lymphoma

Viral lymphadenopathy

Throglossal duct /thymic cyst

Branchial Cleft Cyst

Laryngeal neoplasm

Salivary gland neoplasms

Parasitic Lymphadenopathy

Laryngocele

Vascular lesions

..      Fig. 19.5  Algorithm of neck masses above the age of 40 years old

19

Fluorescent Markers

tory changes and reactive tissue from dysplasia and malignancy. For those studies that presented a 100% sensitivity, it Autofluorescence and chemiluminescence techniques are was deemed the lesions were clinically apparent by standard based on the principle that light-absorbing and light-­ visual examination. A new technique based upon the alterareflecting properties of normal mucosa changes as the tissue tions in expression of certain glycan residues on the surface becomes dysplastic and during malignant progression. A sys- of cancer and dysplastic cells has shown initial promising tematic review showed the sensitivity and specificity of che- results [7, 8]. A chairside in vivo study was undertaken to test miluminescence in the published studies range from 0% to a specific fluorescent conjugated lectin to target this aberrant 100% and from 0% to 75%, respectively, and the sensitivity glycosylation on cancerous and dysplastic cells in the oral and specificity of autofluorescence range from 30% to 100% cavity. The study reported a sensitivity of 89% and a specificand from 15.3% to 100%, respectively [5, 6]. However, both ity of 82% [7]. 7 Chapter 9 provides more detailed account techniques had limited value when distinguishing inflamma- on currently available adjunctive techniques. 19.3.2 

 

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245 General Workup Prior to the Treatment Phase of Oral Cancer

19.3.3 

Stains and Dyes

Toluidine blue is a vital staining technique that that has been adopted for the detection of malignancies and lesions with dysplasia. It is a metachromatic dye that has high affinity for anionic groups such as those found in nucleic acids. The application of toluidine blue can provide a guide to the clinician to select a specific area to biopsy. The technique unfortunately does not discriminate high-risk lesions from low-risk lesions. Overall, the sensitivity and the specificity for toluidine blue in the literature range from 57% to 81% and 56% to 67%, respectively [5, 9]. Both the specificity and sensitivity increase with the severity of dysplasia. Lugol’s iodine solution has been used to identify cancerous lesions based on its affinity to bind to glycogen found in normal or healthy mucosa. Dysplastic mucosa and malignant mucosa have negligible glycogen stores if any and do not bind the stain. Lugol’s iodine is an effective adjunct in guiding the clinician to select the biopsy site and assists during surgical resection to obtain clear margins.

19.4 

Biopsy Techniques of Neck Masses

Fine needle aspiration biopsy (FNA) is usually the first-line diagnostic procedure for neck lymphadenopathy. It is particularly useful in guiding therapy and allowing differentiation between lymphoma, thyroid malignancy, oropharyngeal malignancy, oral malignancy, salivary gland malignancy and other types of malignant or benign tumors of the head and neck. This distinction can potentially avoid extraneous interventions. If lymphoma is either diagnosed or strongly suspected on FNA, it directs the surgeon to a simple node excision for histologic examination and flow cytometry. If the neck mass is FNA positive for carcinoma and a primary tumor is still elusive after a thorough and repeat head and neck examination, then a direct laryngoscopy with biopsies of the base of tongue and tonsils in Waldeyer’s ring is recommended. The sensitivity and specificity of FNA range from 89% to 98% in the literature. Non-­diagnostic samples can be up to 25% in the literature but on average range from 5% to 16%. If FNA is inconclusive, an open biopsy of the lymph node should be undertaken.

19.4.1 

Sentinel Lymph Node Biopsy (SLNB)

A new but potentially promising methodology for further workup of a clinically benign neck is SLNB. Occult regional metastasis into the nodes of the neck can be as high as 30% in the literature. There is an ongoing debate as to whether or not to perform a prophylactic selective neck dissection of the clinically negative neck at the expense of increased patient morbidity and mortality and increased healthcare cost. The purpose of a SNLB is primarily diagnostic and to provide a definitive indication to perform a neck dissection in a preoperative clinical N0/benign neck by diagnosing regional metas-

tasis. SLNB follows the principal lymphatic basins that drain the tumor site. Sentinel lymph nodes are mapped using conventional lymphoscintigraphy with a radioactive technetium99 dye. The dye is initially injected around the lesion circumferentially and traced to the lymph node basin or groups that drain the lesion (lymphoscintigraphy). The patient is then transferred to surgery, and the lymph node with the highest radioactive dye uptake will be detected by the performing clinician using a handheld gamma probe. This procedure is usually performed at the same time during resection of the tumor. The SNLB is then sent for frozen section. If the biopsy returns as negative for carcinoma, there is no indication for elective neck dissection. If the SLN is positive, the surgeon can proceed to an immediate or staged neck dissection. The SENT trial showed a sensitivity of 86%, negative predictive value of 95%, and false negative rate of 14% [10]. >>Important Correctly staging neck disease is important to avoid local recurrent disease following treatment.

19.5 

Imaging

Common imaging modalities for oral cancer include the panoramic radiograph, ultrasonography (US), computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography, and combined PET/CT as well as sometimes a plain film chest x-ray. The role of pretreatment imaging is to further shed light on extent of lesion size, depth, bone and muscle infiltration, perineural invasion, regional metastasis into lymph nodes, and distant metastasis to the lungs. The results of these imaging modalities combined with histopathology and the physical exam will lead to a more precise clinical stage and will help guide therapy. A detailed account of imaging modalities and their efficacy can be found in 7 Chapter 11.  

19.5.1 

Orthopantomography

The panoramic radiograph is a readily available modality in most health centers that is cost-effective with a relatively low radiation exposure. However, its use in clinical staging of oral cancer is limited to gross bony involvement since it only depicts hard tissues and will require at least 33% bone demineralization for a radiographic change to manifest (. Fig. 19.6). Its main use is for dental assessment and treatment planning for the dentition prior to initiating cancer therapy [11].  

19.5.2 

Chest Radiographs

Chest radiographs (posterior, anterior, and lateral views) allow the clinician to screen for lung metastasis from occult primary lung malignancy or a concurrent primary lung neoplasm. If a suspicious lesion is found on chest radiograph, further investigation with a CT scan of the chest is

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..      Fig. 19.6  Orthopantomogram showing cortical erosion of the left posterior mandible

appropriate. The specificity and sensitivity are 73% and 80%, respectively, for a utility of plain chest radiography in the evaluation of pulmonary metastasis for patients with head and neck tumors. 19.5.3 

Computed Tomography (CT) and Contrast-Enhanced CT (CECT)

CT imaging is a fundamental and one of the superior imaging modalities in the workup for oral cancer when it comes to assessing for cortical infringement by tumor and detection of any calcifications within the tumor (. Fig. 19.7). The sensitivity and specificity of this test can be as high as 82.6% and 86.9%, respectively, with an accuracy of 85% [12]. CECT includes the addition of iodine contrast to provide soft tissue detail and lymph node involvement. The CECT technique has been shown to be superior to the physical examination in detecting lymph node involvement. In addition to detecting pathologic lymph nodes, CECT can also detect extranodal extension within the nodes. Image slice thickness should be no larger than 5  mm for adequate spatial resolution and is optimally 1 mm–3 mm in thickness. In the neck, the sensitivity and specificity of the CECT in detecting nodal metastasis are 52% and 93%, respectively [13]. Newer modalities that include multispectral and dual-energy CT have improved tissue resolution of conventional CECT and may have increased accuracy during clinical staging.  

19

19.5.4 

Magnetic Resonance Imaging (MRI)

The information obtained from MRI in combination with CT imaging is synergistic at the primary site, for assessing bone invasion, and for lymph node metastasis. The most yielding sequences are the contrast-enhanced T1-weighted images with fat suppression, T1-weighted images, and T2-weighted images with fat suppression in axial and coronal views. As in CECT slices should be no larger than 3 mm. It is widely accepted that MRI is superior to CT when it comes to soft tissue detail, perineural spread, bone marrow

..      Fig. 19.7  CECT showing cortical erosion

invasion, and non-calcified cartilage involvement. However, it is equivocal as to which is superior for lymph node metastasis [11]. In the neck, the sensitivity and specificity of the MRI in detecting nodal metastasis are 65% and 81%, respectively [13].

 ositron Emission Tomography (PET) P and Combined PET/CT

19.5.5 

PET scanning is a functional imaging that is based on the metabolic activity of malignant lesions. The isotope F-18 deoxyglucose (FDG) is injected into the patient and then a PET is performed. Metabolically active cells will take up the traces and light up on PET. It is important for the clinician to have a background knowledge of where this is normal in the head and neck region like in the tonsils and brain and where it would be abnormal. The hybrid integration of PET and CT imaging further enhances correlation between function and morphology in one image. The main use of PET/CT in oral cancer is identification of detection of subclinical regional neck metastasis (. Fig.  19.8) or distant metastasis into the lungs (. Fig. 19.9) and other areas of the body and posttreatment surveillance. A meta-analysis performed on 987 patients using integrated PET/CT showed a pooled sensitivity and specificity of 89.3% and 89.5%, respectively, in detecting head and neck carcinoma [14]. The same study also performed a meta-analysis on 517 patients that had standard conventional imaging (MRI and CT) and found a pooled sensitivity and specificity of 71.6% and 78%, respectively, in detecting head and neck carcinoma [14]. Of note is that the PET/CT modality is currently unable to detect micrometastasis especially those that are less than 5 mm in size.  

 

19.5.6 

PET/MRI

A relatively new hybrid technique combines the functional imaging of a PET and the superior soft tissue resolution of an

247 General Workup Prior to the Treatment Phase of Oral Cancer

..      Fig. 19.10  US showing lymphadenopathy and core needle biopsy being performed

19.5.7  ..      Fig. 19.8  PET/CT showing right regional metastasis involving level IV

Ultrasonography (US)

US is a cost-effective, minimally invasive, and readily available imaging mobility that can be performed chairside in the hands of an experienced clinician or by a radiologist/ultrasonographer. Its main use in oral cancer is in the assessment of nodal metastasis in the neck and guiding FNA biopsy (. Fig. 19.10). However, it has limited use at the primary site. It is historically considered to be the most accurate method in detecting lymph node metastasis and primary thyroid malignancies. A study performed on 85 necks showed the sensitivity, specificity, and accuracy of US to be 78.9%, 68.75%, and 73.25%, respectively [16].  

19.6 

..      Fig. 19.9  PET/CT showing distant left lung metastasis

MRI.  Again, the 18-FDG isotope is injected and an MRI sequence is captured. A meta-analysis performed by pooled sensitivity and specificity showed 91% and 63% in lesion detection [15]. Ongoing studies are being performed to further assess the utility of this imaging technique, but it has yet to prove itself more effective than the current treatment modalities including the PET/CT.

Medical Workup, Optimization, and Impact of Comorbidity

A thorough and preoperative medical, anesthetic, and surgical assessment is to be undertaken to identify pathophysiology and determine perioperative risk stratification, anesthetic management, medical management, surgical management, and medical optimization. A complete history and physical examination is to be performed by the surgeon, the anesthesiologist, and the patient’s primary care physician. Basic and standard preoperative labs include a complete metabolic panel to screen for liver function, blood glucose level, renal function, and any acid-base derangements; a complete blood count is to be performed to screen for leukocytosis, leukopenia, thrombocytosis, thrombocytopenia, and anemia; and a coagulation panel consisting of prothrombin time (PT), partial thromboplastin time (PTT), and international normalized ratio (INR) is to screen for coagulopathies. Standard preoperative imaging and procedures include an electrocardiogram (ECG) for patients over 55 years old, patients with diabetes, and patients with hypertension or known cardiac risk to screen for cardiac function and a chest X-ray for patients who are known smokers along with pulmonary function tests in patients with documented preexisting pulmonary disease.

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19.6.1 

Optimization

Appropriate referral to a general physician is indicated for patients with serious comorbidities declared in their medical history needing presurgical recommendations and optimization. Preoperative optimization for common ­ comorbidities includes control of the glycemic index, optimal blood pressure control, management of renal insufficiency, and cardiopulmonary optimization. Perioperative smoking cessation and psychological assessment are indicated to optimize outcomes. Cardiopulmonary exercise testing is a powerful tool when used in context for assessment of potential perioperative cardiopulmonary complications, physiologic functional capacity, risk stratification, extent of surgery needed, and postoperative placement in the intensive care unit [17]. The test assesses the physiologic functional capacity of the patient by measuring it in metabolic equivalents and is thus able to quantify the patient’s physical fitness. Decreased physical fitness is associated with increased incidence of postoperative morbidity and mortality. 19.6.2 

Impact of Comorbidity

The Charleston Comorbidity Index (CCI) and the Adult Comorbidity Evaluation-27 (ACE-27) index are validated tools used to measure the degree of comorbidity a patient has. One has not been shown to be more superior than the other. Consideration of comorbidities and how they modulate the treatment of our oral cancer patients extends from the time of diagnosis to post-treatment surveillance. Patients with extensive comorbidities are indeed less likely to withstand optimal treatments as compared to their healthy counterparts. At least 36% of patients will present with comorbid conditions at the time of diagnosis [19]. Up to 20% of oral cancer patients can receive suboptimal intervention because of their comorbid conditions [18]. Multiple studies have shown not only increased complications rates but increased severity of these complications resulting in increased length of hospitalization [20–22]. While the magnitude of the comorbidies may not affect disease-specific survival, it does decrease overall survival and is an independent prognostic factor for risk of death [19].

19

!!Warning Patients with comorbidities may not be able to tolerate optimal therapies and the physical status of the patient should be fully discussed at the tumor board.

19.7 

 unctional Status, Performance Status, F and Frailty

Surgery is often the mainstay of treatment for cancer in the oral cavity. Oral cancers are often amendable to surgical treatment based on the inherent disease stage at diagnosis and/or the physiological capacity of the patient to withstand

the potential adverse outcomes of other treatment modalities. If the health of the patient is not optimal enough to withstand treatment sequelae, then the treatment in itself can lead to patient mortality directly or indirectly more expediently than the patient’s malignant state [23]. In both situations palliative and supportive therapy is to be implemented for symptomatic treatment. The oncologist determines if the patient is healthy enough to withstand treatment, and the decision is based on the interplay of existing comorbidities, patient age, functional status, performance status, and frailty. There is a consensus that advanced age by itself is not a factor in deciding treatment modalities. 19.7.1 

 ssessment of Functional Status A and Performance Status

Functional status is derived directly from the patient’s age, ability to perform activities of daily living (ADLs), instrumental activities of daily living (IADLs), medical comorbidities and can be quantified using performance status scores like the Karnofsky or Eastern Cooperative Oncology Group (ECOG) scales. ADLs are defined as ambulation, bathing, dressing, feeding, and voiding independently [24], while IADLs are defined at a higher level of function and encompass cooking, shopping, taking medications, cleaning, and managing one’s finances. Overall improved survival rate was found in patients undergoing chemotherapy who were able to perform IADLs independently [25]. The ECOG and Karnofsky Performance Status scales (. Tables 19.1 and 19.2) are validated tools used to assess the effect of disease on patient function preoperatively and can aid in determining appropriate medical intervention. Poor preoperative ECOG scores bare a relationship to advanced-­stage disease in the head and neck cancer patient and were an independent predictor of overall survival [26]. The Karnofsky Performance Status scale can also predict survival and quality of life. There is no current literature showing that one scale is more superior to the other and by themselves they will only measure  

..      Table 19.1  ECOG performance status score ECOG score

Description

0

Completely independent and fully active

1

Restricted in strenuous physical activity, able to care for one’s self, and can perform light work

2

Performs self-care but unable to work and ambulatory >50% of the time

3

Limited ability to care for one’s self and confined to a chair or bed for >50% of the time

4

Complete inability to care for one’s self and completely confined to a chair or a bed

5

Dead

249 General Workup Prior to the Treatment Phase of Oral Cancer

..      Table 19.2  Karnofsky performance status score Karnofsky score

Description

100

Normal activity; no evidence of disease

90

Able to carry on normal activity with minor signs and symptoms

80

Normal activity with effort; some signs or symptoms of disease

70

Cares of self but able to work or perform normal activity

60

Requires some assistance, but able to care for self-needs

50

Requires considerable assistance and frequent medical care

40

Disabled; mandating special care

30

Severely disabled; hospitalization indicated

20

Very sick; hospitalized with active support

10

Moribund

0

Dead

the patient’s current functional ability. However, when used in the context of disease stage, patient age and comorbidities, and disease prognosis, these scales will aid the clinician risk stratifying the patient for treatment. 19.7.2 

Frailty Index

Defined originally as “having delicate health and not robust,” this relatively recent concept and index has been implemented to predict perioperative morbidity and mortality in the geriatric head and neck cancer patient [27]. The definition has been refined and is characterized by multisystem dysfunction and a decrease in physiologic reserves [24]. A study performed by Adams et  al. using a modified frailty index (mFI) showed a positive and stepwise correlation with the index score and postoperative complications and mortality [24] in otolaryngology patients undergoing standard surgical procedures. However, the same study showed a similar correlation using the well-established and universally used American Society of Anesthesiology classification system. Again, it is important to emphasize that all these previously stated scales are tools that are meant to be placed into context and should not be used independently to determine treatment modality and intent. 19.7.3 

Nutritional Status and Optimization

Malnutrition is defined as “a subacute or chronic state of nutrition in which a combination of varying degrees of over- or undernutrition and inflammatory activity has led

19

to a change in body composition and diminished function” [28]. Weight loss and malnutrition are prevalent in about 40% of all cancer patients [29]. This is even more pronounced and can be up to 57% for patients with head and neck cancers [30]. Beside the inherent tumor factors and the inflammatory response that lead to a catabolic metabolism, further propagation of malnutrition is due to decreased oral intake secondary to dysphagia, odynophagia, trismus, and oral pain. It is important keep in mind that 60–70% of oral cancer patients will present in late stages and will likely have at least one or a combination of the previously mentioned symptoms. Both inadequate caloric intake and dehydration can occur. Patient social factors that contribute to malnutrition are tobacco use, caffeine use, and alcohol use which contribute to appetite suppression, further inflammatory state, diuresis, catabolism, and cachexia. 19.7.4 

Assessment of Nutrition

Assessing malnutrition includes measurements of nutrient balance, body composition, inflammatory activity, and muscle, immune, and cognitive function [28]. Different methodologies have been used to preoperatively assess patient malnutrition if any and include prealbumin and albumin measurements, body mass index (BMI), Nutritional Risk Score (NRS), CT scanning for muscle mass estimation by looking at the amount of muscle around the third lumbar vertebra (L3MM), and muscle strength performance. The current standard for nutritional assessment is the Nutritional Risk Index (NRI) which is a composite score combining loss of weight as compared to baseline and serum albumin levels [31]. The Nutritional Risk Index (NRI) is calculated according to the following formula: 1.519 × albumin + 0.417 + (current weight/usual weight) × 100. The L3MM is a promising test that shows similar efficacy in identifying malnutrition as compared to the NRI. 19.7.5 

Impact of Malnutrition

Delayed wound healing, increased risk of infection, weakness, depression, and poor quality of life are but a few of the complications associated with malnutrition [32]. Regardless of treatment a weight loss of greater than 15% is associated with a worse prognosis and in itself is the cause of death in 5–25% of cancer patients [29]. A step-wise increase in 30-day mortality rate, increase in quality of life impairment, and increase in hospital resource use were found with increasing NRS [29]. Another study found malnutrition to be associated with prolonged length of admission, frequent re-admissions, and increased inpatient mortality [33]. Optimization pre-­ intervention nutrition in the malnourished oral cancer patient is pivotal in priming not only for surgical success and patient mortality and morbidity but also for patient quality of life and minimizing hospital costs.

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19.7.6 

Treatment of Malnutrition

If malnutrition is suspected or confirmed during the preoperative workup of an oral cancer patient, a dietary consultation is recommended. Depending on the level of current nutrition and the ability of the patient to tolerate oral intake prior to and after surgery, different methods can be implemented to identify not only the optimal calorie intake and supplements but also the ideal route of administration. Patients who can tolerate oral intake prior to surgery should be supplemented with the appropriate supplemental formulae. If the patient cannot tolerate or has inadequate oral intake, a different route of administration should be undertaken, commonly via either a nasogastric feeding tube or a gastrostomy tube. This can be established either preoperatively or intra-operatively depending on the severity of malnutrition and the need for presurgical optimization. It is recommended that the nasogastric feeding tube be the first option because it entails minimal morbidity to the patient; however, if the projected dependence on it is >30 days, then a gastric tube placement should be placed instead due to patient compliance and trauma to the nasal mucosa. A potential complication of nutritional intervention in a malnourished patient is the development of re-feeding syndrome. It is defined as electrolyte and metabolic derangements causing adverse clinical manifestations upon refeeding the malnourished patient. The hallmark of this disease is the occurrence of hypomagnesemia, hyperglycemia, hypokalemia, and decreased thiamine in the background of hypophosphatemia with varied clinical detection, manifestations, and symptoms. These symptoms and signs arise from unstabilized cell membrane potentials in the nerve tissue, cardiac tissue, and skeletal tissue [34]. Clinical manifestation is varied in magnitude and symptomology. Due to this variance in both clinical detection and presentation, its prevalence and incidence rates vary greatly in the literature depending on the definition used [35]. 19.8 

19

Presurgical Anesthesia Workup

A thorough and pre-emptive anesthetic and airway plan is to be undertaken to minimize perioperative complications. The presurgical anesthetic assessment will include the comprehensive physiologic workups included in the previous sections and in addition will also include airway assessment for not only the intra-operative period but the postoperative as well. A close and open communication between the surgeon and the anesthesiologist is paramount in managing the airway perioperatively. For obstruvtive or posterior airway cancers, it would be prudent to have a nasopharyngoscopy exam performed by the anesthesiologist to determine if the patient’s airway is amendable to nasotracheal intubation, be it either routine or fiber-optic. If a difficult or tenuous airway is encountered, the team should plan for and perform an awake tracheostomy. A lengthy operation or if microvascular reconstruction is planned, a tracheostomy is often recommended. It is wise to account for postoperative airway swelling, return

to the operating room, and predict length of intubation postoperatively in planning for a surgical airway. Clinical Assessment Scoring System for Tracheostomy (CASST) is a new tool that has yet to be validated but boasts a 95.5%, 99.5%, 96.9%, and 99.3% sensitivity, specificity, positive predictive value, and negative predictive value, respectively [36]. A preoperative hemodynamic stability and the inherent potential for compensation are to be assessed prior to surgery for fluid management and management of acute blood loss. Can the patient compensate for volume overload and depletion and if so how much and what are the parameter? Ejection fraction is a measurement that will provide information on the hemodynamic compensatory ability of the patient. A transthoracic echocardiogram will provide this measurement and is included in all patients with history of cardiac disease leading to either diastolic or systolic heart failure. The ultimate goal of perioperative management is to bridge medical optimization with surgery and includes tight hemodynamic control and optimal airway management to prevent against cerebrovascular accident, myocardial infarction, fluid overload, airway compromise, and compensation for acute blood loss. 19.9 

Dental Workup and Optimization

The first step and of paramount importance is the initial screening of oral cancer by the dental practitioner and allied staff. Early detection is key in favorable long-term survival and successful management of four inflicted patients. For those patients diagnosed with oral cancer, basic dental intervention in restoring and optimizing oral health in a timely fashion is critical to prevent or at least decrease the incidence of adverse treatment sequelae like wound dehiscence, odontogenic infection, osteoradionecrosis, and other direct and indirect complications of surgery chemotherapy and radiation therapy [37]. A thorough dental cleaning should be performed in sites away from the cancer without seeding to other sites intra-orally. All decayed and restorable teeth should be restored and endodontically treated if necessary. Any teeth with a poor or a hopeless prognosis should be extracted prophylactically. Any surgical dental treatment should be performed at least 2 weeks prior to initiating any type of intervention for oral cancer to allow for mucosal and alveolar bone healing. If a prosthesis is planned for restoration of a residual postsurgical defect, then the impressions are to be performed prior to initiating cancer therapy; fluoride trays should also be fabricated at this time for patients that are planned for postoperative radiation. Optimization of dental health is important throughout the clinical course of patients with oral cancer. 19.9.1 

 ental Therapy During Oral Cancer D Treatment

The ultimate goal during this phase of treatment is not only continued prophylaxis but also therapeutic interventions for

251 General Workup Prior to the Treatment Phase of Oral Cancer

cancer treatment adverse side effects. Prophylactic treatment will include use of soft-bristled toothbrushes, aversion of sugary diet, fluoride application, strict oral hygiene, mouth opening exercises to prevent deconditioning of the masticator muscles and subsequent trismus, and alcohol and tobacco cessation education. Therapeutic interventions can include frequent application of artificial saliva for the treatment of xerostomia, pain management for mucositis using topical rinses like viscous lidocaine and systemic pain management like anti-inflammatories and neurogenic substances for neuropathic pain, and treatment for fungal infections which includes fluconazole.

ing classification system. The current accepted and most utilized system worldwide is the TNM staging classification developed by the American Joint Committee on Cancer (AJCC) and the Union for International for Cancer Control (UICC). Based on this TNM staging, an overall clinical stage is given to the patient. This clinical stage is then used to guide therapy based on national guidelines and recommendations. In this system each component of the TNM staging is given a category, and an overall prognostic stage is derived. Increasing values for each component represent a greater extent and severity of the disease. The 8th edition AJCC/UICC clinical TNM staging criteria is presented in 7 Chapter 6. After clinical staging with consideration of patient morbidity and functional status then treatment planning can be finalized to provide optimal oncologic control while minimizing impact on quality of life [38].  

19.9.2 

 ental Therapy Post-oral Cancer D Treatment

Post-treatment dental management will encompass the various aspects mentioned earlier in the previous sections with additional emphasis on management of xerostomia, mucositis, fibrosis, sensory changes, osteoradionecrosis, and screening for recurrent or a second primary oral cancer. Fibrosis can lead to decreased tongue range of motion resulting in inadequate speech and formation of food bolus; it can also result in trismus. Physical therapy, pain management, and surgical release procedures are the current and established modalities in preventing and treating fibrosis of the oral ­cavity. Osteoradionecrosis (ORN) is a recalcitrant disease, and the goals of therapy are to provide pain control, to prevent propagation to adjacent bone, and to prevent or manage tissue infection in the background of ORN. There is a higher likelihood for a patient diagnosed with oral cancer to develop a new secondary primary as compared to a patient without a history of oral cancer and that is compounded by the persistent use of tobacco and alcohol. Ongoing oral cancer surveillance is integral in the longterm management by the dental practitioner to detect recurrence and new primaries. Eyecatcher

A schema for the workup appropriate for the unit could be made available for the trainees in the form of an APP.

19.10 

Integration and Clinical Staging

Once a thorough and standard workup of oral cancer is performed, the clinician has enough information to grade the primary tumor based on size, to identify the number and location of clinically overt nodal metastasis in the neck, and to assess for distant metastasis. Integration of this information determines the clinical extent and severity of the disease and defines Tumor, Node and Metastasis (TNM) staging. Staging the patient is pivotal in respect to prognosis and treatment planning, for assessing results of clinical trials, and for evaluation of treatment efficacy. It is the system medical and surgical oncologists use worldwide and serves as a unify-

19.11 

Conclusion

Despite our best efforts, most cancer centers have reported only marginal improvement of the overall survival rates of our oral cancer patients. Proper and thorough workup of these patients is the first step in achieving successful management and disease resolution. Advances in imaging and biopsy techniques with increased accuracy have helped us to properly clinically stage our patients. Once clinically staged, patient- and disease-tailored therapy can commence. The ultimate goal of treatment is to provide a disease-free state while minimizing morbidity and mortality to our patients.

References 1. Rennemo E, Zätterström U, Boysen M. Synchronous second primary tumors in 2,016 head and neck cancer patients: role of symptomdirected panendoscopy. Laryngoscope. 2011;121(2):304–9. 2. Merritt RM, et al. Detection of cervical metastasis: a meta-analysis comparing computed tomography with physical examination. Arch Otolaryngol Head Neck Surg. 1997;123(2):149–52. 3. Babshet M, et al. Efficacy of oral brush cytology in the evaluation of the oral premalignant and malignant lesions. J Cytol. 2011;28(4):165–72. 4. Gupta S, et  al. Clinical correlative study on early detection of oral cancer and precancerous lesions by modified oral brush biopsy and cytology followed by histopathology. J Cancer Res Ther. 2014;10(2):232–8. 5. Rhodus NL, Kerr AR, Patel K.  Oral cancer: leukoplakia, premalignancy, and squamous cell carcinoma. Dent Clin N Am. 2014;58(2):315–40. 6. Rashid A, Warnakulasuriya S. The use of light-based (optical) detection systems as adjuncts in the detection of oral cancer and oral potentially malignant disorders: a systematic review. J Oral Pathol Med. 2015;44(5):307–28. 7. Baeten J, et  al. Chairside molecular imaging of aberrant glycosylation in subjects with suspicious oral lesions using fluorescently labeled wheat germ agglutinin. Head Neck. 2018;40(2):292–301. 8. Baeten J, et al. Molecular imaging of oral premalignant and malignant lesions using fluorescently labeled lectins. Transl Oncol. 2014;7(2):213–20.

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9. Portugal LC, Wilson KM, Biddinger PW, et  al. The role of toluidine blue in assessing margin status after resection of squamous cell carci-nomas of the upper aerodigestive tract. Arch Otolaryngol Head Neck Surg. 1996;122:517–9. 10. Schilling C, et al. Sentinel European Node Trial (SENT): 3-year results of sentinel node biopsy in oral cancer. Eur J Cancer. 2015;51(18):2777–84. 11. Blatt S, et al. Diagnosing oral squamous cell carcinoma: how much imaging do we really need? A review of the current literature. J Craniomaxillofac Surg. 2016;44(5):538–49. 12. Sarrion Perez MG, et  al. Utility of imaging techniques in the diagnosis of oral cancer. J Craniomaxillofac Surg. 2015;43(9): 1880–94. 13. Li-Jen L, et al. Detection of cervical lymph node metastasis in head and neck cancer patients with clinically N0 neck-a meta-analysis comparing different imaging modalities. BMC Cancer. 2012; 12(1):236–42. 14. Rohde M, et  al. 18F-fluoro-deoxy-glucose-positron emission tomography/computed tomography in diagnosis of head and neck squamous cell carcinoma: a systematic review and meta-­analysis. Eur J Cancer. 2014;50(13):2271–9. 15. Xiao Y, et al. The value of fluorine-18 fluorodeoxyglucose PET/MRI in the diagnosis of head and neck carcinoma: a meta-analysis. Nucl Med Commun. 2015;36(4):312–8. 16. Chaukar D, et al. Relative value of ultrasound, computed tomography and positron emission tomography imaging in the clinically node-negative neck in oral cancer. Asia Pac J Clin Oncol. 2016;12(2):e332–8. 17. Levett DZH, Grocott MPW. Cardiopulmonary exercise testing, prehabilitation, and Enhanced Recovery After Surgery (ERAS). Can J Anaesth. 2015;62:131–42. 18. Paleri V, et  al. Comorbidity in head and neck cancer: a critical appraisal and recommendations for practice. Oral Oncol. 2010;46(10):712–9. 19. Bøje CR, et  al. The impact of comorbidity on outcome in 12 623 Danish head and neck Cancer patients: a population based study from the DAHANCA database. Acta Oncol. 2013;52(2): 285–93. 20. Borggreven PA, et al. Comorbid condition as a prognostic factor for complications in major surgery of the oral cavity and oropharynx with microvascular soft tissue reconstruction. Head Neck. 2003;25(10):808–15. 21. de Cassia Braga Ribeiro K, Kowalski LP, Latorre Mdo R. Perioperative complications, comorbidities, and survival in oral or oropharyngeal cancer. Arch Otolaryngol Head Neck Surg. 2003;129(2):219–28. 22. de Melo GM, et  al. Risk factors for postoperative complications in oral cancer and their prognostic implications. Arch Otolaryngol Head Neck Surg. 2001;127(7):828–33.

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23. Shuman AG, et al. Optimizing perioperative management of geriatric patients with head and neck cancer. Head Neck. 2014;36(5): 743–9. 24. Adams P, et al. Frailty as a predictor of morbidity and mortality in inpatient head and neck surgery. JAMA Otolaryngol Head Neck Surg. 2013;139(8):783–9. 25. Maione P, et  al. Pretreatment quality of life and functional status assessment significantly predict survival of elderly patients with advanced non-small-cell lung cancer receiving chemotherapy: a prognostic analysis of the multicenter Italian lung cancer in the elderly study. J Clin Oncol. 2005;23(28):6865–72. 26. Corrêa GTB, et al. Analysis of ECOG performance status in head and neck squamous cell carcinoma patients: association with sociodemographical and clinical factors, and overall survival. Support Care Cancer. 2012;20(11):2679–85. 27. van Kan GA, et  al. The assessment of frailty in older adults. Clin Geriatr Med. 2010;26(2):275–86. 28. Soeters PB, et al. A rational approach to nutritional assessment. Clin Nutr. 2008;27(5):706–16. 29. Righini CA, et  al. Assessment of nutritional status at the time of diagnosis in patients treated for head and neck cancer. Eur Ann Otorhinolaryngol Head Neck Dis. 2013;130(1):8–14. 30. Alshadwi A, et al. Nutritional considerations for head and neck cancer patients: a review of the literature. J Oral Maxillofac Surg. 2013;71(11):1853–60. 31. Saroul N, et al. Which assessment method of malnutrition in head and neck cancer? Otolaryngol Head Neck Surg. 2018;158:1065. https://doi.org/10.1177/0194599818755995. 32. Kaderbay A, et al. Malnutrition and refeeding syndrome prevention in head and neck cancer patients: from theory to clinical application. Eur Arch Otorhinolaryngol. 2018;275(5):1049–58. 33. Agarwal E, et al. Malnutrition and poor food intake are associated with prolonged hospital stay, frequent readmissions, and greater in-hospital mortality: results from the nutrition care day survey 2010. Clin Nutr. 2013;32(5):737–45. 34. Friedli N, et al. Revisiting the refeeding syndrome: results of a systematic review. Nutrition. 2017;35:151–60. 35. Rohrer S, Dietrich JW.  Refeeding syndrome: a review of the literature. Z Gastroenterol. 2014;52(6):593–600. 36. Gupta K, et al. Clinical assessment scoring system for tracheostomy (CASST) criterion: objective criteria to predict pre-­operatively the need for a tracheostomy in head and neck malignancies. J Craniomaxillofac Surg. 2016;44(9):1310–3. 37. Miller EH, Quinn AI.  Dental considerations in the management of head and neck cancer patients. Otolaryngol Clin N Am. 2006;39(2):319–29. 38. Korc-Grodzicki B, et al. Surgical considerations in older adults with cancer. J Clin Oncol. 2014;32(24):2647–53.

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Basic Surgical Principles and Techniques Richard J. Shaw, John Edward O’Connell, and Mandeep Bajwa 20.1

Introduction – 254

20.2

Patient Selection for Surgery – 254

20.3

Surgical Decision-Making and Technique – 255

20.3.1 20.3.2

 anagement of the Airway – 255 M Access Surgery – 256

20.4

Mandibular Resection – 258

20.5

Maxillary Resection – 259

20.6

Sentinel Lymph Node Biopsy – 260

20.7

Neck Dissection – 261

20.7.1

Neck Dissection Complications – 265

20.8

 econstruction of the Oral Cavity Following R Tumor Ablation – 266

20.8.1 20.8.2 20.8.3 20.8.4 20.8.5 20.8.6

 econstructive Ladder – 266 R Local and Regional Flaps – 267 Free Flaps – 268 Reconstruction of the Oral Cavity by Anatomic Subsite – 270 Rehabilitation of the Oral Cavity – 275 Virtual Planning – 278

20.9

Postoperative Care – 279

20.10 Complications – 279 20.11 Tissue Engineering and the Future – 279 20.12 Conclusion – 280 References – 280

© Springer Nature Switzerland AG 2020 S. Warnakulasuriya, J. S. Greenspan (eds.), Textbook of Oral Cancer, Textbooks in Contemporary Dentistry, https://doi.org/10.1007/978-3-030-32316-5_20

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Core Messages 55 Surgeons can optimize outcomes by focusing on patient selection, surgical decision-making and technique, reconstruction of form and function, multidisciplinary care, and rehabilitation. 55 Surgical decision-making involves management of the airway, access to the tumor, extent of resection, management of the neck, and choice of reconstruction. 55 Decisions regarding tracheostomy use are made on a case-­by-­case basis with involvement of the anesthetic team. Selective tracheostomy use enables airway protection in high-risk patients, while overnight intubation avoids tracheostomy in lower-risk patients. 55 Access surgery is required for difficult to reach tumors. By facilitating good visualization and palpation, tumor resection is optimized. 55 Resection margins should not be compromised because of concerns regarding complex reconstruction. The evolution of microvascular techniques means that all ablative defects can now be reconstructed to a high level. 55 The principle of oral reconstruction is where possible to replace like with like, regarding the volume of defect and its various bone, skin, and other components. 55 Multidisciplinary postoperative care with involvement of speech and language therapists, dieticians, physiotherapists, and restorative dentists improves patient recovery and rehabilitation.

20.1 

20

Introduction

The surgical management of oral cavity squamous cell carcinoma (OSCC) has evolved considerably over the last century. While the desire to achieve surgical cure has remained the highest priority, the emphasis of surgery has “de-escalated” from being radical toward more function-sparing approaches that confer greater importance to reconstruction and rehabilitation. This evolution has been aided by a number of scientific and technological advances including an improved understanding of disease behavior, more accurate imaging and staging techniques, safer and more advanced anesthesia, and the reliability of microvascular reconstructive techniques. The biological aggression of the tumor, represented by features such as nodal involvement with extracapsular spread (ECS), has the greatest influence on survival in patients with surgically resectable disease [1]. Despite recent advances, the ability to favorably influence biological aggression has not been proven. Therefore, in the current era of surgical oncology, surgeons may optimize the outcomes of patients with OSCC by focusing on the following principles: 1. Patient selection for surgery 2. Surgical decision-making and technique 3. Reconstruction of form and function 4. Multidisciplinary care and rehabilitation

It is inevitable that a proportion of patients who have surgery for OSCC will require adjuvant treatment with either concurrent chemoradiotherapy (CRT) or radiotherapy (RT). This is largely determined by histological features that embody the biological aggression of the tumor (e.g., ECS) and make disease progression or recurrence more likely. Therefore, it needs to be acknowledged that some patients will have worse outcomes than others, sometimes despite receiving optimal care. One of the principal aims of current and future research is to better understand these disease behaviors and develop and refine treatments through rigorous methodology, such that patient care continuously improves [2]. 20.2 

Patient Selection for Surgery

Selecting patients who are suitable for surgery is a vital first step in optimizing outcomes. Careful assessment of the patient’s medical history and social circumstances is paramount. Patients with OSCC often have multiple comorbidities that influence the safety of general anesthesia as well as their ability to recover from surgery and rehabilitate. In high-­risk cases, early multidisciplinary involvement including anesthetists, physicians, and dieticians is important to ensure the patient is optimized as much as possible prior to surgery. Assessing the “operability” of the tumor is also a vital part of patient selection. This assessment is commonly done both clinically and radiologically and encompasses the primary tumor, the extent of nodal involvement, and the presence of distant metastases or second primary tumors. When assessing the extent of the primary tumor, the surgeon should consider what anatomical structures are involved, as this will inform whether surgical resection is technically possible as well as the likely associated morbidity. According to the American Joint Committee on Cancer (AJCC) staging system, T4 (locally advanced) OSCC is divided into T4a and T4b categories [3]. T4b represents tumors that have high rates of unresectability. The features that are designated to T4b include involvement of the masticator space, pterygoid plates, and skull base and/ or encasement of the internal carotid artery. While the T4b category certainly represents very advanced disease with a correspondingly poor prognosis, it is important to assess each tumor individually [4]. Being staged as T4b does not always preclude the patient from surgery. A proportion of tumors involving the masticator space or pterygoid plates may well be surgically resectable [5]. Surgery in the presence of distant metastases is only offered for local control and for palliative benefit [6]. Once all the information regarding the patient and their disease has been gathered, consideration should be given to the surgical options and their likely impact on the patient. It is important to have a full and frank discussion about potential complications as well as the implications on both quan-

255 Basic Surgical Principles and Techniques

tity and quality of life. Obtaining informed consent requires a discussion of all alternative treatment options including CRT, RT, chemotherapy, and palliation. Active involvement of medical and radiation oncologists (as well as palliative care physicians when appropriate) is vital to ensure the patient is informed and able to make meaningful decisions about their care [7]. 20.3 

Surgical Decision-Making and Technique

Once a decision has been made to offer a patient surgery, the operating surgeon has a series of decisions to make. Each of these decisions will have important consequences to the patient’s recovery after surgery as well as their long-term function and survival. Overview Box lists the key surgical decisions. Once the surgical plan has been made, it is ultimately down to the technical ability of the surgical team to ensure that it is executed effectively. How each of these aims is managed varies widely between surgeons and can be controversial. Unfortunately high-quality evidence to guide surgeons through these decisions is sparse [2]. As a result, individual experience and training is often the determining factor. Detailed guidance on the surgical assessment of tumor margins and the management of the neck can be found in their respective chapters (see 7 Chapters 21 and 24). Dental assessment prior to surgery is a key step in the treatment planning process as it is expected that the surgery (in combination with RT if required) will have a detrimental effect on the patient’s oral health, at least in the short term. The extraction of any teeth with a poor prognosis is best done at the time for surgery as this allows adequate time for healing should adjuvant RT be required. In addition to putting the patient through unnecessary psychological stress, the extraction of teeth after surgery and radiotherapy can be more difficult and increase the risk of complications including osteoradionecrosis (see 7 Chapter 19).  

 

>>Important Key surgical decisions 55 Management of the airway 55 Access to the primary tumor 55 Extent of resection 55 Management of the neck 55 Choice of reconstruction

20.3.1 

Management of the Airway

Decisions regarding how the airway will be managed in the perioperative setting are critical to the surgery and the patient’s postoperative recovery. The options available are: 1. Immediate postoperative extubation 2. Overnight intubation or delayed extubation 3. Tracheostomy

There is considerable variation in practice and controversy regarding how the airway should be managed in patients undergoing major surgery for OSCC [8]. Unfortunately there is no high-quality evidence to guide best practice, and therefore it tends to be determined by local policy. The main concerns regarding the airway postoperatively are related to the potential for acute life-threatening events where the airway is lost and cannot be reestablished easily or quickly. For this reason, immediate postoperative extubation is only considered for small tumors in uncomplicated patients. Most institutions adopt a policy of selective tracheostomy use; however, there is some discrepancy regarding the criteria for this decision [8]. It should be noted that tracheostomies in themselves can be associated with potentially life-threatening complications, although these events are relatively rare [9]. It is also Important to mention that patients generally have negative experiences with tracheostomies and wish to avoid them whenever possible [10]. Several authors have developed scoring systems to guide decision-making for tracheostomy use, and while these systems highlight patients at greatest risk of airway issues, they are dogmatic and have not been properly validated in a large series of patients [11–13]. If safe to do so, overnight intubation is preferable and has significant advantages over tracheostomy in terms of reduced hospital stay and the patient’s experience [14]. It is our practice to consider patients on their individual merits and have a discussion with the anesthetist regarding the ease of re-intubation, should it become necessary. . Table 20.1 describes the various thresholds for placing a tracheostomy according to our current practice. Patients undergoing bilateral neck dissection have the potential to develop significant supraglottic edema and airway-threatening hematomas. Consideration is also given to the likely impact of surgery on swallowing mecha 

Table 20.1  Various thresholds for placing a tracheostomy at the time of surgery

55 Low threshold for placing tracheostomy 55 Bilateral neck dissection or have had previous bilateral irradiation 55 Difficult airway (e.g., trismus) or intubation (i.e., oral intubation in an emergency setting will be difficult) 55 Large resections involving the tongue that compromise laryngeal and/or hyoid suspension 55 Patients undergoing segmental mandibulectomy crossing the midline with loss of genial muscle attachments

Intermediate threshold for placing tracheostomy 55 Tumors requiring access mandibulotomy 55 Lateralized tumors involving the tongue or floor of mouth requiring free flap reconstruction 55 Previous unilateral irradiation to the neck 55 Patients undergoing lateralized segmental mandibulectomy High threshold for placing tracheostomy 55 Buccal or small maxillary tumors not extending to the oropharynx 55 Patients requiring no reconstruction or low-volume free flap reconstruction

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nisms. In cases where the swallow is likely to be severely impaired, a cuffed tracheostomy will be placed to prevent aspiration of upper airway secretions and saliva. zz Surgical Tracheostomy Technique Step 1: Preparation

55 Endotracheal tube (ETT) inserted by anesthetist. 55 Confirm tracheostomy tube size and type. 55 Check tracheostomy tube: inflate cuff with air to ensure there are no leaks. Deflate the cuff and lubricate. 55 It is advisable to have two assistants for the procedure.

Step 2: Marking and incision

55 Prepare and drape the neck. 55 Mark the location of the sternal notch and the cricoid cartilage. 55 Three to five centimeter horizontal incision is placed in the midline, midway between these landmarks. The use of local anesthetic with adrenaline is discouraged as this may result in problematic reactionary bleeding later.

Step 3: Dissection to the trachea

55 Sharp dissection through the skin and subcutaneous fat maintaining fastidious hemostasis. 55 Blunt dissection using scissors, spreading them in a cranio-caudal direction and remaining in the midline directly over the trachea. 55 Retractors are used to spread the tissues laterally once a pocket has been created by the scissor dissection. 55 Any blood vessels encountered should be ligated to ensure a completely dry field. The thyroid gland can usually be retracted superiorly to expose the trachea beneath. Division of the thyroid isthmus is seldom required in patients with a normally sized gland.

Step 4: Tracheal stoma

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55 The trachea is isolated, transfixed with a cricoid hook, and pulled superiorly so that the second, third, and fourth tracheal rings are clearly visible in the wound. 55 Inform the anesthetist that you are ready to create the stoma. The anesthetist may wish to push the ETT further down the trachea to avoid puncturing of the cuff when incising the trachea. 55 It is our preference to use a Bjork flap when making the stoma. This has the advantage of being able to secure the flap to the skin, thus enabling some control of the trachea should the tracheostomy tube become displaced or require changing. Some surgeons do not use Bjork flaps because of concerns that the flap may invert into the lumen of the trachea causing airway obstruction. 55 Make the vertical incisions through trachea in a caudo-­cranial (upward) direction to prevent slippage of the blade resulting in bleeding or injury to the

trachea low down where it is more challenging to deal with. 55 Some elderly patients may have calcified rings that require scissors. It is important to have a standardized technique of stoma formation within a particular institution to prevent confusion among ward staff in the event of postoperative airway problems. Step 5: Tracheostomy tube insertion

55 Once the stoma has been created, the anesthetist pulls back on the ETT until the tip has just passed the stoma and is still below the vocal chords. 55 The tracheostomy tube is carefully inserted making sure the pointed introducer does not scrape against the back wall. 55 The assistants should maintain their retraction while the introducer is removed, the cuff inflated, and the anesthetic circuit connected. 55 The tracheostomy tube is securely held in place until bilateral chest movement, O2 saturation, and end-tidal CO2 have been confirmed. 55 Once confirmed, the retractors can be removed and the tracheostomy tube secured in place with sutures. Percutaneous tracheostomy has been shown to be superior to surgical tracheostomy in the critical care setting in terms of wound infection rates and unfavorable scarring [15, 16]; however, its role in patients undergoing major surgery for OSCC is not yet widely established. 20.3.2 

Access Surgery

The aim of ablative surgery is to remove the tumor with clear margins. Good access such that the entire tumor can be visualized and palpated is key to this endeavor. In the majority of cases, this can be done trans-orally; however, certain tumors, particularly those located more posteriorly, may require additional access procedures to ensure an optimal resection can be performed. Lip-Split Mandibulotomy (LSM)  LSM is one of the most

common approaches and classically used to access tumors in the posterior oral cavity that extend into the oropharynx, e.g., tongue base and tonsil. The procedure involves making a fullthickness incision through the lower lip, passing the chin and joining on to the “upstroke” of the neck dissection incision. There are several ways to make the incisions, the most common being the Roux incision [17], the McGregor incision [18], and the “zigzag” or chevron-­type incision [19, 20]. The Roux incision is simply a straight vertical line through the lower lip and chin. The McGregor incision is a vertical line through the lower lip up to the labio-mental groove; at this point the incision curves around the chin. The “zigzag” incision is shown in . Fig. 20.1a. It is important to note that the zigzags are incised down to the muscle layer. The muscle is then incised in a straight vertical line. By incising the muscle in a different plane  

257 Basic Surgical Principles and Techniques

a

b

..      Fig. 20.1  Lip-split mandibulotomy. a The “zigzag” incision. b Illustration of “pre-plating” the mandible prior to completing mandibulotomy. Dashed line indicates lingual incision leading to anterior margin of tumor resection

to the skin and performing a layered closure, significant wound breakdown or fistula formation is less likely [20]. It is our opinion that the “zigzag” incision provides a superior aesthetic outcome compared to other approaches and is therefore our incision of choice. Intraorally, the mucosal incision continues to the attached gingiva. In a dentate patient, extraction of a tooth in the line of the osteotomy should be considered. It is important to continue the mucosal incision lingually until the proposed anterior margin of the tumor resection is reached. This is to prevent unfavorable tearing of the mucosa when parting the mandible. Following the mucosal incisions, a periosteal elevator is used to expose the anterior mandible up to the mental foramen. A reciprocating saw is used to etch the proposed bone cuts into the buccal cortex. It is our practice to position a 90° step below the level of the dental roots as this allows more accurate repositioning of the bone ends at the end of the procedure. The mandible is then pre-plated (commonly using two miniplates) as shown in . Fig. 20.1b. The plates are subsequently removed and set aside for later. The mandibulotomy is then completed using the reciprocating saw. At this point, the mandibulotomy is still held by the attachment of the mylohyoid muscles. Once this attachment is released, the ipsilateral segment of the mandible should move easily and is swung laterally to provide good access to the tumor. One of the main disadvantages of LSM is potential for wound breakdown and fistula formation at the osteotomy site [21]. This can be minimized by ensuring the mucosal incisions do not directly overlay the bone cuts in combination with a meticulous wound closure.

In this approach, an incision is made along the lingual gingiva. The genioglossus, geniohyoid, and mylohyoid muscles are then divided. The entire tongue is then pulled through into the neck to provide good access to the entirety of the tongue. Upon closure of the wound, it is vital to repair the detached muscles in order to preserve function. The disadvantages of this technique are that a bilateral neck incision (from mastoid to mastoid) is required and important swallowing muscles are divided. Devine et al. showed that patients who had LSM reported better speech, swallowing, and chewing function compared to MLRA. Also there were no significant differences in aesthetic outcomes [22]. In our practice, this approach is used for large anterior tongue tumors that cross the midline. Under these circumstances, the anterior excision margin allows the tongue to be dropped down into the neck without the need for a LSM.

Mandibular Lingual Releasing Approach (MLRA)  MLRA is an alternative to the LSM for accessing tongue tumors. MLRA has the advantage of not requiring facial incisions or bone cuts.

Weber-Ferguson  The Weber-Ferguson approach is the most

 

Visor Flap  The visor flap is essentially a mandibular degloving procedure. It is performed via a neck incision which may be either unilateral or, more classically, bilateral. The skin flap is raised in a subplatysmal plane taking care not to injure the marginal mandibular branch of the facial nerve. Once the lower border of the mandible is reached, it is exposed in a subperiosteal plane. Intraorally, an incision is made along the buccal and labial sulci. The mental nerve is often transected at this point to enable good access to the oral cavity. The two planes of dissection are then connected and the flap retracted cephalad [23]. The main role for this type of access in our practice is for tumors that require mandibular resection. In our practice, a unilateral visor flap is commonly employed to facilitate lateral segmental mandibular resections.

commonly used access procedure for maxillary resection. Subsequent modifications [19, 24] of the classical description

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..      Fig. 20.2  Diagram illustrating the Weber-Ferguson incision. The dashed line represents lateral infraorbital extension along an eyelid skin crease

include a lateral infraorbital extension which offers greater access laterally, but this is infrequently required. The procedure involves making a full-­thickness incision through the upper lip. Chevrons are placed along the incision as shown in . Fig. 20.2 to improve the aesthetics of the scar [19]. The upper lip incision can be placed either in the midline or along the philtrum. The incision comes up toward the nose and ends in the nasal sill. The incision continues laterally along the alar base and around to the origin of the nasolabial groove. The lateral nasal incision should be placed in the naso-facial sulcus which is located at the junction of the nasal and cheek aesthetic subunits. Once the medial canthal region has been reached, the lateral extension of the incision is placed within the first lower eyelid crease. Alternatively, if access to the medial orbit is required, it can be continued superiorly as a lynch incision. Intraorally, the full-thickness lip incision is continued laterally within the labial sulcus until the anterior margin of the tumor resection is reached. The flap can then be elevated to expose the anterior maxilla in a suitable plane depending on the extent of the tumor.  

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20.4 

Mandibular Resection

Oral cavity tumors frequently lie close to, abut, or invade the mandible. How the mandible is managed in each of these circumstances is therefore a common decision for surgeons. The mandible is at greatest risk of invasion at the point where the tumor abuts it. Invasion occurs via either an erosive, infiltrative, or mixed pattern. The infiltrative pattern is a marker

of aggressive disease behavior and as such has an association with nodal involvement and ECS. As the pattern of invasion may not be known preoperatively, increasing size of the primary tumor and depth of soft-tissue invasion are predictive factors for the infiltrative pattern of invasion [25]. As mentioned previously, the tumor should be assessed clinically and radiologically. Clinically, features that suggest an infiltrative pattern of invasion are fixity of the tumor to the mandible, mobility of adjacent teeth, evidence of sensory disturbance to the lower lip (inferior alveolar nerve), and pathological fracture. Radiological assessment can include an orthopantomogram (OPT), computed tomography (CT), magnetic resonance imaging (MRI), or single photon emission computed tomography (SPECT/CT) bone scan. Not one of these imaging techniques is completely accurate so clinical correlation is vital. If uncertainty remains, the surgeon may wish to strip the periosteum around the tumor during ­surgery to directly assess the invasive pattern. If there is evidence of infiltrative invasion, either segmental or rim resection of the involved mandible is required. Segmental resection involves removing the full height of the invaded section of the mandible such that there is loss of continuity of the lower border. Rim resection or “marginal mandibulectomy” involves removing a partial thickness of mandible such that continuity of the lower border remains. If there is evidence of gross infiltrative invasion of the mandible, segmental resection is usually the only oncologically safe option. In more equivocal circumstances, rim resection may be appropriate depending on the height of mandibular bone. If the patient has an edentulous mandible, the height of the bone may be reduced, thereby making rim resection unfeasible. Cawood and Howell produced a useful classification of the edentulous mandible that can be used to guide the type of mandibular resection [26]. . Table 20.2 provides a basic guide to when segmental and rim resection is indicated based on the degree  

..      Table 20.2  Guide to mandibular resection based on the degree of invasion and degree of mandibular resorption [29] Cawood and Howell Classification

OPT –ve, MRI –ve, bone scan –ve. No invasion or only periosteal invasion

OPT –ve, MRI +ve, bone scan +ve. Early invasion (5 mm)

I–II (dentate or immediate postextraction)

Rim

Rim

Rim or segment

III–IV (round or knife edge)

Rim

Rim or segment

Segment

V–VI (flat or depressed ridge)

Rim or segment

Segment

Segment

259 Basic Surgical Principles and Techniques

of invasion and degree of mandibular resorption. It is also important to note that mandibular resection is sometimes required to ensure adequate soft-tissue margins where the tumor lies close to the bone, but frank bone invasion is either unproven or absent. Segmental resection of the mandible is usually performed via a combined trans-oral and transcervical approach (e.g., visor flap). The mucosal margin and as much soft-tissue resection as possible is performed trans-orally. It is important to note that tumors involving the floor of the mouth have few barriers to invasion toward the neck due to open tissue planes and may require a wider deep margin than normal (e.g., 1.5–2  cm). Identification of the lower border of the mandible and any additional soft-tissue resection can be continued transcervically from this point onward. The periosteum of the adjacent buccal cortex is then stripped (transcervically) such that a spanning osteosynthesis plate can be pre-located along the lower border of the mandible. This is important to maintain the space between the cut bone ends and facilitate a normal occlusion and chin point after reconstruction. Once the bony margins have been decided and appropriately exposed, the segmental resection is performed using a reciprocating saw. Tumors that deeply invade the floor of mouth are significantly easier to resect once the mandible has been osteotomized and the bony segment is mobilized and retracted buccally. Rim resection can often be completed trans-orally, especially in anterior tumors. In posterior tumors, a combined trans-oral and transcervical approach may enable easier delivery of the specimen. As with segmental resection, it is important to widely expose the adjacent mandible prior to making the bone cut. The rim resection should be angled to take into account the point of entry of the tumor being lower than the crest of the ridge either on the lingual or buccal side. When possible, the bone should be cut in a “saucerized” fashion

I

II

a

III

b

..      Fig. 20.3  Classification of vertical and horizontal maxillectomy and midface defects. Vertical classification: I, maxillectomy not causing an oronasal fistula; II, not involving the orbit; III, involving the orbital adnexa with orbital retention; IV, with orbital enucleation or exenteration; V, orbitomaxillary defect; VI, nasomaxillary defect. Horizontal

avoiding sharp corners. These corners are areas of weakness in the mandible and make pathological fracture more likely. If the rim resection is deep or the presence of sharp corners cannot be avoided, the placement of a “prophylactic” reconstruction plate to strengthen the mandible should be considered. 20.5 

Maxillary Resection

Invasive tumors arising on the upper alveolus, buccal sulcus, or hard palate almost invariably require composite (bone and soft tissue) resection. The mucosa of the palate is tightly adherent to the bone, which is far thinner than the mandible, and therefore the same nuances do not apply. In the case of small tumors with equivocal bone involvement, it is possible to perform a limited resection and await formal histological margin status. Unlike mandibular resection, there is less need to formally reconstruct the defect immediately. It is also important to acknowledge that the tumor visible in the mouth may only be the “tip of the iceberg,” as tumor growth is relatively unhindered within the air-filled cavity of the maxillary sinus. Therefore, careful up-to-date cross-sectional imaging assessment is vital to guide the extent of resection in all three dimensions. It is important to pay particular attention to the integrity of the bony walls of the sinuses as well as orbital, infratemporal fossa, and skull base involvement. The various methods of maxillary resection can be based upon the classification described in . Fig. 20.3 [27]. As the focus of this chapter is on OSCC, class V and VI defects will not be discussed further.  

Class I (Alveolectomy)  This is suitable for small tumors with

equivocal bone involvement. The defect is shallow and does not breach the maxillary sinus. Access procedures, such as the Weber-Ferguson approach, are not required [28].

IV

V

c

VI

d

classification: a palatal defect only, not involving the dental alveolus; b less than or equal to one-half unilateral; c less than or equal to one-half bilateral or transverse anterior; d greater than one-half maxillectomy. Letters refer to the increasing complexity of the dentoalveolar and palatal defect and qualify the vertical dimension [27]

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Class II (Low-Level Maxillectomy)  This is suitable for tumors

that have breached the maxillary sinus but do not reach the orbit. Access procedures may be required based on the individual case. A 1 cm soft-tissue margin is incised with needle diathermy. Extraction of teeth that fall on this margin may be required. Four osteotomies are required to deliver the specimen: 1. Vertical alveolar: A reciprocating saw is used to cut perpendicularly through the dental arch. 2. Le Fort 1 level: This is essentially the superior/horizontal margin. The saw is used to cut through the maxilla at an appropriate height to encompass the tumor. The cut is continued through to the pterygoid plates posteriorly. 3. Pterygoid plates: If the tumor is confined to the maxillary sinus, pterygomaxillary disjunction can be performed with a curved osteotome. If the tumor has escaped through the posterior sinus wall, the pterygoid plates must be cut above the level of the tumor. Care is required at this point as significant bleeding can be encountered if the maxillary artery and pterygoid venous plexus are injured. 4. Palatal: This is a continuation of the vertical alveolar osteotomy medially into the palate.

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these extensive tumors. Access is achieved by combining the Weber-Ferguson approach with a circumorbital incision. The circumorbital incision is extended down to the bone followed by subperiosteal dissection of the superior orbit toward the optic nerve. Releasing the optic nerve early makes the remainder of the resection easier. The remainder of the resection is similar to the class III description above [28]. 20.6 

Sentinel Lymph Node Biopsy

SLNB has now become an established technique for staging the neck in patients with early oral cancer who do not have clinical or radiological evidence of lymph node metastases (cN0). The sentinel node is a first echelon node to which cancer cells are most likely to spread to. SLNB is therefore a technique that informs whether the patient is likely to have regional metastases and, by implication, needs treatment to the neck. D’Cruz et al. demonstrated that in patients with T1/T2N0 OSCC, performing an elective ND was superior to adopting a watch and wait policy in terms of overall survival and disease-free survival [29]. In this study, the rate of neck failure in the watch and wait category was approximately 40%. Therefore, if ND is performed in all patients, a Once these osteotomies have been completed, the specimen significant number will be overtreated. Even in the best should be mobile and any remaining soft-tissue attachments hands ND is not without potential for complications and cut [28]. morbidity. SLNB is a relatively minor and better-tolerated procedure which has the potential to select the patients who Class III (High-Level Maxillectomy Maintaining the actually require a ND, thereby avoiding overtreatment. In Orbit)  This is suitable for tumors that have reached the orbital addition to this, SLNB has the potential to highlight patients floor but show no signs of orbital invasion. Access via a Weber-­ who have contralateral neck drainage of their tumor; this is Ferguson approach is generally required for this type of resecclearly important for planning further treatment if contration. The resection is complicated by the need to preserve the lateral sentinel nodes are positive. It is important to note orbital structures and lacrimal apparatus [28]. The osteotomies that SLNB is not a perfect tool as it has a reported falseare as follows: negative rate of 14% [30]. It is also associated with a learn 1. Vertical alveolar and nasal: The reciprocating saw is used ing curve that needs to be negotiated when starting out. For to cut through the dental arch and includes the nasal SLNB to be as accurate as possible, there needs to be a high piriform. The cut is extended vertically up to the degree of motivation and coordination between surgical, lacrimal crest. Care must be taken to preserve the nuclear medicine, and pathology services [31]. lacrimal sac. 2. Orbital: The orbital floor is included within this reseczz Sentinel Lymph Node Biopsy Technique tion as far as the inferior orbital fissure. The horizontal Step 1: Injections of Technetium-99m radioactive tracer (e.g., bone cut is extended laterally to include the frontal Nanocoll, Lymphoseek) process of the zygoma. 3. Zygomatic: The horizontal cut is linked to the zygomatic 55 Tracer is injected into four sites around the tumor at a depth that corresponds to the depth of invasion. buttress laterally, continuing posteriorly to the pterygoid 55 If surgery is planned for the morning, the injections are plates. given the day before. If surgery is planned for the 4. Pterygoid plates: In this case, the plates need to be afternoon, the injections can be given first thing in the sectioned high and close to the skull base. Needless to morning. say, great care is required to prevent unfavorable propagation of fractures and vascular injury. It is not Step 2: Lymphoscintigraphy using planar gamma camera and always possible to resect the tumor en bloc in these SPECT/CT cases; by removing the main maxillectomy specimen, 55 Imaging is performed immediately after the injections resection of difficult to reach areas is made simpler. are given. Class IV (Radical Maxillectomy with Orbital Exenteration)  55 Dynamic lymphoscintigraphy images using planar This is suitable for tumors that have invaded the orbital congamma camera identifies lymphatic channels and tents. Resection that includes the eyelids is usually required for sentinel nodes. Anatomical correlation is not possible.

261 Basic Surgical Principles and Techniques

55 SPECT/CT provides 3D images to aid localization of sentinel node(s) by overlying SPECT images with CT (. Fig. 20.4). Dynamic views are not possible. 55 Discussion with radiologist to identify sentinel nodes and their location.  

Step 3: Tumor excision

55 Some surgeons advocate injecting methylene blue around the tumor. Blue staining makes identification of sentinel node easier; however, staining tumor and surrounding tissues makes excision more difficult. 55 Indocyanine green is an alternative stain that only shows up with fluorescent camera. 55 The tumor is excised with a 1 cm clinical margin followed by fastidious hemostasis. By removing the tumor before SLNB, the “shine through” phenomenon is reduced (see step 4). Step 4: Sentinel lymph node(s) excision

55 Surgical field re-prepared and draped. 55 Incision placed in natural skin crease. Consideration given to where future ND incision may lie. 55 Subplatysmal dissection to expose neck. Fastidious hemostasis to maintain dry surgical field. 55 Gamma probe aimed at location of sentinel node. Area which gives highest count is where blunt dissection starts. Orientate gamma camera away from the site of primary tumor to avoid a falsely high count (“shine through” phenomenon). 55 Dissection until sentinel node identified and record the highest count (in vivo count). If cluster of nodes present partially, dissect each one and use gamma camera to identify which node(s) has highest count. If gamma

camera identifies activity in more than one node, each active node is excised. 55 Place excised sentinel node on the tip of the gamma probe and record the count (ex vivo count). Aim gamma camera at the wound bed; the count should be no higher than 10% of the ex vivo count. If the count is higher, further dissection toward the source carried out until located and removed. 55 Fastidious hemostasis and wound closure with or without surgical drain. 55 Document counts for each node and whether it is a sentinel node on the pathology form. If vital blue/ indocyanine green is used, record whether node was stained. Sentinel lymph nodes undergo “serial step sectioning” which is a much more thorough pathological assessment than that undertaken for nodes harvested within a ND. As a result, the pathologist is able to identify isolated tumor cells which may otherwise have been missed. The presence of tumor within the sentinel node is an indication for further treatment with either a completion ND or radiotherapy. There is currently no consensus on how to best manage all eventualities of positive sentinel nodes. 20.7 

Neck Dissection

The reasons for performing ND can be for both staging and/ or therapeutic purposes. In patients without clinical evidence of lymph node metastases, either SLNB or ND can be performed to stage the neck and identify possible occult neck disease. In the presence of clinical and/or radiological lymph

..      Fig. 20.4  Scintigraphy image (SPECT/CT) demonstrating a buccal squamous cell carcinoma draining to two sentinel lymph nodes

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node metastases, ND has a therapeutic role. If the patient has more than one positive lymph node or evidence of ECS, adjuvant treatment with RT/CRT is usually indicated. ND can also be performed in the salvage setting if the patient has had primary RT/CRT that has been ineffective. Patients may undergo an “opportunistic” ND. This is when ND is not necessarily required, but it is performed because the patient requires vascular access. Whether the ND is being performed for staging or therapeutic purposes, it is imperative that an adequate number of lymph nodes are harvested. This is to ensure that the ND specimen is representative of the disease within the neck such that adjuvant treatment can be instigated if necessary. This is supported by evidence from the US National Cancer Database which has shown a significant survival advantage if patients have ≥18 lymph nodes harvested [32]. Furthermore, high lymph node density (defined as the number of positive lymph nodes divided by the total number of lymph nodes harvested) is also an independent predictor of poor outcomes in patients with OSCC [33]. Clearly, if patients have a more thorough dissection carried out, this will increase the number of lymph nodes harvested, and their lymph node density will be correspondingly lower. Any pressure to harvest as many lymph nodes as possible has to be counterbalanced by the morbidity of performing a ND. . Figure  20.5 shows the various neck levels and . Table  20.3 describes the anatomical boundaries of each  

 

level as well as important structures that lie within each of them. Historically there have been many different incisions described for ND. Despite having their advantages and disadvantages, only a small proportion of these are routinely used in modern practice. When placing an incision, the surgeon needs to carefully consider the amount of access required and how well the wound will heal. The amount of access required is largely dependent on what neck levels are to be dissected. Healing is dependent on the vascularity of the skin flaps, placing incisions within natural skin creases and avoiding incisions over prominences, e.g., thyroid cartilage. Whenever possible, it is preferable to avoid trifurcations as these are areas where wound dehiscence can occur [34]. If a trifurcation is to be used, it is important to ensure it does not lie directly over the great vessels (carotid artery or internal jugular vein) as this reduces the risk of life-threatening hemorrhage should wound dehiscence occur. The “Apron” incision shown in . Fig. 20.6a affords ample access to levels I–IV and avoids the need for trifurcation. We have modified this incision depending on what access is required. If the patient is having a LSM, the anterior upstroke will continue in a “zigzag” fashion as this improves the overall aesthetics of the scar (. Fig. 20.6b). If the patient is having a unilateral neck dissection, the upstroke is avoided and the incision continued within the skin crease to the contralateral side (. Fig. 20.6c). Continuing the incision to the contralateral side within a skin crease provides a  

 

 

IIB IA

IB IIA

III VA

20 IV

..      Fig. 20.5  Diagram illustrating the boundaries of the various neck levels

VB

263 Basic Surgical Principles and Techniques

..      Table 20.3  Table describing the anatomical boundaries of the various neck levels and the important anatomical structures within them Level

Superior

Inferior

Medial

Lateral

Deep

Important structures

IA

Symphysis of mandible

Body of hyoid bone

Anterior belly of contralateral digastric

Anterior belly of ipsilateral digastric

Mylohyoid

Submental nodes

IB

Body of mandible

Tendon of digastric

Anterior belly of digastric

Posterior belly of digastric

Mylohyoid and floor of mouth

Submandibular nodes, submandibular gland and duct, facial artery and vein, marginal mandibular and lingual nerves

IIA

Skull base (SAN superolaterally)

Horizontal plane of inferior border of hyoid

Stylohyoid

Posterior limit of SCM

Splenius capitis, levator scapulae

Upper jugular nodes, SAN, IJV, ICA, ECA, vagus and hypoglossal nerves, cervical nerve roots

IIB

Skull base

Horizontal plane of inferior border of hyoid

SAN

Posterior limit of SCM

Splenius capitis

Upper jugular nodes, IJV, vagus, SAN, occipital branch of ECA

III

Horizontal plane of inferior border of hyoid

Horizontal plane of inferior border of cricoid

Sternohyoid

Posterior limit of SCM

Levator scapulae, scalene muscles

IJV, CCA, vagus, cervical nerve roots

IV

Horizontal plane of inferior border of cricoid

Clavicle

Sternohyoid

Posterior limit of SCM

Scalene muscles

IJV, CCA, TCA, thoracic duct (left), vagus and phrenic nerves

VA

Convergence of SCM and trapezius

Horizontal plane of inferior border of cricoid

Posterior limit of SCM

Anterior border of trapezius

Splenius capitis, levator scapulae

SAN

VB

Horizontal plane of inferior border of cricoid

Clavicle

Posterior limit of SCM

Anterior border of trapezius

Levator scapulae, scalene muscles

TCA, SAN, brachial plexus

SAN spinal accessory nerve, SCM sternocleidomastoid muscle, IJV internal jugular vein, ICA internal carotid artery, ECA external carotid artery, CCA common carotid artery, TCA transverse cervical artery

superior aesthetic outcome to the standard Apron incision and, with the help of retraction, does not compromise access to level IA (submental region). If access to level V is required, a trifurcating incision can be placed infero-laterally (Schobinger incision) as shown in . Fig. 20.6d. Once the incision is made, the skin flaps are raised in the subplatysmal plane superiorly and inferiorly. Laterally, the sternocleidomastoid muscle (SCM), the external jugular vein (EJV), and the great auricular nerve (GAN) are encountered and preserved as far as possible. If the EJV cannot be preserved, it is important to ligate it as superiorly as possible as it may serve as a potential vessel for microvascular anastomosis (if free flap reconstruction is planned). The platysma does not extend over the entirety of level V, so the skin flaps are raised in a subcutaneous plane. Great care needs to be taken when raising these subcutaneous flaps as the spinal accessory nerve (SAN) is often encountered taking a superficial course. Once the skin flaps have been raised and retracted, it is time to begin dissection of the planned neck levels. The order in which the dissection is performed is highly variable  

and often depends on the individual case and the surgeon’s preference. Each level will be discussed in turn. Level IA (Submental)  The fibro-fatty contents of IA are dissected off the lower border of the mandible until the underlying mylohyoid muscle is seen. Both the ipsilateral and contralateral anterior bellies of digastric are skeletonized, and any tissue on the under-­surface of these muscles is included within the specimen (lymph nodes are often hidden beneath the muscle). The tissue is then dissected off the mylohyoid down to the body of the hyoid bone. Level IB (Submandibular)  The first part of the dissection

often involves dissecting and ligating the facial artery and vein. This is carried out 2 cm below the lower border of the mandible in an effort to avoid injury to the marginal mandibular nerve (MM). Based on the classic work of Dingman and Grabb, the MM nerve runs below to the lower border of the mandible in approximately 20% of cases. Anterior to the facial vessels, it never runs below the lower border [35]. These findings have

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a

b

c

d

..      Fig. 20.6  Diagram illustrating some commonly used neck dissection incisions. a Apron incision. b Apron combined with “zigzag” lip-split mandibulotomy incision. c Transverse incision with contralateral extension. d Schobinger incision

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been disputed by some authors who claim that the nerve runs below the lower border more frequently [36]. This discrepancy may be explained by either variations in patient positioning or ptosis of the nerve and surrounding soft tissue in elderly patients. Once the vessels have been ligated, they are reflected superiorly, and dissection to the lower border of the mandible continues in a plane deep to them (Hayes-Martin maneuver). If the nerve is not easily identified, it is not our practice to carry out further dissection in this area as it increases the risk of injury. The exception to this rule is for buccally placed tumors that may drain to the facial lymph nodes. The facial lymph nodes are found adjacent to the facial vessels and MM nerve. When these nodes are sampled, the risk of injury to the MM nerve is increased. Anteriorly the dissection is in a plane above and over the posterior free border of the mylohyoid muscle. Inferiorly the

submandibular gland is dissected off the hyoglossus muscle. Superiorly the lingual nerve and submandibular duct are identified. The submandibular ganglion, which branches off the lingual nerve, is ligated and cut to free the nerve allowing it to retract into the floor of the mouth. The submandibular duct is also ligated and cut. At this point the lateral tissue, which contains the proximal end of the facial artery, is dissected. The facial artery should be left as long as possible to facilitate a microvascular anastomosis if reconstruction is planned. Level IIA (Upper Jugular)  Dissection starts by incising the fascia along the anterior border of the SCM and continues along the undersurface staying on the muscle. The SAN is soon identified and carefully protected as it inserts into the SCM. The dissection continues along the undersurface of SCM until the posterior limit of the muscle is reached. The tissue lying directly

265 Basic Surgical Principles and Techniques

over the SAN is dissected and cut along the course of the nerve up to the internal jugular vein (IJV). The lateral limit of the dissection is incised until the cervical nerve roots are encountered. This incision is usually made along the entire lateral limit of the planned dissection (dissection along a broad front is preferable). The cervical nerve roots form a plane of dissection toward the carotid sheath along the prevertebral fascia. Care needs to be taken to preserve all nerves in this region as there can be variations in the anatomy of the SAN [37]. The remainder of the dissection continues medially over the IJV with levels III and IV as described below. Level IIB (Submuscular Recess)  As with IIA, the lateral limit

of the dissection is incised at the posterior border of SCM. This incision is taken down to the fascia of the splenius capitis muscle which forms the deep extent of the dissection. Superiorly the tissue is freed off the mastoid tip and medially the tissue is carefully dissected off the IJV. Great care needs to be taken during the medial dissection as injury to the IJV can result in significant bleeding that is difficult to control. This is because any venotomy created can quickly propagate into the jugular foramen. The resulting triangular piece of tissue is dissected down to the SAN and tucked underneath in continuation with level IIA.

Level III (Mid-Jugular) and IV (Lower Jugular)  The posterior limit of dissection is incised in continuity with level II along a broad front. Care must be taken not to go beyond the posterior limit of SCM at this stage, as it is possible to injure the SAN as it exits the muscle. When dissecting level IV, the omohyoid muscle needs to be skeletonized and retracted inferiorly out of the way. With the aid of Allis or Babcock clamps, levels II, III, and IV are retracted medially. Dissection continues along a broad front over the prevertebral fascia toward the IJV.  It is important to maintain the integrity of the prevertebral fascia as the phrenic nerve runs superficially in level IV and can be easily injured if the correct plane is not adhered to. If dissecting level IV, great care needs to be taken when dissecting near the IJV. The termination of the thoracic duct most commonly occurs in the left IJV but may also be present in 5% of right NDs. There is considerable variation in thoracic duct anatomy, but in general it enters the venous system within 5 cm of the clavicle [38]. It is good practice to ask the anesthetist to momentarily increase intrathoracic pressure once the neck specimen has been delivered to check for chyle leak in level IV. Direct repair, ligation, or oversewing the injured duct with muscle is best done at the time of initial surgery. Dissection over the IJV is done with a scalpel, ligating any small branches as they appear. Whether the ansa cervicalis is preserved is down to the surgeon’s preference; however, it is useful to trace its course to the hypoglossal nerve to aid identification. The common facial trunk is preserved if possible as it may be useful if microvascular anastomosis is planned. All the lymphatic tissue between the lateral border of sternohyoid and IJV is dissected up toward the digastric tendon in a plane above the fascia of the strap muscles.

Level V (Posterior Triangle)  Dissection of level V is rarely performed for OSCC unless there are clinically positive nodes present. When nodal disease is present, the IJV, SCM, and/or SAN may need to be sacrificed as part of the dissection. The skin flaps are raised in a subcutaneous plane until the anterior border of trapezius is visible along its entire length from the mastoid to clavicle. The SAN is then identified at both proximal and distal points. Distally it can be found entering the trapezius at the junction between the upper two-thirds and lower one-third of the muscle. Proximally it is found within 1.5 cm above where the cervical plexus emerges from the posterior border of the SCM (Erb’s point). The course of the SAN is traced by carefully dissecting all the surrounding soft tissue free from the nerve. Once the nerve is mobilized, the lateral and inferior margins of the dissection are delineated. Laterally, this involves dissecting along the anterior border of trapezius down to the prevertebral fascia overlying the splenius capitis, levator scapulae, and scalene muscles. Inferiorly, this involves freeing tissue along the length of the clavicle. It is critical not to pull tissue up from behind the clavicle as this increases the risk of injuring the subclavian vessels as well as the pleura, both of which can result in significant complications. The dissection is continued down to the plane above the prevertebral fascia; occasionally the omohyoid may need to be divided. The lymphatic tissue is then dissected off the fascia from lateral to medial mobilizing the SAN as required to deliver the specimen. If the specimen is to be taken in continuity with levels II, III, and IV, the cervical nerve roots need to be sectioned as they emerge from the prevertebral fascia.

20.7.1 

Neck Dissection Complications

zz Intraoperative Complications

IJV injury can result in significant hemorrhage and air embolism. Air embolism can be avoided by placing the patient in the Trendelenburg position (head down) when the injury occurs and while it is repaired. Thoracic duct injury results in chyle leak. Small leaks can be difficult to spot, as the patient will be starved preoperatively. After the neck dissection specimen has been delivered, raising intrathoracic pressure may help identify the injury. Injuries are best dealt with at the time of surgery. A combination of ligation, oversewing with muscle, and adhesive agents are usually effective. Nerve Injuries:

55 Marginal mandibular nerve injury (VII) occurs when raising subplatysmal flaps and dissecting around the lower border of the mandible near the facial vessels and results in weakness of the lower lip depressors and an asymmetric smile. 55 Spinal accessory nerve injury (XI) occurs during dissection of levels II or V and results in weakness of the trapezius muscle which causes pain, shoulder drooping, winging of the scapula, and an inability to raise the arm passed 90° of elevation.

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55 Hypoglossal nerve injury (X) occurs anterior to the great vessels where a plexus of veins overlies it, results in ipsilateral deviation of the tongue on protrusion, and is associated with difficulties in speech and swallow. Attempts to control bleeding in this area may result in injury to the nerve. 55 Lingual nerve injury (V and VII) occurs when dissecting in level IB behind the mylohyoid muscle and results in altered sensation to the lateral border of the tongue as well as altered taste (chorda tympani). 55 Phrenic nerve injury occurs during dissection in level IV and results in weakness to the diaphragm with corresponding problems with respiratory function. 55 Vagus nerve injury occurs when dissecting around the carotid sheath particularly when ligating the IJV during radical neck dissection and results in hoarse voice and swallowing difficulty. zz Early Postoperative Complications

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Hematoma occurs due to reactionary bleeding or slippage of surgical ties and clips. Small hematomas can be managed conservatively, whereas larger hematomas can be a risk to the airway and usually need to be evacuated and controlled in theater. Wound complications including infection, dehiscence, and fistula are more common in patients who have had previous radiotherapy. If the infection lies deep to the platysma muscle, opening the wound and allowing drainage are often required. Fistulas can occur when the resection of the primary tumor communicates with the neck. They present with persistent neck infection. Small fistulas can be managed conservatively by restricting oral intake and antibiotics. More complex fistulas may require further surgery. Persistent chyle leak occurs when thoracic duct injury was not identified intraoperatively and presents as milky collection of fluid in the drain and can be low output (500 ml/24 h). Low output leaks can be managed by compression dressings, octreotide, and fat-free diet. High output leaks need to be actively treated, and this can be done by either interventional radiology, return to theater for exploration and measures described above, or video-assisted thoracoscopic surgery (VATS). Chest infection occurs due to problems with aspiration of upper airway secretions (aspiration pneumonia) and reduced mobility and ventilation after surgery (atelectasis) or as an exacerbation of preexisting lung disease and is managed with physiotherapy and antibiotics. In severe cases, the patient may need critical care support.

zz Late Postoperative Complications

Unfavorable scarring and restriction of movement most commonly occur in patients who have suffered with hematomas, wound infections, and fistulas. Tough scar tissue formed after prolonged healing results in restricted and painful movement.

20.8 

 econstruction of the Oral Cavity R Following Tumor Ablation

Advances in the management of oral malignancy have led to improved survival and functional outcomes. Surgical ablation, however, may result in a significant defect. The goals of any surgical reconstruction are to restore form and function. Notwithstanding the importance of facial aesthetics, within the oral cavity, preservation/restoration of speech, chewing, swallow, and oral continence are of paramount importance. The oral cavity is a unique and complex site. It is the opening to the aerodigestive tract and is critical for speech production. Its constituents include the hard and soft palate, the dentition, the mandible, and the tongue. In addition, it is microbially rich and is continuously bathed in saliva. Furthermore, it is enriched with sensory and motor nerve endings, which enable taste, speech, and some facial expressions. Lastly, many patients requiring reconstruction have been or will be exposed to radiotherapy. Owning to the variety of tissues involved, and indeed the anatomical and physiological/functional complexity, reconstruction of the oral cavity is challenging. Like any defect, reconstruction of the oral cavity should aim to replace resected tissue with similar tissue. We, herein, will outline some general reconstructive principles and discuss techniques that can be employed in the oral cavity. Finally, we will discuss the reconstruction of specific anatomic subunits, namely, the mandible, maxilla, and soft tissues. Eyecatcher

Reconstructive ladder 55 Healing by secondary intention 55 Primary closure 55 Skin grafting 55 Local flaps 55 Regional flaps 55 Microvascular free tissue transfer

20.8.1 

Reconstructive Ladder

The reconstructive ladder (see Box above), which stratifies options by increasing level of complexity, can, in a broad sense, be applied to oral cavity defects. However, as outlined previously, the anatomical and functional complexity of the oral cavity often necessitates the use of many modalities, sometimes simultaneously. Notwithstanding this, general reconstructive principles apply; namely, use the simplest method that will meet reconstruction aims, replace lost tissue with similar tissue, consider vascularized tissue in a previously irradiated recipient site, and always have an alternative should your primary reconstruction fail.

267 Basic Surgical Principles and Techniques

Secondary Intention  Allowing a wound to granulate can be

considered for smaller defects, for example, a wide local excision (WLE) of the tongue, where the wound surfaces will mucosalize. However, the surgeon must be cognizant of the potential for wound contracture and scarring, therefore decreasing mobility and function. This is the common form of management of early lesion ablative defects.

in a previously irradiated area (assuming the proposed flap has not also been irradiated). Local flaps can provide thin, sensate tissue and are often similar to the tissue being replaced. However, like all options, local flaps are not without their disadvantages, including facial scarring, lack of tissue, limited arc of rotation, potential for necrosis at distal tip, and some difficulty in dentate patients.

Primary Closure  This can be done simultaneously with resec-

Tongue Flaps  First described in 1909 [41], the tongue flap is

tion or as a delayed procedure. It is an option in situations where there is sufficient mobility and quantity of surrounding tissue to allow closure without excessive tethering of vital structures.

Skin Graft (Split and Full Thickness)  Skin grafts are useful for

defects that are too large for primary closure and have been described in the successful management of buccal mucosa, and tongue defects, as well as those of the pharynx and esophagus [39, 40]. In addition to directly covering an ablative defect, skin grafts may be used to resurface other pedicled or free flaps (e.g., muscle coverage). However, a well-vascularized recipient bed is required for graft success. Failure, owing to inadequate revascularization, is not uncommon, and the surgeon must be cognizant of the potential resultant problems, such as tethering of the tongue to the floor of the mouth. For this reason, skin grafts are rarely used in our practice. Definition A free flap is a portion of vascularized tissue harvested from a distant donor site and transferred to an area requiring reconstruction where its artery and vein are anastomosed locally, thereby providing an independent blood supply.

20.8.2 

Local and Regional Flaps

While free flaps have revolutionized the management of head and neck malignancy, there are some cases where free tissue transfer is neither possible nor prudent. Medical comorbidities, previous surgery and/or radiation treatment, the lack of surgical experience or expertise, and previous failed free tissue transfer may preclude the use of a free flap, thereby providing a challenge for the reconstructive surgeon. It is in these situations that the ability to utilize local and regional pedicled flaps is important. zz Local Flaps

Due to the extensive and consistent blood supply in the head and neck, local flaps in this region are safe and predictable. Smaller defects not requiring substantial soft tissue or bone for reconstruction can be reliably reconstructed with flaps such as, but not limited to, the facial artery myomucosal (FAMM), nasolabial, buccal fat pad, tongue, and palatal flaps. Local flaps are also indicated in situations where a skin graft will not suffice, for example, when covering exposed bone, or

a versatile and reliable flap that, albeit limited by a short arc of rotation, can be used to reconstruct the floor of the mouth, alveolus, palate, pharynx, and buccal mucosa. Complications associated with this flap are rare. Variations include the posteriorly based dorsal flap, the anteriorly based ventral flap, the laterally based (the so-called double or single door) flaps, the sliding/island flaps, and the median transit flap.

Palatal Flap  Technically simple and reliable, the palatal flap can be raised in an axial (island flap) or random (rotation advancement) fashion. Up to 75% of the palatal mucosa can be used, giving the potential to cover a 16 cm2 defect [42]. Its use has been described in the reconstruction of retromolar, soft palate, posterior floor of the mouth, cheek, as well as oronasal/ antral defects. Nasolabial (NLF) and Facial Artery Myomucosal (FAMM) Flaps  The NLF can be used in a random or axial pattern,

whereas the FAMM flap is a true axial flap. The NLF can be used to reconstruct intraoral sites such as the floor of the mouth, tongue, palate, buccal mucosa, and alveolus [43], usually as a two-stage procedure. Defects up to 5 × 5cm can be reconstructed. Bilateral NLFs can also be used and allow for reconstruction of a larger defect as well as provide facial symmetry. The FAMM flap is an axial myomucosal flap that has been described in the reconstruction of the palate, floor of mouth, alveolus, and tongue [44]. Most intraoral sites, apart from the palate, are reconstructed with an inferiorly based flap. Relative contraindications include ipsilateral neck dissection and/or radiotherapy. zz Regional and Pedicled Flaps

Regional and pedicled flaps include tissue(s) from other parts of the head and neck, such as the temporalis and platysma flaps, as well as those from more distant sites such as the latissimus dorsi, delto-pectoral, and pectoralis major flaps. However, it must be remembered that it is invariably the distal part of these flaps that is used to reconstruct an intraoral defect, and therefore the limit of the vascular territory, making it susceptible to necrosis.

Pectoralis Major  Ariyan first described the use of the pectoralis major flap in head and neck reconstruction in 1979 [45]. Since then, it has been widely adopted. It is now rarely used as a first choice for intraoral reconstruction but is still used as a salvage option and in patients with comorbidities that preclude the use of a free flap. Based on the thoracoacromial artery, this

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myocutaneous flap provides a large volume of vascularized muscle and overlying skin, which carries a minimal risk of necrosis. The addition of a costochondral or sternal segment to the myocutaneous component has been described for reconstruction of a mandibular segmental defect [46, 47].

tumor ablation and flap raising), prolonged wound drainage and seroma formation, and risk of injury to the brachial plexus.

Delto-pectoral Flap  Bakamjian in 1965 first described the

zz Definition

versatility of the delto-­pectoral flap in head and neck reconstruction [48]. While it remains a useful flap for salvage cases where mucosal and/or cutaneous coverage is required, it is now mainly used for cutaneous defects of the neck. It is a fasciocutaneous flap based medially on parasternal perforating branches of the internal mammary artery. Its use has been described in tongue, floor of mouth, and pharyngeal reconstruction, often as a two-stage procedure.

Temporalis Muscle and Temporoparietal Fascia Flap  The

temporalis muscle flap is supplied by the anterior and posterior deep temporal arteries, while the superficial temporal artery supplies the temporoparietal flap. Both flaps have been described for reconstruction of the oral cavity [49, 50]. Unlike the temporalis muscle flap, the temporoparietal flap does not provide any bulk. Unlike most other regional or local flaps from the head and neck, these flaps can incorporate the outer table of the cranium or the coronoid process if a composite flap is required [51]. The reported flap failure rate is 2% [52]. While these flaps have classically been utilized for palatomaxillary/ midface reconstruction, their use in mandibular defects, ranging from 4 to 5 cm, is also reported [53].

Supraclavicular Artery Island Flap  While Mutter [54], in 1842, described a random “shoulder flap” and Kazanjian and Converse [55] in 1949 a charretera flap, it was not until 1983 that Lamberty described the supraclavicular fasciocutaneous island flap [56]. The transverse cervical artery gives rise to the supraclavicular artery in the vast majority of cases. A flap of up to 12 cm × 35 cm can be harvested. Advantages include ease of harvest, a reliable vascular pedicle, thin and pliable skin, and minimal donor site morbidity. For intraoral reconstructions, the flap is de-­epithelialized and tunneled under the neck skin before being passed intraorally to repair the defect.

20

Latissimus Dorsi (LD) Flap  Quillen [57] in 1978 described the LD as a pedicled flap in head and neck reconstruction, while Maxwell [58] first reported its use in free tissue transfer, also in 1978. Ease of dissection, large surface area, and length of the vascular pedicle are some of its advantages. Although it is now more commonly used as a free flap, the pedicled latissimus dorsi flap is still used today. The LD is a fanlike muscle originating medially and extending from the dorsal iliac crest caudally and travelling cranially via the sacral, lumbar, and thoracic (lower 6) vertebrae. The reported success rate is 80–90%. Like all flaps, the pedicled LD is not without its disadvantages including a requirement to turn the patient (precluding simultaneous

20.8.3 

Free Flaps

A free flap is a portion of vascularized tissue harvested from a distant donor site (. Fig. 20.7) and transferred to an area requiring reconstruction where its artery and vein are anastomosed locally, thereby providing an independent blood supply. The advent of microvascular free tissue transfer has revolutionized the management of head and neck malignancy. The ablative surgeon, safe in the knowledge that most defects can now be reconstructed satisfactorily, can resect with sufficient margins, thus increasing the chances of tumor clearance. The variety and versatility of available flaps allows reconstruction of even the most complex defects. Most tissue types, including skin, fascia, muscle, tendon, and bone, can be harvested. The choice of donor site is wide but is influenced by, among other things, the type and shape of tissue that needs to be replaced. Advantages of free flaps include flexible reconstruction that contains soft and osseous tissue tailored to ablative defect, independent blood supply, proven reliability, and robust tissue. Disadvantages include complex technique requiring specific training and experience, increased length of surgery, and need for more rigorous postoperative monitoring.  

zz Soft-Tissue Reconstruction

In oral cavity reconstruction, common soft-tissue flaps used include the radial forearm, anterolateral thigh, rectus abdominis, latissimus dorsi, medial sural artery perforator (. Fig.  20.8), and lateral arm flaps. The relative merits of these flaps are outlined in . Table 20.4.  

 

..      Fig. 20.7  Free flap (tip of scapula with teres major muscle and thoracodorsal artery perforator flap)

269 Basic Surgical Principles and Techniques

a

b

c

d

..      Fig. 20.8  Medial sural artery perforator (MSAP) flap. a Lateral tongue SCC. b Pedicle of MSAP prior to harvesting. c Harvested flap. d Flap inset to defect left tongue/floor of mouth

..      Table 20.4  Relative merits of soft-tissue flap donor sites Donor site

RFFF

ALT

MSAP

TDAP

Lateral arm

Rectus

LD

Donor site morbidity

+

+++

+++

+++

++

++

+++

Pedicle length

++++ 18 cm

+++ 8–14 cm

++ 10 cm

++++ 15 cm

+ 6 cm Increased with ELAF

+ 7 cm

++ 20 cm

Size of vessels Diameter

++++ Artery: 3 mm Vein: 1.5 (3 mm if cephalic)

+++ Artery: 2.1 mm Vein: 2.3 mm

+++ Artery: 1.25 mm Vein: 2 mm

++++ Artery: 2.7 mm Vein: 3.4 mm No atherosclerosis

++ Artery: 1.5 mm Vein: 2.5 mm

++++ Artery: 3.5 mm Vein: 4 mm

++++ Artery: 2.7 mm Vein: 3.4 mm No atherosclerosis

Soft-tissue paddle

++ 12 × 5cm

++++ 16 × 8cm

++ 10 × 5cm

++++ 25 × 10 cm

++ 12 × 5cm

+++ Muscle: 6 × 25cm Skin: 13 × 25cm

++++ Muscle:35 × 20 cm Skin:20 × 35cm

Two-team operating

+++

++++

++++

+

++

+++

+

RFFF radial forearm free flap, ALT anterolateral thigh, TDAP thoracodorsal artery perforator, ELAF extended lateral arm flap, MSAP medial sural artery perforator, LD latissimus dorsi

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The radial forearm free flap (RFFF) remains the “work-­ horse” soft-tissue flap in oral cavity reconstruction. Based on the radial artery, with the cephalic vein and/or paired venae comitantes, it was first described in the Chinese literature in 1978 and subsequently more comprehensively by Yang in 1981 and Song in 1982 [59, 60]. Its advantages include consistent anatomy and ease of dissection, long pedicle with relatively large vessels, superficial and deep venous system affording flexibility with venous anastomosis, thin pliable non-hirsute skin paddle, and facilitating two-team operating. However, donor site morbidities such as loss of skin graft, tendon exposure, and a readily visible and unsightly scar are some of its disadvantages. It is imperative to perform an Allen test preoperatively to ensure that the collateral ulnar artery is adequate to supply the arm when the radial artery has been harvested. The RFFF is suitable for most oral cavity soft-tissue reconstructions but is usually not of sufficient bulk to adequately reconstruct larger tongue defects such as a hemiglossectomy /subtotal glossectomy. First reported as a septocutaneous perforator flap by Song in 1984, the anterolateral thigh (ALT) flap (. Fig. 20.9) has now gained widespread use [61]. It is based on the perforating branches of the descending branch of the lateral circumflex femoral artery. The vast majority (80%) of perforators are musculocutaneous in nature. Relative to the RFFF, it provides a greater bulk of tissue and therefore is often the flap of choice for larger tongue reconstructions. It is a versatile flap that can be raised as a fasciocutaneous, myocutaneous, or subcutaneous flap depending on the reconstructive requirements. Advantages include ease of harvest with relatively consistent anatomy; long pedicle with large vessels; versatility in thickness, components, and design; two-team operating; the ability to harvest a large skin paddle on a single perforator or indeed the potential for multiple skin paddles; and low donor site morbidity. The ability to provide sufficient bulk post tongue resection results in better speech and swallowing outcomes, as the neo-tongue can make contact with the soft palate. The ALT flap has proven to be adequate for this.  

a

zz Composite Reconstruction

The fibula (. Fig. 20.10) is by far the most prevalent bone-­ containing (composite) flap, while the iliac crest (DCIA), scapula (including tip of scapula), and composite radial forearm flaps are other commonly used osseous flaps. Chimeric flaps, where osseous and soft-tissue components are independently mobile, for example, the thoracodorsal system of free flaps, are now routinely used when required [62]. The relative merits of the more common composite flap donor sites are outlined in . Table 20.5.  

 

20.8.4 

 econstruction of the Oral Cavity by R Anatomic Subsite

zz Soft-Tissue Reconstruction

Soft tissue includes the tongue, floor of the mouth, buccal mucosa, oropharynx, and soft palate. While each area requires a tailored approach, some principles apply to all. The restoration of function and mobility are key concerns. Small defects can be closed primarily or allowed to granulate and re-mucosalize. Additionally, split-thickness skin grafts or a tissue matrix can be placed in an attempt to reduce scarring and tethering. Similarly, local and regional pedicled flaps (as outlined previously) can be used in moderate-sized defects, but larger areas of tissue loss require vascularized tissue reconstruction. The ideal free flap would provide thin and pliable tissue, with the potential for re-innervation. The radial forearm and anterolateral thigh flaps are now most commonly used. Given its critical role in speech, swallowing, and airway protection, tongue reconstruction requires special consideration. Defects of less than half the tongue are generally referred to as a partial glossectomy, while the term hemiglossectomy is used when half the tongue is sacrificed. Resections of more than half the tongue are referred to as subtotal or total glossectomy defects. Partial glossectomy defects may be closed primarily or left to granulate. A bulky denervated flap may in fact result in inferior functional outcomes. Larger defects may require a

b

20

..      Fig. 20.9  Anterolateral thigh (ALT) flap. a Harvested flap. b Flap used to reconstruct a floor of mouth/tongue defect

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a

b

c

d

e

f

..      Fig. 20.10  Series demonstrating the management of a T4 SCC involving the anterior mandible (class III) with a fibula free flap. a Tumor preoperatively. b MRI scan demonstrating osseous and

soft-tissue involvement. c Resected tumor. d Mandibular segmental defect following tumor ablation. e Fibula free flap with skin paddle. f Fibula inset

..      Table 20.5  Relative merits of composite flap donor sites Donor site

Fibula

DCIA

Scapula

Thoracodorsal/tip of scapula

Composite RFFF

Donor site morbidity

++

+++

+++

+++

+

Pedicle length

+++

+

+

+++

++++

Quality of vessels

+++/+ (May be affected by atherosclerosis)

++ (Potentially small diameter)

++++ (Large, spared from atherosclerosis)

++++ (Large, spared from atherosclerosis)

+++ (Spared from atherosclerosis)

Volume of bone

++

++++

+++

++

+

Length of bone

++++ (14 cm)

+++ (12 cm)

++ (10 cm)

++ (6 cm)

+++ (12 cm)

Suitability for implants

+++

++++

+++

+

Not suitable

Soft-tissue paddle

+++ (Occasionally unreliable)

+ (Internal oblique or DCIA perforator)

++++ (Two soft-tissue flaps and/or chimera with LD or TAP

++++ (Allows chimeric flap with two independently mobile skin paddles +/− LD muscle)

+++ (Reliable skin flap but lacks bulk)

Two-team operating

++++

+++

+

+

+++

TAP thoracodorsal artery perforator, LD latissimus dorsi, RFFF radial forearm free flap, DCIA deep circumflex iliac artery

local flap such as a facial artery myomucosal or a submental artery island flap. Hemiglossectomy defects are most commonly restored with a radial forearm free flap. It provides a thin pliable graft

with a long consistent pedicle that is easy to harvest. The lateral arm free flap, based on septocutaneous branches of the posterior radial collateral artery, has also been described for the management of hemiglossectomy defects.

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Subtotal or total glossectomy defects require a bulky flap of tissue, sufficient to provide contact between the neo-­ tongue and the soft palate and to seal the oropharynx when required during speech and swallowing. The anterolateral thigh (ALT), latissimus dorsi, and rectus abdominis flaps have all been widely used for restoration of total/subtotal tongue defects. zz Mandible

20

Management of the mandible is one of the most important decisions in the treatment of oral cancer. Tumors frequently present adjacent to, or invading, the mandible, and the requirement for clear bone and soft-tissue margins often dictates some form of mandibular resection. Given that the subsites of oral cancer do not have a differing prognosis if adequately treated [63], restoration of function and aesthetics are of key importance. The amount of mandible resected will be dictated by the extent of mandibular involvement, as well as the size of the mandible, and ranges from a defensive rim resection to segmental resection [64]. Reconstruction with composite free flaps is now the gold standard for segmental mandibular defects. The choice of flap is varied and dependent on factors including the site, size, and complexity of the defect, as well as patient comorbidities and indeed surgeon training and preference. While it may be possible to compromise and leave a small posterior mandibular defect without reconstruction, it is particularly important to adequately reconstruct defects of the anterior mandible, and also patients with a significant dentition, in order to achieve acceptable functional and aesthetic outcomes. The following general principles may help to plan mandibular reconstruction: 55 Reconstruction of the anterior mandible is always more challenging. 55 Use the curvature of the chosen bony flap to follow the natural shape of the mandible, thereby reducing the number of potential osteotomies which have been shown to be associated with nonunion [65]. 55 In an edentulous case, it may be helpful to slightly reduce the span of the mandibular segment in order to avoid a resultant class III appearance. 55 Free bone can become a nidus for persistent infection, particularly following radiotherapy. 55 While the rate of complications associated with miniplates and larger reconstruction plates is similar, the latter are more difficult to remove if required [66].

In 2016, Brown et al. (. Fig. 20.13) proposed a new mandibular defect classification system that is based on the four “corners” of the mandible [67]. In this, the authors do not propose an algorithm for flap choice based on their classification; but they do compare flap use according to the classification and correlate complications with class of defect. The fibula was reported as the most commonly used flap in all classes, followed by the iliac crest, except in class IV in which the scapula is the second most popular choice. Given that the fibula is the longest bone flap, with a long pedicle, and can be double-barreled to increase its height, it is no surprise that it is used most commonly. The iliac crest, in particular, is useful for the reconstruction of the hemimandibulectomy owing to its shape and bone stock. However, it is too bulky for condylar replacement and therefore the fibula is used in these instances. Irrespective of flap choice, the goals and principles are the following: 55 Replace lost tissue(s) with similar tissue(s). 55 Restore form and function. 55 Minimize length of operation and donor site morbidity. 55 Retain the ability for implant-based restorations.  

zz Maxilla

Maxillary reconstruction post tumor ablation is challenging. Both the anatomy and functions of the maxilla are complex. It plays a role in speech, swallowing, and mastication; it provides support for the orbito-zygomatic complex, including the globe with its adnexa; it has a key role in facial contouring and provides a barrier between the antral and nasal cavities and the oropharynx. The main aims of maxillary reconstruction are as follows: 55 Restore facial contours and aesthetics. 55 Separate sino-nasal cavities from the mouth. 55 Restore soft palate competence to facilitate speech and swallowing. 55 Restore/provide for replacement of dentition. 55 Support globe or obliterate orbital cavity in case of exenteration. There are many options for maxillary reconstructions including a prosthetic obturator and local, pedicled, or free flaps, all with or without endosseous implants. A classification system for maxillary defects is useful for both treatment planning and discussion with colleagues. The most widely adopted classification is that proposed by Brown and Shaw [27], which considers both the vertical and horizontal extent of the defect. Class I–VI (. Fig. 20.14) describe the increasing size in a vertical dimension, while the horizontal extent is described by the letters a–c. While not absolute, one of the advantages of this classification system is that it implies management.  

There is no clear consensus regarding the choice of flap for mandibular reconstruction. Many variables influence this decision, including site and size of defect, patient factors, dentate status, soft-tissue loss, as well as surgeon training and experience. The most commonly used osseous flaps include the fibula, iliac crest, scapula (either lateral border or tip), and composite radial forearm (. Table 20.5 and . Figs. 20.10, 20.11 and 20.12).  

 

zz Prosthesis Versus Autologous Reconstruction

Prosthetic obturation has historically been the mainstay of maxillary reconstruction. More recently, reconstruction with

273 Basic Surgical Principles and Techniques

a

b

c

d

e

f

g

h

..      Fig. 20.11  Series demonstrating the management of a T4 SCC invading the floor of mouth, mandible (class III), and overlying skin. a Skin involvement. b MRI demonstrating tumor extent. c Resected tumor. d Mandibular segmental defect. e Scapula donor site. f Flap

demonstrating independently mobile osseous and soft-tissue components. g Osseous component of flap inset. h Skin defect reconstructed

autologous tissue in the form of a local, pedicled, or free flap has gained popularity. Advantages of prosthetic obturation include a shorter operating time, immediate restoration of dentition, ability to do a staged reconstruction, facilitating recurrence/new tumor surveillance (although there is no proven survival benefit), and providing better soft-tissue support than a tissue reconstruction. Prosthetic rehabilitation alone, however, is not without its disadvantages. It requires dexterity for maintenance, and the patient is dependent on it for speech, swallowing, and orona-

sal seal. In addition, it cannot replace a concurrent cutaneous defect. Moreover, the cavity shape and size may change following surgery or radiotherapy, possibly necessitating obturator refinement. Moreno et  al. in a comparison between free flaps and prosthetic obturation for maxillectomy defects found that reconstruction with free flaps resulted in better speech and swallowing outcomes [68]. Others have retrospectively compared the functional and aesthetic outcomes of obturator versus tissue reconstruction, and all indicate an advantage for reconstruction, in particular with larger defects [69, 70].

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a

b

c

d

e

f

..      Fig. 20.12  Series demonstrating the reconstruction of a lateral mandibular segmental defect (class II) with a DCIA/iliac crest free flap. a Tumor preoperatively. b Resected tumor. c Lateral mandibular segmental defect. d Iliac crest/DCIA donor site. e DCIA free flap. f Flap inset

zz Zygomatic Implants

Zygomatic as well as oncologic or co-axis implants, used in conjunction with a fixed or removable prosthesis, or indeed with a free flap, have improved our ability to quickly restore the dentition post maxillectomy. First described by Branemark in 1988 [71], zygomatic implant was developed as an alternative to grafting procedures in the severely atrophic maxilla. Boyes-Varley et  al. reported the successful use of early loaded zygomatic implants in conjunction with prosthetic obturation, in the rehabilitation of post-oncologic maxillary defects [72]. More recently, the use of zygomatic implants which perforate a soft-tissue free flap (used to close an oroantral/oronasal communication) and are placed immediately post tumor ablation has been described [73].

zz Reconstruction by Class of Defect

20

Class I: These defects are straightforward to repair, and the only requirement is to separate the oral and nasal cavities. They can be reconstructed with local flaps such as buccal fat pad, palatal, or tongue flaps, as well as pedicled flaps such as the temporalis/temporoparietal galeal flap. However, the radial forearm is most commonly used [27]. Class II: The reconstructive requirements of class II defects are determined by the position of the defect including its horizontal extent, the condition and position of the remaining dentition, as well as the basic need for separation of the oral and nasal cavities. Posterolateral defects (e.g., class IIb) can be restored with a soft-tissue flap alone, especially if

the ipsilateral canine and incisors are retained, with the inherent ability to retain a denture. The radial forearm and anterolateral thigh flaps are suitable for this (. Fig.  20.15). Composite (bone-containing) free flaps are usually required for anterior defects, and class IIc defects, as well as situations where the existing dentition is not adequate to retain a prosthesis. Class III: In these defects, support for the contents of the orbit is lost, as well as support for the anterior cheek and alveolus. A prosthesis alone will provide a suboptimal result. The reconstructive goals are to support the orbital contents and facial skin, ensure bony continuity between the remaining alveolus and zygomatic buttress (ideally sufficient to facilitate endosseous implant placement), as well seal the oral and nasal cavities. While the use of soft-tissue flaps (with or without non-­ vascularized bone grafts) such as the rectus abdominis has been described, implant-retained prosthetic rehabilitation is difficult, and soft-tissue sequelae such as ectropion are common [74]. In our opinion, the use of a composite free flap satisfies most of the reconstructive requirements for these defects. The DCIA (iliac crest) and thoracodorsal flaps, in particular, are most suited (. Fig. 20.16). The DCIA can be contoured to the shape of the infraorbital rim, while there is also sufficient bone to retain endosseous implants. The attached internal oblique provides an adequate oroantral/ oronasal seal (. Fig. 20.17). The thoracodorsal system of free flaps is increasing in popularity. Its advantages include a long pedicle, as well as  

 

 

275 Basic Surgical Principles and Techniques

Class Ic Lateral with condyle Mean size 84 mm Maximum size 138 mm

Class I Lateral not including canine or condyle Mean size 70 mm Maximum size 123 mm

Class II Hemimandibulectomy includes ipsilateral canine Mean size 85 mm Maximum size 169 mm

Class IIc Hemimandibulectomy and condyle Mean size 126 mm Maximum size 184 mm

Class III Anterior includes both canines Mean size 100 mm Maximum size 160 mm

Class IV Extensive includes canines and angles Mean size 152 mm Maximum size 282 mm

Class IVc Extensive includes canines, angles, and condyles Mean size 168 mm Maximum size 312 mm

..      Fig. 20.13  Classification of mandibular defects. (Reproduced with permission from Brown JS, Shaw RJ, Lancet Oncol 2016 [67])

independently mobile soft and osseous tissue components. It is possible to include the tip of scapula, the latissimus dorsi muscle, as well as the skin based on the thoracodorsal artery perforators if required [62]. Class IV: These defects are similar to class III. However, the prognosis for these patients is poor, and loss of the orbital contents means that obturation of the orbit often supersedes dental rehabilitation. Again, the DCIA and thoracodorsal system are our favored reconstructions. The thoracodorsal flap, with the latissimus dorsi muscle, is particularly suited for obturation of the orbit, as well as obliterating the oroantral/oronasal communications.

20.8.5 

Rehabilitation of the Oral Cavity

The contemporary management of oral cavity tumors involves both surgical reconstruction and prosthetic rehabilitation (. Fig. 20.18) [75]. A detailed discussion on prosthetic rehabilitation is beyond the scope of this chapter. Nevertheless, it is important to highlight a few key points: 55 Patients with oral cancer involving the alveolus rarely retain their adjacent teeth, and most will not be able to tolerate or retain a conventional lower denture. 55 Tongue volume and space for function need to be considered during prosthetic planning.  

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Vertical component

Horizontal component

1

2

3

4

1

a

b

c

Local flap Pedical flap Obturator Soft tissue FF Composite FF ..      Fig. 20.14  Maxillectomy defect classification and proposed reconstructions. (Reproduced with permission from Brown JS et al. Head and Neck 2000, 22:17)

20

..      Fig. 20.15  Class IIb defect reconstructed with RFFF and partial denture

277 Basic Surgical Principles and Techniques

a

b

c

..      Fig. 20.16  Class IIIb defect with illustrated reconstructions using a fibula, b TDAA, and c DCIA flaps, along with a titanium mesh to orbital floor. (Reproduced with permission from Brown JS, Shaw RJ. Lancet Oncol, 2010; 11: 001–08)

..      Fig. 20.17  Class III maxillectomy defect reconstructed with a DCIA flap

20

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..      Fig. 20.18  Radiographs demonstrating endosseous implants placed in free flaps to facilitate prosthetic rehabilitation

20

a

b

c

d

..      Fig. 20.19  Virtual planning case. a Pre-op radiograph demonstrating benign tumor of the right mandible. b Surgery performed virtually.

c Prefabricated reconstruction plate and dental implants placed on the fibula bone prior to detachment from leg. d Postoperative radiograph

55 Many oncology patients do not meet the conventional criteria for implant placement. Nevertheless, in selected cases, good long-term outcomes can be achieved. 55 Relative indications include reasonable prognosis, sufficient motivation and oral hygiene, expected return of oral function (namely, speech and swallowing), and sufficient bone and inter-arch distance to accommodate implants/prosthesis. 55 Osseo-integrated implants can be inserted as a primary (at the time of resection) or a secondary (after completion of treatment) procedure. Placement at the time of resection is preferable. 55 While there is no clear consensus on whether implants should be placed prior to or after radiotherapy, it seems that radiotherapy does not greatly affect implant outcome. 55 The management of a height discrepancy between the native mandible and osseous component of a free flap

can be challenging. Potential solutions include “double-­ barreling” a fibula, using a vascularized free flap which provides an adequate stock of bone (e.g., iliac crest or scapula), and prosthetic design incorporating a larger milled superstructure.

20.8.6 

Virtual Planning

It is now possible to preoperatively fabricate patient-specific surgical stents and cutting guides using CT scans and software. The surgeon performs the surgery virtually, and based on the resection and therefore the size and shape of reconstruction required, cutting guides are provided for both the oral resection and donor site harvesting (. Fig.  20.19). Prefabricated reconstruction plates can also be used. Potential  

279 Basic Surgical Principles and Techniques

advantages include improved accuracy of reconstruction and reduction of operative time [76]. 20.9 

Postoperative Care

Most patients post tumor resection and reconstruction require an extended but varying period of inpatient care. Their care consists of both general, as applies to any postsurgical patient, and specific (e.g., flap donor and recipient sites) considerations, as outlined in . Table 20.6. It is routine for head and neck oncology patients to spend the initial 24–48 postoperative hours in the intensive care unit (ICU).  

!!Warning Some patients may experience long-term effects after cancer surgery. These risks are explained by the surgeon or a specialist nurse at the time of consenting.

20.10 

Complications

Complications in head and neck cancer ablation/reconstruction are common. Most complications in this cohort of patients are related to preexisting medical comorbidities rather than technical failures or the magnitude of surgery. We have previously listed the main surgical complications associated with ND earlier in the chapter. In terms of complications associated with reconstruction, flap failure is uncommon (2–5%) and is similar across all donor sites. Orocutaneous fistulae are possible in larger resections but are generally managed conservatively and are less problematic with free tissue transfer. Late complications are often related to the fact that many of these patients receive radiotherapy as well as surgery. If irradiated, the majority of osteosynthesis plates become chronically infected and need to be removed [66]. Additionally, 2–22% of patients will develop osteoradionecrosis (ORN). This rate, however, is decreasing, despite an increase in the “at-risk” population as the incidence of oral cancer is ever increasing. The management of ORN is beyond the scope of this chapter, but advanced disease (Notani III) invariably requires resection with free flap reconstruction. Issues in relation to speech and swallowing correlate more with the extent of soft-tissue resection, and the provision of radiotherapy provided that the resected mandible is adequately restored. Long-term gastrostomy tubes and permanent tracheostomies can generally be avoided. 20.11 

Tissue Engineering and the Future

Maxillofacial and oral cavity reconstruction has evolved over the last 70  years from non-vascularized bone grafts, skin grafts, and pedicled flaps to the contemporary use of vascularized free flaps and implant-retained prosthesis, often with

..      Table 20.6  Postoperative care Postoperative management General

Prophylactic antibiotics, if indicated VTE prophylaxis; fluid replacement

Specific   Airway

Tracheostomy care Vigilant for signs/symptoms of airway compromise

 

S ite of tumor ablation (e.g., tongue, floor of mouth, maxilla)

Monitor for swelling, bleeding, and airway embarrassment

 

Free flap

Routine flap observation; early recognition of flap compromise and potential salvage (color, capillary refill, temperature, Doppler signal [handheld or implantable])

 

Neck

Retain suction in drains Monitor for evidence of collection

 

F ree flap donor site

Monitor for evidence of neurovascular compromise if limb involved

Nutrition

Assess for NG, PEG/RIG requirement Ensure adequacy of nutritional intake Monitor for refeeding

SALT

Determines safety of swallow/risk of aspiration Speech assessment, therapy

VTE venous thromboembolism prophylaxis, NG nasogastric, PEG percutaneous enterogastrostomy, RIG radiologically inserted gastrostomy, SALT speech and language therapy

the benefit of virtual surgical planning. Large ablative composite defects can now be predictably restored, and patients can expect a speedy return to near premorbid form and function. Improved immunosuppression regimes have facilitated recent successful facial allotransplantation. Tissue engineering, where replacement tissue derived from patients’ own (autologous) cells is grown in vivo (inside the patient) or in vitro (outside the patient), has the potential to revolutionize the way in which we replace lost tissue. A detailed description of the process involved is beyond the scope of this chapter, but put simply tissue engineering involves cell signaling to firstly encourage cell specialization into a specific type of tissue and secondly proliferate in order to fill a defect. A vascular supply along with a scaffold and mechanical loading are other key components. To date, the clinical use of tissue engineering in maxillofacial surgery has primarily been limited to bone and epithelium replacement [77–79]. Ultimately, the goal is to have the ability to replace lost tissue with a custom-made vascularized and innervated composite graft, engineered from autogenous progenitor stem cells.

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Conclusion

The surgical management of oral cavity SCC has evolved from radical mutilating procedures to a more bespoke patient-specific approach where adequate tumor ablation, preservation of function, and appropriate reconstruction are paramount. Key principles relate to appropriate patient selection and rational perioperative decisions. In particular, the surgeon must be cognizant of how the airway is to be managed and how to gain access to the tumor to ensure adequate margins. Sentinel lymph node biopsy may allow the safe de-­ escalation of occult neck metastasis management. Nevertheless, many patients will require a neck dissection, and the appropriate levels, with adequate numbers of lymph nodes, need to be dissected. Adequate reconstruction and rehabilitation of ablative defects is crucial for function, aesthetics, and quality of life. The advent of microvascular free tissue transfer ensures that most defects can now be satisfactorily reconstructed. The anatomic area to be reconstructed and the tissues to be replaced will largely dictate the choice of donor site.

References

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1. Shaw RJ, Lowe D, Woolgar JA, Brown JS, Vaughan ED, Evans C, et al. Extracapsular spread in oral squamous cell carcinoma. Head Neck. 2010;32(6):714–22. 2. Shaw RJ, Holsinger FC, Paleri V, Evans M, Tudur-Smith C, Ferris RL. Surgical trials in head and neck oncology: renaissance and revolution? Head Neck. 2015;37(7):927–30. 3. Lydiatt WM, Patel SG, O'Sullivan B, Brandwein MS, Ridge JA, Migliacci JC, et al. Head and neck cancers-major changes in the American Joint Committee on cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67(2):122–37. 4. Tirelli G, Gatto A, Boscolo Nata F, Bussani R, Piccinato A, Marcuzzo AV, et al. Prognosis of oral cancer: a comparison of the staging systems given in the 7th and 8th editions of the American Joint Committee on cancer staging manual. Br J Oral Maxillofac Surg. 2018;56(1):8–13. 5. Ganly I, Patel SG, Singh B, Kraus DH, Bridger PG, Cantu G, et al. Complications of craniofacial resection for malignant tumors of the skull base: report of an international collaborative study. Head Neck. 2005;27(6):445–51. 6. Wiegand S, Zimmermann A, Wilhelm T, Werner JA.  Survival after distant metastasis in head and neck cancer. Anticancer Res. 2015;35(10):5499–502. 7. Main BG, McNair AGK, Huxtable R, Donovan JL, Thomas SJ, Kinnersley P, et al. Core information sets for informed consent to surgical interventions: baseline information of importance to patients and clinicians. BMC Med Ethics. 2017;18(1):29. 8. Scott N, Bater M, Fardy M. Tracheostomy in head and neck oncology. Results of the 2014 tracheostomy survey of the BAOMS Oncology Specialist Interest Group. Br J Oral Maxillofac Surg. 2015;53(8):779–81. 9. Cipriano A, Mao ML, Hon HH, Vazquez D, Stawicki SP, Sharpe RP, et al. An overview of complications associated with open and percutaneous tracheostomy procedures. Int J Crit Illn Inj Sci. 2015;5(3):179–88. 10. Rogers SN, Russell L, Lowe D. Patients' experience of temporary tracheostomy after microvascular reconstruction for cancer of the head and neck. Br J Oral Maxillofac Surg. 2017;55(1):10–6.

11. Cameron M, Corner A, Diba A, Hankins M. Development of a tracheostomy scoring system to guide airway management after major head and neck surgery. Int J Oral Maxillofac Surg. 2009;38(8): 846–9. 12. Gupta K, Mandlik D, Patel D, Patel P, Shah B, Vijay DG, et al. Clinical assessment scoring system for tracheostomy (CASST) criterion: objective criteria to predict pre-operatively the need for a tracheostomy in head and neck malignancies. J Craniomaxillofac Surg. 2016;44(9):1310–3. 13. Leiser Y, Barak M, Ghantous Y, Yehudai N, Abu El-Naaj I. Indications for elective tracheostomy in reconstructive surgery in patients with oral cancer. J Craniofac Surg. 2017;28(1):e18–22. 14. Coyle MJ, Tyrrell R, Godden A, Hughes CW, Perkins C, Thomas S, et al. Replacing tracheostomy with overnight intubation to manage the airway in head and neck oncology patients: towards an improved recovery. Br J Oral Maxillofac Surg. 2013;51(6): 493–6. 15. Dempsey GA, Grant CA, Jones TM. Percutaneous tracheostomy: a 6 yr prospective evaluation of the single tapered dilator technique. Br J Anaesth. 2010;105(6):782–8. 16. Brass P, Hellmich M, Ladra A, Ladra J, Wrzosek A. Percutaneous techniques versus surgical techniques for tracheostomy. Cochrane Database Syst Rev. 2016;7:CD008045. 17. Roux PJ.  Diseases of the tongue, etc. [With a bibliography.]. In: Butlin HTSB, Spencer WG, editors. (New enlarged edition.) by H. T. Butlin ... and Walter G.  Spencer, etc. London: Cassell & Co.; 1900. p. 359. 18. McGregor IA, MacDonald DG.  Mandibular osteotomy in the surgical approach to the oral cavity. Head Neck Surg. 1983;5(5): 457–62. 19. Hayter JP, Vaughan ED, Brown JS.  Aesthetic lip splits. Br J Oral Maxillofac Surg. 1996;34(5):432–5. 20. Mehanna P, Devine J, McMahon J.  Lip split and mandibulotomy modifications. Br J Oral Maxillofac Surg. 2010;48(4):314–5. 21. Cilento BW, Izzard M, Weymuller EA, Futran N.  Comparison of approaches for oral cavity cancer resection: lip-split versus visor flap. Otolaryngol Head Neck Surg. 2007;137(3):428–32. 22. Devine JC, Rogers SN, McNally D, Brown JS, Vaughan ED.  A comparison of aesthetic, functional and patient subjective outcomes following lip-split mandibulotomy and mandibular lingual releasing access procedures. Int J Oral Maxillofac Surg. 2001;30(3): 199–204. 23. Fernandes R, Ord R. Access surgery for oral cancer. Oral Maxillofac Surg Clin North Am. 2006;18(4):565–71. 24. Hernandez Altemir F. Transfacial access to the retromaxillary area. J Maxillofac Surg. 1986;14(3):165–70. 25. Brown J. Mechanisms of cancer invasion of the mandible. Curr Opin Otolaryngol Head Neck Surg. 2003;11(2):96–102. 26. Cawood JI, Howell RA. A classification of the edentulous jaws. Int J Oral Maxillofac Surg. 1988;17(4):232–6. 27. Brown JS, Shaw RJ.  Reconstruction of the maxilla and midface: introducing a new classification. Lancet Oncol. 2010;11(10):1001–8. 28. Brown JS. Jaw resection. In: Langdon JD, Patel MF, Ord RA, Brennan PA, editors. Operative Oral and Maxillofacial Surgery. 2nd ed. London: Hodder Arnold. p. 317. 29. D'Cruz AK, Vaish R, Kapre N, Dandekar M, Gupta S, Hawaldar R, et al. Elective versus therapeutic neck dissection in node-negative oral cancer. N Engl J Med. 2015;373(6):521–9. 30. Schilling C, Stoeckli SJ, Haerle SK, Broglie MA, Huber GF, Sorensen JA, et al. Sentinel European node trial (SENT): 3-year results of sentinel node biopsy in oral cancer. Eur J Cancer. 2015;51(18):2777–84. 31. Schilling C, Shaw R, Schache A, McMahon J, Chegini S, Kerawala C, et al. Sentinel lymph node biopsy for oral squamous cell carcinoma. Where are we now? Br J Oral Maxillofac Surg. 2017;55(8):757–62. 32. Divi V, Chen MM, Nussenbaum B, Rhoads KF, Sirjani DB, Holsinger FC, et al. Lymph node count from neck dissection predicts mortality in head and neck cancer. J Clin Oncol. 2016;34(32):3892–7.

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33. Patel SG, Amit M, Yen TC, Liao CT, Chaturvedi P, Agarwal JP, et  al. Lymph node density in oral cavity cancer: results of the international consortium for outcomes research. Br J Cancer. 2013;109(8):2087–95. 34. Yii NW, Patel SG, Williamson P, Breach NM.  Use of apron flap incision for neck dissection. Plast Reconstr Surg. 1999;103(6): 1655–60. 35. Dingman RO, Grabb WC. Surgical anatomy of the mandibular ramus of the facial nerve based on the dissection of 100 facial halves. Plast Reconstr Surg Transplant Bull. 1962;29:266–72. 36. Ziarah HA, Atkinson ME. The surgical anatomy of the mandibular distribution of the facial nerve. Br J Oral Surg. 1981;19(3):159–70. 37. Lanisnik B, Zargi M, Rodi Z. Identification of three anatomical patterns of the spinal accessory nerve in the neck by neurophysiological mapping. Radiol Oncol. 2014;48(4):387–92. 38. Phang K, Bowman M, Phillips A, Windsor J. Review of thoracic duct anatomical variations and clinical implications. Clin Anat. 2014;27(4):637–44. 39. Schramm VL Jr, Myers EN. Skin grafts in oral cavity reconstruction. Arch Otolaryngol. 1980;106(9):528–32. 40. Rush BF Jr, Swaminathan A, Knightly JJ. Use of split thickness grafts in the repair of excisions of the oropharynx, base of the tongue, and larynx. Am J Surg. 1974;128(4):553–6. 41. Lexer E. Wangenplastik. Disch Z Chir. 1909;100:206. 42. Urken ML. Atlas of regional and free flaps for head and neck reconstruction: flap harvest and insetting. 2nd ed. Philadelphia: Lippincott Williams & Wilkins. 43. Varghese BT, Sebastian P, Cherian T, Mohan PM, Ahmed I, Koshy CM, et  al. Nasolabial flaps in oral reconstruction: an analysis of 224 cases. Br J Plast Surg. 2001;54(6):499–503. 44. Pribaz J, Stephens W, Crespo L, Gifford G. A new intraoral flap: facial artery musculomucosal (FAMM) flap. Plast Reconstr Surg. 1992;90(3):421–9. 45. Ariyan S. The functional pectoralis major musculocutaneous island flap for head and neck reconstruction. Plast Reconstr Surg. 1990;86(4):807–8. 46. Green MF, Gibson JR, Bryson JR, Thomson E. A one-stage correction of mandibular defects using a split sternum pectoralis major osteomusculocutaneous transfer. Br J Plast Surg. 1981;34(1):11–6. 47. Cuono CB, Ariyan S. Immediate reconstruction of a composite mandibular defect with a regional osteomusculocutaneous flap. Plast Reconstr Surg. 1980;65(4):477–84. 48. Bakamjian VY. A two-stage method for pharyngoesophageal reconstruction with a primary pectoral skin flap. Plast Reconstr Surg. 1965;36:173–84. 49. Abubaker AO, Abouzgia MB. The temporalis muscle flap in reconstruction of intraoral defects: an appraisal of the technique. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2002;94(1): 24–30. 50. Pinto FR, de Magalhaes RP, Capelli Fde A, Brandao LG, Kanda JL. Pedicled temporoparietal galeal flap for reconstruction of intraoral defects. Ann Otol Rhinol Laryngol. 2008;117(8):581–6. 51. Matsuba HM, Hakki AR, Little JW 3rd, Spear SL. The temporal fossa in head and neck reconstruction: twenty-two flaps of scalp, fascia, and full-thickness cranial bone. Laryngoscope. 1988;98(4):444–9. 52. Clauser L, Curioni C, Spanio S. The use of the temporalis muscle flap in facial and craniofacial reconstructive surgery. A review of 182 cases. J Craniomaxillofac Surg. 1995;23(4):203–14. 53. Parhiscar A, Har-El G, Turk JB, Abramson DL. Temporoparietal osteofascial flap for head and neck reconstruction. J Oral Maxillofac Surg. 2002;60(6):619–22. 54. Mutter TD. Case of deformity from burns relieved by operation. Am J Med Sci. 1842;4:66–80. 55. Kazanjian VH, Converse JM. The surgical treatment of facial injuries. London; printed in U.S.A.: Ballie\0300re, Tindall & Cox; 1949.

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56. Lamberty BG, Cormack GC. Misconceptions regarding the cervico-­ humeral flap. Br J Plast Surg. 1983;36(1):60–3. 57. Quillen CG, Shearin JC Jr, Georgiade NG. Use of the latissimus dorsi myocutaneous island flap for reconstruction in the head and neck  area: case report. Plast Reconstr Surg. 1978;62(1): 113–7. 58. Maxwell GP, Stueber K, Hoopes JE. A free latissimus dorsi myocutaneous flap: case report. Plast Reconstr Surg. 1978;62(3): 462–6. 59. Yang G, Chen B, Gao Y. Forearm free skin flap transplantation. Natl Med J China. 1981;61:139. 60. Song R, Gao Y, Song Y, Yu Y, Song Y. The forearm flap. Clin Plast Surg. 1982;9(1):21–6. 61. Song YG, Chen GZ, Song YL. The free thigh flap: a new free flap concept based on the septocutaneous artery. Br J Plast Surg. 1984;37(2):149–59. 62. O'Connell JE, Bajwa MS, Schache AG, Shaw RJ.  Head and neck reconstruction with free flaps based on the thoracodorsal system. Oral Oncol. 2017;75:46–53. 63. Shaw RJ, McGlashan G, Woolgar JA, Lowe D, Brown JS, Vaughan ED, et al. Prognostic importance of site in squamous cell carcinoma of the buccal mucosa. Br J Oral Maxillofac Surg. 2009;47(5): 356–9. 64. Brown J, Chatterjee R, Lowe D, Lewis-Jones H, Rogers S, Vaughan D. A new guide to mandibular resection for oral squamous cell carcinoma based on the Cawood and Howell classification of the mandible. Int J Oral Maxillofac Surg. 2005;34(8):834–9. 65. Ferri J, Piot B, Ruhin B, Mercier J. Advantages and limitations of the fibula free flap in mandibular reconstruction. J Oral Maxillofac Surg. 1997;55(5):440–8; discussion 8-9. 66. Shaw RJ, Kanatas AN, Lowe D, Brown JS, Rogers SN, Vaughan ED.  Comparison of miniplates and reconstruction plates in mandibular reconstruction. Head Neck. 2004;26(5):456–63. 67. Brown JS, Barry C, Ho M, Shaw R. A new classification for mandibular defects after oncological resection. Lancet Oncol. 2016;17(1): e23–30. 68. Moreno MA, Skoracki RJ, Hanna EY, Hanasono MM.  Microvascular free flap reconstruction versus palatal obturation for maxillectomy defects. Head Neck. 2010;32(7):860–8. 69. Rogers SN, Lowe D, McNally D, Brown JS, Vaughan ED.  Health-­ related quality of life after maxillectomy: a comparison between prosthetic obturation and free flap. J Oral Maxillofac Surg. 2003;61(2):174–81. 70. Genden EM, Okay D, Stepp MT, Rezaee RP, Mojica JS, Buchbinder D, et  al. Comparison of functional and quality-of-life outcomes in patients with and without palatomaxillary reconstruction: a preliminary report. Arch Otolaryngol Head Neck Surg. 2003;129(7): 775–80. 71. Branemark PI.  Surgery and fixture installation. In: AB NB, editor. Zygomaticus fixture clinical procedures. 1st ed. Goteburg: Nobel Biocare AB; 1988. p. 1. 72. Boyes-Varley JG, Howes DG, Lownie JF.  The zygomaticus implant protocol in the treatment of the severely resorbed maxilla. SADJ. 2003;58(3):106–9, 13-4. 73. Butterworth CJ, Rogers SN.  The zygomatic implant perforated (ZIP)  flap: a new technique for combined surgical reconstruction and rapid fixed dental rehabilitation following low-level maxillectomy. Int J Implant Dent. 2017;3(1):37. 74. Cordeiro PG, Santamaria E, Kraus DH, Strong EW, Shah JP. Reconstruction of total maxillectomy defects with preservation of the orbital contents. Plast Reconstr Surg. 1998;102(6):1874–84; discussion 85-7. 75. Shaw RJ, Sutton AF, Cawood JI, Howell RA, Lowe D, Brown JS, et al. Oral rehabilitation after treatment for head and neck malignancy. Head Neck. 2005;27(6):459–70.

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76. Rodby KA, Turin S, Jacobs RJ, Cruz JF, Hassid VJ, Kolokythas A, et al. Advances in oncologic head and neck reconstruction: systematic review and future considerations of virtual surgical planning and computer aided design/computer aided modeling. J Plast Reconstr Aesthet Surg. 2014;67(9):1171–85. 77. Warnke PH, Springer IN, Wiltfang J, Acil Y, Eufinger H, Wehmoller M, et  al. Growth and transplantation of a custom vascularised bone graft in a man. Lancet. 2004;364(9436):766–70. 78. Mesimaki K, Lindroos B, Tornwall J, Mauno J, Lindqvist C, Kontio R, et al. Novel maxillary reconstruction with ectopic bone formation by GMP adipose stem cells. Int J Oral Maxillofac Surg. 2009;38(3): 201–9. 79. Izumi K, Feinberg SE, Iida A, Yoshizawa M.  Intraoral grafting of an ex vivo produced oral mucosa equivalent: a preliminary report. Int J Oral Maxillofac Surg. 2003;32(2):188–97.

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Further Readings Cohen JI, Clayman GL, editors. Atlas of Head & Neck Surgery. 1st ed. Philadelphia: Elsevier/Saunders; 2011. Eisele DW, Smith RV, editors. Complications in head and neck surgery. 2nd ed. Philadelphia: Mosby. Elsevier; 2009. Cernea CR, Dias FL, Fliss D, Lima RA, Myers EN, Wei WI, editors. Pearls and pitfalls in head and neck surgery: practical tips to minimize complications. 2nd ed. Basel: Karger; 2012. Urken ML, Cheney ML, Blackwell KE, Harris JR, Hadlock TA, Futran N. Atlas of regional and free flaps for head and neck reconstruction: flap harvest and insetting. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2012. Cohen JI, Clayman GL.  Atlas of head & neck surgery. Philadelphia: Elsevier/Saunders; 2011.

283

Assessment of Surgical Margins Ziv Gil and Shorook Na’ara 21.1

Introduction – 284

21.2

Tumor Margins in Head and Neck Tumors – 284

21.3

How to Achieve Negative Margins? – 284

21.4

Intraoperative Pathological Assessment of Surgical Margins – 285

21.5

Evidence from Clinical Trials or Retrospective Studies – 286

21.6

Management of Patients with Positive Margins – 288

21.7

Future Directions for Intraoperative Assessment of Margins – 288

21.8

Conclusion – 289 References – 289

© Springer Nature Switzerland AG 2020 S. Warnakulasuriya, J. S. Greenspan (eds.), Textbook of Oral Cancer, Textbooks in Contemporary Dentistry, https://doi.org/10.1007/978-3-030-32316-5_21

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Core Message In oral cavity SCCs, tumor margin status is an important prognostic factor. Achieving negative margins depends primarily on the surgeon skills and the accuracy of intraoperative margin assessment. Tumor margin of less than 5  mm is considered as close margin, while ≥5  mm is defined as negative margin. In patients with early-stage SCC of the oral cavity, close margins were associated with over twofold increase in the risk of recurrence, compared with negative margins. Patients with positive/close margins are amenable to adjuvant radiation or chemoradiation therapy. The utility of specimen-­driven margin analysis is associated with a higher rate of negative margins than the traditional patient-driven margin analysis. Specimen-driven margin analysis can prevent escalation of adjuvant treatment in up to 30% of the patients.

21.1 

Introduction

As a general rule, solid cancers arising from the oral mucosa are treated by surgery if complete resection is possible. The T stage of the tumor is primarily taken into account when deciding on the initial treatment. Small and superficial malignant neoplasms of the oral cavity are amendable for surgical excision through the mouth, while advanced tumors or those involving the bone and base of the tongue demand extensive surgical techniques for exposure and excision [1]. Surgical margin status after surgical resection is one of the significant prognostic factors for recurrence-free disease in oral cancer. Negative margins are achieved when resected tumor distance is 5 mm or more from the resected margins, close is when tumor distance from the surgical margin is 4 mm or less, and positive margins are when tumor cells are involved in the resected margin [2]. Patients with advanced cancers, either presenting in T3 or T4 stages or with spread to regional lymph nodes, are considered for combined modality treatment. A multidisciplinary team from specialties including diagnostic imaging, pathology, head and neck surgery, oncology, rehabilitation services, prosthodontics, speech therapy, and psychosocial support is needed for comprehensive management of a surgical patient. 21.2 

21

 umor Margins in Head and Neck T Tumors

zz Squamous Cell Carcinoma (SCC) of the Oral Cavity

In oral cavity SCC, among other prognostic factors, the tumor margin status plays a significant role. The ability to completely resect the tumor with wide negative margins is largely dependent on the skills of the surgeon. Tumor excision with positive margins increases recurrence rates, requires escalation of treatment, and significantly decreases the overall survival of the patients.

The best outcome for patients with oral cavity SCC is accomplished by complete tumor resection with free margins of 5  mm or above [3–5]. The exact margins are likely to change from tumor to tumor according to size, depth of invasion, pattern of spread, and site. Advanced tumors, those with depth of invasion >8  mm, and recurrent tumors are likely to require margins >1 cm, while several mm free margins may be adequate for early exophytic primary tumors. While adequate margins are needed for cure, the surgeon should minimize the excision of unnecessary healthy tissue to preserve organ function. Definition Adequate margins in oral cavity SCC are 5 mm or more, while 5  mm as negative margin [6–8].  

21.3 

How to Achieve Negative Margins?

Adequate resection with free margins depends on the technical abilities of the surgeon and the pathology team. If the surgeon doubts that complete resection with negative margins is feasible, other means of treatment should be discussed with the multidisciplinary team and introduced to the patient. Methodological limitations and incorrect technique are the main reasons for the surgeon’s failure to achieve proper resection. This will imminently lead to worsening of the patients’ outcome and to escalation of treatment. Therefore, proper technique should be pursued by the team which includes the surgeon and the pathologist. Also, surgeons should follow and recognize their results, learn from failures, and continuously seek to improve their scores of negative margins. The first step toward achieving adequate resection is the operative technique. Following general anesthesia, the tumor is assessed from all sides and compared with the preoperative imaging. In oral cavity, this should include both CT an MRI scans. Next, the outline of the resection is drawn based on the visible (recognizable) and/or palpable tumor margins. Marking is performed with the tissue in relaxed and normal position. It is ill advised to pull or stretch the tissue when marking as this will imminently lead to close

285 Assessment of Surgical Margins

margins due to ­shrinkage. Such shrinkage occurs immediately when the tissue is relaxed and not due to formalin storage. The margins are always marked with the aid of a ruler with 1 cm macroscopic distance around the tumor. As it is estimated that the microscopic margins are approximately 5  mm from the macroscopic margins, this aims toward >5 mm microscopic margin. Advanced tumors, infiltrating or invasive ones, as well as prior surgery or radiotherapy may necessitate that the marking will be 1–2  cm from the tumor borders. The main two mistakes of most surgeons are in this stage, when they stretch the tissue during marking and do not use a ruler. The eye always will give you smaller margins than what you target for. After the resection margins are marked, the tissue can be stretched as needed to facilitate exposure. The surgery is performed from the known to the unknown margins. For example, if the tumor is in the oral tongue, the resection will start with a monopolar cautery, from the area where the margins are visible superficially. The resection is continued circumferentially using LigaSure Precise™ tissue fusion open instrument (Medtronic®). This allows meticulous placement of the cuts while minimizing bleeding and thermal damage. The visual margin part should be done first, followed by the deep part which is more difficult to assess. The operation continues circumferentially toward the deep and more posterior part of the oral cavity. This system maximizes our control of the margins from all sites. The surgeon should aim toward not encountering tumorigenic tissue along the procedure. However, if the tumor is breached, the surgeon should stop the procedure, suture the violated part, and start again from step 1, i.e., assessment and marking of the margins. In composite resections, effort should be made to achieve en bloc resection. We usually do not perform segmental mandibulectomy if the mandible is not involved by the tumor. In other words, the mandible should not be resected as margins just because the tumor is close. Bear in mind that a cortical mandibulectomy or marginal mandibulectomy can serve to improve margin status in selected cases. After the tumor is resected, the surgeon should examine the specimen again and evaluate if extension of the resection is required. The tumor bed is also irrigated, and hemostasis is performed. The specimen is oriented by the surgical team and marked with sutures to allow orientation by the pathologist. At this stage, one of the surgeons carries the specimens to the pathology laboratory for further assessment. Alternatively, the pathologist can come to the surgical suite for briefings and orientation regarding the procedure. The pathologist and surgeon should always meet and discuss eyeball to eyeball the case before further analysis as communication through phone or papers is misleading and sloppy. >>Important In oral cavity SCCs, tumor margin status is the single most important prognostic factor which is dependent on the surgeon.

21.4 

Intraoperative Pathological Assessment of Surgical Margins

Patients with positive or close margin status have significant higher risk of tumor recurrence. The poor outcome of these patients is taken into consideration when deciding on adjuvant therapy. Due to the complexity of head and neck cancers, complete tumor resection with negative margin area is achieved in 80% of the patients in the best cancer centers in the world. Of note is that lower rates were reported recently by several university hospitals [9, 10]. These studies call for strategic plans toward improving the ability of head and neck surgeons to pursue the guidelines of treatment which is 5 mm clear margins. Intraoperative frozen section evaluation of the surgical margins is often used to determine the adequacy of resection in oral cavity SCC as it provides a rapid assessment of the pathological margins. Assessment of margins requires teamwork in the operating room and in the pathology lab. However, there is lack of consensus regarding the right intraoperative method of assessment for margins. A method demonstrating the intraoperative analysis of tumor margins is illustrated in . Fig. 21.1. Frozen section samples could be taken in two fashions: (1) from the resected pathological specimen itself or (2) from the patient’s side, i.e., from the tumor bed. While it was shown that the former one is more accurate for true intraoperative margin assessment, the latter one is the most common sampling method among surgeons. A survey of about 500 head and neck surgeons who were members of the American Head and Neck Society was conducted to better understand the attitude toward the intraoperative frozen sectioning. As for the surgeon’s definition to clear surgical margins, the majority of surgeons (46%) agreed to the definition that a clear margin was ≥5  mm on microscopic examination. When asked about intraoperative margin assessment, the vast majority (99%) of the surgeons revealed they use frozen sections as a tool to evaluate tumor margins in head and neck tumors. Among them, >90% stated they were using frozen sections in oral cavity tumors. Most responders reported sampling the surgical bed to provide frozen sections rather than obtaining samples from the tumor specimen (76% compared to 14%, respectively) [11]. Although this is the most popular method, sampling of the tumor bed has significant limitations. The real margin status is underestimated by this method, i.e., close margins are often labeled as negative margins. The failure is attributed partly to the difficulties encountered by the pathologists in identifying small tumor islands in the specimen, in the absence of the tumor core. Furthermore, the small fragments of tissue sent by the majority of surgeons are difficult to orientate [12]. Data suggest poor accuracy of frozen sections for T3–T4 lesions (37.5% and 22.2%, respectively) and worse in cases with bone involvement [13]. A summary of the caveats of patient’s margin assessment using frozen samples from the surgical bed is listed below:  

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..      Fig. 21.1  Representative figure demonstrating the intraoperative analysis of margins. a. In situ picture showing the tumor in the lateral left tongue. The line represents the extent of the surgical margins (A, anterior; P, posterior; S, superior; I, inferior). b. The tumor after

resection. c. The tumor margins after marking of the margins with black ink. d. Axial cut is performed to reveal the tumor in the sagittal margins. d. The sagittal extents of the tumor. Dashed line encircles the visible tumor

1. It is not possible to assess the distance between the tumor cells and the tumor margin: only involvement or lack of involvement of cancer can be disclosed. 2. Identification of tumor cells is difficult due to lack of body of the tumors. 3. Artifacts following electrocautery curbs the detection of cancer cells. 4. Random sampling error plays a role.

21.5 

The second method, assessment of specimen margins, is based on frozen section analysis of the resected tumor itself. This technique involves real measurement of the surgical margin to the invasive front, in the same way as final pathological assessment. After tumor extirpation, the whole specimen is taken by the operating surgeon to the pathology laboratory. Orientation of the specimen is performed jointly by the surgeon and the pathologist. After orientation, the borders of the specimen are stained with black and green inks and sectioned in the XYZ orientation (. Fig. 21.1). Samples are excised from the specimen using a standard technique and imbedded in wax blocks. Following sectioning, the evaluation of frozen sections is performed under the microscope from the tumor front to the specimen periphery (the inked side) in each dimension. The tumor is examined, and margins are microscopically assessed with a micrometer caliper. If the pathologist’s frozen section evaluation reveals margins of ≤5  mm in any dimension, the surgeon would undertake an extension of the surgical resection. This is carefully undertaken by removing an additional 5- to 10-mm strip of tissue from the tumor bed, at each involved side. This method does not allow to inspect the bone margins. If the tumor margin is close to the bone, then specimens are taken from the mucosa of soft tissue overlying the bone or by scraping of the bone for frozen section analysis.  

21

Z. Gil and S. Na’ara

 vidence from Clinical Trials or E Retrospective Studies

A prospective study was conducted by us to evaluate the two methods of assessing surgical margins of oral SCC. We compared the data from the specimen-driven assessment of margins (Group 1) against the patient-driven assessment of margins (Group 2). In the first group, the margins were measured from the excised specimens using frozen section evaluation and, in the second group, the margins were sampled from the tissue at the margin of the cavity in the patient’s mouth after tumor resection. We analyzed a total of 71 patients who were randomized to each technique [5]. The primary endpoint of the study was the rate of positive or close surgical margins (presence of tumor cells ≤5 mm from the surgical margin) in the two groups in final pathological examination. Twenty patients (29%) were allocated to Group 1 and 51 (71%) to Group 2. Patients in the two arms were comparable in their demographic or clinical variables, TNM status, or the complexity of the surgical procedure. The mean number of frozen sections submitted for analysis in Group 1 was 3.1  ±  2.1 and did not differ significantly from the number of frozen sections examined in Group 2 (3.9 ± 1.6; p  =  0.1). Tissue shrinkage due to fixation was similar in both groups (10% to 14%; p = 0.6). This was an important finding from our study which contradicts refuted mythologies that tumor shrinkage is responsible for positive margins [5]. At the final analysis, positive or close margins were evident in 45% in Group 1 compared to 16% in Group 2 (p  =  0.02). A subgroup analysis was undertaken to assess whether the T size contributed to these differences. Among patients with advanced disease (T3–T4 stages), a significantly higher rate of positive/close margins was observed in Group

21

287 Assessment of Surgical Margins

2 (63% vs 21%,respectively; p  =  0.01). Among the patients with T1 and T2 SCCs, any differences in margin clearance in the two groups were less pronounced and did not reach statistical significance (33% in Group 2 vs 14% in Group 1; p = 0.06) [5]. Overall evaluation of data from our study [5] was as follows: Specimen-driven margin technique: 55 Sensitivity, 91%; specificity, 93% 55 False positives, 9%; false negatives, 17%

Eyecatcher

A prospective study showed that specimen-driven margin is superior to patients-driven margins.

In a multicenter international study (including centers from Italy, Australia, Brazil, Germany, India, USA, and Taiwan), we compared the survival of patients with oral cavity SCC who were surgically treated during 1990–2000 with those treated during 2001–2011 [4]. In the later era, patients were older and had more advanced T stages than in the early period. In correlation, there was a higher rate of distant metastases during the last decade (the 5-year metastases rate rose from 7% to 13%). These patients received selective neck dissection (which was less extensive) and more often received adjuvant radiotherapy. Though patients treated in the latter period had a higher rate of metastasis, the rate of ­close/positive margins in this group was significantly lower. A significant improvement was noted by us in the 5-year OS, from 59% to 70% in the latter group compared to the early one. DSS also improved from 69% to 81%, respectively [4] (. Fig. 21.2).

Patient-driven margin technique: 55 Sensitivity, 22%; specificity, 100% 55 False positives, 0%; false negatives, 44% We also analyzed the effect of margin technique on adjuvant treatment in both groups. The patients in Group 2 (patients side margins) required escalation of treatment (radiation or chemoradiation) in 35% of the cases due to positive or close margin status. In contrast, the patients in Group 1 (specimen margins) required escalation of treatment in only 8% of the cases (p = 0.01) [5].

Overall survival

a 1.0 0.9 0.8

2001−2011 5y-81%

0.7 Surviving

0.6 0.5 1990−2000 5y-59%

0.4 0.3 0.2 0.1

Disease specific survival

b 1.0 0.9 0.8

2001−2011 5y-70%

0.7 Surviving

 

P < .001

0.0

0.6 0.5

1990−2000 5y-69%

0.4 0.3 0.2 0.1

P < .001

0.0 0

20

40

60

80

100

120

0

20

40

Time (months) c

Disease free survival

1.0 0.9 0.8

0.0

Failing

Surviving

1990−2000 5y-65%

0.4 0.3 0.2 0.1

P = 0.03

0.6 0.5 0.4 0.3 0.2 0.1

P = 0.005

2001−2011 5y-13% 1990−2000 5y-7%

0.0 0

20

40

60

80

100

120

0.7

0.7 0.6 0.5

100

Distant metastasis

d 1.0 0.9 0.8

2001−2011 5y-69%

60 80 Time (months)

120

Time (months) ..      Fig. 21.2  Kaplan-Meier 5-year (5y) curves illustrate the survival of patients who underwent surgery during the two periods (1990–2000 [red line] and 2001–2011 [blue line]), including a overall survival, b

0

20

40

60

80

100

Time (months) disease-specific survival, c disease-free survival, and d distant metastasis. (Adopted from Amit et al. [4])

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Z. Gil and S. Na’ara

Hence, our data suggest that improvement in surgical techniques, particularly margin clearance, led to a higher rate of total tumor resection, improving outcome in the current era. !!Warning Failure of reaching negative margins in all stages is associated with poor outcome and therefore requires adjuvant therapy.

21.6 

 anagement of Patients with Positive M Margins

For patients with oral cavity tumors, achieving negative surgical margins following resection significantly contributes to improved survival. Resurgery is an effective treatment for cases found with positive margins after initial surgery, but it may not even be possible, especially in cases who receive immediate reconstruction. In cases for which resurgery is not amenable, adjuvant therapy may be offered (see 7 Chapter 22). The observations from two prospective randomized trials of adjuvant chemoradiotherapy have shown that patients who have extracapsular extension of disease in metastatic cervical lymph nodes and those who have positive margins have a significant improvement in local regional control and disease free survival by addition of chemotherapy to postoperative radiation therapy compared to post-operative radiation therapy alone [14, 15]. An international multicentric study analyzed the role of adjuvant therapy in patients with early-stage SCC of the oral cavity with close/positive margins without nodal involvement [3]. Close/positive margins were associated with a twofold increase in the risk of locoregional recurrence (p  3  cm, treatment delay greater than 6 weeks, and Zubrod performance status ≥2). Patients with one of these factors were considered intermediate risk as long as they did not consist of ECE or positive margins. The study demonstrated that 63 Gy in 7 weeks was the optimal dose for high-risk patients and 57.6  Gy for intermediate-­risk patients. 22.3.1 

I mpact of Treatment Package Time in High-Risk Patients

In a follow-up to the Peter’s study, a multi-institutional randomized trial of high-risk patients reported by Ang et  al. validated the utility of the risk stratification system proposed by Peters and investigated the benefit of accelerated fractionated postoperative adjuvant radiation for high-risk patients [7]. Patients with no risk factors were classified as low risk, while patients with one feature and patients with two or more features or ECE were stratified as intermediate and high risk, respectively. Low-risk patients were observed postoperatively, while intermediate-risk patients received conventionally fractionated radiation (57.6 Gy in 1.8 Gy fractions, over 6.5 weeks). High-risk patients were randomized to high-dose conventional radiation over 7 weeks (63 Gy in 1.8 Gy fractions, once daily) or accelerated course radiation by delayed concomitant boost over 5 weeks (63 Gy in 1.8 Gy fractions, once daily for initial 3  weeks and then twice daily for last 2 weeks). Five-year locoregional control (LRC) and survival was significantly higher in the low- and intermediate-risk population compared to the high-risk population (p = 0.003 and p = 0.0001, respectively), despite receiving no adjuvant RT or lower-dose adjuvant RT, respectively. There was a nonsignificant improvement in outcomes in high-risk patients who underwent accelerated radiation. 22.3.2 

 iming of Treatment Package in HighT Risk Patients

The benefit of accelerated radiation was attributed to the shortened treatment package time to overcome tumor repopulation [7]. Among high-risk patients stratified by duration of treatment course, LRC was significantly higher for courses less than 11 weeks (76%) as compared to 11–13 weeks (62%) and greater than 13  weeks (38%). Thus, conventional

293 Chemoradiotherapy in Oral Cavity Cancer

f­ ractionation when done in a timely fashion could also benefit high-risk patients. As such, radiation therapy should start 4–6 weeks after surgery to allow for adequate wound healing and to optimize the overall treatment time. Accelerated radiation may be considered in those with treatment delay. >>Important Among high-risk patients stratified by duration of treatment course, LRC was significantly higher for courses less than 11 weeks (76%) as compared to 11–13 weeks (62%) and greater than 13 weeks (38%).

22.4 

Overview of Radiation Therapy

Radiation therapy in oral cavity cancer is delivered via external beam radiation therapy (EBRT) and/or brachytherapy. Radiation therapy creates DNA damage in irradiated cells and its efficacy lies in the differential capability of DNA repair between cancerous and normal tissue [8]. EBRT is delivered via high-energy photons produced by a linear accelerator. The patient is immobilized on a radiation treatment table to minimize target motion and maximize positional reproducibility. In preparation for radiation, CT simulation is routinely performed to facilitate 3D conformal and intensity-­ modulated radiation therapy (IMRT). Patients are typically positioned supine with neck extended. Immobilization devices may include a bite block and thermoplastic mask. EBRT is typically administered in a fractionated format with daily treatments over several weeks. Conventional dosing regimens prescribe 1.8–2.0 Gy per fraction [9]. Altered fractionation regimens are also used, as discussed above in 7 Section 22.3.1. EBRT can be administered with 3D conformal technique or intensity-modulated radiation therapy (IMRT). IMRT technique assigns an algorithmic priority to various designated structures in order to optimize both target dose coverage and normal tissue sparing. Multiple collimated beams are designated from various coplanar angles around the patient, and a conformal dose distribution is achieved. Principles of brachytherapy technique are described in detail in 7 Section 22.7 below.

22

..      Table 22.1  Results of EORTC/RTOG phase III trials assessing the benefit of concurrent high-dose cisplatin with conventionally fractionated postoperative radiation RTOG 9501

EORTC 22931

Median follow-up

46 months

60 months

Locoregional failurea

3 yr: 22% vs 33% (p = 0.01)

5 yr: 18% vs 31% (p = 0.007)

Disease-free survivala

3 yr: 47% vs 36% (p = 0.04)

5 yr: 47% vs 36% (p = 0.04)

Overall survivala

3 yr: 56% vs 47% (p = 0.09)

5 yr: 53% vs 40% (p = 0.02)

Distant metastasesa

3 yr: 20% vs 23% (p = 0.46)

5 yr: 21% vs 24% (p = 0.61)

≥Grade 3 acute toxicitya

77% vs 34% (p 13  weeks. On multivariate analysis, treatment time >13 weeks vs ≤13 weeks independently increased mortality risk (HR 1.10, p  ≤  0.001). Recursive partitioning analysis identified that overall treatment time greater than approximately 14 weeks most consistently increased the risk of death.

22

IV HNSCC who have undergone gross total surgical resection with at least one of the following high-risk pathologic feature: ECE or positive surgical margins. The phase II component aims to select the better experimental arm to improve DFS over the control arm of radiation and cisplatin. The phase III component will determine whether the selected experimental arm will improve OS over the control arm of radiation and high-dose cisplatin. See 7 Chapter 27 for more details on molecular targeted therapy for advanced oral cancer.  

22.7 

Immunotherapy

The role of immune system dysfunction in the biology of HNSCC and the applications of concurrent immunotherapy with radiation therapy are a subject of recent interest [18]. Notably, immune checkpoint pathways such as the programmed death receptor-1 (PD-1) and its ligand (PD-L1) have presented promising therapeutic targets. The receptor-­ ligand interaction is a major mechanism used by tumors to evade the immune system. The normal function of PD-1 is to downregulate unwanted or excessive immune responses such as autoimmune interactions. Given that ionizing radiation is understood to induce adaptive immune responses via several 22.6  Adjuvant Concurrent Radiation interactions, preclinical studies have assessed the synergy of with Cetuximab radiation and immunotherapy. These models suggest that fractionated RT is sufficiently immunogenic to be paired While adjuvant cisplatin-based chemoradiation is estab- with an anti-PD-1 monoclonal antibody and that a loading lished as the standard-of-care in high-risk postoperative dose prior to initiation of RT and concurrently during RT head and neck cancer, the role of biologic therapies targeting may be of therapeutic value. On such study by Dovedi et al. the epidermal growth factor receptor (EGFR) has been found that anti-PD-1 or anti-PD-L1 monoclonal antibodies explored. In patients with intermediate-risk HNSCC includ- delivered concurrently with fractionated radiotherapy ing those with multiple nodes, an ongoing phase III trial improved local control, long-term survival, and protection (RTOG 0920) seeks to compare concurrent postoperative against tumor rechallenge in mouse models [19]. Such approaches are especially relevant in patients with therapy with cetuximab and radiation vs radiation alone [16]. Enrollment criteria include having one or more recurrent or metastatic HNSCC, given their poor prognosis “intermediate”-risk factors (PNI, LVI, single lymph node and limited therapeutic options. In a phase III randomized greater than 3 cm or two lymph nodes involved, close mar- trial, Ferris et al. demonstrated an OS benefit with the use of gins) without positive surgical margins or ECE.  Data from nivolumab (an anti-PD-1 monoclonal antibody) in platinum-­ this trial will elucidate whether the addition of cetuximab to refractory, recurrent HNSCC compared to standard, second-­ line systemic therapy (such as methotrexate, docetaxel, or RT improves OS in this patient population. An RTOG phase II trial in high-risk postoperative cetuximab) [20]. Median OS was 7.5 months in the nivolumab patients compared weekly docetaxel and cetuximab to weekly group vs 5.1 months in the standard therapy group with less cisplatin and cetuximab [17]. With a median follow-up of severe toxicity in the immunotherapy group. These promising results form the basis of evaluating 4.4 years, this study showed that LRF in both arms was similar to the concurrent chemoradiation arm of RTOG 9501. immunotherapy approaches in high-risk non-metastatic However, the docetaxel-cetuximab arm notably demon- patients. Pembrolizumab, another anti-PD-1 monoclonal strated improved DFS and OS compared to the cisplatin-­ antibody, is the subject of a phase I NRG-HN003 protocol cetuximab arm, due to a decrease in the incidence of distant which evaluates pembrolizumab with adjuvant concurrent metastases (25% in the cisplatin arm and 13% in the docetaxel cisplatin and intensity-modulated radiotherapy (IMRT) in high-risk HNSCC. Eligibility criteria include stage III or IV arm). Based on the aforementioned trial, there is an ongoing HNSCC patients who underwent gross total surgical resecRTOG 1216 randomized phase II/III trial of surgery and tion with either ECE or positive surgical margins. Results postoperative radiation with concurrent cisplatin with from this study will determine the recommended phase II docetaxel vs docetaxel and cetuximab for high-risk schedule for combination of pembrolizumab and standard HNSCC. Eligibility criteria include patients with stage III or adjuvant cisplatin radiotherapy in this cohort.

295 Chemoradiotherapy in Oral Cavity Cancer

See 7 Chapter 28 for more details on immunotherapy for advanced oral cancer.

While there is no recommended optimal dose schedule for HDR treatment in oral tongue cancer, higher biologically equivalent dose (BED) seems to be related to local control. In >>Important a report of 92 patients with stage I and II oral tongue cancer In patients who are unable to undergo or refuse surgery, treated with HDR brachytherapy alone (40–52 Gy) or in comdefinitive radiotherapy options exist and ideally bination with EBRT (40 Gy EBRT and 18–24 Gy brachytherincorporate brachytherapy as a component of treatment. apy), Bansal et  al. found higher five-year local control rate with brachytherapy alone (68.2%) compared to combined brachytherapy and EBRT (57.6%) [26]. The authors attributed Eyecatcher the higher local recurrence rates in the combined group to Brachytherapy which involves direct placement of lower BED achieved in this group. The combined radiation radiation sources into the tumor enables dose escalation group received a BED10 of 58.3–65.3  Gy compared to while sparing adjacent normal tissues. 56–72.8 Gy with brachytherapy alone. The authors concluded that dose escalation with brachytherapy alone and/or in combination with EBRT is needed to control primary tumors. 22.8  Definitive Treatment of Oral Cavity For more advanced cases, Santos et al. reported the outCancers come of 24 patients with locally advanced tongue carcinoma treated with HDR interstitial brachytherapy (18–24 Gy) as a In patients who are unable to undergo or refuse surgical boost to gross tumor volume (GTV) following initial chemomanagement, definitive radiotherapy and chemoradiation therapy and 50–60 Gy EBRT to the oral cavity and cervical approaches have been studied. Interstitial brachytherapy nodes [27]. The series included 11 patients with stage III and (. Fig.  22.1a–c) is usually included as part of management 13 patients with stage IV cancer, and all but one patient since direct placement of radiation sources into the tumor received chemotherapy. Brachytherapy was delivered using enables dose escalation while sparing adjacent normal tis- parallel catheters spaced 10–12 mm apart targeting residual sues. Brachytherapy (BT) has several additional advantages palpable tumor and pretreatment volume. Four-year local in the treatment of oral cavity cancers including shortened control, cause-specific survival, and regional control rates treatment times and permits a reduced dose of external beam were 80%, 68%, and 76%, respectively. All patients experiradiation therapy. Several series have evaluated brachyther- enced acute mucositis that resolved 4–6  weeks after treatment completion. Late complications including mucositis apy alone or as a boost after the completion of EBRT. Historic series investigating low-dose-rate (LDR) brachy- and dysphagia were observed in five patients, and one case of therapy for oral tongue cancer showed high rates of local con- osteoradionecrosis was observed. Large-scale database reviews revealed the impact of trol for patients with oral tongue and lip cancers [21, 22]. One study included over 600 oral tongue patients with T1–T3 dis- brachytherapy in definitive treatment of the oral cavity. In a ease treated with radium implants, and the other included 166 2016 SEER database review, 12% of 5161 definitively treated patients with T1–T2 disease treated with iridium implants. oral cavity SCC patients received brachytherapy [28]. The use Local control rates were 70–80%, with higher rates of local of brachytherapy declined at a rate of 0.58% per year from control for smaller lesions (86%, 80%, and 68% for T1, T2, and 1973 to 2012. The rate of decline of brachytherapy use for T3 tumors, respectively) [21]. The European Curietherapy tongue cancer was 1.0% per year. Nevertheless, addition of Group reported the largest series of 2363 patients treated for brachytherapy was associated with a decreased risk of death lip cancer from 23 centers. The majority of patients had T1– (HR 0.71) on multivariate analysis. Specifically, in the 2030 T2 N0 disease, and 1870 patients received brachytherapy with patients with tongue cancer (37% received BT alone and 56% iridium, radium, or cesium treatments using rigid or flexible received EBRT with BT), the addition of brachytherapy to catheters delivering 60–85  Gy. Recurrence rates were 2.5%, EBRT was associated with a decreased risk of death with HR of 0.73 (95% CI 0.65–0.83). Similar results were found in 5%, and 11% for T1, T2, and T3 tumors, respectively [23]. To decrease radiation exposure to hospital personnel, another analysis of SEER data of patients with oral cavity modern series have explored high-dose-rate (HDR) brachy- SCC receiving definitive or adjuvant radiation [29]. Among therapy techniques which deliver treatment in shielded 19,343 patients with tongue (56.6%), lip (1.8%), floor of the rooms over short sessions. A phase III randomized trial com- mouth (17.4%), and gingival cancers (24.2%), multivariate paring high-dose-rate (HDR) and LDR treatments for early-­ analysis showed that brachytherapy combined with EBRT stage tongue cancer demonstrated similar rates of LRC was associated with improved overall survival compared to between the two groups [24]. In this study including 51 EBRT alone (HR 0.61) or brachytherapy alone (HR 0.70). patients with T1–T2  N0 cancers, 26 patients were treated Size of the tumor was found to be inversely associated with with LDR brachytherapy (70  Gy over 4–9  days) and 25 survival, with an estimated 2% increase in HR for every patients were treated with HDR brachytherapy (60 Gy in 10 increase in centimeter. The authors attributed this observaBID fractions). Five-year local control rates were 84% vs tion to the fact that EBRT best treated tumor cells in the 87%, respectively. Similar rates of local control were reported periphery, whereas brachytherapy best targeted neoplastic cells in the center of the tumor. in other non-randomized studies [25].  

 

22

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B. A. Shah et al.

With regard to definitive EBRT without brachytherapy in oral cavity cancer, recent data from a single-institution retrospective series showed reasonable rates of disease control [30]. One-hundred and eight patients were treated with radical definitive radiation therapy instead of primary surgery (76 treated with definitive IMRT alone and 32 treated with concurrent chemoradiation). Dose fractionation regimens included 70 Gy in 35 fractions, 60 Gy in 25 fractions, 64 Gy in 40 fractions twice daily over 4 weeks, and 66 Gy in 33 fractions. The majority of patients were locally advanced (20% stage III and 47% stage IVA). Outcomes at 3 years were compared between clinically node-negative (cN-) and node-­ positive (cN+) patients. In the cN- and cN+ cohorts, local control was 76% and 71%, regional control was 96% and

90%, distant control was 98% and 81% (p = 0.004), and OS was 65% and 44% (p = 0.005), respectively. Seventeen (15%) patients received subsequent surgery and eleven (64%) were successfully salvaged to achieve LRC.  Only one of these patients failed distantly after salvage. While further exploration is warranted in this area, definitive radiotherapy without surgery may present reasonable rates of disease control while also allowing for organ preservation. Definition The use of IMRT allows for dose conformality and avoidance of OARs (i.e., swallowing muscles, salivary glands) to reduce treatment toxicity.

a

b

22 ..      Fig. 22.1  a Oral tongue primary. b IMRT prior to interstitial brachytherapy boost (axial, coronal, and sagittal views), sparing OARs such as the pharyngeal constrictors, larynx, and parotid glands. c Interstitial brachytherapy boost (axial, coronal, and sagittal views),

sparing OARs such as the mandible, salivary glands, and constrictor muscles. d Dose-volume histogram of IMRT with dose-painting (multiple PTVs) and sparing of OARs

297 Chemoradiotherapy in Oral Cavity Cancer

c

..      Fig. 22.1 (continued)

22

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B. A. Shah et al.

d

..      Fig. 22.1 (continued)

22.9 

22

Principles of Radiation Planning

Using CT-based planning software, areas of gross disease at the primary site and/or neck are contoured as gross tumor volume (GTV), while clinical target volumes (CTV) are defined as a 3–5 mm margin around the GTV and areas at increased risk of subclinical disease such as routes of tumor spread along the primary and perineural pathways as well as regional disease. Organs at risk (OAR) are also designated, which should include the brachial plexus, brain, brainstem, pharyngeal constrictors, esophagus, lacrimal glands, larynx, mandible, optic nerves, optic lenses, parotid glands, spinal cord, and submandibular glands. Historically, opposed lateral fields were used; however, these have generally been replaced by 3D conformal and IMRT techniques. The use of IMRT allows for dose conformality and avoidance of OARs (i.e., swallowing muscles, salivary glands) to reduce treatment toxicity. With the use of IMRT, a dose-painting technique can be used to define high-, intermediate-, and low-risk areas and deliver corresponding dose per fraction to these levels. For

example, gross disease may be treated with 2.12 Gy/fraction, while elective nodal areas can be prescribed 1.7–1.8 Gy/fraction, simultaneously over 30–33 fractions. . Figure  22.1d contains a sample dose-volume histogram from a patient with oral cavity SCC treated with this method. The integrated “boost” achievable with dose-painting allows for individualized tailoring of treatment plans while also preventing prolongation of overall treatment times.  

!!Warning A mean parotid gland dose of ≤26 Gy was proposed as a treatment planning goal for sparing of gland function.

22.10 

Dosimetric Implications for Toxicity

Several studies have evaluated dosimetric implications on normal tissue in head and neck cancer to minimize toxicities such as xerostomia, dysphagia, and dental events. Seminal studies by Eisbruch et al. assessed dose, volume, and function relationships

299 Chemoradiotherapy in Oral Cavity Cancer

in parotid salivary glands following RT for head and neck cancer [31]. A mean parotid gland dose of ≤26 Gy was proposed as a treatment planning goal for sparing of gland function. Treatment-related xerostomia was the subject of a randomized, phase III multicenter trial comparing conventional radiotherapy with IMRT [32]. At 24 months, grade 2 or worse xerostomia was significantly lower in the IMRT group than in the conventional radiotherapy group (29% vs 83%, p 10 pack years with more limited nodal disease of N0–N2a) versus an intermediate-­risk group (>10 pack years and more Definition advanced nodal involvement of N2b-N3) [1]. In the low-risk group, the 3-year overall survival rate was 93% versus 70.8% The landscape of deintensification approaches for HPV+ in the intermediate-risk group. The high-risk group included oropharyngeal squamous cell carcinoma is evolving. all HPV- patients except for patients with ≤10 pack years with tumors of stage T2 or T3; the high-risk group had a 3-year overall survival rate of 46.2%. It should be noted that this RTOG analysis was based on 23.2  Strategies for Deintensification a chemoradiation framework and conducted using the seventh edition staging system which was in place at the time 23.2.1  Alteration or Reduction of Chemotherapy or Radiation [5]. All major analyses related to HPV+ OPSCC have, to this point, been based on the seventh edition staging system, and this chapter uses the seventh edition staging classifications 23.2.1.1 Replacing Cisplatin with Cetuximab exclusively. Investigation of alternative systemic agents to administer in Surgical case series have confirmed the prognostic impor- conjunction with radiation is appealing, given the acute and tance of HPV status, T stage, N stage, and smoking. In one late toxicities of cisplatin. Cetuximab, a monoclonal antibody

305 Deintensification of Treatment for HPV-Associated Cancers of the Oropharynx

to the epidermal growth factor receptor, once appeared to be a strong candidate to substitute for cisplatin, based on level I evidence demonstrating a 9.2% 5-year benefit in overall survival from the addition of cetuximab to standard radiation in treating patients with locally advanced head and neck squamous cell carcinoma (HNSCC) [22]. While this trial was not restricted to HPV+ patients, post hoc subset analyses indicated that the benefit of adding cetuximab to radiation therapy was retained in both the HPV+ and HPV− cohorts [23]. Based on these results, several large-scale clinical trials were developed to directly compare the combination of radiation with either concurrent cisplatin or concurrent cetuximab. These trials were unsuccessful in demonstrating the equivalence of cetuximab to cisplatin. RTOG 1016, a randomized phase III trial, analyzed 849 HPV+ (using the biomarker of p16+ as a surrogate eligibility criterion) patients at a median follow-up of 4.5 years and the result was an inferior survival in the patients receiving 70 Gy of accelerated radiation with cetuximab as compared to two cycles of high-dose cisplatin [24]. De-ESCALaTE HPV, a similarly randomized phase III study conducted in Ireland, the Netherlands, and the United Kingdom which specifically targeted the “lowrisk” HPV+ population, showed no advantage for cetuximab in severe (grade 3–5) toxicity between the groups at 2 years, and in addition, the 2-year overall survival was inferior in the cetuximab-treated patients versus those receiving three cycles of high-dose cisplatin (89.4% versus 97.5%, respectively) [25]. Results from the maturing TROG 12.01 trial, which randomized low-risk patients to either weekly cetuximab or weekly cisplatin in combination with standard radiation to 70 Gy, are awaited. Regardless, at this point, given the major evidence accumulated thus far, HPV+ patients who are eligible for treatment with cisplatin in combination with their radiation should not receive cetuximab. 23.2.1.2  Reducing Cisplatin and Radiation

Doses

A single-institution phase II trial of moderate deintensification of both cisplatin and radiation has been reported [26]. Patients with p16+ OPSCC (T0–T3, N0–N2c) and minimal smoking history were treated to 60 Gy in 30 fractions with weekly cisplatin (given at a lower than usual dosing of 30 mg/ m2) followed by pathologic evaluation of the primary site, and dissection of neck levels which were involved pretreatment. A pathologic complete response at 6–14  weeks after finishing radiation was seen in 86% of patients, but all six patients with microscopic residual disease were alive with no evidence of disease at 34 months follow-­up. At 3-year followup, the locoregional control rate was 100%, and the overall survival rate was 95% [27]. One question is whether concurrent cisplatin is necessary for the treatment of limited-extent disease. A retrospective series from the Princess Margaret Cancer Center compared the outcomes of radiation alone (including accelerated fractionation regimens) to chemoradiation in patients with stage

IV HPV+ OPSCC who had ≤10 pack year smoking history; the investigators found no difference in 3-year OS, local or regional control with the omission of chemotherapy [28]. In this case series, patients undergoing radiation alone tended to be older or have medical contraindications for chemotherapy yet demonstrated a 3-year cancer-specific survival of 92% and a local control rate of 95%. This finding is reinforced by the findings of a small clinical trial, RTOG 0022, in which patients with T1–T2 N0–N1 OPSCC, without regard to their smoking or HPV status, were administered 66 Gy in 30 fractions without chemotherapy, with a result of a 2-year locoregional failure rate of 9% [29]. In this study, all cases of locoregional failure, distant metastasis, or second primary cancer occurred among patients who were current/former smokers. These findings led to the design of the international phase II clinical trial NRG-HN002, which randomized patients with p16+ SCCOP (T1–T2, N1–N2b or T3, N0–N2b) with ≤10 pack years of smoking history to either dose-reduced chemoradiation (60  Gy in 30 fractions over 6  weeks with weekly cisplatin at 40 mg/m2) or accelerated radiation therapy alone (60 Gy in 30 fractions given over 5 weeks, using twice-daily radiation one time per week). This trial has completed accrual, and the 2-year progression-free survival (PFS) results are close to maturity. At this point in time, it should be stated that reduced-dose radiation approaches, or the removal of cisplatin from treatment regimens intended for fit patients with locoregionally advanced head and neck cancers, remain strictly experimental in nature. 23.2.1.3  Reducing the Radiation Volume

Of note, NRG-HN002 allowed for ipsilateral radiation in patients with tonsil primaries based on the American College of Radiology Appropriateness criteria [30], with the additional option of ipsilateral radiation in patients with N2b disease in level 2 without extranodal extension. Reduction in the radiation volume to the ipsilateral involved side is further supported by multiple case series of surgery and postoperative ipsilateral radiation (with chemotherapy for high-­risk features) in patients with T1–T2 well-lateralized tonsil cancers and N0–N2b nodal involvement, demonstrating no contralateral failures at a median follow-up of over 5 years [31, 32]. In addition, a recent meta-analysis of over 1100 patients with OPSCC treated with ipsilateral (chemo)radiation suggests that the incidence of contralateral failure is quite low, averaging 2.4%, and associated with midline involvement [33]. However, careful patient selection is essential to the success of this approach, and in these cases, the increased sensitivity of PET/CT may be useful. Institutional case series have suggested the superior negative predictive value of PET/CT over CT and MRI in predicting pathologic nodal i­ nvolvement in HNSCC patients undergoing bilateral neck dissection [34]. The prospectively obtained results of ACRIN 6685, a study of 287 patients undergoing surgery at 23 accredited institutions, likewise indicate a high negative predictive value of PET/CT of 92.4% [35]. Though data on ipsilateral radiation in the context of HPV+ OPSCC are limited, reputable case series suggest that despite the potential for a higher rate of nodal disease

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in patients with HPV-driven tumors, contralateral nodal failure rates are low and comparable to HPV-­negative tumors in the setting of good patient selection for this technique [36]. The ipsilateral radiation technique has been integrated into current radiation oncology practice although its application remains limited to highly selected patients, and it is a practice that requires a high level of clinical experience in this regard. 23.2.1.4  Hypoxia-Based Selection

for Deintensification

A pilot study at Memorial Sloan Kettering used 18F-FMISO PET to identify normoxic nodes prior to treatment or resolution of hypoxia in nodes after 1 week (10 Gy) of chemoradiation, which were subsequently treated with radiation that was reduced by 10 Gy (to 60 Gy in 30 fractions); the primary tumor was still treated to a total dose of 70 Gy [37]. Using this approach, 10 of 33 patients were able to receive reduced-dose radiation to the node(s). At a median follow-up of 32 months, the 2-year locoregional control was 100%. A much more aggressive dose deintensification protocol was subsequently reported; in a cohort of patients who underwent resection of the primary tumor, 18F-FMISO was similarly used to identify normoxic lymph nodes after 1 week of treatment. Fourteen patients who had normoxic 18F-FMISO scans were treated to a total dose of 30  Gy with concurrent cisplatin and then underwent neck dissection 3–4 months later. Eleven of the 14 patients had a pathologic complete response, and the remaining three were felt to have residual but nonviable disease [38]. Biologically based dosing of radiation based on tumor hypoxia has increasingly been studied, though almost exclusively in small cohorts of patients such as these [39]. Hypoxic conditions limit the fixation of radiation-induced DNA double-strand-­breaks and may also limit the delivery of chemotherapeutic agents, together rendering tumor cells more resistant to treatment [40]. Hence, there is appeal in the concept of a noninvasive imaging technique that might accurately reflect hypoxia and select patients for either intensification or deintensification. However, historically, hypoxic cell sensitization (nimorazole, tirapazamine) has failed to demonstrate benefit in HPV+ OPSCC [41, 42]. It remains to be proven if hypoxia can be reliably translated into the clinic and whether there is a point at which selection based on hypoxia becomes generally relevant, given the apparent increased sensitivity to radiation and chemotherapy of most HPV+ OPSCC patients. 23.3  Induction Chemotherapy

with Subsequent Deintensification

23

Another deintensification strategy is to use induction chemotherapy followed by dose-reduced chemoradiation. A recently published single-arm phase II study evaluated response-based radiation dose reduction following two cycles of induction carboplatin (AUC 6) and paclitaxel (175 mg/m2) given 21 days apart [43]. Radiation was given to

54 Gy in those with a complete or partial response (n = 24) and 60 Gy in those with a minor response or stable disease (n = 20), with concurrent weekly paclitaxel (30 mg/m2). The 2-year PFS was 92%. The use of response to induction chemotherapy to guide the radiation dose has been further explored through an ECOG-ACRIN cancer research group phase II trial (ECOG 1308) [44]. Eighty patients with locoregionally advanced HPV+ OPSCC received three cycles of induction chemotherapy every 21 days, on a regimen of cisplatin (75 mg/m2 D1), paclitaxel (90 mg/m2 D1/8/15), and cetuximab (250 mg/ m2 weekly). Complete response at the primary site was defined as no evidence of disease on exam and fiber-optic nasopharyngolaryngoscopy, whereas nodal disease was assessed with exam only. Regions with clinical complete response were treated to 54 Gy in 27 fractions, with weekly cetuximab. In regions without a complete response, the radiation dose was 69.3 Gy in 33 fractions. In patients treated to 54 Gy to the primary site (who may have received a standard dose to the neck), the overall 2-year progression-free survival was 80%. In patients who received reduced-dose radiation to at least the primary site and who had favorable clinical features (Important Deintensification research for HPV+ oropharyngeal cancer patients proceeds from the presumption that the excellent prognosis observed with standard therapies will be confirmed for reduced-intensity approaches.

23.4  Surgery with Subsequent

Deintensification

Surgery has not historically been the most common upfront treatment for oropharyngeal cancer due to the limited access and morbidity of the open surgery approach [49]. This has changed with the advent of transoral surgery, which is approved for the surgical removal of T1–T2 oropharyngeal tumors and can be done with more limited morbidity [50]. A number of studies are examining whether an initial surgery can be used as a mechanism to deliver a lower dose of radiation postoperatively or to eliminate chemotherapy from the treatment package. ECOG 3311 is a trial of transoral surgery for HPV+ OPSCC patients which assigns them, based on their pathologic results, to a low-, intermediate-, or high-risk category that determines their subsequent treatment. Low-risk (≤T2, ≤N1 with wide margins and no adverse pathologic features) patients receive no further treatment, whereas intermediate-­ risk (lymph node >3  cm, multiple pathologically involved nodes, close margins, or other minor adverse pathologic features) patients are randomized to 60 Gy or 50 Gy of postoperative radiation therapy. High-risk patients (positive margins, >1  mm extranodal extension, or >5 involved lymph nodes) receive 66 Gy of radiation therapy with concurrent weekly cisplatin at 40  mg/m2. This trial has fully accrued and the 2-year progression-free survival results are awaited. Among surgically treated “high-risk” patients such as those defined in ECOG 3311, there is contention that concurrent cisplatin may not be needed in conjunction with postoperative radiation. The Post-operative Adjuvant Treatment for HPV-positive Tumours (PATHOS) trial in the United Kingdom is likewise testing an intermediate-risk group with doses of 50 and 60 Gy of radiation therapy but furthermore randomizes patients with a microscopically positive margin or extranodal extension to 60 Gy of radiation with or without chemotherapy. This trial remains in progress. A challenge facing the general adoption of transoral surgical approaches in the deintensification of OPSCC is the evidence supporting its proper employment in specialized, high-volume centers of excellence. The use of surgery in inappropriately selected patients, which may be followed by

chemoradiation, risks intensification of the treatment regimen and added expense and morbidity. Population-based data indicate that surgical approaches are very frequently followed by chemoradiation [51]. 23.5  Technological Evolution

A factor which is somewhat unpredictable but should be stated is that systemic therapies, surgical instruments, and radiation technologies are all in a state of flux. The development of novel targeted therapies and immune modulation including vaccines, adoptive therapy, and engineered and virally directed therapies may produce additional candidate agents for testing in this population [52]. Transorally introduced robotic instrumentation is rapidly becoming smaller, more flexible, and more mobile, potentially offering minimally invasive surgical options for a greater range of anatomic applications and patients [53]. Finally, the advent of commercially supported, widespread availability of proton therapy [54], as well as other refinements in radiation accuracy and delivery mechanisms and techniques, may result in improvements in quality of life for HPV+ OPSCC patients treated either definitively or postoperatively with radiation therapy [55]. These factors could separately or in combination alter the balance of toxicities incurred from these major categories of treatment. !!Warnings At this time, deintensification of any sort should be considered strictly experimental. Research approaches should not be translated to the clinical practice setting until results are known from large, randomized phase III trials.

23.6  Conclusion

The landscape of deintensification is complicated at this time by numerous competing approaches, none of which have been securely established. It should be recalled that the excellent outcomes associated with the diagnosis of HPV+ OPSCC have been obtained using standard, non-deintensified therapies. These at present consist of radiation or surgery as monotherapy for very limited disease versus upfront chemoradiation or surgery followed by (chemo)radiation for locoregionally advanced disease. While it is known that the late-term toxicities and quality of life of these patients are affected by the combinatorial intensity of the treatment(s) they undergo, it remains unclear which of these traditional therapies may be deintensified safely, either individually or in concert. This is an area of very active investigation, with a rapid escalation of the variety and complexity of treatment paradigms expected to occur over the next several years, as clinical trial data and competing innovative technologies and approaches mature.

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References

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1. Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tân PF, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363(1):24–35. 2. Fakhry C, Westra WH, Li S, Cmelak A, Ridge JA, Pinto H, 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. 3. Cleary C, Leeman JE, Higginson DS, Katabi N, Sherman E, Morris L, et al. Biological features of human papillomavirus-related head and neck cancers contributing to improved response. Clin Oncol (R Coll Radiol). 2016;28(7):467–74. 4. Beitler JJ, Switchenko JM, Dignam JJ, McDonald MW, Saba NF, Shin DM, et al. Smoking, age, nodal disease, T stage, p16 status, and risk of distant metastases in patients with squamous cell cancer of the oropharynx. Cancer. 2019;125(5):704–11. 5. Edge SB, American Joint Committee on Cancer, editors. AJCC cancer staging manual. 7th ed. New York: Springer; 2010. 648 p. 6. Haughey BH, Sinha P. Prognostic factors and survival unique to surgically treated p16+ oropharyngeal cancer. Laryngoscope. 2012;122(Suppl2):S13–33. 7. Fakhry C, Zhang Q, Nguyen-Tan PF, Rosenthal D, El-Naggar A, Garden AS, et al. Human papillomavirus and overall survival after progression of oropharyngeal squamous cell carcinoma. J Clin Oncol. 2014;32(30):3365–73. 8. Trotti A, Pajak TF, Gwede CK, Paulus R, Cooper J, Forastiere A, et al. TAME: development of a new method for summarising adverse events of cancer treatment by the Radiation Therapy Oncology Group. Lancet Oncol. 2007;8(7):613–24. 9. Machtay M, Moughan J, Trotti A, Garden AS, Weber RS, Cooper JS, et  al. Factors associated with severe late toxicity after concurrent chemoradiation for locally advanced head and neck cancer: an RTOG analysis. J Clin Oncol. 2008;26(21):3582–9. 10. Hutcheson KA, Barrow MP, Barringer DA, Knott JK, Lin HY, Weber RS, et al. Dynamic Imaging Grade of Swallowing Toxicity (DIGEST): scale development and validation. Cancer. 2017;123(1):62–70. 11. Hutcheson KA, Barrow MP, Lisec A, Barringer DA, Gries K, Lewin JS. What is a clinically relevant difference in MDADI scores between groups of head and neck cancer patients? Laryngoscope. 2016;126(5):1108–13. 12. Levendag PC, Teguh DN, Voet P, van der Est H, Noever I, de Kruijf WJM, et al. Dysphagia disorders in patients with cancer of the oropharynx are significantly affected by the radiation therapy dose to the superior and middle constrictor muscle: a dose-effect relationship. Radiother Oncol. 2007;85(1):64–73. 13. Beetz I, Steenbakkers RJHM, Chouvalova O, Leemans CR, Doornaert P, van der Laan BFAM, et al. The QUANTEC criteria for parotid gland dose and their efficacy to prevent moderate to severe patient-rated xerostomia. Acta Oncol. 2014;53(5):597–604. 14. Gabryś HS, Buettner F, Sterzing F, Hauswald H, Bangert M. Parotid gland mean dose as a xerostomia predictor in low-dose domains. Acta Oncol. 2017;56(9):1197–203. 15. Chyan A, Chen J, Shugard E, Lambert L, Quivey JM, Yom SS. Dosimetric predictors of hypothyroidism in oropharyngeal cancer patients treated with intensity-modulated radiation therapy. Radiat Oncol. 2014;9:269. 16. Truong MT, Romesser PB, Qureshi MM, Kovalchuk N, Orlina L, Willins J. Radiation dose to the brachial plexus in head-and-neck intensitymodulated radiation therapy and its relationship to tumor and nodal stage. Int J Radiat Oncol Biol Phys. 2012;84(1):158–64. 17. Gelblum DY, Thompson M, Wolden SL, Schupak KD, Berry SL, Lee N.  Neck spasms: a late sequela of head and neck irradiation. Oral Oncol. 2016;57:e4–5. 18. Nonnekens J, Hoeijmakers JH.  After surviving cancer, what about late life effects of the cure? EMBO Mol Med. 2017;9(1):4–6.

19. Deschuymer S, Nevens D, Duprez F, Laenen A, Dejaeger E, De Neve W, et  al. Clinical factors impacting on late dysphagia following radiotherapy in patients with head and neck cancer. Br J Radiol. 2018;91(1088):20180155. 20. Lango MN, Egleston B, Ende K, Feigenberg S, D’Ambrosio DJ, Cohen RB, et  al. Impact of neck dissection on long-term feeding tube dependence in patients with head and neck cancer treated with primary radiation or chemoradiation. Head Neck. 2010;32(3):341–7. 21. Gane EM, Michaleff ZA, Cottrell MA, McPhail SM, Hatton AL, Panizza BJ, et  al. Prevalence, incidence, and risk factors for shoulder and neck dysfunction after neck dissection: a systematic review. Eur J Surg Oncol. 2017;43(7):1199–218. 22. Bonner JA, Harari PM, Giralt J, Cohen RB, Jones CU, Sur RK, 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. 23. Rosenthal DI, Harari PM, Giralt J, Bell D, Raben D, Liu J, et  al. Association of Human Papillomavirus and p16 status with outcomes in the IMCL-9815 phase III registration trial for patients with Locoregionally advanced oropharyngeal squamous cell carcinoma of the head and neck treated with radiotherapy with or without cetuximab. J Clin Oncol. 2016;34(12):1300–8. 24. Gillison ML, Trotti AM, Harris J, Eisbruch A, Harari PM, Adelstein DJ, et  al. Radiotherapy plus cetuximab or cisplatin in human papillomavirus-­ positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial. Lancet. 2019;393(10166):40–50. 25. Mehanna H, Robinson M, Hartley A, Kong A, Foran B, Fulton-Lieuw T, et al. Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-­ESCALaTE HPV): an open-label randomised controlled phase 3 trial. Lancet. 2019;393(10166):51–60. 26. Chera BS, Amdur RJ, Tepper J, Qaqish B, Green R, Aumer SL, et  al. Phase 2 trial of de-intensified chemoradiation therapy for favorable-­ risk human papillomavirus-associated oropharyngeal squamous cell carcinoma. Int J Radiat Oncol Biol Phys. 2015;93(5):976–85. 27. Chera BS, Amdur RJ, Tepper JE, Tan X, Weiss J, Grilley-Olson JE, et al. Mature results of a prospective study of deintensified chemoradiotherapy for low-risk human papillomavirus-­associated oropharyngeal squamous cell carcinoma. Cancer. 2018;124(11):2347–54. 28. O’Sullivan B, Huang SH, Perez-Ordonez B, Massey C, Siu LL, Weinreb I, et  al. Outcomes of HPV-related oropharyngeal cancer patients treated by radiotherapy alone using altered fractionation. Radiother Oncol. 2012;103(1):49–56. 29. Eisbruch A, Harris J, Garden AS, Chao CKS, Straube W, Harari PM, et al. Multi-institutional trial of accelerated hypofractionated intensity-modulated radiation therapy for early-stage oropharyngeal cancer (RTOG 00-22). Int J Radiat Oncol Biol Phys. 2010;76(5): 1333–8. 30. Expert Panel on Radiation Oncology--Head & Neck Cancer, Yeung AR, Garg MK, Lawson J, McDonald MW, Quon H, et al. ACR appropriateness criteria® ipsilateral radiation for squamous cell carcinoma of the tonsil. Head Neck. 2012;34(5):613–6. 31. Chin R-I, Rao YJ, Hwang MY, Spencer CR, Pierro M, DeWees T, et al. Comparison of unilateral versus bilateral intensity-modulated radiotherapy for surgically treated squamous cell carcinoma of the palatine tonsil. Cancer. 2017;123(23):4594–607. 32. Rackley TP, Namelo WC, Palaniappan N, Cole N, Owens DMJ, Evans M. Unilateral radiotherapy for surgically resected lateralized squamous cell carcinoma of the tonsil. Head Neck. 2017;39(1): 17–23. 33. Al-Mamgani A, van Werkhoven E, Navran A, Karakullukcu B, Hamming-­Vrieze O, Machiels M, et al. Contralateral regional recurrence after elective unilateral neck irradiation in oropharyngeal carcinoma: a literature-based critical review. Cancer Treat Rev. 2017;59:102–8.

309 Deintensification of Treatment for HPV-Associated Cancers of the Oropharynx

34. Nguyen A, Luginbuhl A, Cognetti D, Van Abel K, Bar-Ad V, Intenzo C, et al. Effectiveness of PET/CT in the preoperative evaluation of neck disease. Laryngoscope. 2014;124(1):159–64. 35. Lowe VJ, Duan F, Subramaniam RM, Sicks JD, Romanoff J, Bartel T, et al. Multicenter trial of [18F]fluorodeoxyglucose positron emission tomography/computed tomography staging of head and neck cancer and negative predictive value and surgical impact in the N0 neck: results from ACRIN 6685. J Clin Oncol. 2019;37:1704. https:// doi.org/10.1200/JCO.18.01182. 36. Huang SH, Waldron J, Bratman SV, Su J, Kim J, Bayley A, et  al. Re-­ evaluation of ipsilateral radiation for T1-T2N0-N2b tonsil carcinoma at the Princess Margaret Hospital in the Human Papillomavirus era, 25 years later. Int J Radiat Oncol Biol Phys. 2017;98(1):159–69. 37. Lee N, Schoder H, Beattie B, Lanning R, Riaz N, McBride S, et  al. Strategy of using intratreatment hypoxia imaging to selectively and safely guide radiation dose de-escalation concurrent with chemotherapy for locoregionally advanced human papillomavirus-­ related oropharyngeal carcinoma. Int J Radiat Oncol Biol Phys. 2016;96(1):9–17. 38. Riaz N, Sherman E, Katabi N, Leeman JE, Higginson DS, Boyle JO, et  al. A personalized approach using hypoxia resolution to guide curative-intent radiation therapy dose-reduction to 30 Gy: a novel de-escalation Paradigm for HPV-associated oropharynx cancers treated with concurrent chemoradiation therapy. Int J Radiat Oncol. 2017;99(2):S136. 39. Löck S, Perrin R, Seidlitz A, Bandurska-Luque A, Zschaeck S, Zöphel K, et al. Residual tumour hypoxia in head-and-neck cancer patients undergoing primary radiochemotherapy, final results of a prospective trial on repeat FMISO-PET imaging. Radiother Oncol. 2017;124(3):533–40. 40. Bristow RG, Hill RP. Hypoxia and metabolism. Hypoxia, DNA repair and genetic instability. Nat Rev Cancer. 2008;8(3):180–92. 41. Rischin D, Young RJ, Fisher R, Fox SB, Le Q-T, Peters LJ, et  al. Prognostic significance of p16INK4A and human papillomavirus in patients with oropharyngeal cancer treated on TROG 02.02 phase III trial. J Clin Oncol. 2010;28(27):4142–8. 42. Toustrup K, Sørensen BS, Lassen P, Wiuf C, Alsner J, Overgaard J, et al. Gene expression classifier predicts for hypoxic modification of radiotherapy with nimorazole in squamous cell carcinomas of the head and neck. Radiother Oncol. 2012;102(1):122–9. 43. Chen AM, Felix C, Wang P-C, Hsu S, Basehart V, Garst J, et  al. Reduced-dose radiotherapy for human papillomavirus-associated squamous-cell carcinoma of the oropharynx: a single-arm, phase 2 study. Lancet Oncol. 2017;18(6):803–11. 44. Marur S, Li S, Cmelak AJ, Gillison ML, Zhao WJ, Ferris RL, et al. E1308: phase II trial of induction chemotherapy followed by reduced-dose

23

radiation and weekly cetuximab in patients with HPV-associated resectable squamous cell carcinoma of the oropharynx- ECOGACRIN Cancer Research Group. J Clin Oncol. 2017;35(5):490–7. 45. Villaflor VM, Melotek JM, Karrison TG, Brisson RJ, Blair EA, Portugal L, et  al. Response-adapted volume de-escalation (RAVD) in  locally advanced head and neck cancer. Ann Oncol. 2016;27(5):908–13. 46. Seiwert T, Melotek JM, Foster CC, Blair EA, Karrison TG, Agrawal N, et  al. OPTIMA—A phase 2 trial of induction chemotherapy response-stratified radiation therapy dose and volume de-­ escalation for HPV+ oropharyngeal cancer: efficacy, toxicity, and HPV subtype analysis. Int J Radiat Oncol. 2018;100(5):1309. 47. Cohen EEW, Karrison TG, Kocherginsky M, Mueller J, Egan R, Huang CH, et al. Phase III randomized trial of induction chemotherapy in patients with N2 or N3 locally advanced head and neck cancer. J Clin Oncol. 2014;32(25):2735–43. 48. Haddad R, O’Neill A, Rabinowits G, Tishler R, Khuri F, Adkins D, et al. Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in  locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial. Lancet Oncol. 2013;14(3):257–64. 49. Parsons JT, Mendenhall WM, Stringer SP, Amdur RJ, Hinerman RW, Villaret DB, et al. Squamous cell carcinoma of the oropharynx: surgery, radiation therapy, or both. Cancer. 2002;94(11):2967–80. 50. Adelstein DJ, Ridge JA, Brizel DM, Holsinger FC, Haughey BH, O’Sullivan B, et  al. Transoral resection of pharyngeal cancer: summary of a National Cancer Institute Head and Neck Cancer Steering Committee clinical trials planning meeting, November 6-7, 2011, Arlington, Virginia. Head Neck. 2012;34(12):1681–703. 51. Kelly JR, Park HS, An Y, Yarbrough WG, Contessa JN, Decker R, et al. Upfront surgery versus definitive chemoradiotherapy in patients with human papillomavirus-associated oropharyngeal squamous cell cancer. Oral Oncol. 2018;79:64–70. 52. Nasser H, St John M. Immunotherapeutic approaches to head and neck cancer. Crit Rev Oncog. 2018;23(3–4):161–71. 53. Orosco RK, Arora A, Jeanon JP, Holsinger FC.  Next-generation robotic head and neck surgery. ORL J Otorhinolaryngol Relat Spec. 2018;80(3–4):213–9. 54. Wang L, Wang X, Li Y, Han S, Zhu J, Wang X, et al. Human papillomavirus status and the relative biological effectiveness of proton radiotherapy in head and neck cancer cells. Head Neck. 2017;39(4):708–15. 55. Langendijk JA, Steenbakkers RJHM.  Optimizing radiotherapy in HPV-associated oropharyngeal cancer patients. Recent Results Cancer Res. 2017;206:161–71.

311

Treatment of the Neck Robert M. Brody and Terry A. Day 24.1

Introduction – 312

24.2

History of Neck Dissection – 312

24.2.1 24.2.2 24.2.3

 adical Neck Dissection – 312 R Modified Radical Neck Dissection – 313 Selective Neck Dissection (Specific Consideration to Supraomohyoid) – 313

24.3

Important Terminology in Neck Dissection – 314

24.3.1 24.3.2 24.3.3

L evels of the Neck – 314 Staging of the Neck by AJCC Criteria – 314 Classifications of Neck Dissection – 314

24.4

Indications for Neck Dissection in Oral Cavity Cancer – 315

24.4.1 24.4.2 24.4.3

T herapeutic Neck Dissection – 316 Elective Neck Dissection for Squamous Cell Carcinoma – 318 Neck Dissection for Non-Squamous Cell Carcinoma Pathology – 320

24.5

Indications for Neck Dissection in Oropharynx Cancer – 321

24.6

Structures to be Resected/Preserved – 321

24.6.1 24.6.2 24.6.3 24.6.4 24.6.5

S ubmental Triangle (Level IA) – 321 Submandibular Triangle (Level IB) – 322 Jugulodigastric Chain – 322 Posterior Triangle – 323 Transcervical Approaches to the Oral Cavity and Oropharynx – 324

24.7

Conclusions – 324 References – 324

© Springer Nature Switzerland AG 2020 S. Warnakulasuriya, J. S. Greenspan (eds.), Textbook of Oral Cancer, Textbooks in Contemporary Dentistry, https://doi.org/10.1007/978-3-030-32316-5_24

24

312

R. M. Brody and T. A. Day

Core Message Neck dissection has evolved from a radical resection to a more conservative operation targeting the highest risk cervical lymphatics while sparing surrounding neurovascular structures. The location of the primary site of malignancy, the pathology of that malignancy, and the clinical and radiographic nodal burden will help predict whether a neck dissection is required. Selective neck dissection involving levels I–III has become the standard operation for oral cavity cancers that warrant a neck dissection, while levels II–IV have become standard levels to dissect for oropharyngeal cancers. Additional levels may be added to these selective neck dissections in order to more aggressively stage the patient or more aggressively treat the patient as indicated. Neck dissection provides a transcervical approach to oral cavity and oropharynx tumors which require increased exposure to achieve adequate margins. Neck dissection results in the identification of important structures, including the extrinsic tongue musculature, the mandible, and the pharynx and more proximal aspects of the hypoglossal nerve, lingual nerve, lingual artery, and facial artery. These structures may be preserved or sacrificed as needed for complete tumor extirpation to optimize survival and improve quality of life.

24.1 

Introduction

Neck management of oral cavity cancers is critical to provide the best outcomes and survival. It is important that consideration be given to evaluating and treating the neck, even with the smallest of tongue and floor of mouth cancers. The American Joint Committee on Cancer (AJCC) staging system, Eight Edition, for oral cancers incorporates depth of invasion (DOI) as a variable in staging of the primary site which is useful in predicting occult nodal metastasis [1]. With a high rate of regional metastases, appropriate management of the neck is crucial in the treatment of all oral cavity cancers. Understanding the risk of metastasis to the neck in different cancers or the oral cavity and oropharynx allows the head and neck cancer specialist to electively treat the clinically negative neck when appropriate. In the electively treated neck and the clinically positive neck, the extent of dissection is dependent on the identification of structures that must be resected and those that should be preserved. A detailed discussion defining discrete node-bearing regions of the neck and the indications for when and how to dissect those regions will be elaborated during this chapter. 24.2 

24

History of Neck Dissection

Historically, neck dissection has evolved from a philosophy of removing all structures in the region to the current state of selectively removing only node-bearing tissue while preserving all non-involved structures. Radical neck dissection

..      Table 24.1  Classification of neck dissection [2] Neck dissection term

Levels dissected

Structures sacrificed

Radical neck dissection

I, II, III, IV, V

Internal jugular vein, sternocleidomastoid muscle, spinal accessory nerve

Modified radical neck dissection

I, II, III, IV, V

One or all of the above structures preserved

Selective neck dissection

Less levels than I–V. Each variation formally described by the levels removed (i.e., SND 2–4)

All structures preserved

(a) Supraomohyoid

SND (I, II, III)

All structures preserved

(b) Lateral

SND (II, III, IV)

All structures preserved

(c) Posterolateral

SND (II, III, IV, V)

All structures preserved

(d) Anterior

SND (VI)

All structures preserved

Extended neck dissection

Additional lymph node levels (i.e., suboccipital)

Additional structures resected (i.e., carotid artery)

Modified from Robbins et al. (2002)

(RND) was the early terminology for all neck dissections but is rarely used in the twenty-first century. The following descriptions provide the reader with the evolution of this procedure over time supporting the role of more conservative techniques used in recent years (. Table 24.1).  

!!Warning It is important to consider recommendations regarding the boundaries between levels I and II and between levels III/IV and VI and the terminology of the superior mediastinal nodes.

24.2.1 

Radical Neck Dissection

The surgical treatment of cervical lymphatics in head and neck cancer became feasible in the mid-nineteenth century with the advent of improved anesthesia and surgical techniques. Incomplete descriptions of cervical lymphadenectomy were described by multiple European surgeons in the late 1800s, including the prominent surgeons Billroth and Kocher [3]. The first complete description of an en bloc neck dissection can be found in the Polish literature and was published by Franciszek Jawdynski in 1881 [4]. In the early twen-

313 Treatment of the Neck

tieth century, neck dissection was popularized by George Crile of the Cleveland Clinic who described a series of 132 neck dissections in 1906 [5]. Crile’s publication documented his approach to neck dissection described as an en bloc resection of cervical lymphatics in continuity with the primary tumor. This approach is similar in philosophy to the approach espoused by Crile’s contemporary, William Halsted, for the treatment of breast cancer. Crile’s descriptions and drawings included a full spectrum of cervical lymphadenectomy procedures ranging from a radical neck dissection to a more limited supraomohyoid neck dissection [5]. Throughout the early twentieth century, surgeons became more facile with neck dissection techniques, and these procedures became widespread. In 1951, Hayes Martin of Memorial Hospital in New York presented 599 neck dissections which involved dissection of levels I through V including resection of the sternocleidomastoid (SCM), internal jugular vein (IJV), and spinal accessory nerve [6]. This standardized lymphadenectomy, referred to as a radical neck dissection, was the default procedure for patients with regional metastases to the neck. At the time, it was felt that a radical neck dissection was the only approach that could safely ensure all node-bearing tissue was removed. 24.2.2 

Modified Radical Neck Dissection

While surgeons of the early twentieth century predominantly utilized radical neck dissection in their practice, many began to perform more limited dissections that did not result in the same functional and aesthetic morbidity as well as mortality associated radical neck dissection. Throughout the mid-­twentieth century, continued reports of modifications to the radical neck dissection were published and became more formalized. Bocca and Pignataro, in a 1967 publication, described a series of 90 patients who underwent a “conservation neck dissection” or “functional neck dissection” which would today be described as a modified radical neck dissection (MRND) [7]. After discussing the anatomy of the cervical fascia described by Truffert in the 1920s, they describe a more conservative neck dissection which may spare the sternocleidomastoid muscle, jugular vein, and spinal accessory nerve as long as there is a fascial plane separating each structure from the tumor. After this landmark publication, additional studies continued to show similar results, including Jesse et  al., who reviewed 300 neck dissections that spared the spinal accessory nerve, and Chu et al., who reviewed 261 patients who had no difference in outcomes whether a radical or a modified radical neck dissection was performed [8, 9]. In a “Surgical Grand Rounds” paper from Memorial Hospital in 1981, the progression from radical neck dissection in the 1950s, as described by Martin, to modified radical neck dissection in the 1980s is outlined [10]. The mid-twentieth century resulted in a transition from radical resection of surrounding muscle and neurovasculature in the neck to a more focused approach on the cervical lymphatics and the

fascia that envelops them. The late-twentieth century was marked by a transition from the modified radical neck dissection to the selective neck dissection. 24.2.3 

 elective Neck Dissection (Specific S Consideration to Supraomohyoid)

The selective neck dissection gained popularity in the late twentieth century as multiple surgeons began to evaluate whether a comprehensive removal of the entirety of the cervical lymphatics was required to achieve local and regional control in head and neck cancers. The unique distribution of neck metastases from the different subsites of the upper aerodigestive tract was outlined in a series of 2044 patients from MD Anderson in 1972 [11]. Additional studies helped to define specific regions of the neck that required dissection and excision to achieve acceptable rates of regional control. The posterior triangle was shown to have a low rate of regional metastases with one study showing no involvement of the posterior triangle in a series of 50 elective and therapeutic neck dissections [12]. A suprahyoid neck dissection involving only the submandibular triangle but omitting the jugulodigastric chain was deemed to be inadequate as there were higher rates of regional recurrence in a series of 261 patients [9]. The “regional neck dissection” espoused by Ballantyne at MD Anderson in the 1970s involves tailoring the extent of neck dissection to the specific primary site of the tumor. An early study, following a retrospective cohort of greater than 400 patients at MD Anderson, showed comparable rates of control in these regional neck dissections compared to modified radical and radical neck dissections [8]. These “various types of modified radical neck dissections” were further defined by Byers in his description of approximately 1000 neck dissections performed at MD Anderson from 1970 to 1980 [13]. In this paper, the supraomohyoid (levels I, II, III) and anterior (levels II, III, IV) neck dissections are described. Additional study demonstrated specific patterns of occult spread along the submaxillary lymph nodes and upper jugulodigastric chain during elective neck dissection in N0 disease of the oral cavity [14]. This same pattern of regional spread was further demonstrated at Memorial Sloan Kettering Cancer Center among 1081 patients over a 20-year period. After looking at the patterns of spread in over 1000 radical neck dissection specimens, Shah recommended that, when an elective neck dissection is indicated, a supraomohyoid neck dissection should be performed for oral cavity cancers, and an anterolateral neck dissection (similar to Byer’s anterior neck dissection) should be performed for oropharynx cancers [15]. Over a 100-year period of time, a progression of more radical surgery to more conservative surgery occurred in the treatment of the neck for oral cavity and oropharynx cancers. In the late twentieth century and early twenty-first century, these operations would be further standardized and defined for the purposes of improved communication and ­higher-­quality research.

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24.3 

Important Terminology in Neck Dissection

As the use of neck dissection expanded among surgeons in the twentieth century, so did the use of varying terms to describe the location of cervical lymphatics and the method by which those lymphatics were removed from the neck. At the end of the twentieth century and the beginning of the twenty-first century, a concerted effort among the head and neck surgery and oncology community resulted in standardized terms for the location of lymph nodes within the neck as well as standardized terms for the different types of neck dissections that can be performed. 24.3.1 

Levels of the Neck

Lymph nodes and their associated lymphatic channels can be found running throughout the fibrofatty regions of the neck. The French anatomist Henri Rouvière in his seminal work Anatomy of the Human Lymphatic System described the rich lymphatic system of the neck using topographical anatomy that is still used today [16]. Further study showed the specific patterns of spread from the upper aerodigestive tract to the cervical lymphatics but often required more complex terms or detailed drawings [11]. Though topographical anatomy provides information about the location of a given cervical lymph node, these terms may vary from author to author and result in difficulty compiling data across institutions. The Memorial Sloan Kettering group outlined their diagrammatic representation of cervical lymph nodes by level in a 1981 publication [10]. These levels were ultimately adopted by the Committee for Head and Neck Surgery and Oncology of the American Academy of Otolaryngology–Head and Neck Surgery (AAO-HNS) [17]. The addition of a seventh level as well as refinement of the original six levels occurred during future meetings resulting in more descriptive anatomic boundaries and subdivisions of level I, II, and V [2, 18] (. Table 24.2).  

24.3.2 

24

Staging of the Neck by AJCC Criteria

In addition to the location of lymph nodes within the neck, it is of paramount importance to clearly define the burden of regional lymph node metastases in each patient diagnosed with head and neck cancer. The American Joint Committee on Cancer (AJCC) staging criteria stratifies patients into different groups based upon the degree of regional lymphatic spread which ultimately informs the overall stage of that patient’s cancer. Early studies showed that lymph node burden and distribution impacted outcomes [19, 20]. The AJCC system takes into account lymph node size, number, and laterality to separate patients into different groups. The most recent AJCC Cancer Staging Manual, Eight Edition, also takes into account

additional factors including extracapsular spread and human papillomavirus positivity which have both been shown to influence prognosis in head and neck cancer [1] (. Table 24.3).  

>>Important Standardization of terminology for neck dissection is important for communication among clinicians and researchers.

24.3.3 

Classifications of Neck Dissection

As the approach to dissection evolved from a radical procedure to a more selective procedure, multiple terms were coined by different authors. Different terms were used to describe the same procedure, while the same term sometimes described two different procedures. The Committee for Neck Dissection Classification of the American Head and Neck Society and the Committee for Head and Neck Surgery and Oncology of the AAO-HNS have come to a consensus regarding appropriate neck dissection nomenclature [18]. A radical neck dissection (RND) includes the removal of levels I through V.  By definition, this also involves the removal of the sternocleidomastoid muscle, internal jugular vein, and spinal accessory nerve. A radical neck dissection also includes removal of the submandibular gland (SMG) and often intraparotid nodes within the posterior aspect of the submandibular triangle. An extended radical neck dissection includes additional lymph node groups such as the suboccipital triangle, retropharyngeal nodes, superior mediastinal nodes, or paratracheal nodes as well as nonlymphatic structures such as muscles or nerves that have been directly invaded by tumor. A modified radical neck dissection (MRND) also involves the removal of levels I through V but preserves at least one of the nonlymphatic structures removed in a radical neck dissection. It is advised that when performing a MRND, the preserved structures should be specifically named. A selective neck dissection (SND) refers to a cervical lymphadenectomy in which there is preservation of one or more lymph node levels which are removed in a RND. Most elective and even therapeutic neck dissections performed today are selective neck dissections sparing level V. As discussed previously, level V can be preserved for the majority of upper aerodigestive squamous cell carcinomas (SCC) as there is a low propensity for metastasis to this region [12, 15]. It is recommended that the levels dissected be written in parenthesis after the term SND in order to provide an accurate account of the surgery. Although writing in each level dissected for a SND is preferred, the supraomohyoid neck dissection and anterolateral neck dissection are two variations which merit further discussion. The supraomohyoid neck dissection was the term previously used to signify a SND (levels I, II, III) which is commonly utilized in the setting of an elective neck dissection for oral cavity cancer. The anterolateral neck dissection is a SND (levels II, III, IV) uti-

315 Treatment of the Neck

..      Table 24.2  Delineation of nodal levels in the electively treated neck based upon anatomic boundaries [2, 17, 18] Level

Superior

Inferior

Anterior/medial

Posteriorateral

Deep

IA

Inferior border of the mandible

Hyoid bone

Anterior belly contralateral digastric muscle

Anterior belly of ipsilateral digastric muscle

Mylohyoid muscle

IB

Inferior border of the mandible

Posterior belly of digastric muscle

Anterior belly of ipsilateral digastric muscle

Stylohyoid muscle

Hyoglossus muscle

IIA

Skull base

Inferior edge of hyoid

Posterior border of SMG or stylohyoid muscle

Spinal accessory nerve and deep surface of the SCM

Levator scapulae and splenius capitis

IIB

Skull base

Inferior edge of the hyoid

Spinal accessory nerve and internal jugular vein

Deep surface of the SCM

Levator scapulae and splenius capitis

III

Inferior edge of the hyoid

Inferior edge of the cricoid and transverse plane at which omohyoid crosses IJV

Lateral border of the sternohyoid muscle

Deep surface of the SCM and sensory branches of the cervical plexus

Scalene muscles and levator scapulae

IV

Inferior edge of the cricoid and transverse plane at which omohyoid crosses IJV

Clavicle/transverse cervical vessels

Lateral border of the sternohyoid muscle

Deep surface of SCM and sensory branches of the cervical plexus

Scalene muscles and levator scapulae

Va

Apex of the convergence of the sternocleidomastoid and trapezius muscles

Horizontal plane defined by the lower border of the cricoid cartilage

Posterior border of the SCM and/or sensory branches of the cervical plexus

Anterior border of the trapezius

Scalene muscles and levator scapulae

Vb

Horizontal plane defined by the lower border of the cricoid cartilage

Clavicle

Posterior border of the SCM and/or sensory branches of the cervical plexus

Anterior border of the trapezius

Scalene muscles and levator scapulae

VI

Hyoid bone

Subclavian artery/ innominate artery

Trachea

Common carotid artery/carotid sheath

Anterior scalene muscle and longus colli muscle

Adapted from Robbins et al. (1991, 2002, 2008)

lized in the setting of an elective neck dissection for oropharyngeal cancer as well as laryngeal and hypopharyngeal cancers. Lastly, a super selective neck dissection involves the removal of one to two contiguous neck levels. Although this surgery is not indicated as a primary method for therapeutic or elective neck dissection, it is useful in salvage surgery after primary chemoradiation to limit dissection in a radiated field. 24.4 

I ndications for Neck Dissection in Oral Cavity Cancer

Cervical lymphadenectomy allows for therapeutic treatment of clinically evident nodal metastases during the excision of the primary oral cavity tumor or as a staged procedure. In the N0 neck, it allows for the removal of occult disease. It addi-

tionally provides pathologic staging of the cervical lymphatics which informs adjuvant therapy. Unfortunately, when a patient initially presents with a lesion in the oral cavity, it is unknown if it is benign, premalignant, or malignant until a biopsy is performed. Even with a biopsy, the tissue removed and sent to the pathologist may not represent the entire lesion. The surgeon must be prepared for a lesion of the oral cavity to have various components including various grades of dysplasia, carcinoma in situ, and invasive squamous cell carcinoma. The new staging system also incorporates both surface area measurements and depth of invasion (DOI) which can confuse the surgeon if the initial biopsy did not include the deepest part of the lesion. In this scenario, the final DOI and need to treat the neck may not be fully known until after the pathology is finalized from an excision of the primary site. The following algorithm is used by the authors to evaluate and manage the neck in early oral cancer (. Fig. 24.1).  

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..      Table 24.3  AJCC cervical lymph node staging system N category

Clinical criteria

Pathologic criteria

Nx

Regional lymph nodes cannot be assessed

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

No regional lymph node metastasis

N1

Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension and ENE (−)

Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension and ENE (−)

N2

Metastasis in a single ipsilateral node larger than 3 cm, but not larger than 6 cm in greatest dimension and ENE (−); or in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest dimension and ENE (−)

Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension and ENE (+); or larger than 3 cm, but not larger than 6 cm in greatest dimension and ENE (−); or metastases in multiple ipsilateral lymph nodes, none larger than 6 cm in greatest dimension and ENE (−);or in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest dimension and ENE (−)

N2a

Metastasis in a single ipsilateral node larger than 3 cm, but not larger than 6 cm in greatest dimension and ENE (−)

Metastasis in a single ipsilateral or contralateral node 3 cm or smaller in greatest dimension and ENE (+); or a single ipsilateral node larger than 3 cm, but no larger than 6 cm in greatest dimension and ENE (−)

N2b

Metastasis in multiple ipsilateral nodes, none larger than 6 cm in greatest dimension and ENE (−)

Metastasis in multiple ipsilateral nodes, none larger than 6 cm in greatest dimension and ENE (−)

N2c

Metastasis in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest dimension and ENE (−)

Metastasis in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest dimension and ENE (−)

N3

Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE (−) or metastasis in any node (s) and clinically overt ENE [ENE (+)]

Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE (−) or in a single ipsilateral node larger than 3 cm in greatest dimension and ENE (+)

N3a

Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE (−)

Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE (−)

N3b

Metastasis in any node(s) and ENE (+)

Metastasis in a single ipsilateral node larger than 3 cm in greatest dimension and ENE (+) or multiple ipsilateral, contralateral, or bilateral nodes, any with ENE (+)

Note: A designation of “U” or “L” may be used for any N category to indicate metastasis above the lower border of the cricoid (U) or below the lower border of the cricoid (L) Similarly, clinical and pathologic ENE should be recorded as ENE (−) or ENE (+) Used with permission of the American College of Surgeons, Chicago, Illinois. The original and primary source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017), published by Springer International Publishing

Eyecatcher

Decisions regarding the elective and therapeutic management of cervical lymph node metastases are made mainly on clinical findings in the neck as it is always difficult to predict cervical lymph node metastasis from the size and extent of invasion of the primary tumors.

24.4.1 

24

Therapeutic Neck Dissection

Therapeutic neck dissection implies there is known cancer in the cervical nodes, and they are removed to therapeutically treat rather than stage or diagnose the neck. The role of the

therapeutic neck dissection is to surgically excise all regional metastases. Accordingly, the type of neck dissection required must be tailored to the regional metastases that are present. Although a radical neck dissection may be necessary for bulky neck disease which has invaded the internal jugular vein, sternocleidomastoid, and spinal accessory nerve, this type of regional spread is fortunately uncommon. The radical neck dissection is, thus, uncommon in modern head and neck practice. A modified neck dissection may be utilized for bulky lymphadenopathy which has invaded the internal jugular vein, sternocleidomastoid muscle, or spinal accessory nerve in order to remove all tumors within the neck. The more commonly seen clinical scenario involves N1 or greater disease within the neck without clinical or radiographic signs of spread beyond the cervical lymphatics.

317 Treatment of the Neck

Oral cavity lesion

Low risk findings: Thin T1 Tongue/FOM/buccal lesion Maxilla, upper/lower Alveolus Lesion without bone invasion

No bony erosion, no significant depth, no pathologic LAD

DOI T1 lesion in oral tongue or Floor of mouth Palpable depth in oral tongue or floor of mouth Female Sex

Imaging

Mandible invasion, deep invasion, Pathologic LAD – necrotic/enlarged

Biopsy

Depth of invasion > 4mm Poorly differentiated

Surgical management

Observation

Need for neck exposure due to regional flap or free tissue transfer for vessel exploration

Neck dissection

..      Fig. 24.1  Algorithm for neck dissection in oral cavity cancer

The selective neck dissection is currently the most common type of neck dissection used for the treatment of oral cavity cancer with regional metastatic disease. Studies from the late twentieth century have reported regional recurrence rates of 10–24% utilizing selective neck dissection [13, 21, 22]. These large retrospective case series provided a benchmark that further research has attempted to improve upon into the twenty-first century. It is important to note that radiation therapy and chemotherapy protocols each evolved as neck dissection techniques evolved throughout the twentieth century. The outcomes listed in studies from the 1980s and 1990s include a mix of patients who received either preoperative radiation therapy or postoperative radiation therapy [15, 13, 23]. The presence of extracapsular extension and increased nodal burden were noted to result in worse outcomes and informed the need for additional adjuvant radiation [24]. Trends toward postoperative radiation or chemoradiation dictated by these adverse pathologic features have resulted in improved regional control when selective neck dissection is performed [25, 26]. The landmark studies

by the European Organization for Research and Treatment of Cancer (EORTC) and Radiation Therapy Oncology Group (RTOG) helped to standardize the indications for postoperative chemoradiation further [27, 28]. In the setting of a primary oral cavity cancer with clinically evident regional lymphatic spread, it is the author’s preference to perform a selective neck dissection of levels IA, IB, IIA, IIB, III, and IV. Adjuvant radiotherapy or chemoradiotherapy is then given depending on the final pathology of the surgical specimen. A modified radical neck dissection would be performed if lymphadenopathy extended into level V.  An extended neck dissection of the previously described ­selective dissection would be performed to the spinal accessory nerve, internal jugular vein, or sternocleidomastoid muscle if gross invasion was noted preoperatively or intraoperatively. Not uncommonly, a level I node is noted to be invading the mandible and may appear contiguous with the primary tumor. It is the authors practice to incorporate the cervical lymphatics with the specimen en bloc in this scenario.

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In the event of carotid artery invasion, a balloon test occlusion (BTO) is performed to provide preoperative counseling to the patient and assist with operative planning. Early experience with carotid artery sacrifice in head and neck cancer showed unacceptable outcomes regarding perioperative cerebrovascular accident and mortality at 45% and 30%, respectively [29]. Biller and colleagues showed decreased rates of cerebrovascular injury and mortality and improved outcomes with carotid resection [30]. Over the years, techniques in vascular surgery, interventional radiology, and reconstructive surgery have improved. Carotid reconstruction is now routinely performed at many centers using autologous vein grafts. Interventional radiologists, neurologists, and neurosurgeons now perform angiography and additional preoperative testing including BTO to assess blood flow and intervene on occluded grafts. Microvascular free tissue transfer provides musculocutaneous cover over the repaired carotid in these complex ablative defects. A recent study by Mourad et al. has shown a 3.9% rate of vascular accident in the immediate postoperative period and an overall 2-year survival of 82% [31]. In patients with carotid involvement, we offer a carotid resection with vascular reconstruction after a frank discussion with the patient regarding the significant risks and benefits related to their advanced disease. 24.4.2 

24

 lective Neck Dissection E for Squamous Cell Carcinoma

Elective neck dissection implies that although there are no clinically detectable regional lymph nodes, there is a suspicion that occult microscopic regional metastases may be present. Thus, the neck dissection is performed to diagnose and stage the neck. If cancer was present, the type of neck dissection that was originally performed should ideally have resulted in a therapeutic neck dissection that removed all nodal tissue at risk of harboring metastatic disease. In the setting of oral cavity cancer without clinically apparent regional disease, there has always been controversy over the management of the neck. The decision to perform an elective neck dissection is based upon the pathology of the primary tumor as well as its subsite within the oral cavity. The alternative to elective neck dissection has historically been “watchful waiting” with possible therapeutic neck dissection in the event of recurrence. Additional research has investigated the role of sentinel lymph node biopsy (SLNB) to determine whether a neck dissection is indicated. While surgery is the primary treatment modality for the majority of oral cavity cancers, the treatment of the N0 neck is less well-defined. When radical surgery was popular in the early twentieth century, large groups of patients were treated with extirpation of their primary tumor and radical neck dissection to clear any clinically evident or occult regional metastases. As radical surgery gave way to more conservative methods in the late twentieth century, a more nuanced approach to elective dissection evolved. This approach placed importance on the risk of occult nodal metastasis and where

those metastases might be harbored. A discussion with the patient would then include the risk of occult regional disease, the extent of neck dissection required, and the morbidity associated with that neck dissection. While many authors feel that rates of occult disease greater than 20% are an indication for elective neck dissection, the risk that a patient is willing to accept varies depending on many different factors. Early studies did not show a significant difference in survival for patients treated with elective neck dissection versus therapeutic neck dissection (which would occur after regional recurrence to salvage the patient) [32, 33]. More recent analyses have shown better outcomes when elective neck dissection is performed. An elective neck dissection can more accurately stage the patient’s neck and inform whether he or she requires adjuvant radiation or chemoradiation. This approach ultimately decreases recurrence rates and results in better survival [34, 35, 36]. If elective neck dissection is not performed, the cancer may be deemed unresectable if it recurs regionally. Additional study has also shown that salvage neck dissection provides worse regional control than upfront elective neck dissection [37, 38, 35, 36]. It is therefore important to know when an elective neck dissection is indicated for oral cavity squamous cell carcinomas and which levels need to be dissected. The rate of occult and clinical metastases is known to be directly associated with increasing tumor stage [39, 37, 40, 41, 42, 43]. This rate varies from subsite to subsite within the oral cavity. The location of the primary tumor also dictates whether lymphatic spread will be primarily ipsilateral or whether there is a risk for spread to the contralateral neck [40]. In squamous cell carcinoma of the lip, there is a high rate of cure at approximately 90% and a low rate of regional metastasis. Occult and clinical metastases to the neck are associated with worse survival. Tumor size greater than 3 cm, grade IV histology, and local recurrence are all predictors of regional recurrence; however, this rate is still below 10% [44]. Neck dissection in cancer of the lip should be considered in cases with clinically positive nodal disease or in patients with large, aggressive tumors. More extensive literature exists for cancers of the oral tongue and floor of the mouth (FOM) due to their increased prevalence compared to other subsites. The rich lymphatic channels and vascularity of these subsites predispose them to regional metastatic spread. T2 lesions of these subsites have been shown to harbor occult metastases in greater than 20% of patients. A bilateral neck dissection is warranted for midline lesions, especially for lesions of the floor of the mouth [40]. With the additional risk of a bilateral elective neck ­dissection, appropriately stratifying a patient’s likelihood of harboring occult metastatic disease is imperative. In earlier tumor stage lesions, additional variables associated with the primary tumor have been sought to predict which patients require an elective neck dissection In oral cavity cancers, deep ulceration and deep infiltration have been shown to be important factors in the risk for neck metastases [39]. Two objective measures for tumor

319 Treatment of the Neck

infiltration that are quantified by pathologic analysis are tumor thickness and depth of invasion. Tumor thickness is meant to measure the distance between the surface of the tumor and the deepest extent of the infiltrative ulcer. Depth of invasion (DOI) measures the deepest extent of invasion beyond the mucosal basement membrane. DOI requires the creation of a horizontal plane connecting two regions of intact squamous mucosa adjacent to the tumor, since the basement membrane is often distorted or destroyed by the invasive front of squamous cell carcinomas. A “plumb line” is then dropped from that horizon to the deepest extent of invasion [1]. Despite their differing definitions, these two terms are often used interchangeably in the literature. Depth of invasion has been utilized by the AJCC since its Sixth Edition, and the more recent Eight Edition utilizes depth of invasion as a variable in determining tumor stage (. Table 24.4) [1]. Additional analyses have shown that either tumor thickness or depth of invasion can provide helpful prognostic value in the event that an institution uses one measure more consistently than the other [45]. The first report which described tumor thickness as predictive of occult nodal metastases in oral tongue and floor of the mouth squamous cell carcinoma stratified patients into three groups consisting of thickness less than 2  mm and greater than 2 mm [46]. Fukano et al. determined that 5 mm was the significant cutoff in an analysis of 34 patients in 1997 [47]. In 2004, Sparano et al. performed a multivariate analysis of 45 patients and identified multiple factors associated with occult nodal disease. These factors included tumor thickness greater than 4  mm, perineural invasion (PNI), angiolymphatic invasion, an infiltrative invasive front, and  

..      Table 24.4  T Category for oral cavity cancer, Eight Edition, staging manual T category

T criteria

Tx

Primary tumor cannot be assessed

Tis

Carcinoma in situ

T1

Tumor