2017 ESMO Essentials For Clinicians Head Neck Cancers

www.esmo.org www.esmo.
org
Lisa Licitra · Michalis V Karamouzis

edited by
HEAD & NECK HEAD & NECK

Lisa Licitra
Michalis V Karamouzis
CANCERS CANCERS
E S S E N T I A L S forC L I N I C I A N S E S S E N T I A L S forC L I N I C I A N S
HEAD & NECK CANCERS

Sinus
Nasal cavity
Salivary
glands
Nasopharynx Oral cavity

edited by
Lisa Licitra & Michalis V Karamouzis Oropharynx
Hypopharynx
Head & Neck Cancers is part of the “Essentials for Clinicians” series
produced by the European Society for Medical Oncology (ESMO). Head Oesophagus Larynx
and neck tumours are the seventh most common cancer type worldwide
and are associated with several risk factors. This book provides the Trachea
most clinically relevant and updated information for optimal prevention,

diagnosis and treatment of this heterogeneous group of tumours.
Head & Neck Cancers: Essentials for Clinicians is structured into
a section covering the basics of what every oncologist should know
and a section providing more advanced information and novel
developments. The high quality illustrations and clear structure
make the book an easy-to-use and accessible source of knowledge,
E S S E N T I A L S forC L I N I C I A N S
and provide a balanced and up-to-date knowledge of the Radiation Medical

Oncologist Oncologist
current state of the art for students and physicians interested
in cancers of the head and neck. Head
Nutritionist and Neck
Surgeon
Swallowing
expert patient Pathologist
Radiologist Psychologist
Social
Dentist Worker
Nurse
ESMO Press
ISBN 978-88-941795-2-1
ESMO Press · ISBN 978-88-941795-2-1
ESMO Press ESMO Press
9 788894 179521
Head & Neck Cancers
Essentials for Clinicians
Head & Neck Cancers
Essentials for Clinicians
Edited by
Lisa Licitra
Head and Neck Cancer Medical Oncology Department,
Fondazione IRCCS “Istituto Nazionale dei Tumori”, Milan;
Università degli Studi Milano, Milan, Italy
Molecular Oncology Unit, Department of Biological Chemistry,
First Department of Internal Medicine, Laiko Hospital Medical School,
National and Kapodistrian University of Athens, Athens, Greece
Series editor
Michele Ghielmini
Oncology Institute of Southern Switzerland, Ospedale San Giovanni,
Bellinzona, Switzerland
ESMO Press
First published in 2017 by ESMO Press
© 2017 European Society for Medical Oncology
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Contents
Preface vi
Contributors vii
Abbreviations ix
Acknowledgements x
A. What every oncologist should know

1. Epidemiology, risk factors and pathogenesis of squamous cell tumours 1
P Economopoulou & A Psyrri
2. Diagnosis and staging of squamous cell tumours 7
R Mesía & M Taberna
3. Histopathological and molecular characterisation of squamous cell tumours 13
L Martin & KD Hunter
4. Site- and stage-driven treatment strategy in non-metastatic disease 19
L Licitra, S Alfieri & M Imbimbo
5. Principles of surgery of squamous cell tumours 24
A Dietz & S Wiegand
6. Principles of radiotherapy of squamous cell tumours 30
N Slevin & LW Lee
7. Treatment of recurrent or metastatic disease 36
MV Karamouzis
8. Thyroid carcinomas 42
R Elisei, A Matrone & C Romei
B. More advanced knowledge

9. Nasopharyngeal carcinoma 49
A Chan, SF Leung & EP Hui
10. Salivary glands tumours 53
LD Locati & M Imbimbo
11. Individualised supportive care before and during curative treatment of head and neck tumours 57
P Bossi, P Economopoulou & A Psyrri
12. Emerging targets and new agents in squamous head and neck tumours 62
E Seront & JP Machiels
Appendices
1. WHO Classification 67
2. Selected treatment schedules 70
Image sources 76
Declarations of interest 77
Index 78
Contents
Preface
The complexity and heterogeneity of Head and Neck Cancers (HNCs) would seemingly only conflict with the
concise and practical format of ESMO’s Essentials for Clinicians book series. Overcoming this incongruity
(particularly in Section A: “What every oncologist should know”) allows readers to really appreciate the
‘mission’ of this ESMO initiative: to extend knowledge to every oncologist of tumours commonly considered
a field of special interest for a few highly-specialised professionals. This objective arises from existing needs.
First, HNCs, though classified as rare cancers, together represent a very large group of malignancies, lying
around fifth in terms of absolute worldwide incidence (this volume also includes thyroid cancers). Second,
although highly-selected expertise is needed to optimally comply with the complex multidisciplinary health
care provision in this cancer setting, we believe that education is pivotal in supporting the role of the medical
oncologist within the management team.
Section B: “More advanced knowledge” has been properly thought out to cater for oncologists dedicated
to HNCs. Notably, this section seeks to address some unmet needs or particular aspects of the therapeutic
management of HNCs. This includes discussion of rarer subtypes of HNC (e.g. nasopharyngeal cancer,
salivary gland cancers) and other challenges (e.g. supportive therapies, new emerging agents), no less
important in the treatment of HNCs.
Dr Lisa Licitra Dr Salvatore Alfieri

Milan, Italy Milan, Italy
vi
Preface
Contributors
S Alfieri
Head and Neck Cancer Medical Oncology Department, Fondazione IRCCS “Istituto Nazionale dei Tumori”, Milan, Italy
P Bossi
A Chan
Partner State Key Laboratory of Oncology in South China, Department of Clinical Oncology, Sir Y.K. Pao Center for
Cancer, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
(SAR), China
A Dietz
Department of Otolaryngology, Head and Neck Surgery, and Department of Head Medicine and Oral Health, University
of Leipzig, Leipzig, Germany
P Economopoulou
Department of Internal Medicine, Section of Medical Oncology, Attikon University Hospital, National Kapodistrian
University of Athens, School of Medicine, Athens, Greece
R Elisei
Endocrine Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy
EP Hui
Partner State Key Laboratory of Oncology in South China, Department of Clinical Oncology, Sir Y.K. Pao Center for
Cancer, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
(SAR), China
KD Hunter
Unit of Oral and Maxillofacial Pathology, School of Clinical Dentistry, Sheffield Teaching Hospitals University NHS Trust,
Sheffield, UK
M Imbimbo
MV Karamouzis
Molecular Oncology Unit, Department of Biological Chemistry, First Department of Internal Medicine, Laiko Hospital
Medical School, National and Kapodistrian University of Athens, Athens, Greece
LW Lee
The Christie NHS Foundation Trust, Manchester, UK
SF Leung
Department of Clinical Oncology, Prince of Wales Hospital, Hong Kong Special Administrative Region (SAR), China
L Licitra
Head and Neck Cancer Medical Oncology Department, Fondazione IRCCS “Istituto Nazionale dei Tumori”, Milan;
Università degli Studi Milano, Milan, Italy
LD Locati
JP Machiels
Institut Roi Albert II, Department of Medical Oncology, Cliniques Universitaires Saint-Luc and Institut de Recherche
Clinique et Expérimentale (Pole MIRO), Université Catholique de Louvain, Brussels, Belgium
L Martin
Unit of Oral and Maxillofacial Pathology, School of Clinical Dentistry, Sheffield Teaching Hospitals University NHS Trust,
Sheffield, UK
A Matrone
vii
Contributors
R Mesía
Catalan Institute of Oncology, Medical Oncology Department, Head and Neck Unit, Universitat de Barcelona,
Barcelona, Spain
A Psyrri
Department of Internal Medicine, Section of Medical Oncology, Attikon University Hospital, National Kapodistrian
University of Athens, School of Medicine, Athens, Greece
C Romei
E Seront
Institut Roi Albert II, Department of Medical Oncology, Cliniques Universitaires Saint-Luc and Institut de Recherche
Clinique et Expérimentale (Pole MIRO), Université Catholique de Louvain, Brussels; Department of Medical Oncology,
Centre Hospitalier de Jolimont, Haine Saint-Paul, Belgium
N Slevin
The Christie NHS Foundation Trust, Manchester, UK
M Taberna
Catalan Institute of Oncology, Medical Oncology Department, Head and Neck Unit, Universitat de Barcelona,
Barcelona, Spain
S Wiegand
Department of Otolaryngology, Head and Neck Surgery, University of Leipzig, Leipzig, Germany
viii
Contributors
Abbreviations
3D-CRT Three-dimensional conformal radiotherapy MTX Methotrexate

ACC Adenoid cystic carcinoma NPC Nasopharyngeal carcinoma
ADCC Antibody dependent cell-mediated cytotoxicity OPC Oropharyngeal cancer
AJCC American Joint Committee on Cancer ORR Overall response rate
AR Androgen receptor OS Overall survival
ATC Anaplastic thyroid carcinoma OSC Oropharyngeal squamous cell carcinoma
ChT Chemotherapy PDTC Poorly differentiated thyroid carcinoma
ChT-RT Chemoradiotherapy PET Positron emission tomography
CS Cavernous sinus PFS Progression-free survival
Ct Calcitonin PI3K Phosphatidylinositol 3 phosphate
CT Computed tomography PS Performance status
DARS Dysphagia/aspiration related structures pRB Retinoblastoma protein
DTC Well-differentiated thyroid carcinoma PTC Papillary thyroid carcinoma
EBV Epstein-Barr virus QoL Quality of life
ECOG Eastern Cooperative Oncology Group Rb Retinoblastoma
EGFR Epidermal growth factor receptor RS Relative survival
ENE Extranodular extension RT Radiotherapy
ENT Ear, nose and throat SCC Squamous cell carcinoma
ESA Erythropoiesis-stimulating agent SDC Salivary duct carcinoma
FDA Food and Drug Administration SGC Salivary gland cancer
FNA Fine needle aspiration SIB Simultaneous integrated boost
FTC Follicular thyroid carcinoma SRT Stereotactic radiotherapy
G-CSF Granulocyte colony-stimulating factor TC Thyroid carcinoma
Gy Gray Tg Thyroglobulin
H&E Haematoxylin & eosin TgAb Thyroglobulin autoantibodies
Hb Haemoglobin TGCA The Cancer Genome Atlas
HNC Head and neck cancer TK Tyrosine kinase
HNSCC Head and neck squamous cell carcinoma TKI Tyrosine kinase inhibitor
HPV Human papillomavirus TLMS Transoral laser microsurgery
IChT Induction ChT TLR Toll-like receptor
IG Intermediate grade TNM Tumour-node-metastasis
IGRT Image-guided radiotherapy TORS Transoral robotic surgery
IHC Immunohistochemistry TPF Docetaxel-cisplatin-fluorouracil
IMRT Intensity modulated radiotherapy TSG Tumour suppressor gene
ISH In situ hybridisation TSH Thyroid stimulating hormone
LB Lobectomy TTx Total thyroidectomy
LG Low grade US Ultrasound
mAb Monoclonal antibody VC Verrucous carcinoma
MEC Mucoepidermoid carcinoma VEGF Vascular endothelial growth factor
MRI Magnetic resonance imaging WBS Whole body scan
MTC Medullary thyroid carcinoma WHO World Health Organisation
mTOR Mechanistic target of rapamycin
ix
Abbreviations
Acknowledgements
The editors would like to thank the members of the ESMO Publishing Working Group and Educational
Steering Committee for their support in this initiative. The editors wish to thank Dr Keith McGregor,
Claire Bramley, Aude Galli and Jennifer Lamarre of ESMO for their support in the preparation of
this publication.
Michalis Karamouzis & Lisa Licitra
x
Acknowledgements
A
What every oncologist should know

1 Epidemiology, risk factors and
pathogenesis of squamous cell tumours
Epidemiology
Head and neck squamous cell carcinoma (HNSCC) Anatomical sites and subsites of the head and neck.
encompasses a variety of tumours originating The approximate distribution of head and neck cancer is
in the lip, oral cavity, hypopharynx, oropharynx, oral cavity, 44%; larynx, 31%; and pharynx, 25%
nasopharynx or larynx.
Nasal antrum
It is the sixth most common malignancy worldwide,
accounting for approximately 6% of all cancer cases,
Oral cavity
responsible for an estimated 1%–2% of all cancer deaths. Lip
Nasopharynx
Buccal mucosa Pharynx
Alveolar ridge and
Oral cavity and laryngeal cancers are the most retromolar trigone
Floor of mouth Oropharynx
common head and neck cancers globally (age-adjusted Hard palate Base of tongue
Oral tongue Soft palate
standardised incidence rate 3.9 and 2.3 per 100 000, (anterior two-thirds) Tonsillar pillar
and fossa
respectively). Larynx Hypopharynx
Supraglottis
False cords
Arytenoids
Epiglottis
Arytenoepiflottic fold
Glottis Oesophagus
Subglottis
World HNSCC is predicted to account for 742 270 new cases

Lip, oral cavity, larynx, nasopharynx, other pharynx and 407 037 deaths worldwide, for the year 2015. It is
Number of new cancers in 2015 (all ages) the most common cancer in Central Asia.
Male 556 080

In the United States, more than 54 000 new cases were
diagnosed in 2014, resulting in an annual incidence of 15
per 100 000, with 12 000 deaths attributed to the disease.
Female 186 190
In Europe, HNSCC incidence and mortality rates
0 100 000 200 000 300 000 400 000 500 000 600 000 700 000 are higher, with approximately 140 000 new cases
Incidence in 2012 Demographic effect diagnosed in 2014, corresponding to an annual
incidence of 43/100 000.
HNSCC incidence trends have been strongly influenced U.S. Head and neck cancer incidence
30
by patterns of tobacco use over time and across
Incidence per 100 000
25
countries. 20
15
10
In the USA, overall incidence of oral cavity and 5
pharyngeal cancers began decreasing 30 years ago 0
1991 1995 1999 2003 2007 2011
and stabilised in 2003. Overall incidence of laryngeal
U.S. Head and neck cancer mortality
cancer began declining in the 1990s. 10
Mortality per 100 000
9
8
7
In Eastern Europe and China (high tobacco consumption 6
5
rates), a rise in HNSCC is anticipated. Infection with 4
3
2
human papillomavirus (HPV) is responsible for a growing 1
0
ratio of oropharyngeal tumours. 1991 1995 1999 2003 2007 2011
Whites African Americans Hispanics*
Asians/Pacific Islanders* American Indians/Alaska Natives*
*Incidence and mortality data not available before 1992.
REVISION QUESTIONS
1. Which is the most common head and neck cancer globally?
2. What is the trend of HNSCC incidence in the USA and Europe in the last 20 years?
3. What is the percentage of deaths due to head and neck cancer among all cancer-related deaths?
1
Economopoulou & Psyrri
Clinical features and survival rates
Survival in HNSCC is predicted primarily by anatomical Oral cavity and pharyngeal cancer
site, stage and HPV status, with other pathological and Percentage of cases by stage
clinical factors influencing prognosis to a lesser degree. 5% Unknown
In the recent EUROCARE population-based study, five-

year relative survival was poorest for hypopharyngeal
18% Distant
cancer (25%) and highest for laryngeal cancer (59%). 31% Localised
For oral cavity and pharyngeal cancer, 31% of cases

are localised at the time of diagnosis. For laryngeal
cancer, 55% of patients are diagnosed with localised
disease.
47% Regional
Oral cavity and pharyngeal cancer: new cases and deaths

For oral cavity and pharyngeal cancer, 5-year survival
15 New cases rates have increased from 57% in 1992 to 65.1% in
Number per 100,000 persons
2003. Death rates have not changed over 2003–2012.

10
For cancer of the larynx, 5-year survival rates have not
5 changed significantly over the past 30 years.
Deaths The survival improvement is greatest for tonsil cancer
0 (39.7% to 69.8%). This trend is attributed to HPV-positive
1975 1980 1984 1988 1992 1996 2000 2004 2008 2012
tumour status, which is a strong predictor for survival.
High cure rates are reported for localised and locoregional

100
disease. However, the 3-year survival rate does not exceed Low risk
40% in a subset of patients with localised HNSCC.
75
Intermediate risk
Overall survival (%)
HPV-positive oropharyngeal cancer (OPC) patients

show better response to treatment, and survival is 50
High risk
improved by approximately 50%. Improvement in
survival is reduced in smokers. 25
Despite advances in multimodality treatment, survival

0
rates for recurrent/metastatic disease remain dismal. 0 1 2 3 4 5
Years since randomisation
No. at risk
Low risk 114 111 106 102 95 46
Intermediate risk 79 70 64 54 44 24
High risk 73 52 43 33 28 8
REVISION QUESTIONS
1. What is the 5-year survival rate of head and neck cancer in Europe by anatomical site?
2. What is the trend of survival rates for oral cavity and pharyngeal cancer and cancer of the larynx in the past 20 years?
3. What is the 3-year survival rate of head and neck cancer according to stage?
2
Epidemiology, risk factors and pathogenesis of squamous cell tumours
Risk factors
Tobacco: Approximately 90% of patients with HNSCC

Head and neck cancers
have a history of tobacco use.
60
Compared to non-smokers, tobacco users have a
4–5-fold increased risk for cancer in the oral cavity, 50
oropharynx and hypopharynx and a 10-fold increased 40
Relative risk
risk of laryngeal cancer.
30
Risk of HNSCC is related to the frequency, intensity 20

and duration of tobacco consumption; association is
10
dose-dependent.
0
0 10 20 30 40 50 60 70 80
Consumption (packs per year)
Stopping smoking at age 45-54

100
Percentage survival from age 50
Stopped smoking
80
Cigarette smokers
60
Non-smokers
40
Smoking cessation may reduce risk of HNSCC. Risk
20
decreases with time since smoking cessation.
0
Stopping smoking at age 55-64
100 Smokeless (chewing) tobacco increases the risk of cancer
Percentage survival from age 60
Stopped smoking
80
of the oral cavity. In India and Sudan, 50%–60% of oral
Cigarette smokers cavity cancers are attributed to smokeless tobacco.
60
Non-smokers
40
It is estimated that tobacco smoking increases the risk of
HPV infection and persistence; therefore it may contribute to
20
development of HPV-positive OPC.
0
40 50 60 70 80 90 100
Age (years)
Alcohol: Alcohol use independently increases the risk of Head and neck cancer:
HNSCC, with 1%–4% of cases attributed to alcohol alone. Percentage of new cases by age group
It specifically increases the risk of hypopharyngeal cancer. 40
35
Percentage of new cases
It acts synergistically with tobacco, resulting in an 29.9%

30
approximately 35-fold increase in HNSCC risk in heavy
25
smokers (>2 packs/day) and drinkers (>4 drinks/day). 19.4%
22.4%
20
15 14.2%
Gender, age: Men have a 2- to 5-fold greater risk of
10
HNSCC than women. HNSCC risk also increases with 5.4% 6.1%
5
age, with a median age of diagnosis in the late 60s 0.6%
2.0%
0
and 70s. <20 20-34 35-44 45-54 55-64 65-74 75-84 >84
Age
REVISION QUESTIONS
1. What percentage of patients with HNSCC have a history of tobacco use?
2. Which type of head and neck cancer has the strongest association with tobacco?
3. How much is the risk of HNSCC increased by the combined effect of tobacco and alcohol?
3
Risk factors (continued)
HPV infection: It is the cause of a distinct subset of Parameter HPV- HPV+

HNSCCs that occur primarily in the oropharynx. Gender 2-3 fold more common in men 4-5 fold more common in men
The proportion of HPV-positive (HPV+) OPCs is growing. Age at diagnosis Median age late 60s and 70s Median age early 50s
Race More common in Whites
HPV Type 16 (HPV16) is responsible for more than 90% Smoking 90% smoking history 50%-65% smoking history
of HPV+ OPCs. The time from first oral HPV infection to Sexual behaviour Not a significant risk factor Number or oral and vaginal sex
partners is an important risk factor
the development of cancer is estimated to be more than
Site Oral cavity and larynx most Oropharynx
a decade. commonly HPV+ <20% at other sites
Measures of sexual behaviour (number of vaginal and oral Clinical picture Varies Early T stage, enlarged nodes
Incidence trends Decreasing Increasing
partners, history of genital warts) have been associated
Survival rates All sites: 65% 5-year survival 60%-80% 5-year survival
with HPV+ OPC. Oropharynx: 25% 5-year
survival
HPV-, Human papillomavirus negative; HPV+, human papillomavirus positive.
Overall Survival According to Tumour HPV Status

100
Patients with HPV+ OPC are less likely to be smokers
HPV-positive than HPV-negative (HPV-) patients. However,
approximately 50% of patients with HPV+ OPC have a
Overall Survival (%)
75
history of tobacco use.
50 Individuals with HPV+ OPC tend to be male and white,

although these characteristics do not predict HPV
HPV-negative
positivity. In addition, they present at a younger age
25
at diagnosis.
Hazard ratio for death, 0.38 (0.26– P< 0.55); 0.001
0
0 1 2 3 4 5
HPV+ OPC is characterised by an earlier T stage at
Years since Randomisation presentation but with extensive nodal involvement.
No. at Risk However, prognosis is better compared with
HPV-positive 206 193 179 165 151 73 tobacco-related HNSCC.
HPV-negative 117 89 76 65 51 22
HPV, Human papillomavirus.
Incidence patterns by ethnic origin have changed over

time. Incidence of HNSCC in Black people has been
declining since the 1990s and is currently lower than in
White people.
Other risk factors for HNSCC include immunosuppression
(organ transplant recipients, human immunodeficiency
virus), systemic diseases (lichen) and genetic diseases
(Fanconi anaemia).
Nasopharyngeal and paranasal sinus cancers

are associated with the Epstein-Barr virus (EBV).
Nasopharyngeal cancer is common in endemic areas
(Southern China, Northern Africa).
EBV, Epstein-Barr virus; NPC, nasopharyngeal cancer.
REVISION QUESTIONS
1. Which type of HPV is associated with the majority of HPV+ OPCs?
2. What are the clinical features of HPV+ OPC?
3. Which virus is associated with nasopharyngeal cancer?
4
Pathogenesis
Normal-appearing Severe
Transformation of normal mucosa into invasive epithelium Hyperplasia Mild dysplasia dysplasia or
carcinoma in situ
Invasive carcinoma
HNSCC follows a molecular progression

model of multistep carcinogenesis.
Loss of genetic material from chromosome

region 9p21 and inactivation of p16 tumour
suppression gene are the earliest alterations
Carcinogen
identified at transition to hyperplastic mucosa. exposure
9p21 deletion
3p deletions
11q13
18q deletion
p16/p14 inactivation 13q21
Trisomy 7 TP53 mutations 10q23
Genetic 8p deletion
Subsequent transition to dysplasia is changes
Epidermal growth factor receptor Tetraploidy Aneuploidy
3q26
PTEN inactivation
Telomerase activation Cyclin D1 amplification
characterised by loss of 3p and 17p and by Epigenetic
aberrations Genomic
p53 inactivation. Loss of 11q, 13q and 14q (Promoter
methylation status, instability
precedes transition to carcinoma in situ. histone code)
Immune escape
PTEN, Phosphatase and tensin homologue.
a) Leukoplakia b) Erythroplakia
Loss of 6p, 8p and 4q is identified during transformation

to invasive HNSCC. Tobacco-related HNSCC is
associated with mutation of p53 and downregulation of
p16 protein.
c) Normal oral mucosa d) Moderate dysplasia Leukoplakia and erythroplakia are the precursors
of invasive HNSCC in the oral mucosa. Leukoplakia
appears as white plaques and erythroplakia as a red
zone of mucosa.
Field carcinogenesis refers to carcinogen distribution

over large areas in upper aerodigestive tracts, due to
continuous exposure, rendering mucosa a potential site
for cancer.
HPV infection carcinogenesis: The integration

of HPV DNA into the host genome disrupts Senescence and
DNA damage Cyclin A CDK1 Mitogens
the expression of factor E2, the transcriptional differentiation
repressor of E6 and E7 viral proteins. Cyclin B CDK1
p53 p53 p16

E6 and E7 encode oncoproteins that bind and p53 p53 M
degrade p53 and retinoblastoma (Rb) tumour G0 CDK4 or Cyclin D1
CDK6
suppressors, respectively. Degradation of Rb G2 G1
induces expression of p16INK4A. p53 E2F RB

S
E2F
Rb is a negative regulator of p16 protein; low E6 E7
P
Rb levels lead to p16 upregulation. HPV+ p21 Cyclin E CDK2 RB RB
P P
OPC is typically p53 and Rb1 wild-type and
demonstrates high p16 protein levels.
REVISION QUESTIONS
1. Which molecular abnormalities are associated with tobacco-related HNSCC?
2. What are the molecular features of HPV+ OPC?
3. What are the premalignant lesions of invasive squamous cancer in the oral mucosa?
5
Summary: Epidemiology, risk factors and pathogenesis of squamous
cell tumours
• HNSCC encompasses a heterogeneous group of upper aerodigestive malignancies originating in the lip, oral cavity,
pharynx and larynx
• It is the sixth most common cancer worldwide, accounting for 1%–2% of all cancer-related deaths
• Historically, HNSCC has been associated with tobacco smoking and alcohol use
• Globally, the incidence of tobacco-related HNSCC is associated with patterns of tobacco use and is decreasing in
countries with declining rates of tobacco consumption
• In the past decade, infection with high-risk HPV and especially with HPV16 has been implicated in the pathogenesis
of a growing subset of HNSCCs, mainly those arising from the oropharynx
• HPV-related OPC represents a distinct entity in terms of biology and clinical behaviour
• Five-year survival rates for all stages of HNSCC is approximately 65%. High cure rates are reported with localised and
locoregional disease, but prognosis is dismal for recurrent or metastatic disease
• For HNSCC, malignant transformation of normal mucosa to invasive carcinoma follows a molecular progression model
of multistep carcinogenesis
• Tobacco-related HNSCC demonstrates mutation of the p53 gene and downregulation of the p16 protein
• On the contrary, HPV-associated OPC is typically characterised by wild-type p53 and Rb genes and upregulation
of p53 protein levels
Further Reading
Chaturvedi AK, Engels EA, Anderson WF, Gillison ML. Incidence trends for human papillomavirus-related and -unrelated oral squamous
cell carcinomas in the United States. J Clin Oncol 2008; 26:612–619.
Gatta G, Botta L, Sánchez MJ, et al. Prognoses and improvement for head and neck cancers diagnosed in Europe in early 2000s:
The EUROCARE-5 population-based study. Eur J Cancer 2015; 51:2130–2143.
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 Biomarkers Prev 2009; 18:541–550.
Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010; 60:277–300.
Klein JD, Grandis JR. The molecular pathogenesis of head and neck cancer. Cancer Biol Ther 2010; 9:1–7.
Marur S, D’Souza G, Westra WH, Forastiere AA. HPV-associated head and neck cancer: a virus-related cancer epidemic. Lancet Oncol
2010; 11:781–789.
Park BJ, Chiosea SI, Grandis JR. Molecular changes in the multistage pathogenesis of head and neck cancer. Cancer Biomark 2010;
9:325–339.
Psyrri A, Rampias T, Vermorken JB. The current and future impact of human papillomavirus on treatment of squamous cell carcinoma
of the head and neck. Ann Oncol 2014; 25:2101–2115.
Psyrri A, Seiwert TY, Jimeno A. Molecular pathways in head and neck cancer: EGFR, PI3K, and more. Am Soc Clin Oncol Educ Book
2013:246–255.
Rampias T, Sasaki C, Psyrri A. Molecular mechanisms of HPV induced carcinogenesis in head and neck. Oral Oncol 2014; 50:356–363.
Rettig EM, D’Souza G. Epidemiology of head and neck cancer. Surg Oncol Clin N Am 2015; 24:379–396.
6
2 Diagnosis and staging of squamous cell tumours
Natural history
Head and neck squamous cell carcinoma (HNSCC)

arises from the upper aerodigestive mucosa, which holds
important functional roles such as respiration, swallowing,
speech and hearing.
HNSCC is a heterogeneous disease with different
anatomical sites: oral cavity, oropharynx, hypopharynx,
larynx, nasopharynx and sinus.
An understanding of the anatomical origins of HNSCC

is essential for an appropriate diagnosis, treatment and
follow-up.
HNSCC is the final stage of a process of progressive

steps: from hyperplasia to dysplasia, carcinoma in situ
and to invasive carcinoma.
Limitless replicative potential of head and neck

cancer cells is often caused by abrogation of p53 and
retinoblastoma pathways that perturb cell regulation.
Some HNSCC become independent from growth factors,
Hyperplasia Mild dysplasia Moderate Severe Carcinoma
dysplasia dysplasia due to somatic change in the epidermal growth factor
Inactivation of p16
3p,9p LOH 8p,17p LOH
Additional LOHs
receptor (EGFR) signalling pathway.
Telomerase inactivation Amplification (Cyclin D1)
4q,8q,13p
EGFR overexpression p53 mutation
EGFR, Epidermal growth factor receptor; LOH, loss of heterogeneity.
Cervical lymphadenopathy in a patient

Carcinomas usually originate in the mucosa; they initially
grow by local infiltration. Locoregional invasion occurs
early into muscles, and later into bones and nerves.
Lymphatic dissemination patterns depend on the

degree of differentiation, tumour size and primary
tumour site. 5% of patients present only with neck
lymphadenopathy.
Haematological spread occurs later (10%–12%). Lung

followed by bones are the organs more commonly
affected. Spread occurs more often in hypopharyngeal
cancer.
REVISION QUESTIONS
1. What are the most relevant molecular changes from dysplasia to invasive carcinoma?
2. Which is the organ most frequently affected by distant metastases?
3. Can severe dysplasia generate distant metastases?
7
Mesía & Taberna
Symptoms and physical examination
A confirmed screening test to detect premalignant Clinical symptoms related to primary tumour site
lesions in the head and neck is not yet available. Clinical Location Symptom
symptoms vary and depend on the location of the tumour. -Oral cavity injury
-Oral pain
Oral cavity
-Dysphagia
A detailed history of previous malignancies, treatments, -Swelling
patient’s comorbidities, family history, birth place and -Dysphagia
ethnicity should be carried out. -Odynophagia: sore throat
Oropharynx -Otalgia
Social situation and occupational history is needed. -Globus sensation
-Cervical nodes
Tobacco and alcohol consumption should be investigated -Hoarseness
to help in the cessation of toxic habits. -Cough
Larynx -Dysphonia
-Shortness of breath
-Cervical nodes
-Dysphagia
-Odynophagia
Hypopharynx
-Dysphonia
-Cervical nodes
Levels of cervical lymph node description Physical examination should include: Eastern Cooperative
Levels Location Oncology Group (ECOG) performance status, oral
IA Submental nodes cavity inspection, endoscopy, neurological, cardiac and
IB Submandibular nodes pulmonary examination, and complete blood tests.
IIA Upper jugular: anterior to spinal accessory nerve
IIB Upper jugular: posterior to spinal accessory nerve Assessment of regional lymph node status is essential
III Middle jugular nodes in the evaluation of head and neck cancer patients.
IV Lower jugular nodes Lymph node group classification includes 7 levels.
VA Posterior triangle: above the inferior border of the cricoid
VB Posterior triangle: below the inferior border of the cricoid At the time of diagnosis, in case of respiratory or digestive
VI Anterior compartment symptoms, the coexistence of other tumours should be
VII Superior mediastinal nodes excluded (10%–15% synchronous tumours).
Patient with a base of the tongue tumour

Indirect laryngoscopy by mirror is very useful to examine
the vallecula and base of tongue, but a flexible endoscope
is the best option.
Chewing, swallowing, breathing and phonation should

be explored. Stability of the airway must be assessed;
bleeding or obstructing mass may require tracheotomy.
Special assessment is required of dentistry, nutrition,

social situation, physiotherapy and psycho-oncology
needs during diagnosis, following treatment and
follow-up.
REVISION QUESTIONS
1. Which is the area of the head and neck most frequently affected by hoarseness?
2. If an enlarged lymph node appears in the middle jugular area, to which lymph node group are we referring?
3. What is the percentage of synchronous tumours?
8
Diagnosis and staging of squamous cell tumours
Histological confirmation and extension study
Final diagnosis is provided by histological examination of

the primary tumour. If not possible, a puncture of one of
the affected lymph nodes should be performed. Biopsy
is always better than fine needle aspiration.
80% of head and neck cancers are squamous

cell carcinomas. Pathological diagnosis should be
made according to the World Health Organisation
classification.
Human papillomavirus (HPV) testing (p16

immunohistochemistry and other biomarkers if possible,
such as HPV DNA polymerase chain reaction/in situ
hybridisation) should be conducted for oropharyngeal cancer.
Computed tomography (CT) or cervico-facial magnetic

resonance imaging (MRI) are needed to explore tumour
extension.
A head and neck endoscopic work-up with multiple

biopsies may be needed to find the primary tumour and
to visualise the oropharynx, larynx and hypopharynx.
Chest CT is recommended in advanced stages, while
abdominal CT or bone study are recommended in the
presence of signs or symptoms of disease distant spread.
Positron emission tomography (PET)/CT is superior to

both CT/MRI to detect cervical lymph nodes, distant
metastases and second primary tumours resulting in
alteration of treatment.
PET/CT is suggested for initial staging of oral cavity,

oropharyngeal, hypopharyngeal, glottic and supraglottic
cancers in Stages III-IV disease.
PET/CT has limitations in spatial resolution, to
detect nodal necrosis, as well as in the detection of
osteomedullary invasion of the mandible and jawbone.
REVISION QUESTIONS
1. What is the anatomical location most frequently affected by HPV?
2. When is chest CT recommended?
3. What are the limitations of PET/CT imaging in head and neck cancer diagnosis?
9
Mesía & Taberna
Diagnostic algorithm and staging
A diagnostic algorithm for head and neck cancer

patients is shown here. Persistent symptoms should
always be explored.
A multidisciplinary team is required to optimise diagnosis,

clinical work-up and treatment decisions for head and
neck cancer patients.
Squamous head and neck cancers should be staged
according to the tumour-node-metastasis (TNM) system
and grouped into categories, according to the American
Joint Committee on Cancer (AJCC) classification.
CT, Computed tomography; MRI, magnetic resonance imaging; PET, positron emission
tomography.
Lymph node involvement

• N0: no regional lymph node metastasis
T definitions are different, depending on the T location.
• N1: metastasis in a single ipsilateral lymph node, ≤3 cm in greatest
dimension without extranodal extension T is usually based on the size of the tumour, local invasion
• N2a: metastasis in a single ipsilateral lymph node, 3-6 cm in and its relation to adjacent anatomical structures affected.
greatest dimension without extranodal extension
• N2b: metastases in multiple ipsilateral lymph nodes, none >6 cm in The definition of category N (lymph node involvement)
greatest dimension without extranodal extension is the same for all locations of head and neck cancer
• N2c: metastases in bilateral or contralateral lymph nodes, none (except for nasopharyngeal cancer and HPV-related/
>6 cm in greatest dimension without extranodal extension p16-positive oropharyngeal cancer, which have their
• N3a: Metastasis in a lymph node more than 6 cm in greatest own TNM classifications) .
dimension without extranodal extension
• N3b: Metastasis in a single or multiple lymph nodes with clinical
extranodal extension
Category M for the presence of distant metastasis:

M0: no distant metastasis
M1: distant metastasis present Histological grade
Histological grade as shown in the table opposite. • G1: well differentiated • G3: poorly differentiated
• G2: moderately differentiated • G4: undifferentiated
When surgery is performed, pathological stage should be
described (e.g. pT2pN1).
REVISION QUESTIONS
1. Does the multidisciplinary head and neck unit need to participate in the head and neck cancer initial clinical work-up?
2. Is the histological grade part of the TNM classification system?
3. Is the N classification similar for all tumours?
10
Unknown primary tumour; prognostic factors
Squamous cell carcinoma of an unknown primary

of the head and neck is defined as metastatic in the X
lymph nodes without any evidence of primary tumour. X
It accounts for 3%–7% of all head and neck cancers. X
A complete clinical examination and imaging should be
performed, including panendoscopy with biopsies.
X X
Epstein-Barr virus (nasopharynx) and HPV (oropharynx)
should be tested on the biopsy sample to direct clinical
and radiological primary tumour identification.
X
X
X
Patient-related factors include: Eastern Cooperative

Oncology Group (ECOG) performance status, advanced
age, gender, tobacco use and immune system status.
The stage of the tumour based on TNM is the most

important factor for prognosis and survival. The location
of the tumour is also important: hypopharynx has the
worst prognosis whereas glottis has the best.
Treatment-related factors: response to induction
chemotherapy and radiotherapy is the most important.
ECOG, Eastern Cooperative Oncology Group; HPV, human papillomavirus;

PS, performance status; TNM, tumour-node-metastasis.
Overall survival according to tumour HPV status
HPV-related oropharyngeal squamous cell carcinoma 100

(OSC) has distinct epidemiology, clinical and molecular HPV positive
characteristics. 75
Most HPV-related OSC patients respond better to 50

treatment and have better survival than non-related
HPV negative
patients.
25
HPV detection should be performed for OSC to assess Hazard ratio for death, 0.38 (0.26-0.55); P<0.001
prognosis, but no changes in the therapeutic approach 0
0 1 2 3 4 5
should yet be made, unless participating in a clinical trial. Years since randomisation
REVISION QUESTIONS
1. What are the viral tests that should be performed in a squamous cell carcinoma of unknown primary of the head and neck?
2. What is the location of the tumour with the worst prognosis in the head and neck area?
3. Should we apply any therapeutic change when HPV-related OSC is diagnosed?
11
Mesía & Taberna
Summary: Diagnosis and staging of squamous cell tumours
• HNSCC is a heterogeneous disease with different anatomical sites
• The head and neck area has important functional roles, such as respiration, swallowing, speech and hearing
• Clinical symptoms are varied and depend on the location of the primary tumour
• A complete medical history and physical examination (flexible endoscope) are needed
• Dental status, nutritional status, social situation, rehabilitation and psychological needs should be assessed
• The definitive diagnosis is provided by histology of the primary tumour, if possible
• CT or MRI are needed to explore tumour extension. PET/CT may be necessary for better assessment
• A multidisciplinary team is required to optimise initial diagnostic work-up, treatment, supportive care, and follow-up
decision-making
• Squamous head and neck cancer should be staged by the TNM system
• HPV-related OSC has distinct epidemiology, molecular and clinical characteristics
Further Reading
Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 2010;
363:24–35.
Georgopoulos R, Liu JC. Examination of the patient with head and neck cancer. Surg Oncol Clin N Am 2015; 24:409–421.
Gillison ML, Chaturvedi AK, Anderson WF, Fakhry C. Epidemiology of human papillomavirus-positive head and neck squamous cell
carcinoma. J Clin Oncol 2015; 33:3235–3242.
Grégoire V, Lefebvre JL, Licitra L, Felip E. Squamous cell carcinoma of the head and neck: EHNS-ESMO-ESTRO Clinical Practice
Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010; 21(Suppl 5):vi184–vi186.
Hayes DN, Van Waes C, Seiwert TY. Genetic landscape of human papillomavirus-associated head and neck cancer and comparison to
tobacco-related tumors. J Clin Oncol 2015; 33:3227–3234.
Leemans CR, Braakuis BJ, Brakenhoff RH. The molecular biology of head and neck cancer. Nat Rev Cancer 2011; 11:9–22.
Martin JM, Galloway TJ. Evaluation and management of head and neck squamous cell carcinoma of unknown primary. Surg Oncol Clin
N Am 2015; 24:579–591.
Miller FR, Hussey D, Beeram M, et al. Positron emission tomography in the management of unknown primary head and neck
carcinoma. Arch Otolaryngol Head Neck Surg 2005; 131:626–629.
Som PM, Curtin HD, Mancuso AA. An imaging- based classification for the cervical nodes designed as an adjunct to recent clinically
based nodal classifications. Arch Otolaryngol Head Neck Surg 1999; 125:388–396.
Tantiwongkosi B, Yu F, Kanard A, Miller FR. Role of 18F-FDG PET/CT in pre and post treatment evaluation in head and neck carcinoma.
World J Radiol 2014; 6:177–191.
12
3 Histopathological and molecular
characterisation of squamous cell tumours
Introduction – epithelial dysplasia and early squamous cell carcinoma
Macroscopic
In cases of suspected squamous cell carcinoma (SCC), examination and Tissue processing
specimens are examined macroscopically prior to tissue dissection
processing and histopathological analysis.
Sampled tissue is dehydrated and paraffin-embedded.

Then 2–5 µm sections are cut on a microtome. Routine
staining is performed with haematoxylin & eosin (H&E).
Additional staining techniques, including periodic
acid–Schiff, immunohistochemistry (IHC) and in-situ
hybridisation (ISH) techniques, may also be used for
diagnostic purposes.
Tissue sectioning Slide staining
Epithelial dysplasia is regarded as potentially malignant

and is diagnosed by the presence of architectural and
cytological changes within the epithelium.
Conventional grading systems separate epithelial

dysplasia into mild, moderate, severe and carcinoma in
situ, based on the degree and extent of changes.
Features of dysplasia include nuclear and cellular

pleomorphism, abnormal mitoses and keratinisation,
altered cellular polarity and drop-shaped rete pegs.
Mild Severe
Widespread accumulation of genomic abnormalities

within the epithelium is known as “field change”, from 500
Diploid
which dysplasia and primary SCC may arise. Despite 400
Single diploid
adequate resection of primary tumours, field change may
Number of nuclei
300
peak: normal DNA

result in development of subsequent SCCs. 200
content, low risk
100
The severity of dysplasia is the most useful guide to the 0

1C 2C 4C 5C 8C 9C 16C
Integrated optical density
risk of SCC development, but other tests, such as DNA

ploidy or loss of heterozygosity, may be useful. 45
Aneuploid
Early invasive SCC is characterised by penetration of 30

Multiple peaks:
Number of nuclei
the basement membrane and invasion of the underlying abnormal DNA

content, high risk
stroma, and can be difficult to diagnose. 15
Early invasive SCC

1C 2C 4C 5C 8C 9C
Integrated optical density
SCC, Squamous cell carcinoma.
REVISION QUESTIONS
1. How are SCC specimens processed?
2. What cytological atypia are seen in epithelial dysplasias?
3. What is meant by the term “field change” and why is it important?
13
Martin & Hunter
Histopathology of squamous cell carcinoma
SCC is graded based on its resemblance to squamous

epithelium and can be subject to inter-examiner variation.
Well-differentiated SCCs are obviously squamous with

recognisable intracellular bridges and keratinisation.
The majority of SCCs are moderately differentiated.
Poorly differentiated SCCs show little to no keratinisation

and may require IHC for cytokeratins to confirm their
epithelial origin.
Well Moderate Poor
Morphological characteristics of the invasive front of

squamous carcinoma are used as a prognostic factor and
are indicative of the tumour’s aggressiveness.
SCC comprising large solid sheets with a broad front is

regarded as possessing a cohesive invasive front, and
has a more favourable outcome.
Tumours with diffusely infiltrating small islands ahead of

the main tumour body are non-cohesive and have an
increased likelihood of metastasis and poorer outcome.
Tumour Infiltration
invades with a by small tumour
broad front islands
Interactions between tumour and host immune

and stromal cells result in the formation of the
tumour microenvironment, which contributes to
tumourigenesis.
Proliferation of stromal fibroblasts and production of a

desmoplastic fibrous stroma is often seen surrounding
islands of SCC, and is related to poor prognosis.
Variable host-immune responses may be seen
surrounding tumour islands, usually dominated by
infiltrates of lymphocytes and plasma cells.
Inflammatory
Desmoplastic response surrounding
stroma tumour islands
REVISION QUESTIONS
1. How is SCC graded? How is this determined?
2. How does the invasive front influence the prognosis of SCC?
3. What is meant by the tumour microenvironment and why is it important?
14
Histopathological and molecular characterisation of squamous cell tumours
Histopathology of squamous cell carcinoma (continued)
Islands of tumour
As a tumour grows, local invasion of surrounding Tumour invading
infiltrating between
bone
tissues is influenced by anatomical features. Tumour muscle fibres
can infiltrate sizeable distances along muscle fibres.
Oral SCC frequently invades bone by spread down

the periodontal ligament or through the alveolar crest.
Subsequent spread occurs through marrow spaces.
Bone invasion is an important prognostic factor for
SCC and upgrades the staging of the disease to T4,
irrespective of the tumour size or depth of invasion.
Muscle
SCC can spread by vascular and lymphatic invasion,

as well as infiltration along the nerve sheath within the
perineural space.
Perineural infiltration has implications in tumour

management and is associated with increased
locoregional recurrence and poorer prognosis.
SCC may infiltrate along and invade blood vessels.
Vascular invasion is another adverse prognostic factor
due to its role in tumour metastases.
Perineural invasion Vascular invasion

Residual normal
lymph node
Lymphatic spread from the primary tumour to regional

lymph nodes is variable but often relates to the site,
size and invasive front of the tumour.
The extent and distribution of lymph node metastases,

including extracapsular extension of tumour, is a reliable
adverse prognostic factor.
Lymphatic drainage of the head and neck is relatively
predictable, but sentinel lymph node biopsy may aid
staging and treatment planning in clinically N0 necks.
Metastatic Extracapsular
carcinoma spread of tumour
REVISION QUESTIONS
1. Why is identification of bone invasion an important determinant in SCC?
2. List three routes of SCC spread and how they impact prognosis.
3. What is sentinel lymph node biopsy? Why would it be carried out?
15
Martin & Hunter
Variants of squamous cell carcinoma and aids to diagnosis
Verrucous carcinoma (VC) is a low-grade variant of

SCC. It usually presents as a slow-growing wart-like
growth on the cheek and gingivae of older males.
VC is locally invasive, has a high recurrence rate but rarely

metastasises. Histologically, there are keratin projections,
bulbous rete pegs and little cellular atypia.
Spindle cell carcinoma is a high-grade biphasic tumour
with SCC and malignant spindle cell components, which
expresses epithelial and mesenchymal markers.
Verrucous carcinoma Spindle cell carcinoma
Basaloid SCC arises predominantly in the upper

respiratory tract and is characterised by its aggressive
behaviour.
Histologically, basaloid SCC comprises both squamous

and basaloid elements. There is a higher association
of human papillomavirus (HPV) infection with basaloid
variants of SCC.
Other rare variants include acantholytic SCC, papillary

SCC and adenosquamous SCC.
Basaloid SCC Adenosquamous carcinoma
In most cases, the H&E-stained section is sufficient, but IHC Antibody Use in Head and Neck SCC
in some circumstances, such as very poorly differentiated Pancytokeratin (AE1/AE3) In poorly differentiated and anaplastic lesions to detect
tumours, it is essential to prove it is SCC. squamous differentiation
Cytokeratin 5/6 May suggest squamous origin in poorly differentiated
IHC may be used to aid diagnosis. The technique uses and anaplastic lesions
antibodies against markers of interest to show their p63 May suggest squamous origin in poorly differentiated
expression in the tumour. and anaplastic lesions
p16 Overexpression of p16 is associated with HPV-positive SCC
The main uses of IHC are to demonstrate cytokeratin TTF-1 Expression of TTF-1 in neck nodes may indicate a
expression, but other antibodies are used in some metastasis of lung origin
circumstances, as shown in the table. Neuroendocrine markers: In basaloid and undifferentiated SCC to exclude
Chromogranin A, neuroendocrine carcinoma and small cell carcinoma
Synaptophysin, CD56
HPV, Human papillomavirus; IHC, immunohistochemistry; SCC, squamous cell carcinoma.
REVISION QUESTIONS
1. How does VC differ from conventional SCC?
2. What virus is strongly associated with the basaloid variant of SCC?
3. List three variants of SCC most commonly found in the upper respiratory tract.
16
Molecular characterisation
Molecular characterisation by next generation sequencing

of SCC has identified some common genetic changes, Examples of p53, p16INK4a Cyclin D1, PTEN ?
EGFR
genes involved
but SCC is very heterogeneous. Chromosomal LOH at 3p, Gain 11q, 7p, LOH at 8p, ?
17p, 9p Loss 6p, 4q 10q,
changes
Proto-oncogenes have normal cell functions, but when
Potentially
altered can lead to tumour development. Examples Normal
mucosa malignant Carcinoma Metastasis ECS
changes
include Cyclin D1 and epidermal growth factor receptor
(EGFR). EGFR is often amplified in SCC, leading to
uncontrolled cell growth. May be evident: Note: Many of these
1. Clinically (white/red patch) molecular changes are not
2. On histology (dysplasia) seen in HPV+ HNSCC dues
Tumour suppressor genes (TSGs) are involved in cell 3. By molecular changes only to viral oncogenes
growth and division and are inactivated in SCC. Examples

ECS, Extracapsular spread; EGFR, epidermal growth factor receptor; HNSCC, head and neck
include TP53, p16 (CDKN2a) and Notch1. squamous cell carcinoma; LOH, loss of heterogeneity; PTEN, phosphatase and tensin homologue.
TP53 encodes p53 protein, which has a role in

genome stability. TP53 is commonly mutated in
SCC and its detection in margins may indicate
risk of recurrence.
Cetuximab is an EGFR-inhibiting monoclonal

antibody used for treatment of SCC, and
was the first United States Food and Drug
Administration (FDA)-approved targeted
therapeutic in head and neck SCC.
Groups of mutations that frequently occur

together are termed “tumour signatures” and
may be useful in the development of future
diagnostic biomarkers.
EGFR, Epidermal growth factor receptor; mTOR, mechanistic target of rapamycin.
HPV types 16 and 18 have been identified as causative

factors in oropharyngeal carcinoma. Viral proteins E6 and
E7 inactivate TSGs.
p16 is encoded by CDKN2A and is involved in cell

cycle regulation. IHC for p16 is used as an initial screen
for HPV-related carcinoma.
DNA and RNA ISH probes directed against HPV

oncoproteins E6/E7 can also be used to confirm
HPV-related carcinoma.
Basaloid SCC (H&E) Positive IHC staining for p16 Positive ISH for HPV DNA
H&E, Haematoxylin & eosin; HPV, human papillomavirus; IHC, immunohistochemistry; ISH, in situ
hybridisation; SCC, squamous cell carcinoma.
REVISION QUESTIONS
1. What is meant by the terms “oncogene” and “tumour suppressor gene”? Give examples of each.
2. What is the clinical significance of identification of gene mutations in the treatment of SCC?
3. Which molecular techniques can be used to identify HPV-related SCC?
17
Martin & Hunter
Summary: Histopathological and molecular characterisation of
squamous cell tumours
• Epithelial dysplasia is characterised by cellular and architectural changes within the epithelium and is graded as mild,
moderate, severe or carcinoma in situ
• SCC is graded into well, moderately and poorly differentiated, dependent on its resemblance to squamous epithelium
• The morphology of the invasive front of SCC is linked to the tumour’s aggressiveness and has prognostic value
• SCC is locally invasive but can spread by perineural, vascular and lymphatic invasion
• Bone invasion by SCC is an adverse prognostic factor and upgrades the TNM disease staging to T4
• Lymph node metastasis indicates poor prognosis, particularly if there is extracapsular extension of tumour
• The World Health Organisation recognises distinct histological variants of SCC
• Verrucous carcinoma and basaloid squamous cell carcinoma have a higher association with HPV
• Oncogenes and TSGs are involved in cancer progression. Their identification can be used to develop new
targeted agents
• Immunohistochemistry (p16) and ISH are techniques that can be used to identify HPV-related SCC
Further Reading
da Silva SD, Ferlito A, Takes RP, et al. Advances and applications of oral cancer basic research. Oral Oncol 2011; 47:783–791.
El-Naggar AK, Chan JKC, Grandis JR, et al. World Health Organisation Classification of Head and Neck Tumours. Lyon: IARC
Press, 2017.
Hunt JL, Barnes L, Lewis JS Jr, et al. Molecular diagnostic alterations in squamous cell carcinoma of the head and neck and
portential diagnostic applications. Eur Arch Otorhinolaryngol 2014; 271:211–223.
Leemans CR, Braakhuis BJ, Brakenhoff RH. The molecular biology of head and neck cancer. Nat Rev Cancer 2011; 11:9–22.
Marur S, D’Souza G, Westra WH, Forastiere AA. HPV-associated head and neck cancer: a virus-related cancer epidemic.
Lancet Oncol 2010; 11:781–789.
Speight PM. Update on oral epithelial dysplasia and progression to cancer. Head Neck Pathol 2007; 1:61–66.
Suvarna KS, Layton C, Bancroft JD (Eds). Bancroft’s Theory and Practice of Histological Techniques, 7th edn. London: Churchill
Livingstone, 2012.
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; 37:127–133.
Woolgar JA, Scott J, Vaughan ED, et al. Survival, metastasis and recurrence of oral cancer in relation to pathological features.
Ann R Coll Surg Engl 1995; 77:325–331.
Woolgar JA, Triantafyllou A. Squamous cell carcinoma and precursor lesions: clinical pathology. Periodontol 2000 2011; 57:51–72.
18
4 Site- and stage-driven treatment strategy
in non-metastatic disease
Oral cavity | L ip, floor of the mouth, oral tongue, buccal mucosa, upper and lower
gingiva, hard palate (including retromolar trigone)
Stage I tumours can be treated with surgery or radiotherapy Oral cavity subsites: anatomical classification
(RT), e.g. brachytherapy. If transoral resection without functional
sequelae is feasible, surgery is preferred.
Lip (upper and lower)
In Stage II tumours, surgery is the standard of care. For
Tongue (anterior 2/3rds)
lesions <3 cm, infiltration <1 cm and tumour thickness <4
Floor of mouth
mm, RT can be considered if there is adequate distance
from bone structures. Gingiva (upper and lower)
Buccal mucosa
In Stage III-IV tumours, surgery usually followed by RT +/- Retromolar trigone
chemotherapy (ChT) is preferred. In unresectable disease, Hard palate
concomitant chemoradiotherapy (ChT-RT) is the standard of care.
Predictive value of tumour thickness in squamous cell carcinoma

of the tongue and floor of the mouth
Tumour
Postoperative RT is indicated in case of pathological minor
<2 mm 2-8 mm >8 mm thickness risk factors:
Mucosa
2 mm • Poor differentiation grade (G3)
• Perineural and/or vascular invasion
Submucosa
8 mm
• Number of pathologically positive lymph nodes (≥2)
• pT3, pT4
Risk of occult 7.5% 25.7% 41.2%
metastasis In selected non-radical excision, re-excision can be
considered.
Concurrent ChT-RT is indicated in case of pathological major
In clinically negative neck disease, prophylactic neck
risk factors:
dissection can be avoided in T1 lesions and T2 lesions
• R1 resection (resection with microscopic residual disease)
of the hard palate, upper lip and upper gingiva. Strict
• Lymph node extranodular extension (ENE)
follow-up is advised.
Prophylactic neck dissection should always be indicated
if primary tumour infiltration depth is >3 mm in T1-T2
Overall survival curves by treatment arm
lesions. Prophylactic neck surgery is mandatory in all
1.0
T3-T4 lesions arising from the oral cavity.
0.9 Treatment
Surgery is preferred for prophylactic neck treatment; Control
0.8
RT can be considered in selected cases (e.g. if
0.7
postoperative RT on T is indicated, or in case of
anaesthetic contraindications). 0.6
Probability
0.5
3–5 year overall survival (OS) for Stage I-II tumours after 0.4 No improvement in OS
radical treatment is 70%–85%. In Stage III-IV tumours, with neoadjuvant ChT in
0.3 resectable oral cavity
5-year OS is ~50%. squamous cell cancer
0.2
The local control rate is 60%, with significant variation by
0.1
stage and site.
0.0
0 12 24 36 48 60
Neoadjuvant ChT showed no improvement in OS, thus Months
it can be considered only within clinical trials.
ChT, Chemotherapy; OS, overall survival.
REVISION QUESTIONS
1. What is the standard treatment in locally advanced (Stage III-IV) unresectable oral cavity cancer?
2. What is the best management strategy in T1 radically resected oral tongue cancer with infiltration depth >3 mm?
3. What is the 5-year OS rate in Stage III-IV oral cavity cancer?
19
Licitra et al
Oropharynx | S
oft palate, base of tongue, tonsillar area
Tumours, clinically staged as T1-T2 N0, can be equally

treated with radical surgery or RT, though RT is generally
preferred for better functional outcome.
New conservative surgical techniques (e.g. transoral

robotic surgery [TORS] and transoral laser microsurgery
[TLMS]) have shown promising results in terms of
functional outcome, but surgical expertise is needed.
Prophylactic treatment of clinically negative neck disease

is always indicated, as any lesion arising in the oropharynx
has a risk of subclinical neck disease >20%.
Absolute 5-year survival Postoperative RT is indicated in case of pathological minor risk factors:
(%) benefit with addition of • Poor differentiation grade (G3)
concomitant ChT to RT
• pT3, pT4
In selected cases of non-radical excision, a re-excision can be
considered.
Concurrent ChT-RT is indicated in case of pathological major risk factors:
• R1 resection • Lymph node ENE
Tumours, clinically staged as T3-T4 N0 or any T and N+, may

be generally treated with RT associated with platinum-based
ChT. Bioradiation (bio-RT; cetuximab plus RT) is an alternative
approved option. However, ChT-RT is preferred because a
formal comparison between these two therapeutic options is still
needed. Bio-RT is advisable for patients unfit to receive cisplatin.
When concurrent chemo- or bio-RT is not feasible, altered

ChT, Chemotherapy; RT, radiation therapy.
fractionation RT (accelerated or hyperfractionated, with highest
survival benefit for the latter) should be considered.
Overall survival according to tumour HPV status

100
HPV-positive
Several prognostic factors have been established:
Overall Survival (%)
human papillomavirus (HPV) tumoural status, smoking 75
history and clinical stage. Early stage HPV-related

tumours have a 5-year OS of 90%, therefore there 50
are many ongoing clinical trials aimed at treatment HPV-negative
deintensification. At present, the treatment of HPV- 25
positive oropharynx remains unchanged (see above).
Hazard ratio for death, 0.38 (0.26– P< 0.55); 0.001
0
Neoadjuvant ChT showed no improvement in OS, thus it 0 1 2 3 4 5
can be considered only within clinical trials. Years since Randomisation
No. at Risk Different OS (%) for
HPV, Human papillomavirus; OS, overall survival. oropharyngeal cancer patients
HPV-positive 206 193 179 165 151 73
HPV-negative 117 89 76 65 51 with
22 HPV-positive and
HPV-negative tumours
REVISION QUESTIONS
1. What is the standard of care in locally advanced oropharyngeal cancer?
2. What is the prognostic impact of HPV-related oropharyngeal cancer?
3. What is the role of neoadjuvant ChT in oropharyngeal cancer?
20
Site- and stage-driven treatment strategy in non-metastatic disease
Hypopharynx | Posterior pharyngeal wall, post-cricoid/pharyngo-oesophageal
junction, piriform sinus
Stage I-II tumours can be equally treated with surgery
Hypopharynx subsites: anatomical classification
or RT. RT is preferred to extensive surgery due to the
functional outcomes but conservative surgery, if feasible,
is an alternative.
Posterior
Resectable Stage III-IV tumours can be cured with pharyngeal
surgery followed by RT +/- ChT. Unresectable tumours wall
are treated with chemo-/bio-RT. Piriform sinus
Post-cricoid area
Prophylactic treatment of clinically negative neck disease
is always indicated, as any lesion of the hypopharynx has
a risk of subclinical neck disease >20%.
Pathological major risk

factors for postoperative
concomitant ChT-RT in radically
resected HNSCC
Postoperative RT is indicated in case of pathological
minor risk factors:
RTOG • Poor differentiation grade (G3)
Stage III-IV
OP, OC with
level 4 or 5 LN • pT3, pT4
Margins +
2+ pos. nodes
In case of non-radical excision, a re-excision can be
Perineural ENE considered.
disease
Concurrent ChT-RT is indicated in case of pathological
Vascular major risk factors:
embolisms
• R1 resection
EORTC • Lymph node ENE
In patients who are candidates for total laryngectomy, an

ChT-RT, Chemoradiotherapy; ENE, lymph node extranodular extension; EORTC, European Organisation organ preservation multimodality strategy can be adopted.
for Research and Treatment of Cancer; HNSCC, head and neck squamous cell carcinoma; LN, lymph
node; OC, oral cavity; OP, oropharynx; RTOG, Radiation Therapy Oncology Group.
5-year relative survival
rate (RS, %) in hypopharyngeal
cancer patients across
Carefully selected patients can be treated with concurrent European regions
definitive ChT-RT or with induction ChT (IChT), followed Hypopharynx
by exclusive RT (IChT → RT) in responding patients. IChT 80
→ RT is associated with a better long-term survival but a 70 Northern Europe
lower organ preservation rate. 60
Five-year RS
Ireland and UK
50
The standard regimen for IChT is docetaxel-cisplatin- Central Europe
40
fluorouracil (TPF), while cisplatin is the standard Southern Europe
30
chemotherapeutic agent for ChT-RT.
20 Eastern Europe
10 Europe
The 5-year OS for Stage I-II tumours is 70%–80%. In
1999-2001 2002-2004 2005-2007
Stage III-IV tumours, prognosis is dismal with a 5-year Period
OS of about 30%.
REVISION QUESTIONS
1. What is indicated in case of lymph node ENE?
2. What is the standard ChT regimen before RT in the organ-preservation strategy?
3. What is the prognosis of locally advanced (Stage III-IV) hypopharyngeal cancer?
21
Licitra et al
Larynx | Supraglottic: infra- and supra-hyoid epiglottis, aryepiglottic fold (laryngeal side),
arytenoid, false vocal cords; glottic: true vocal cords, anterior and posterior
commissure; subglottic
Laser
endoscopic surgery
Supraglottic tumours: of the larynx
Stage I-II tumours can be equally treated with
conservative surgery (endoscopic or open) or exclusive
RT. When radicality is expected, surgery is preferred.
Glottic tumours:
Stage I-II tumours can be equally treated with
conservative surgery (laser endoscopic) or RT. For T1
tumours, RT is equivalent to or better than surgery in
terms of quality of the voice. RT is preferred in case
of anterior commissure involvement and subglottic
extension.
Subglottic tumours: Prophylactic treatment of clinically negative neck disease is

Stage I-II tumours are treated with exclusive RT. indicated in selected cases of supraglottic subsite (e.g. T2).
In presence of inadequate margins (<5 mm in open In T4 patients, surgery followed by RT +/- ChT is
surgery and <2–3 mm in endoscopic surgery), another considered state of the art. Unresectable tumours are
treatment (RT or endoscopic surgery) is needed. treated with chemo-/bio-RT.
In T2, T3 supra- or glottic tumours that are candidates for Postoperative RT is indicated in case of pathological
total laryngectomy, an organ preservation multimodality minor risk factors:
strategy can be adopted. Data on this strategy in • Poor differentiation grade (G3)
subglottic tumours are not available, but it could be • Perineural and/or vascular invasion
considered in selected cases (e.g. T3N0). • Number of pathologically positive lymph nodes (≥2)
• pT3, pT4
In case of non-radical excision, a re-excision can be
considered.
Concurrent ChT-RT is indicated if pathological major risk
factors:
• R1 resection Cancer-related
• Lymph node ENE survival (%) significantly
lower in concomitant ChT-RT
used for organ-preservation
The organ preservation multimodality strategy includes 100
multimodality strategy
concurrent definitive ChT-RT or IChT followed by
exclusive RT in responding patients (IChT → RT). 80
IChT → RT is associated with a better long-term
Survival (%)
survival but a lower organ preservation rate. The 60
standard regimen for IChT is TPF, while cisplatin is

40
the standard chemotherapeutic agent for ChT-RT.
RT + ind.
20
The local control rate is about 80%–95% in early stage RT + conc.
RT only
supraglottic and glottic tumours and 60%–70% in early
stage subglottic tumours. In advanced stage disease, the 0 1 2 3 4 5 6 7 8 9 10
local control rate is about 60% with surgery + RT (+/- ChT) Time Since Random Assignment (years)
or organ preservation strategy.
ChT-RT, Chemoradiotherapy; RT, radiotherapy.
REVISION QUESTIONS
1. When is RT preferred to surgery in the treatment of early stage glottic tumours?
2. Which laryngeal cancers can be treated with an organ preservation strategy?
3. What are the results of this strategy?
22
Site- and stage-driven treatment strategy in non-metastatic disease
Summary: Site- and stage-driven treatment strategy in
non-metastatic disease
• In early stage disease, Stage I-II (cT1-2N0), of HNSCC, surgery or RT are equally good therapeutic options
• In early stage oral cancers, if a transoral resection is feasible without significant sequelae, surgery might be preferred to RT
• In early stage oral cancers, in case of clinically negative neck disease, prophylactic neck dissection should be
performed if the primary tumour infiltration depth is >3 mm
• In locally advanced disease, Stage III-IV (cT3-4N-/N+) HNSCC, concurrent ChT-RT is the standard of care. For larynx
or hypopharynx, ChT-RT may be also suggested in resectable cases as an organ-preservation approach, but only for
unresectable disease in oral cavity
• In concurrent ChT-RT, ChT consists of platinum-based regimens (cisplatin preferred to carboplatin). No differences
between thrice- or once-weekly schedules have been demonstrated
• Bio-RT (cetuximab plus RT) is an alternative approved therapeutic option, advisable for patients unfit to receive cisplatin
• Altered fractionation RT (accelerated or hyperfractionated) should be considered when ChT-RT or bio-RT are not
feasible
• IChT with the TPF regimen, followed by RT +/- ChT, is a real alternative therapy (vs ChT-RT or bio-RT) only in larynx
or hypopharynx subsites as a multimodality organ-preservation strategy; otherwise it may be an option only within
clinical trials
• Postoperative ChT-RT is indicated in case of major risk factors (R1 resection and/or lymph node ENE)
• HPV is a validated positive prognostic factor only for the oropharyngeal subsite
Further Reading
Amin MB, Edge S, Green F, et al (Eds). AJCC Cancer Staging Manual, 8th edition. New York: Springer, 2017.
363:24–35.
Bernier J, Domenge C, Ozsahin M, et al; European Organization for Research and Treatment of Cancer Trial 22931. Postoperative
irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 2004; 350:1945–1952.
Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med
2006; 354:567–578.
Bourhis J, Overgaard J, Audry H, et al; Meta-Analysis of Radiotherapy in Carcinomas of Head and neck (MARCH) Collaborative Group.
Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis. Lancet 2006; 368:843–854.
Cooper JS, Pajak TF, Forastiere AA, et al; Radiation Therapy Oncology Group 9501/Intergroup. Postoperative concurrent radiotherapy
and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004; 350:1937–1944.
D’Cruz AK, Vaish R, Kapre N, et al; Head and Neck Disease Management Group. Elective versus therapeutic neck dissection in node-
negative oral cancer. N Engl J Med 2015; 373:521–529.
Forastiere AA, Zhang Q, Weber RS, et al. Long-term results of RTOG 91-11: a comparison of three nonsurgical treatment strategies to
preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol 2013; 31:845–852.
Pignon JP, le Maître A, Maillard E, Bourhis J; MACH-NC Collaborative Group. Meta-analysis of chemotherapy in head and neck cancer
(MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol 2009; 92:4–14.
Posner MR, Hershock DM, Blajman CR, et al; TAX 324 Study Group. Cisplatin and fluorouracil alone or with docetaxel in head and neck
cancer. N Engl J Med 2007; 357:1705–1715.
Vermorken JB, Remenar E, van Herpen C, et al; EORTC 24971/TAX 323 Study Group. Cisplatin, fluorouracil, and docetaxel in
unresectable head and neck cancer. N Engl J Med 2007; 357:1695–1704.
23
Licitra et al
Principles of surgery of squamous cell tumours 5
Principles and goals in head and neck surgery
Early head and neck squamous cell carcinoma

Summary of some key recommendations (Lefebvre and Ang 2009)
(HNSCC) can usually be treated with either surgery or
Patient selection Eligible patients should have T2 or T3 laryngeal (glottic or supraglottic)
radiotherapy. Multimodality treatment of HNSCC (required or hypopharyngeal squamous cell carcinoma not considered for partial
in advanced cases) has drawbacks such as toxicities, laryngectomy
Exclusion criteria should include laryngeal dysfunction (defined as
reduced functional outcome and treatment failure and is pretreatment tracheotomy, tumour-related dysphagia requiring feeding
contraindicated in patients with many comorbidities. tube, or recurring pneumonia within the preceding 12 months requiring
hospitalisation). Patients aged >70 years should also be considered
Assesments Baseline assessments for speech and swallowing function (e.g. a barium
Lefebvre and Ang (2009) established a list of oesophagram) may be useful for longitudinal comparison
guidelines for better outcome specification after Assessment of voice should be done with a simple, validated instrument
(e.g. Voice Handicap Index-10 or Voice-Related Quality of Life) at 1 and 2 years
organ-preservation therapy in patients with laryngeal Endpoints The primary endpoint should combine assessment of survival and preservation
and hypopharyngeal cancer, which should be used in of organ function, as in the new composite endpoint laryngo-oesophageal
dysfunction (LED)-free survival (includes death, local relapse, total or partial
further clinical trials. laryngectomy, tracheotomy at ≥2 years, or feeding tube at ≥2 years)
Recommended secondary endpoints include freedom from LED, overall
These guidelines describe a new endpoint: “laryngo- survival, progression-free survival, locoregional control, time to tracheotomy,
time to laryngectomy, time to discontinuation of feeding tube, and quality of
oesophageal dysfunction-free survival”, implicating the life/patient-reported outcomes
highly important issue of late functional outcome. Tissue banking Recommended proof-of-principle correlative biomarker studies for
and biomarker near-term trials include EGFR (total, p-EGFR, and EGFRvIII) defined by
assessment immunohistochemistry, excision repair cross-complementation group 1 gene,
E-cadherin and β-catenin, epiregulin and amphiregulin, and TP53 mutation
EGFR, Epidermal growth factor receptor.
Reconstruction with a radial forearm flap
HNSCC treatment guidelines are based on phase III trials

and meta-analyses, with an excess of chemoradiotherapy
(ChT-RT) studies at the expense of surgical trials.
Due to the disproportion between surgical and non-surgical
trials, it is difficult to set up clinical recommendations for
HNSCC treatment based on the evidence.
Well-established and proven standards in surgery

of HNSCC are defined as state-of-the-art tumour
resection and reconstruction procedures.
Instruments for evaluating best surgical practice are Minimal distance of 5 mm between tumour and resection margin
different from methodological standards in non-surgical
phase II or III trials.
The inclusion of the minimal distance between
tumour tissue and resection margins into the current
R-classification would be useful. The R-classification
is used and is recommended by the American
Joint Committee on Cancer (AJCC) / Tumour Node
Metastasis (TNM) system.
In HNSCC surgery, a distance of 5 mm at minimum

(except in tumours of the vocal cord) is highly
recommended.
REVISION QUESTIONS
1. Which outcome-defining endpoint was proposed by Lefebvre and Ang?
2. From which field do the majority of high-impact publications on HNSCC come: surgery or ChT-RT?
3. How wide is an oncological-sufficient resection margin in HNSCC?
24
Principles of surgery of squamous cell tumours
Principles and goals in head and neck surgery (continued)
Standardised neck dissection should be included in

Robbins classification of lymph node levels
the tumour stage-related surgical concept.
Level Ia and Ib Submental and submandibular lymph nodes
Level IIa and Ib Upper jugular lymph nodes
Neck lymph nodes are divided into levels according
Level III Middle jugular group
to the Robbins classification.
Level IV Lower jugular group
Level Va and Vb Posterior triangle group
Primary surgery and additional adjuvant treatment Level VI Anterior compartment group
of HNSCC is always recommended if R0 resection
is possible.
Tumour board
The choice of either surgery or non-surgical primary

approaches is mainly based on clinical experience and
medical culture.
Several studies showed that patients treated in high-
volume centres have a better outcome than those treated
in low-volume centres.
The treatment decision should be based on an

interdisciplinary view (tumour board) on best survival,
late functional outcome and patient’s needs.
Operative finding after pharyngo-laryngectomy
Head and neck oncology is experiencing a renaissance in

surgery, due to new techniques, less radical approaches
and better reconstruction, and also to late toxicity
problems after primary ChT-RT.
The dense anatomical structures in the head and neck,
coupled with limited soft tissue redundancy, must be
allowed for in surgical planning.
A consequent oncologically sound resection must

be performed, even if a larger or more challenging
reconstructive defect may result.
REVISION QUESTIONS
1. Which lymph node levels are defined according to Robbins?
2. Who should make decisions about cancer treatment?
3. What are the reasons for the renaissance in primary and salvage surgery of HNSCC?
25
Dietz & Wiegand
Goals of reconstruction: wound healing, vital structure protection,
function and cosmesis
The first principle in reconstructive surgery applies to Reconstructive ladder
the creation of a defect. The repair follows a sequence Primary closure
often referred to as the “reconstructive ladder”.
Skin grafts
Wound management should begin with the simplest Local flaps
technique first, and then progress to more complex
Distant pedicled flaps
rearrangement and transfers, as needed.
Microvascular tissue transfer
The strategy ultimately chosen should provide the best
functional and cosmetic outcomes for patients, yet pose
the least surgical risk.
Reconstruction with a pectoralis major flap
The reconstruction of a surgical defect follows a

generalised set of principles applied to the patient’s
anatomical and functional deficit(s).
These principles allow the surgeon to reconstruct a

wide variety of defects to achieve optimal functional
and aesthetic outcomes for patients.
Before a patient is taken to the operating room, the

defect and functional and aesthetic results should be
known and accepted by both the patient and surgeon.
Reconstruction of the tongue with a radial forearm flap
The overarching goal of reconstructive surgery is to

create new tissue arrangements that serve in place of
native structures.
Surgery of the head and neck poses unique challenges
in achieving reconstructive results that go beyond simple
wound healing.
The reconstructive surgeon must preserve a patient’s

ability to eat, speak, swallow and breathe, in addition to
yielding a good aesthetic outcome and quality of life.
REVISION QUESTIONS
1. What is meant by the term “reconstructive ladder”?
2. What methods of tissue repair do you know?
3. What is the goal of reconstructive surgery?
26
Goals of reconstruction: wound healing, vital structure protection,
function and cosmesis (continued)
A “flap” refers to tissue that is moved from a donor to a Radial forearm flap
recipient site and carries its own blood supply. The main
types are pedicled and microvascular free flaps.
These two flaps differ from each other in that pedicled
free flaps remain connected to their native blood supply,
either random or axial.
Microvascular free flaps are tissue units with axial

vessels, completely separated from their donor site and
connected to a vein and artery at the defect.
Pectoralis major myocutaneous flap
Pedicled flaps are best suited to defects requiring tissue

bulk for a multilayer tissue closure in which minimal tissue
folding is required.
A pedicled flap offers some advantages in head and

neck reconstruction, as exemplified by the pectoralis
major myocutaneous flap, popularised in 1979.
Pedicled flaps can be inset into a wound in a single step,

and bring with them a robust and reliable blood supply.
Reconstruction of the soft palate with a radial forearm flap

Microvascular free tissue transfers offer distinct
advantages in reconstruction for use in scalp, facial, oral,
pharyngeal and osteocutaneous defects.
The ability to mould and sculpt microvascular free flaps
to three-dimensional forms allows them to be used in a
multitude of settings.
The radial forearm free flap has become a workhorse

flap in head and neck reconstruction, especially for
soft-tissue replacement. Postoperative radiotherapy
can start two to three weeks after the operation,
depending on wound healing.
REVISION QUESTIONS
1. How does a flap differ from a graft?
2. What are the advantages of pedicled flaps?
3. What are the advantages of microvascular free flaps?
27
Dietz & Wiegand
Transoral surgery triggered by HPV16 in oropharyngeal cancer treatment
Tonsil cancer
In North America and Western Europe, the incidence of
human papillomavirus (HPV) 16-related HNSCC of the
oropharynx is increasing dramatically.
Today, there are no data showing by direct comparison

the superiority of surgical or non-surgical treatment in
HPV-positive disease.
Current data show that HPV16-positive oropharyngeal
cancer patients do much better than HPV16-negative
patients, regardless of receiving surgery or ChT-RT.
Intraoperative finding after laser resection of

cancer of the base of tongue
Transoral Robotic Surgery (TORS) is used in routine
treatment for lesions of the tonsillar region and base of
tongue in many US centres, with good results.
In Europe, TORS is in strong competition with

Transoral Laser Microsurgery (TLMS). Use of TLMS is
limited, especially in the base of tongue lesions, but is
highly efficient in well-trained hands in most head and
neck regions.
Evidence for the superiority of TORS over TLMS does not

exist, and reimbursement policies in Europe do not cover
its costs.
Reconstruction with a radial forearm flap
The small volume of the oropharynx and limited tissue

redundancy restrict reconstructive options. Healing by
secondary intention may cause unwanted scarring.
An open wound may pose risk to surrounding structures
if a communication exists between the oropharynx and
deep neck.
Skin grafts can be used to restore superficial tissue

loss. More involved defects of the oropharynx or soft
palate are best treated with a regional or free flap.
REVISION QUESTIONS
1. Are there any data showing the superiority of surgical or non-surgical treatment in HPV-positive disease?
2. What are the advantages of TORS compared with TLMS?
3. What reconstructive options do we have for covering oropharyngeal defects?
28
Summary: Principles of surgery of squamous cell tumours
• The field of head and neck surgery has advanced enormously
• Head and neck oncology is currently experiencing a renaissance in primary and salvage surgery
• New techniques and late toxicity problems after primary ChT-RT dominate the interdisciplinary view on therapy
of HNSCC
• The surgeon must not compromise the complete excision of neoplastic disease, even if a larger or more challenging
reconstructive defect may result
• The type of flap which offers the best functional and cosmetic outcome should be used for coverage of defects
• Microvascular free tissue transfers offer distinct advantages in reconstruction
• No evidence for superiority of TORS over TLMS exists
• Health insurance policies in Europe do not cover the costs of TORS; therefore this technique is not recommended for
first-choice routine treatment
• Current evidence is not in favour of abandoning primary surgery in HPV16-positive patients with oropharyngeal cancer,
nor of changing routine treatment options beyond clinical trials
• Future concepts also have to include surgical aspects, which have to be reflected within new clinical trial approaches
Further Reading
Ariyan S. The pectoralis major myocutaneous flap. A versatile flap for reconstruction in the head and neck. Plast Reconstr Surg 1979;
63:73–81.
Higgins KM, Wang JR. State of head and neck surgical oncology research – a review and critical appraisal of landmark studies. Head
Neck 2008; 30:1636–1642.
Kenney Magill C, Haughey BH. Principles and new approaches in surgical reconstruction. Chapter 33. In: Bernier J (Ed): Head and Neck
Cancer. New York: Springer, 2011.
Lefebvre JL, Ang KK; Larynx Preservation Consensus Panel. Larynx preservation clinical trial design: key issues and recommendations
– a consensus panel summary. Int J Radiat Oncol Biol Phys 2009; 73:1293–1303.
Markey J, Knott PD, Fritz MA, Seth R. Recent advances in head and neck free tissue transfer. Curr Opin Otolaryngol Head Neck Surg
2015; 23:297–301.
Robbins KT, Shaha AR, Medina JE, et al; Committee for Neck Dissection Classification, American Head and Neck Society. Consensus
statement on the classification and terminology of neck dissection. Arch Otolaryngol Head Neck Surg 2008; 134:536–538.
Shah JP, Patel SG, Singh B. Head and Neck Surgery and Oncology, 4th edition. New York: Mosby Ltd, 2012.
Weinstein GS, O’Malley BW Jr, Rinaldo A, et al. Understanding contraindications for transoral robotic surgery (TORS) for oropharyngeal
cancer. Eur Arch Otorhinolaryngol 2015; 272:1551–1552.
Wittekind C, Compton C, Quirke P, et al. A uniform residual tumor (R) classification: integration of the R classification and the
circumferential margin status. Cancer 2009; 115:3483–3488.
29
Dietz & Wiegand
Principles of radiotherapy of squamous cell tumours 6
Introduction; general principles of radiotherapy
Radiotherapy (RT) plays an important role in the

management of head and neck cancers.
RT is given either as a sole curative modality or combined

with systemic treatment (such as chemotherapy [ChT],
hypoxia modifiers or monoclonal antibodies). RT can also be
given as an adjuvant treatment following surgery (either as a
sole modality or in combination with ChT).
For some head and neck cancer subsites, RT offers the
chance for organ sparing and function preservation by
avoiding the use of surgery.
Radiation kill cells primarily by causing ionisation, which

leads to single strand or double strand DNA damage.
If the DNA damage cannot be repaired by cellular DNA
repair mechanisms, the injury leads to cell death.
Normal cells have a greater capacity to repair the DNA

damage compared with malignant cells, leading to
preferential cancer cell death.
The aim of RT is to deliver adequate dose to the tumour

Radiation kills cancer to eradicate the cancer cells, while ensuring the dose
by damaging DNA
delivered minimises acute and long-term damage to the
surrounding normal tissue.
Radiation dose is measured in Gray (Gy), which is the

absorption of 1 Joule of energy per kilogram of water.
Photons tend to cause more sparse ionising cell changes

compared to particles such as protons and other heavy
particles, which have higher linear energy transfer,
resulting in dense ionisation along the track.
Most RT is delivered through an external source such
as a linear accelerator, but sometimes can be given
by brachytherapy, which delivers radiation directly into
(interstitial), or adjacent to (intracavity), the tumour.
REVISION QUESTIONS
1. What are the treatment modalities for head and neck cancer?
2. How does radiation kill cancer cells?
3. How does radiation allow for organ sparing and function preservation?
30
Principles of radiotherapy of squamous cell tumours
Preparation for radiotherapy
As head and neck cancers affect the organs that influence Immobilisation of a patient with a mould
eating, swallowing, speech, vision and hearing, which
are in close proximity to critical structures such as the
brainstem, spinal cord and temporal lobes, accurate
delivery of radiation to the cancer while sparing the organs
at risk is critical in head and neck cancer RT.
To facilitate this, patients are accurately immobilised

with individualised thermoplastic moulds that
effectively restrict patient movement from the top of
the head to the shoulders.
Patient being set up for treatment
The patients then undergo a planning computed

tomography (CT) scan with intravenous contrast, to allow
accurate delineation of the cancer and the organs at risk.
Magnetic resonance imaging (MRI) and positron

emission tomography (PET)/CT scans can also be used
as adjunct to the planning process.
Treatment contouring and planning
GTV
CTV1_65
CTV2_60
Once the planning imaging has been acquired, the
CTV2_54
oncologist carefully delineates the cancer and the areas CTV3_54
and nodal regions at risk of microscopic spread. The
organs at risk are also delineated.
The dosimetrist then carefully plans the treatment

using sophisticated computer-based planning systems
to optimise the doses that will be delivered to these
different areas.
GTV: All gross disease on imaging or exam; CTV1: “Microscopic margin”;

CTV2: “High risk” nodal volumes and mucosal sites; CTV3: “Elective” uninvolved nodal
regions at risk for microscopic disease
REVISION QUESTIONS
1. Why are patients immobilised with a mould for RT?
2. What imaging do patients receive in order for the radiation oncologist to plan RT?
3. What are the areas the oncologist has to delineate to plan RT?
31
Slevin & Lee
Preparation for radiotherapy (continued)
3D-CRT: Blue indicates the target. Yellow line is 95% isodose

Three-dimensional conformal radiotherapy (3D-CRT)
refers to the delivery of RT that conforms to the target
volume and the patient’s anatomy.
The ability to spare the critical organs is further improved

by modulating multiple non-uniform beams with a
technique known as intensity modulated RT (IMRT).
Randomised trials have shown that IMRT reduces
certain long-term side effects compared to 3D-CRT
(Nutting 2011).
CRT, Conformal radiotherapy.
IMRT: Coverage of target better than 3D-CRT

IMRT can be delivered much faster through a
rotational arc IMRT, which allows the treatment head
to continuously modulate the delivered dose as it is
moving around the patient.
To ensure that the treatment is accurately delivered,

image-guided radiotherapy (IGRT) is delivered with the
use of 3D cross-sectional imaging during treatment to
minimise set up inaccuracies.
The concept of image-guided adaptive RT is currently in
development. This technique incorporates re-planning of
the RT based on anatomical and volume changes of the
cancer, and the organs at risk during treatment.
CRT, Conformal radiotherapy; IMRT, intensity modulated radiotherapy.
Since RT can affect a patient’s dentition, eating and Acute side effects of head and neck RT
swallowing, it is advisable for patients to be reviewed Lethargy, xerostomia, mucositis, dermatitis, pain,
by a dentist, dietician and speech & language therapist thickened secretions, dysphagia, nausea, loss of taste,
prior to RT. malnutrition, oedema
Chronic side effects of head and neck RT

To reduce the risk of osteoradionecrosis, any teeth
Xerostomia, fibrosis, dysphagia, osteoradionecrosis,
that are likely to require extraction in the future are best restriction of movement, shrinkage of tissue
extracted prior to starting RT.
RT, Radiotherapy.
Patients are also advised to stop smoking and given
smoking cessation treatment. For more detailed
information, please refer to Chapter 11.
REVISION QUESTIONS
1. How is IMRT better than 3D-CRT?
2. How can an oncologist ensure that treatment is accurately delivered?
3. What other allied health professionals are needed to help care for a patient undergoing head and neck RT?
32
Radiotherapy indications, dose and fractionation
RT is often given as the definitive treatment for some head Overall survival by HPV status
and neck subsites such as oropharynx, hypopharynx, 1.0
nasopharynx and larynx, with good local control.

0.8
Overall survival (probability)

Local control with RT depends on the physical size of
the tumour as well as the biological characteristics of the 0.6
cancer. For instance, studies have shown that cancers
which are human papillomavirus (HPV)-positive have 0.4
better prognosis and local control (Ang 2010).
0.2 HPV negative (Events/n = 4/14)
HPV positive (Events/n = 0/12)
P = 0.046
0 1.0 2.0 3.0

Time (years)
Risk factors for recurrence: RT can also be given as a postoperative treatment in

most head and neck subsites where it is felt that there
• Close or positive microscopic margins is a risk of postoperative recurrence.
• Perineural invasion
• Vascular invasion
• Presence of lymph node metastasis Delay of more than 6 weeks after surgery before starting
• Presence of extracapsular spread postoperative RT is also a poor prognostic factor. For
further details please refer to Chapter 4.
RT is often given in multiple fractions (traditionally
5 fractions per week) to take advantage of the radiological
differences in cancer and normal tissue response to
radiation. There is evidence of dose response in head
and neck cancer.
The international conventional dose of RT is a
radiobiological equivalent dose of around 70 Gy in 35
fractions (over 7 weeks) for definitive RT, and around 60
Gy in 30 fractions (over 40 days) to 66 Gy in 33 fractions
(over 45 days) for postoperative RT. There is, however,
considerable variation to this practice.
Using IMRT, different target regions can be treated
with different doses in the same number of fractions, a
concept known as simultaneous integrated boost (SIB).
Some centres may boost a particular target area with Compensation for unavoidable or unscheduled interruptions to RT
additional dose after completion of treatment to the other
target areas. • Twice-daily fractions, minimum 6 hours interval
• Weekend treatment
• Use of biologically equivalent dose in fewer fractions to achieve
Interruptions to the RT schedule, which increase the planned overall time
overall treatment time, are to be avoided if possible, as • Additional fractions where compensation cannot be achieved within
uncompensated treatment gaps have been shown to the original planned time
reduce local control.
RT, Radiotherapy.
33
Slevin & Lee
Radiotherapy indications, dose and fractionation (continued)
Studies have shown altered fractionation improves local Altered fractionation strategies have been tested in head
control with increase in early toxicities (Overgaard et al 1998). and neck cancer
The MARCH meta-analysis of altered fractionation trials has The main approaches are:
i. Hyperfractionation (giving multiple small fractions per day
shown that altered fractionation can give better local control to a higher than conventional total dose). For example,
on the primary (6.4% benefit in 5 years), although its impact on 80.5 Gy in 70 fractions, twice daily fractions over 47 days
nodal control is less pronounced (Bourhis et al 2006). There is ii. Accelerated fractionation (giving conventional or lower total
an absolute benefit in overall survival of 3.4%. doses over a shorter overall treatment time). For example,
70 Gy in 35 fractions over 40 days
However, the benefit of altered fractionation is not seen when
concurrent ChT is given with RT (Nyugen-Tan 2014).
REVISION QUESTIONS
1. What affects the local control of cancers by RT?
2. In the postoperative setting, what risk factors predict cancer relapse?
3. Why are treatment gaps in RT detrimental?
Radiotherapy with concomitant systemic therapy

An intergroup comparison of standard radiation therapy and For patients with advanced head and neck squamous
concurrent chemoradiotherapy in patients with unresectable squamous carcinoma (Stage 3, 4a, 4b), the addition of
cell head and neck cancer
1.0 concomitant systemic treatment has been shown to be
0.9 beneficial in terms of local control and overall survival
0.8 (Pignon et al 2009). Cisplatin is most commonly used.
Survival probability
0.7
0.6 Radiation plus chemo In the postoperative setting, the addition of ChT has
0.5 Cisplatin 100 mg/m2 d1, 22 and 43
been shown to improve survival in those patients with
0.4
0.3 Radiation alone (70 Gy)
evidence of extracapsular nodal spread or positive
0.2 excision margins (Bernier et al. 2005).
0.1
0.0
0 10 20 30 40 50 60 70 80 90 100 100
Months
Locoregional Control (%)
Most head and neck squamous carcinomas over-express 80
epidermal growth factor receptor (EGFR). The concomitant

60
use of a monoclonal antibody against EGFR, cetuximab,
Radiotherapy plus cetuximab
has also been shown to be beneficial (Bonner et al 2006).
40
However, when cetuximab is added to cisplatin-based 20 Radiotherapy

concurrent chemoradiotherapy, there is no improvement
of outcome, but increased toxicities (Ang et al 2014). 0
0 10 20 30 40 50 60 70
Hypoxia modifiers such as nimorazole, when added to Months
RT, have also been shown to improve locoregional control No. at Risk
Radiotherapy 213 122 80 51 30 10
and cancer-related deaths. There is a non-statistically Radiotherapy 211 143 101 66 35 9
plus cetuximab
significant trend towards improved overall survival
(Overgaard et al 1998).
REVISION QUESTIONS
1. Which stages benefit from the addition of concomitant systemic treatment?
2. What are the concomitant systemic options?
3. Are there any benefits in adding two different types of concomitant systemic agent?
34
Summary: Principles of radiotherapy of squamous cell tumours
• RT is an effective modality in the treatment of head and neck cancer
• The aim of RT is to deliver an adequate dose to kill cancer cells, but minimise the dose to normal tissues to reduce
long-term complications
• RT requires accurate target immobilisation and treatment planning
• RT gives good local control and allows for organ preservation
• For advanced stage cancers, the addition of concomitant systemic treatment improves local control and overall survival
• In the postoperative setting, RT reduces the risk of locoregional relapse and improves overall survival in cases with high
risk of relapse
• Altered fractionation has been shown to improve local control
• Emerging technologies with IMRT and IGRT improve the outcome for patients
• RT can result in various side effects, some acute, some long term
• Patients on RT require the assistance of allied health professionals such as dentist, dietician and speech and language
therapist, to optimise their function and help with patients’ compliance to treatment
Further Reading
363:24–35.
Ang KK, Trotti, A, Brown BW, et al. Randomized trial addressing risk features and time factors of surgery plus radiotherapy in advanced
head-and-neck cancer. Int J Radiat Oncol Biol Phys 2001; 51:571–578.
Ang KK, Zhang Q, Rosenthal DI, et al. Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without
cetuximab for stage III to IV head and neck carcinoma: RTOG 0522. J Clin Oncol 2014; 32:2940–2950.
Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and neck cancers: a comparative analysis of
concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (#9501). Head Neck 2005; 27:843–850.
Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med
2006; 354:567–578.
Bourhis J, Overgaard J, Audry H, et al; Meta-Analysis of Radiotherapy in Carcinomas of Head and neck (MARCH) Collaborative Group.
Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis. Lancet 2006; 368:843–854.
Nguyen-Tan PF, Zhang Q, Ang KK, et al. Randomized phase III trial to test accelerated versus standard fractionation in combination with
concurrent cisplatin for head and neck carcinomas in the Radiation Therapy Oncology Group 0129 trial: long-term report of efficacy and
toxicity. J Clin Oncol 2014; 32:3858–3866.
Nutting CM, Morden JP, Harrington KJ, et al; PARSPORT trial management group. Parotid-sparing intensity modulated versus
conventional radiotherapy in head and neck cancer (PARSPORT): a phase 3 multicentre randomised controlled trial. Lancet Oncol 2011;
12:127–136.
Overgaard J, Hansen HS, Overgaard M, et al. A randomized double-blind phase III study of nimorazole as hypoxic radiosensitizer of
primary radiotherapy in supraglottic larynx and pharynx carcinoma. Results of the Danish Head and Neck Cancer Study (DAHANCA)
Protocol 5-85. Radiother Oncol 1998; 46:135–146.
35
Slevin & Lee
Treatment of recurrent or metastatic disease 7
Introduction
About one half of the patients treated for Stage III and IV Local Regional
disease will develop locoregional relapse or have locally Recurrence Recurrence
persistent disease.
About one third of the patients treated for earlier stage 25% 15% 8%
disease will develop distant metastases.
10%
Locoregional or distant relapses are usually detected
in two thirds of cases within the first 2 years after prior
treatment.
33%
Distant
Metastasis
Postoperative re-irradiation combined with chemotherapy

after salvage surgery compared with salvage surgery alone in
head and neck carcinomas
Disease-free survival Surgery is recommended for resectable recurrent or

100 but NOT overall survival was persistent disease. Adjuvant (radio/chemo) therapy should
improved with increased be considered, if feasible, after local salvage surgery.
Disease-free survival (%)
80 acute and late toxicity
60
Chemo re-irradiation
If the local recurrence is considered unresectable and the
40
No treatment patient did not have prior radiotherapy (RT), then RT with
or without systemic therapy is recommended.
20
Log-rank P=0.006 For patients not candidates for curative-intent surgery
0 1 2 3 4 5 and/or RT, the treatment is the same as for patients with
Time (years) metastatic disease.
No. of patients at risk
65 32 18 7 5 3
65 19 7 7 5 2
Factors associated with clinical outcome in patients with recurrent

and/or metastatic squamous cell head and neck cancer
Patient-related
Poor performance status
Presence of comorbidity
Poor cognitive functioning
Lack of social support
Ongoing carcinogen use
For patients with metastatic disease, systemic therapy Tobacco
remains the standard-of-care. Betel quid
Alcohol
Disease-related
Performance status (PS) at relapse is the strongest
Advanced stage, bulky locoregional or metastatic disease
predictive factor of clinical outcome. History of aggressive disease
Hypercalcaemia of malignancy
The main treatment objectives are to prolong survival and/ Treatment-related
or provide symptom palliation. Prior treatment
Lack of or minimal response to treatment
REVISION QUESTIONS
1. What is the incidence of recurrent and/or metastatic disease?
2. Are surgery and RT used in recurrent disease?
3. Which are the main factors associated with clinical outcome?
36
Treatment of recurrent or metastatic disease
Single-agent chemotherapy
Comparison of chemotherapy (ChT) versus supportive

Active single agents in the treatment of recurrent and/or metastatic
care has not been evaluated in well-designed
squamous cell head and neck cancer with response rate >15%
randomised clinical trials.
Cisplatin
Cisplatin monotherapy versus no treatment resulted in a Carboplatin
10-week median survival prolongation in a small study. 5-Fluorouracil
Methotrexate
Various chemotherapeutic agents are active as single- Vinblastine
agent treatment. Bleomycin
Ifosfamide
Doxorubicin
Cyclophosphamide
Hydroxyurea
Pemetrexed
A comparison of carboplatin plus methotrexate versus methotrexate

alone in patients with recurrent and/or metastatic squamous cell
head and neck cancer
1.0
0.9 CBDCA+MTX Single-agent ChT achieves less than 10% response rate
n=20
0.8 MTX and shows no significant survival improvement.
n=20
0.7
0.6 The addition of platinum agents to methotrexate (MTX)
% Surviving
0.5 is not superior to MTX alone.

0.4
0.3 Single-agent cisplatin and MTX are both considered
0.2 standard-of-care single-agent treatment options.
0.1
0.0
0 3 6 9 12 15 18 21 24 27 30 33
Months
CBDCA, Carboplatin; MTX, methotrexate.
Comparison of docetaxel versus methotrexate in patients with

recurrent squamous cell head and neck cancer
Paclitaxel and docetaxel have produced responses of 1.0

0.9 Methotrexate
20% to 40% in phase II clinical trials.
0.8
Docetaxel
0.7
There are limited data on paclitaxel compared with Weekly docetaxel
0.6
produced higher response
docetaxel, as well as between taxanes and other agents. 0.5
rate than weekly methotrexate
0.4 (27% versus 15%)
0.3
Taxanes can be used as single-agent treatment in
0.2
patients with renal dysfunction, for whom cisplatin and 0.1
MTX are difficult to use. 0.0
0 1 2 3 4 5 6 7 8 9 10 11 12
Time (months)
REVISION QUESTIONS
1. Is single-agent ChT or supportive care better?
2. Is there a standard single-agent treatment?
3. What is the therapeutic index of taxanes?
37
Karamouzis
Combination chemotherapy
Combination ChT is associated with higher response

Comparison of cisplatin plus fluorouracil and carboplatin plus
rates than single-agent therapy. fluorouracil versus methotrexate for patients with recurrent and/or
metastatic squamous cell head and neck cancer
Combination ChT has not produced better survival 100%
outcomes compared with monotherapy. Median survival (months)
Cisplatin + FU (87 pts) = 6.6
80% Carboplatin + FU (86 pts) = 5.0
Combination chemotherapy is associated with more high- Methotrexate (88 pts) = 5.6
grade toxicity. 60%
CRs + PRs were
32% for cisplatin + FU
40%
versus 10% for
methotrexate (P = 0.001)
20%
10%
0 12 24 36 48 60
Months after registration
At least 9-month survival
was 31% for cisplatin + FU,
30% for carboplatin + FU CR, Complete remission; FU, fluorouracil; PR, partial remission.
and 27% for methotrexate
Comparison of cisplatin and fluorouracil as single agents and in

combination for patients with recurrent and/or metastatic
squamous cell head and neck cancer
Cisplatin-based combinations have been compared
1.0 with single agents in phase III clinical trials.
0.9 Median survival (months)
0.8 Cisplatin (79 pts) = 5
Fluorouracil (83 pts) = 6.1 Cisplatin-fluorouracil combination is considered the
Proportion surviving
0.7
0.6
Cisplatin + FU (83 pts) = 5.5 standard-of-care reference regimen.
0.5
0.4 Cisplatin-based combinations have resulted in median
0.3 survival of 6 to 9 months, and 1-year survival rate of 20%
0.2
0.1
to 40%.
0.0
0 5 10 15 20 25 30 35 40 45 50
Months
Patients with poorly
differentiated tumours and FU, Fluorouracil; PS, performance status.
Comparison of cisplatin plus fluorouracil versus cisplatin plus paclitaxel
better PS had superior for recurrent and/or metastatic squamous cell head and neck cancer
survival
1.0
Treatment: Cisplatin +FU
0.9 Paclitaxel + cisplatin
0.8
The combination of taxanes with platinum compounds Log-rank P=0.49
has produced high response rates and median survival of 0.7
5–12 months in phase II clinical trials. 0.6 Median survival

Median survival (months)
(months)
Cisplatin ++ FU
Cisplatin FU == 8.7
8.7
0.5
Cisplatin++paclitaxel
Cisplatin Paclitaxel = 8.1
Paclitaxel-cisplatin combinations failed to show 0.4
significant differences regarding response rate and
0.3
overall survival compared with cisplatin-fluorouracil.
0.2
Triple-agent schedules containing a taxane, a platinum 0.1
compound and other agents (e.g. cetuximab) have given

0
high response rates and promising survival outcomes in 10 20 30
Months
40 50 60
phase II trials.
FU, Fluorouracil.
REVISION QUESTIONS
1. Is mono- or polychemotherapy better?
2. What is the clinical benefit of combination ChT?
3. Is there a role for taxanes in combination strategy?
38
EGFR inhibitors
Epidermal growth factor receptor (EGFR) is over-

expressed in 80%–100% of head and neck squamous
cell carcinomas.
Increased EGFR expression has been correlated with
worse clinical outcome.
EGFR dimerisation causes activation of the receptor-

linked tyrosine kinase (TK), recruitment of signalling
complexes and phosphorylation (activation) of multiple
downstream cascades.
EGFR, Epidermal growth factor receptor; IGF, insulin growth factor; PTEN, phosphatase and
Phase III studies evaluating EGFR inhibitors in recurrent and/or metastatic tensin homologue; TK, tyrosine kinase.
squamous cell head and neck cancer
Agent Treatment Primary Results Source
endpoint
Cetuximab Cisplatin plus PFS 4.2 versus Burtness et al EGFR targeting can be done either with monoclonal
cetuximab or 2.7 months (P=0.07) JCO 2005 antibodies targeting the extracellular domain, or
placebo OS: 9.2 versus
8 months (P=0.21) with small molecule TK inhibitors (TKIs) targeting the
Cetuximab Platinum/5-FU ± OS 10.1 versus Vermorken et al intracellular domain.
cetuximab 7.4 months NEJM 2008
(Extreme Trial) (P=0.036)
Some phase III clinical trials have been evaluating
Panitumumab Cisplatin/5-FU ± OS 11.1 versus 9 months Vermorken et al
panitumumab (P=0.14) Lancet Oncol 2013 EGFR inhibitors.
(Spectrum Trial)
Gefitinib Gefitinib 250 mg OS 5.6 versus 6 versus Stewart et al Cetuximab is the only EGFR inhibitor that has shown
or 500 mg versus 6.7 months (P=0.12 JCO 2009
methotrexate & 0.39)
overall survival benefit.
Gefitinib Docetaxel plus OS 7.3 versus 6 months Argiris et al
gefitinib 250 mg (P=0.60) JCO 2013
or placebo
5-FU, 5-Fluorouracil; EGFR, epidermal growth factor receptor; OS, overall survival;
PFS, progression-free survival. A
1.0
Probability of Overall Survival
|
|||
| Hazard ratio (95% CI): 0.80 (0.6 4–0.99)
0.9
Cetuximab increased
|
|
| |
P = 0.04
0.8 ||
|
0.7
0.6
|
Chemotherapy plus
median overall survival from
0.5 cetuximab (N = 222)
7.4 to 10.1 months
|
0.4
The addition of cetuximab to cisplatin-fluorouracil ChT

|
|
0.3 Chemotherapy (N = 220)
| | | ||||
||
||| |||
|| |
| | || | | || | |
| ||| ||
0.2 ||
|| |
| |||
| | ||
| || | ||| | | |
| | | | ||| | | | | | | || ||
| |
is the standard first-line treatment, as it resulted in a

0.1
0.0
0 3 6 9 12 15 18 21 24
2.7 month increase of median survival and a 2.3 month No. at Risk
Months
Chemotherapy
prolongation of progression-free survival.
220 173 127 83 65 47 19 8 1
Chemotherapy 222 184 153 118 82 57 30 15 3
plus cetuximab
B
Probability of Progression-free
1.0
Cetuximab-associated Grade 3/4 side effects are skin

|
Hazard ratio (95% CI): 0.54 (0.43–0.67)
0.9
0.8
| | |||||||
||
||
|
|
||| |
|
P< 0.001
Cetuximab increased
toxicity, hypomagnesaemia and infusion-related reactions. progression-free survival from
|
0.7 ||
|
| |
Survival
0.6 |
|
| |
|
3.3 to 5.6 months

| |
0.5 |
||
|
0.4 ||| |
| || |
|
Chemotherapy plus
Cetuximab 500 mg/m every 2 weeks can be safely

|
2 0.3 |
||
|
| cetuximab ( N = 222)
0.2
|
0.1 Chemotherapy (N = 220)

| |
administered in combination with ChT, and as maintenance

|
0.0
|
0 3 6 9 12 15
single-agent treatment until disease progresses.

Months
No. at Risk
Chemotherapy 220 103 29 8 3 1
Chemotherapy 222 138 72 29 12 7
plus cetuximab
CI, Confidence interval.
REVISION QUESTIONS
1. What is the role of EGFR in head and neck carcinogenesis?
2. What are the main EGFR-targeting strategies?
3. How has cetuximab changed the treatment landscape?
39
Karamouzis
Second-line therapy
Phase II clinical trials have evaluated various drugs.

Activity of selected agents in second-line treatment in recurrent
and/or metastatic squamous cell head and neck cancer
Overall, clinical trials showed a response rate up to 20%. Agent Response rate (%) Median survival (months)
Paclitaxel 9 8
No significant benefit was found regarding response Docetaxel 11 6.5
duration, progression-free survival and overall survival. Capecitabine 20 7.5
Cetuximab 13 6
Gefitinib 3-11 6-8
Erlotinib 4 6
Sunitinib 3 3.5
Cabazitaxel 0 5
Pembrolizumab 18.5 NR
NR, Not reached.
Major criteria for the selection of second-line treatment in

patients with recurrent and/or metastatic squamous cell head
and neck cancer
Patient-related The choice of therapy should be based on patient-
Poor performance status related factors, factors related to disease outcome and
Presence of comorbidity previous treatments.
Poor cognitive functioning
Lack of social support
Disease-related Best supportive care is an acceptable treatment option in
Bulky locoregional and/or metastatic disease patients with poor PS.
Oropharyngeal primary site
Prior RT New immunotherapy drugs (anti-PD-1 antibodies) have
Tumour differentiation shown survival benefit in second-line treatment and
Treatment-related represent a standard-of-care option.
Prior first-line treatment
Toxicity of previous treatment
Disease-free interval
Treatment-free time period
RT, Radiotherapy.
Afatinib versus methotrexate as second-line treatment in patients with

recurrent and/or metastatic squamous cell carcinoma of the head and neck
EGFR TKIs (gefitinib) have been tested in phase III A 100 Afatinib Methotrexate
Progression-free survival (%)
PFS events 275 (85%) 135 (84%)

Median PFS, months (95% CI) 2.6 (2.0-2.7) 1.7 (1.5-2.4)
clinical trials in patients after platinum failure, with 80
HR (95% CI)
P value
0.80 (0.65-0.98)
0.030
60
discouraging results. 40
Afatinib (n=322)
20 Methotrexate (n=161)
Afatinib (a new oral irreversible ERBB-receptor family 0

0 3 6 9 12 15 18
Number at risk
blocker) has improved progression-free survival Afatinib 322
Methotrexate 161
93
28
26
6
9
2
3
0
1
0
0
0
compared with methotrexate. B 100 Afatinib Methotrexate
OS events 237 (74%) 121 (75%)
Median OS, months (95% CI) 6.8 (6.1-7.7) 6.0 (5.2-7.8)
80
HR (95% CI) 0.96 (0.77-1.19)
Various novel agents are being evaluated in this 60 P value 0.70
clinical setting. 40
20
0
0 3 6 9 12 15 18 21 24 27
Time (months)
Number at risk
Afatinib 322 255 172 89 53 28 14 6 1 0
Methotrexate 161 115 76 48 29 16 9 7 3 0
CI, Confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival.
REVISION QUESTIONS
1. What is the standard-of-care second-line treatment?
2. What are the factors that govern treatment decisions?
3. Are there new effective agents?
40
Summary: Treatment of recurrent or metastatic disease
• Locoregional relapses and/or distant metastases are frequent in head and neck cancer patients
• Locoregional or distant relapses are usually detected in two thirds of cases within the first 2 years after prior treatment
• The main treatment objectives in this patient group are to prolong survival and/or provide symptom palliation
• Recurrent disease after multimodal local treatment is generally considered incurable if the patient cannot be salvaged
by surgery and/or additional RT
• PS predicts patients’ clinical outcome
• Platinum-based ChT in combination with cetuximab is considered the standard-of-care in fit patients
• Cisplatin, methotrexate and taxanes can be used as single-agent treatment
• Combination ChT has not produced better survival outcomes compared with single-agent treatment
• Anti-PD-1 immunotherapy drugs represent a standard-of-care second-line treatment
• Based on the improvement in knowledge of squamous cell head and neck cancer molecular biology, new compounds
are currently being investigated
Further Reading
Argiris A, Ghebremichael M, Gilbert J, et al. Phase III randomized, placebo-controlled trial of docetaxel with or without gefitinib in
recurrent or metastatic head and neck cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol 2013; 31:1405–1414.
Argiris A, Karamouzis MV, Raben D, Ferris RL. Head and neck cancer. Lancet 2008; 371:1695-1709.
Bossi P, Kornek G, Lanzetta G, et al. Safety and feasibility of every-other-week maintenance cetuximab after first-line chemotherapy in
patients with recurrent or metastatic head and neck squamous cell cancer. Head Neck 2013; 35:1471–1474.
Burtness B, Goldwasser MA, Flood W, et al. Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab
in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol 2005; 23:8646–8654.
Colevas AD. Chemotherapy options for patients with metastatic or recurrent squamous cell carcinoma of the head and neck. J Clin
Oncol 2006; 24:2644-2652.
Karamouzis MV, Grandis JR, Argiris A. Therapies directed against epidermal growth factor receptor in aerodigestive carcinomas. JAMA
2007; 298:70–82.
Machiels JP, Haddad RI, Fayette J, et al; LUX-H&N 1 investigators. Afatinib versus methotrexate as second-line treatment in patients with
recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head &
Neck 1): an open-label, randomised phase 3 trial. Lancet Oncol 2015; 16:583–594.
Stewart JS, Cohen EE, Licitra L, et al. Phase III study of gefitinib compared with intravenous methotrexate for recurrent squamous cell
carcinoma of the head and neck. J Clin Oncol 2009; 27:1864–1871.
Urba S, van Herpen CM, Sahoo TP, et al. Pemetrexed in combination with cisplatin versus cisplatin monotherapy in patients with
recurrent or metastatic head and neck cancer: final results of a randomized, double-blind, placebo-controlled, phase 3 study. Cancer
2012; 118:4694–4705.
Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008;
359:1116–1127.
41
Karamouzis
Thyroid carcinomas 8
Epidemiology and pathogenesis
Thyroid carcinomas (TCs) are rare (3.6% of all human 1969-2014: Local series of well-differentiated thyroid carcinomas
200
tumours) but are the most frequent endocrine
180
malignancies. Their incidence has been growing
160 Males
in the last decades.
140 Females
This increased incidence is essentially due to the 120
Subjects
detection of small carcinomas, <1 cm, likely to be a 100
consequence of the wide use of neck ultrasound (US). 80
60
Female/male ratio is 4/1; the median age at diagnosis
40
is 45–50 years; children are rarely affected. The only
20
risk factor recognised so far is exposure to ionising
0
radiation. 1-10 11-20 21-30 31-40 41-50 51-60 61-70 71-80 81-90
Years
TCs are classified as: (1) well differentiated (DTC); (2)

% HISTOTYPE DISTRIBUTION
80 poorly differentiated (PDTC); (3) anaplastic (ATC); (4)
70 medullary (MTC); (5) other non-epithelial.
60 DTC, PDTC and ATC originate from follicular cells and the
Local series 1969-2014
degree of differentiation is related to the ability to produce

50
thyroglobulin, take up iodine and respond to thyroid
40 stimulating hormone (TSH).
30
DTC are the most frequent and are categorised
20 into papillary (PTC, 80%) and follicular (FTC, 10%).
10 PDTC, ATC and MTC are rare (5%, 2% and 5%–7%,
respectively).
0
PTC FTC MTC PDTC ATC OTHERS
ATC, Anaplastic thyroid carcinoma; FTC, follicular thyroid carcinoma; MTC, medullary thyroid
carcinoma; PDTC, poorly differentiated thyroid carcinoma; PTC, papillary thyroid carcinoma.
PTC FTC
The most frequent oncogenic alterations in PTC are RET/PTC N-RAS
RET/PTC rearrangements (20%) and BRAFV600E BRAF TERT
N-RAS TSH-R
mutation (45%). Other rarer alterations have recently
H-RAS Other
been found. PAX8/PPARγ
Other
Unknown
Unknown
The most frequent oncogenic alterations in PDTC and
ATC are p53 and TERT promoter point mutations. Other ATC BRAF+TERT+TP53
MTC
BRAF+TERT
oncogenic alterations have been described. BRAF+TP53 RET
RAS+TERT+TP53 RAS
The most frequent oncogenic alterations in MTC are RET RAS+TERT Unknown
RAS+TP53
activating point mutations, which are found as germinal in TERT_TP53
hereditary cases, and somatic in sporadic cases. Other
carcinoma; PTC, papillary thyroid carcinoma.
REVISION QUESTIONS
1. How frequent are TCs?
2. Which is the most frequent histotype?
3. What is the most frequent oncogenic alteration in ATC?
42
Thyroid carcinomas
Clinical presentation; prognosis
In the majority of cases, TC presentation is a single

thyroid nodule or a nodule in the context of a multinodular
goitre identified by neck palpation or US.
Only 5% of thyroid nodules are malignant. These

latter have peculiar US features, but the diagnosis of
malignancy is performed by fine needle aspiration.
No presurgical serum markers are known for DTC, PDTC A B

and ATC, while elevated levels of pre-surgical serum
calcitonin (Ct) are diagnostic of MTC. Suspicious ultrasound features
A. Hypoechogenicity, no halo
B. Irregular borders,
microcalcifications (arrows)
C. Irregular blood flow
C
The prognosis of TC is correlated with the degree of

differentiation: while PTC and FTC patients are long
survivors, ATC patients rarely survive >6 months.
At multivariate analysis, the poor prognostic factors for

both survival and recurrence are either an advanced age
(>65) or stage (Stage III and IV) at diagnosis.
The prognosis of MTC, either when sporadic or familial,
is greatly dependent on the stage at diagnosis, and
definitive cure can be obtained only if intrathyroidal.
carcinoma; PTC, papillary thyroid carcinoma.
PTC Classical variant

Among PTCs, the histological variant also plays a PTC Variants:
prognostic role: the follicular variant is the “good”, the a. Classical
classical is the “bad” and the tall cells is the “ugly”.
Controversial data are reported on the prognostic role of

b. Follicular
c. Tall cells } Most
frequent
}
BRAFV600E mutation, which is, indeed, more frequent in d. Solid
e. Sclerosing
the tall cell variant and older patients. Rare
f. Columnar
A bad prognostic role in terms of both recurrence and g. Warthin like
survival is recognised for somatic RET point mutations in
sporadic MTC, particularly for the M918T RET mutation. PTC, Papillary thyroid carcinoma.
REVISION QUESTIONS
1. Which diagnostic tool is able to identify TC in a nodule?
2. Is the prognosis for ATC as good as for DTC?
3. Why is it important to know the histological variant of a PTC?
43
Elisei et al
Initial treatment
According to the recent publication of the international Intrathyroidal carcinoma

guidelines for the treatment of TC, surgery can be either
PTC MTC
a hemithyroidectomy (or lobectomy [LB]) or a total
thyroidectomy (TTx).
Lobectomy or total Total thyroidectomy
Prophylactic node dissection is not indicated in DTC. thyroidectomy +
Central compartment
Lymph node surgery, either of the central or lateral Cervical node dissection
compartments, is due if US shows node metastases.

Lymphadenectomy, Latero-cervical
If MTC is diagnosed before surgery, TTx and either central or
latero-cervical
lymphadenectomy,
only if metastatic lymph
prophylactic central neck node dissection are always Upper
compartment, only if nodes have been
metastatic lymph nodes detected at
indicated. Mediastinum
have been detected at neck ultrasound
neck ultrasound
MTC, Medullary thyroid carcinoma; PTC, papillary thyroid carcinoma.
Surgical complications of LB or TTx that must be

Tracheostomy taken into consideration are vocal cord palsy and
Trachea hypoparathyroidism, both of which can be transient or
permanent.
PDTC and ATC are usually locally very advanced with
infiltration of other neck structures, which makes surgery
rarely complete. R2 debulking is still useful.
Tracheal compression or infiltration may require a

tracheostomy or, whenever possible, an endotracheal
stent or laser treatment of the infiltrating tissue.
Tumoural Ant Post

mass compressing
and infiltrating the
trachea
After TTx, DTC with an intermediate or high risk of

recurrence should be treated with radioiodine (131-I),
after stimulation with recombinant TSH. A post 131-I
whole body scan (WBS) will show the sites of iodine
uptake.
PDTC and ATC patients with local infiltration should be

locally treated with external radiotherapy, with palliative
intent.
131-I therapy does not play any role in MTCs since Post-surgical thyroid replacement
they derive from parafollicular C cells, which have a
neuroendocrine origin and are not able to take up iodine. No other sites of 131-I uptake
REVISION QUESTIONS
1. What is the initial surgical treatment of DTC?
2. Is prophylactic node dissection always indicated in DTC and MTC?
3. Why can MTC not be treated with 131-I?
44
Thyroid carcinomas
Follow-up
The follow-up of DTC and MTC is based on the

periodical measurement of thyroglobulin (Tg) plus its Secreted by C cells:
autoantibodies (TgAb) and Ct, respectively, associated the serum Ct is a marker
with neck US. of MTC both pre- and after
surgery
DTC patients treated with TTx and 131-I will likely have
low or undetectable serum Tg, and the patient will be
Calcitonin
considered as “cured” if neck US is also negative.
Thyroglobulin
DTC patients treated with LB or TTx but not 131-I will
likely have detectable serum Tg: the trend of increase,
decrease or stabilisation will be considered thereafter.
Secreted by follicular
Post-therapeutic WBS cells: the serum Tg is a Ct, Calcitonin; DTC, differentiated
marker of recurrent or persistent thyroid carcinoma; MTC, medullary
Ant Post thyroid carcinoma; Tg, thyroglobulin
disease in DTC but only
after surgery
Biochemical, clinical and US monitoring should be

performed in DTC patients: every 18 months in patients
considered as cured, more frequently (6–12 months) if
biochemical evidence (detectable levels of serum Tg) or
evidence of metastatic lesions at imaging is still present.
If necessary, 131-I treatment can be repeated, at least

until there is evidence of clinical benefit and evidence of
lesions still able to take up 131-I.
When a post-131-I WBS is negative, and the possibility

of iodine contamination can be excluded, no more 131-I
treatments should be administered.
131-I avid lung metastases
WBS, Whole body scan.
MTC patients with a postoperative undetectable basal or

stimulated serum Ct have a risk of recurrence of 10% and
3%, respectively. Neck US should also be performed.
Patients with a post-TTx serum Ct detectable but
<150 pg/ml are rarely positive at conventional imaging,
but these patients must be monitored every 6–12 months.
Neck US, computed tomography (CT) scan of the

chest, and magnetic resonance imaging (MRI) of the
liver and brain are indicated to check the possible sites
of metastasis in MTC patients with high levels of Ct.
CT, Computed tomography.
REVISION QUESTIONS
1. What are the post-surgical serum markers for DTC and MTC?
2. What should you do if the serum level of Tg suggests persistence of disease in DTC?
3. What is the risk of recurrence in MTC patients with an undetectable level of basal Ct?
45
Elisei et al
Treatment of advanced cases
Radioiodine-refractory advanced and progressive

DTC were orphan of any therapy until a few years ago.
Chemotherapy (mainly doxorubicin) was ineffective.
Similarly, no chemotherapy has been shown to be
effective in advanced and symptomatic MTCs, which,
moreover, cannot be treated with 131-I due to their nature.
RET, RAS and BRAF mutations represent the major

rationale for treatment of advanced DTC and MTC with
tyrosine kinase inhibitors (TKIs) targeted against these
activated receptors.
TKI, Tyrosine kinase inhibitor.
DRUG TC PTS (n) PR (%) SD >6 PFS AE >30% of Sorafenib and lenvatinib have been investigated in
(Reference) months (median months) patients
advanced DTC in phase III studies: the primary end point
Vandetanib MTC 331 45 87 ne Diarrhoea
(Wells et al Skin rash was progression-free survival (PFS) in patients treated
2012) Nausea
Hypertension with drug versus placebo.
Cabozantinib MTC 330 28 ne 11.2 Diarrhoea
(Elisei et al H-F syndrome
2013) Weight loss Similarly, vandetanib and cabozantinib have been studied
Anorexia
Nausea in advanced/progressive MTC. In these studies also, the
Fatigue
Sorafenib DTC 417 12.2 42 10.8 H-F syndrome
primary endpoint was PFS in the 2 arms.
(Brose et al Alopecia
2013) Skin rash
Fatigue
Weight loss
The 4 studies demonstrated a significant increase
Hypertension
Anorexia
of PFS in patients treated with the drugs. After these
Lenvatinib DTC 392 64.8 29.8 18.3 Hypertension studies sorafenib and lenvatinib, as well as vandetanib
(Sclumberger Diarrhoea
et al 2015) Anorexia
Weight loss
and cabozantinib, were approved for advanced/
Nausea
Stomatitis
progressive DTC and MTC, respectively.
AE, Adverse event; DTC, well-differentiated thyroid carcinoma; H-F, hand and foot; MTC, medullary thyroid
carcinoma; PFS, progression-free survival; PR, partial remission; PTS, patients; SD, stable disease;
TC, thyroid carcinoma.
A B
ATCs are still orphan of any drug and are almost invariably
lethal. In the near future a phase II/III study with lenvatinib
should start in several countries.
Other therapeutic strategies are under evaluation, such as
the use of selumetinib, a MEK inhibitor, to re-induce the
lost ability to take up 131-I.
Immunotherapies, used alone or in combination with A. PTC with lymphocytic infiltration

lenvatinib, are under consideration on the basis of the B. Intratumoural lymphocytic
frequent association of TC with lymphocytic infiltration. infiltration
C. Secondary lymphocytic follicles
C
PTC, Papillary thyroid carcinoma.
REVISION QUESTIONS
1. What is the rationale for the use of TKIs in TC?
2. Have some TKIs been approved for the treatment of advanced DTC and MTC?
3. Which other therapeutic strategies are under investigation?
46
Thyroid carcinomas
Summary: Thyroid carcinomas
• TC is a rare malignancy but its occurrence is still increasing worldwide
• Females are affected 4 times more often than males, and ionising radiation exposure is the only well recognised
risk factor
• No presurgical serum markers are known for DTC, while high levels of serum Ct are diagnostic of MTC
• The most common oncogenic alterations are BRAFV600E and RET/PTC rearrangements in DTC, and RET point
mutations in MTC
• The prognostic factors for both recurrence and survival are advanced age and/or an advanced stage at diagnosis
• Thyroidectomy is the initial treatment of thyroid carcinoma. Lymphadenectomy should be performed only if there is
evidence of metastatic lesions at neck US
• 131-I treatment is performed in DTC cases with an intermediate or high risk of recurrence, while it cannot be used in
MTC or in ATC
• DTC and MTC patients can be followed by measuring serum Tg and Ct, respectively. Neck US is fundamental in their
follow-up
• New targeted therapies have recently been approved for the treatment of advanced and progressive DTC and MTC
• ATC is still orphan of successful therapies, and are still lethal
Further Reading
Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell 2014; 159:676–690.
Durante C, Montesano T, Attard M, et al; PTC Study Group. Long-term surveillance of papillary thyroid cancer patients who do not
undergo postoperative radioiodine remnant ablation: is there a role for serum thyroglobulin measurement? J Clin Endocrinol Metab 2012;
97:2748–2753.
Elisei R, Ugolini C, Viola D, et al. BRAF(V600E) mutation and outcome of patients with papillary thyroid carcinoma: a 15-year median
follow-up study. J Clin Endocrinol Metab 2008; 93:3943–3949.
Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Association Management Guidelines for Adult Patients with
Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and
Differentiated Thyroid Cancer. Thyroid 2016; 26:1–133.
Ho AL, Grewal RK, Leboeuf R, et al. Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N Engl J Med 2013;
368:623–632.
Mallick U, Harmer C, Yap B, et al. Ablation with low-dose radioiodine and thyrotropin alfa in thyroid cancer. N Engl J Med 2012;
366:1674–1685.
Romei C, Tacito A, Molinaro E, et al. Twenty years of lesson learning: how does the RET genetic screening test impact the clinical
management of medullary thyroid cancer? Clin Endocrinol (Oxf) 2015; 82:892–899.
Shi X, Liu R, Basolo F, et al. Differential clinicopathological risk and prognosis of major papillary thyroid cancer variants. J Clin Endocrinol
Metab 2016; 101:264–274.
Viola D, Materazzi G, Valerio L, et al. Prophylactic central compartment lymph node dissection in papillary thyroid carcinoma: clinical
implications derived from the first prospective randomized controlled single institution study. J Clin Endocrinol Metab 2015; 100:1316–
1324.
Viola D, Valerio L, Molinaro E, et al. Treatment of advanced thyroid cancer with targeted therapies: ten years of experience. Endocr Relat
Cancer 2016; 23:R185–R205.
Wells SA Jr, Asa SL, Dralle H, et al; American Thyroid Association Guidelines Task Force on Medullary Thyroid Carcinoma. Revised
American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 2015; 25:567–610.
47
Elisei et al
B
More advanced knowledge

9 Nasopharyngeal carcinoma
Histology; key physical signs; staging
Histology
Squamous cell carcinoma may be found in low-

incidence populations (Western Europe) related
to smoking, with less favourable prognosis than
keratinising carcinoma.
Non-keratinising carcinoma predominates in intermediate-

incidence/endemic regions (Mediterranean basin,
South-east Asia), consistently associated with
Epstein-Barr virus (EBV). Squamous cell EBER stain in a
carcinoma metastatic neck node
EBV-based diagnostic tools for nasopharyngeal carcinoma suggests NPC origin
NPC, Nasopharyngeal carcinoma.
(NPC): in tissue (e.g. EBER stain in a metastatic neck node)
and in blood (e.g. EBV DNA and EBV antibodies).
Lymph nodes of the head and neck

Physical signs
Cervical lymphadenopathy (common):

Posterior auricular
Proceed from upper (N1, 2) to lower (N3) neck
Occipital
Preauricular
direction. Retropharyngeal nodal metastases (N1)
Parotid
Superficial cervical
Lower ear and parotid Tonsillar
detection requires magnetic resonance imaging
Deep cervical
Other nodes of head and neck, occipital scalp,
(jugulogastric)
(MRI). Determine prognosis and therapy decision.
Submental
ear, back of neck, tongue, trachea, nasopharynx, Lower lip, floor of mouth, apex of tongue
nasal cavities, palate, oesophagus
Submandibular
Posterior cervical Check, side of nose, lower lip, gums,
anterior tongue
Cranial nerve palsy (uncommon):
Confers T4 stage. V and VI nerves most commonly
Supraclavicular
Subclavicular
Thorax and abdomen involved. Coronal MRI shows nasopharynx tumour
Thorax and abdomen
extending superiorly to left cavernous sinus (CS),
Left VI cranial nerve palsy causing V and VI nerve palsies.
Right: Normal Left eye: does not abduct

Direction of gaze
Work-up & staging Stage I Stage II
Consider MRI of nasopharynx and neck. T = nasal, oropharyngeal T = parapharyngeal

Metastatic screening: positron emission tomography N = nil N = one side upper-mid neck
(PET) scan may be considered for locoregionally
advanced disease (e.g. N3).
Dental assessment: ear, nose and throat (ENT) Stage III Stage IVA
assessment (need for intervention of middle ear T = intracranial,
T = skull base
effusion); nutritional assessment. cranial nerves
N = both sides upper-mid neck
N = lower neck or >6 cm
REVISION QUESTIONS
1. What is the application of EBV-based blood markers in the management of NPC?
2. What is the pattern of lymph node metastases in NPC and how is this reflected by the staging?
3. Cranial nerve palsies can be one of the presenting symptoms of NPC. Which are the most commonly involved cranial nerves?
49
Chan et al
Treatment
Stage I, II disease
Radiotherapy (RT) alone. Role of concurrent

chemotherapy (ChT) for Stage II is optional.
RT directed to nasopharynx, skull base, cervical

lymphatics on both sides (lower neck spared for N0 cases).
Delivered as intensity-modulated RT (IMRT): helps to
reduce parotid irradiation (hence less xerostomia) and
improve tumour target coverage. Meticulous delineation
of targets and margins is essential. Dose: 70 Gy,
although a lower dose level of 66 Gy was also used in Parotid gland dose
the pre-IMRT era. reduced by IMRT
IMRT, Intensity-modulated radiotherapy.
Stage III, IVA disease
Concurrent chemotherapy with radiotherapy: Neoadjuvant ChT is not a standard treatment; it may be
considered for locally advanced tumours encroaching
E.g. 3-weekly schedule (cisplatin 100 mg/m2 on d1, 22, 43) on vital organs (optic chiasm, brainstem) to aim for a
E.g. Weekly schedule (cisplatin 40 mg/m2 weekly from d1, debulking effect, facilitating RT planning. Usually 3
for 6–8 cycles) courses are given with cisplatin-based ChT.
Adjuvant ChT (cisplatin 80 mg/m2 d1, 5-fluorouracil

infusion 1 g/m2 d1, 2, 3, 4 for 3 cycles) following
concurrent chemoradiation is controversial. May apply
only to high-risk group defined by biomarker (EBV DNA):
studies are ongoing.
Stage IVB (M1) disease

Palliative ChT is considered, and RT may also
be considered for locoregional disease and
oligometastases.
REVISION QUESTIONS
1. What is the recommended treatment for Stage I-II NPC?
2. What is the recommended treatment for Stage III-IV NPC?
3. What is the benefit of using the IMRT mode of RT, compared to conventional RT, in the treatment of NPC?
50
Nasopharyngeal carcinoma
Follow-up; outcome; recurrence
Follow-up
Nasopharyngoscopy and biopsy (possible false-positive

Follow-up should be more frequent in the first years post-therapy,
biopsy before 12 weeks). e.g. every 3–4 months.
MRI in the early (e.g. <6 month) period may be difficult

to interpret (residual thickening and small nodes at the
originally affected sites). PET scan, if considered, should
be performed no earlier than 3 months post-therapy.
A persistently detectable EBV DNA level after therapy
strongly correlates with recurrence.
Possible long-term effects of radiotherapy
Hypopituitarism (uncommon), suspect if fatigue

Temporal lobe injury (rare), oedema focus
Middle ear, inner ear dysfunction (common)
Xerostomia (common), lessened with IMRT
Dysphagia: muscle fibrosis and incoordination

Carotid stenosis: rarely severe and symptomatic
Hypothyroidism: uncommon
Outcome
Clinical stage Number of patients 5-Year disease specific survival
I 51 100.0
Prognosis is more favourable than for other head and neck II 214 96.4
cancers of corresponding stage. Overall local control rates III 413 82.7
are >85%, and the main challenge is distant failure. IVA 190 70.4
100
//
Recurrence
/ / /
/ / / // / / / / //
75 // / //// /////// // / / ///
/ / / / // / //// // /// // / / ///
Survival (%)
50 Treatment of local recurrence: More options for limited

recurrence (nasopharyngectomy, brachytherapy,
25 stereotactic RT [SRT], or combinations). Some skull base
Progression-free survival
Overall survival
recurrence can be treated by SRT, IMRT.
Treatment of distant failure: palliative ChT. A small

0 1 2 3
Time Since Registration (years)
No. of patients at risk:
PFS
OS
68
68
54
60
42
47
17
17
subset of patients with oligometastases, especially if
intrathoracic or limited skeletal, may have long survival.
OS, Overall survival; PFS, progression-free survival.
REVISION QUESTIONS
1. What is the treatment outcome expected for EBV-associated NPC?
2. What are the common long-term side effects of RT for NPC?
3. If a patient complains of unexplained fatigue on follow-up of previously treated NPC, what treatment-related complication should
be considered?
51
Chan et al
Summary: Nasopharyngeal carcinoma
• In low-incidence areas, the well-differentiated histology is common; undifferentiated carcinoma is prevalent in high-
incidence regions, and associated with EBV
• The close association of EBV with cancer is exploited to develop diagnostic tools based on detection of EBV material,
such as in tissue (e.g. EBER) or in blood (e.g. EBV DNA, EBV antibodies)
• Currently the most important application of tumour markers is using EBV DNA in blood to detect residual disease after
therapy and recurrent disease on follow-up
• Enlarged neck nodes, typically in the upper neck, are a common presenting symptom of NPC. Cranial nerve palsies,
usually of the V and VI nerves, are an uncommon presenting symptom
• MRI of the head and neck is an important staging tool
• IMRT is the mainstay of therapy, its main advantages being to minimise parotid irradiation and provide better coverage
of the tumour target
• For locoregionally advanced disease (Stage III to IVA), concurrent ChT is added. For Stage II disease, this is optional
• The role of adjuvant ChT after concurrent ChT is controversial
• The role of neoadjuvant ChT is considered investigational. It may be applied in specific cases where advanced stage
tumours pose complications related to RT
• Therapy outcome, especially of the undifferentiated type, is much more favourable compared with other head and neck
cancers of similar stages, with 5-year survival rates around 80%–95% for Stage I-II disease, and 60%–80% for Stage III-IV
Further Reading
Blanchard P, Lee A, Marguet S, et al; MAC-NPC Collaborative Group. Chemotherapy and radiotherapy in nasopharyngeal carcinoma:
an update of the MAC-NPC meta-analysis. Lancet Oncol 2015; 16:645–655.
Brierley JD, Gospodarowicz MK, Wittekind C (Eds). TNM Classification of Malignant Tumours, 8th edition. Hoboken: John Wiley, 2016.
Chen L, Hu CS, Chen XZ, et al. Concurrent chemoradiotherapy plus adjuvant chemotherapy versus concurrent chemoradiotherapy
alone in patients with locoregionally advanced nasopharyngeal carcinoma: a phase 3 multicentre randomised controlled trial. Lancet
Oncol 2012; 13:163–171.
Chen QY, Wen YF, Guo L, et al. Concurrent chemoradiotherapy vs radiotherapy alone in stage II nasopharyngeal carcinoma: phase III
randomized trial. J Natl Cancer Inst 2011; 103:1761–1770.
Lai SZ, Li WF, Chen L, et al. How does intensity-modulated radiotherapy versus conventional two-dimensional radiotherapy influence the
treatment results in nasopharyngeal carcinoma patients? Int J Radiat Oncol Biol Phys 2011; 80:661–668.
Lee AW, Fee WE Jr, Ng WT, Chan LK. Nasopharyngeal carcinoma: salvage of local recurrence. Oral Oncol 2012; 48:768–774.
Lee AW, Ma BB, Ng WT, Chan AT. Management of nasopharyngeal carcinoma: current practice and future perspective. J Clin Oncol
2015; 33:3356–3364.
Raab-Traub N. Epstein-Barr virus in the pathogenesis of NPC. Semin Cancer Biol 2002; 12:431–441.
Sun X, Su S, Chen C, et al. Long-term outcomes of intensity-modulated radiotherapy for 868 patients with nasopharyngeal carcinoma:
an analysis of survival and treatment toxicities. Radiother Oncol 2014; 110:398–403.
Zhang W, Chen Y, Chen L, et al. The clinical utility of plasma Epstein-Barr virus DNA assays in nasopharyngeal carcinoma: the dawn of a
new era?: a systematic review and meta-analysis of 7836 cases. Medicine (Baltimore) 2015; 94:e845.
52
10 Salivary gland tumours
Epidemiology and histopathology
Salivary gland cancers (SGCs) are rare epithelial Major salivary gland cancer incidence rates (age-adjusted)
in several world male populations (2003-2007)
tumours. Worldwide annual incidence varies between
<0.05 and 4 per 100 000, with an incidence of 1.2 per New Zealand: Maori
Australia, Queensland
100 000 in European countries. Paediatric cases are

Italy, Turin
Brazil, San Paulo
Ukraine
very uncommon, with an incidence of 0.8–1.4 per million Israel, Jews
USA, NPCR (42 states): White
in the population under 20 years old. Philippines, Rizal

Canada
Cuba, Villa Clara
Poland, Lower Silesia
Finland
They are most common in the 6th-7th decades of life. India, New Delhi
China, Hong Kong
Age, previous irradiation and pleomorphic adenoma

USA, NPCR (42 states): Black
UK, England
Republic of Korea
diagnosed at a younger age may be related to SGC Israel, Non-Jews
New Zealand
development. Italy, Varese

Germany, Munich
USA, NPCR (42 states): Asian and Pacific Islander
The Netherlands
USA, NPCR (42 states): American Indian
Japan, Osaka Prefecture
Tunisia, North
0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6
Secretory unit of salivary gland NPCR, National Program of Cancer Registries.
Intercalated duct Striated duct Excretory duct
Salivary glands comprise 3 pairs of major salivary

glands – the parotid, the submandibular and the
sublingual – and from 450 to 750 glandular structures,
distributed throughout the whole head and neck region
and the upper aerodigestive tract. Based on their
Acinic cell ca Basaloid tumours Warthin’s Mucoepidermoid morphology and mucous production, the latter are
Adenoid cystic ca oncocytic salivary duct ca defined as minor salivary glands.
PLGA tumours Adenocarcinoma
Myoepithelial ca
Epi-myoepithelial ca
Pleomorphic adenoma
Ca, Cancer; PLGA, polymorphous low-grade adenocarcinoma. Malignant tumours

Mucoepidermoid carcinoma 8430/3
Adenoid cystic carcinoma 8200/3
The new edition of the World Health Organisation Acinic cell carcinoma 8550/3
Polymorphous adenocarcinoma 8525/3
(WHO) classification (2017) includes more than Clear cell carcinoma 8310/3
20 malignant histotypes, each one characterised Basal cell adenocarcinoma 8147/3
Intraductal carcinoma 8500/2
by a different morphology, histological grading, Adenocarcinoma, NOS 8140/3
immunoprofile and outcome. Salivary duct carcinoma 8500/3
Myoepithelial carcinoma 8982/3
Epithelial-myoepithelial carcinoma 8562/3
Mucoepidermoid carcinoma (MEC) is the most common Carcinoma ex pleomorphic adenoma 8941/3
subtype. It comprises low- (LG), intermediate- (IG) and Secretory carcinoma 8502/3
Sebaceous adenocarcinoma 8410/3
high-grade carcinomas, the latter having the worst Carcinosarcoma 8980/3
outcome. CRTC1-MAML2 gene fusion is reported to have Poorly differentiated carcinoma
Undifferentiated carcinoma 8020/3
prognostic significance, but this is still controversial. Large cell neuroendocrine carcinoma 8013/3
Small cell neuroendocrine carcinoma 8041/3
Adenoid cystic carcinoma (ACC) is an aggressive and Lymphoepithelial carcinoma 8082/3
slow-growing cancer. It is constituted of epithelial and Squamous cell carcinoma 8070/3
Oncocytic carcinoma 8290/3
myoepithelial cells in variable proportion, resulting in Uncertain malignant potential
tubular, cribriform and solid growth patterns. MYB-NFIB Sialoblastoma 8974/1
fusion gene is found in about 80% of cases; its prognostic ICD-0: International Classification of Disease for Oncology; behaviour is coded /0 for benign
tumours; /1 for unspecified, borderline or uncertain behaviour; /2 for carcinoma in situ and
role is still currently unclear. grade III intraepithelial neoplasia;/ 3 for malignant tumours.
REVISION QUESTIONS
1. What is the incidence of SGCs worldwide?
2. How numerous are the salivary glands?
3. How many malignant epithelial histotypes are reported in the WHO classification?
53
Locati & Imbimbo
Clinical presentation and diagnosis
Malignancies of the major salivary glands may be Adenocarcinoma, not otherwise specified of the hard palate
clinically indistinguishable from benign tumours.
The rate of malignancy increases with the reduction
of gland dimension, being about 25% in parotid,
50% in submandibular and 80% in sublingual glands.
Minor SGCs arise more often in the hard palate, nasal

cavity and paranasal sinuses; masses are malignant
in more than 50% of cases. Typical presentation is an
asymptomatic submucosal mass.
Adenoid cystic carcinoma of the tongue base, investigated by

magnetic resonance imaging
Fine needle aspiration (FNA) has good accuracy

(87% to 96%) for diagnosis. Open biopsy is not
recommended because of the risk of seeding.
Magnetic resonance imaging (MRI) is indicated in case

of (1) larger tumours (>4 cm); (2) involvement of deep
lobe of parotid; (3) minor SGCs of the head and neck
region. Whole body computed tomography (CT) scan
or positron emission tomography (PET)/CT may be
indicated in advanced stage and high-grade tumours.
Thorax CT scan may be useful in locally advanced ACC.
Molecular and immunohistochemical analyses can be A positive immunoreactivity for AR AR-negative immunoreaction
useful in cases of uncertain diagnosis.
MYB-NFIB gene fusion and wild-type c-kit are reported

in about 80% of ACC; MALM2-CRTC1 is associated
with IG- and LG-MEC; ETV6-NTRK3 fusion gene has
been reported in the mammary analogue secretory
carcinoma, as well as EWSR rearrangements.
Androgen receptor (AR) and HER2 overexpression are
typically found in salivary duct carcinoma (SDC). AR, Androgen receptor.
REVISION QUESTIONS
1. What is the role of FNA in the diagnostic work-up?
2. Is a skilled pathologist recommended?
3. Can molecular and immunohistochemical analyses contribute to diagnosis?
54
Salivary gland tumours
Treatment and prognosis
Radical surgery is the main treatment, followed by Adenoid cystic carcinoma of ethmoid sinus (Stage T4b) treated by
Volumetric Modulated Arc Therapy (VMAT) with a dose of 72 Gy.
radiotherapy (RT) in cases of high-grade malignancies, Red line: high risk target volume; Yellow line: 72 Gy; Blue line: 65 Gy
close margins, high T stage, perineural invasion and
lymph node metastases.
RT alone is reserved for unresectable disease. Intensity-

modulated RT (IMRT) plus carbon ion boost seems to
increase local control, progression-free survival (PFS)
and overall survival (OS) in ACC.
Data on the efficacy of combined chemoradiotherapy in
the postoperative setting and as exclusive treatment
are limited.
Bilateral lung metastases from adenoid cystic carcinoma
Locoregional recurrence occurs in 16%–85% of cases.

It can be managed with further surgery and/or RT only
in very selected cases. Re-irradiation with carbon ion
therapy could play a role in this setting.
Distant metastases are the principal cause of failure,

being diagnosed in 25%–55% of patients. Only 20%
of patients with distant metastases are alive at 5 years.
Locoregional relapse of an AR-expressing salivary duct cancer:

before (left) and two months after complete androgen blockade (right)
Platinum-based chemotherapy (ChT) is recommended in
metastatic patients; cisplatin plus doxorubicin has shown
a higher activity with more toxicity. Single-agent ChT has
demonstrated a 10%–20% response rate. No advantage
for ChT has yet been demonstrated on OS.
Complete androgen blockade may be beneficial in

AR-expressing cases; anti-HER2 monoclonal antibodies
could be useful in HER2 3+ cases.
Several molecular-driven therapies as well as antiangiogenic

compounds are currently under investigation. AR, Androgen receptor.
REVISION QUESTIONS
1. When is a combination of surgery and RT indicated?
2. What is the role of carbon ion radiotherapy?
3. What is the role of ChT?
55
Locati & Imbimbo
Summary: Salivary gland tumours
• Salivary gland tumours are a rare and heterogeneous group of epithelial malignancies that should be managed only in
referral centres
• FNA combined with ultrasound is the best tool for diagnosis
• More than 20 malignant tumours are listed in the updated WHO classification; almost every histotype is characterised
by a specific immunohistochemical profile rather than a peculiar clinical history
• A skilled pathologist is needed for pathological diagnosis; a second pathological opinion in a referral centre is
recommended if the diagnosis has been performed in low-volume head and neck cancer institutes
• Surgery is the mainstay of treatment both in major and minor salivary gland tumours
• Surgery plus adjuvant RT is recommended in high-grade tumours and in cases of high-risk pathological features
• RT alone is recommended in unresectable tumours; heavy-ion RT could have a role in ACC
• Retreatment by surgery or RT should always be considered in cases of locoregional relapse
• ChT is delivered in cases of systemic disease, although an improvement in PFS or OS has never been proven
• New compounds (e.g. antiangiogenic agents) are under investigation, and a randomised phase II trial (EORTC 1206)
is currently ongoing to test the superiority of androgen blockade versus ChT in metastatic AR-expressing salivary
gland tumours
Further Reading
Andry G, Hamoir M, Locati LD, et al. Management of salivary gland tumors. Expert Rev Anticancer Ther 2012; 12:1161–1168.
Barnes L, Eveson JW, Reichart P, Sidransky D (Eds); World Health Organization. Classification of tumours. Salivary glands.
In: Pathology and Genetics of Head and Neck Tumours. Lyon: IARC Press, 2005; 209–273.
Cancer Incidence in Five Continents, Vol. X (electronic version). Lyon: International Agency for Research on Cancer.
Available from: http://ci5.iarc.fr (last accessed September 8, 2016).
Carlson J, Licitra L, Locati L, et al. Salivary gland cancer: an update on present and emerging therapies. Am Soc Clin Oncol Educ Book
2013:257–263.
Cesmebasi A, Gabriel A, Niku D, et al. Pediatric head and neck tumors: an intra-demographic analysis using the SEER* database.
Med Sci Monit 2014; 20:2536–2542.
Jensen AD, Nikoghosyan AV, Lossner K, et al. COSMIC: a regimen of intensity modulated radiation therapy plus dose-escalated,
raster-scanned carbon ion boost for malignant salivary gland tumors: results of the prospective phase 2 trial. Int J Radiat Oncol Biol
Phys 2015; 93:37–46.
Jensen AD, Nikoghosyan AV, Poulakis M, et al. Combined intensity-modulated radiotherapy plus raster-scanned carbon ion boost for
advanced adenoid cystic carcinoma of the head and neck results in superior locoregional control and overall survival. Cancer 2015;
121:3001–3009.
Locati LD, Perrone F, Cortelazzi B, et al. Activity of abiraterone in rechallenging two AR-expressing salivary gland adenocarcinomas,
resistant to androgen-deprivation therapy. Cancer Biol Ther 2014; 15:678–682.
Locati LD, Perrone F, Cortelazzi B, et al. Clinical activity of androgen deprivation therapy in patients with metastatic/relapsed androgen
receptor-positive salivary gland cancers. Head Neck 2016; 38:724–731.
Regezi JA, Batsakis JG. Histogenesis of salivary gland neoplasms. Otolaryngol Clin North Am 1977; 10:297–307.
Seethala RR. Histologic grading and prognostic biomarkers in salivary gland carcinomas. Adv Anat Pathol 2011; 18:29–45.
Yin LX, Ha PK. Genetic alterations in salivary gland cancers. Cancer 2016; 122:1822–1831.
56
Salivary gland tumours
11 Individualised supportive care before and during
curative treatment of head and neck tumours
The burden of the problem
Treatment of locally advanced head and neck cancer

(HNC) requires a multimodal approach, for therapeutic Radiation Medical
and supportive care decisions. Oncologist Oncologist
Head and Neck

Nutritionist
Toxicities induced by oncological therapies (surgery, Surgeon
chemotherapy and radiotherapy) may strongly affect
patients’ quality of life (QoL) and impact on treatment Swallowing Expert Patient Pathologist
compliance.
Accurate patient selection and an individualised Radiologist Psychologist
supportive care approach are mandatory before
treatment initiation. Dentist Nurse Social Worker
Cancer diagnosis
Cancer “pathway” Competing disease
“pathway” Concurrent chemoradiotherapy (ChT-RT) for HNC is
Initial associated with severe acute toxicities, which can result
treatment
in a mortality rate ranging from 2% to 9.3%.
Tumour Competing
Time
progression/recurrence health event Competing event is defined as an intercurrent or

treatment-related mortality.
Salvage
treatment It is not only a matter of acute toxicity, as late adverse
events may compromise patients’ QoL and possibly
cause late death.
Cancer mortality Non-cancer mortality
Risk factors for competing events: age, comorbidity,

50 50
low body mass index and female sex. Low- and 45
Competing mortality
Cancer events 45
Competing mortality
Cancer events
high-risk groups may be identified.

Cumulative Incidence (%)
Cumulative Incidence (%)
40 40
35 35
HIGH RISK
Within a multimodality approach, decreasing treatment 30 30
25 25
toxicities is an important aim to improve patients’ 20 20
survival. 15 LOW RISK 15
10 10
Supportive care may reduce acute/late effects, increase 5 5
compliance and dose intensity, improve QoL, reduce 0 1 2 3 4 5 0 1 2 3 4 5
costs of treatment, and possibly improve survival. Time (years) Time (years)
REVISION QUESTIONS
1. How should toxicities induced by treatment in HNC be managed?
2. Acute and late toxicities: what are the risk factors and impact on patients’ QoL and survival?
3. What are the benefits of a strong supportive care programme?
57
Bossi et al
Risk factors, mucositis and dysphagia
Head and neck cancer patients are frail, due to:

• Patient-related factors: malnutrition, poor immune Intracellular and Interorgan Cachexia
signalling
status, dysphagia, comorbidities, bad oral cavity intercellular
signalling loops TNF-
Decreased muscle
strength
Muscles Adrenal Low fat free max
condition. IL-6
TGF- family Medulla index
members
• Treatment-related factors: mucositis, dysphagia, Fever
Fatigue
Anorexia
RT
neutropaenia/lymphopaenia, infections, dermatitis, HPA
Drowsiness
CT
tracheostomy. IL-6
Procoagulative
status
Acute phase proteins SIRS

Toxicities due to radiotherapy +/- chemotherapy IL-1
(Endogenous origin)
IL-6 Two or more of

or targeted therapy should be considered as a (1) core temperature >38°C
whole, with local adverse effects possibly leading TNF-
or <36°C
(2) heart rate >90 beats/min
to systemic complications. IL-1
IL-6 (3) respiratory rate >20
Chemokines breaths/min or PaCO2
Bone <32 mmHg
C-RP
marrow IL-6 (4) leukocyte count >12,000/ L
or <4000/ L
Leucocyte Sepsis
production (Pathogen associated SIRS)
C-RP, C-reactive protein; CT, chemotherapy; IL, interleukin; RT, radiotherapy; SIRS, systemic inflammatory
response syndrome; TGF, transforming growth factor; TNF, tumour necrosis factor.
Differences in symptoms reported by patient with radiation alone Mucositis develops in 90%–100% of cases with ChT-RT
(dark grey line) or concurrently with chemotherapy (light grey line) (Grade 3-4 in 40%–50% of patients), consisting of
inflammatory and/or ulcerative lesions of the oral and/or
gastrointestinal tract. An expert dental examination is part
of the patient’s assessment.
During treatment, adequate oral care is a key preventive

measure, with frequent mouthwashes and soft-bristle
toothbrush use. Pain due to mucositis is one of the most
distressing consequences, possibly inducing nutritional
deficits. Use of chemotherapy increases the risk.
Suggested preventive/therapeutic treatments are:

morphine mouthwashes (0.2%), low-level laser therapy,
doxepin mouthwashes and zinc supplementation.
Patients should also stop smoking.
The importance
given by the patients to
Dysphagia should be assessed before and during treatment. the swallowing functions
100 at different timepoints
Patient-reported scales (i.e. MDADI) and instrumental 90
80
evaluations are practical options for dysphagia screening.
No. of patients
70
60
50
It is recommended to minimise the dose to the main 40
DARS (Dysphagia/Aspiration Related Structures) 30
20
and salivary glands without reducing primary tumour 10
radiotherapy volume doses. 0
Preventive swallowing exercises during ChT-RT may

reduce long-term dysphagia; if enteral nutrition is UWQOL domains
adopted, patients should be encouraged to continue to pre- 3m 6m 12m
swallow. Dental care is also crucial in this effort.
UWQOL, University of Washington Quality of Life Questionnaire.
REVISION QUESTIONS
1. Why are HNC patients frail?
2. What are the preventive and therapeutic strategies for mucositis?
3. Which approaches may reduce the risk of acute and late dysphagia?
58
Individualised supportive care before and during curative treatment of head and neck tumours
Nausea and vomiting; anaemia; leukopaenia
In head and neck squamous cell carcinoma (HNSCC),

cisplatin-based chemotherapy is used in the majority Sight, pain, smell, fear
of cases. Cisplatin is highly emetogenic and can cause
Benzodiazepines
acute (within first 24 h) and delayed (>24 h) nausea.
DRUGS
Chemotherapy, Higher cortical centre
antibiotics in the brain
A 3-drug regimen with a 5-HT3 receptor antagonist,
NK1 antagonist
dexamethasone, and an NK1 receptor antagonist
NAUSEA
is suggested for the prevention of cisplatin-induced Chemoreceptor
trigger zone *
Vomiting centre
AND
in the medulla
nausea and vomiting. VOMITING
5-HT3 antagonists NK1 antagonist
There are several factors impacting on nausea and Gastrointestinal Labyrinths in the ear
vomiting during ChT-RT: dysgeusia, sticky saliva, tract
employment of feeding tube, concurrent use of opioids.

*Histamine, dopamine and muscarinic antagonists, cannabinoids
Site of action of drugs
Comparison of erythropoiesis-stimulating agents All causes of anaemia should be identified and corrected.
Erythropoiesis-stimulating agents (ESAs) may be used in
Erythropoiesis Epoetin alfa Darbepoetin alfa
stimulating patients receiving chemotherapy if haemoglobin (Hb)
agents
<10 mg/dl (until reaching Hb levels of 12 mg/dl).
Primary Anaemia due to: concurrent Anaemia due to: concurrent
indication myelosuppressive chemotherapy in myelosuppressive chemotherapy
patients with cancer; chronic kidney in patients with cancer; CKD ESAs should be used with caution in patients with liver
disease (CKD); associated with HIV
(zidovudine) therapy. Reduction of
disease and increased risk of thromboembolic events,
allogeneic red blood cell transfusion for and are not recommended in patients treated with
elective, noncardiac, nonvascular surgery
curative intent with radiotherapy.
Route of Subcutaneous or intravenous Subcutaneous or intravenous
administration
Half-life 4 to 13 hours (intravenous) Cancer, adult, subcutaneous: Haematopoietic growth factors should be used for primary
16 to 67 hours (subcutaneous) 74 hours (range: 24 to 144 hours) prophylaxis of chemotherapy-induced neutropaenia only if
CKD, subcutaneous, non-dialysis: the risk of febrile neutropaenia is ≥20%.
70 hours (range: 35 to 139 hours)
CKD, subcutaneous, dialysis:
46 hours (range: 12 to 89 hours)
Dosing: renal No dosage adjustment necessary No dosage adjustment necessary
impairment
Excretion Faeces (majority); urine (small amounts, Adults: 1.6 ± 1.0 ml/hour/kg
10% unchanged in normal volunteers)
Pregnancy risk Category C Category C
CKD, Chronic kidney disease.
REVISION QUESTIONS
1. Which antiemetic agents are used for prevention of cisplatin-related acute and delayed nausea?
2. When should ESAs be used with caution?
3. When should haematopoietic growth factors be used?
59
Bossi et al
Skin care; infections; malnutrition
The following recommendations should be given for skin Type of RT Toxicity Grade 0–2 skin Grade ≥3 skin
care during ChT-RT: wash with lukewarm water and mild grading scale toxicity (%) toxicity (%)
soap, avoid microtraumas, tapes and adhesives. EORTC 47 11 (Grade 3)
Conventional RTOG 73 27 (Epidermitis)
Consider topical or systemic antimicrobials if positive skin RTOG 94 7 (Grade 3)
cultures or documented infections are present; topical Accelerated RT WHO Not reported
6.4 (Grade 3),
0.7 (Grade 4)
steroids should not be employed as prevention.
Accelerated RT with split RTOG 85 3 (Grade 3)
Very accelerated RT RTOG 66 33 (Epidermitis)
In the presence of toxicity Grade 3 or less, every effort Accelerated RT with concomitant
RTOG 85 11 (Grade 3)
should be taken not to stop the radiotherapy; with boost
Grade 4, consider interrupting both systemic therapy Hyperfractionated RT RTOG 81
11 (Grade 3),
<1 (Grade 4)
and radiotherapy. Hyperfractionated accelerated RT EORTC Not reported 46 (Grade 3/4)
18 (Grade 3),
IMRT (not randomised) RTOG 75
7 (Grade 4)
EORTC, European Organisation for Research and Treatment of Cancer; IMRT, intensity-modulated
radiotherapy; RT, radiotherapy; RTOG, Radiation Therapy Oncology Group; WHO, World Health Organisation.
Detrimental Lack of
Febrile neutropaenic HNC patients should be considered
effect of the use of long-term benefit at high risk for complications, requiring hospitalisation and
100 Epoetin b 100 when EPO was added prompt start of antibiotic intravenous therapy.
during radiation to radiation
Loco-regional progression-free
Loco-regional progression-free
80
75
p=0·04
Primary prophylaxis with granulocyte colony-
survival (%)
survival (%)
60
40
Placebo 50
stimulating factor (G-CSF) is not indicated during
20 Epoetin 25 ChT-RT; in case of anaemia, red blood cell transfusions
RT
RT+EPO should preferably be used over ESAs.
0 0
0 1 2 3 4 5 6
Numbers at risk
Patients at risk Years after randomisation
Placebo
Epoetin
171
180
104
94
69
54
32
24
18
15
4
6
RT 69 50 40 34 29 22 21 In case of suspected or confirmed sepsis, empirical
RT+EPO 72 42 35 30 24 19 16
antibiotic therapy should be promptly started, both anti-
EPO, Erythropoietin; RT, radiotherapy. Gram-positive and anti-Gram-negative.
Malnutrition screening should be undertaken on all

patients at diagnosis, to identify those at nutritional risk, Feeding tube use
and then be repeated at intervals. In your institution, do you use feeding tube (check all that apply)
58% 58%
Dietary counselling and/or supplements should be
started at the beginning of oncological treatment. In
selected cases, prophylactic tube feeding should be 32%
29%
considered before starting any treatment.
3% 19%
During treatment, with a food intake <50% for more
Preventive Preventive Preventive Preventive During During
than 5 days despite nutrition counselling, enteral tube in all cases in most (swallowing (weight loss) treatment treatment
cases disorder) (with swallowing (with
feeding should be used to help minimise weight loss and disorder) weight loss)
dehydration.
REVISION QUESTIONS
1. Which approach should be adopted in case of Grade 3 and Grade 4 skin toxicities during ChT-RT?
2. What is the preferred strategy for red and white blood series support?
3. Which criteria suggest use of enteral tube feeding during ChT-RT?
60
Individualised supportive care before and during curative treatment of head and neck tumours
Summary: Individualised supportive care before and during curative
treatment of head and neck tumours
• Treatment of locally advanced HNC requires a multimodal approach
• Accurate patient selection and individualised supportive care are mandatory
• Mortality rate, the tip of the iceberg of toxicities, may be up to 9% in HNC trials
• Supportive care may reduce acute/late effects and treatment costs, improve dose intensity and QoL
• HNC patients are frail, due to patient- and treatment-related factors
• Adequate oral care is a key preventive measure for mucositis
• Dysphagia should be assessed and prevented before and during treatment
• Cisplatin-based chemotherapy is the cornerstone of treatment. A combination of antiemetic agents is used to prevent
acute and delayed nausea
• ESAs should be employed in patients with Hb <10 mg/dl only when treated with palliative intent and not when receiving
curative radiotherapy
• In case of Grade 3 skin toxicity, do not stop radiotherapy; in case of Grade 4, stop systemic treatment and radiotherapy
• Febrile neutropaenic HNC patients should be hospitalised
• Malnutrition screening should be undertaken on all patients at diagnosis
Further Reading
Argiris A, Brockstein BE, Haraf DJ, et al. Competing causes of death and second primary tumors in patients with locoregionally
advanced head and neck cancer treated with chemoradiotherapy. Clin Cancer Res 2004; 10:1956–1962.
Bernier J, Bonner J, Vermorken JB, et al. Consensus guidelines for the management of radiation dermatitis and coexisting acne-
like rash in patients receiving radiotherapy plus EGFR inhibitors for the treatment of squamous cell carcinoma of the head and
neck. Ann Oncol 2008; 19:142–149.
Koyfman SA, Adelstein DJ. Enteral feeding tubes in patients undergoing definitive chemoradiation therapy for head-and-neck
cancer: a critical review. Int J Radiat Oncol Biol Phys 2012; 84:581–589.
Lalla RV, Bowen J, Barasch A, et al; Mucositis Guidelines Leadership Group of the Multinational Association of Supportive Care in
Cancer and International Society of Oral Oncology (MASCC/ISOO). MASCC/ISOO clinical practice guidelines for the management
of mucositis secondary to cancer therapy. Cancer 2014; 120:1453–1461.
Langius JA, Zandbergen MC, Eerenstein SE, et al. Effect of nutritional interventions on nutritional status, quality of life and mortality
in patients with head and neck cancer receiving (chemo) radiotherapy: a systematic review. Clin Nutr 2013; 32:671–678.
Lassig AA, Joseph AM, Lindgren BR, et al. The effect of treating institution on outcomes in head and neck cancer. Otolaryngol
Head Neck Surg 2012; 147:1083–1092.
Mell LK, Dignam JJ, Salama JK, et al. Predictors of competing mortality in advanced head and neck cancer. J Clin Oncol 2010;
28:15–20.
Mirabile A, Numico G, Russi EG, et al. Sepsis in head and neck cancer patients treated with chemotherapy and radiation: literature
review and consensus. Crit Rev Oncol Hematol 2015; 95:191–213.
Schindler A, Denaro N, Russi EG, et al. Dysphagia in head and neck cancer patients treated with radiotherapy and systemic
therapies: literature review and consensus. Crit Rev Oncol Hematol 2015; 96:372–384.
Wuthrick EJ, Zhang Q, Machtay M, et al. Institutional clinical trial accrual volume and survival of patients with head and neck
cancer. J Clin Oncol 2015; 33:156–164.
61
Bossi et al
Emerging targets and new agents in
squamous head and neck tumours 12
HER family and cell-cycle inhibitors
Epidermal growth factor receptor (EGFR) is overexpressed

in 90% of cases of head and neck squamous cell
carcinoma (HNSCC). Cetuximab, a chimaeric IgG1 anti-
EGFR monoclonal antibody (mAb), improves overall survival
when combined with radiotherapy or chemotherapy.
New anti-EGFR mAbs are under investigation.

Necitumumab, nimotuzumab and zalutumumab are
fully human IgG1 mAbs. Panitumumab is a human IgG2
mAb. ABT-806 targets an epitope exposed in EGFRvIII.
Sym004 is composed of 2 anti-EGFR mAbs.
Only a minority of patients benefit from anti-EGFR mAbs:
objective response rate (ORR) of single agents is around
6%–13%. Predictive biomarkers are needed.
Crosstalk among ErbB receptors could limit the clinical

efficacy of EGFR-targeted therapies and may promote
treatment resistance.
MEHD7945A is a human IgG1 mAb targeting both EGFR

and HER3, resulting in comparable activity to cetuximab
in a phase II trial.
Afatinib and dacomitinib are irreversible pan-HER

inhibitors. Afatinib improves progression-free survival in
recurrent HNSCC. Predictive biomarkers are needed.
p16INK4A is inactivated in 90% and CCND1 (encoding

for cyclin D1) is amplified in 20%–30% of human
papillomavirus (HPV)-negative HNSCC.
These alterations activate the cyclin-dependent

kinases 4 and 6 (CDK 4/6), with phosphorylation of
the retinoblastoma protein (pRb) and release of E2F
transcription factor.
This promotes cell-cycle transition from G1 to S phase.
CDK 4/6 inhibitors and other cell-cycle inhibitors are
currently being investigated in p16-negative HNSCC.
REVISION QUESTIONS
1. What are the limitations of the use of anti-EGFR therapies in HNSCC?
2. What is the rationale to develop pan-HER inhibitors?
3. What are the genetic alterations that support the investigation of CDK inhibitors in HNSCC?
62
Emerging targets and new agents in squamous head and neck tumours
Growth factor and angiogenesis inhibitors
c-Met is overexpressed and mutated in 75% and 14%

of HNSCC, respectively. Excessive activation of c-Met
is implicated in cetuximab resistance.
Two tyrosine kinase inhibitors (TKIs), dasatinib and

saracatinib, targeting the non-receptor tyrosine kinase
Src are currently under evaluation in cetuximab-pretreated
HNSCC patients.
Silencing of tumour suppressor genes caused by
hypermethylation is an epigenetic mechanism implicated
in HNSCC. Demethylating agents such as decitabine are
under investigation.
The phosphatidylinositol 3 phosphate (PI3K)/Akt/

mechanistic target of rapamycin (mTOR) pathway is
frequently activated in HNSCC.
PI3KCA amplification/mutations are found in 34%

and 56% of HPV-negative and -positive HNSCC,
respectively. Around 20% of HPV-positive HNSCC
have an activating PI3KCA mutation.
PI3K inhibitors (BKM120, BYL19, PX-866), perifosine

(PI3K and AKT inhibitor), and mTOR inhibitors (everolimus,
temsirolimus) are examples of agents under investigation.
Increased expression of vascular endothelial growth

factor (VEGF) is associated with resistance to EGFR
inhibitors and with poor prognosis in HNSCC, suggesting
that angiogenesis is a reliable target.
Combination strategies against the EGFR family and

angiogenesis are being investigated. Vandetanib targets
EGFR, RET and VEGFR2, and was shown in vitro and in
vivo to overcome cisplatin and radioresistance in HNSCC.
Anti-VEGF agents that are being or have been evaluated:

the mAb bevacizumab targeting VEGF, and different
TKIs such as sunitinib, sorafenib and cediranib. Bleeding,
ulceration and fistulae are known adverse events of these EGFR,Epidermal growth factor receptor; PDGFR, platelet-derived growth factor receptor;
compounds. VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.
REVISION QUESTIONS
1. Why could Met inhibitors be interesting to use in HNSCC therapeutics?
2. Which pathway is frequently altered in HPV-positive HNSCC?
3. What are the risks of anti-VEGF therapy in HNSCC?
63
Seront & Machiels
Immunotherapy and personalised treatment
Naive T-cells are activated by dendritic cells that present

the tumour antigens. After activation, T-cells express
CTLA-4 and bind to B7, thus blocking immune response.
The activated T-cells will recognise the antigen on the

tumour cells to initiate cell killing, but this can be blocked
by the PD-1/ PD-L1 pathway.
PD-1/PD-L1 inhibitors are under investigation. Nivolumab
(anti-PD1) has been shown to improve survival in patients
who progress after platinum therapy.
Cytokines and toll-like receptors (TLRs) amplify the

natural killer cell capacity for cytolysis. Interleukin-12
and VTX-2337, a TLR agonist, are under investigation.
New mAbs such as ertumaxomab block the EGFR

family and stimulate immune effector cells, enhancing
antibody dependent cell-mediated cytotoxicity (ADCC).
Lenalinomide is a thalidomide analogue with

antiangiogenic and immunomodulatory effects, supposed
to enhance the ADCC of cetuximab.
ADCC, Antibody dependent cell-mediated cytotoxicity
The Cancer Genome Atlas (TCGA) work has identified

other genetic alterations that may also be targeted by
new compounds.
The fibroblast growth factor receptor family genes are

altered in around 10%. EphA2 and DDR2 could be targeted
by dasatinib. RAS, NF1/2, RASA1, PTEN, INPP4B, TSC1/2,
AKT also appear as potential targets.
Gene expression profiling identified 3 HNSCC
supergroups called inflamed/mesenchymal (I/M),
basal (B) or classical (CL). HPV+ HNSCC are part of the
I/M and CL groups.
HNSCC, Head and neck squamous cell carcinoma.
REVISION QUESTIONS
1. Explain the main mechanism of action of anti-CTLA-4 mAbs.
2. Explain the main mechanism of action of mAbs targeting the PD-1/PD-L1 pathway.
3. What is the objective response rate of mAbs targeting the PD-1/PD-L1 pathway?
64
Emerging targets and new agents in squamous head and neck tumours
Summary: Emerging targets and new agents in squamous head and
neck tumours
• Up to 90% of HNSCC express high levels of EGFR
• Overexpression of EGFR as well as high EGFR gene copy number are associated with poor prognosis
• Cetuximab improves overall survival, either as curative treatment in combination with radiation therapy, or as palliative
treatment in combination with chemotherapy
• Only a minority of patients derive long-term benefit from anti-EGFR treatment, emphasising the importance of
developing novel treatment strategies
• Potentially more potent anti-EGFR compounds as well as combination strategies are under investigation to improve
treatment efficacy
16INK4A is inactivated in 90% of HNSCC and CCND1 is amplified in 20%-30% of HPV-negative HNSCC. Therefore,
•p
there is a strong rationale to investigate cell-cycle inhibitors in HNSCC
•T
he PI3K/Akt/mTOR pathway is frequently activated in HNSCC
•H
PV-positive HNSCC have frequent PI3KCA hotspot mutations
• Immune checkpoint inhibitors are under investigation with an ORR around 15%–20% in phase II trials, especially with
agents targeting the PD-1/PD-L1 pathway
Further Reading
Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival
data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 2010; 11:21–28.
Cancer Genome Atlas Network. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature 2015;
517:576–582.
Juric D, Dienstmann R, Cervantes A, et al. Safety and pharmacokinetics/pharmacodynamics of the first-in-class dual action HER3/
EGFR antibody MEHD7945A in locally advanced or metastatic epithelial tumors. Clin Cancer Res 2015; 21:2462–2470.
Keck MK, Zuo Z, Khattri A, et al. Integrative analysis of head and neck cancer identifies two biologically distinct HPV and three non-HPV
subtypes. Clin Cancer Res 2015; 21:870–881.
Krigsfeld GS, Chung CH. Novel targets in head and neck cancer: should we be optimistic? Clin Cancer Res 2015; 21:495–497.
Lui VW, Hedberg ML, Li H, et al. Frequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers. Cancer
Discov 2013; 3:761–769.
Machiels JP, Haddad RI, Fayette J, et al; LUX-H&N 1 investigators. Afatinib versus methotrexate as second-line treatment in patients with
recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head &
Neck 1): an open-label, randomised phase 3 trial. Lancet Oncol 2015; 16:583–594.
Machiels JP, Henry S, Zanetta S, et al. Phase II study of sunitinib in recurrent or metastatic squamous carcinoma of the head and neck:
GORTEC 2006-01. J Clin Oncol 2010; 28:21–28.
Machiels JP, Subramanian S, Ruzsa A, et al. Zalutumumab plus best supportive care versus best supportive care alone in patients with
recurrent or metastatic squamous-cell carcinoma of the head and neck after failure of platinum-based chemotherapy: an open-label,
randomised phase 3 trial. Lancet Oncol 2011; 12:333–343.
Schmitz S, Ang KK, Vermorken J, et al. Targeted therapies for squamous cell carcinoma of the head and neck: current knowledge and
future directions. Cancer Treat Rev 2014; 40:390–404.
Seiwert TY, Haddad RI, Gupta S, et al. Antitumor activity and safety of pembrolizumab in patients (pts) with advanced squamous cell
carcinoma of the head and neck (SCCHN): Preliminary results from KEYNOTE-012 expansion cohort. J Clin Oncol 33, 2015 (suppl; abstr
LBA6008).
Seiwert TY, Zuo Z, Keck MK, et al. Integrative and comparative genomic analysis of HPV-positive and HPV-negative head and neck
squamous cell carcinomas. Clin Cancer Res 2015; 21:632–641.
Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008;
359:1116–1127.
65
Seront & Machiels
66
Appendix 1: WHO Classification, 4th Edition (2017)
Tumours of the nasal cavity, Benign and borderline lesions

Hairy polyp
paranasal sinuses and skull base Ectopic pituitary adenoma
Craniopharyngioma
Carcinomas Soft tissue tumours
Keratinizing squamous cell carcinoma Nasopharyngeal angiofibroma
Non-keratinizing squamous cell carcinoma
Spindle cell (sarcomatoid) squamous cell carcinoma Haematolymphoid tumours
Lymphoepithelial carcinoma Notochordal tumours
Sinonasal undifferentiated carcinoma
NUT carcinoma Chordoma
Neuroendocrine carcinoma
Adenocarcinoma
Intestinal-type adenocarcinoma Tumours of the hypopharynx, larynx,
Non–intestinal-type adenocarcinoma
trachea and parapharyngeal space
Teratocarcinosarcoma
Sinonasal papillomas Malignant surface epithelial tumours
Conventional squamous cell carcinoma
Sinonasal papilloma, inverted type
Verrucous squamous cell carcinoma
Sinonasal papilloma, oncocytic type
Basaloid squamous cell carcinoma
Sinonasal papilloma, exophytic type
Papillary squamous cell carcinoma
Respiratory epithelial lesions Spindle cell squamous cell carcinoma
Respiratory epithelial adenomatoid hamartoma Adenosquamous carcinoma
Seromucinous hamartoma Lymphoepithelial carcinoma
Salivary gland tumours Precursor lesions
Pleomorphic adenoma Dysplasia
Squamous cell papilloma & squamous cell papillomatosis
Malignant soft tissue tumours
Fibrosarcoma
Neuroendocrine tumours
Undifferentiated pleomorphic sarcoma Well-differentiated neuroendocrine carcinoma
Leiomyosarcoma Moderately differentiated neuroendocrine carcinoma
Rhabdomyosarcoma Poorly differentiated neuroendocrine carcinoma
Angiosarcoma Salivary gland tumours
Malignant peripheral nerve sheath tumour
Adenoid cystic carcinoma
Biphenotypic sinonasal sarcoma
Pleomorphic adenoma
Synovial sarcoma
Oncocytic papillary cystadenoma
Borderline / low-grade malignant soft tissue tumours Soft tissue tumours
Desmoid-type fibromatosis
Granular cell tumour
Sinonasal glomangiopericytoma
Liposarcoma
Solitary fibrous tumour
Inflammatory myofibroblastic tumour
Epithelioid haemangioendothelioma
Benign soft tissue tumours Cartilage tumours
Chondroma and chondrosarcoma
Leiomyoma
Haemangioma Haematolymphoid tumours
Schwannoma
Neurofibroma
Other tumours Tumours of the oral cavity and
Meningioma
Sinonasal ameloblastoma
mobile tongue
Chondromesenchymal hamartoma Malignant surface epithelial tumours
Haematolymphoid tumours Squamous cell carcinoma
Extranodal NK/T-cell lymphoma Oral potentially malignant disorders & oral epithelial dysplasia
Extraosseous plasmacytoma
Oral potentially malignant disorders
Neuroectodermal / melanocytic tumours Oral epithelial dysplasia
Ewing sarcoma / primitive neuroectodermal tumours Proliferative verrucous leukoplakia
Olfactory neuroblastoma Papillomas
Mucosal melanoma
Squamous cell papilloma
Condyloma acuminatum
Tumours of the nasopharynx Verruca vulgaris
Multifocal epithelial hyperplasia
Nasopharyngeal carcinoma Tumours of uncertain histogenesis
Nasopharyngeal papillary adenocarcinoma Congenital granular cell epulis
Ectomesenchymal chondromyxoid tumour
Salivary gland tumours Soft tissue and neural tumours
Adenoid cystic carcinoma Granular cell tumour
Salivary gland anlage tumour Rhabdomyoma
Lymphangioma
67
Appendix 1: WHO Classification
Haemangioma Carcinosarcoma
Schwannoma and neurofibroma Poorly differentiated carcinoma
Kaposi sarcoma Lymphoepithelial carcinoma
Myofibroblastic sarcoma Squamous cell carcinoma
Oral mucosal melanoma Oncocytic carcinoma
Sialoblastoma
Salivary type tumours Benign tumours
Mucoepidermoid carcinoma Pleomorphic adenoma
Pleomorphic adenoma Myoepithelioma
Haematolymphoid tumours Basal cell adenoma
CD30-positive T-cell lymphoproliferative disorder Warthin tumour
Plasmablastic lymphoma Oncocytoma
Langerhans cell histiocytosis Lymphadenoma
Extramedullary myeloid sarcoma Cystadenoma
Sialadenoma papilliferum
Ductal papillomas
Tumours of the oropharynx Sebaceous adenoma
Canalicular adenoma and other ductal adenomas
(base of tongue, tonsils, adenoids) Non-neoplastic epithelial lesions
Squamous cell carcinoma Sclerosing polycystic adenosis
Nodular oncocytic hyperplasia
Squamous cell carcinoma, HPV-positive Lymphoepithelial sialadenitis
Squamous cell carcinoma, HPV-negative Intercalated duct hyperplasia
Salivary gland tumours Benign soft tissue lesions
Pleomorphic adenoma Haemangioma
Adenoid cystic carcinoma Lipoma/sialolipoma
Polymorphous adenocarcinoma Nodular fasciitis
Haematolymphoid tumours Haematolymphoid tumours
Hodgkin lymphoma Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue
Burkitt lymphoma (MALT lymphoma)
Follicular lymphoma
Mantle cell lymphoma
T-lymphoblastic leukaemia/lymphoma
Follicular dendritic cell sarcoma
Odontogenic and maxillofacial
bone tumours
Tumours and tumour-like lesions Odontogenic carcinomas
of the neck and lymph nodes Ameloblastic carcinoma
Primary intraosseous carcinoma, NOS
Tumours of unknown origin Sclerosing odontogenic carcinoma
Clear cell odontogenic carcinoma
Carcinoma of unknown primary Ghost cell odontogenic carcinoma
Merkel cell carcinoma
Heterotopia-associated carcinoma Odontogenic carcinosarcoma
Haematolymphoid tumours Odontogenic sarcomas
Cysts and cyst-like lesions Benign epithelial odontogenic tumours
Branchial cleft cyst Ameloblastoma
Thyroglossal duct cyst Ameloblastoma, unicystic type
Ranula Ameloblastoma, extraosseous/peripheral type
Dermoid and teratoid cysts Metastasizing ameloblastoma
Squamous odontogenic tumour
Calcifying epithelial odontogenic tumour
Tumours of salivary glands Adenomatoid odontogenic tumour
Benign mixed epithelial & mesenchymal odontogenic tumours
Malignant tumours
Ameloblastic fibroma
Mucoepidermoid carcinoma Primordial odontogenic tumour
Adenoid cystic carcinoma Odontoma
Acinic cell carcinoma Dentinogenic ghost cell tumour
Polymorphous adenocarcinoma
Clear cell carcinoma Benign mesenchymal odontogenic tumours
Basal cell adenocarcinoma Odontogenic fibroma
Intraductal carcinoma Odontogenic myxoma/myxofibroma
Adenocarcinoma, NOS Cementoblastoma
Salivary duct carcinoma Cemento-ossifying fibroma
Myoepithelial carcinoma Odontogenic cysts of inflammatory origin
Epithelial–myoepithelial carcinoma
Carcinoma ex pleomorphic adenoma Radicular cyst
Secretory carcinoma Inflammatory collateral cysts
Sebaceous adenocarcinoma
68
Odontogenic and non-odontogenic developmental cysts Tumours of the ear
Dentigerous cyst
Odontogenic keratocyst Tumours of the external auditory canal
Lateral periodontal cyst and botryoid odontogenic cyst Squamous cell carcinoma
Gingival cysts Ceruminous adenocarcinoma
Glandular odontogenic cyst Ceruminous adenoma
Calcifying odontogenic cyst
Orthokeratinized odontogenic cyst Tumours of the middle and inner ear
Nasopalatine duct cyst Squamous cell carcinoma
Malignant maxillofacial bone and cartilage tumours Aggressive papillary tumour
Endolymphatic sac tumour
Chondrosarcoma Otosclerosis
Mesenchymal chondrosarcoma Cholesteatoma
Osteosarcoma Vestibular schwannoma
Benign maxillofacial bone and cartilage tumours Meningioma
Chondroma Middle ear adenoma
Osteoma
Melanotic neuroectodermal tumour of infancy
Chondroblastoma Paraganglion tumours
Chondromyxoid fibroma Carotid body paraganglioma
Osteoid osteoma Laryngeal paraganglioma
Osteoblastoma Middle ear paraganglioma
Desmoplastic fibroma Vagal paraganglioma
Fibro-osseous and osteochondromatous lesions
Ossifying fibroma
Familial gigantiform cementoma
Fibrous dysplasia
Cemento-osseous dysplasia
Osteochondroma
Giant cell lesions and simple bone cyst
Central giant cell granuloma
Peripheral giant cell granuloma
Cherubism
Aneurysmal bone cyst
Simple bone cyst
Haematolymphoid tumours
Solitary plasmacytoma of bone
69
Appendix 2: Selected treatment schedules
Squamous cell carcinomas

A. Locally advanced disease (systemic therapy plus radiotherapy)
Regimen Chemotherapy Dose Route Schedule

High-dose cisplatin (1, 2)
Cisplatin 100 mg/m 2
i.v. Day 1
q 3 weeks for 3 cycles
Weekly cisplatin (3, 4) Cisplatin 40 mg/m2 i.v. Weekly
Cetuximab (5)
Cetuximab Initially 400 mg/m and then 250 mg/m
2 2
i.v. Weekly
CF (6-8)
Carboplatin 70 mg/m 2
i.v. Days 1–4
or
cisplatin 60 mg/m2 Day 1
5-FU 600–800 mg/m 2
i.v. (C.I.) Days 1–4
CP (9, 10)
Carboplatin 100 mg/m 2
i.v. Weekly
or
cisplatin 20 mg/m 2
Paclitaxel 30–45 mg/m2 i.v. Weekly

5-FU / Hydroxyurea (9)
Hydroxyurea 1g p.o. 2/day
5-FU 800 mg/m2 i.v. Daily
B. Recurrent, unresectable or metastatic disease (with no surgery or radiotherapy option)

B.1. Combination chemotherapy

Cetuximab-based chemotherapy, 1st line (11) Cetuximab Initially 400 mg/m2 and then 250 mg/m2 i.v. Weekly
Carboplatin AUC=5 i.v. Day 1
or
cisplatin 100 mg/m2
5-FU 1000 mg/m2 i.v. (C.I.) Days 1–4
Cetuximab maintenance in pts with PR / SD
PF, 1st line (12) Cisplatin 100 mg/m2 i.v. Day 1
5-FU 1000 mg/m 2
q 3–4 weeks
CP, 1st line (12)
Cisplatin 75 mg/m 2
i.v. Day 1
Paclitaxel 175 mg/m 2
i.v. Day 1
q 3 weeks
TP, 1st line (13) Cisplatin 75 mg/m2 i.v. Day 1
Docetaxel 75 mg/m 2
i.v. Day 1
q 3 weeks
TC, 1st line (14) Carboplatin AUC=6 i.v. Day 1
Docetaxel 65 mg/m2 i.v. Day 1
q 3 weeks
TPEx, 1st line (15)
2 2
i.v. Weekly
Cisplatin 75 mg/m2 i.v. Day 1
Docetaxel 75 mg/m 2
i.v. Day 1
Cetuximab maintenance in patients with PR/SD
CE, 1st line (16, 17) Cisplatin 75–100 mg/m2 i.v. Day 1
2 2
i.v. Weekly
q 3–4 weeks
70
B.2. Single-agent chemotherapy

Nivolumab, 2nd line (18)
Nivolumab 3 mg/kg i.v. Day 1
q 2 weeks
Methotrexate, 2nd line (19, 20) Methotrexate 40–60 mg/m2 i.v. Weekly
Pembrolizumab, 2nd line (21) Pembrolizumab 200 mg i.v. Day 1
q 3 weeks
Cisplatin, 2nd line (22)
i.v. Day 1
q 3 weeks
5-FU, 2nd line (22)
5-FU 1000 mg/m 2
q 3 weeks
Docetaxel, 2nd line (23)
Docetaxel 75 mg/m 2
i.v. Day 1
q 3 weeks
Paclitaxel, 2nd line (24)
i.v. Weekly
Cetuximab, 2nd line (25)
2 2
i.v. Weekly
Vinorelbine, 2nd line (26) Vinorelbine 30 mg/m2 i.v. Weekly
Capecitabine, 2nd line (27)
Capecitabine 1250 mg/m 2
p.o. Days 1–14
q 3 weeks
Abbreviations: 2/d, twice a day; 5-FU, 5-fluorouracil; AUC, area under the curve; C.I., continuous infusion; i.v., intravenous; p.o., oral; PR, partial response; SD, stable disease.
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71
A. Locally advanced disease: concurrent chemotherapy plus radiotherapy

High-dose cisplatin (1, 2)
i.v. Days 1, 22 and 43
Weekly cisplatin (3-5)
Cisplatin 40 mg/m 2
i.v. Weekly
for 6-8 cycles
Carboplatin (6) Carboplatin 100 mg/m2 or i.v. Weekly
AUC=2 for 6-8 cycles
B. Locally advanced disease: induction / neoadjuvant chemotherapy

PF (7-9)
i.v. Day 1
5-FU 1000 mg/m2 i.v. (C.I.) Days 1–4
q 3 weeks
TP (10)
Cisplatin 75 mg/m 2
i.v. Day 1
Docetaxel 75 mg/m 2
i.v. Day 1
q 3 weeks
TC (11)
Carboplatin AUC=6 i.v. Day 1
i.v. Days 1, 8 and 15
q 3 weeks
GP (12) Cisplatin 75 mg/m2 i.v. Day 1
Gemcitabine 1000 mg/m 2
i.v. Days 1 and 8
q 3 weeks
TPF (Asian doses) (13) Cisplatin 60 mg/m2 i.v. Day 1
Docetaxel 60 mg/m 2
i.v. Day 1
5-FU 600 mg/m 2
q 3 weeks
TPF (European doses) (14) Cisplatin 75 mg/m2 i.v. Day 1
Docetaxel 75 mg/m 2
i.v. Day 1
5-FU 750 mg/m 2
q 3 weeks
C. Locally advanced disease: adjuvant chemotherapy

PF or CF (1, 6) Cisplatin 80 mg/m2 i.v. Day 1
or
carboplatin AUC=5
5-FU 1000 mg/m2 i.v. (C.I.) Days 1–4
q 4 weeks x3
72
D. Recurrent, unresectable or metastatic disease (with no surgery or radiotherapy option)
D.1. Combination chemotherapy

PF or CF (15-17) Cisplatin 75 mg/m2 i.v. Day 1
or
carboplatin AUC=5
5-FU 1000 mg/m2 i.v. (C.I.) Days 1–4
q 3 weeks
GP (15, 16)
Cisplatin 75 mg/m 2
i.v. Day 1
i.v. Days 1 and 8
q 3 weeks
CP (16)
Cisplatin 75 mg/m 2
i.v. Day 1
i.v. Day 1
q 3 weeks
TC (18) Carboplatin AUC=5 i.v. Day 1
i.v. Day 1
q 3 weeks
TP (19) Cisplatin 75 mg/m2 i.v. Day 1
Docetaxel 75 mg/m2 i.v. Day 1
q 3 weeks
D.2. Single-agent chemotherapy

Gemcitabine (20)
Gemcitabine 1000–1250 mg/m 2
i.v. Days 1 and 8
q 3 weeks
Capecitabine (21)
Capecitabine 1250 mg/m 2
p.o. Days 1–14
q 3 weeks
Paclitaxel (22)
i.v. Day 1
q 3 weeks
Docetaxel (23)
Docetaxel 75 mg/m 2
i.v. Day 1
q 3 weeks
Abbreviations: AUC, Area under the curve; C.I., continuous infusion; i.v., intravenous; p.o., oral.
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Salivary gland carcinomas

A. Recurrent, unresectable or metastatic disease (with no surgery or radiotherapy option)
A.1. Adenoid cystic carcinoma

CAP (1-4) Cyclophosphamide 500 mg/m2 i.v. Day 1
Doxorubicin 50 mg/m 2
i.v. Day 1
Cisplatin 50 mg/m 2
i.v. Day 1
q 3 weeks
Cisplatin (5)
i.v. Day 1
q 3–4 weeks
Epirubicin (6)
Epirubicin 30 mg/m 2
i.v. Day 1
Weekly
Vinorelbine (7)
Vinorelbine 30 mg/m 2
i.v. Day 1
Weekly
A.2. Non-adenoid cystic carcinoma*

CAP (4, 8)
Cyclophosphamide 500 mg/m 2
i.v. Day 1
Doxorubicin 50 mg/m2 i.v. Day 1
Cisplatin 50 mg/m 2
i.v. Day 1
q 3 weeks
Gemcitabine plus cisplatin (9)
i.v. Days 1–8
q 3 weeks
Vinorelbine plus cisplatin (10)
Vinorelbine 25 mg/m 2
i.v. Days 1–8
q 3 weeks
Carboplatin plus paclitaxel (11) Carboplatin AUC=6 i.v. Day 1
i.v. Day 1
q 3 weeks
Paclitaxel (12)
i.v. Day 1
q 3 weeks
*This definition includes histotypes different from adenoid cystic carcinoma
Abbreviations: AUC, Area under the curve; i.v., intravenous.
74
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Chapter 5 While every effort has been made to contact the copyright holders of all images, the
Figure 1. Lefebvre JL, et al. Int J Radiat Oncol Biol Phys 2009;73:1293-1303. publisher would be grateful for any additional information about any images where they
have been unable to trace or obtain permissions and will be glad to make amendments
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76
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Declarations of interest
S Alfieri: No conflicts of interest. LD Locati: No conflicts of interest.
P Bossi: No conflicts of interest. JP Machiels: Advisor for Boerhinger-Ingelheim,

Merck Sharp & Dohme; research grants from Bayer,
A Chan: No conflicts of interest. Janssen, Novartis.
A Dietz: No conflicts of interest. L Martin: No conflicts of interest.
P Economopoulou: No conflicts of interest. A Matrone: Travel grants from Genzyme, Bayer.
R Elisei: Consultant and speaker bureau for Eisai, R Mesía: Advisory boards and educational meetings
Exelixis, Bayer, AstraZeneca, Genzyme. as faculty and speaker for Merck Serono, Bayer,
AstraZeneca; occasional travel fund from Merck Serono.
EP Hui: No conflicts of interest.
A Psyrri: No conflicts of interest.
KD Hunter: No conflicts of interest.
C Romei: Consultant for Eisai; travel grants from
M Imbimbo: No conflicts of interest. Genzyme and Bayer.
MV Karamouzis: No conflicts of interest. E Seront: No conflicts of interest.
LW Lee: No conflicts of interest. N Slevin: No conflicts of interest.
SF Leung: No conflicts of interest. M Taberna: Advisory boards as speaker for

Merck Serono Group.
L Licitra: Consultancy/advisory boards for
Bristol-Myers Squibb, MSD, Merck-Serono, S Wiegand: No conflicts of interest.
Boehringer Ingelheim, Debiopharm, SOBI, Novartis,
AstraZeneca, Roche; research grants from EISAI,
MSD, Merck-Serono, Boehringer Ingelheim, Novartis,
AstraZeneca, Roche; travel grants from Merck-Serono,
Debiopharm, SOBI, Bayer.
77
Declarations of interest
Index
Note: Abbreviations used in the index are listed on page ix
A broad front, invasion (HNSCC), 14

ABT-806, 62 buccal mucosal cancer, 19
acantholytic squamous cell carcinoma, 16 C
accelerated fractionation, 34, 60 c-kit, 54
adenoid cystic carcinoma (ACC), 53–54, 67–68 c-Met, overexpression, 63
ethmoid sinus, 55 cabazitaxel, 40
metastases, 55 cabozantinib, 46
recurrent/metastatic, chemotherapy, 74 calcitonin (Ct), 43, 45
tongue base, 54 Cancer Genome Atlas (TCGA), 64
adenosquamous carcinoma, 16 CAP regimen, 74
afatinib, 40, 62 capecitabine, 40, 71, 73
age carboplatin
HNSCC risk, 3–4 HNSCC, 37–38, 70
salivary gland tumours, 53 nasopharyngeal carcinoma, 72–73
thyroid carcinomas, 43 salivary gland carcinomas, 74
unknown primary tumour, prognosis, 11 carcinogen(s), 3–5, 36
AJCC, TNM system, 10, 24 carcinogenesis, 4–5
AKT inhibitor, 63–64 field, 5, 13
alcohol use, 3, 6, 8 multistep, 5, 7
cessation, 8 carcinoma in situ, 5, 7, 13, 53
anaemia, 59–60 CCND1 amplification, 62
anatomical sites/subsites, 1, 7 CD56, 16
hypopharynx, 21 CDKN2a gene (p16 gene), 5, 7, 17
oral cavity, 1, 19 cediranib, 63
androgen receptor (AR) cell-cycle inhibitors, 62
blockade, 55 cell-cycle regulation, 17
overexpression, 54–55 cell death, radiation causing, 30
angiogenesis, 63 cervical lymph nodes, 44
inhibitors, 63–64 detection, 9
anterior commissure, cancer, 22 dissection see neck dissection
anti-HER2 monoclonal antibodies, 55 levels, 8, 25
anti-PD-1 antibodies, 40, 64 tumours/tumour-like lesions, 68
anti-VEGF agents, 63 cervical lymphadenopathy
antibiotic intravenous therapy, 60 HNSCC, 7
antibody-dependent cell-mediated cytotoxicity (ADCC), 64 nasopharyngeal carcinoma, 49
antimicrobials, 60 PET/CT imaging, 9
aryepiglottic fold, tumours, 22 cetuximab, in HNSCC, 17, 62, 70
arytenoid, cancer, 22 bioradiation, 20
Asia, head and neck cancer epidemiology, 1, 49 cisplatin-based chemoradiation and, 34
cisplatin/cisplatin-FU, with, 39
maintenance single-agent therapy, 39
B recurrent/metastatic HNSCC, 39, 70–71
B7 (protein), 64 resistance, 63
basaloid SCC, 16–17 RT with, oropharyngeal cancer, 20
basaloid tumours, salivary gland, 53 second-line treatment, 40
benzodiazepines, 59 side effects, 39
bevacizumab, 63 chemoradiotherapy (ChT-RT), concurrent
biomarkers HNSCC, 70
HER family, 62 advanced HNSCC, 34, 70
HNSCC, 9, 17, 24 hypopharyngeal cancer, 21
nasopharyngeal carcinoma, 49–50 laryngeal cancer, 22
biopsy oral cavity cancer, 19
HNSCC, 9, 11 oropharyngeal cancer, 20
nasopharyngeal carcinoma, 51 postoperative, 34
salivary glands tumours, 54 supraglottic cancer, 22
bioradiation (bio-RT), 20–22 unresectable, standard RT vs, 34
bleomycin, 37 nasopharyngeal carcinoma, 50, 72
blood supply, flaps, 27 salivary gland tumours, 55
bone invasion, oral SCC, 15 skin care during, 60
bone tumours, maxillofacial, WHO classification, 68–69 toxicities, 58
brachytherapy, 19, 30, 51 acute, 57
BRAF mutations, 46 late, 25, 57
BRAFV600E mutation, 42–43 mucositis, 58
breathing, 8, 26 skin toxicities (Grades 3 and 4), 60
78
Index
chemotherapy (ChT) cyclin D1, 17, 62
HNSCC cyclin-dependent kinases 4, 6 (CDK4/6), 62
adjuvant ChT, after surgery, 36 cyclophosphamide, 37, 74
hypopharyngeal cancer, 21 cytokeratins, 14, 16
induction ChT, 11, 21, 22 cytokines, 64
laryngeal cancer, 22 cytological atypia, 13
locally advanced disease, 70
neoadjuvant ChT, 19–20
oral cavity cancer, 19
D
dacomitinib, 62
oropharyngeal cancer, 20
DARS (Dysphagia/Aspiration Related Structures), 58
triple-agent regimens, 38
dasatinib, 63–64
HNSCC, recurrent/metastatic
DDR2 gene, 64
combination ChT, 38, 70
decitabine, 63
single-agent ChT, 37, 71
demethylating agents, 63
inflammatory response, 58
dental assessment, 8, 32, 49, 58
nasopharyngeal carcinoma, 72–73
dental care, 58
adjuvant therapy, 72
dentistry, 8, 32, 49
desmoplastic stroma, 14
neoadjuvant therapy, 50, 72
development, HNSCC, 5, 7, 13, 17
palliative therapy, 50–51
dexamethasone, 59
recurrent/metastatic disease, 73
diagnostic algorithm, 10
radiotherapy with see chemoradiotherapy
dietary counselling, 60
salivary gland tumours, 55, 74–75
dietician, 32
thyroid carcinomas, 46
digestive symptoms, 8
toxicities, 38, 58–59
disease-related factors
chest CT, 9
second-line treatment selection, 40
chewing, 3, 8
treatment toxicity risk, 58
children, salivary gland tumours, 53
DNA
China, HNSCC epidemiology, 4
content, abnormal, 13
chromogranin A, 16
damage, radiation, 30
chromosome loss, HNSCC pathogenesis, 5, 7
HPV, integration into host genome, 5, 9
ChT-RT see chemoradiotherapy (ChT-RT), concurrent
nasopharyngeal carcinoma, EBV, 49–50
cisplatin, 20–22, 34
repair, 30
HNSCC, 70
docetaxel
combination therapy, 38–39
HNSCC, 37, 39–40, 70–71
hypopharyngeal cancer, 21
laryngeal cancer, 22
docetaxel-cisplatin-fluorouracil (TPF) regimen, 21–22, 72
doxepin mouthwash, 58
doxorubicin
recurrent/metastatic, 37–39, 70–71
HNSCC, metastatic, 37
RT with, 34
salivary gland tumours, 55, 74
single-agent use, 37, 70–71
nasopharyngeal carcinoma, 50, 72–73
dysphagia, 8, 24, 32, 51, 58
nausea and vomiting, 59
dysplasia, epithelial, 5, 13
resistance, vandetanib effect, 63
features, and grading, 5, 7, 13
salivary gland tumours, 55, 74
severity as guide to SCC risk, 13
clinical features
HNSCC, 2, 8
salivary gland tumours, 54 E
thyroid carcinomas, 43 E2F transcription factor, 62
clinical trials, HNSCC, 24, 39–40 ear, tumours, 69
cohesive invasive front, 14 early invasive SCC, 13, 24
comorbidities, 8, 24, 36, 40, 57–58 eating,
competing event, 57 radiotherapy, 31–32
computed tomography (CT), 9 surgery goal, 26
medullary thyroid carcinoma, 45 EBER staining, 49
radiotherapy planning, HNSCC, 31 ECOG performance status, 8, 11
thorax, salivary gland tumours, 54 EGFR gene, amplified, 17
cosmetic outcomes, 26–27 endocrine malignancies, 42
cranial nerve palsy, 49 endoscopy, 8
CRTC1-MAML2 gene fusion, 53 enteral feeding, 58, 60
CTLA-4, 64 EphA2, 64
cure rates, HNSCC, 2
79
Index
epidemiology flaps, 27
HNSCC, 1, 9 oropharyngeal cancer, 28
salivary gland tumours, 53 pectoralis major, 26–27
thyroid carcinomas, 42 radial forearm, 24, 26– 28
epidermal growth factor receptor (EGFR), 7, 17, 46, 62 flexible endoscope, 8
as biomarker, SCC surgery, 24 floor of mouth, cancer, 19
dimerisation, 39 5-fluorouracil (5-FU)
inhibitors, 39–40 HNSCC, 37–39, 70
resistance, 62–63 recurrent/metastatic, 38, 70–71
see also tyrosine kinase inhibitors (TKIs) nasopharyngeal carcinoma, 50, 72–73
monoclonal antibody, 17, 34 frailty of patients, 58
new, 39, 62, 64
response, prediction, 62
see also cetuximab
G
gefitinib, 39–40
overexpression in HNSCC, 7, 17, 34, 39, 62, 64
gemcitabine, 72–74
clinical outcome and, 39
gender
targeting, strategies, 39
HNSCC risk, 3–4
epigenetic aberrations, 5, 63
unknown primary tumour, prognosis, 11
epiglottis, tumours, 22
gene deletions, 5
epirubicin, 74
gene expression profiling, 64
epithelial dysplasia see dysplasia, epithelial
gene mutations, 5, 17
epoetin β, 60
see also specific genes
Epstein-Barr virus (EBV), 11
genetic changes, 5, 13, 17
DNA, 49– 51
HNSCC, 62–63
nasopharyngeal cancer, 4, 49
salivary gland tumours, 54
paranasal sinus cancer, 4
ErbB-receptor family blocker, 40
genetic diseases, HNSCC risk factor, 4
ErbB receptors, cross-talk, 62
gingiva,
erlotinib, 40
lower/upper, cancer, 19
ertumaxomab, 64
verrucous carcinoma, 16
erythroplakia, 5
glottic cancer
erythropoiesis-stimulating agents (ESAs), 59
PET/CT imaging, 9
erythropoietin, 60
treatment, 22
ethmoid sinus, carcinoma, 55
goitre, 43
ethnic factors, 4, 8
grading, HNSCC, 13–14
ETV6-NTRK3 gene fusion, 54
granulocyte colony-stimulating factor (G-CSF), 60
EUROCARE study, 2
Gray (Gy), 30, 33
Europe
growth factors, 7, 59, 63
HNSCC epidemiology, 1
HPV-related oropharyngeal cancer, 28
nasopharyngeal carcinoma, 49 H
salivary gland tumours, 53 haematological spread, 7, 15
everolimus, 63 haematopoietic growth factors, 59
EWSR rearrangements, 54 haematoxylin & eosin (H&E) staining, 13, 16–17
extension of tumours, exploration, 9 haemoglobin levels, 59
extracapsular spread, SCC, 15, 33, 34 hard palate, cancer, 1, 19, 54
Extreme Trial, 39 head and neck SCC (HNSCC)
advanced, chemoradiotherapy, 34, 70
F anatomical sites/subsites, 1, 7
clinical features, 2, 8
factor E2, 5, 62
coexistence of other tumours, 8–9
false vocal cords, cancer, 22
diagnostic algorithm, 10
Fanconi anaemia, 4
epidemiology, 1, 9
febrile neutropaenia, 59–60
extension of tumours, exploration, 9
fibroblast growth factor receptor family genes, 64
grading, 10, 13–14
fibroblasts, proliferation, 14
heterogeneity, 7, 17
field carcinogenesis, 5, 13
histological examination, 9–10
“field change”, 13
histopathology, 13–15
fine needle aspiration (FNA)
imaging, 9–11, 31–32, 45, 49, 54
HNSCC, 9
invasive see invasive SCC
locally advanced, treatment schedules, 34, 70
thyroid nodules, 43
locoregional invasion, 2, 7, 15, 34, 36, 40, 49–50, 55
80
Index
lymph nodes see lymph node(s), in HNSCC type 18 (HPV18), 17
metastases see metastatic disease hydroxyurea, 37, 70
moderately-differentiated, 10, 14 hyperfractionation, radiotherapy, 34, 60
mortality, 1–2 hypermethylation, 63
natural history, 5, 7 hyperplasia, 5, 7, 67–68
pathogenesis, 5, 7, 17 hypoparathyroidism, 44
physical examination, 8 hypopharyngeal cancer, 7
poorly differentiated, 10, 14, 16, 42, 53 anatomical subsites, 21
postoperative RT indication, 19–22 haematological spread, 7
prognostic factors see prognostic factors PET/CT imaging, 9
recurrent see recurrent disease, HNSCC prognosis, 11, 21
risk, dysplasia severity as guide, 13 risk factors, 3, 21
risk factors see risk factors surgery, 21, 24
spread, 7, 15 survival rate, 2, 21
staging, 7, 9–10, 15, 49 symptoms, 8
supergroups, gene expression profiling, 64 treatment, 21
survival rates see survival rates unresectable, treatment, 21
symptoms, 8-10 WHO classification, 67
TNM system, staging, 10–11, 24 hypopharynx, 1, 7, 21
tobacco-related, 1, 3–5 hypoxia modifiers, 30, 34
treatment
chemotherapy see chemotherapy (ChT)
choice, factors affecting, 40
I
IChT (induction chemotherapy), 11, 21–22
ChT-RT see chemoradiotherapy (ChT-RT), concurrent
ifosfamide, 37
immunotherapy, 40, 46, 64
image-guided radiotherapy (IGRT), 32
novel agents, 40, 55, 62–64
imaging
personalised, 64
HNSCC, 9
radiotherapy see radiotherapy (RT)
radiotherapy planning, 31
risk factors for toxicity, 57–58
immune response/system, 14, 64
site-driven see specific cancer sites (e.g. oropharyngeal cancer)
status, unknown primary tumour prognosis, 11
stage-driven, 19
immunohistochemistry
surgical see surgery
HNSCC, 13–14, 16–17
toxicities, 24, 34, 57–60
HPV, 9
unknown primary, 11, 68
well-differentiated, 10, 14, 42, 67
immunosuppression, 4
WHO classification, 53, 67–68
immunotherapy, 40, 46, 64
hemithyroidectomy, 44
in situ hybridisation (ISH), 9, 13, 17
HER family, 62
indirect laryngoscopy, 8
HER2, 54–55, 62
induction chemotherapy see chemotherapy and IChT
HER3, 62
infections, 60
monoclonal antibody, 62
inflammatory response, 14, 58, 67–68
HER4, 62
INPP4B gene, 64
heterogeneity of SCC, 7, 17
intensity modulated radiotherapy (IMRT), 32–33
histological examination, HNSCC, 9–10
histopathology, 13
HNSCC, 13–15
skin toxicity, 60
nasopharyngeal carcinoma, 49
interdisciplinary decision, 25, 57
interstitial radiotherapy, 30
HNSCC see head and neck SCC (HNSCC)
intracavity radiotherapy, 30
5-HT3 receptor antagonist, 59
intracellular bridges, 14
human immunodeficiency virus (HIV), 4
invasive SCC
human papillomavirus (HPV), 1, 4, 9
development, 5, 7
basaloid SCC association, 16
early, 13, 24
carcinogenesis mechanism, 5
local, 2, 15–16
detection/testing, 9, 11, 17
precursors, 5
DNA integration into host genome, 5, 9
ionising radiation, 30, 42
E6 and E7 oncoproteins, 5, 17
HPV-negative HNSCC, 4, 11, 20, 28, 62–63, 68
HPV-positive HNSCC, 2–4, 20, 28, 63–64, 68 J
see also under oropharyngeal cancer jawbone invasion, 9
infection risk increased by smoking, 3 jugular nodes, 8, 25
type 16 (HPV16), 4, 17, 28
81
Index
K mechanistic target of rapamycin (mTOR), 63
keratin projections, 16 mammary analogue secretory carcinoma, 54
keratinisation, 13–14 mandible invasion, 9
MARCH meta-analysis, 34
medical history, 8
L MEHD7945A, 62
lapatinib, 62 MEK inhibitor, 46
laryngeal cancer, 1, 7 metastatic disease, HNSCC, 7, 36
epidemiology, 1–2 chemotherapy, 36, 70–71
localised, 2 combination chemotherapy, 38, 70
risk factors, 3–4, 22 second-line therapy, 40
surgery, 22, 24 single-agent, 37, 71
survival rate, 2, 22 distant, 7, 36
symptoms, 8 EGFR inhibitors, 39
treatment, 22, 33 histology, 15
WHO classification, 67 locoregional, 2, 7, 36
laryngectomy, 21–25 non-cohesive/small tumour islands, 14
laryngo-oesophageal dysfunction-free survival, 24 PET/CT imaging, 9
laryngoscopy, indirect, 8 predictive factors for outcome, 36
laser endoscopic surgery, supraglottic cancer, 22 risk, 36
lenalinomide, 64 oral cavity cancer thickness, 19
lenvatinib, 46 survival rates, 2
leukopaenia, 59 timing for development, 36
leukoplakia, 5, 67 TNM system, 10
lichen sclerosus, 4 treatment objectives, 36
lip cancer, 1, 19 please add: unknown primary tumour, 11
lobectomy (LB), 44 metastatic disease, medullary thyroid carcinoma, 45
locoregional invasion, HNSCC, 2, 7, 15, 36 methotrexate (MTX), 37–40, 71
control, hypoxia modifiers with RT, 34 microvascular free flaps, 27
locoregional relapse, 36, 55 mitoses, abnormal, 13
loss of heterogeneity (LOH), 7, 17 molecular analysis/characterisation
lung metastases HNSCC, 17
adenoid cystic carcinoma, 55 salivary gland tumours, 54
HNSCC, 7 molecular progression model, 5, 7, 17
thyroid carcinomas, 45 monoclonal antibodies (mAbs), 17, 30, 34, 39, 55, 62
lymph node(s), in HNSCC, 10 morphine mouthwash, 58
biopsy, sentinel, 15 mortality rates
cervical see cervical lymph nodes competing events and, 57
levels, 8, 25 HNSCC, 1–2
pathologically positive, postoperative RT, 19–22 moulds, thermoplastic, 31
prophylactic dissection see neck dissection mouthwashes, 58
spread to, metastases, 7, 15, 33 mTOR, 63
as prognostic factor, 15 inhibitors, 63
unknown primary, 11 mucositis, 32, 58
status, assessment, 8 multidisciplinary team, 10, 25, 57
TNM classification, 10 multilayer tissue closure, 27
lymph node extranodular extension (ENE) multimodality strategy, 21–22, 24, 57
hypopharyngeal cancer, 21 organ preservation, 22, 24
laryngeal cancer, 22 multistep carcinogenesis, 5, 7, 17
oral cavity cancer, 19 muscle, tumour islands infiltrating, 15
oropharyngeal cancer, 20 MYB-NFIB gene fusion, 53–54
lymphatic dissemination, 7, 15
N
M nasal cavity
M918T RET mutation, 43 minor salivary gland cancers, 54
macroscopic examination, 13 tumours, WHO classification, 67
magnetic resonance imaging (MRI) nasopharyngeal carcinoma, 7, 49–51
HNSCC, 9–10, 31 EBV association, 4, 49
medullary thyroid carcinoma, 45 histology, 49
nasopharyngeal carcinoma, 49, 51 non-keratinising, 49
salivary gland tumours, 54 physical signs, 49
MALM2-CRTC1 gene fusion, 54 prognosis, 51
malnutrition, 32, 58, 60 recurrence, 51
82
Index
retropharyngeal nodal metastases, 49 oral mucosa, 19
squamous cell, 49 carcinoma development, 5, 7
TNM system, 10 dysplasia, 5
treatment, 50–51, 72–74 leukoplakia and erythroplakia, 5
chemotherapy see chemotherapy (ChT) normal, 5
follow-up and outcome, 51 organ preservation multimodality strategy, 21–22, 24
radiotherapy, 50–51 organ transplant recipients, 4
WHO classification, 67 oropharyngeal cancer, 7
work-up and staging, 49 causative factors, 17
nasopharyngeal tumours, WHO classification, 67 HPV-negative, 62
nasopharyngoscopy, 51 survival rates, 11, 20
nasopharynx, 1, 7, 11, 33, 49, 50, 67 treatment, outcomes, 28
natural history, HNSCC, 7 HPV-positive, 1–2, 4
natural killer cells, 64 age and gender, 4
nausea, 32, 46, 59 prognosis, 4, 11, 20
necitumumab, 62 radiotherapy, 33
neck dissection, 25 smoking relationship, 4
prophylactic survival rates, 2, 11, 20, 33
hypopharyngeal cancer, 21 time to cancer development, 4
lymph node levels, 8, 25 TNM system, 10
oral cavity cancer, 19 transoral surgery, 28
oropharyngeal cancer, 20 HPV testing, 9
supraglottic tumours, 22 PET/CT imaging, 9
thyroid carcinomas, 44 prognostic factors, 20
see also lymph node(s) prophylactic treatment, 20
neck lymphadenopathy see cervical lymphadenopathy risk factors, 3, 20
neck tumours/tumour-like lesions, 68 symptoms, 8
nerve palsy, 49 treatment, 20
neuroendocrine markers, 16 WHO classification, 68
neutropaenia, febrile, 59–60 oropharynx, 1, 7
next generation sequencing, 17 reconstruction options, 28
NF1/2 genes, 64 OSC see oropharyngeal cancer
nimorazole, 34 osteoradionecrosis, 32
nimotuzumab, 62
nivolumab, 64, 71
NK1 receptor antagonist, 59
P
p16 gene, 5, 7, 17
non-cohesive front, 14
p16 protein, 5, 9, 17
Notch1 gene, 17
downregulation, 5
novel therapeutic agents, 40, 55, 62–64
p16-negative HNSCC, 62
nutrition, 8, 32, 49, 58, 60
upregulation, 5, 16
p16INK4A, 5, 62
O p53 gene, 5, 17
odontogenic tumours, 68–69 mutation, 5, 17, 42
oncoproteins, 5, 17 p53 protein, 5, 7, 17
oral care, 58 p63 protein, 16
oral cavity, 1, 19 paclitaxel, 74
tumours, WHO classification, 67–68 HNSCC, 37–38, 40, 70–71
oral cavity cancer, SCC, 1 nasopharyngeal carcinoma, 72–73
chemotherapy, 19 salivary gland carcinomas, 74
epidemiology, 1 pancytokeratin (AE1/AE3), 16
invasion, 15 panitumumab, 39, 62
PET/CT staging, 9 papillary squamous cell carcinoma, 16
radiotherapy, 19 parafollicular C cells, 44
risk factors, 3, 19 paraganglion tumours, 69
smokeless (chewing) tobacco and, 3 paranasal sinus cancer, 4, 54
survival rate, 2, 19 WHO classification, 67
symptoms, 8 parotid gland
T1-T2 lesions, 19 RT for nasopharyngeal carcinoma, 50
thickness, predictive value, 19 tumours, 53–54
treatment, 19 pathogenesis
unresectable, therapy, 19 HNSCC, 5, 7, 17
USA incidence, 1 thyroid carcinomas, 42
pathological stage, 10
83
Index
patient-related factors, 57 radiation
risk factors for treatment toxicity, 58 doses (Gray), 30, 33
second-line treatment, selection, 40 ionising, 30, 42
unknown primary, 11 mechanism of action, 30
patient selection, 57 radioiodine (131-I), 44–46
PD-1/PD-L1 pathway, 64 radiotherapy (RT)
inhibitors, 64 accelerated, 20, 34, 60
pectoralis major flap, 26–27 accurate delivery, 31–32
pedicled free flap, 27 aims, 30
pembrolizumab, 40, 71 altered fractionation, 20, 34
pemetrexed, 37 chemotherapy with see chemoradiotherapy
performance status (PS), at relapse, 36, 38, 40 combined with systemic treatment, 30, 34, 70
perifosine, 63 delineation of cancer/regions at risk, 31
perineural invasion, SCC, 15 dose, 33–34
postoperative RT indication, 19–22, 33 minimisation, dysphagia, 58
perineural space, 15 nasopharyngeal carcinoma, 50
periodic acid–Schiff staining, 13 optimisation, 31
personalised treatment, 64 ESAs caution, 59
pharyngeal cancer, 1, 2 fractionation, 33–34
phonation, 8, 24, 26 HNSCC
phosphatase and tensin homologue (PTEN), 5, 17 adjuvant RT, 30, 36
phosphatidylinositol 3 phosphate (PI3K)/AKT/mTOR pathway, 63 as definitive treatment, 33, 59
photons, 30 early disease, 24
physical examination, 8, 11 hypopharyngeal cancer, 21
physiotherapy, 8 hypoxia modifiers with, 34
PI3K inhibitors, 63 indications, 33
PI3KCA amplification/mutations, 63 laryngeal cancer, 22
platinum compounds locally advanced disease, 70
HNSCC, 38–39 oral cavity cancer, 19
salivary gland tumours, 55 oropharyngeal cancer, 20
see also carboplatin; cisplatin postoperative see below
pleomorphism, nuclear and cellular, 13 recurrent disease, 33, 36
positron emission tomography (PET)/CT response, prognostic factor, 11
HNSCC, 9, 31 subglottic tumours, 22
limitations, 9 supraglottic cancer, 22
nasopharyngeal carcinoma, 49, 51 survival rates after, 33–34
radiotherapy planning, 31 hyperfractionation, 20, 34, 60
salivary gland tumours, 54 image-guided (IGRT), 32
posterior commissure, cancer, 22 immobilisation of patients, 31
prognosis inflammatory response, 58
HNSCC, 2–4 intensity modulated see intensity modulated radiotherapy (IMRT)
hypopharyngeal cancer, 21 international conventional dose, 33
nasopharyngeal carcinoma, 49, 51 nasopharyngeal carcinoma, 50–51, 72
salivary gland tumours, 55 normal tissue damage minimisation, 30
thyroid carcinomas, 43 organ sparing and function preservation, 30–32
see also survival rates planning, imaging for, 31–32
prognostic factors, HNSCC, 11, 14–15 postoperative, 33
oropharyngeal cancer, 20 delays, prognosis after, 33
unknown primary tumour, 11 hypopharyngeal cancer, 21
proto-oncogenes, 17 laryngeal cancer, 22
psycho-oncology, 8 oral cavity cancer, 19
PTEN, 5, 17 oropharyngeal cancer, 20
PTEN gene, 64 recurrent disease, 36
preparation for, 31–32
Q principles, 30–34
quality of life, 24, 26, 57–58
resistance, HNSCC, 63
salivary gland tumours, unresectable, 55
R schedule interruptions, compensation for, 33
R-classification, 24 simultaneous integrated boost (SIB), 33
R1 resection see surgery stereotactic (SRT), 51
radial forearm flap, 24, 26–28 three-dimensional conformal, 32
84
Index
thyroid carcinomas, 44 major salivary glands, 53–54
toxicities/side effects, 32, 58 metastases, 55
dysphagia, 58 minor salivary glands, 53–54
Grades 3 and 4, 60 mucoepidermoid, 53–54, 68
long-term, 51 polymorphous low-grade adenocarcinoma, 53
RAS mutation, 46 prognosis, 55
RASA1 gene, 64 treatment, 55, 74–75
“reconstructive ladder”, 26 WHO classification, 53, 67–68
reconstructive surgery, 24–27 saracatinib, 63
flaps see flaps SCC see head and neck SCC (HNSCC)
HPV-positive oropharyngeal cancer, 28 second-line therapy, HNSCC, 40
recurrent disease, HNSCC, 13 selumetinib, 46
chemotherapy, 70–71 sentinel lymph node biopsy, 15
combination, 36, 38, 70 sepsis, 60
second-line therapy, 40 sexual behaviour, 4
single-agent, 37, 71 simultaneous integrated boost (SIB), 33
clinical outcome, predictive factors, 36 skin care, 60
EGFR inhibitors, 39 skin grafts, 28
radiotherapy, 36 skin toxicities, 39, 60
risk factors, 33 slide staining, 13
second-line therapy, 40 smokers
surgery, 36 HNSCC, 1, 3–5
survival rates, 2 nasopharyngeal SCC, 49
TP53 gene mutation and, 17 oropharyngeal cancer, 20
treatment, and objectives of, 36 smoking cessation, 3, 8, 32, 58
red blood cell transfusion, 59–60 social circumstances, 8
renal dysfunction, 37 soft palate
respiratory symptoms, 8 cancer, 20
RET mutations, 42–43, 46 reconstruction, 27–28
RET/PTC rearrangements, 42 sorafenib, 46, 63
rete pegs, 13, 16 Spectrum Trial, 39
retinoblastoma (Rb) tumour suppressor, 5, 7, 62 speech and language therapist, 32
retromolar trigone, 19 spindle cell carcinoma, 16
retropharyngeal nodal metastases, 49 spread of SCC, 7, 15
risk factors squamous cell tumours see head and neck SCC (HNSCC)
for competing events, 57 Src, TKIs targeting, 63
HNSCC, 1, 3–4 staging, 7, 10, 49
hypopharyngeal cancer, 3, 21 staining techniques, 13, 16
laryngeal cancer, 22 standard-of-care single-agent treatment, 37
oral cavity SCC, 3, 19 stereotactic radiation therapy (SRT), 51
oropharyngeal cancer, 3, 20 subglottic tumours, 22
postoperative RT indication, 19 sublingual gland, 53–54
for recurrence, 33 submandibular gland, 53–54
thyroid carcinoma, 42 sunitinib, 40, 63
for treatment toxicities, 57–58 supportive care, 37, 40
Robbins classification, lymph node levels, 8, 25 benefits and aims, 57
RT see radiotherapy individualised, 57–60
supraglottic cancer
PET/CT imaging, 9
S survival rates, 22
salivary duct carcinoma (SDC), 54, 68
treatment, 22, 24
salivary gland(s), 53
surgery
secretory unit, 53
HNSCC
salivary gland cancers (SGCs), 53–55
choice, vs non-surgical therapy, 25
adenoid cystic carcinoma, 53, 55, 67–68, 74
early HNSCC, 24
clinical presentation, 54
functional/aesthetic outcomes, 26
diagnosis and investigations, 54
hypopharyngeal cancer, 21
epidemiology, 53
laryngeal cancer, 22
gene fusion/rearrangements, 53–54
minimal distance from tumour, 24
histopathology/histotypes, 53
oral cavity cancer, 19
incidence (by country), 53
locoregional recurrence, 55
planning, sound resections, 25
magnetic resonance imaging, 54
principles and goals, 24–26
85
Index
R0 resection, 25 epidemiology, 42
R1 resection, 19–22 follicular (FTC), 42–43
renaissance in, 25 histotype distribution, 42
resectable recurrent disease, 36 lymphocytic infiltration, 46
salvage, 25, 36 medullary (MTC), 42–43
standards/guidelines, 24 advanced, treatment, 46
subglottic tumours, 22 follow-up treatment, 45
supraglottic cancer, 22 metastases, 45
R-classification, 24 parafollicular C cell origin, 44
reconstruction (in HNSCC), 24–25 prognosis, 43
flaps, 24–27 recurrence risks, 45
goals, 26 surgery, 44
salivary gland tumours, 55 oncogenic alterations, 42
thyroid carcinomas, 44 papillary (PTC), 42–43
complications, 44 classical variant, 43
transoral, 19–20, 28 histological variants, prognosis, 43
survival rates, 57 lymphocytic infiltration, 46
HNSCC, 2 surgery, 44
HPV-negative OSC, 11, 20 pathogenesis, 42
HPV-positive OSC, 2, 11, 20, 33 poorly differentiated (PDTC), 42–43
hypopharyngeal cancer, 21 initial treatment (RT), 44
laryngeal cancer, 2, 22 prognosis/prognostic factors, 43
with new agents, 62, 64 recurrence risk, 44
oral cavity cancer, 2, 19 treatment
recurrent/metastatic, 37–39 advanced disease, 46
unknown primary tumour, 11 follow-up, 45
nasopharyngeal carcinoma, 51 initial, 44
salivary gland tumours, 55 surgical, 44
thyroid carcinomas, 43 TK inhibitors, 46
see also prognosis well differentiated (DTC), 42–44
swallowing advanced, treatment, 46
assessment, 8, 24, 58 “cured”, follow-up, 45
difficulties, 57–58, 60 follow-up treatment, 45
radiotherapy, organ sparing, 31–32 recurrent/persistent disease, 45
surgery goal, 26 surgery, 44
Sym004, 62 thyroid lobectomy, 44
Symptoms thyroid nodule, 43
HNSCC, 8, 10 thyroid stimulating hormone (TSH), 42, 44
NPC, 51 thyroidectomy, 44
palliation, 36 tissue processing, 13
synaptophysin, 16 tissue sectioning, 13
synchronous tumours, 8 TK inhibitors (TKIs) see tyrosine kinase inhibitors (TKIs)
systemic diseases, HNSCC risk factor, 4 TNM system, 10, 24
tobacco, 1, 3
T alcohol synergistic effect, 3
T-cell activation, 64
assessment of use, 8
targeted therapy, 17, 58
chewing, 3
see also cetuximab, in HNSCC
HNSCC association, 1, 3–5
taxanes, 37–38
nasopharyngeal SCC, 49
TCGA (The Cancer Genome Atlas), 64
temsirolimus, 63
toll-like receptors (TLRs), 64
TERT mutation, thyroid carcinomas, 42
tongue lymph nodes, 49
three-dimensional conformal radiotherapy (3D-CRT), 32
tongue tumour, 19
three-dimensional forms, flaps, 27
base of tongue, 8, 20, 28
thyroglobulin (Tg), 42, 45
adenoid cystic carcinoma, 54
autoantibodies, 45
transoral surgery, 28
thyroid carcinomas, 42–46
reconstruction, 26
anaplastic (ATC), 42–43
WHO classification, 67–68
advanced, treatment, 46
tonsil cancer, 20, 28
initial treatment (RT), 44
survival improvements, 2
classification, 42
transoral robotic surgery, 28
clinical presentation, 43
WHO classification, 68
86
Index
total thyroidectomy, 44 W
TP53 gene, 17 Warthin’s oncocytic tumours, 53, 68
see also p53 gene well-differentiated
TPF (docetaxel-cisplatin-fluorouracil) regimen, 21–22, 72 SCC, 10, 14
tracheal compression, 44 thyroid carcinomas, 42
tracheal infiltration by thyroid carcinoma, 44 white plaques, 5
tracheostomy, 44 WHO classification, 9, 67–69
transoral laser microsurgery (TLMS), 20, 28 salivary gland tumours, 53
transoral resection, 19 whole body scan (WBS)
transoral robotic surgery (TORS), 20, 28 salivary gland tumours, 54
treatment see specific cancers, treatment modalities thyroid carcinoma, 44–45
true vocal cords, cancer, 22 wound healing, 27–28
TSC1/2 gene, 64 wound management, 26, 28
TTF-1, 16
tumour islands, 14–15
tumour microenvironment, 14 Z
tumour-node-metastasis (TNM) system see TNM system zalutumumab, 62
“tumour signatures”, 17 zinc supplementation, 58
tumour suppressor genes (TSGs), 5, 17, 63
silencing, 63
tyrosine kinase (TK), 39, 63
tyrosine kinase inhibitors (TKIs), 39–40, 46, 63
cross-talking, 46
U
ultrasound, neck, 42–45
unknown primary tumour, 11, 68
USA
HNSCC epidemiology/mortality, 1
HPV-related oropharyngeal cancer, 28
salivary gland cancer incidence, 53
V
vandetanib, 46, 63
variants of SCC, 16
vascular endothelial growth factor (VEGF), 63
vascular invasion, SCC, 15
postoperative RT indication, 19–22, 33
verrucous carcinoma (VC), 16, 67
vinblastine, 37
vinorelbine, 71, 74
vital structure protection, 26–27
vocal cord cancer, 22, 24
vocal cord palsy, 44
vomiting, 59
87
Index
www.esmo.org www.esmo.org
Lisa Licitra · Michalis V Karamouzis

edited by
HEAD & NECK HEAD & NECK

Lisa Licitra
CANCERS CANCERS
E S S E N T I A L S forC L I N I C I A N S E S S E N T I A L S forC L I N I C I A N S
HEAD & NECK CANCERS

Sinus
Nasal cavity
Salivary
glands
Nasopharynx Oral cavity

edited by
Lisa Licitra & Michalis V Karamouzis Oropharynx
Hypopharynx
Head & Neck Cancers is part of the “Essentials for Clinicians” series
produced by the European Society for Medical Oncology (ESMO). Head Oesophagus Larynx
and neck tumours are the seventh most common cancer type worldwide
and are associated with several risk factors. This book provides the Trachea
most clinically relevant and updated information for optimal prevention,

diagnosis and treatment of this heterogeneous group of tumours.
Head & Neck Cancers: Essentials for Clinicians is structured into
a section covering the basics of what every oncologist should know
and a section providing more advanced information and novel
developments. The high quality illustrations and clear structure
make the book an easy-to-use and accessible source of knowledge,
E S S E N T I A L S forC L I N I C I A N S
and provide a balanced and up-to-date knowledge of the Radiation Medical

Oncologist Oncologist
current state of the art for students and physicians interested
in cancers of the head and neck. Head
Nutritionist and Neck
Surgeon
Swallowing
expert patient Pathologist
Radiologist Psychologist
Social
Dentist Worker
Nurse
ESMO Press
ISBN 978-88-941795-2-1
ESMO Press · ISBN 978-88-941795-2-1
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Lisa Licitra · Michalis V Karamouzis

HEAD & NECK HEAD & NECK

HEAD & NECK CANCERS

Nasopharynx Oral cavity

most clinically relevant and updated information for optimal prevention,

and provide a balanced and up-to-date knowledge of the Radiation Medical

ESMO Press ESMO Press

© 2017 European Society for Medical Oncology

Printed through s | s | media limited, Rickmansworth, Hertfordshire, UK

A. What every oncologist should know

B. More advanced knowledge

Dr Lisa Licitra Dr Salvatore Alfieri

3D-CRT Three-dimensional conformal radiotherapy MTX Methotrexate

Michalis Karamouzis & Lisa Licitra

What every oncologist should know

World HNSCC is predicted to account for 742 270 new cases

Male 556 080

In the recent EUROCARE population-based study, five-

For oral cavity and pharyngeal cancer, 31% of cases

Oral cavity and pharyngeal cancer: new cases and deaths

2003. Death rates have not changed over 2003–2012.

High cure rates are reported for localised and locoregional

HPV-positive oropharyngeal cancer (OPC) patients

Despite advances in multimodality treatment, survival

Tobacco: Approximately 90% of patients with HNSCC

oropharynx and hypopharynx and a 10-fold increased 40

Risk of HNSCC is related to the frequency, intensity 20

Stopping smoking at age 45-54

It acts synergistically with tobacco, resulting in an 29.9%

HPV infection: It is the cause of a distinct subset of Parameter HPV- HPV+

Overall Survival According to Tumour HPV Status

50 Individuals with HPV+ OPC tend to be male and white,

HPV, Human papillomavirus.

Incidence patterns by ethnic origin have changed over

Nasopharyngeal and paranasal sinus cancers

EBV, Epstein-Barr virus; NPC, nasopharyngeal cancer.

HNSCC follows a molecular progression

Loss of genetic material from chromosome

PTEN, Phosphatase and tensin homologue.

Loss of 6p, 8p and 4q is identified during transformation

Field carcinogenesis refers to carcinogen distribution

HPV infection carcinogenesis: The integration

p53 p53 p16

induces expression of p16INK4A. p53 E2F RB

Head and neck squamous cell carcinoma (HNSCC)

An understanding of the anatomical origins of HNSCC

HNSCC is the final stage of a process of progressive

Limitless replicative potential of head and neck

EGFR, Epidermal growth factor receptor; LOH, loss of heterogeneity.

Cervical lymphadenopathy in a patient

Lymphatic dissemination patterns depend on the

Haematological spread occurs later (10%–12%). Lung

Patient with a base of the tongue tumour

Chewing, swallowing, breathing and phonation should

Special assessment is required of dentistry, nutrition,

Final diagnosis is provided by histological examination of

80% of head and neck cancers are squamous

Human papillomavirus (HPV) testing (p16

Computed tomography (CT) or cervico-facial magnetic

A head and neck endoscopic work-up with multiple

Positron emission tomography (PET)/CT is superior to

PET/CT is suggested for initial staging of oral cavity,

A. What every oncologist should know