ETIOPATHOGENESIS OF HEAD AND NECK CANCER.pptx

ETIOPATHOGENESIS
OF
HEAD AND NECK CANCER
Department of Surgical Oncology
Government Royapettah Hospital
Prof. S. Subbiah et al

CONTENTS
• INTRODUCTION
• CHEMICAL CARCINOGENS
• OCCUPATIONAL EXPOSURES
• DIETARY FACTORS
• VIRAL CARCINOGENESIS
• RADIATION
• ORAL POTENTIALLY MALIGNANT DISORDERS(OPMDs)
• EPIGENETICS

INTRODUCTION
• Cancer development ‘mutation’
• Carcinogenesis - a multi-step process involving both the
genotype and phenotype of a cell.
• When this process occurs at a phenotypic level, it is
known as ‘tumor progression’ .

Field Cancerization
• First suggested by Slaughter et al in 1953
• Normal epithelium from upper aero-digestive tract
carcinomas was found to have altered histology.
• Entire region’s mucosa had undergone a change related
to carcinogen exposure.
• Explain why multiple primary and second primary tumors
occur in HNSCC patients.
• Multiple tumors share a clonal origin and migrate to
different sites - acquire distinct genetic changes.

• Loss of heterozygosity (LOH) or allelic loss at the
genetic locus 9p21 appears to be the commonest genetic
change,
• Results in the inactivation of the tumor suppressor gene
p16 which encodes a cyclin-dependent kinase inhibitor
(prevents cell proliferation by arresting the cell cycle in
G1 stage).
• Another frequent mutation is LOH of the p53 gene
located at 17p13.

CHEMICAL CARCINOGENS

Tobacco
• Tobacco use remains one of the leading causes of death worldwide.
• Tobacco was recognized as a causative factor for cancer in the
1964 U.S. Surgeon General’s Report (SGR) on Smoking
• Tobacco is commonly described as the largest preventable cause of
cancer
• Nicotine is the primary addictive component and primary driver of
smoking behavior
– increases extracellular concentrations of dopamine in the nucleus
accumbens - nicotine’s rewarding effect
– 12-month cessation rates of approximately 40% only relative to
placebo

Mechanism of Carcinogenesis
• Induce cp450 systems - formation of electrophilic DNA
Adducts
• Miscoding at DNA Replication - cause G:A and G:T
mutations,
• Inactivation of P53, Activation of KRAS
• Nicotine - not a carcinogen in itself

Other mechanism
• Salivary IgA - is lowered in smokers
• Dose-related and reversible on cessation
of smoking
• Langerhans cells- antigen-presenting
cells found in the epithelium
• Reduced number in smokers.
• Increased production of salivary
acetaldehyde .

• The International Agency for Research
on Cancer (IARC), Lyons, France has
classified both cigarette smoke and
smokeless tobacco as Group 1
carcinogens.
• Identified 72 measurable carcinogens
in cigarette smoke
• Group 1 (carcinogenic to humans)
• 2A (probably carcinogenic to humans)
• 2B (possibly carcinogenic to humans)

Carcinogens in Cigarette smoke
• N-nitrosamines (also in smokeless tobacco)- During Curing of
tobacco leaves-
• NNK - (methylnitrosamino)-1-(3-pyridyl)-1-butanone
• NNN - N-nitrosonornicotine
• Benzene
• 1,3-butadiene
• aromatic amines - 2-aminonaphthalene & 4-aminobiphenyl
• cadmium
• Polycyclic aromatic hydrocarbons (PAH) – DNA Adducts
• benzo(a)pyrene (BaP)
• These carcinogens cause DNA alkylation, which can induce mutations.

Tabacco Smoking
• Cigarette smoking -
-The strongest association is with laryngeal SCC:
estimates of risk are as high as 60 for those smoking
more than 30 cigarettes/day.
-Odds ratios from 6.5–13.0 for all HNSCC sites
associated with ever smoking.
• Cigar and pipe - the strongest association appears to
be with development of oral cancer.

Other forms of smoking-
• Bidi smoking - wrapped in a tendu or temburni leaf
higher levels of nicotine, tar and carbon monoxide than
traditional cigarettes.
-similar relative risks for all-cause mortality compared to
ciggerates .
• Kreteks (from Indonesia) contain cloves as well as tobacco.
• Reverse smoking -where the lighted end of a cigar or
cigarette is held in the mouth. associated with development
of cancerous lesions of the palate.
• Chutta, a homemade cigar or cheroot found in Southeast
India.
• Hooka (nargile in Arabic) -common in the Middle East
• Clay pipe smoking

Smokeless tobacco
Includes chewing tobacco and snuff
Chewing tobacco- available in loose leaf, plug or twist forms
-also called as spit tabacco
-nass, naswar, khaini, mawa, mishri ,hans and gudakhu.
-chewed with other constituents such as areca nut and betel
leaf
Snuff is a finely ground tobacco packageddry or moist which
the user places between the cheek and gum or sniffs into
the nose.
-contains 28 known carcinogens.

Betel Quid
• Important risk factor -Indian subcontinent, Southeast
Asia, Melanesia and southern and eastern Africa.
• Mixture of areca nut (Areca catechu Linn.), betel leaf
(Piper betle Linn.) and slaked lime (calcium
hydroxide).
• This may or may not be chewed along with tobacco
• Commercial betel quid products- flavoured and
sweetened mixtures of areca nut, catechu and slaked
lime with tobacco (gutkha) or without tobacco (pan
masala)

Tobacco Use
1. Never smoking - smoked less than 100 cigarettes in a person’s
lifetime and no current cigarette use
Categories 2 through 4 require that a person has smoked at least
100 cigarettes in their lifetime – Ever Smokers
2. Former smoking is typically defined as no current cigarette use,
usually within the past year.
3. Recent smoking (or recent quit) is generally defined as having
stopped smoking within the recent past, typically for a period of 1 week
to 1 year.
4. Current smoking is typically defined as smoking one or more
cigarettes per day every day or some days.

Current Smoking after Cancer Diagnosis
• Increased overall mortality across most disease sites, tumor
stages, treatment modalities
• Increase cancer recurrence and cancer-related mortality
• Increase complications from surgery, pulmonary complications,
toxicity from RT, mucositis, hospitalization and vasomotor symptoms
• Increased the risk of developing a second tobacco-related
primary cancer twofold, with no increased risk in former smokers
• Mortality 1% increase in risk per pack-year smoked in HPV+
SCC
• Above Effects are reversible by cessation of current smoking
• 7 years of smoking cessation have been shown to reduce
mortality. Prof. S. Subbiah et al

Public Health Service (PHS) Guidelines
• The 5 A’s:
• 1. Ask about tobacco use for every patient.
• 2. Advise every tobacco user to quit.
• 3. Assess the willingness of patients to quit.
• 4. Assist patients with quitting through counseling and
pharmacotherapy.
• 5. Arrange follow-up cessation support, preferably within
the first week after the quit date.

Nicotine Dependence
• NRT - Nicotine Replacement Therapy - gums, lozenges,
patches, sprays, inhalers – Dual NRT – Higher Quit rates
• Buprinorphine - only FDA-approved antidepressant for
nicotine dependence
• Varenicline (Chantix) is a α4β2 nAChR(nicotine Acetyl choline
Receptor) partial agonist - sustained dopamine release -
helps to reduce craving and withdrawal
• Clonidine and nortriptyline—as second-line pharmacotherapies
for tobacco dependence

ALCOHOL
• Second most important risk factor
• 75% of HNSCC, particularly cancers of the oral cavity,
oropharynx, larynx and hypopharynx.
• A case-control study( Bruguere et al ) -a relative risk
(adjusted for tobacco) in individuals with an alcohol
consumption of 100–160 g/day (12.5–20 units/day )
-13.5 for oral carcinoma
-15.2 for cancers of the oropharynx
-28.6 for the hypopharynx

Mechanism
 Local effects
• Solvent for potential carcinogens
• Mucosal injury—aids carcinogen uptake
• Acetaldehyde production by oral bacteria
• Chronic alcoholics
-poor salivary flow
-gastro oesophageal reflux

Systemic effects
• Alcohol metabolism—acetaldehyde
• Production of free radicals
• Chronic alcoholics
- CYP2E1 enzyme induction
- nutritional deficiencies
-altered retinoid metabolism
-reduced immune surveillance

OCCUPATIONAL EXPOSURES

Strong Evidence
• Arsenic
• Cement / Stone dust
• Chromate
• Formaldehyde
• Nickel compounds / alloys
• Polycyclic aromatic hydrocarbons
(PAH)
• Radium
• Vinyl chloride
• Wood dust
Weak Evidence
• Asbestos
• Bis-chloroethyl ether
• Coal dust
• Dyes
• Synthetic mineral vitreous fibres
• Pesticides
• Diesel/petrol exhaust (containing PAH)
• Metal working fluids
• Mustard gas
• Oil/grease (containing PAH)
• Solvents/paints (containing chromium)
• Rubber/bitumen
• Sulphuric acid mist

• Exposure to wood dust (especially hardwood)
- most important occupational risk factor for
adenocarcinoma of the nasal cavity and paranasal
sinuses.
 Leather and Textile industry
• The carcinogens that are likely to be responsible
for this increase in risk include hexavalent
chromium, azo and benzidine-based dyes.
 Woodworking andCarpentry

Metal Industry
• Associations with laryngeal and pharyngeal
cancer.
• Risk estimates varying from 1.5–7.4 after
adjustment for smoking and alcohol.
• Implicated carcinogens - nickel, chromium and
polycyclic aromatic hydrocarbons (PAH).
• Nickel -associated with laryngeal carcinoma ,
major salivary glands.
• Vinyl chloride- an elevated risk of oral cavity and
pharyngeal cancers.

 DIETARY FACTORS
Increased risk of HNSCC -
-major vitamin deficiencies- Vitamins A, C, E,
beta carotene and riboflavin .
-deficiency of iron, zinc and selenium.
 Protective effect-
-associated with increased fruit and
vegetable intake.
-contain high levels of micronutrients such
as lycopene, vitamin C, folate, phytosterol and
flavonoids Prof. S. Subbiah et al

Specific considerations
Iron-deficiency anemia
- Plummer–Vinson or Patterson–Brown–Kelly syndrome
-upper esophageal web
-associated with post-cricoid carcinoma
-the incidence is higher in women.
Traditional salted fish
-associated with nasopharyngeal carcinoma
-seen in southern Chinese population.
-carcinogens : N-nitroso compounds such as
nitrosamine

VIRAL CARCINOGENESIS

Human Papilloma Virus
• Double-stranded DNA virus
• Papavoviridae family
• Replicates within epithelial cells of the host’s
mucosa and skin
• Sexually transmitted

Mechanism of Carcinogenesis
• E2 serves as a transcriptional repressor,
– loss of E2 expression (typically through integration of the viral
episome into the host cell DNA) results in the upregulation of early
gene expression
• E6 protein of high-risk HPV types--> destruction of p53
• E7 interacts with Rb --> LXCXE motif --> blocking the ability of pRB to
trigger cell cycle arrest
• Epidermodysplasia verruciformis (EV) is a rare immunodeficiency --
> numerous flat, wartlike lesions across wide areas of skin - contain
betapapillomaviruses, such as HPV5 or HPV8.
– frequently develop squamous cell carcinomas (SCC) in sun-
exposed skin areas (suggesting that ultraviolet [UV] light exposure is a
cofactor

• Late phase with L1 & L2 capsid proteins --> found only in
differentiating keratinocytes (surface of the skin or
mucosa)
• HPV found in Zones of transition between stratified
squamous epithelia and the single-layer (columnar)
epithelia
• The lifetime risk of sexual exposure to a HR HPV type has
been estimated to be >70%
• HPV 16 & 18 --> 70% of all cervical SCC
• Late phase: L1 and L2 capsid proteins
• Early region genes: E1, E2, E4, E5, E6, and E7

Epstein Barr virus (EBV)
• EBV, also called human herpesvirus 4 [HHV-4]) - IARC
Class 1 Carcinogen
• Double-stranded DNA virus
• Infects B lymphocytes and and squamous epithelial cells
of the oropharynx
• Over 90% of the worldwide adult population being
asymptomatic, healthy carriers.
• The usual source of transmission is by saliva through
aerosol or direct contact
• Transform cultured B cells and is the agent responsible
for infectious mononucleosis and Endemic Burkitt
Lymphoma
• Increased risk for Nasopharyngeal Carcinoma

Human Immunodeficiency Virus
• Strong association with cancer.
• Kaposi sarcoma (KS) and non-Hodgkin lymphoma
(NHL).
• Kaposi Sarcoma is associated with human herpes
virus 8 (HHV 8).
• Hodgkin lymphoma is also more prevalent in HIV
patients.
• HIV-associated Hodgkin disease is positive for Epstein–
Barr virus in 80%–100% cases compared to 40% of
normal Hodgkin lymphoma

Human Herpes Virus 8
• Found in over 95% of Kaposi Sarcoma
• Mediterranean region and in eastern parts sub-
Saharan Africa
• HIV/AIDS pandemic --> a dramatic increase in the
incidence of highly aggressive forms of Kaposi
Sarcoma
• In endemic regions, KS is third MC cancer among
adults
• Two forms of B-cell proliferative disorder
– multicentric Castleman disease (MCD)
– primary effusion lymphoma (PEL)

Radiation
 Ionising Radiation
• Certain specific head and neck cancers are
associated with radiation exposure.
• Environmental sources, occupational exposure or
through therapeutic radiation.
• Radiotherapy - Thyroid and salivary gland
carcinomas and sarcomas of the head and neck.

• Risk - inversely related to age at irradiation and was highest
among children exposed under age 10.
• No association with diagnostic x-rays, radioactive isotope
scans or occupational radiation exposure.
• An association with occupational radiation exposure and
development of salivary gland tumors.
• Environmental exposure includes natural background radiation
(e.g., radon) or fallout from nuclear reactor accidents (e.g.,
Chernobyl), or the atomic bomb explosions in Japan.
• For example, 6.7% of the survivors of Hiroshima and Nagasaki
developed papillary thyroid cancers, far higher than that expected in
the general population

Sunexposure
• Exposure to ultraviolet radiation is associated with
squamous cell carcinomas of the skin in the head and neck
region, and includes sites such as the lip.
• In equatorial and tropical countries like Australia .
• Occupations that work outside are at an increased risk.
• For example, a study in northern France found that farming
was associated with development of lip cancer

Oral Potentially Malignant Disorders
(OPMDs)

• Leukoplakia
• Erythroplakia
• Proliferative verrucous leukoplakia
• Oral lichen planus
• Oral submucous fibrosis
• Palatal lesions in reverse smokers
• Lupus erythematosus
• Epidermolysis bullosa
• Dyskeratosis congenita

Introduction:
• A significant group of mucosal disorders
• May precede the diagnosis of oral squamous cell carcinoma
• “Precancer”, “epithelial precursor lesions”, “premalignant”,
“precancerous”, and “intra-epithelial lesion” -previously used
• New terminology has resulted in better reporting of this
important group of disorders.
• Lesions and conditions were combined into one category of
“disorders”.

• Defined as “any oral mucosal abnormality that is
associated with a statistically increased risk of developing
oral cancer.”
• Middle-aged or elderly patients
• Predominantly males
• In western populations, elderly females with long-standing
leukoplakia ,paradoxically, a significant risk of progression
to cancer.

Leukoplakia
“A predominantly white plaque
of questionable risk having
excluded (other) known
diseases or disorders that
carry no increased risk for
cancer”
(Warnakulasuriya et al., 2007).

Clinical criteria for diagnosis of oral leukoplakia:
1. A predominantly white patch/plaque that cannot be rubbed off
2. Most homogeneous leukoplakias affect a circumscribed area and
have well-demarcated borders. A smaller subset can present with
diffuse borders.
3. Non-homogeneous leukoplakias typically present with more diffuse
borders and may have red or nodular components.
4. No evidence of chronic traumatic irritation to the area (e.g. a sharp
tooth)
5. Is not reversible on elimination of apparent traumatic causes
6. Does not disappear or fade away on stretching (retracting) the tissue
7. Exclusion of other white or white/red lesions

Leukoplakia
Homogenous
-a uniformly thin white plaque/patch
smooth surface
sharply demarcated
exhibit shallow surface cracks/fissures
Non-homogenous
-present with diverse clinical presentations
-speckled ( erythroleukoplakia )
- nodular (small polypoid projections, round)
- verrucous
-higher risk of transformation
- carcinomas in 12% of incisional biopsies

Proliferative verrucous leukoplakia
• Proliferative Multifocal Leukoplakia /Proliferative leukoplakia
• Progressive clinical course, changing clinical and
histopathologic feature
• Highest proportion of oral cavity cancer development
compared with other OPMDs
• Criteria included the disorder affecting more than two different
oral sites, and the existence of a verrucous area
• develops oral cancer-estimated the proportion to be 49.5%

Erythroplakia
• Sharply demarcated, flat or
depressed erythematous area
of mucosa with a matt
appearance
• Most oral erythroplakias, at
the time of diagnosis, are
either histopathologically a
squamous cell carcinoma or
show high-grade epithelial
dysplasia.

Actinic Keratosis/Actinic Cheilitis
• Effect of actinic (solar, predominantly ultraviolet) radiation
to exposed areas.
• Predominantly the skin and vermilion of the (lower) lip.
• Middle-aged and light-skinned men with outdoor
occupations.
• Flaking plaques or scaly lesions.
• Hyperplasia or atrophy, disordered maturation, varying
degrees of keratinisation or parakeratinisation, cytological
atypia and increased mitotic activity.

Oral Submucous Fibrosis (OSF)
• Characterised by fibrosis of the oral mucosa (and
submucosa)
• ‘A chronic, insidious disease that affects the oral mucosa,
initially resulting in loss of fibroelasticity of the lamina
propria and as the disease advances, results in fibrosis of
the lamina propria and the submucosa of the oral cavity
along with epithelial atrophy'.
• Burning sensation of the oral mucosa and intolerance to
spicy foods.

• Initial signs include a leathery
mucosa, pallor, loss of tongue
papillae, petechiae and
occasionally vesicles
• Fibrous bands hallmark feature
• Leads to a limited mouth
opening
• Genetic susceptibility and
family history

Palatal lesions in reverse smokers
• In reverse smoking, the
burning end of a cigarette or
cigar is held inside the mouth.
• As 50% of all oral
malignancies are found on the
hard palate, a site usually
spared other OPMDs, except
among pipe smokers.
• Reverse smoking is an
endemic tobacco habit
practised in the coastal rural
Andhra Pradesh.

Oral lupus erythematosus
• Chronic auto-immune disease
• Subdivided into 3 forms:
(1) systemic,
(2) drug-induced
(3) discoid
• Presents as a central circular
zone of atrophic mucosa, with
superficial ulceration
surrounded by whitish striae
• Buccal mucosae, palate and
lips are most commonly
affected. Prof. S. Subbiah et al

Oral lichen planus
• Bilateral white reticular
patches affecting buccal
mucosae, tongue, and
gingivae.
• More severe presentations
include erosions/areas of
atrophy and ulceration.
• Disorder without clear
causative factors

Dyskeratosis Congenita
• Also called as Zinsser-Cole-Engman syndrome
• Rare hereditary condition of dysfunctional telomere
maintenance
• Potentially malignant disorder
• The condition often arises early and should always be
considered and excluded in a child presenting with oral
leukoplakia.
• Triad of oral leukoplakias , hyperpigmentation of the skin
(usually with a reticular pattern on the neck) and nail
dystrophy

Disorders with insufficient epidemiological evidence
• Not recommended for inclusion within the OPMD group of
disorders.
 Chronic hyperplastic candidosis (CHC)
• Adherent white patch caused by a chronic fungal
infection, usually Candida albicans
• Thick white plaques, or mixed red and nodular non-
homogenous white patches

Exophytic verrucous hyperplasia)/Oral verrucous
hyperplasia
• May resemble verrucous carcinoma
• VH was considered a precurser of verrucous carcinoma
• Absence of deep induration is a cardinal feature

EPIGENETICS
• Stable but potentially reversible alterations in a cell's genetic information
• Results in changes in gene expression
• Do not involve changes in the DNA sequence.
• Cause remodelling of the chromatin-activation or inactivation of a gene
• Development of diseases including malignancies.

Epigenetic mechanisms
• Divided into three main categories:
1. DNA modifications,
2. Histone modifications and
3. Modifications of noncoding
RNAs (ncRNAs).

RNA Modifications:
• Occur in the ncRNAs - classified according to their size
- first group of small ncRNAs-include siRNAs and P-element
induced wimpy testis-interacting RNAs
- a second group of micro RNAs (miRNAs).

miRNAs
• Essential role in modifying gene expression
• Controls DNA methylation and histone modifications.
• Can function as both oncogenes and tumor suppressors
genes
• regulate target genes -TPM1, PTEN and bcl-2.
• The role of miR-21, miR-345 and miR-181b in oral
cancer progression has been established

• Development of oral cancer - multistep process
• Accumulation of genetic and epigenetic alterations
Cellular dysregulation and uncontrolled growth.
• Hypermethylation- silencing of several tumor suppressor
genes .

• The genes found hypermethylated include -
 Cell cycle control genes (p16, p15),
 Apoptosis genes (p14, DAPK, p73 and RASSF1A),
 Wnt signaling genes (APC, WIF1, RUNX3),
 Cell-cell adhesion genes (E-cadherin),
 DNA-repair genes (MGMT, BRCA1 and hMLH1),
 Tumor suppressor genes (p16, MLH1, BRCA1 CDKN2A, pRB, APC, PTEN,
BRCA1, VHL and CDH1),
 Metastasis-related genes,
 Hormone receptor genes and genes inhibiting angiogenesis.
• Biomarkers for early detection of oral cancers.-HOXA9, HS3ST2, NPY, EYA4
and WT1

• Inherited epigenetic susceptibility to tobacco-related cancers-
 Identification of susceptible individuals
 Allow more focused prevention strategies in oral cancers.
• The cell cycle regulator p15 predicts malignant transformation
and has been targeted.
• Screening for epigenetic alterations in oral tissues-DNA from oral
rinses and buccal swabs .

• Epigenetics can be utilized for the development of novel
therapeutic interventions
 Developmental diseases
 Addiction.
• Epigenetic therapy is now a reality that can change
our future for good.

THANK YOU

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