Cancer of the oral cavity

CARCINOGENESIS
AND ORAL CANCER
AUREUS DESOUZA
POST GRADUATE STUDENT
ORAL MEDICINE AND RADIOLOGY

CONTENTS
• 1. INTRODUCTION
• 2. EPIDEMIOLOGY
• RISK FACTORS
• CARCINOGENS
• HALLMARKS OF CANCER
• FIELD CANCERIZATION
• THEORIES OF CARCINOGENESIS

“A neoplasm is an abnormal mass of tissue, the growth of
which exceeds and is uncoordinated with that of the normal
tissues and persists in the same excessive manner after
cessation of the stimuli which evoked the change.” (Willis)
NEOPLASIA “New Growth”
Tumor and cancer  synonymously with neoplasia

EPIDEMIOLOGY OF ORAL CANCER
-15th MC cancer in the world (http://www.wcrf.org , 2012)
-Oral cancer in india is among the three most common cancers
affecting indian population
-30% of all cancers in the country
-8th most frequent cancer of the world among males and 14th among
females
-1,45000 deaths globally and 50,000 in india annually in 2011.

-U.S.  oral cavity cancer 3% of malignancies
-India 30% of all cancers in India
(Variation  regional differences in the prevalence of risk factors)
-World wide  Tongue and floor of the mouth MC
-Indian  Buccal mucosa (pattern of usage)
EPIDEMIOLOGY OF ORAL CANCER

The main risk factors identified globally are tobacco and
alcohol use
Other factors include :
1. HPV
2. Dietary deficiency
3. Poor oral hygiene
4. Radiation
RISK FACTORS

• Independent risk factor
• Responsible for 85% of oral SCCs
• The main tobacco plant in the world is Nicotiana
tabacum
• Tobacco needs to be cured before consumption.
• Products contain more than 300 carcinogens
TOBACCO
SMOKE
- cigarettes,
- pipes,
- cigars ,
- beedis
SMOKELESS
TOBACCO
- paan,
- snuff

Carcinogenesis: mechanism of induction of tumor
Carcinogens: Agents which induce tumor
The term “carcinogen” generally refers to an agent, mixture or
exposure that can increase the age-specific incidence of human cancer

• It includes about 1010 particles per ml and 4800 compounds, of which
66 are carcinogens
• Polycyclic aromatic hydrocarbons and tobacco specific nitrosamines are
the most important.
•Aromatic amines, benzene and heavy metals, independently
established as carcinogenic to humans
SMOKED FORM OF TOBACCO

• Six carcinogens present in tobacco smoke are known to form DNA
adducts in human tissue: benzo[a]pyrene (BaP), NNK, NDMA (N-
nitrosodimethylamine), NNN (N’-nitrosonornicotine), ethylene oxide
and 4-aminobiphenyl
• Nitrous oxide, nitric oxide, peroxynitrite and nitrosamines 
induce formation of reactive oxygen species  promote and amplify
DNA damage

- Intensity of exposure to tobacco smoke is determined by
the smoking device used (cigarette, cigar, pipe, hookah,
etc.) and
- by the “depth” of inhalation
- all smoking tobacco products has potential for
carcinogenesis
1 Cigarette Small cylinder of finely cut tobacco leaves rolled in thin
paper for smoking
Aromatic hydrocarbons 1 to 35 mg; nicotine: 1 to mg
2 Electronic
cigarette
Heating element that vaporizes the liquid solution,
battery operated, delivers less nicotine
3 Bidi Crushed and dried tobacco is wrapped in dried,
rectangular piece of temburni leaf
Tobacco <; tar and toxic agents >; nicotine>
4 Cigar Tobacco wrapped in a leaf of tobacco
5 Chutta Coarse tobacco cigars smoked in coastal areas of india
6 Reverse chutta
smoking
Lightened end inside the mouth; andhra pradesh >;
females >
7 Dhumti Rolling leaf tobacco in the leaf of a jack fruit tree; goa>

Bidi
Cigar
Chutta
Dhumti
Cigarette

OTHER FORMS OF SMOKE TOBACCO IN INDIA
HOOKLI
( Claypipe,
used in Gujarat)
CHILUMS
( Claypipe,
used in Northeast India)
HOOKAH

SMOKELESS FORM OF TOBACCO
-There are over 30 carcinogens in smokeless tobacco, including
volatile and tobacco specific nitrosamines, nitrosamino acids,
polycyclic aromatic hydrocarbons, aldehydes, metals
- Smokeless tobacco use entails the highest known non-
occupational human exposure to the carcinogenic nitrosamines,
NNN and NNK

SMOKELESS FORM OF TOBACCO
1 Pan (Betel quid) Betel leaf, Areca nut, Slaked lime
Catechu
2 PAN MASALA Commercial preparation containing
areca nut, slaked lime, catechu
3 MANIPURI
TOBACCO
Mixture of tobacco, slaked lime ,
finely cut areca nut, camphor and
cloves
4 MAWA Thin shavings of areca nut with
addition of tobacco and slaked lime

OTHER PREPARATIONS OF
SMOKELESS TOBACCO
KHAINI- tobacco with
slaked lime
MISHRI
TOBACCO PRODUCTS FOR
APPLICATION :
A- mishri; B- gudhaku
C- bajjar; D- creamy snuff
SNUFF USED
FOR
INHALATION

BETEL NUT
- Also called areca nut from “ Areca catechu”
- Betel Nut without tobacco was recognized as a group I carcinogen to
human by the International Agency for Research on Cancer (IARC) and
World Health Organization (WHO) in 2004
-Consumed as:
1. Supari (fruit is sun dried, fibrous shells removed and dry nuts
consumed)
2. Raw fruit – kwai or tambul
( in northeastern India)

CONSTITUENTS OF BETEL NUT AND ITS ACTIVE PRINCIPLES
BETEL NUT
ARECAIDINE
BETEL NUT
EXTRACT
TRACE
ELEMENTS
POLYPHENOLS,
TANNINS
ALKALOIDS
GUVACOLINE
GUVACINE
ARECOLINIDINE
ARECOLINE ON CELLULAR
METABOLISM
REACTIVE
OXYGEN
SPECIES WILL
GENERATE AT
ALKALINE pH
SODIUM,
MAGNESIUM,
COPPER,
BROMINE ,
CALCIUM,
MANGANESE
CATECHINS ,
FLAVANOIDS,
GALLOTANNIC
ACID
DNA
ADDUCTS
AND DNA
STRAND
BREAKS
INHIBIT PROTEIN
SYNTHESIS,
COLLAGEN
PRODUCTION,
FIBROBALST
PROLIFERATION,
CYTOTOXICITY,
DECREASE BRCA
EXPRESSION IN
HGF
AUTOOXIDATION
GENERATES
ROS
COPPER INCREASES
LYSYL OXIDASE
ACTIVITY
PRENEOPLASTIC TRANSFORMATION
CANCER

ALCOHOL
• Considered as second independent risk factor for oral cancer ;
important in non-smokers
•Association between alcohol and cancer varies between oral cavity
sites, with a higher risk of tongue cancer reported in alcoholics

TYPES OF ALCOHOL AND RISK
There are significant differences of content between various alcoholic
beverages:
-Beer contains the carcinogen nitrosodimethylamine,
-Wines have a high content of tannin
- When comparing various hard liquors, dark liquors (eg, whiskey, dark
rum, cognac) contain greater amounts of organic compounds
( nitosoamines, hydrocarbons ) than light liquors (eg, vodka, gin, light rum).
ALCOHOL

VIRUS
-Various viral genomes have been identified in cancer cells
- viruses are known to modify the DNA and induce proliferative
changes
- viruses known to cause cancer in head and neck are :
: human papilloma virus
: ebstein barr virus
: herpes simplex virus
: human immunodeficiency virus

-HPV are classified as high risk and low risk according to their
oncogenic potential
- HPV 6 and 16 are most commonly associated with oral cancer
-
HUMAN PAPILLOMA VIRUS (HPV)
• more commonly affects pharyngeal and tonsillar regions
•Verrucous carcinomas have the squamous histology with the
strongest association with HPV

HUMAN IMMUNODEFICIENCY VIRUS
• Human immunodeficiency virus (HIV) has shown an emerging
association with head and neck squamous cell carcinoma.
• The site of tumor presentation did not vary with respect to HIV
status, but tumors were larger and more advanced in the HIV group.
• In reported cases, concomitant history of use of tobacco and alcohol
was found; so a definite role of HIV in carcinogenesis is not well
established other than its immunosupressive action

•Herpes simplex virus (HSV) has been associated with cancer of the
oral cavity
• produce co-carcinogenic effect with tobacco (in animal studies)
• neutralizing antibodies to HSV are present in the serum of patients
with oral cancer
• however, HSV has not been detected in human squamous cell
carcinoma
HERPES SIMPLEX VIRUS

-its contribution to the malignant transformation of B lymphocytes has
been well established,
- EBV is more frequently detected in oral lesions such as oral lichen
planus and oral squamous cell carcinoma in comparison with healthy oral
epithelium
- studies reported the lack of a conclusive relation between EBV and oral
cancer or premalignant lesions
EBSTEIN BARR VIRUS

-Oral verrucous and squamous cell carcinomas have been reported in
HCV-infected patients
-HCV infection has been found to be more prevalent in patients with
oral lichen planus and 1–2% of the patients with oral lichen lanus
develop squamous cell carcinoma of the oral cavity, which implies the
existence of common pathogenic mechanisms among them
- no definite correaltion is established
HEPATITIS C VIRUS

-Studies have shown :high fruit and vegetable intake with a
decreased risk of head and neck squamous cell carcinoma.
- The association between fruit and vegetable consumption and a
reduced cancer risk may reflect increased intake of micronutrients
vitamins C , E and beta carotene which have antioxidant properties
NUTRITIONAL FACTORS

-Significant reduction in risk of oral, pharyngeal and esophageal cancers
has been associated with high intake of tomatoes, an important source
of vitamin C .
- certain dietary deficiencies may cause epithelial atrophy make mucosa
vulnerable to carcinogens
- Various studies have shown that diet low in vitamin A, C, E, iron , folate
is associated with an increased risk of oral, laryngeal, ovarian cancers

GERD: Chronic irritation from gastric reflux into the pharynx and larynx
has been suggested to be a risk factor for cancers of these sites.
DENTURES: Painful or ill-fitting dentures have also been associated
with oral or oropharyngeal cancer. The results may describe the role of
chronic inflammation as a risk for oral cancer.
CHRONIC INFLAMMATION

- Poor oral hygiene is associated with oral cancer, but no causal
relationship has been established
- poor oral hygiene is correlated with higher levels of oral microflora
and so a increase in rate of microbial associated conversion of
ethanol to acetaldehyde may be considered
- Poor oral hygiene contribute to chronic inflammation
POOR ORAL HYGIENE

•The Li-Fraumeni syndrome, inherited as an autosomal dominant trait,
involves mutation of one allele of the p53 tumor suppressor gene. This
has been associated with head and neck cancer in some patients with
minimal tobacco exposure, and may indicate increased susceptibility to
environmental carcinogens in these patients.
•Fanconi’s anemia, Bloom syndrome and ataxia-telangiectasia are
autosomal recessive disorders that are associated with increased
chromosomal fragility and cancer susceptibility.
GENETIC AND IMMUNOLOGICAL PREDISPOSITION

-Carcinogens are broadly divided into 4 groups :
1. Chemical carcinogens
2. Physical carcinogens
3. Hormonal carcinogens
4. Biologic carcinogens
CARCINOGENS

Based on the epidemiological evidence, the evidence in experimental
animals, and the mechanistic and other relevant data, the Working Group
(IARC) classifies each agent into one of the following groups :
––Group 1: The agent is carcinogenic to humans.
––Group 2A: The agent is probably carcinogenic to humans.
––Group 2B: The agent is possibly carcinogenic to humans.
––Group 3: The agent is not classifiable as to its carcinogenicity to humans.
––Group 4: The agent is probably not carcinogenic to humans.

CHEMICAL CARCINOGENS
-Require prolonged exposure
- induction of cancer depends on :
: dose and mode of transmission
: individual susceptibility
: other predisposing factors

- Cellular transformation by chemical carcinogens involve two sequential
stages:
1. Initiation
2. Promotion
- Chemical carcinogens can be directly or indirectly acting :
Directly acting : can induce cellular transformation without undergoing
any prior metabolic activation
Indirectly acting : requires metabolic conversion within the body
CHEMICAL CARCINOGENS

Initiation of carcinogenesis
After metabolic
activation ( both direct
and indirect) chemical
carcinogens
Substances become
electron deficient
Bind to electron rich
portion of other
molecules e.g. RNA,
DNA
If DNA damage is
irreparable , cell undergoes
one cycle of proliferation
and DNA damage becomes
permanent and irreversible
Induce DNA damage

DIRECT ACTING CARCINOGENS
ALKYLATING AGENTS (anti cancer
drugs e.g. cyclophosphamide,
busulfan etc)
Lymphomas, leukemias
Acylating agents ( acetyl imidazole) Lymphomas, leukemias
INDIRECT ACTING CARCINOGENS
Polycyclic aromatic hydrocarbons (
component in tobacco smoke, fossil
fuel, industrial pollution)
Lung cancer , skin cancer, cancer of
oral cavity
Aromatic amines Bladder cancer
Naturally occuring products (betel
nuts, aflatoxin)
Hepatocellular carcinoma, cancer of
oral cavity

Promotion of carcinogenesis
-Promoters are not mutagenic , they cause expansion of mutated
cells by activation of growth factor pathways
-Do not produce sudden change
- change induced may be reversible
- promoters include : phenols, drugs, artificial sweetners etc

PHYSICAL CARCINOGENESIS
-Divided into two groups :
1. Radiation :
- UV light and
- ionizing radiation
2. Non radiation physical agents: injury etc

ULTRAVIOLET RAYS AS CARCINOGEN
-UV rays derived from the sun cause an increased incidence of
squamous cell carcinoma, basal cell carcinoma, and possibly melanoma
of the skin
- The degree of risk depends on :
the type of UV rays,
the intensity of exposure, and
the quantity of the light-absorbing “protective mantle” of melanin in
the skin

-The UV portion of the solar spectrum can be divided into three
wavelength ranges:
- UVA (320–400 nm),
-UVB (280–320 nm), and
-UVC (200–280 nm).
-Of these, UVB is believed to be responsible for the induction of
cutaneous cancers.
-UVC, a potent mutagen, is not considered significant because it is
filtered out by the ozone shield around the earth

-The carcinogenicity of UVB light is attributed to its formation of
pyrimidine dimers in DNA.
- This type of DNA damage is repaired by the nucleotide excision repair
pathway.
- With excessive sun exposure, the capacity of the nucleotide excision
repair pathway is impaired

IONIZING RADIATIONS AS CARCINOGENS
-Electromagnetic (x-rays, γ rays) and particulate (α particles, β
particles, protons, neutrons) radiations are all carcinogenic
-In humans there is a hierarchy of vulnerability of different tissues to
radiation-induced cancers.
- Most frequent are the acute and chronic myeloid leukemia.
- In the intermediate category are cancers of the breast, lungs, and
salivary glands.

NON RADIATION PHYSICAL CARCINOGENESIS
-Mechanical injury secondary to stones in gall bladder, in UTI
- chronic trauma because of jagged tooth
- implant or foreign body inside the body

HORMONAL CARCINOGENESIS
-In tissues which undergo proliferation under the influence of
hormone stimulation
- insignificant in oral cancers

BIOLOGIC CARCINOGENESIS
1. Virus induced
2. Parasitic induced: schistosomiasis known to cause bladder cancer
3. Bacterial induced : Helicobacter pylori known to cause gastric
lymphoma and gastric carcinoma

VIRAL CARCINOGENESIS
-Based on the nucleic acid content oncogenic virus fall into two groups :
1. DNA oncogenic viruses:
e.g. human papilloma virus, EBV, HHV-8
2. RNA oncogenic viruses
e.g. HTLV-1, HTLV-2, HCV

1 Self sufficiency in growth signals
2 Insensitivity to growth inhibitory signals
3 Altered cellular metabolism
4 Evasion of apoptosis
5 Limitless replicative potential
6 Sustained angiogenesis
7 Ability to invade and metastasize
8 Ability to evade host immune response
HALLMARKS OF CANCER

SELF SUFFICIENCY IN GROWTH SIGNALS
(Proto-oncogenes, oncogenes, onco-proteins,
Unregulated cell proliferation)
• Tumors proliferate without external stimuli  oncogene activation
Proto-oncogenes Normal cellular genes whose products
promote cellular proliferation
Oncogenes Mutated versions of proto-oncogenes
that function autonomously
Onco-proteins Protein encoded by oncogene that drives
increased cell proliferation
Unregulated cellular proliferation Onco-proteins resemble normal products
of proto-oncogenes(bearing mutation
that inactivate internal regulatory
elements, freed from normal cell check
points)

Growth factors
(GF)
Growth factor
receptor (GFR)
Signal transducers Transcriptional
activators
MYC
Cell cycle
regulators
CYCLIN
CDK4
Soluble growth
factors (created by
one cell, act on
neighbour cell) 
paracrine action
Induce different
cellular
responses in
response to the
binding of specific
ligands that
represent external
stimuli
Receptor tyrosine
kinase (+) RAS and
two other pathways
MAPK and PI3K
• Pro-growth
metabolism
• Inc protein
synthesis
Cell cycle
progression
Cancer cells
synthesize the same
growth factors to
which they are
responsive creating
an autocrine loop
ErbB1/ Her-1/EGFR
(proliferation of
epithelial
cells)
H-, K- and N-ras
oncogenes result in
continous activation
of cellular
proliferation
Eg: FGF (breast
CA); TGF-
alpha(astrocytomas)
EGFR ( oral tumors,
premalignant
lesions) ErbB2 (oral
cancer)
Indian  H Ras>
MAP and ERK
kinases
MYC
translocation(Burkitt
lymphoma)
Cyclins (multiple
myeloma)
Cyclin dependent
kinase (CDK4)
(melanoma)
Cyclin B (tongue
CA)
(Proto-oncogenes, oncogenes, onco-proteins,
Unregulated cell proliferation)

SMALL SCALE MUTATIONS: affecting one or two nucleotide
1. Point mutation: exchange of a single nucleotide
e.g. AG transition (purine purine )
AC tranversion (purine  pyrimidine)
2. Insertions: add one or more extra nucleotide
3. Deletions: remove one or more nucleotide
MUTATIONS

LARGE SCALE MUTATIONS: affecting chromosome structure
1. Amplification : leading to multiple copies of all chromosomal
regions, increasing the dosage of the genes located within them.
2. Loss of heterozygosity: loss of one allele, either by a deletion
or recombination event, in an organism that previously had two
different alleles.
3. Deletions: leading to loss of genes
MUTATIONS

LARGE SCALE MUTATIONS: affecting chromosome structure
4. Translocation : interchange of genetic parts from non homologous
chromosomes
5. Inversion : reversing the orientation of a chromosomal segment.
MUTATIONS

CELL CYCLE REGULATORY PROTEINS
Progression through cell cycle : cyclin dependent kinases (CDK) and cyclins
CDK –cyclin complexes phosphorylate crucial
target proteins  driving cell through cell cycle
If activated
Arrest cell cycle progression
If damage cannot be repaired
Initiate apoptosis
Defects in G1S checkpoint
leading to dysregulated growth
+ mutator phenotype enabling
cancer development +
Progression

Cell cycle component Main function
Cyclins and Cyclin-Dependent Kinases
CDK4; D Cyclins Forms a complex that phosphorylates RB,
allowing cell to progress through G1 restriction
point
CELL CYCLE INHIBITORS
CIP/KIP family (p21, p27) Block cell cycle by binding with cyclin-CDK
complexes
p21: induced by tumor suppressor p53
p27: responds to growth suppressors such as
TGF-β
INK4/ ARF family P16/INK4a binds to cyclin D-CDK4, promotes
inhibitory effects of RB
P14/ARF increases p53 levels by inhibiting
MDM2 activity
CELL CYCLE CHECKPOINT COMPONENTS
RB Tumor suppressive “pocket” protein binding
E2F transcription factors (hypophosphorylated
state) preventing G1/S transistion; interacts
with other transcription factors
p53 Causes cell arrest and apoptosis, acts through
p21 to cause cell arrest; required for G1/S
checkpoint ; main component of G2/M

INSENSITIVITY TO GROWTH INHIBITORY SIGNALS
(TUMOR SUPPRESSOR GENES)
• Products of tumor suppressor genes  apply brakes to cell proliferation
• Abnormalities in these genes failure of growth inhibition
• These genes recognize genotoxic stress  shut down proliferation
• Protein products of these genes function as transcription factors, cell clycle
inhibitors, signal transduction molecules, cell surface receptors, regulators
of cellular responses to DNA damage
RB gene P53 gene

RB gene Governor of cell cycle
RB gene controls cell differentiation
Active state  hypophosphorylated  cell cycle inhibited
Inactive state  hyperphosphorylated  cell cycle promoted
A key negative regulator of G1/S cell cycle transition
Directly or Indirectly inactivated in most human cancers
Inactivation can be by
1. Mutations affecting RB gene
2. Gene amplification of CDK4 and cyclin D genes
3. Loss of cyclin dependent kinase inhibitors (p16/
INK4a)
4. Viral oncoproteins bind and inhibit RB gene(E7
protein of HPV)

p53 gene Guardian of Genome
-The p53 gene is located on chromosome 17p13.1,
-it is the most common target for genetic alteration in human tumors
- p53 acts as a “molecular policeman” that prevents the propagation
of genetically damaged cells , control G1S and G2M check point of
cell cycle

Permanent cell cycle
arrest
Blocked from cell cycle
progression
Transient arrest
DNA damage repaired
p53 falls cell reverts
to normal cell cycle
Irreversible DNA
damage
Ultimate
protection against
neoplastic
transformation
BAX, PUMA gene
tip the cell in
favour of apoptosis

Location Tumor supressor
gene
Function Tumors
associated
Cell surface TGF- β receptor Growth inhibition Carcinoma of
colon
E- cadherin Cell adhesion Carcinoma of
stomach
Inner aspect of
plasma membrane
NF1 Inhibition of RAS
signal transduction
and of p21 cell
cycle inhibitor
Neuroblastoma,
neurofibromatosis
type 1 , sarcomas
Cytoskeleton NF2 Cytoskeletal
stability
Neurofibromatosis
type 2 ,
schwannomas
Cytosol APC-β catenin Inhibition of signal
transuction
Familial
adenomatous
polyposis coli

Location Tumor supressor
gene
Function Tumors
associated
Nucleus RB1 Regulation of cell
cycle
Retinoblastoma,
osteosarcoma
p53 Cell cycle arrest
and apoptosis in
response to DNA
damage
Li-Fraumeni
syndrome; multiple
carcinomas and
sarcomas
WT1 Nuclear
transcription
Wilm’s tumor
P16/INK4a Regulation of cell
cycle by inhibition
of cyclin
dependent kinases
Malignant
melanoma
BRCA1 and
BRCA2
DNA repair Breast and ovary
carcinoma

ALTERED CELLULAR METABOLISM
(Warburg effect)
Even in the presence of ample oxygen, cancer cells show characteristic
high levels of glucose uptake & increased conversion of
glucose to lactose (fermentation) via glycolytic pathway
WARBURG metabolism
Warburg metabolism is not cancer specific , it is a general property of growing
cells that becomes “fixed “ in cancer cells

Reason:
1. Aerobic glycolysis provides rapidly dividing tumor cells with
metabolic intermediates
2. In rapidly dividing normal cells aerobic glycolysis ceases when the
tissue is no longer growing, in cancer cells this reprogramming persists
due to action of
oncogenes and tumor suppressor genes
(Warburg effect)

(Autophagy)
State of severe nutrient deficiency  cells arrest their own growth by cannibalising on
Its own organelles for energy production
If this adaptation fails  cells die
Tumor cells grow during marginal environmental conditions without triggering autophagy
Mostly
If they do, this allows them to survive the hard times for long periods
These cells are believed to be resistant to therapies that kill actively dividing cells
 therapeutic failures

EVASION OF APOPTOSIS
Apoptosis can be initiated through extrinsic or intrinsic pathways (activation of a
proteolytic cascade of caspases )
• Mitochondrial outer membrane permeabilization is regulated by the balance between
pro-apoptotic (e.g., BAX, BAK) and anti-apoptotic molecules (BCL2, BCL-XL). BH-
3–only molecules activate apoptosis by tilting the balance in favor of the pro-apoptotic
molecules
• Stress may also induce cells to consume their components in a process called
autophagy. Cancer cells may accumulate mutations to avoid autophagy, or may corrupt
the process to provide parts for continued growth.

LIMITLESS REPLICATIVE POTENTIAL
In normal cells, which lack expression of telomerase, the
shortened telomeres generated by cell division eventually activate
cell cycle checkpoints, leading to senescence and placing a limit
on the number of divisions a cell may undergo
• In cells that have disabled checkpoints, DNA repair pathways are
inappropriately activated by shortened telomeres, leading to
massive chromosomal instability and mitotic crisis
• Tumor cells reactivate telomerase, thus staving off mitotic
catastrophe and achieving immortality.

SUSTAINED ANGIOGENESIS
Vascularization ,essential for their growth controlled by the balance between
angiogenic and antiangiogenic factors ( tumor and stromal cells)
• Hypoxia triggers angiogenesis through the actions of HIF- 1α on the transcription
of the pro-angiogenic factor VEGF. Because of its ability to degrade HIF-1α and
thereby prevent angiogenesis, VHL acts as a tumor suppressor.
• Other factors regulate angiogenesis; for example, p53 induces synthesis of the
angiogenesis inhibitor TSP-1.

ABILITY TO INVADE AND METASTASIZE
LOOSENING OF TUMOR CELLS
E-cadherin function is lost in
almost all epithelial cancers, either
by :
1. mutational inactivation of
E-cadherin genes,
2. activation of β-catenin genes
3. inappropriate expression of the
SNAIL and TWIST transcription
factors, which suppress E-
cadherin expression

DEGRADATION OF THE BASEMENT MEMBRANE AND INTERSTITIAL
CONNECTIVE TISSUE
• Either secrete proteolytic enzymes themselves or induce stromal cells (e.g.,
fibroblasts and inflammatorycells) to elaborate proteases
• Eg: matrix metalloproteinases (MMPs), cathepsin D, and urokinase plasminogen
activator
• MMPs regulate tumor invasion by remodeling insoluble components of the
basement membrane and interstitial matrix but also by releasing ECM-
sequestered growth factors. Indeed, cleavage products of collagen and
proteoglycans also have chemotactic, angiogenic, and growth-promoting effects

CHANGES IN ATTACHMENT OF TUMOR CELLS TO ECM PROTEINS
• Loss of adhesion in normal cells  induction of apoptosis, while, tumor cells
are resistant to it
• Matrix itself is modified in ways that promote invasion and metastasis
• For example,
• Cleavage of the basement membrane proteins, collagen IV and laminin, by
MMP-2 or MMP-9 generates novel sites that bind to receptors on tumor cells
and stimulate migration

LOCOMOTION  the final step of invasion, propelling tumor cells through the
degraded basement membranes and zones of matrix proteolysis.
• Migration is complex, multistep process that involves many families of
receptors and signaling proteins that eventually impinge on the actin
cytoskeleton (tumor cell–derived cytokines like autocrine motility factors)
• Cleavage products of matrix components (e.g., collagen, laminin) and some
growth factors (e.g., insulin-like growth factors I and II) have chemotactic
activity for tumor cells. Stromal cells also produce paracrine effectors of cell
motility such as hepatocyte growth factor/scatter factor (HGF/SCF), which
binds to receptors on tumor cells

VASCULAR DISSEMINATION AND HOMING OF
TUMOR CELLS
In circulation, tumor cells either form aggregates with platelets and
leucocytes or travel single , are vulnerable to destruction by host immune
cells (discussed later)
Extravasation these cells is by adhesion to the vascular endothelium,
followed by egress through the basement membrane into the organ
parenchyma by mechanisms similar to those involved in invasion
Site of extravasation and the organ distribution of metastases 
predicted by the location of the primary tumor and its vascular or
lymphatic drainage

VASCULAR DISSEMINATION AND HOMING OF
TUMOR CELLS
The natural pathways of drainage do not readily explain the distribution of
metastases
1. Expression of adhesion molecules by tumor cells whose ligands are
expressed preferentially on the endothelium of target organs
2. Expression of chemokines and their receptors
3. Once they reach a target, the tumor cells must be able to colonize
the site.. After extravasation, tumor cells are dependent on a receptive
stroma for growth.

METASTASIS
- meta- ‘next’, stasis- ‘placement’
- complex process that involves the spread of a tumor or cancer to
distant parts of the body from its original site
Theories of metastasis :
1. Seed and soil hypothesis
2. Mechanical and anatomical hypothesis
3. Homing concept

1. SEED SOIL THEORY :
- Given by Stephen Paget in 1889
- Tumor cells (seed) has a specific affinity for the target organ (soil)
which provides the appropriate micro-environment for the seed .
- For example: Malignant melanoma favors melanocytes and nerves
and thus may spread to the brain – because the neural tissue and
melanocytes arise from the same cell line in the embryo.

2. MECHANICAL AND ANATOMICAL HYPOTHESIS:
- Given by Ewing in 1928
- metastasis occurs purely by anatomic and mechanical routes.
- First capillary bed reached is the most common site of metastasis
- 50-70% of the metastasis can be predicted by venous drainage

3. HOMING CONCEPT OF METASTASIS:
- Tumor cells have adhesion molecules whose ligands are expressed
preferentially on endothelial cells of target organ
a) Role of chemokines:
breast carcinoma express chemokine receptors for CXCR4 and CCR 7 ;
cytokines highly expressed in lung : ca breast metastasize to lungs
b) Role of chemoattractants:
molecules liberated by target cells that recruit tumor cells e.g. IGF-1
and 2

ABILITY TO EVADE HOST IMMUNE RESPONSE
Most tumors arise in immunocompetent hosts; accordingly, a likely
strategy for success is to trick the immune system in such a way
that the tumor fails to be recognized or eliminated despite the fact
the affected person’s body has an army of cells that are quite
capable of thwarting a microbial infection or rejecting an allogeneic
organ transplant

FIELD CANCERIZATION
-First description was given by Slaughter et al in 1953
- definition of field cancerization: “the presence of one or
more areas consisting of epithelial cells that have genetic
alterations. A field lesion (or shortly ‘field’) has a
monoclonal origin, and does not show invasive growth and
metastatic behavior, the hallmark criteria of cancer.”

Oral field cancerization implies that oral cancer does not
arise as an isolated cellular phenomenon, but rather as an
anaplastic tendency involving many cells at once that
results into a multifocal development process of cancer at
various rates within the entire field in response to a
carcinogen, such as in particular tobacco

Warren and Gates initially formulated a set of criteria to diagnose
multiple primary carcinomas which were modified later by Hong et
al.
The criteria to be met are as follows:
i) the neoplasm must be distinct and anatomically separate. A multi-
centric primary neoplasm is diagnosed when a dysplastic mucosa is
present next to it
ii) a potential second primary carcinoma which represents a metastasis
or a local relapse should be excluded. It has to occur 3 years after the
initial diagnosis or it should be separate from the first tumor by at least
2 cm from the normal epithelium.

Lateral cancerization was coined later to suggest the lateral
spread of tumors, which occurs due to a progressive
transformation of the tissue adjacent to the tumor rather than
the expansion of pre-existing cancer cells into the adjacent
tissue

Three theories have been proposed to explain the common clonal
origin of multiple primary tumors:
1. single cells or small clusters of cells migrate through the
submucosa or,
2. Cells are shed in the lumen of an organ (e.g., the oral cavity or
the bladder) at one place and regrow at another
3. a large contiguous genetically altered field exists in the
epithelium in which multiple clonally related neoplastic lesions
develop.

The concept of field cancerization was extended to
other organs, including oropharynx, esophagus, lungs,
stomach, colon, cervix, anus, skin and bladder.

• Risk factors and carcinogenesis
• Theories of carcinogenesis
• Metastasis and staging
• Clinical presentation
• Early diagnostic aids

Aromatic hydrocarbons (benzopyrene) and tobacco specific
nitrosamines
act locally on keratinocytes stem cells
produce DNA adducts
interfere with DNA replication
TOBACCO-carcinogenesis
- Interaction of DNA with benzopyrene  G to T tranversion in p53 gene
pathogenesis of tobacco induced malignancy

• Alkaloids of BN are suspected to be its main carcinogenic constituent.
•Arecoline inhibited both expression and transactivation functions of p53.
• it causes formation of both DNA single strand breaks and DNA protein
cross links.
BETEL NUT-CARCINOGENESIS

• Alcohol has also been shown to decrease the activity of DNA-repair
enzymes, and increase chromosomal damage (because of its
metabolite – acetaldehyde)
•it may act as a solvent, allowing increased cellular permeability of
other carcinogens through mucosa of the upper aerodigestive tract
•the non-alcohol constituents of various alcoholic beverages may
have carcinogenic activities
ALCOHOL AND CARCINOGENESIS

•Other possible effects of alcohol include impaired immunity resulting
from a reduction in T cell number, decreased mitogenic activity and/or
reduced macrophage activity
•Alcoholic liver disease minimizes the detoxification of carcinogens
• Alcohol because of its high calorific value , suppress appetite in heavy
drinkers thus predisposes to nutritional deficiency
•chronic alcohol use may upregulate enzymes of the cytochrome P-450
system : contribute to activation of procarcinogens to carcinogens
ALCOHOL AND CARCINOGENESIS

CARCINOGENESIS BY DNA ONCOGENIC VIRUSES
INTEGRATION OF
VIRAL GENOME
INTO THE HOST
CELL
REPLICATION
OCCURS AND
NEW VIRION GET
ASSEMBELED IN
NUCLEUS
VIRAL DNA
INCORPORATED IN
HOST NUCLEUS
DNA VIRUS INVADE
THE HOST CELL

CARCINOGENESIS BY RNA ONCOGENIC VIRUSES
INTEGRATION OF
VIRAL GENOME
BRING
REPLICATION OF
VIRAL
COMPONENTS
DOUBLE SRANDED
DNA GETS
INCORPORATE IN
HOST GENOME
SYNTHESIS OF DOUBLE
STRANDEDDNA USING
REVERSE TRANSCRIPTASE
RNA VIRUS INVADE
THE HOST CELL

-Genomic region of high-risk HPVs are
capable of forming specific
complexes with vital cell-cycle
regulators:
E6, which binds to p53 and induces
its degradation, and
E7, which interacts with pRb and
blocks its tumor supression activity
HPV AND CARCINOGENESIS

THEORIES OF CARCINOGENESIS
1. THE GENETIC THEORY
- Suggests that cell becomes neoplastic because of alterations in the
DNA
- The mutated cells transmit their characters to next progeny
Examples :
- Patients with xeroderma pigmentosa are excessively prone to develop
skin cancer due to inherent inability to repair DNA damage
- CML asociated with philadelphia chromosome
- Familial case of Retinoblastoma : Knudson’s hypothesis

2. EPIGENETIC THEORY :
-The carcinogenic agent act on supressors and activators of genes rather
than directly on the genes
- is not well supported

3. MULTISTEP THEORY (molecular progression model)
- Carcinogenesis is a multi step process
-1ST model was given by Fearon and Vogelstein (colon carcinogenesis)
- specific molecualr events including oncogene activation ,
inactivation of tumor supressor genes, lead to progression from
normal cell growth to frank neoplasia .
- the accumualation of events rather than their ordered occurences
leads to cancer

Theoretical model of carcinogenesis in the oral cavity based on the ‘‘multiple hit’’
hypothesis. The majority of the molecular/genetic lesions that accompany the
histological transition from normal to cancerous epithelium persist during later
stages, but they are presented in the stage of their appearance.

4.IMMUNE SURVEILLANCE THEORY :
-immune deficient individuals has higher incidence of cancer
-Most cancers occur in old age when host immune response is weak
- tumors with good host imune response have better prognosis
- in experimental animals, there is rising titer of circulating immune
complexes in initial few weeks of tumor induction

6. MONOCLONAL THEORY (CLONAL EVOLUTION) :
- proposed by Nowell in 1976
- Based on theory of natural selection
- Cancer cell develop strategies to survive a hostile host environment
and use host resources to grow and proliferate
- According to this theory cancer arise from a single clone of
transformed cells

In resulting malignancy , majority of
cells developed from a single clone
(monoclonal)
New cells will evolve with additional
characteristics e.g. invasion
Only dominant cell
population fluorishes
Most of the offsprings do not survive because
of immunologic surveillance , apoptosis or
metabolic derangement
Cell proliferatesRepeated carcinogenic insult
in a cell

METASTASIS
-META: transformation ; STASIS: residence
- spread of the tumor to form secondary masses at distant site
- routes of metastasis:
1. Lymphatic spread
2. Haematogenous spread
3. Spread along body cavities

LYMPHATIC SPREAD
-Carcinomas metastasise by lymphatic route while sarcomas favour
hematogenous route
1. Lymphatic permeation: walls of lymphatics are invaded by cancer cells
and form a continous growth in lymphatic channels
2. lymphatic emboli: malignant cells may detach to form emboli so as to
carried along the lymph to next draining node

CHARACTERISTICS OF LYMPHATIC METASTASIS
-REGIONAL LYMPH NODE METASTASIS: generally tumor involves the
regional draining lymph node
- SKIP METASTASIS: lymphatic metastasis do not develop first in the lymph
node nearest to tumor because of venous lymphatic anastmosis or due to
obliteration of lymphatics by inflammation or radiation
- RETROGRADE METASTASIS: due to obstruction of the lymphatics by tumor
cells, the lymph flow is disturbed and tumor cells spread against the flow of
lymph at unusual sites

HAEMATOGENOUS SPREAD
-Common with sarcomas
- sites where blood borne metastasis commonly occurs are: liver, lung,
brain, bones, kidney and adrenals
1. VEINS:
Systemic veins : blood from limbs, head and neck and pelvis drain into
lungs though vena cava ; cancer of these site often metastasize to
lungs
Portal veins: drain blood from bowel, spleen and pancreas into the liver .
Thus tumors of these organs have secondaries in liver

2. ARTERIES:
Less likely ; arteries are thick walled and contain elastic tissue which is
resistant to invasion
- Arterial spread may occur when tumor cells pass through pulmonary
capillary bed or through pulmonary arterial branches which have
thin walls

NODAL METASTASIS
-The risk of nodal metastasis depends on :
1. Location of primary tumor
- Risk increases from anterior to posterior
- lips<oral cavity < oropharynx
2. Tumor characteristics
- Endophytic tumors metastasize more than exophytic tumors
3. Histology of tumor
- Poorly differentiated tumors have higher risk of nodal metastasis
4. Tumor thickness
- For carcinoma of tongue and floor of the mouth – tumor thickness is
related to risk of nodal metastasis

CHARACTERISTICS OF NODAL METASTASIS:
-the first echelon lymph node - those that receive drainage from a
organ
-tumour spread along lymph vessels will be in the direction of
drainage

LEVEL I A LYMPH NODES
Submental
nodes
-Between anterior bellies of digastric muscles
- above hyoid bone

LEVEL I B LYMPH NODES
Submandibular
nodes
-Between anterior and posterior bellies of digastric
muscles
- above hyoid bone

LEVEL II LYMPH NODES
Upper jugular
nodes
- around upper portion of internal jugular vein and
spinal nerve
- from base of skull to bifurcation of carotid artery /
hyoid bone
- anterior limit – posterior border of sternohyoid
- posterior limit – posterior border of SCM

LEVEL III LYMPH NODES
Middle jugular
nodes
- around middle portion of internal jugular
- from level II to omohyoid muscle/ inferior border of
cricoid cartilage

LEVEL IV LYMPH NODES
Lower jugular
nodes
- around lower portion of internal jugular
- from level III to clavicle

LEVEL V LYMPH NODES
Posterior
triangle
nodes
- around lower portion of spinal accessory nerve
and transverse cervical vessels
- anterior limit – posterior border of SCM
- posterior limit – anterior border of trapezius
- inferiorly- clavicle

LEVEL VI LYMPH NODES
Central
compartment
nodes
- consists of prelaryngeal, pretracheal and
paratracheal lymphh nodes
- hyoid bone to suprasternal notch
- between medial borders of carotid sheath

CLINICAL SIGNS OF ORAL CANCER
EARLY SIGNS
• Persistent red or white patch
• Non healing ulcer
• Progressive swelling or
enlargement
• Unusual surface changes
• Sudden tooth mobility without
apparent cause
• Unusual oral bleeding or epistaxis
• prolonged hoarseness of voice
LATE SIGNS
• Indurated area
• Paresthesia
• airway obstruction
• otalgia
• Trismus and dyspahgia
• Cervcal lymphadenopathy
• persistent pain
• altered vision
• Epiphora

EXOPHYTIC GROWTH
EXOPHYTIC GROWTH

SQUAMOUS CELL CARCINOMA OF LIP
-Second most common type of OSCC
- lower lip > upper lip > commisures
- most patients have outdoor occupations
- occur in fair complexioned people
- occur chiefly in elderly men
- Male : Female (6:1)
- greatest incidence between 55-75 yrs

-most common etiological factor is use of tobacco (pipe smoking), sunlight
- tumor usually begin on the vermilion border to one side of midline
- begin as small area of thickening , induration and ulceration
SCC OF VERMILION BORDER
( BETEL QUID CHEWER )
EXTENSIVE SCC OF LOWER
LABIAL MUCOSA
( KHAINI USER )
SCC OF LOWER LABIAL
MUCOSA ( KHAINI USER )

- Ca of lip tends to be localized , mostly shows lateral growth than
invasion
- Perineural invasion : numbness of chin/ lower lip
- SCC of upper lip and commisural areas are more aggressive and shows
early cervical metastasis

- Primary lymph node involved are level I
-Ca of upper lip and commisures can metastasize to periparotid and
preauricular nodes
- ca of midline can show bilateral metastasis

SQUAMOUS CELL CARCINOMA OF TONGUE
-Comprises of 20-50% of all intra oral cancers
- tobacco and alcohol are significant risk factors
- many investigators found relationship between Ca tongue and syphilis
- other factors : source of chronic irritation ( broken tooth, ill fitting
denture )
- incidence of ca of tongue is higher in men except certain geographic
areas where there is high incidence of Plummer Vinson syndrome

- ca of tongue may arise in apparently normal epithelium, in areas of
leukoplakia or preexisting chronic glossitis
- frequently present as painless mass or ulcer that fails to heal
- anterior portion of tongue is mostly involved
- most common site is lateral border of the tongue at the junction
between middle and posterior thirds

-local infiltration of floor of the mouth, tongue base and tonsillar
pillars is common
- often asymptomatic
- in advanced disease  local pain, ipsilateralateral otalgia and jaw
pain
- carcinoma of posterior third show extensive infiltration at the time
of diagnosis , so carry poor prognosis

-30% of patients present with ipsilateral cervical node metastasis
- Ca of midline can cause bilateral neck metastasis
- the primary basin for cervical metastasis includes level 1 to 3 ,
especially jugular nodes (II), occult metastasis to level IV or V

SQUAMOUS CELL CARCINOMA OF FLOOR
OF THE MOUTH
- accounts for 10-15% of oral Ca
- anterior segment more involved
-harder to control because of loose submucosal tissue
- Often asymptomatic
- may arise in region of erythroplakia or leukoplakia

-as tumor enlarges may cause pain, ulceration, submandibular duct
obstruction
- deep infiltration :
: weakness of hypoglossal nerve  restricted tongue mobility 
change in quality of speech and difficulty in articulation,
: numbness of lingual nerve and mental nerve
- lateral spread mandibular alveolus, retromolar trigone
- metastasis frequently involve submandibular lymph node

SQUAMOUS CELL CARCINOMA OF BUCCAL
MUCOSA
-Comprises 10% of ca oral cavity
- tobacco (smokeless tobacco), areca nut and alcohol are risk factors
- other factors include : ill fitting dentures, preexisting potentially
malignant disorders
- arises more commonly from pre-existing leukoplakia
- the lesion develop most frequently along or inferior to level of occlusion

-usually appear as exophytic or verrucous mass or non healing ulcer
- can spread laterally to involve buccal pad of fat, underlying
musculature
- in advanced disease: facial paralysis, induration or frank infiltration
of skin , trismus
- most common site of metastasis are the submandibular lymph nodes

SQUAMOUS CELL CARCINOMA OF GINGIVA
-Early lesions are similar to dental infections so difficult to diagnose
- Ca of mandibular gingiva more common than maxillary gingiva
- usually manifest initially as an area of ulceration or erosion which
later exhibit exophytic growth
- may or may not be painful
- attached gingiva is more commonly involved than marginal gingiva
- lesion usually arise in edentulous areas

-Easily invade underlying periosteum and bone
- maxillary ca often involve maxillary sinus
- metastasis is common sequelae
- mandibular ca metastasize more commonly
- metastasis occur to submandibular or cervical lymph nodes

EXOPHYTIC OSCC ON
MAXILLARY GINGIVA
EXOPHYTIC OSCC ON
MANDIBULAR GINGIVA

SQUAMOUS CELL CARCINOMA OF PALATE
-Rare (0.5%)
- usually manifest as poorly defined ulcerated , painful lesion on
one side of the midline
- may extend laterally to involve palatal gingiva or posteriorly to
involve tonsillar pillar
- spread of tumor anteriorly numbness
- spread of tumor superiorly  nasal obstruction
- spread of tumor postero- laterally  trismus

-rarely metastasize
- clinical metastasis rate is 10 to 25%
- mostly level I and level II lymph nodes are involved
ULCERATIVE OSCC ON HARD
PALATE IN BIDI SMIKER

SQUAMOUS CELL CARCINOMA OF
RETROMOLAR TRIGONE
-Primary ca of retromolar trigone is rare
- clinically present as pain or burning from non healing ulcer
-nasopharyngeal extension and eustachian tube involvement 
otalgia
- inferior alveolar involvement  numbness
- aggressive show rapid spread
- frequently metastasize to level II and level III lymph nodes

AREA PATTERN OF METASTASIS
CARCINOMA OF
FLOOR OF MOUTH
- metastasis frequently involve submandibular lymph node
CARCINOM A OF
BUCCAL MUCOSA
-most common site of metastasis are the submandibular lymph
nodes
CARCINOM A OF
GINGIVA
- metastasis occur to submandibular or cervical lymph nodes
CARCINOM A OF
HARD PALATE
- mostly level I and level II lymph nodes are involved
PATTERN OF METASTASIS

AREA PATTERN OF METASTASIS
CARCINOMA OF
LIP
-- Primary lymph node involved are level I
- Ca of upper lip and commisures can metastasize to
periparotid and preauricular nodes
- ca of midline can show bilateral metastasis
CARCINOM A OF
TONGUE
-30% of patients present with ipsilateral cervical node
metastasis
- Ca of midline can cause bilateral neck metastasis
- the primary basin for cervical metastasis includes
level 1 to 3 , especially jugular nodes (II), occult
metastasis to level IV or V
PATTERN OF METASTASIS

STAGING AND GRADING OF TUMOR
- Staging is clinical term , assessment based on clinical presentation
of tumor
- Grading is histological assessment of gross and microscopic degree
of differentiation

- American Joint Committee for cancer staging has divided oral
cavity into different parts for cancer staging:

OBJECTIVES:
1. To aid the clinician in planning treatment
2. To give an indication of prognosis
3. To facilitate exchange of information between treatment centres
4. To assist in continuing investigation of cancer

TNM STAGING
-The tumor-node-metastasis (TNM) staging system was first reported
by Pierre Denoix in the 1948.
-The International Union Against Cancer (UICC) adapted the system
and compiled the first edition of the TNM staging system in 1968 for
23 body sites .

CLASSIFICATION OF STAGING TIMES :
1. Clinical classification (cTNM or TNM):
- Based on evidence acquire before treatment
- The evidence arises after : physical examination, imaging , biopsy
- The impact of diagnostic imaging – “stage migration”

2. Pathologic classification (pTNM):
-Based on evidence acquired before treatment
- supplemented and modified by evidence acquired after pathologic
examination of resected specimen
3. Retreatment classification (rTNM):
- Used after a disease free interval and when further definitive treatment
is planned

4. Autopsy classification (aTNM):
- If classification of cancer is done after the death of a patient

STAGING OF TUMOR
- TNM ( tumor – node - metastasis ) system of classification
TX
• Primary tumor cannot be assessed
T0
• No evidence of primary tumor
Tis • Carcinoma in situ
T1
• Tumor 2cm or less in greatest dimension
T2
• Tumor more than 2 cm but not more than 4cm in greatest dimension
T3
• Tumor more than 4cm in greatest dimension
T4a
• LIP: tumor invades through cortical bone, inferior alveolar nerve, floor of mouth, or
skin of face
T4a
• ORAL CAVITY : tumor invades through cortical bone into deep extrinsic muscles of
tongue, maxillary sinus or skin of face
T4b
• Tumor involves masticator space, pterygoid plates, or skull base and / or encase
internal carotid artery

NX
• Regional lymph node cannot be assessed
N0
• No regional lymph node metastasis
N1
• Metastasis in single ipsilateral lymph node, 3cm or less in greatest dimension
N2a
• metastasis in a single ipsilateral lymph node more than 3cm but not more than 6cm
in greatest dimension
N2b
• Metastasis in multiple ipsilateral lymph nodes , none more than 6cm in greatest
dimension
N2c
• Metastasis in bilateral or contralateral lymph nodes, none more than 6cm in
greatest dimension
N3
• Metastasis in a lymph node more than 6cm in greatest dimension

MX
• Distant metastasis cannot be assessed
M0
• No distant metastasis
M1
• Distant metastasis

STAGE T N M
STAGE 0 TIS No Mo
STAGE 1 T1 No Mo
STAGE 2 T2 No Mo
STAGE 3 T3 No Mo
T1 N1 Mo
T2 N1 Mo
T3 N1 Mo
STAGE 4 T4 ANY N Mo
ANY T N2 OR N3 Mo
ANY T ANY N M1

LIMITATIONS OF CURRENT TNM SYSYTEM:
-Stage migration: because of new diagnostic technology subclinical
lesions can be detected
- characteristics of lymph node involvement which are important
prognostic factors are not included in the classification : size of largest
node, consistency of node , level of node
- involvement of adjacent structures not included

CONVENTIONAL ORAL EXAMINATION
1 Characteristics Standard visual and tactile examination of the
oral mucosa under normal (incandescent)
light
2 Classification of
response
Positive  Presence of an abnormality with a
suspicion of malignancy or potential
Negative test Absence
3 Advantage Quick and easy once trained, minimally
invasive
4 Disadvantage Subjective
Dysplasia may be present in regions that look
normal to the eye

VITAL STAINING
-Method of staining living cells without killing them
- Two types:
1. Intravital staining in the living body (in vivo) and
2. Supravital staining outside the body usually applied to slide
preparation of detached cell.
- stains used in oral cavity :
1. Toluidine blue
2. Methylene blue
3. Lugol’s iodine

Toludine Blue
(Tolonium chloride, Methylanaline or Aminotoluene)
Chemical composition: It is an acidophilic metachromatic dye that selectively stains
acidic tissue components (sulfates, carboxylates, and phosphate radicals).
Isoforms: Ortho-toluidine, para-toluidine, and meta-toluidine
Applications in oral cancer:
1. To verify clinically suspicious lesions as neoplastic
2. To delineate margins of premalignant and malignant growth
3. To detect unnoticed or satellite tumors
4. Can detect multicentric or second tumors and can help in the followup of
patients with oral cancer

CONCENTRATION :
- TBlue 630 is patented commercially available toluidine blue
-TB is generally prepared in 1% concentration for oral application:
- A 100 mL of 1% TB consists of : 1 gm TB powder,
: 10 mL of 1% acetic acid,
: 4.19 mL absolute alcohol, and
: 86 mL distilled water to make up 100 mL.
- The pH is usually regulated to 4.5
Toludine Blue

Toludine Blue
1 Principle Metachromasia, hydrophilic cationic dye selectively stains
acidic tissue components nuclear material of tissues with a
high DNA and RNA content
2 Classification of response Positive  a dark blue (royal or navy) stain
Negative test No colour
Doubtful light blue staining
3 Advantage Quick and easy, cost effective
highly sensitive and moderately specific for malignant
lesions
4 Disadvantage • Subjective ; regarding the color
• False positives: Tendency to stain common benign
conditions such as nonspecific ulcerations, epithelial
hyperplasias, chronic frictional keratoses, and other
similar lesions
• Less sensitive for premalignant lesions with false
negative rates of up to 58%
Sridharan, G., & Shankar, A. A. (2012). Toluidine blue: A review of its chemistry and clinical utility. Journal of
Oral and Maxillofacial Pathology : JOMFP, 16(2), 251–255.

PROCEDURE
the mouth is rinsed twice with
water to rinse mechanically
retained stain
2 rinses with 1% acetic acid to reduce the
extent of mechanically retained stain.
1% TB application for 20 s either with
cotton swab when a mucosal lesion can be
seen or given as rinse when no obvious
lesion can be detected.
1% acetic acid is then applied
for 20 s to remove ropey saliva
-rinsing of the mouth twice with
water for 20 s to remove debris

METHYLENE BLUE
1 Principle Metachromasia, hydrophilic cationic dye selectively stains
acidic tissue components nuclear material of tissues with a
high DNA and RNA content similar to TBlue
2 Classification of response Positive  a dark blue (royal or navy) stain
Negative test faint blue/ No colour
Variable response for potentially malignant disorders and
malignant lesions
4 Disadvantage • Subjective ; regarding the color
• False positives: Retention of stain in inflamed and
trauma areas, contamination of saliva and plaque,
retention of dye material in papilla of the tongue or
minor salivary gland ducts over the mucosa
Chen, Ya-Wei; Lin, Jiun-Sheng; Wu, Cheng-Hsien; Lui, Man-Tien; Kao, Shou-
Yenet al .Application of in vivo stain of methylene blue as a diagnostic aid in the early detection and screening of oral
squamous cell carcinoma and precancer lesions.. (2007)
Journal of the Chinese Medical Association : JCMA vol. 70 (11) p. 497-503

Dry the target area
with gauze
Rinse mouth with 1%
lactic acid for 30
seconds
rinse the mouth
with water
Rinse again with 1
% lactic acid to
wash out excessive
dye
Apply methylene blue with cotton
bud and leave the area for 30
seconds
Interpretation
based on the
pattern of dye
retention

LUGOL’S IODINE (2%)
1 Principle Iodine reacts with glycogen producing a brown black stain
Glycogen content is inversely related to degree of
keratinisation
2 Classification of response Positive  No stain (proliferating keratinizing tissue)
Negative test brown stain
3 Advantage • Quick and easy, cost effective
• High specificity can be used along with toluidine blue
which has low specificity and high sensitivity
4 Disadvantage • Can not be used for lesions arising on keratinized
mucosa (hard palate and attached gingiva)
• It has low sensitivity but high specificity

Watanabe A1, Taniguchi M, Tsujie H, Hosokawa M, Fujita M, Sasaki
S.Clinical impact of iodine staining for diagnosis of carcinoma in situ in the floor of mouth, and decision of
adequate surgical margin. Auris Nasus Larynx. 2012 Apr;39(2):193-7.

ROSE BENGAL DYE
1 Principle Stains the cells, wherever there is poor protection of the
surface epithelium
2 Classification of response Positive  intense dark pink, mild pink
Negative test no stain
3 Advantage • Quick and easy
• High sensitivity and low specificity
4 Disadvantage • False negative  late clinical expression of genetically induced
changes in the cells or inability of the stain to penetrate the
deeper layers of epithelium showing the dysplastic changes
Du GF, Li CZ, Chen HZ, Chen XM, Xiao Q, Cao ZG. Rose bengal staining in detection of oral precancerous
and malignant lesions with colorimetric evaluation: a pilot study. Int J Cancer. 2007;120:1958–63

Mild intense pink stain Intense pink stain
Mittal N, Palaskar S, Shankari M.. Rose Bengal staining - diagnostic aid for potentially malignant and
malignant disorders: a pilot study. Indian J Dent Res. 2012 Sep-Oct;23(5):561-4.

• Vinuth, D., Agarwal, P., Kale, A. D., Hallikeramath, S., & Shukla, D. (2015). Acetic acid as an adjunct vital stain in diagnosis
of tobacco-associated oral lesions: A pilot study. Journal of Oral and Maxillofacial Pathology : JOMFP,19(2), 134–138.
• Marina, O. C., Sanders, C. K., & Mourant, J. R. (2012). Effects of acetic acid on light scattering from cells. Journal of
Biomedical Optics, 17(8), 085002.
1 Principle Acetowhitening nuclear protein precipitation, so
tissues with increased nuclear protein displays this
phenomenon. Cytokeratin expression
(hypothesized to also be essential)
2 Classification of
response
Positive  Appearance of opaque white
Negative test Presence of transparent white/
absence of white
4 Disadvantage Subjective
Staining intensity between keratotic, inflammatory
malignant or potentially malignant disorders of the
oral mucosa is also difficult.
5% Acetic Acid

CYTOBRUSH (OralCDx)
1 Principle Method of collecting a trans-epithelial sample of cells from
a mucosal lesion with representation of the superficial,
Intermediate and parabasal/basal layers of the epithelium
analysed by computer algorithm and a human
cytopathologist’s
2 Classification of response 1. Negative : no cytologic abnormality
2. Atypical : denotes deviations from normal cytology that
arouse concern about, but are not unequivocal
evidence of precancer or cancer
3. Positive :findings suggestive of dysplasia or carcinoma
3 Advantage Does not cause pain/minimal pain ,little or no bleeding
-demonstrate better cell spreading on objective slides
compared with smears obtained by using the conventional
wooden spatula
- improvement in the cellular adequacy of the smears
4 Disadvantage It does not provide definitive diagnosis

IDENTIFY THE AREA
BRUSH THE LESION
APPLY DIRECT FORCE AND
ROTATE THE BRUSH
CLOCKWISE 5-15 TIMES
UNTIL PINPOINT BLEEDING
CAN BE SEEN
RUB ALL THE SIDES OF
BRUSH ON THE SLIDE
TO CREATE A VISIBLE
LAYER
SLIDE TO BE FIXED
ATLEAST FOR 10
MINUTES
SLIDE CAN BE PLACED
IN CONTAINER
TO TAKE SAMPLE FROM
KERATINIZED MUCOSA –
EXTRA ROTATIONS AND
FIRMER PRESSUR IS
REQUIRED
FOR ULCERATIVE
LESION – ONLY THE
PERIPHERY OF THE
AREA SHOULD BE
BRUSHED

When cells interact with the light of particular wavelength, they become excited
and re-emit light of varying wavelength (color) autofluorescence
Produced by fluorophores (naturally present in human body like collagen,
tryptophan, elastin, keratin, hemoglobin and NADH etc.)
Potentially malignant disorders and cancerous conditions cause a change in the
concentration of these fluorophores, alteration in the light scattering
This spectral property of mucosa can be detected and can be used as a tool in
diagnosing the potentially malignant disorders and cancerous conditions.
AUTOFLUORESCENCE

AUTOFLUORESCENCE
1 Principle Method of collecting a trans-epithelial sample of cells from a mucosal
lesion with representation of the superficial, Intermediate and
parabasal/basal layers of the epithelium analysed by computer algorithm
and a human cytopathologist’s
2 Classification
of response
1. Normal: Fluorescence in UV and natural light (collagen in
connective tissue); epithelium shows weak response due to
mitochondrial NADH, FAD in basal cells, keratin also fluoresces
2. Neoplasia loss of stromal collagen loss of autofluorescence
3. Epithelial dysplasia increases mitochondrial fluorescence of the
epithelium.
3 Advantage Non invasive procedures
Can be performed on medically compromised patients who are
contraindicated for biopsies
As in vivo chair side procedures, which can be used to define surgical
margins of a lesion
As a tool in mass screening procedures

1. Visual autofluorescence (visually enhanced lesion scope [VELscope]
2. Autofluorescence imaging
3. Autofluorescence spectroscopy.
AUTOFLUORESCENCE

Visual autofluorescence (Visually Enhanced Lesion Scope)
narrow-emission tissue fluorescence
It consists of a handheld device or scope which illuminated the mucosa with a
fluorescent light of wavelength 400 – 460 nm (narrow band) and a manual unit for
direct visualization
CLASSIFICATION OF RESPONSE :
Normal mucosa  green autofluorescence
Abnormal mucosa  dark due to the reduction or change in the quantity and
quality of fluorophores in the mucosa which occurs due to abnormal or neoplastic
changes of the mucosa

ADVANTAGE:
1. Capable of identifying lesions that cannot be seen using normal
(incandescent) light
2. Rapid and easy way of detecting cancerous changes in the mucosa
3. Useful in detecting tumor margin
4. Useful in mass screening campaigns
DISADVANTAGE:
1. Subjective to observer’s skill of identifying the lesion
• Sawan, D., & Mashlah, A. (2015). Evaluation of premalignant and malignant lesions by fluorescent light (VELscope). Journal
of International Society of Preventive & Community Dentistry, 5(3), 248–254.
• Carreras-Torras, C., & Gay-Escoda, C. (2015). Techniques for early diagnosis of oral squamous cell carcinoma: Systematic
review. Medicina Oral, Patología Oral Y Cirugía Bucal, 20(3), e305–e315. http://doi.org/10.4317/medoral.20347
•

AUTOFLUORESCENCE IMAGING
Autofluorescence imaging digital images are captured and they can be compared
with the normal algorithm chart to find out high risk or lesional areas.
PROCEDURE:
• Tissues are illuminated with a light source, in the near UV to the green
spectral range
• Images  recorded using a camera
• Captured digital images are used to interpret the lesion
 Photosensitizers, which act as fluorescent markers and increases fluorescence
of the tissue thereby favoring detection and demarcation of tumors
 5-aminolevulinic acid

AUTOFLUORESCENCE SPECTROSCOPY
• This system consists of a light source usually in the near-UV to visible
wavelength range that excites the tissue through a fiber
• The fluorescence that is produced in the tissue is received with an analyzer
probe. This probe can be disinfected with chlorhexidine gluconate and dried
before use on a patient
• Measurements were performed under a low ambient light level with the probe in
contact with the oral mucosa
• The obtained wavelengths are analyzed by a spectrograph
• The recorded fluorescence spectra can be saved to a computer

AUTOFLUORESCENCE SPECTROSCOPY
LIMITATIONS:
- It is not feasible to scan the entire oral cavity using
small optical fibers

IDENTAFI 3000
Combines anatomical imaging with fluorescence, fiber optics and confocal
microscopy to map and delineate precisely the lesion in the area being
screened
Apart from the fluorescence like VEL Scope it has the amber light is thought to enhance
the reflective properties of the oral mucosa
ADVANTAGE: 1. Evaluating the status of tumor angiogenesis
2. Small size and easy accessibility to all tissues in the oral cavity
DISADVANTAGE: Expensive
Messadi, D. V. (2013). Diagnostic aids for detection of oral precancerous conditions. International Journal of
Oral Science, 5(2), 59–65. http://doi.org/10.1038/ijos.2013.24

Non-healing ulcer on the
right lateral border of the tongue
(regular light)
violet fluorescent light shows dark area
(loss of autoflurescence) in suspicious
areas.
green amber reflectance light
show increase vascularity in the
suspicious areas

CHEMILUMINESCENSE
-Marketed as VIZILITE, VIZILITE PLUS , MICRO-LUX DL
PROCEDURE :
NORMAL
CELLS
APPEAR BLUE
ABNORMAL
DYSPLASTIC CELLS
WILL APPEAR
WHITE
DIRECT VISUAL
EXAMINATION OF
ORAL CAVITY UNDER
BLUE WHITE LIGHT
SOURCE (490-510nm)
RINSE THE MOUTH WITH
1% ACETIC ACID

PRINCIPLE:
Acetic acid removes glycoprotein barrier and dessicate the mucosa
(change the refractory properties of mucosa )
Dysplastic cells with higher nuclear/cytoplasmic ratio will reflect the
blue/white light in a different way than normal cells

VIZILITE PLUS : provides a tolonium chloride solution (TBlue), which
is intended to aid in the marking of an acetowhite lesion for
subsequent biopsy once the light source is removed.
MICROLUX: provided with a reusable battery powered light source
(ViziLite Plus uses a disposable chemiluminescent light packet)

PRECAUTIONS :
-Before application of acetic acid removable prosthesis should be
removed
- not to be used when any active source of inflammation is present in
oral cavity
- precaution should be taken to prevent accidental swallow of light
source

INDICATIONS: To be used as an adjunct to conventional visual
examination
LIMITATIONS: the reported sensitivity of ViziLite was consistently high
across studies (w95%–100%), its diagnostic specificity was consistently
low (0%–10%).
Well-controlled clinical trials are needed that specifically investigate the
ability of these devices to detect precancerous lesions that are invisible
by conventional oral examination alone

CARCINOGENESIS “creation of cancer”
•Synonyms: tumorigenesis , oncogenesis
• It is characterized by a progression of changes at the cellular, genetic
and epigenetic level that ultimately reprogram a cell to undergo
uncontrolled cell division, thus forming a malignant mass.

CELL
CELL
PROLIFERATION
AND
DIFFERENTIATION
CELLULAR
ADAPTATIONS
- Atrophy
- Hyperplasia
- Hypertrophy
- Metaplasia
CELLULAR DAMAGE
NEOPLASIA-
uncontrolled
proliferation
APOPTOSIS
Repair
Irreparable
Irreparable

CELLULAR ADAPTATIONS
Adaptation Atrophy Hypertrophy Hyperplasia Metaplasia
Description Reduction in
no. of
parenchymal
cells
Increase in size
of
parenchymal
cells
Increase in
no. of
parenchymal
cells
Reversible change with
replacement of one
type of cell with
another type (more
suited to environment)
Clinical
Implication
OSMF Candidal
leukoplakia
Barett’s esophagus

Neoplasia can be : Benign (slow growing , localized) or Malignant (rapid
proliferation)
Two basic components:
1. Parenchyma : proliferating tumor cells
2. Supportive stroma: composed of fibrous connective tissue and blood
vessels; it provides the framework on which the parenchymal tumor cells
grow

NOMENCLATURE
• The tumors derive their nomenclature on the basis of the
parenchymal component comprising them
• The suffix “oma “ is added to denote benign tumors
• Exception- melanoma, lymphoma, leukemia

• Malignant tumors arising in mesenchymal tissue are usually called
sarcomas (Greek sar = fleshy),
(e.g., fibrosarcoma, chondrosarcoma, leiomyosarcoma, and
rhabdomyosarcoma).
• Malignant neoplasms of epithelial cell origin, derived from any of the
three germ layers, are called carcinomas.
(e.g. squamous cell carcinoma , basal cell carcinoma)
NOMENCLATURE

CELL
CELL
PROLIFERATION
AND
DIFFERENTIATION
CELLULAR
ADAPTATIONS
- Atrophy
- Hyperplasia
- Hypertrophy
- Metaplasia
CELLULAR DAMAGE
NEOPLASIA-
uncontrolled
proliferation
APOPTOSIS
Repair
Irreparable
Irreparable
-Tumor suppressor genes
- Apoptosis regulatory genes
-Protooncogenes
- DNA repair genes
-Oncogenes
- Defective DNA
repair genes
-Inactivation of tumor suppressor
genes
- Abnormal

Cancer of the oral cavity

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