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MALIGNANT TUMORS OF THE
EPITHELIAL
TISSUE ORIGIN
SQUAMOUS CELL CARCINOMA
(Epidermoid carcinoma)
Introduction
Definition
Squamous cell carcinoma is defined
as “a malignant epithelial neoplasm
exhibiting squamous differentiation as
characterized by the formation of
keratin and/or the presence of
intercellular bridges” (Pindborg JJ et
al, 1997)
 most common malignant neoplasm of
the oral cavity (more than 90%)
Epidemiology
 The incidence - ranges from approximately
2–10 per 100,000 population per year
 differs widely in various parts of the world -
basis of environmental differences or lifestyle
and habits among certain populations, such
as betel quid chewing, snuff dipping or the
habit of reverse smoking
 The incidence of oral carcinoma in blacks is
somewhat lower than in whites
 after the fourth decade
 male-female ratio is approximately 2 : 1
 Carcinoma of the vermilion border of the
lower lip - strong male predominance
Epidemiology
South-East Asian scenario
 In India, oral cancer, constituting 9.8% of an
estimated 644,600 incident cancer cases in
1992, ranks first among all cancer cases in
males
 Third most common among females in many
regions, with age standardized incidence
rates
 7–17/100,000 persons/ year; the incidence
rate being higher than the western rate of 3–
4/100,000/ year
 the mortality rate is lowest for lip cancer (0.04
per 100,000)
 the mortality rate is highest for the tongue
(0.7 per 100,000)
Epidemiology
 80% of oral
cancers were
preceded by oral
precancerous
lesions or
conditions
 Sometimes oral
cancer arises from
otherwise clinically
normal mucosa
Etiology
 Multifactorial
 No single causative agent or factor
(carcinogen) has been clearly defined
or accepted
 more than a single factor is needed to
produce such a malignancy
(cocarcinogenesis)
Etiology
Oral
Squamous
Cell
Carcinoma
Extrinsic
Factors
Tobacco
Smoke
Alcohol
(for vermilion
cancers only)
Sunlight
Intrinsic
Factors
(systemic
or
generalized
states)
malnutrition
iron-deficiency
anemia
dyskeratosis
congenita
Fanconi
anemia
Etiology
Tobacco Smoking
 Tobacco smoke contains more than 70
carcinogens
1. nitrosamines,
2. arsenic,
3. benzo[a]pyrene, and
4. benzene
 In addition, smoking produces free radicals
and oxidants that promote the destruction
and counteract the protective effects of
endogenous antioxidants (such as,
glutathione-S-transferase, glutathione
reductase, and superoxide dismutase)
Etiology
Tobacco Smoking
 Much indirect clinical evidence implicates
tobacco smoking in the development of
oral squamous cell carcinoma
 The proportion of smokers (80%) among
patients with oral carcinoma is about four
times greater than that among the
general population
 For patients who quit smoking, the risk
for developing oral cancer declines over
time
Etiology
Tobacco Smoking
 the pooled risk for oral cancer is
approximately three times greater among
smokers than non smokers
 Moreover, the relative risk (smoker’s risk for
oral cancer compared with that of a
nonsmoker) is dose-dependent
 The risk also increases the longer a person
smokes
 cigar or pipe smoking is associated with a
similar or greater risk for oral cancer
compared to cigarette smoking
Etiology
Tobacco Smoking
 In India, bidi smoking is associated
with an approximately threefold
greater risk of oral cancer compared
to cigarette smoking
 The highest - practice of reverse
smoking is popular, especially among
women
 In reverse smoking 50% of all oral
malignancies are found on the hard
Etiology
Smokeless Tobacco
 Smokeless tobacco use - risk for oral
carcinoma by a factor ranging from less than
two to as high as 26
 lower risk associated with moist snuff and
chewing tobacco and a higher risk associated
with dry snuff
 abnormal male-to-female ratio for oral
carcinoma (>1.0 : 1.5) in geographic areas
where the habit is more popular among
women than among men.
 approximately 50% of all oral cancers in
smokeless tobacco users occur at the site
where the tobacco is habitually placed
Etiology
Betel Quid (Paan)
 combination of natural substances (i.e., areca
palm nuts, betel leaf, slaked lime, and
perhaps tobacco leaf ) chewed for their
psychostimulating effects
 The carcinogenicity of betel quid traditionally
has been attributed to tobacco, although
areca nut alone also appears to be
carcinogenic
 the lifetime risk of developing oral cancer is a
remarkable 8%
 also is associated with development of
precancers, such as leukoplakia
Etiology
Alcohol
 alcohol in combination with tobacco is
a significant risk factor for oral cancer
development
 generally appears to be dose
dependent and time-dependent
 approximately one-third of male
patients with oral cancer are heavy
alcohol users
 cirrhosis of the liver is found in at least
20% of male patients with oral cancer
Etiology
Alcohol
 The exact role of alcohol in oral carcinogenesis is
not well understood
 Ethanol in alcoholic beverages is metabolized
into acetaldehyde, which is a known carcinogen
 In addition, carcinogenic impurities—such as,
polycyclic aromatic hydrocarbons and
nitrosamines—may be present in some alcoholic
beverages
 Moreover, alcohol may help solubilize other
carcinogenic compounds and may increase the
permeability of oral epithelium to these
compounds
 Nutritional deficiencies associated with heavy
alcohol consumption also may be a contributory
factor
Etiology
Occupational Exposures and Environmental
Pollutants
 increased oral cancer risk for workers in the
wood products industry chronically exposed
to certain chemicals, such as phenoxyacetic
acids
 In regions of Taiwan with a particularly high
incidence of oral cancer, investigators have
reported elevated levels of heavy metal
pollutants (e.g., nickel, chromium, and
arsenic) in farm soil and increased blood
concentrations of some of these metals in
affected patients
Etiology
Radiation
 radiotherapy to the head and neck
area increases the risk for later
development of a new primary oral
malignancy, either a carcinoma or
sarcoma
 dosedependent
Etiology
Vitamin/Mineral Deficiencies and Dietary Factors
 Iron deficiency, especially the severe, chronic form
known as the Plummer-Vinson or Paterson-Kelly
syndrome is associated with an elevated risk for
squamous cell carcinoma of the esophagus,
oropharynx, and posterior mouth.
 develop at an earlier age
 Iron deficiency may cause impaired cell-mediated
immunity
 In addition, because the epithelium of the upper
digestive tract has a relatively high turnover rate, rapid
loss of iron-dependent enzymes may lead to
degenerative changes, including mucosal atrophy and
esophageal webs (intertwining fibrous bands of scar
tissue), with heightened susceptibility to malignant
transformation
Etiology
Vitamin/Mineral Deficiencies and
Dietary Factors
 Vitamin-A deficiency produces
excessive keratinization of the skin
and mucous membranes
 this vitamin may help to prevent oral
precancer and cancer
Etiology
Vitamin/Mineral Deficiencies and
Dietary Factors
 high intake of fruits and vegetables
decreases the risk for numerous cancer
types, including oral cancer
 may be related to the protective effects
of not only vitamin A but also various
other substances (e.g., vitamins C and
E, folate, flavonoids, fiber, lycopene, and
phytosterols) present within plant foods
 animal fats and processed or salted
meat may increase the risk for oral
cancer
Etiology
Bacteria
 oral bacteria may interact with tobacco
and alcohol
 Ethanol is metabolized into
thecarcinogen acetaldehyde by not only
hepatocytes and oral epithelial cells but
also bacteria
 high levels of acetaldehyde production
have been associated with certain
Streptococcus species, Neisseria
species, and other bacteria
 Candida may contribute to acetaldehyde
production
Etiology
Bacteria
 Periodontal disease-causing bacteria
may induce production of pro-
inflammatory cytokines
 may enhance cell proliferation and inhibit
apoptosis, thereby producing a
microenvironment favorable for
carcinogenesis
 tertiary syphilis has been associated with
a fourfold increased risk for development
of dorsal tongue carcinoma
Etiology
Candida
 Hyperplastic candidiasis frequently is
cited as an oral precancerous
condition(also has been called
candidal leukoplakia
 However, the evidence for the
promotion of oral carcinogenesis by
Candida is largely circumstantial
Etiology
Oncogenic Viruses
 Oncogenic (tumor producing) viruses
may play a major role in a wide variety of
cancers
 Viral integration into the host’s genetic
material may result in abnormal cell
growth and proliferation
 The oncogenic viruses may immortalize
the host cell, thereby facilitating
malignant transformation
 play a role in the development of oral
carcinoma - HPV and HIV
Etiology
Oncogenic Viruses
 HPV actually is best known for its role in the
development of cancers of the anogenital region
(especially the uterine cervix but also the anus, vulva,
vagina, and penis)
 only a small subset of oral carcinomas has been
attributed to HPV infection
 The high-risk HPV types are most closely associated
with dysplasia and squamous cell carcinoma
 detection of HPV 16 in exfoliated oral epithelial cells is
associated with a nearly fourfold increased risk for oral
cancer and a more than fourteen fold increased risk for
oropharyngeal cancer
 the proportion of oral carcinomas caused by HPV
infection appears to be small
Etiology
Oncogenic Viruses
 The characteristic risk profile for patients with
HPV positive head and neck squamous cell
carcinoma
1. male predilection
2. 10 years younger among the HPV-positive group
3. affect individuals of higher socioeconomic status
4. more strongly associated with certain
parameters of sexual behavior (e.g., increased
number of lifetime sexual or oral sexual partners,
early age at sexual debut)
5. Less likely to occur in patients with an extensive
history of tobacco and alcohol history
Etiology
Immunosuppression
 some malignancies of the upper
aerodigestive tract
 Persons with HIV infection and those
who are undergoing immunosuppressive
therapy for malignancy or organ
transplantation are at increased risk for
oral squamous cell carcinoma and other
head and neck malignancies, especially
when tobacco smoking and alcohol
abuse are present
Etiology
Oncogenes and Tumor Suppressor Genes
 The molecular basis of carcinogenesis involves an
accumulation of mutations or epigenetic changes in two
broad classes of genes: proto-oncogenes and tumor
suppressor genes
 Proto-oncogenes may be transformed into activated
oncogenes by environmental agents (e.g., viruses,
irradiation, and chemical carcinogens) or inherited
changes
 Activated oncogenes promote uncontrolled cell division
and are involved in the initiation and progression of a
wide variety of malignancies
 Tumor suppressor genes, on the other hand, inhibit cell
division and indirectly allow tumor production when they
become inactivated or mutated
 an accumulation of several genetic aberrations is
necessary before the affected cell expresses a
malignant phenotype
Etiology
Oncogenes and Tumor Suppressor Genes
 Genetic aberrations commonly identified in oral
squamous cell carcinomas include abnormalities
of the ras, myc, and epidermal growth factor
receptor (EGFR; also known as c-erbB1)
oncogenes, and the TP53, pRb, p16, and E-
cadherin tumor suppressor genes
 Head and neck squamous cell carcinomas
associated with tobacco and alcohol use often
exhibit mutated TP53, pRb overexpression, and
decreased p16 expression
 In contrast, HPV-associated cases typically
express wild-type TP53, low levels of pRb, and
increased levels of p16
Clinical Features
 Mostly older men
 minimal pain during the early growth phase
 Oral squamous cell carcinoma has a varied
clinical presentation, including the following:
• Exophytic (mass-forming; fungating, papillary,
and verruciform)
• Endophytic (invasive, burrowing, and
ulcerated)
• Leukoplakic (white patch)
• Erythroplakic (red patch)
• Erythroleukoplakic (combined red-and-white
patch)
Clinical Features
 The leukoplakic and
erythroplakic
examples are
probably early cases
that have not yet
produced a mass or
ulceration
 clinical features are
identical to those
described for
premalignant
leukoplakia and
erythroplakia
Clinical Features
 An exophytic lesion - surface that is
irregular, fungating, papillary, or
verruciform
 color - normal to white or red
(depending on the amount of keratin
and vascularity)
 surface is often ulcerated
 feels hard (indurated) on palpation
Oral squamous cell carcinoma
Clinical Features
 endophytic growth
pattern - central,
depressed, irregularly
shaped ulcer with a
surrounding “rolled”
border of pink, red, or
white mucosa
 The rolled border results
from invasion of the
tumor downward and
laterally under adjacent
epithelium
 Perineural invasion may
cause paresthesia
 Destruction of underlying
bone, when present,
may be painful or
completely painless
Clinical Features
D/D of endophytic growth pattern :
 Traumatic granulomas,
 deep fungal infections,
 tuberculosis,
 tertiary syphilis, and
 oral lesions of Wegener
granulomatosis or Crohn’s disease
Radiological Features
 Destruction of
underlying bone
appears on
radiographs as a
“moth-eaten”
radiolucency with
ill-defined or
ragged margins (an
appearance similar
to osteomyelitis)
Lip Vermillion Carcinoma
 found in light skinned persons with
chronic exposure to UV radiation from
sunlight
 Seventy percent of affected individuals
have outdoor occupations
 elderly men
 usually is associated with actinic
cheilosis
 may arise at the site where the patient
holds a cigarette, cigar, or pipe
 Almost 90% of lesions are located on the
lower lip
Lip Vermillion Carcinoma
Clinical Features
 crusted, oozing, non tender, indurated
ulceration
 usually less than1 cm in greatest diameter
 grows slowly
 Metastasis is a late event; at diagnosis, fewer
than 10% of patients have lymph node
metastasis, usually in the submental region
 Perineural invasion may result in extension of
the tumor into the mandible through the
mental foramen
 patient neglect can result in considerable
destruction of normal tissue
Oral squamous cell carcinoma
Intraoral Carcinoma
 the most common sites for intraoral
carcinoma are the
1. tongue (usually the posterior lateral and
ventral surfaces)
2. floor of mouth
3. gingiva,
4. Alveolar bone,
5. buccal mucosa,
6. labial mucosa, and
7. hard palate
Carcinoma of Tongue
 25 to 50% of all intraoral cancer
 less common in women than in men
 essentially a disease of the elderly, but it
may occur in relatively young persons
Etiology
1. Syphilis
2. Leukoplakia
3. poor oral hygiene
4. chronic trauma
5. alcohol and tobacco
Carcinoma of Tongue
Clinical Features
 Painless masses or ulcers
 lesion ultimately becomes painful, especially
when it becomes secondarily infected
 may begin as a superficially indurated ulcer with
slightly raised borders
 proceed either to develop a fungating, exophytic
mass or to infiltrate the deep layers of the
tongue, producing fixation and induration without
much surface change
 Mostly posterior lateral border
 20% occur on anterior lateral or ventral surfaces,
and
 only 4% occur on the dorsum (syphilitic glossitis)
Carcinoma of Tongue
Clinical Features
 Lesions near the base of the tongue are
particularly insidious
 asymptomatic until far advanced
 presenting manifestations may be a sore
throat and dysphagia
 the lesions on the posterior portion of the
tongue are usually of a higher grade of
malignancy, metastasize earlier and offer a
poorer prognosis, especially because of their
inaccessibility for treatment
 Metastases occur with great frequency in
cases of tongue cancer
Oral squamous cell carcinoma
Carcinoma of Floor of the Mouth
 15% of all intraoral carcinomas
 Average age – 57 years
 Mostly men
 most often associated with the development of a
second primary malignancy
 Floor of mouth carcinomas most often arise in the
midline region near the frenum
Etiology
 preexisting leukoplakia or erythroplakia
 Alcohol
 Tobacco
 Poor oral Hygiene
Carcinoma of Floor of the Mouth
Clinical Features
 indurated ulcer of varying size
 one side of the midline
 may or may not be painful
 more frequently in the anterior portion of the floor than in the
posterior area
 Early extension into adjacent tissues
 may invade the deeper tissues and may even extend into the
submaxillary and sublingual glands
 limitation of motion of tongue, often induces a peculiar
thickening or slurring of the speech
 Metastases from the floor of the mouth are found most
commonly in the submaxillary group of lymph nodes, and
since the primary lesion frequently occurs near the midline
where a lymphatic cross drainage exists, contralateral
metastases are often present
 Fortunately, distant metastases are rare
Oral squamous cell carcinoma
Carcinoma of Gingiva
Etiology
 least associated with tobacco smoking
 no more specific or defined
 may speculate the possible role of
chronic irritation
Clinical Features:
 usually painless
 most frequently arise from keratinized,
posterior mandibular mucosa
 have the greatest predilection for
females
Carcinoma of Gingiva
Clinical Features:
 61 years – average age
 mandibular gingiva > maxillary gingiva
 initially as an area of ulceration which may be a
purely erosive lesion or may exhibit an exophytic,
granular or verrucous type of growth
 have a special propensity to mimic common,
benign inflammatory and reactive lesions, such
as the pyogenic granuloma, gingivitis and
periodontal disease
 arises more commonly in edentulous areas
 fixed gingiva is more frequently involved primarily
than the free gingiva
Carcinoma of Gingiva
Clinical Features:
 Often destroy the underlying bone and cause tooth
mobility
 Pathologic fracture sometimes occur
 The lesion may go unrecognized until after tooth
extraction, when it proliferates out of the socket to
mimic the hyperplastic granulation tissue of an epulis
granulomatosa
 Cancers that develop in an edentulous area may “wrap
around” a denture flange and superficially resemble
inflammatory fibrous hyperplasia (epulis fissuratum)
 Metastasis is a common sequela of gingival carcinoma
 Cancer of the mandibular gingiva metastasizes more
frequently than cancer of the maxillary gingiva
Oral squamous cell carcinoma
Carcinoma of Alveolar Bone
 alveolar carcinomas - usually painless
 most frequently arise from posterior
mandibular region
 Sometimes as extension of gingival
carcinoma
 mimic common, benign inflammatory
and reactive lesions
 Tumors of the maxillary alveolar ridge
may extend onto the hard palate
Oral squamous cell carcinoma
Carcinoma of Buccal Mucosa
 approximately 10 times more common
in men than in women
 occurs chiefly in elderly persons
 average age at occurrence was 58
years
Etiology
 not better understood
 use of chewing tobacco
 habit of chewing betel nut
 Leukoplakia - precursor
Carcinoma of Buccal Mucosa
Clinical Features:
 more aggressive
 recurrence – high
 common site where betel quid use is prevalent
 develop most frequently along or inferior to a line
opposite the plane of occlusion
 painful ulceration
 induration and infiltration of deeper tissues are common
 Sometimes - superficial and appear to be growing
outward from the surface rather than invading the
tissues - called exophytic or verrucous growths
 Metastases - relatively high
 The most common sites of metastases are the
submaxillary lymph nodes
Carcinoma of right buccal
mucosa
Carcinoma of the Palate
 not a particularly common lesion
 Less percentage of occurrence – approx
0.5%
Clinical Features:
 poorly defined, ulcerated, painful lesion
on one side of the midline (tumors of
accessory salivary gland origin, even the
malignant lesions, are often not
ulcerated, but are covered with an intact
mucosa. This fact may be of some aid in
helping to distinguish clinically between
these two types of neoplasms)
Carcinoma of the Palate
Clinical Features:
 frequently crosses the midline
 may extend laterally to include the
lingual gingiva or posteriorly to involve
the tonsillar pillar or even the uvula
 may invade into the bone or occasionally
into the nasal cavity, while infiltrating
lesions of the soft palate may extend into
the nasopharynx
 Metastases to regional lymph nodes –
considerable percentage of cases
Oral squamous cell carcinoma
Carcinoma of Retromolar
Trigone
 may spread to
numerous adjacent
structures, including
the oropharynx,
buccal mucosa,
alveolar ridge, and
pterygomandibular
raphe
 Invasion of the
pterygomandibular
raphe may lead to
involvement of the
skull base,
masticator space,
and floor of mouth
Oropharyngeal Carcinoma
 base of tongue, tonsillar region (i.e., tonsil, tonsillar
fossa, and pillars), and posterior pharyngeal wall
 the tonsillar region accounts for the majority
(approximately 70% to 80%) of cases
 Favored site for HPV-associated carcinomas
 Oropharyngeal carcinomas - same basic clinical
appearance as more anterior carcinomas
 posterior location lesions often go unrecognized for long
periods
 persistent sore throat,
 difficulty in swallowing (dysphagia),
 pain on swallowing (odynophagia)
 pain may be dull or sharp
 frequently is referred to the ear
Oral squamous cell carcinoma
Carcinoma of Maxillary Sinus
 an exceedingly dangerous disease
 Uncommon malignancy
 unknown cause
 squamous cell carcinomas of the
paranasal sinuses have been
associated only weakly with tobacco
use
 HPV may be an etiologic factor in
some cases
Carcinoma of Maxillary Sinus
Clinical Features:
 only 3% of all head and neck carcinomas
 asymptomatic or mimic sinusitis for long
periods
 chronic unilateral nasal stuffiness or an
ulceration or mass of the hard palate or
alveolar bone
 The tumor grows to fill the sinus
 Perforate through the surrounding bone
 more common in men
 chiefly a disease of elderly persons
Carcinoma of Maxillary Sinus
Clinical and Radiographic Features
 If the tumor perforates the lateral wall of the
sinus, unilateral facial swelling and pain are
usually present
 With medial extension, nasal obstruction and
hemorrhage are common
 Superior extension results in displacement or
protrusion of the eyeball
 Approximately 9% to 14% of patients have
cervical or submandibular lymph node
metastasis at the time of diagnosis
 Distant metastasis is uncommon until late in
the progression of disease
Carcinoma of Maxillary Sinus
Clinical Features:
 When the second division of the trigeminal nerve
is involved, intense pain or paresthesia of the
midface or maxilla may occur, perhaps simulating
a toothache.
 Adjacent teeth may become loose
Radiographic Features:
 Dental radiographs often reveal a “moth-eaten”
destruction of the lamina dura and surrounding
bone
 A panoramic radiograph shows a cloudy sinus
with destruction of its bony wall; however, the
extent of the tumor is best visualized by CT or
MRI
Oral squamous cell carcinoma
Metastasis
 Largely via the lymphatics to the ipsilateral
cervical lymph nodes
 A cervical lymph node that contains metastatic
carcinoma is usually firm to stony hard,
nontender, and enlarged
 if the malignant cells have perforated the capsule
of the node and invaded into surrounding tissues,
then the node will feel “fixed,” or not easily
movable
 Extracapsular spread (extension of metastatic
deposits outside of the lymph node capsule) is a
microscopic feature associated with poor
prognosis
 Occasionally, contralateral or bilateral metastatic
deposits, distant (“below the clavicles”)
metastasis at diagnosis
Metastasis
 most common sites of distant
metastasis are the lungs, liver, and
bones, but any part of the body may
be affected
 Carcinoma of the lower lip and oral
floor - submental nodes
 posterior portions of the mouth - the
superior jugular and digastric nodes
 oropharyngeal carcinoma -
jugulodigastric or retropharyngeal
Oral squamous cell carcinoma
Multiple Carcinomas
 Patients with one carcinoma of the
mouth or throat are at increased risk
for additional concurrent
(synchronous) or, more commonly,
later (metachronous) primary surface
epithelial malignancies of the upper
aerodigestive tract, stomach, lungs,
and other sites
 6% - 44%
 male patients
Multiple Carcinomas
 This tendency - field cancerization - a process whereby exposure to
carcinogens, such as tobacco and alcohol, creates a diffuse field of
altered epithelial cells with increased potential for malignant
transformation
 Molecular analyses of various markers, including loss of
heterozygosity (LOH), microsatellite alterations, TP53 tumor
suppressor gene mutations, and X-chromosome inactivation, have
identified genetic alterations shared between tumor tissue and
adjacent clinically normal appearing tissue in one-third to one-half of
cases examined
 significant proportion of second primary tumors develop from the
same preneoplastic precursor lesion or “field,” with the remaining
cases representing tumors that develop independently
 patches of clonal cells can progress to develop additional mutations
and give rise to subclones in a process known as clonal divergence,
which would account for the genetic heterogeneity typically seen
among these tumors
 Interestingly, field cancerization does not appear to be associated
with malignancies attributed to HPV infection
TNM Staging
 Tumor size and the extent of metastatic spread are the
best prognostic indicators for oral squamous cell
carcinoma
 Quantifying these clinical parameters is called staging
 three basic clinical features:
1. T—Size of the primary tumor, in centimeters
2. N—Regional lymph node involvement
3. M—Distant metastasis
 These three parameters are tallied together to
determine the stage
 the higher the stage, the worse the prognosis
 But survival rates are similar for patients with stage I, II,
and III disease
 HPV status appears to be the most important
prognostic factor for patients with oropharyngeal
carcinoma
Oral squamous cell carcinoma
Oral squamous cell carcinoma
Histopathology
 Squamous cell carcinoma arises from
dysplastic surface epithelium
 invasive islands and cords of malignant
squamous epithelial cells
 At the earliest moment of invasion, the
adjectives superficially invasive or
microinvasive often are used
 Invasion is represented by irregular
extension of lesional epithelium through
the basement membrane and into
subepithelial connective tissue
Histopathology
 Individual squamous cells and sheets or islands of cells
proliferate within the connective tissue, without
attachment to the surface epithelium
 The invading tumor destroys normal tissue and may
extend deeply into underlying adipose tissue, muscle,
or bone
 Lesional cells may breach the perineurium that encases
nerve bundles (perineural invasion) or may invade the
lumina of veins or lymphatics (vascular invasion)
 strong inflammatory or immune cell response to
invading epithelium
 necrosis may be present
 may induce dense fibrosis (desmoplasia or scirrhous
change) and the formation of new blood vessels
(angiogenesis)
Oral squamous cell carcinoma
Histopathology
 The lesional cells - abundant eosinophilic
cytoplasm with large, often darkly
staining (hyperchromatic) nuclei
 an increased nuclear-to-cytoplasmic ratio
 Varying degrees of cellular and nuclear
pleomorphism
 keratin pearls (a round focus of
concentrically layered, keratinized cells)
 Individual cells also may undergo
keratinization
Histopathology
 Histopathologic grading of squamous cell
carcinoma is based upon the degree of
resemblance to normal squamous
epithelium and the amount of keratin
production
 Lesions are graded on a three-point
(grades I to III) or a four-point (grades I
to IV) scale
 The less differentiated tumors receive
the higher numerals
 The histopathologic grade of a tumor is
related somewhat to its biologic behavior
Histopathology
 Low-grade, grade
I, or well-
differentiated - a
tumor that is
mature enough to
closely resemble
its tissue of origin
often grows at a
slightly slower pace
and metastasizes
later in its course
Histopathology
 High-grade, grade III/IV,
poorly differentiated,
or anaplastic - a tumor
with marked
pleomorphism and little
or no keratin production
may be so immature that
it becomes difficult to
identify the tissue of
origin. In such cases,
immunohistochemical
studies (e.g., for
cytokeratins or p63) may
be needed to support an
epithelial origin. Such
tumors often enlarge
rapidly, metastasize
early
Histopathology
 Grade II,
Moderately
differentiated - A
tumor with a
microscopic
appearance
somewhere
between these two
extremes
Oral squamous cell carcinoma
Histopathology
Oropharyngeal Carcinoma
 For oropharyngeal squamous cell carcinoma, detection of
transcriptionally active HPV infection is especially important in
determining prognosis
 HPV-positive oropharyngeal squamous cell carcinomas often are
poorly differentiated and nonkeratinizing with basaloid cytologic
features
 The gold standard for determining whether a carcinoma likely was
caused by HPV is high-risk HPV E6 and lE7 oncogene expression
analysis by quantitative reverse transcriptase polymerase chain
reaction (qRT-PCR)
 best suited for fresh frozen tissue
 technically demanding
 detection of p16 by immunohistochemistry is more widely available,
is readily performed on formalin-fixed paraffin-embedded tissue, and
is considered a highly sensitive (albeit not highly specific) surrogate
for transcriptionally active, high-risk HPV infection in oropharyngeal
carcinomas
Histopathology
 p16 immunoreactivity may be useful in
directing the search for the primary tumor to
the oropharynx
 in situ hybridization (ISH) for HPV 16 exhibits
strong agreement with
 p16 immunohistochemistry
 RNA ISH probes complementary to E6 and
E7 mRNA allows for detection of
transcriptionally active HPV in routinely
processed tissue
 liquid-phase hybridization assays for
detection of HPV in cytologic preparations
from head and neck squamous cell
carcinomas
Histopathology
 p16 immunohistochemistry -oral
squamous cell carcinomas - low positive
predictive value for transcriptionally
active HPV infection
 not useful for prognostication
 only limited data regarding qRT-PCR
analysis of high-risk HPV E6 and E7
expression in oral squamous cell
carcinoma, with no significant correlation
with prognosis demonstrated thus far
Oral squamous cell carcinoma
Oral squamous cell carcinoma
Histopathological Grading of
OSCC
 Classic microscopic histopathologic
alterations observed with squamous cell
carcinoma include:
a. Enlarged nuclei as well as cell size
b. Large and prominent nucleoli
c. Increased nuclear/cytoplasmic ratio
d. Hyperchromatic (dark staining) nuclei
e. Dyskeratosis (premature keratinization
of cells)
f. Increased and/or aberrant mitotic
activity.
Oral squamous cell carcinoma
Histopathology
 Grading is a somewhat subjective
process, depending on the area of the
tumor sampled and the individual
pathologist’s criteria for evaluation
 Moreover, clinical staging correlates
much better with the prognosis than
microscopic grading
 Broder’s system (1920) was first
established on the basis of the
proportion of highly differentiated cells in
the tumor
 poor predictor for survival or metastasis
Histopathological Grading of
OSCC
 1973, Jakobsson et al, developed a multifactorial
grading system which had the advantage of scoring
tumor–host interactions and tumor characteristics
 proved to be useful only when applied to tongue
cancers
 Later, Anneroth et al (1984) proposed a modification of
Jakobsson system based on the assessment of six
histomorphological parameters including degree of
keratinization, nuclear pleomorphism, pattern of
invasion, host response and mitotic activity
 Bryne et al (1989) modified Anneroth’s grading system
and developed a malignancy grading focusing on the
invasive front of the tumor
 less time consuming
 was not sufficiently homogeneous to allow grading
parameters to be assessed individually
Histopathology
Lip Carcinoma:
 well differentiated (classified as grade I
carcinoma)
 tends to metastasize late in the course of
the disease
Carcinoma of Maxillary Sinus:
 Although the antrum is lined by
respiratory epithelium, the great majority
of maxillary sinus carcinomas are
squamous cell carcinomas, usually
moderately or poorly differentiated
Treatment & Prognosis
 Clinical staging guides the treatment of
squamous cell carcinoma
 For intraoral squamous cell carcinoma, early-
stage lesions usually are treated with surgery
 definitive radiation therapy may be an
alternative for patients unable to tolerate
surgery
 Moderately advanced tumors typically are
treated with surgery followed by either
radiation therapy or concurrent
chemoradiation therapy
 Very advanced disease or cases in which
surgery would result in unacceptable
functional outcomes may be treated with
radiation therapy and/or chemotherapy
Treatment & Prognosis
 In addition to advanced stage, indications for
postoperative (adjuvant) radiation or
chemoradiation therapy in the treatment of
intraoral carcinoma may include close or positive
resection margins, high-grade histopathologic
features, extracapsular spread, and perineural or
angiolymphatic invasion
 Intensity-modulated radiation therapy (IMRT)
often is used to target the treatment area while
minimizing damage to neighboring tissue
 Brachytherapy (placement of tiny, radioactive
seeds) may be used for select applications (e.g.,
definitive treatment of small intraoral tumors or
as an adjunct with IMRT to deliver an additional
radiation dose)
Treatment & Prognosis
 intraoral carcinoma, cervical lymph
node involvement - 30% of cases and
occult (or subclinical) in about 10% to
40% of cases
 modified radical neck dissection
(similar to radical neck dissection but
with preservation of nonlymphatic
structures)
 selective neck dissection (removal
of only select cervical lymph node
Treatment & Prognosis
 depth of invasion - the distance from the
basement membrane to the deepest
portion of the tumor
 tumor thickness - the distance from the
tumor surface to the deepest portion of
the tumor
 sentinel-node biopsy - biopsy of the first
lymph node in the lymphatic basin to
receive drainage from the tumor
 significantly increased risk for nodal
metastasis with a depth of invasion or
tumor thickness greater than about 3 to 5
mm;
Treatment & Prognosis
 Chemotherapeutic agents
1. platinum-containing compounds (e.g.,
cisplatin and carboplatin),
2. 5-fluorouracil, and
3. taxanes (e.g., paclitaxel and docetaxel)
 Induction or neoadjuvant chemotherapy may
be administered initially to shrink a tumor
prior to additional therapy
 postoperative concurrent chemoradiation
therapy (especially incorporating cisplatin) for
optimal locoregional control and disease-free
survival
Treatment & Prognosis
 targeted therapies
1. monoclonal antibodies (e.g., cetuximab
and panitumumab)
2. small molecule tyrosine kinase inhibitors
(e.g., erlotinib) directed against
epidermal growth factor receptor (EGFR)
3. anti-vascular endothelial growth factor
(VEGF) antibodies
4. mammalian target of rapamycin (mTOR)
inhibitors
Treatment & Prognosis
oropharyngeal squamous cell
carcinoma
 either definitive radiation therapy or
surgery;
 advanced stage - multimodal therapy
involving various combinations of
surgery, radiation therapy, or
chemotherapy
Treatment & Prognosis
 in the United
States, the
estimated 5-year
relative survival
rate for oral and
pharyngeal
cancers combined
is approximately
64%
 The prognosis
varies considerably
by tumor stage and
subsite
Treatment & Prognosis
 Various molecular markers associated
with oral squamous cell carcinoma,
such as TP53 mutations, have shown
equivocal results as prognostic
indicators
 overexpression of survivin (a member
of the inhibitor of apoptosis protein
family) is associated with poor
prognosis
Treatment and Prognosis
Carcinoma of lip
 Carcinoma of the lip has been treated by either surgical
excision (typically a wedge resection) or X-ray radiation
with approximately equal success
 factors influencing the success or failure of treatment
1. The size of the lesion,
2. its duration,
3. the presence or absence of metastatic lymph nodes
4. the histologic grade of the lesion
 a notable exception is squamous cell carcinoma of the
upper lip vermilion (very rare), which exhibits a high risk
for regional lymph node metastasis (apparently related
to the extensive lymphatic network in this location)
Treatment and Prognosis
Carcinoma of Tongue
 The treatment of cancer of the tongue is
a difficult problem
 judicious combination of surgery and X-
ray will be of greatest benefit to the
patient
 The prognosis of cancer in this location
is not good
 The most significant factor affecting
prognosis of these patients is the
presence or absence of cervical
metastases
Treatment and Prognosis
Carcinoma of Floor of the mouth:
 difficult
 Frequently unsuccessful
 Even small tumors are apt to recur after
surgical excision
 X-ray radiation and the use of radium often
give far better results than surgery
 The problem is complicated, however, if there
is concomitant involvement of the mandible
 The prognosis for patients with carcinoma of
the floor of the mouth is fair
Treatment and Prognosis
Carcinoma of Gingiva:
 X-ray radiation – not indicated -
damaging effect of the X-rays on bone
 surgical
 The prognosis of cancer of the gingiva
is not particularly good
Treatment and Prognosis
Carcinoma of Buccal Mucosa:
 either surgery or X-ray radiation
 combined use of these two forms of
treatment
 The prognosis of this neoplasm depends
upon the presence or absence of
metastases
Carcinoma of Palate:
 Both surgery (hemimaxillectomy) and X-
ray radiation
 prognosis is not good
Variants of Squamous Cell
Carcinoma
Some of the variants of squamous cell
carcinoma are:
 Verrucous Carcinoma
 Spindle Cell Carcinoma
 Adenoid Squamous Cell Carcinoma
 Basaloid Squamous Cell Carcinoma
 Adenosquamous Carcinoma
VERRUCOUS CARCINOMA (SNUFF
DIPPER’S CANCER; ACKERMAN’S TUMOR)
 low-grade variant of oral squamous cell
carcinoma
 In 1948, Ackerman described this lesion in
detail
 might be associated with smokeless tobacco
use
 chronically use chewing tobacco or snuff
 combine habits (i.e., smokeless tobacco,
smoking, and alcohol), exclusively smoke
tobacco, or have no identifiable risk factors
 HPV types 6, 11, 16, and 18 - minority of oral
verrucous carcinomas
VERRUCOUS CARCINOMA (SNUFF
DIPPER’S CANCER; ACKERMAN’S TUMOR)
Clinical Features:
 predominantly in
men older than 55
years (average age:
65 to 70 years
 mandibular
vestibule, buccal
mucosa, gingiva,
tongue, and hard
palate
 involved area often
corresponds to the
site of chronic
tobacco placement
VERRUCOUS CARCINOMA (SNUFF
DIPPER’S CANCER; ACKERMAN’S TUMOR)
Clinical Features:
 diffuse, well-demarcated,
painless, thick plaque with
papillary or verruciform
surface projections
 typically white but also may
appear erythematous or
pink
 The color depends on the
amount of keratin produced
and the degree of host
inflammatory response to
the tumor
 May destroy underlying
structures
 Enlarged cervical lymph
nodes (inflammatory)
VERRUCOUS CARCINOMA (SNUFF
DIPPER’S CANCER; ACKERMAN’S TUMOR)
Clinical Features:
 Leukoplakia or tobacco pouch
keratosis may be seen on adjacent
mucosal surfaces, and verrucous
carcinoma is a lesion that may
develop from the high-risk precancer,
proliferative verrucous leukoplakia
(PVL)
Oral squamous cell carcinoma
VERRUCOUS CARCINOMA (SNUFF
DIPPER’S CANCER; ACKERMAN’S TUMOR)
Histopathology
 deceptively benign
microscopic
appearance
 wide and elongated
rete ridges that appear
to “push” into the
underlying connective
tissue
 abundant keratin
(usually parakeratin)
production
 papillary or verruciform
surface
VERRUCOUS CARCINOMA (SNUFF
DIPPER’S CANCER; ACKERMAN’S TUMOR)
Histopathology:
 Parakeratin typically fills
the depressions
(parakeratin clefts)
between the surface
projections
 projections - long and
pointed or short and
blunted
 The lesional epithelial cells
- no significant cytologic
atypia
 intense inflammatory cell
infiltrate in the subjacent
connective tissue
 The histopathologic
diagnosis - adequate
incisional biopsy
Oral squamous cell carcinoma
VERRUCOUS CARCINOMA (SNUFF
DIPPER’S CANCER; ACKERMAN’S TUMOR)
Treatment & Prognosis:
 surgical excision(not extensive)
 If cervical lymph node enlargement -
selective neck dissection
 Radiotherapy is an alternative primary
treatment
SPINDLE CELL CARCINOMA (SARCOMATOID SQUAMOUS CELL
CARCINOMA; POLYPOID SQUAMOUS CELL CARCINOMA;
CARCINOSARCOMA; PSEUDOSARCOMA)
 rare variant of squamous cell carcinoma
 dysplastic surface epithelium in conjunction with an
invasive spindle cell element
 it may be indistinguishable from connective tissue
sarcomas or other spindle cell malignancies in routine
light microscopy
 Spindle cell carcinoma of the upper aerodigestive tract
is closely associated with tobacco and alcohol use
 Some cases develop after radiotherapy for a more
differentiated squamous cell carcinoma, a phenomenon
known as dedifferentiation
 dysfunctional cadherin-catenin complex important for
intercellular adhesion causes the tumor cells to shift
from a squamous to a spindled type, with increased
infiltrative behavior
SPINDLE CELL CARCINOMA (SARCOMATOID SQUAMOUS CELL
CARCINOMA; POLYPOID SQUAMOUS CELL CARCINOMA;
CARCINOSARCOMA; PSEUDOSARCOMA)
Clinical Features:
 may arise anywhere within the upper
aerodigestive tract, with a predilection for
the larynx and oral cavity
 In the mouth, the alveolar mucosa,
tongue, buccal mucosa, and lower lip are
common sites
 Males
 the mean age at diagnosis is 57 years
(range: 29 to 93 years)
SPINDLE CELL CARCINOMA (SARCOMATOID SQUAMOUS CELL
CARCINOMA; POLYPOID SQUAMOUS CELL CARCINOMA;
CARCINOSARCOMA; PSEUDOSARCOMA)
Clinical Features:
 pedunculated, polypoid
mass, but occasionally it
may appear as a sessile,
nodular or fungating mass
 The surface often is
ulcerated
 Pain and paresthesia
 grows rapidly,
 tends to metastasize early
 Lower lip lesions seem to
have a special propensity
to travel along nerves
through the mental
foramen and into the
mandibular canal
SPINDLE CELL CARCINOMA (SARCOMATOID SQUAMOUS CELL
CARCINOMA; POLYPOID SQUAMOUS CELL CARCINOMA;
CARCINOSARCOMA; PSEUDOSARCOMA)
Histopathology:
 predominantly of
fascicles of anaplastic,
spindle-shaped cells
 Some spindle cells may
appear as obvious
epithelial elements, but
others strongly resemble
atypical mesenchymal
cells
 On rare occasions,
bone, cartilage, or
muscle differentiation
may be seen
 Numerous mitotic figures
SPINDLE CELL CARCINOMA (SARCOMATOID SQUAMOUS CELL
CARCINOMA; POLYPOID SQUAMOUS CELL CARCINOMA;
CARCINOSARCOMA; PSEUDOSARCOMA)
Histopathology:
 The squamous component - dysplasia or carcinoma in
situ of the overlying surface epithelium but may appear
as islands of atypical squamous epithelium among the
spindle cells
 Direct transition between the two cell types may be
seen
 Because of frequent surface ulceration, a neoplastic
surface component may be difficult to discern
 Metastatic lesions may show only spindle cells, only
squamous cells, or a combination of spindle and
squamous cells
 epithelial marker, such as cytokeratin, epithelial
membrane antigen (EMA), or p63
 vimentin
SPINDLE CELL CARCINOMA (SARCOMATOID SQUAMOUS CELL
CARCINOMA; POLYPOID SQUAMOUS CELL CARCINOMA;
CARCINOSARCOMA; PSEUDOSARCOMA)
Treatment and Prognosis:
 radical surgery, with neck dissection when
clinically positive nodes are present
 radiotherapy and chemotherapy are
ineffective
 The 5-year disease-free survival rate is
approximately 30% for oral lesions, with most
deaths occurring within 1 year of diagnosis
 Negative prognostic factors include
endophytic (rather than polypoid) growth and
an origin from a previously irradiated
carcinoma
ADENOID SQUAMOUS CELL CARCINOMA
(ADENOACANTHOMA, PSEUDOGLANDULAR
SQUAMOUS CELL CARCINOMA)
 A squamous cell carcinoma containing
pseudo glandular spaces or lumina is an
interesting tumor of the skin which also
occurs with considerable frequency on
the lips
 This variant is produced as a result of
acantholysis and degeneration within
islands of a squamous cell carcinoma
 The result is a
pseudoadenocarcinomatous
appearance, but there is no evidence of
glandular differentiation or of secretory
activity or products
ADENOID SQUAMOUS CELL CARCINOMA
(ADENOACANTHOMA, PSEUDOGLANDULAR
SQUAMOUS CELL CARCINOMA)
Clinical Features:
 50 years of age or older
 Men
 The lesions on the skin - simply
elevated nodules that may show
crusting, scaling or ulceration
 Sometimes there is an elevated or
rolled border to the lesion
ADENOID SQUAMOUS CELL CARCINOMA
(ADENOACANTHOMA, PSEUDOGLANDULAR
SQUAMOUS CELL CARCINOMA)
Histopathology:
 proliferation of surface dysplastic
epithelium into the connective tissue as
in the typical epidermoid carcinoma
 However, the lateral or deep extensions
of this epithelium show the characteristic
solid and tubular ductal structures which
typify the lesion
 These duct like structures are lined by a
layer of cuboidal cells and often contain
or enclose acantholytic or dyskeratotic
cells
ADENOID SQUAMOUS CELL CARCINOMA
(ADENOACANTHOMA, PSEUDOGLANDULAR
SQUAMOUS CELL CARCINOMA)
Treatment and Prognosis:
 surgical excision
 On only rare occasions does it
metastasize or cause death of the
patient
ADENOSQUAMOUS CARCINOMA
 rare squamous cell carcinoma variant
 characterized histopathologically by a
combination of adenocarcinoma and
squamous cell carcinoma
 The adenoid (glandular) pattern, which
includes mucus production, has been
demonstrated clearly in metastatic
deposits
 tobacco and alcohol use
 Transcriptionally active HPV
ADENOSQUAMOUS CARCINOMA
Clinical Features:
 tongue, oral floor, and other mucosal
surfaces
 older adults
 male predilection
 nodular, broad-based, variably painful
mass with orwithout surface ulceration
 cervical lymph node metastasis at
diagnosis
ADENOSQUAMOUS CARCINOMA
Histopathologic Features:
 admixture of a surface squamous cell
carcinoma and an underlying
adenocarcinoma
 The glandular component tends to be
most prominent in deeper portions of the
tumor
 Mucicarmine staining demonstrates
intracytoplasmic mucin in most cases
 Both squamous and glandular
components immunoreact with
antibodies directed against high
molecular–weight cytokeratins (KL1)
ADENOSQUAMOUS CARCINOMA
Treatment and Prognosis:
 Radical surgical excision, at times
supplemented with radiation or
chemoradiation therapy
 The prognosis is poor
BASALOID SQUAMOUS CARCINOMA
(BASALOID SQUAMOUS CELL
CARCINOMA)
 recently described squamous cell
carcinoma variant
 primarily in the upper aerodigestive tract,
with a predilection for the larynx,
hypopharynx, and tongue base
 Heavy tobacco and alcohol use
 HPV may play an important role in the
etiopathogenesis of a distinct subset of
oropharyngeal basaloid squamous cell
carcinomas—particularly those arising in
the palatine and lingual tonsils
BASALOID SQUAMOUS CARCINOMA
(BASALOID SQUAMOUS CELL
CARCINOMA)
Clinical Features:
 occur in persons 40 to 85 years of age
 arises more commonly in males than
females
 fungating mass or ulcer and may be
painful or interfere with swallowing
(dysphagia)
BASALOID SQUAMOUS CARCINOMA
(BASALOID SQUAMOUS CELL
CARCINOMA)Histopathologic Features:
 two microscopic components
 superficial, well differentiated or moderately differentiated squamous
cell carcinoma
 surface ulceration, multifocal origin, and areas of carcinoma in situ
 The second, deeper component is an invasive basaloid epithelium
arranged in islands, cords, and glandlike lobules
 palisading of peripheral cells, central necrosis, and occasional
squamous differentiation
 This component appears similar to basal cell carcinoma, adenoid
cystic carcinoma, basal cell adenocarcinoma, or neuroendocrine
carcinoma
 The interface between the two components is typically sharp and
distinct, but gradual transition from squamous to basaloid cells may
be seen occasionally
 The tumor islands often are surrounded by mucoid stroma (basal
lamina material)
 Microcystic spaces filled with PAS positive basal lamina material
may be interspersed among the tumor islands as well
Oral squamous cell carcinoma
BASALOID SQUAMOUS CARCINOMA
(BASALOID SQUAMOUS CELL
CARCINOMA)
Treatment and Prognosis:
 surgery, often followed by radiation or
chemoradiation therapy
 highly aggressive malignancy, with a
mean survival of only 23 months
Oral squamous cell carcinoma

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Oral squamous cell carcinoma

  • 1. MALIGNANT TUMORS OF THE EPITHELIAL TISSUE ORIGIN SQUAMOUS CELL CARCINOMA (Epidermoid carcinoma)
  • 2. Introduction Definition Squamous cell carcinoma is defined as “a malignant epithelial neoplasm exhibiting squamous differentiation as characterized by the formation of keratin and/or the presence of intercellular bridges” (Pindborg JJ et al, 1997)  most common malignant neoplasm of the oral cavity (more than 90%)
  • 3. Epidemiology  The incidence - ranges from approximately 2–10 per 100,000 population per year  differs widely in various parts of the world - basis of environmental differences or lifestyle and habits among certain populations, such as betel quid chewing, snuff dipping or the habit of reverse smoking  The incidence of oral carcinoma in blacks is somewhat lower than in whites  after the fourth decade  male-female ratio is approximately 2 : 1  Carcinoma of the vermilion border of the lower lip - strong male predominance
  • 4. Epidemiology South-East Asian scenario  In India, oral cancer, constituting 9.8% of an estimated 644,600 incident cancer cases in 1992, ranks first among all cancer cases in males  Third most common among females in many regions, with age standardized incidence rates  7–17/100,000 persons/ year; the incidence rate being higher than the western rate of 3– 4/100,000/ year  the mortality rate is lowest for lip cancer (0.04 per 100,000)  the mortality rate is highest for the tongue (0.7 per 100,000)
  • 5. Epidemiology  80% of oral cancers were preceded by oral precancerous lesions or conditions  Sometimes oral cancer arises from otherwise clinically normal mucosa
  • 6. Etiology  Multifactorial  No single causative agent or factor (carcinogen) has been clearly defined or accepted  more than a single factor is needed to produce such a malignancy (cocarcinogenesis)
  • 8. Etiology Tobacco Smoking  Tobacco smoke contains more than 70 carcinogens 1. nitrosamines, 2. arsenic, 3. benzo[a]pyrene, and 4. benzene  In addition, smoking produces free radicals and oxidants that promote the destruction and counteract the protective effects of endogenous antioxidants (such as, glutathione-S-transferase, glutathione reductase, and superoxide dismutase)
  • 9. Etiology Tobacco Smoking  Much indirect clinical evidence implicates tobacco smoking in the development of oral squamous cell carcinoma  The proportion of smokers (80%) among patients with oral carcinoma is about four times greater than that among the general population  For patients who quit smoking, the risk for developing oral cancer declines over time
  • 10. Etiology Tobacco Smoking  the pooled risk for oral cancer is approximately three times greater among smokers than non smokers  Moreover, the relative risk (smoker’s risk for oral cancer compared with that of a nonsmoker) is dose-dependent  The risk also increases the longer a person smokes  cigar or pipe smoking is associated with a similar or greater risk for oral cancer compared to cigarette smoking
  • 11. Etiology Tobacco Smoking  In India, bidi smoking is associated with an approximately threefold greater risk of oral cancer compared to cigarette smoking  The highest - practice of reverse smoking is popular, especially among women  In reverse smoking 50% of all oral malignancies are found on the hard
  • 12. Etiology Smokeless Tobacco  Smokeless tobacco use - risk for oral carcinoma by a factor ranging from less than two to as high as 26  lower risk associated with moist snuff and chewing tobacco and a higher risk associated with dry snuff  abnormal male-to-female ratio for oral carcinoma (>1.0 : 1.5) in geographic areas where the habit is more popular among women than among men.  approximately 50% of all oral cancers in smokeless tobacco users occur at the site where the tobacco is habitually placed
  • 13. Etiology Betel Quid (Paan)  combination of natural substances (i.e., areca palm nuts, betel leaf, slaked lime, and perhaps tobacco leaf ) chewed for their psychostimulating effects  The carcinogenicity of betel quid traditionally has been attributed to tobacco, although areca nut alone also appears to be carcinogenic  the lifetime risk of developing oral cancer is a remarkable 8%  also is associated with development of precancers, such as leukoplakia
  • 14. Etiology Alcohol  alcohol in combination with tobacco is a significant risk factor for oral cancer development  generally appears to be dose dependent and time-dependent  approximately one-third of male patients with oral cancer are heavy alcohol users  cirrhosis of the liver is found in at least 20% of male patients with oral cancer
  • 15. Etiology Alcohol  The exact role of alcohol in oral carcinogenesis is not well understood  Ethanol in alcoholic beverages is metabolized into acetaldehyde, which is a known carcinogen  In addition, carcinogenic impurities—such as, polycyclic aromatic hydrocarbons and nitrosamines—may be present in some alcoholic beverages  Moreover, alcohol may help solubilize other carcinogenic compounds and may increase the permeability of oral epithelium to these compounds  Nutritional deficiencies associated with heavy alcohol consumption also may be a contributory factor
  • 16. Etiology Occupational Exposures and Environmental Pollutants  increased oral cancer risk for workers in the wood products industry chronically exposed to certain chemicals, such as phenoxyacetic acids  In regions of Taiwan with a particularly high incidence of oral cancer, investigators have reported elevated levels of heavy metal pollutants (e.g., nickel, chromium, and arsenic) in farm soil and increased blood concentrations of some of these metals in affected patients
  • 17. Etiology Radiation  radiotherapy to the head and neck area increases the risk for later development of a new primary oral malignancy, either a carcinoma or sarcoma  dosedependent
  • 18. Etiology Vitamin/Mineral Deficiencies and Dietary Factors  Iron deficiency, especially the severe, chronic form known as the Plummer-Vinson or Paterson-Kelly syndrome is associated with an elevated risk for squamous cell carcinoma of the esophagus, oropharynx, and posterior mouth.  develop at an earlier age  Iron deficiency may cause impaired cell-mediated immunity  In addition, because the epithelium of the upper digestive tract has a relatively high turnover rate, rapid loss of iron-dependent enzymes may lead to degenerative changes, including mucosal atrophy and esophageal webs (intertwining fibrous bands of scar tissue), with heightened susceptibility to malignant transformation
  • 19. Etiology Vitamin/Mineral Deficiencies and Dietary Factors  Vitamin-A deficiency produces excessive keratinization of the skin and mucous membranes  this vitamin may help to prevent oral precancer and cancer
  • 20. Etiology Vitamin/Mineral Deficiencies and Dietary Factors  high intake of fruits and vegetables decreases the risk for numerous cancer types, including oral cancer  may be related to the protective effects of not only vitamin A but also various other substances (e.g., vitamins C and E, folate, flavonoids, fiber, lycopene, and phytosterols) present within plant foods  animal fats and processed or salted meat may increase the risk for oral cancer
  • 21. Etiology Bacteria  oral bacteria may interact with tobacco and alcohol  Ethanol is metabolized into thecarcinogen acetaldehyde by not only hepatocytes and oral epithelial cells but also bacteria  high levels of acetaldehyde production have been associated with certain Streptococcus species, Neisseria species, and other bacteria  Candida may contribute to acetaldehyde production
  • 22. Etiology Bacteria  Periodontal disease-causing bacteria may induce production of pro- inflammatory cytokines  may enhance cell proliferation and inhibit apoptosis, thereby producing a microenvironment favorable for carcinogenesis  tertiary syphilis has been associated with a fourfold increased risk for development of dorsal tongue carcinoma
  • 23. Etiology Candida  Hyperplastic candidiasis frequently is cited as an oral precancerous condition(also has been called candidal leukoplakia  However, the evidence for the promotion of oral carcinogenesis by Candida is largely circumstantial
  • 24. Etiology Oncogenic Viruses  Oncogenic (tumor producing) viruses may play a major role in a wide variety of cancers  Viral integration into the host’s genetic material may result in abnormal cell growth and proliferation  The oncogenic viruses may immortalize the host cell, thereby facilitating malignant transformation  play a role in the development of oral carcinoma - HPV and HIV
  • 25. Etiology Oncogenic Viruses  HPV actually is best known for its role in the development of cancers of the anogenital region (especially the uterine cervix but also the anus, vulva, vagina, and penis)  only a small subset of oral carcinomas has been attributed to HPV infection  The high-risk HPV types are most closely associated with dysplasia and squamous cell carcinoma  detection of HPV 16 in exfoliated oral epithelial cells is associated with a nearly fourfold increased risk for oral cancer and a more than fourteen fold increased risk for oropharyngeal cancer  the proportion of oral carcinomas caused by HPV infection appears to be small
  • 26. Etiology Oncogenic Viruses  The characteristic risk profile for patients with HPV positive head and neck squamous cell carcinoma 1. male predilection 2. 10 years younger among the HPV-positive group 3. affect individuals of higher socioeconomic status 4. more strongly associated with certain parameters of sexual behavior (e.g., increased number of lifetime sexual or oral sexual partners, early age at sexual debut) 5. Less likely to occur in patients with an extensive history of tobacco and alcohol history
  • 27. Etiology Immunosuppression  some malignancies of the upper aerodigestive tract  Persons with HIV infection and those who are undergoing immunosuppressive therapy for malignancy or organ transplantation are at increased risk for oral squamous cell carcinoma and other head and neck malignancies, especially when tobacco smoking and alcohol abuse are present
  • 28. Etiology Oncogenes and Tumor Suppressor Genes  The molecular basis of carcinogenesis involves an accumulation of mutations or epigenetic changes in two broad classes of genes: proto-oncogenes and tumor suppressor genes  Proto-oncogenes may be transformed into activated oncogenes by environmental agents (e.g., viruses, irradiation, and chemical carcinogens) or inherited changes  Activated oncogenes promote uncontrolled cell division and are involved in the initiation and progression of a wide variety of malignancies  Tumor suppressor genes, on the other hand, inhibit cell division and indirectly allow tumor production when they become inactivated or mutated  an accumulation of several genetic aberrations is necessary before the affected cell expresses a malignant phenotype
  • 29. Etiology Oncogenes and Tumor Suppressor Genes  Genetic aberrations commonly identified in oral squamous cell carcinomas include abnormalities of the ras, myc, and epidermal growth factor receptor (EGFR; also known as c-erbB1) oncogenes, and the TP53, pRb, p16, and E- cadherin tumor suppressor genes  Head and neck squamous cell carcinomas associated with tobacco and alcohol use often exhibit mutated TP53, pRb overexpression, and decreased p16 expression  In contrast, HPV-associated cases typically express wild-type TP53, low levels of pRb, and increased levels of p16
  • 30. Clinical Features  Mostly older men  minimal pain during the early growth phase  Oral squamous cell carcinoma has a varied clinical presentation, including the following: • Exophytic (mass-forming; fungating, papillary, and verruciform) • Endophytic (invasive, burrowing, and ulcerated) • Leukoplakic (white patch) • Erythroplakic (red patch) • Erythroleukoplakic (combined red-and-white patch)
  • 31. Clinical Features  The leukoplakic and erythroplakic examples are probably early cases that have not yet produced a mass or ulceration  clinical features are identical to those described for premalignant leukoplakia and erythroplakia
  • 32. Clinical Features  An exophytic lesion - surface that is irregular, fungating, papillary, or verruciform  color - normal to white or red (depending on the amount of keratin and vascularity)  surface is often ulcerated  feels hard (indurated) on palpation
  • 34. Clinical Features  endophytic growth pattern - central, depressed, irregularly shaped ulcer with a surrounding “rolled” border of pink, red, or white mucosa  The rolled border results from invasion of the tumor downward and laterally under adjacent epithelium  Perineural invasion may cause paresthesia  Destruction of underlying bone, when present, may be painful or completely painless
  • 35. Clinical Features D/D of endophytic growth pattern :  Traumatic granulomas,  deep fungal infections,  tuberculosis,  tertiary syphilis, and  oral lesions of Wegener granulomatosis or Crohn’s disease
  • 36. Radiological Features  Destruction of underlying bone appears on radiographs as a “moth-eaten” radiolucency with ill-defined or ragged margins (an appearance similar to osteomyelitis)
  • 37. Lip Vermillion Carcinoma  found in light skinned persons with chronic exposure to UV radiation from sunlight  Seventy percent of affected individuals have outdoor occupations  elderly men  usually is associated with actinic cheilosis  may arise at the site where the patient holds a cigarette, cigar, or pipe  Almost 90% of lesions are located on the lower lip
  • 38. Lip Vermillion Carcinoma Clinical Features  crusted, oozing, non tender, indurated ulceration  usually less than1 cm in greatest diameter  grows slowly  Metastasis is a late event; at diagnosis, fewer than 10% of patients have lymph node metastasis, usually in the submental region  Perineural invasion may result in extension of the tumor into the mandible through the mental foramen  patient neglect can result in considerable destruction of normal tissue
  • 40. Intraoral Carcinoma  the most common sites for intraoral carcinoma are the 1. tongue (usually the posterior lateral and ventral surfaces) 2. floor of mouth 3. gingiva, 4. Alveolar bone, 5. buccal mucosa, 6. labial mucosa, and 7. hard palate
  • 41. Carcinoma of Tongue  25 to 50% of all intraoral cancer  less common in women than in men  essentially a disease of the elderly, but it may occur in relatively young persons Etiology 1. Syphilis 2. Leukoplakia 3. poor oral hygiene 4. chronic trauma 5. alcohol and tobacco
  • 42. Carcinoma of Tongue Clinical Features  Painless masses or ulcers  lesion ultimately becomes painful, especially when it becomes secondarily infected  may begin as a superficially indurated ulcer with slightly raised borders  proceed either to develop a fungating, exophytic mass or to infiltrate the deep layers of the tongue, producing fixation and induration without much surface change  Mostly posterior lateral border  20% occur on anterior lateral or ventral surfaces, and  only 4% occur on the dorsum (syphilitic glossitis)
  • 43. Carcinoma of Tongue Clinical Features  Lesions near the base of the tongue are particularly insidious  asymptomatic until far advanced  presenting manifestations may be a sore throat and dysphagia  the lesions on the posterior portion of the tongue are usually of a higher grade of malignancy, metastasize earlier and offer a poorer prognosis, especially because of their inaccessibility for treatment  Metastases occur with great frequency in cases of tongue cancer
  • 45. Carcinoma of Floor of the Mouth  15% of all intraoral carcinomas  Average age – 57 years  Mostly men  most often associated with the development of a second primary malignancy  Floor of mouth carcinomas most often arise in the midline region near the frenum Etiology  preexisting leukoplakia or erythroplakia  Alcohol  Tobacco  Poor oral Hygiene
  • 46. Carcinoma of Floor of the Mouth Clinical Features  indurated ulcer of varying size  one side of the midline  may or may not be painful  more frequently in the anterior portion of the floor than in the posterior area  Early extension into adjacent tissues  may invade the deeper tissues and may even extend into the submaxillary and sublingual glands  limitation of motion of tongue, often induces a peculiar thickening or slurring of the speech  Metastases from the floor of the mouth are found most commonly in the submaxillary group of lymph nodes, and since the primary lesion frequently occurs near the midline where a lymphatic cross drainage exists, contralateral metastases are often present  Fortunately, distant metastases are rare
  • 48. Carcinoma of Gingiva Etiology  least associated with tobacco smoking  no more specific or defined  may speculate the possible role of chronic irritation Clinical Features:  usually painless  most frequently arise from keratinized, posterior mandibular mucosa  have the greatest predilection for females
  • 49. Carcinoma of Gingiva Clinical Features:  61 years – average age  mandibular gingiva > maxillary gingiva  initially as an area of ulceration which may be a purely erosive lesion or may exhibit an exophytic, granular or verrucous type of growth  have a special propensity to mimic common, benign inflammatory and reactive lesions, such as the pyogenic granuloma, gingivitis and periodontal disease  arises more commonly in edentulous areas  fixed gingiva is more frequently involved primarily than the free gingiva
  • 50. Carcinoma of Gingiva Clinical Features:  Often destroy the underlying bone and cause tooth mobility  Pathologic fracture sometimes occur  The lesion may go unrecognized until after tooth extraction, when it proliferates out of the socket to mimic the hyperplastic granulation tissue of an epulis granulomatosa  Cancers that develop in an edentulous area may “wrap around” a denture flange and superficially resemble inflammatory fibrous hyperplasia (epulis fissuratum)  Metastasis is a common sequela of gingival carcinoma  Cancer of the mandibular gingiva metastasizes more frequently than cancer of the maxillary gingiva
  • 52. Carcinoma of Alveolar Bone  alveolar carcinomas - usually painless  most frequently arise from posterior mandibular region  Sometimes as extension of gingival carcinoma  mimic common, benign inflammatory and reactive lesions  Tumors of the maxillary alveolar ridge may extend onto the hard palate
  • 54. Carcinoma of Buccal Mucosa  approximately 10 times more common in men than in women  occurs chiefly in elderly persons  average age at occurrence was 58 years Etiology  not better understood  use of chewing tobacco  habit of chewing betel nut  Leukoplakia - precursor
  • 55. Carcinoma of Buccal Mucosa Clinical Features:  more aggressive  recurrence – high  common site where betel quid use is prevalent  develop most frequently along or inferior to a line opposite the plane of occlusion  painful ulceration  induration and infiltration of deeper tissues are common  Sometimes - superficial and appear to be growing outward from the surface rather than invading the tissues - called exophytic or verrucous growths  Metastases - relatively high  The most common sites of metastases are the submaxillary lymph nodes
  • 56. Carcinoma of right buccal mucosa
  • 57. Carcinoma of the Palate  not a particularly common lesion  Less percentage of occurrence – approx 0.5% Clinical Features:  poorly defined, ulcerated, painful lesion on one side of the midline (tumors of accessory salivary gland origin, even the malignant lesions, are often not ulcerated, but are covered with an intact mucosa. This fact may be of some aid in helping to distinguish clinically between these two types of neoplasms)
  • 58. Carcinoma of the Palate Clinical Features:  frequently crosses the midline  may extend laterally to include the lingual gingiva or posteriorly to involve the tonsillar pillar or even the uvula  may invade into the bone or occasionally into the nasal cavity, while infiltrating lesions of the soft palate may extend into the nasopharynx  Metastases to regional lymph nodes – considerable percentage of cases
  • 60. Carcinoma of Retromolar Trigone  may spread to numerous adjacent structures, including the oropharynx, buccal mucosa, alveolar ridge, and pterygomandibular raphe  Invasion of the pterygomandibular raphe may lead to involvement of the skull base, masticator space, and floor of mouth
  • 61. Oropharyngeal Carcinoma  base of tongue, tonsillar region (i.e., tonsil, tonsillar fossa, and pillars), and posterior pharyngeal wall  the tonsillar region accounts for the majority (approximately 70% to 80%) of cases  Favored site for HPV-associated carcinomas  Oropharyngeal carcinomas - same basic clinical appearance as more anterior carcinomas  posterior location lesions often go unrecognized for long periods  persistent sore throat,  difficulty in swallowing (dysphagia),  pain on swallowing (odynophagia)  pain may be dull or sharp  frequently is referred to the ear
  • 63. Carcinoma of Maxillary Sinus  an exceedingly dangerous disease  Uncommon malignancy  unknown cause  squamous cell carcinomas of the paranasal sinuses have been associated only weakly with tobacco use  HPV may be an etiologic factor in some cases
  • 64. Carcinoma of Maxillary Sinus Clinical Features:  only 3% of all head and neck carcinomas  asymptomatic or mimic sinusitis for long periods  chronic unilateral nasal stuffiness or an ulceration or mass of the hard palate or alveolar bone  The tumor grows to fill the sinus  Perforate through the surrounding bone  more common in men  chiefly a disease of elderly persons
  • 65. Carcinoma of Maxillary Sinus Clinical and Radiographic Features  If the tumor perforates the lateral wall of the sinus, unilateral facial swelling and pain are usually present  With medial extension, nasal obstruction and hemorrhage are common  Superior extension results in displacement or protrusion of the eyeball  Approximately 9% to 14% of patients have cervical or submandibular lymph node metastasis at the time of diagnosis  Distant metastasis is uncommon until late in the progression of disease
  • 66. Carcinoma of Maxillary Sinus Clinical Features:  When the second division of the trigeminal nerve is involved, intense pain or paresthesia of the midface or maxilla may occur, perhaps simulating a toothache.  Adjacent teeth may become loose Radiographic Features:  Dental radiographs often reveal a “moth-eaten” destruction of the lamina dura and surrounding bone  A panoramic radiograph shows a cloudy sinus with destruction of its bony wall; however, the extent of the tumor is best visualized by CT or MRI
  • 68. Metastasis  Largely via the lymphatics to the ipsilateral cervical lymph nodes  A cervical lymph node that contains metastatic carcinoma is usually firm to stony hard, nontender, and enlarged  if the malignant cells have perforated the capsule of the node and invaded into surrounding tissues, then the node will feel “fixed,” or not easily movable  Extracapsular spread (extension of metastatic deposits outside of the lymph node capsule) is a microscopic feature associated with poor prognosis  Occasionally, contralateral or bilateral metastatic deposits, distant (“below the clavicles”) metastasis at diagnosis
  • 69. Metastasis  most common sites of distant metastasis are the lungs, liver, and bones, but any part of the body may be affected  Carcinoma of the lower lip and oral floor - submental nodes  posterior portions of the mouth - the superior jugular and digastric nodes  oropharyngeal carcinoma - jugulodigastric or retropharyngeal
  • 71. Multiple Carcinomas  Patients with one carcinoma of the mouth or throat are at increased risk for additional concurrent (synchronous) or, more commonly, later (metachronous) primary surface epithelial malignancies of the upper aerodigestive tract, stomach, lungs, and other sites  6% - 44%  male patients
  • 72. Multiple Carcinomas  This tendency - field cancerization - a process whereby exposure to carcinogens, such as tobacco and alcohol, creates a diffuse field of altered epithelial cells with increased potential for malignant transformation  Molecular analyses of various markers, including loss of heterozygosity (LOH), microsatellite alterations, TP53 tumor suppressor gene mutations, and X-chromosome inactivation, have identified genetic alterations shared between tumor tissue and adjacent clinically normal appearing tissue in one-third to one-half of cases examined  significant proportion of second primary tumors develop from the same preneoplastic precursor lesion or “field,” with the remaining cases representing tumors that develop independently  patches of clonal cells can progress to develop additional mutations and give rise to subclones in a process known as clonal divergence, which would account for the genetic heterogeneity typically seen among these tumors  Interestingly, field cancerization does not appear to be associated with malignancies attributed to HPV infection
  • 73. TNM Staging  Tumor size and the extent of metastatic spread are the best prognostic indicators for oral squamous cell carcinoma  Quantifying these clinical parameters is called staging  three basic clinical features: 1. T—Size of the primary tumor, in centimeters 2. N—Regional lymph node involvement 3. M—Distant metastasis  These three parameters are tallied together to determine the stage  the higher the stage, the worse the prognosis  But survival rates are similar for patients with stage I, II, and III disease  HPV status appears to be the most important prognostic factor for patients with oropharyngeal carcinoma
  • 76. Histopathology  Squamous cell carcinoma arises from dysplastic surface epithelium  invasive islands and cords of malignant squamous epithelial cells  At the earliest moment of invasion, the adjectives superficially invasive or microinvasive often are used  Invasion is represented by irregular extension of lesional epithelium through the basement membrane and into subepithelial connective tissue
  • 77. Histopathology  Individual squamous cells and sheets or islands of cells proliferate within the connective tissue, without attachment to the surface epithelium  The invading tumor destroys normal tissue and may extend deeply into underlying adipose tissue, muscle, or bone  Lesional cells may breach the perineurium that encases nerve bundles (perineural invasion) or may invade the lumina of veins or lymphatics (vascular invasion)  strong inflammatory or immune cell response to invading epithelium  necrosis may be present  may induce dense fibrosis (desmoplasia or scirrhous change) and the formation of new blood vessels (angiogenesis)
  • 79. Histopathology  The lesional cells - abundant eosinophilic cytoplasm with large, often darkly staining (hyperchromatic) nuclei  an increased nuclear-to-cytoplasmic ratio  Varying degrees of cellular and nuclear pleomorphism  keratin pearls (a round focus of concentrically layered, keratinized cells)  Individual cells also may undergo keratinization
  • 80. Histopathology  Histopathologic grading of squamous cell carcinoma is based upon the degree of resemblance to normal squamous epithelium and the amount of keratin production  Lesions are graded on a three-point (grades I to III) or a four-point (grades I to IV) scale  The less differentiated tumors receive the higher numerals  The histopathologic grade of a tumor is related somewhat to its biologic behavior
  • 81. Histopathology  Low-grade, grade I, or well- differentiated - a tumor that is mature enough to closely resemble its tissue of origin often grows at a slightly slower pace and metastasizes later in its course
  • 82. Histopathology  High-grade, grade III/IV, poorly differentiated, or anaplastic - a tumor with marked pleomorphism and little or no keratin production may be so immature that it becomes difficult to identify the tissue of origin. In such cases, immunohistochemical studies (e.g., for cytokeratins or p63) may be needed to support an epithelial origin. Such tumors often enlarge rapidly, metastasize early
  • 83. Histopathology  Grade II, Moderately differentiated - A tumor with a microscopic appearance somewhere between these two extremes
  • 85. Histopathology Oropharyngeal Carcinoma  For oropharyngeal squamous cell carcinoma, detection of transcriptionally active HPV infection is especially important in determining prognosis  HPV-positive oropharyngeal squamous cell carcinomas often are poorly differentiated and nonkeratinizing with basaloid cytologic features  The gold standard for determining whether a carcinoma likely was caused by HPV is high-risk HPV E6 and lE7 oncogene expression analysis by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR)  best suited for fresh frozen tissue  technically demanding  detection of p16 by immunohistochemistry is more widely available, is readily performed on formalin-fixed paraffin-embedded tissue, and is considered a highly sensitive (albeit not highly specific) surrogate for transcriptionally active, high-risk HPV infection in oropharyngeal carcinomas
  • 86. Histopathology  p16 immunoreactivity may be useful in directing the search for the primary tumor to the oropharynx  in situ hybridization (ISH) for HPV 16 exhibits strong agreement with  p16 immunohistochemistry  RNA ISH probes complementary to E6 and E7 mRNA allows for detection of transcriptionally active HPV in routinely processed tissue  liquid-phase hybridization assays for detection of HPV in cytologic preparations from head and neck squamous cell carcinomas
  • 87. Histopathology  p16 immunohistochemistry -oral squamous cell carcinomas - low positive predictive value for transcriptionally active HPV infection  not useful for prognostication  only limited data regarding qRT-PCR analysis of high-risk HPV E6 and E7 expression in oral squamous cell carcinoma, with no significant correlation with prognosis demonstrated thus far
  • 90. Histopathological Grading of OSCC  Classic microscopic histopathologic alterations observed with squamous cell carcinoma include: a. Enlarged nuclei as well as cell size b. Large and prominent nucleoli c. Increased nuclear/cytoplasmic ratio d. Hyperchromatic (dark staining) nuclei e. Dyskeratosis (premature keratinization of cells) f. Increased and/or aberrant mitotic activity.
  • 92. Histopathology  Grading is a somewhat subjective process, depending on the area of the tumor sampled and the individual pathologist’s criteria for evaluation  Moreover, clinical staging correlates much better with the prognosis than microscopic grading  Broder’s system (1920) was first established on the basis of the proportion of highly differentiated cells in the tumor  poor predictor for survival or metastasis
  • 93. Histopathological Grading of OSCC  1973, Jakobsson et al, developed a multifactorial grading system which had the advantage of scoring tumor–host interactions and tumor characteristics  proved to be useful only when applied to tongue cancers  Later, Anneroth et al (1984) proposed a modification of Jakobsson system based on the assessment of six histomorphological parameters including degree of keratinization, nuclear pleomorphism, pattern of invasion, host response and mitotic activity  Bryne et al (1989) modified Anneroth’s grading system and developed a malignancy grading focusing on the invasive front of the tumor  less time consuming  was not sufficiently homogeneous to allow grading parameters to be assessed individually
  • 94. Histopathology Lip Carcinoma:  well differentiated (classified as grade I carcinoma)  tends to metastasize late in the course of the disease Carcinoma of Maxillary Sinus:  Although the antrum is lined by respiratory epithelium, the great majority of maxillary sinus carcinomas are squamous cell carcinomas, usually moderately or poorly differentiated
  • 95. Treatment & Prognosis  Clinical staging guides the treatment of squamous cell carcinoma  For intraoral squamous cell carcinoma, early- stage lesions usually are treated with surgery  definitive radiation therapy may be an alternative for patients unable to tolerate surgery  Moderately advanced tumors typically are treated with surgery followed by either radiation therapy or concurrent chemoradiation therapy  Very advanced disease or cases in which surgery would result in unacceptable functional outcomes may be treated with radiation therapy and/or chemotherapy
  • 96. Treatment & Prognosis  In addition to advanced stage, indications for postoperative (adjuvant) radiation or chemoradiation therapy in the treatment of intraoral carcinoma may include close or positive resection margins, high-grade histopathologic features, extracapsular spread, and perineural or angiolymphatic invasion  Intensity-modulated radiation therapy (IMRT) often is used to target the treatment area while minimizing damage to neighboring tissue  Brachytherapy (placement of tiny, radioactive seeds) may be used for select applications (e.g., definitive treatment of small intraoral tumors or as an adjunct with IMRT to deliver an additional radiation dose)
  • 97. Treatment & Prognosis  intraoral carcinoma, cervical lymph node involvement - 30% of cases and occult (or subclinical) in about 10% to 40% of cases  modified radical neck dissection (similar to radical neck dissection but with preservation of nonlymphatic structures)  selective neck dissection (removal of only select cervical lymph node
  • 98. Treatment & Prognosis  depth of invasion - the distance from the basement membrane to the deepest portion of the tumor  tumor thickness - the distance from the tumor surface to the deepest portion of the tumor  sentinel-node biopsy - biopsy of the first lymph node in the lymphatic basin to receive drainage from the tumor  significantly increased risk for nodal metastasis with a depth of invasion or tumor thickness greater than about 3 to 5 mm;
  • 99. Treatment & Prognosis  Chemotherapeutic agents 1. platinum-containing compounds (e.g., cisplatin and carboplatin), 2. 5-fluorouracil, and 3. taxanes (e.g., paclitaxel and docetaxel)  Induction or neoadjuvant chemotherapy may be administered initially to shrink a tumor prior to additional therapy  postoperative concurrent chemoradiation therapy (especially incorporating cisplatin) for optimal locoregional control and disease-free survival
  • 100. Treatment & Prognosis  targeted therapies 1. monoclonal antibodies (e.g., cetuximab and panitumumab) 2. small molecule tyrosine kinase inhibitors (e.g., erlotinib) directed against epidermal growth factor receptor (EGFR) 3. anti-vascular endothelial growth factor (VEGF) antibodies 4. mammalian target of rapamycin (mTOR) inhibitors
  • 101. Treatment & Prognosis oropharyngeal squamous cell carcinoma  either definitive radiation therapy or surgery;  advanced stage - multimodal therapy involving various combinations of surgery, radiation therapy, or chemotherapy
  • 102. Treatment & Prognosis  in the United States, the estimated 5-year relative survival rate for oral and pharyngeal cancers combined is approximately 64%  The prognosis varies considerably by tumor stage and subsite
  • 103. Treatment & Prognosis  Various molecular markers associated with oral squamous cell carcinoma, such as TP53 mutations, have shown equivocal results as prognostic indicators  overexpression of survivin (a member of the inhibitor of apoptosis protein family) is associated with poor prognosis
  • 104. Treatment and Prognosis Carcinoma of lip  Carcinoma of the lip has been treated by either surgical excision (typically a wedge resection) or X-ray radiation with approximately equal success  factors influencing the success or failure of treatment 1. The size of the lesion, 2. its duration, 3. the presence or absence of metastatic lymph nodes 4. the histologic grade of the lesion  a notable exception is squamous cell carcinoma of the upper lip vermilion (very rare), which exhibits a high risk for regional lymph node metastasis (apparently related to the extensive lymphatic network in this location)
  • 105. Treatment and Prognosis Carcinoma of Tongue  The treatment of cancer of the tongue is a difficult problem  judicious combination of surgery and X- ray will be of greatest benefit to the patient  The prognosis of cancer in this location is not good  The most significant factor affecting prognosis of these patients is the presence or absence of cervical metastases
  • 106. Treatment and Prognosis Carcinoma of Floor of the mouth:  difficult  Frequently unsuccessful  Even small tumors are apt to recur after surgical excision  X-ray radiation and the use of radium often give far better results than surgery  The problem is complicated, however, if there is concomitant involvement of the mandible  The prognosis for patients with carcinoma of the floor of the mouth is fair
  • 107. Treatment and Prognosis Carcinoma of Gingiva:  X-ray radiation – not indicated - damaging effect of the X-rays on bone  surgical  The prognosis of cancer of the gingiva is not particularly good
  • 108. Treatment and Prognosis Carcinoma of Buccal Mucosa:  either surgery or X-ray radiation  combined use of these two forms of treatment  The prognosis of this neoplasm depends upon the presence or absence of metastases Carcinoma of Palate:  Both surgery (hemimaxillectomy) and X- ray radiation  prognosis is not good
  • 109. Variants of Squamous Cell Carcinoma Some of the variants of squamous cell carcinoma are:  Verrucous Carcinoma  Spindle Cell Carcinoma  Adenoid Squamous Cell Carcinoma  Basaloid Squamous Cell Carcinoma  Adenosquamous Carcinoma
  • 110. VERRUCOUS CARCINOMA (SNUFF DIPPER’S CANCER; ACKERMAN’S TUMOR)  low-grade variant of oral squamous cell carcinoma  In 1948, Ackerman described this lesion in detail  might be associated with smokeless tobacco use  chronically use chewing tobacco or snuff  combine habits (i.e., smokeless tobacco, smoking, and alcohol), exclusively smoke tobacco, or have no identifiable risk factors  HPV types 6, 11, 16, and 18 - minority of oral verrucous carcinomas
  • 111. VERRUCOUS CARCINOMA (SNUFF DIPPER’S CANCER; ACKERMAN’S TUMOR) Clinical Features:  predominantly in men older than 55 years (average age: 65 to 70 years  mandibular vestibule, buccal mucosa, gingiva, tongue, and hard palate  involved area often corresponds to the site of chronic tobacco placement
  • 112. VERRUCOUS CARCINOMA (SNUFF DIPPER’S CANCER; ACKERMAN’S TUMOR) Clinical Features:  diffuse, well-demarcated, painless, thick plaque with papillary or verruciform surface projections  typically white but also may appear erythematous or pink  The color depends on the amount of keratin produced and the degree of host inflammatory response to the tumor  May destroy underlying structures  Enlarged cervical lymph nodes (inflammatory)
  • 113. VERRUCOUS CARCINOMA (SNUFF DIPPER’S CANCER; ACKERMAN’S TUMOR) Clinical Features:  Leukoplakia or tobacco pouch keratosis may be seen on adjacent mucosal surfaces, and verrucous carcinoma is a lesion that may develop from the high-risk precancer, proliferative verrucous leukoplakia (PVL)
  • 115. VERRUCOUS CARCINOMA (SNUFF DIPPER’S CANCER; ACKERMAN’S TUMOR) Histopathology  deceptively benign microscopic appearance  wide and elongated rete ridges that appear to “push” into the underlying connective tissue  abundant keratin (usually parakeratin) production  papillary or verruciform surface
  • 116. VERRUCOUS CARCINOMA (SNUFF DIPPER’S CANCER; ACKERMAN’S TUMOR) Histopathology:  Parakeratin typically fills the depressions (parakeratin clefts) between the surface projections  projections - long and pointed or short and blunted  The lesional epithelial cells - no significant cytologic atypia  intense inflammatory cell infiltrate in the subjacent connective tissue  The histopathologic diagnosis - adequate incisional biopsy
  • 118. VERRUCOUS CARCINOMA (SNUFF DIPPER’S CANCER; ACKERMAN’S TUMOR) Treatment & Prognosis:  surgical excision(not extensive)  If cervical lymph node enlargement - selective neck dissection  Radiotherapy is an alternative primary treatment
  • 119. SPINDLE CELL CARCINOMA (SARCOMATOID SQUAMOUS CELL CARCINOMA; POLYPOID SQUAMOUS CELL CARCINOMA; CARCINOSARCOMA; PSEUDOSARCOMA)  rare variant of squamous cell carcinoma  dysplastic surface epithelium in conjunction with an invasive spindle cell element  it may be indistinguishable from connective tissue sarcomas or other spindle cell malignancies in routine light microscopy  Spindle cell carcinoma of the upper aerodigestive tract is closely associated with tobacco and alcohol use  Some cases develop after radiotherapy for a more differentiated squamous cell carcinoma, a phenomenon known as dedifferentiation  dysfunctional cadherin-catenin complex important for intercellular adhesion causes the tumor cells to shift from a squamous to a spindled type, with increased infiltrative behavior
  • 120. SPINDLE CELL CARCINOMA (SARCOMATOID SQUAMOUS CELL CARCINOMA; POLYPOID SQUAMOUS CELL CARCINOMA; CARCINOSARCOMA; PSEUDOSARCOMA) Clinical Features:  may arise anywhere within the upper aerodigestive tract, with a predilection for the larynx and oral cavity  In the mouth, the alveolar mucosa, tongue, buccal mucosa, and lower lip are common sites  Males  the mean age at diagnosis is 57 years (range: 29 to 93 years)
  • 121. SPINDLE CELL CARCINOMA (SARCOMATOID SQUAMOUS CELL CARCINOMA; POLYPOID SQUAMOUS CELL CARCINOMA; CARCINOSARCOMA; PSEUDOSARCOMA) Clinical Features:  pedunculated, polypoid mass, but occasionally it may appear as a sessile, nodular or fungating mass  The surface often is ulcerated  Pain and paresthesia  grows rapidly,  tends to metastasize early  Lower lip lesions seem to have a special propensity to travel along nerves through the mental foramen and into the mandibular canal
  • 122. SPINDLE CELL CARCINOMA (SARCOMATOID SQUAMOUS CELL CARCINOMA; POLYPOID SQUAMOUS CELL CARCINOMA; CARCINOSARCOMA; PSEUDOSARCOMA) Histopathology:  predominantly of fascicles of anaplastic, spindle-shaped cells  Some spindle cells may appear as obvious epithelial elements, but others strongly resemble atypical mesenchymal cells  On rare occasions, bone, cartilage, or muscle differentiation may be seen  Numerous mitotic figures
  • 123. SPINDLE CELL CARCINOMA (SARCOMATOID SQUAMOUS CELL CARCINOMA; POLYPOID SQUAMOUS CELL CARCINOMA; CARCINOSARCOMA; PSEUDOSARCOMA) Histopathology:  The squamous component - dysplasia or carcinoma in situ of the overlying surface epithelium but may appear as islands of atypical squamous epithelium among the spindle cells  Direct transition between the two cell types may be seen  Because of frequent surface ulceration, a neoplastic surface component may be difficult to discern  Metastatic lesions may show only spindle cells, only squamous cells, or a combination of spindle and squamous cells  epithelial marker, such as cytokeratin, epithelial membrane antigen (EMA), or p63  vimentin
  • 124. SPINDLE CELL CARCINOMA (SARCOMATOID SQUAMOUS CELL CARCINOMA; POLYPOID SQUAMOUS CELL CARCINOMA; CARCINOSARCOMA; PSEUDOSARCOMA) Treatment and Prognosis:  radical surgery, with neck dissection when clinically positive nodes are present  radiotherapy and chemotherapy are ineffective  The 5-year disease-free survival rate is approximately 30% for oral lesions, with most deaths occurring within 1 year of diagnosis  Negative prognostic factors include endophytic (rather than polypoid) growth and an origin from a previously irradiated carcinoma
  • 125. ADENOID SQUAMOUS CELL CARCINOMA (ADENOACANTHOMA, PSEUDOGLANDULAR SQUAMOUS CELL CARCINOMA)  A squamous cell carcinoma containing pseudo glandular spaces or lumina is an interesting tumor of the skin which also occurs with considerable frequency on the lips  This variant is produced as a result of acantholysis and degeneration within islands of a squamous cell carcinoma  The result is a pseudoadenocarcinomatous appearance, but there is no evidence of glandular differentiation or of secretory activity or products
  • 126. ADENOID SQUAMOUS CELL CARCINOMA (ADENOACANTHOMA, PSEUDOGLANDULAR SQUAMOUS CELL CARCINOMA) Clinical Features:  50 years of age or older  Men  The lesions on the skin - simply elevated nodules that may show crusting, scaling or ulceration  Sometimes there is an elevated or rolled border to the lesion
  • 127. ADENOID SQUAMOUS CELL CARCINOMA (ADENOACANTHOMA, PSEUDOGLANDULAR SQUAMOUS CELL CARCINOMA) Histopathology:  proliferation of surface dysplastic epithelium into the connective tissue as in the typical epidermoid carcinoma  However, the lateral or deep extensions of this epithelium show the characteristic solid and tubular ductal structures which typify the lesion  These duct like structures are lined by a layer of cuboidal cells and often contain or enclose acantholytic or dyskeratotic cells
  • 128. ADENOID SQUAMOUS CELL CARCINOMA (ADENOACANTHOMA, PSEUDOGLANDULAR SQUAMOUS CELL CARCINOMA) Treatment and Prognosis:  surgical excision  On only rare occasions does it metastasize or cause death of the patient
  • 129. ADENOSQUAMOUS CARCINOMA  rare squamous cell carcinoma variant  characterized histopathologically by a combination of adenocarcinoma and squamous cell carcinoma  The adenoid (glandular) pattern, which includes mucus production, has been demonstrated clearly in metastatic deposits  tobacco and alcohol use  Transcriptionally active HPV
  • 130. ADENOSQUAMOUS CARCINOMA Clinical Features:  tongue, oral floor, and other mucosal surfaces  older adults  male predilection  nodular, broad-based, variably painful mass with orwithout surface ulceration  cervical lymph node metastasis at diagnosis
  • 131. ADENOSQUAMOUS CARCINOMA Histopathologic Features:  admixture of a surface squamous cell carcinoma and an underlying adenocarcinoma  The glandular component tends to be most prominent in deeper portions of the tumor  Mucicarmine staining demonstrates intracytoplasmic mucin in most cases  Both squamous and glandular components immunoreact with antibodies directed against high molecular–weight cytokeratins (KL1)
  • 132. ADENOSQUAMOUS CARCINOMA Treatment and Prognosis:  Radical surgical excision, at times supplemented with radiation or chemoradiation therapy  The prognosis is poor
  • 133. BASALOID SQUAMOUS CARCINOMA (BASALOID SQUAMOUS CELL CARCINOMA)  recently described squamous cell carcinoma variant  primarily in the upper aerodigestive tract, with a predilection for the larynx, hypopharynx, and tongue base  Heavy tobacco and alcohol use  HPV may play an important role in the etiopathogenesis of a distinct subset of oropharyngeal basaloid squamous cell carcinomas—particularly those arising in the palatine and lingual tonsils
  • 134. BASALOID SQUAMOUS CARCINOMA (BASALOID SQUAMOUS CELL CARCINOMA) Clinical Features:  occur in persons 40 to 85 years of age  arises more commonly in males than females  fungating mass or ulcer and may be painful or interfere with swallowing (dysphagia)
  • 135. BASALOID SQUAMOUS CARCINOMA (BASALOID SQUAMOUS CELL CARCINOMA)Histopathologic Features:  two microscopic components  superficial, well differentiated or moderately differentiated squamous cell carcinoma  surface ulceration, multifocal origin, and areas of carcinoma in situ  The second, deeper component is an invasive basaloid epithelium arranged in islands, cords, and glandlike lobules  palisading of peripheral cells, central necrosis, and occasional squamous differentiation  This component appears similar to basal cell carcinoma, adenoid cystic carcinoma, basal cell adenocarcinoma, or neuroendocrine carcinoma  The interface between the two components is typically sharp and distinct, but gradual transition from squamous to basaloid cells may be seen occasionally  The tumor islands often are surrounded by mucoid stroma (basal lamina material)  Microcystic spaces filled with PAS positive basal lamina material may be interspersed among the tumor islands as well
  • 137. BASALOID SQUAMOUS CARCINOMA (BASALOID SQUAMOUS CELL CARCINOMA) Treatment and Prognosis:  surgery, often followed by radiation or chemoradiation therapy  highly aggressive malignancy, with a mean survival of only 23 months