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
33.
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
39.
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
44.
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
47.
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
51.
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
53.
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
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
59.
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
62.
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
67.
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
70.
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
74.
75.
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)
78.
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
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
88.
89.
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.
91.
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
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)
114.
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
117.
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
136.
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