ALL Oral Epithelial Tumors I and II and III (Slide 7+8+9)

Dent 355 Oral Epithelial Tumors, Melanocytic Nevi, and Melanoma I
HPV-Associated Lesions Squamous Cell Carcinoma Premalignant Lesions and Conditions Basal Cell Carcinoma Melanocytic Nevi and Melanoma
Dr. Rima Safadi
Human Papilloma Virus-Associated Lesions

HPV: DNA virus of >75 types. At least 16 types isolated from oral lesions. Associated with a number of benign lesions of skin and mucosa. Role in leukoplakia and SSC? May be present in normal epithelium.
Human Papilloma Virus-Associated Lesions: Squamous Cell Papilloma

Common benign tumor of oral
mucosa.
Most occur in adults. Variable size, may be sessile or
pedunculated.
Presents as a warty or
cauliflower-like growth with a
white or pink surface.

No reports of malignant
transformation, treated by conservative excision.
Squamous Papilloma

Histopathologic Features:
Finger-like epithelial
proliferation supported by thin fibrovascular cores.

Variable keratosis.
Mitotic figures in basal
layer, no dysplasia.
Fibrovascular core
keratin
Human Papilloma Virus-Associated Lesions: Verruca Vulgaris (Common Wart)

Similar clinically to squamous papilloma;
sessile or pedunculated.
May be single or multiple. White due to hyperkeratosis. Common on fingers in children. Autoinoculation from fingers to lips.
Treated by surgical excision, cryosurgery or
chemical cautery. HPV types 2 or 4.
Human Papilloma Virus-Associated Lesions: Verruca Vulgaris (Common Wart)

Papillary finger-like epithelial
proliferation supported by thin fibrovascular cores. Acanthosis and hyperkeratosis.

Hyperplastic rete ridges
around margins slope inwards towards center. Large vacuolated cells (koilocytes) with prominent keratohyalin granules.
Verruca Vulgaris
Human Papilloma Virus-Associatedlesions: Condyloma Acuminatum (Venereal Wart)

Occur in the anogenital
area, may be seen intraorally.
Multiple pink nodules
which grow and coalesce to form soft, pink, pedunculated or sessile papillary lesions.
manifestations of HIV infection.
One of the oral
HPV types 6, 11, and 16.
Condyloma Acuminatum
Human Papilloma Virus-Associated Lesions: Condyloma Acuminatum

Prominent acanthosis with
marked broadening and elongation of rete ridges.

Koilocytosis.
Keratinization is not a
prominent feature.
Focal epithelial hyperplasia

Multiple small elevated epithelial plaques Lower lip and buccal mucosa Hyperkeratosis and acanthosis
HPV 13, 32
Squamous Cell Carcinoma: Epidemiology

Accounts for 90% of all oral malignancies. Variable incidence worldwide: - Oral cancer: UK & USA: < 4% of all cancers. - Oral Cancer: India & SE Asia: up to 40% of all
cancers. Regional and ethnic variation in large countries.

Oral Cancer:
4th commonest cancer in men and 6th in women on a global basis, 6th for both combined.
8th in
incidence in developed, but 3rd in developing countries.

Incidence in developed countries is on the
increase despite previous decrease in incidence and mortality rates.

Most cases occur above age 40 years, but age of affected patients is declining. More common in men than in women but ratio is changing.

Geographical variations in oral sites particularly at
risk reflect different etiological factors.

Tongue in UK while buccal mucosa in India
Geographical variation in mortality rates: 30-40% in Western societies. Despite advances in treatment, mortality rates have not significantly changed. 5-year survival rates have increased significantly.
Squamous Cell Carcinoma: Etiological Factors, Tobacco

Main carcinogenic agents in tobacco, regardless of how
it is used are nitrosamines derived from nicotine.

Tobacco smoke also has polycyclic aromatic
hydrocarbons.
Carcinogens in tobacco smoke may dissolve in saliva
and collect in areas where saliva tends to pool, increasing risk in FOM, dorsal and ventral tongue, and soft palate.
Etiological Factors, Tobacco

Risk factor is: number of cigarettes per day
Type of tobacco, curing and method influence
the relative risk.

Pipe and cigar lip cancer
Reverse smaoking palate cancer Relative risk of reverse smokers is 40 times more than non smokers Regular smokers: FOM, tongue, soft palate

Tobacco and alcohol are
the two most important
factors.
Evidence linking tobacco to
oral cancer is firmly established regardless of its type.

Heavy smokers (40+
cigarettes/day) are at 1020 times increased risk.

Smokeless tobacco:
snuff dipping, tobacco sachets, tobacco chewing.
Squamous Cell Carcinoma:

Etiological Factors, Betel Quid & Other Chewing Habits
Betel quid (pan), chewing habits, areca nut (submucous fibrosis).

Leukoplakia where the pan is
held Development of papilliferous and ulcerated mass Possible interactions between components of pans
Chewing Habits
In India: Betel nut and lime and tobacco in betel leaf:
Alkaloids are released from the nut
Alkaloids are carcinogenic
In Malysia: without tobacco

Tobacco increase the risk when placed in the pan
Areca nut chewing: increase the risk of submucous fibrosis
Squamous Cell Carcinoma: Etiological Factors, Alcohol

All Forms of Alcohol consumption are DANGEROUS Second major factor. Dose/time relationship. Pure ethanol has not been shown to be carcinongenic, but
other chemicals in the beverage, congeners, may be responsible for increased cancer risk.
Increasing incidence of oral cancer, especially in younger
groups, may be linked to increased alcohol consumption.

Close association with tobacco since most heavy drinkers are
heavy smokers, too. Synergistic effect
Mechanism of Alcohol
Possible carcinogenic effect of chemicals other than ethanol Alcohol may enhance transport of carcinogens across mucosal
barrier. Nutritional deficiencies in alcoholism may impair mucosal barrier function.

Alcohol and tobacco usage have been associated with mucosal
atrophy.
Chronic alcohol intake may impair ability of liver to detoxify
carcinogens, and can suppress immune responses needed to fight cancer.

Concerns about high alcohol
content in some mouthwashes?
Squamous Cell Carcinoma: Etiological Factors, Diet and Nutrition

Increased risk for
esophageal, pharyngeal, and oral cancer in primary sideropenic anemia (Plummer-Vinson or Patterson-Kelly syndrome).
Iron defeciency lichen planus and
Epithelial atrophy:
tertiary syphilis
Render mucosa more susceptible to carcinogens.

Etiological Factors, Diet and Nutrition
Vitamin A is also important in
maintenance of oral epithelium.

A diet high in the antioxidant vitamins A, C,
& E is believed to lower the risk of oral cancer.
Squamous Cell Carcinoma: Etiological Factors, Dental Factors

Poor oral hygiene, faulty restorations, sharp edges of
teeth, and ill-fitting dentures have been incriminated in etiology of oral cancer
Some oral cancer patients have poor dentitions but they also smoke and drink heavily. Mechanical irritation can act as a cancer promoter, but not initiator in experiments.
Squamous Cell Carcinoma: Etiological Factors, Occupational Risks

High exposure to UV light
is important in SCC of skin, including lips.

Lip cancer is more
common in lower lip in fairskinned males with outdoor occupations.

SCC of the lip may be
preceded by solar keratosis (actinic cheilitis).
Squamous Cell Carcinoma: Etiological Factors, Viruses

HSV can be carcinogenic or co carcinogenic in laboratory
experiments. It only rarely produce tumors
HPV HPV types 16 & 18 important factors in SCC of uterine cervix.

Evidence for role of HPV in some oral premalignant and
malignant lesions increasing. detected in normal mucosa.
HPV 16 is the most common isolate, but it has also been
Some HPV proteins : inactivation of tumor-suppressor genes p53 and Rb. significant step in development of oral cancer. HPV is likely to be an important cofactor in at least some oral cancers.

EBV is important in development of some nasopharyngeal carcinomas and lymphomas, but a similar role in oral cancer has not been established. EBV is probably an incidental passenger virus found in some lesions.
Squamous Cell Carcinoma: Etiological Factors, Immunosuppression

Increased risk of lip cancer Smoking, alcohol, and iron
reported following renal and other transplants linked to immunosuppressive therapy.

Increased incidence of oral
deficiency may impair cellmediated immunity, but significance of this role is not established.
cancer with AIDS.

Inconclusive evidence of
increased risk in HIV-positive patients.
Squamous Cell Carcinoma: Etiological Factors, Chronic Infections

Chronic candidal infection associated
with some speckled leukoplakias, and chronic hyperplastic candidosis (candidal leukoplakia) have relatively high malignant transportation rates.
However, other chronic oral candidal
infections are not associated with malignant transformation.

Role of candida therefore is uncertain.

Etiological Factors, Chronic Infections
Historically, tertiary syphilis has been
linked to oral cancer, especially anterior 2/3rds of dorsal tongue.

Epithelial atrophy in late stages may
render mucosa more susceptible to carcinogens.

Syphilitic leukoplakia may precede
invasive carcinoma.
However, late stage syphilis is rare
now.
Squamous Cell Carcinoma: Etiological Factors Summary

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
Tobacco smoking: pipes, cigars, cigarettes, bidis, reverse smoking. Smokeless tobacco: snuff dipping, tobacco sachets, tobacco chewing. Betel chewing, betel quid, areca nut. alcohol: spirits, wines and beers, alcohol and tobacco synergism. Diet and nutrition: iron deficiency, vitamins A & C, nutritional deficiencies & alcoholism. Dental factors. Ultraviolet light. Viruses: HSV, HPV, HIV. Immunosuppression. Chronic infections: candidosis, syphilis. Occupation.
Oncogenes and Tumor-Suppressor Genes

Cellular proliferation: 1. growth-promoting proto-oncogenes 2. growth inhibitory tumor-suppressor genes.
Oral cancer has a multifactorial etiology and is the result of
damage to these genes allowing uncontrolled cellular proliferation.

Carcinogenesis is a multistep process
multiple sequential mutations which accumulate within the
cell.
Model for genetic progression

The development of oral cancer involves progressive
accumulation of genetic changes:
Model for genetic progression based on loss of heterozygosity (LOH):

( loss of genetic material from specific locations on chromosomes) 1. normal mucosa, LOH at 9p: predysplastic 2. predysp, additional loss LOH at 3p, 17p: dysplasia 3. dysplasia:- additional LOHat 13q, 11q, 14q: carcinoma in situ (CIS) 4. CIS: LOH at p, 8, 4q: invasion
During carcinogenesis: a. proto-oncogenes may undergo mutation and become activated oncogenes, or: b. tumor suppressor genes may be mutated and their products inactivated.
The result in both cases leads to deregulation of cell proliferation and tumor formation.

Overexpression and mutations of the oncogenes c-
myc, ras, and erb B-1 has been reported in oral SCC.

Abnormalities in the tumor-suppressor gene p53 are
involved in many human cancers, including oral cancer.

The p53 is essential for normal cell growth and division since
its product blocks the cell cycle in the G1 phase.
Squamous Cell Carcinoma: Clinical Presentation
Clinical presentation of oral SCC
can take many forms.
Early diagnosis is the most important factor
influencing prognosis.
Clinicians must be suspicious of any lesion
for which no cause can be found or which does not respond as expected when putative causes are eliminated.
Squamous Cell Carcinoma: Clinical Presentation, Early Lesions

Early lesions are usually
asymptomatic.
Many forms of
presentation, most commonly: 1. White patch. 2. Small exophytic growth which in early stages shows no ulceration or erythema

3. Small indolent ulcer. 4. Erythroplakia.
Squamous cell cracinoma
Squamous cell carcinoma

Suspicious clinical features 1. 2. 3. 4. 5.
6.
for early carcinoma: Persistent ulceration. Induration. Fixation to underlying structures. Destruction of underlying bone in alveolar ridge lesions. Enlarged reactive regional lymph nodes. Carcinoma of vermilion border of lip: slightly raised swelling, or crusty, lesion resembling delayed healing of herpes labialis.
Squamous Cell Carcinoma: Clinical Presentation, Advanced Lesions

Advanced lesions may
present as:
1. Broad-based, exophytic mass with rough, nodular, warty, hemorrhagic, or necrotic surface.

2. Deeply destructive, craterlike ulcer with raised, rolled everted edges.

3. Infiltration of musculature may result in functional disturbances including impaired speech and difficult swallowing. 4. Pain may be a feature.

5. Radiographic evidence of bone destruction. 6. Mobility of teeth. 7. Altered sensation over distribution of mental nerve. 8. Pathologic fracture of mandible.

9. Metastatic spread to regional lymph nodes.
Size of surface lesion
does not indicate extent of underlying invasion.
Squamous Cell Carcinoma: Pathology

Considerable variation. Invasion and destruction of local tissues accounts for induration and fixation detected clinically. Cytologically malignant squamous epithelium with variable degrees of differentiation. Keratinization varies with degree
of differentiation.

Well-differentiated tumors:
- Obvious squamous differentiation. - Masses of prickle cells with limiting layer of basal cells around them. - Recognizable intercellular bridges. - Central keratin pearl formation. - Nuclear and cellular pleomorphism is not prominnemt. - Relatively few mitotic figures.

Moderately differentiated
tumors: - Less keratinization. - More pleomorphism of cells and nuclei. - Abundant and atypical mitotic figures. - Still readily identified as squamous type.

Poorly differentiated tumors:
- Keratinization usually absent. - Marked atypical features. - Cells may be hardly recognizable as epithelial. - The need for immunohistochemistry - Subjectivity and overlap in grading.
Poorly differentiated SCC stained for cytokeratin
Brown stain: epithelial cells positive for cytokeratin
In general:
- variable lymphocytic and plasma cell infiltration in supporting stroma, probably an immune reaction to tumor antigens, necrosis and ulceration.
Pattern of infiltration affects prognosis: Cohesive invasive fronts: Broad front of
invasion:
Better prognosis
Non- Cohesive:
Separate islands Individual malignant cells
Different patterns of invasion immunostaiuned for Cytokeratins

Variable pattern of local
infiltration and destruction: - lymphatic permeation - Vascular invasion - Sarcolemmal spread - perineural spread - bone invasion, edentulous/dentate.
- Through alveolar crest - Through PDL - Extent of bone invasion may
be greater than that seen on radiographs

Metastatic spread to regional lymph nodes: Intracapsular extracapsular surrounding tissue - Fixation seen clinically. - Has adverse effect on prognosis - Distant mets increases with increased involvement of LN Late blood-borne metastasis.
Squamous Cell Carcinoma: Verrucous Carcinoma

A variety of low-grade SCC. thick white warty plaque of
heaped up folds of tissue with deep cleft-like spaces in between.

prognosis is good.
Some cases transform into
a regular SCC with metastasis.*

In the mouth, most
common location is mandibular buccal sulcus and adjacent buccal mucosa.*

Mainly affects the elderly.* Particularly seen in tobacco
chewers and snuff dippers.*

Histopathologic Features: Very well differentiated, heavily keratinized SCC with little or no cytological atypia.
Slowly pushing cohesive front

Local destruction but no mets
Mitoses are rare.

Although it is an exophytic tumor, it also has a slowly
advancing, pushing, cohesive invasive front causing local destruction.
Strict criteria for diagnosis should be employed, and it
i.
ii.
Must be differentiated from:

Well-differentiated SCC with a papillary component. Leukoplakias with warty surfaces variously called verrucous hyperplasia or verrucous leukoplakia.
Squamous Cell Carcinoma: Carcinoma-In-Situ

A term used to
describe severe epithelial dysplasia in which the whole, or almost the whole thickness of epithelium is involved, but basement membrane is intact and there is no invasion of lamina propria.

Usually presents
clinically as leukoplakia or erythroplakia.

In some patients it may progress to invasive carcinoma, but in others it may remain static or even regress.

Field cancerization:
dysplasia or carcinoma-in-situ in epithelium surrounding an invasive carcinoma, which may suggest a field change in a wide area of mucosa
It is probable that some
carcinomas thought to be recurrent tumors, represent new primary lesions arising in such a field change.
Oral Premalignant Lesions and Conditions

Premalignant lesion: a morphologically altered tissue in
which cancer is more likely to occur than in its normal counterpart, e.g. leukoplakia, i.e. the lesion itself undergoes malignant transformation.
Premalignant condition: a generalized disorder associated
with a significantly increased risk of cancer developing somewhere in the mouth, e.g. submucous fibrosis.
However, relatively few oral SCCs are preceded by a
recognizable premalignant lesion or condition.
The following may be considered premalignant lesions or conditions:
1. Precancerous lesions: a) Leukoplakia- homogeneous, non-homogeneous, nodular, and speckled types, including chronic hyperplastic candidosis and proliferative verrucous leukoplakia. b) erythroplakia c) carcinoma in situ.

2. Precancerous conditions: a) oral submucous fibrosis. b) lichen planus. c) actinic keratosis or cheilitis. d) other conditions associated with oral epithelial atrophy, e.g. sideropenic dysphagia.
Basal Cell Carcinoma (Rodent Ulcer): Clinical Features

Common neoplasm of skin,
especially face.
Affects old people with
chronic exposure to UV radiation. lips, particularly upper lip. spreading to involve vermilion border.
Occasionally presents on
Many may be skin tumors

Typically presents as a slow growing nodule that eventually ulcerates centrally, and may cause extensive damage if not treated.

Multiple basal cell carcinomas arising at younger age and on non-sun-exposed sites are a feature of basal cell nevus syndrome.
Basal Cell Carcinoma (Rodent Ulcer): Histopathologic Features

Histologically consists
of malignant basaloid cells arranged in various patterns , invading adjacent tissues.
Melanocytic Nevi and Melanoma

Melanocytes are dendritic cells of neuroectodermal origin. They are located mainly in the basal layer of epidermis and
some mucous membranes.

They are widely distributed and present in large numbers in
oral mucosa of clinically pigmented and non-pigmented races, the difference being of activity and not number.
Their function is to produce melanin which they pass to
adjacent keratinocytes.
Acquired Melanocytic Nevi: Clinical Features

Nevus: any developmental on skin or
mucosa, from Latin naevus = birthmark.

very common, particularly on skin of head and neck. adolescence. nevi.
Acquired melanocytic nevi or moles, are
Most present in childhood and
The average person may develop 20-30

Malignant change can rarely occur in nevi.
Acquired Melanocytic Nevi: Clinical Features

Melanocytic nevi are rare in
the oral mucosa.
Most reported intraoral
nevi present in adult life as slightly elevated, pigmented lesions on the hard palate or buccal mucosa.
Acquired Melanocytic Nevi: Histopathologic Features
Melanocytic nevi are considered hamartomatous lesions formed by proliferation of melanocytes or their precursors, with variable melanin pigment production.
There are different stages in the natural history of melanocytic nevi.
They are separated histologically based on location of nevus cells relative to epithelium:
1. Junctional nevus.
2. Compound nevus. 3. Intramucosal (intradermal). Most oral nevi are of this type.

Junctional Nevus Compound nevus
Nevus cells
Nevus cells
Nevus cells
Malignant Melanoma-In-Situ and Malignant Melanoma

Excessive exposure to UV light is
most important factor, hence many arise in head and neck area.
Skin lesions may present as
pigmented plaques or nodular lesions and may be preceded by melanoma in situ characterized by horizontal spread within epithelium.
Vertical spread into dermis
characterizes invasive melanoma and prognosis depends mainly on depth of invasion at time of diagnosis.
Malignant Melanoma: Clinical Features
ABCD Clinical Features: 1. Asymmetry (uncontrolled growth pattern) 2. Border irregularity 3. Color variation 4. Diameter greater than 6 mm
Malignant Melanoma: Histopathologic Features

Highly pleomorphic neoplasms. Variable melanin production,
may be absent (amelanotic melanoma).

Immunohistochemical studies
using specific markers for malignant melanocytes (S-100 and HMB-45) are useful.
Ultrastructural examination to
identify immature melanosomes can be used.
Oral Malignant Melanoma

Oral melanoma is rare.
Slightly more common in
males than females.
> 70% involve posterior
maxillary alveolar ridge and hard palate. there is history of previous pigmentation in the area.
In about a third of cases,
Oral Malignant Melanoma

Oral melanomas present as dark
brown or bluish black slightly raised lesions with an uneven nodular or papillary surface.
Amelanotic lesions tend to appear
reddish.
Growth may be rapid with extensive
destruction of bone and loosening of teeth.
Most are advanced at presentation,
with both regional lymph node and blood-borne metastases common.
Prognosis is poor.

ALL Oral Epithelial Tumors I and II and III (Slide 7+8+9)

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Dent 355 Oral Epithelial Tumors, Melanocytic Nevi, and Melanoma I

Dr. Rima Safadi

Human Papilloma Virus-Associated Lesions

Human Papilloma Virus-Associated Lesions: Squamous Cell Papilloma

Most occur in adults. Variable size, may be sessile or

cauliflower-like growth with a

white or pink surface.

transformation, treated by conservative excision.

Human Papilloma Virus-Associated Lesions: Squamous Cell Papilloma

proliferation supported by thin fibrovascular cores.

Mitotic figures in basal

Human Papilloma Virus-Associated Lesions: Squamous Cell Papilloma

Human Papilloma Virus-Associated Lesions: Verruca Vulgaris (Common Wart)

Treated by surgical excision, cryosurgery or

chemical cautery. HPV types 2 or 4.

Human Papilloma Virus-Associated Lesions: Verruca Vulgaris (Common Wart)

proliferation supported by thin fibrovascular cores. Acanthosis and hyperkeratosis.

Human Papilloma Virus-Associatedlesions: Condyloma Acuminatum (Venereal Wart)

area, may be seen intraorally.

Multiple pink nodules

One of the oral

HPV types 6, 11, and 16.

Human Papilloma Virus-Associated Lesions: Condyloma Acuminatum

marked broadening and elongation of rete ridges.

Focal epithelial hyperplasia

Squamous Cell Carcinoma: Epidemiology

cancers. Regional and ethnic variation in large countries.

Squamous Cell Carcinoma: Epidemiology

incidence in developed, but 3rd in developing countries.

Squamous Cell Carcinoma: Epidemiology

increase despite previous decrease in incidence and mortality rates.

Squamous Cell Carcinoma: Epidemiology

risk reflect different etiological factors.

Squamous Cell Carcinoma: Etiological Factors, Tobacco

it is used are nitrosamines derived from nicotine.

Etiological Factors, Tobacco

the relative risk.

Squamous Cell Carcinoma: Etiological Factors, Tobacco

the two most important

oral cancer is firmly established regardless of its type.

cigarettes/day) are at 1020 times increased risk.

Squamous Cell Carcinoma: Etiological Factors, Tobacco

snuff dipping, tobacco sachets, tobacco chewing.

Squamous Cell Carcinoma:

Betel quid (pan), chewing habits, areca nut (submucous fibrosis).

Alkaloids are carcinogenic

In Malysia: without tobacco

Areca nut chewing: increase the risk of submucous fibrosis

Squamous Cell Carcinoma: Etiological Factors, Alcohol

groups, may be linked to increased alcohol consumption.

Squamous Cell Carcinoma: Etiological Factors, Alcohol

heavy smokers, too. Synergistic effect

barrier. Nutritional deficiencies in alcoholism may impair mucosal barrier function.

Chronic alcohol intake may impair ability of liver to detoxify

carcinogens, and can suppress immune responses needed to fight cancer.

Squamous Cell Carcinoma: Etiological Factors, Alcohol

content in some mouthwashes?

Squamous Cell Carcinoma: Etiological Factors, Diet and Nutrition

Render mucosa more susceptible to carcinogens.

Squamous Cell Carcinoma:

maintenance of oral epithelium.

& E is believed to lower the risk of oral cancer.