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 cauliflowerlike growth with a white or pink

surface.

No reports of malignant transformation, treated by conservative excision.

Squamous Papilloma

Human Papilloma Virus-Associated Lesions: Squamous Cell Papilloma

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

Mitotic figures in basal layer, no dysplasia.

Human Papilloma Virus-Associated Lesions: Squamous Cell Papilloma

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)

Histopathologic Features: 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.

One of the oral manifestations of HIV infection.

HPV types 6, 11, and 16.

Condyloma Acuminatum

Human Papilloma Virus-Associated Lesions: Condyloma Acuminatum

Histopathologic Features: 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.

Squamous Cell Carcinoma: Epidemiology

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.

Squamous Cell Carcinoma: Epidemiology

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.

Squamous Cell Carcinoma: Epidemiology

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

Squamous Cell Carcinoma: Etiological Factors, Tobacco

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.

Squamous Cell Carcinoma: Etiological Factors, Tobacco

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.

Squamous Cell Carcinoma: Etiological Factors, Alcohol

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.

Squamous Cell Carcinoma: Etiological Factors, Alcohol

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).

Epithelial atrophy:
Iron defeciency lichen planus and tertiary syphilis

Render mucosa more susceptible to carcinogens.

Squamous Cell Carcinoma:

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 fair-skinned 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

Squamous Cell Carcinoma: Etiological Factors, Viruses

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.

HPV 16 is the most common isolate, but it has also been detected in normal mucosa.

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.

Squamous Cell Carcinoma: Etiological Factors, Viruses

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 reported following renal and other transplants linked to immunosuppressive therapy. Smoking, alcohol, and iron deficiency may impair cellmediated immunity, but significance of this role is not established.

Increased incidence of oral 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.

Squamous Cell Carcinoma:

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. 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.

6. 7. 8. 9. 10. 11.

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

Oncogenes and Tumor-Suppressor Genes

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.

Oncogenes and Tumor-Suppressor Genes

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

Oncogenes and Tumor-Suppressor Genes

Oncogenes and Tumor-Suppressor Genes

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

Squamous Cell Carcinoma: Clinical Presentation, Early Lesions

3. Small indolent ulcer. 4. Erythroplakia.

Squamous cell cracinoma

Squamous cell carcinoma

Squamous Cell Carcinoma: Clinical Presentation, Early Lesions

Suspicious clinical features for early carcinoma: 1. Persistent ulceration. 2. Induration. 3. Fixation to underlying structures. 4. Destruction of underlying bone in alveolar ridge lesions. 5. Enlarged reactive regional lymph nodes. 6. 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.

Squamous Cell Carcinoma: Clinical Presentation, Advanced Lesions

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

Squamous Cell Carcinoma: Clinical Presentation, Advanced Lesions

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

Squamous Cell Carcinoma: Clinical Presentation, Advanced Lesions

5. Radiographic evidence of bone destruction. 6. Mobility of teeth.

7. Altered sensation over distribution of mental nerve. 8. Pathologic fracture of mandible.

Squamous Cell Carcinoma: Clinical Presentation

9. Metastatic spread to regional lymph nodes. Size of surface lesion does not indicate extent of underlying invasion.

Squamous Cell Carcinoma: Clinical Presentation

Squamous Cell Carcinoma: Clinical Presentation

Squamous Cell Carcinoma: Clinical Presentation

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.

Squamous Cell Carcinoma: Pathology

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.

Squamous Cell Carcinoma: Pathology

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

Squamous Cell Carcinoma: Pathology

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

Squamous Cell Carcinoma: Pathology

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

Squamous Cell Carcinoma: Pathology

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

Squamous Cell Carcinoma: Pathology

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.*

Squamous Cell Carcinoma: Verrucous Carcinoma

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.*

Squamous Cell Carcinoma: Verrucous Carcinoma

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.

Squamous Cell Carcinoma: Verrucous Carcinoma

Histopathologic Features: Although it is an exophytic tumor, it also has a slowly advancing, pushing, cohesive invasive front causing local destruction.

Squamous Cell Carcinoma: Verrucous Carcinoma

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.

Squamous Cell Carcinoma: Carcinoma-In-Situ

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.

Squamous Cell Carcinoma: Carcinoma-In-Situ

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.

Oral Premalignant Lesions and Conditions

The following may be considered premalignant lesions or conditions:

1. Precancerous lesions: a) Leukoplakia- homogeneous, nonhomogeneous, nodular, and speckled types, including chronic hyperplastic candidosis and proliferative verrucous leukoplakia. b) erythroplakia c) carcinoma in situ.

Oral Premalignant Lesions and Conditions

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. Occasionally presents on lips, particularly upper lip. Many may be skin tumors spreading to involve vermilion border.

Basal Cell Carcinoma (Rodent Ulcer): Clinical Features

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

Basal Cell Carcinoma (Rodent Ulcer): Clinical Features

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

Acquired Melanocytic Nevi: Histopathologic Features

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.

Acquired Melanocytic Nevi: Histopathologic Features

Junctional Nevus Compound nevus

Nevus cells

Nevus cells

Acquired Melanocytic Nevi: Histopathologic Features

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.

In about a third of cases, there is history of previous pigmentation in the area.

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.