Oral cancer pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Sargun Singh Walia M.B.B.S.[2];Simrat Sarai, M.D. [3]

Pathophysiology

• It is understood that oral cavity carcinoma is the result of dysfunction of either :

Tumor suppressor genes (TSGs)

• Oral cavity cancer may be the result of allelic imbalance which is caused by chromosomal changes particularly in chromosome 3,9,11 and 17.
• These changes lead to mutation in tumor suppressor genes (TSGs).
• Normally TSGs modulate normal growth.
• Mutation of these TSGs leads to dysfunctional growth control.
• Mutation most commonly occurs in either of the following:
  • Short arm of chromosome 3
  • TSG termed P16 on chromosome 9
  • TSG termed TP53 on chromosome 17
• Cytochrome P450 genotypes is related to mutations in some TSGs and lead to oral squamous cell carcinoma.
• In western countries (eg, United Kingdom, United States, Australia) TP53 mutations are the most common molecular change that leads to oral squamous cell carcinoma.

Oncogenes

• Cancer may also occur if there is mutation to other genes that control cell growth, mainly oncogenes.
• Oncogenes most commonly involved are:
  • Chromosome 11 (PRAD1)
  • Chromosome 17 (Harvey ras [H-ras])
• In eastern countries (eg, India, Southeast Asia), ras oncogenes is a more common cause of oral squamous cell carcinoma.

Carcinogen-metabolizing enzymes

• Carcinogen-metabolizing enzymes are known to cause cancer in some patients.
• Cytotoxic enzymes such as alcohol dehydrogenase result in the production of:
  • Free radicles
  • DNA hydroxylated bases
• These cytotoxic enzymes especially predispose oral squamous cell carcinoma.

Alcohol

• Alcohol dehydrogenase oxidizes ethanol to acetaldehyde which is cytotoxic in nature.
• cytochrome P450 IIEI (CYP2E1) also metabolizes ethanol to acetaldehyde.
• Alcohol dehydrogenase type 3 genotype predisposes to oral squamous cell carcinoma.
• Carcinogenic potential increases when combined with tobacco use.

Tobacco

• Cigarette smoke has various carcinogens which can lead to oral cancers.
• Low reactive free radicals in cigarette smoke interact with redox-active metals in saliva.
• This makes saliva to loose its antioxidant potential and become a potent pro-oxidant milieu.

Pathology of classical or conventional squamous cell carcinoma

• Most cancers of the oral cavity are classical or conventional squamous cell carcinoma.
• This type of SCC starts in the squamous epithelium that lines the oral cavity and occurs most often on the lower lip, tongue and floor of the mouth.
• The microscopic features of classical SCC include:
  • Epithelial pearls
    • These are circular layers of squamous cells around a collection of keratin (a tough fibrous protein) in the centre.

• The cancer starts in the squamous cells of the epithelium and invades the deeper layers of the oral cavity.

Pathology of variants of squamous cell carcinoma

• These squamous cell carcinomas have distinct microscopic features that make them look and behave differently from classical SCC.

• Verrucous carcinoma
  • These tumours make up less than 5% of all oral cavity tumours.
  • They have a wart-like appearance and develop most often on the gums (gingiva), lining of the cheeks (buccal mucosa) and larynx.
  • Verrucous carcinomas are low grade, slow growing and rarely spread.
  • They are associated with the chronic use of snuff or chewing tobacco.
• Basaloid SCC
  • This is a rare but aggressive subtype of squamous cell carcinoma.
  • It is more common in men older than 60 years.
• Papillary SCC
  • This is a rare subtype of squamous cell carcinoma that grows outward from the surface of the epithelium (exophytic).
  • HPV infection may have a role in the development of this type of cancer.
• Spindle cell carcinoma (SpCC)
  • This is an aggressive, rare variant of squamous cell carcinoma.
  • These tumors contain a mixture of conventional squamous cell carcinoma and spindle cells that resemble a sarcoma.

It is also known as sarcomatoid carcinoma, pseudosarcoma, carcinosarcoma, pleomorphic carcinoma, metaplastic carcinoma, collision tumor and Lane tumor.

• Acantholytic SCC
  • This is a rare variant of SCC in which the connections between the malignant squamous cells break down.
  • This results in microscopic spaces in the tumour tissue, which appear like glands or vascular spaces.
• Adenosquamous carcinoma
  • This is a very rare, aggressive type of squamous cell carcinoma.
  • It looks like classical squamous cell carcinoma, but also has mucus-containing gland cells.
• Lymphoepithelial carcinoma
  • This is a rare subtype of squamous cell carcinoma.
  • The microscopic appearance is similar to undifferentiated nasopharyngeal carcinoma.
  • It is also called undifferentiated carcinoma.

Gross pathology

• Squamous cell carcinoma is the most common malignancy of the oral cavity.
• It typically has three gross morphologic growth patterns: exophytic, ulcerative, and infiltrative.
• The infiltrative and ulcerative are the types most commonly observed on the tongue.
• The macroscopic appearance of tongue cancer depends on the following:
  • Duration of the lesion
  • The amount of keratinization
  • The changes in the adjoining mucosa
  • A fully developed tongue lesion appears as an exophytic bulky lesion that is gray to grayish-red and has a rough, shaggy, or papillomatous surface.

Gross pathology of oral SCC, source: By Luca Pastore, Maria Luisa Fiorella, Raffaele Fiorella, Lorenzo Lo Muzio - http://www.plosmedicine.org/article/showImageLarge.action?uri=info%3Adoi%2F10.1371%2Fjournal.pmed.0050212.g001, CC BY 2.5, https://commons.wikimedia.org/w/index.php?curid=15252632

Microscopic Pathology

• Microscopically, tongue cancers are broadly based and invasive through papillary fronds.
• Tongue cancer constitutes of highly differentiated squamous cells lacking frank cytologic criteria of malignancy with rare mitoses.
• The surface of the lesion is covered with compressed invaginating folds of keratin layers. A stroma-like inflammatory reaction and a blunt pushing margin may be seen.

• SCC is subdivided by the WHO into:
  • Keratinizing type: Worst prognosis.
  • Undifferentiated type: Intermediate prognosis, EBV association.
  • Nonkeratinizing type: Good prognosis, EBV association.

Microscopic picture of oral SCC, source: By No machine-readable author provided. KGH assumed (based on copyright claims). - No machine-readable source provided. Own work assumed (based on copyright claims)., CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=486166

References

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