Oral cancer pathophysiology

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]; Grammar Reviewer: Natalie Harpenau, B.S.[4]

It is understood that oral cancers occur as a the result of carcinogen–metabolizing enzymes, alcohol, tobacco and genetic factors. Cytotoxic enzymes such as alcohol dehydrogenase result in the production of free radicals and hydroxylation of DNA base units. Alcohol dehydrogenase oxidizes ethanol to acetaldehyde which is cytotoxic in nature. 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.The development of oral cancer is the result of multiple genetic mutations. These mutations occur in tumor suppressor genes (TSGs) and oncogenes. Squamous cell carcinoma is the most common malignancy of the oral cavity. It typically has three gross morphological growth patterns, which are exophytic, ulcerative, and infiltrative. Microscopically, oral cancers are broadly based and invasive through papillary fronds. Oral cancer consists 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.

It is understood that oral cancer occurs as a the result of carcinogen–metabolizing enzymes, alcohol, tobacco and genetic factors.

• Carcinogen–metabolizing enzymes are known to cause cancer in some patients.
• Cytotoxic enzymes such as alcohol dehydrogenase result in the production of:
  • Free radicals
  • DNA hydroxylated bases
• These cytotoxic enzymes dominantly play a key role in the development of oral squamous cell carcinoma.

• 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.

• 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.
• saliva then looses its antioxidant potential and becomes a potent pro-oxidant milieu.^[1]

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

• Cancer starts in the squamous cells of the epithelium, and then invades the deeper layers of the oral cavity.

• The following squamous cell carcinomas have distinct microscopic features that make them look and behave differently from classical SCC:

• Verrucous carcinoma
  • These tumors make up less than 5% of all oral cavity tumors.
  • 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 sub-type of squamous cell carcinoma.
  • It is more common in men older than 60 years old.
• Papillary SCC
  • This is a rare sub-type of squamous cell carcinoma that grows outward from the surface of the epithelium (exophytic).
  • HPV infections 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 are broken down.
  • This results in microscopic spaces in the tumor 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-producing gland cells.
• Lymphoepithelial carcinoma
  • This is a rare sub-type of squamous cell carcinoma.
  • The microscopic appearance is similar to undifferentiated nasopharyngeal carcinoma.
  • It is also known as undifferentiated carcinoma.

• The development of oral cancer is the result of multiple genetic mutations.
• These mutations include:
  • Tumor suppressor genes (TSGs)
  • Oncogenes

• Oral cavity cancer may be the result of an 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).
• In non-cancerous situations, TSGs modulate normal growth.
• Mutation of these TSGs lead to dysfunctional growth control.
• Mutation most commonly occurs in one of the following:
  • Short arm of chromosome 3
  • TSG termed P16 on chromosome 9
  • TSG termed TP53 on chromosome 17
• The Cytochrome P450 genotype is related to mutations in some TSGs and leads to oral squamous cell carcinoma.
• In western countries (eg. United Kingdom, United States, or Australia), TP53 mutations are the most common molecular change that leads to oral squamous cell carcinoma.

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

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

• Microscopically, oral cancers are broadly based and invasive through papillary fronds.
• Oral 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:^[2]
  • Keratinizing type: Worst prognosis
  • Undifferentiated type: Intermediate prognosis and EBV association^[3]
  • Non-keratinizing type: Good prognosis and EBV association

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