Genetic Susceptibility

Family history of oral cancer is considered a risk factor. Head and neck cancer patients show an increased susceptibility to chromosome damage by mutagens. Some studies suggest that lip cancers have shown some amount of genetic predisposition. Mork et al (1999) reported a significantly increased odds ratio for developing head and neck squamous cell carcinoma in female patients, aged less than 45 years, who had first-degree relatives with cancer. It is suggested that familial oral cancer may be attributed to both shared environmental factors within families and a common oral cancer susceptibility gene with low penetrance.

Immune Status

It has been noticed that immunosuppressed individuals tend to show an increased incidence of oral malignancies. It is also a well-known fact that the host response diminishes with advancing age. HIV-positive immunocompromised individuals, may usually exhibit Kaposi’s sarcoma and non-Hodgkin’s lymphomas.

Environmental Factors

Consumption of Tobacco in India

It is estimated that 80–85% of tobacco is consumed for smoking either as beedis or cigarettes (Figure 1). Almost 13% chew tobacco in the form of paan (Figure 2, betel leaf, areca nut, tobacco, slaked lime and flavoring agents) or gutkha. Almost 15% are addicted to both habit of chewing and smoking. Only about 1–3% use tobacco in the form of snuff.

Smokeless Form of Tobacco

People in the Indian subcontinent exhibit various forms of tobacco chewing habits such as khaini, mishri, zarda, gutkha (Figure 3), mawa and nass. Paan is chewed (betel quid) and the quid is usually placed in the buccal vestibule.

Tobacco is also used in the form of a powder for inhalation (Figure 4, snuff). Tobacco (Figure 5) contains nicotine (nitrosamine), nitrosodiethanolamine, nitrosoproline, polonium and polycyclic aromatic hydrocarbon (tars). Areca nut (Figure 6 contains cholinergic muscarinic alkaloids such as arecholine and guavacoline) chewing is also widely practiced in India.

Smoke Form of Tobacco

In India, beedi (Figure 7), cigarette and chutta smoking is commonly seen. However, other popular forms of smoking include use of pipe, cigar and hookah. It is believed that cigar and pipe smoking is more hazardous than cigarette smoking. Palatal cancers are more common in individuals who place the lit end of the beedis and cigarettes inside the mouth (reverse smoking). It has been proposed that smoking causes pooling of carcinogens in saliva thereby increasing the incidence of cancers of the floor of the mouth, ventral and lateral surface of tongue.

It is estimated that in the combustion mainstream of one cigarette (Figure 8), there are approximately 500 mg (92%) of gaseous content (mainly oxygen, nitrogen and carbon dioxide and to a little extent carbon monoxide) and 8% of particulate matter. Aromatic hydrocarbons in the form of ‘tars’ may constitute less than 1 g to 35 mg. Nicotine content varies from 1 to 3 mg. Other constituents of tobacco smoke include carbon monoxide, hydrogen cyanide and thiocyanate. Benzopyrene is considered the most potent carcinogen. It preferentially binds to nucleoproteins. The enzyme aryl hydrocarbon hydroxylase that is principally produced in human leukocytes, is said to increase the carcinogenic potential of benzopyrene.

The carcinogenic properties of marijuana smoke are similar to those of tobacco. Marijuana may interact with mutagen sensitivity and other risk factors to increase the risk of head and neck cancer. Marijuana smoke has a four times higher tar burden and 50% higher concentrations of benzpyrene and aromatic hydrocarbons than are present in tobacco smoke.

 Ethyl alcohol increases the permeability of oral mucosa. It also dehydrates the mucosa. It has a solvent action on the keratinocyte membrane thereby allowing the passage of carcinogens into proliferating cells where they may exert a mutagenic action.

 The immediate metabolite of ethanol is acetaldehyde, which readily damages cells. It is believed that those who are rapid acetylators are at increased risk of developing cancers.

 Alcoholic liver disease is common in heavy drinkers and this minimizes the detoxification of carcinogens.

 Alcohol, owing to its high calorific value, suppresses appetite in heavy drinkers. This predisposes to nutritional deficiency which in turn is a risk factor for cancers. Compared to non-users, alcohol users are 3.6 times more likely to have oropharyngeal cancer, 5.8 times for tobacco users, and 19 times for users of both alcohol and tobacco.

Ionizing Radiation

Exposure to large amounts of ionizing radiation such as in a nuclear mishap is a known risk for causing cancers. Radiation exposure, known to cause DNA damage, may be a potential source of field cancerization of the upper aerodigestive tract.

Hashibe et al (2005) evaluated the possible risk of developing second primary cancers following radiotherapy for head and neck cancers in 30,221 oral squamous cell carcinoma patients. Patients treated with radiation only or radiation with surgery had elevated risks of developing a second primary tumor, whereas patients treated with surgery only did not appear to be at increased risk. They also suggested that the expected latent period between radiation exposure and tumor occurrence, radiation became a risk factor after 10 years of follow-up for solid cancers of the oral cavity, pharynx, esophagus, and lung, and after 1–5 years of follow-up for second primary leukemia.

Role of Viruses

The role of viruses remains unclear. Varying viral genomes have been frequently found within cancer cells. Viruses have been known to modify the DNA and the chromosomal structures and induce proliferative changes in the cells they infect.

Evidence of a viral carcinogenesis is perhaps strongest for infection with human papilloma viruses (HPV). D’souza et al (2007) in a multicenter case-control study reported that infection with HPV-16 increased the risk of cancer of the oral cavity and particularly oropharynx.

The role of infection with Epstein–Barr virus (EBV) and herpes simplex viruses (HSV) remains uncertain. The role of HSV, HSV-1 and HSV-2, as co-factors in association with tobacco, alcohol, or HPV-16 infection has also been proposed in causing oral cancers.

Human immunodeficiency virus (HIV), due its effect on immunosurveillance, acts as a cofactor along with other viruses such as EBV and cytomegalovirus in predisposing the affected individual to oral cancer.

Role of Nutrition

Various studies have shown that a diet with low vitamin A, vitamin C, vitamin E, iron, selenium, folate and other trace element content is associated with an increased risk of oral, laryngeal, lung, gastric, ovarian, breast and cervical cancers. Certain dietary deficiencies may cause epithelial atrophy which renders the epithelium vulnerable to the action of carcinogens. The relationship between sideropenic dysphagia and oral cancer is well recognized (sideropenic dysphagia may be associated with epithelial atrophy in the upper alimentary tract).

Garewal (1994) summarized the findings of 54 studies that evaluated fruit and vegetable intake in the development of cancers in the upper aerodigestive tract; he found that 52 of the studies demonstrated a protective effect of the antioxidant content of fruits and vegetables.

It has been shown that patients who ingest high levels of vitamin C and fiber have half the risk of developing oral cancer as those with minimal level of consumption. Block (1991) and Mirvish (1986) showed that a low intake of vitamin C is associated with an increased risk of cancers of the stomach, esophagus, oral cavity, larynx, and cervix.

Gridley et al (1992) in a study involving 2,000 individuals proposed that the use of vitamin E supplements correlated with a diminished risk for oral and pharyngeal cancers.

Oral Hygiene and Dental Factors

Though the exact etiological role of poor oral hygiene, faulty restorations, ill-fitting dentures, sharp teeth in causing oral cancers is not substantiated, these may be the possible contributing factors. It is believed that chronic trauma along with other carcinogens may aid in the malignant transformation of epithelial cells.

Shah (2003) suggests that the microorganisms from dental plaque, by way of chemical carcinogenesis, may produce nitrosating enzymes which are toxic. It is also believed that individuals who do not maintain good oral hygiene (inadequate brushing) may fail to dilute the carcinogens present in the oral cavity, especially derived from various tobacco-related habits.

Cellular Kinetics

Generation time is the time required for a quiescent cell to enter the cell cycle and give rise to two daughter cells. Malignant cells usually have a shorter generation time than non-malignant cells and a smaller percentage of cells in G0 (resting phase), so a larger proliferation fraction exists. Initial exponential tumor growth is followed by a plateau phase when cell death equals the rate of formation of daughter cells. Compared to large tumors, small tumors have a greater percentage of actively dividing cells and thus show greater rates of proliferation.

Tumor Growth and Metastasis

As a tumor grows, nutrients are provided by direct diffusion from the circulation. Local growth is facilitated by enzymes (e.g. collagenases) and cytokines that alter or destroy adjacent tissues. As the ratio of surface area to volume becomes smaller with increased tumor growth, tumor angiogenesis factors are produced, forming the independent vascular supply required for further tumor growth. Almost from inception, a tumor may shed cells into the circulation. From animal models, it is estimated that a 1-cm tumor sheds more than 1 million cells/24 h into the venous circulation. Although most circulating tumor cells die as a result of intravascular trauma, a tiny number (much less than 1 in 1 million) adhere to the vascular endothelium and penetrate into surrounding tissues, generating independent tumors (metastases) at distant sites. Metastatic tumors grow in much the same manner as primary tumors and may subsequently give rise to other metastases. Experiments suggest that metastasis is not a random event and that the primary tumor may regulate the growth of metastatic tumors, for example, removal of the primary tumor sometimes results in rapid growth of the metastases.

Molecular Abnormalities

Genetic mutations are largely responsible for the generation of malignant cells. These mutations alter the quantity or function of protein products that regulate cell growth and division and DNA repair. Two major categories of mutated genes are oncogenes and tumor suppressor genes.

Oncogenes are abnormal forms of normal genes (protooncogenes) that regulate cell growth. Mutation of these genes may result in direct and continuous stimulation of the molecular biologic pathways (e.g. intracellular signal transduction pathways, transcription factors, secreted growth factors) that control cellular growth and division.

There are more than 100 known oncogenes that may contribute to human neoplastic transformation, for example, the ras gene encodes the Ras protein, which regulates cell division. Mutations may result in the inappropriate activation of the Ras protein, leading to uncontrolled cell growth and division. In fact, the Ras protein is abnormal in about 25% of human cancers. Other oncogenes have been implicated in specific cancers. These include various protein kinases (bladder cancer, breast cancer), bcr-abl (chronic myelocytic leukemia, B-cell acute lymphocytic leukemia), C-myc (small cell lung cancer), N-myc (small cell lung cancer, neuroblastoma), and C-erb B-2 (breast cancer).

Specific oncogenes may have important implications for diagnosis, therapy, and prognosis (see individual discussions under the specific cancer type). Oncogenes typically result from acquired somatic cell mutations secondary to point mutations (e.g. from chemical carcinogens), gene amplification (e.g. an increase in the number of copies of a normal gene), or from insertion of viral genetic elements into host DNA. Occasionally, mutation of germ cell lines results in vertical transmission and a higher incidence of cancer development in an offspring.

Tumor suppressor genes are inherent genes that play a role in cell division and DNA repair and are critical for detecting inappropriate growth signals in cells. If these genes, as a result of inherited or acquired mutations, become unable to function, genetic mutations in other genes can proceed unchecked, leading to neoplastic transformation.

As with most genes, two alleles are present that encode for each tumor suppressor gene. A defective copy of one gene may be inherited, leaving a person with only one functional allele for the individual tumor suppressor gene. If an acquired mutation occurs in the other allele, the normal protective mechanisms of the tumor suppressor gene are lost, and dysfunction of other protein products or DNA damage may escape unregulated, leading to cancer.

Another mechanism that results in defective function and transcription of tumor suppressor genes is aberrant methylation of the promoter region of these genes, which inhibits gene transcription. Greater degrees of aberrant methylation and greater numbers of affected genes cause tumors to be more malignant and are associated with shortened survival in lung, bladder, and prostate cancers. In vitro alteration of the aberrant methylation has caused reversion to a non-malignant, non-proliferative phenotype, suggesting a potential therapeutic target.

Another important regulatory protein, p53, prevents replication of damaged DNA in normal cells and promotes cell death (apoptosis) in cells with abnormal DNA. Inactive or altered p53 allows cells with abnormal DNA to survive and divide. Mutations are passed to daughter cells, conferring a high probability of neoplastic transformation. The p53 gene is defective in many human cancers.

Gross chromosomal abnormalities can occur through deletion, translocation, or duplication. If these alterations activate or inactivate genes that result in a proliferative advantage over normal cells, then a tumor may develop. Chromosomal abnormalities occur in certain human cancers. In some congenital diseases (Bloom syndrome, Fanconi syndrome, Down’s syndrome), chromosomes break easily, putting children at high risk of developing acute leukemia and other cancers.

Most cancers are likely to involve several of the mechanisms described above that lead to neoplastic conversion. As with oncogenes, mutation of tumor suppressor genes in germ cell lines may result in vertical transmission and a higher incidence of cancer in an offspring. Telomeres are nucleoprotein complexes that cap the ends of chromosomes and maintain their integrity. Telomere shortening (with aging) results in replicative senescence, increased genetic instability, and potential tumor formation. Telomerase is an enzyme that carries out telomere synthesis and maintenance, thus telomerase may potentially allow for cellular immortality. Telomerase activity may promote tumors through multiple, complex mechanisms, especially by subverting the normal DNA synthetic checkpoints.