INTRODUCTION
The two main factors which influence most diseases are genetic and epigenetic factors. Development of oral or head and neck squamous cell carcinoma (HNSCC) and minor salivary gland carcinomas is influenced by both these factors namely tobacco, alcohol, diet and nutrition, viruses, radiation, ethnicity, familial and genetic predisposition, oral thrush, immunosuppression, use of mouthwash, syphilis, dental factors, occupational risks, and mate.
EPIGENETIC FACTORS
Tobacco
Tobacco consumption continues to prevail as the most important cancer risk as it alone accounts for millions of cancer deaths annually. The neoplastic diseases caused by smoking include cancers of the lung, oral cavity, pharynx, larynx, esophagus, urinary bladder, renal, pelvis, and pancreas. The relationship between smoking and oral cancer has been established firmly by epidemiological studies.[1] The most important carcinogens in tobacco smoke are the aromatic hydrocarbon benz-pyrene and the tobacco-specificnitrosamines (TSNs) namely 4-(nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN). Animal studies have shown that NNK and NNN in the tobacco products cause tumors of the oral cavity, lung, esophagus, and pancreas. NNK, NNN, and their metabolites covalently bind with deoxyribonucleic acid (DNA) of keratinocyte stem cells forming DNA adducts.[2] These adducts are responsible for critical mutations involved in DNA replication. The metabolism of these carcinogens involves oxygenation by P450 enzymes in cytochromes and conjugation by glutathione-S-transferase (GST).[2] Genetic polymorphisms in the genes coding for these enzymes are suspected to play a key role in the genetic predisposition to tobacco-induced head and neck cancers.[3]
Certain other classes of enzymes are involved in the activation or degradation of carcinogens and procarcinogens. They are termed xenobiotic metabolizing enzymes (XMEs). These enzymes are found mainly in the liver and also in the mucosa of the upper aerodigestive tract. Many of the XMEs are polymorphic and they strongly influence the individual's biological responses to carcinogens by formation of DNA adducts. Hence, certain XME genotype may increase individual susceptibility to cancer through erroneous carcinogen metabolism leading to increased carcinogen exposure.[2]
The ability to repair carcinogen-induced DNA damage, has also been found to be reduced in head and neck cancer patients.[4] Marijuana, a popular name for dried flowering leaves of the plant Cannabis sativa, is also called bhang or ganja. It is smoked as cigarettes. The cannabinoids release potent carcinogens like benz (o) pyrene, phenols, phytosterols, acids, and terpenes when burnt. Studies have shown that marijuana smoking is not an independent risk factor for oral cancer development.[4] Moreover, tobacco usually forms a part of marijuana smoking mix.[5]
The use of smokeless tobacco (tobacco consumed without combustion) has become prevalent all over the world. Smokeless tobacco is placed inside the oral cavity in contact with the mucous membranes where the nicotine is absorbed to provide the desired effect. Smokeless tobacco has been used in many forms in different parts of the world. For instance, the use of oral snuff (wet or moist snuff) is more common in the west and the MiddleEast. Betel quid chewing, in a variety of forms and various ingredients is widespread in Asia, where it is a custom and cultural habit since tobacco reached India via the Portuguese, who brought it to Europe and Asia from South America. Consumption of smokeless tobacco causes mainly oral precancer and cancer. In Western Europe and North America, the main types of chewing tobacco are plug, loose-leaf, and twist. Their use is declining in these regions, albeit still prevailing in certain subpopulations. Moist snuff (ground tobacco) is particularly common in North America and Scandinavia. The habit of oral snuff (referred to as snuff-dipping) causes a condition called 'snuff-dipper's cancer' classically described as verrucous carcinoma. Snuff, as manufactured in Europe and North America, is very different from snuff-like products used in the Middle East, which are made by small-scale industries.[6]
Betel quid
Betel quid chewing with different ingredients is the most common habit in Southeast Asia, especially in the Indian subcontinent. Betel quid (also referred to as pan or paan) usually contains betelleaf (leaf of Piper betel vine), areca nut, slaked lime, and tobacco. Other ingredients are often added namely, spices such as cardamom, cloves, or aniseed to the quid in India and turmeric in Thailand. Some of the common forms of these mixtures are khaini (tobacco and lime), mishri (burned tobacco), zarda (boiled tobacco), gadakhu (tobacco and molasses), and mawa (tobacco, lime and areca) consumed in different parts of India; nass (tobacco, ash, cotton or sesame oil), naswar/niswar (tobacco, ash and lime) in Central Asia and Middle East; shammah (tobacco, ash and lime) in Saudi Arabia, and toombak (tobacco and sodium bicarbonate) in Sudan. Studies have shown the association of these products with oral cancer development. Studies have shown the association of tobacco chewing with oral cancer and precancer namely leukoplakia, erythroplakia, and oral submucous fibrosis.[7]
Considerable research has been focused in the recent past on the carcinogenic, mutagenic, and genotoxic potential of betel quid ingredients, especially tobacco and areca nut.[8]In vitro studies on oral mucosal fibroblasts using DNA damage, cytotoxicity, and cell proliferation assays have shown that some essential betel quid ingredients are genotoxic, cytotoxic, and also stimulate cell proliferation. It has been shown that reactive oxygen species (ROS), methylating agents, and reactive metabolic intermediates from betel quid induced various kinds of DNA damage.[8]
Alcohol
Alcohol has been implicated in the development of oral cancer. Alcoholic beverages have been considered carcinogenic to humans causing in particular, tumors of the oral cavity, pharynx, larynx, esophagus, and liver; although ethanol per se has not been proven carcinogenic in animal studies.[9] Alcohol consumption has been shown to act synergistically with tobacco in the increased risk of development of oral cancer. Few studies have managed to do analysis with patients who drink alcohol but are nonsmokers and in patients who smoke but are nondrinkers.[9] In one such study, alcohol has been found to be an independent risk factor for oral leukoplakia in an Indian population.[10] However, similar studies evaluating the oral epithelial dysplasia occurrence in alcohol drinkers who are nonsmokers, found that the role of alcohol in development of oral epithelial dysplasia is crucial only when considered in conjunction with tobacco.[11] No association of minor salivary gland tumors with heavy smoking or heavy alcohol consumption could be demonstrated by Keller.[12]
Hence, the role of alcohol as an independent factor in oral carcinogenesis is still unclear albeit epidemiological evidence establishes the synergistic role played by alcohol with tobacco. Alcohol is shown to increase the permeability of oral mucosa producing an alteration in morphology characterized by epithelial atrophy, which in turn leads to easier penetration of carcinogens into theoral mucosa.[11]
Substances that have been believed to be carcinogenic to humans have been seen in alcoholic beverages. A few examples are, N-nitroso compounds, mycotoxins, urethane, inorganic arsenic, and others. The major metabolite of alcohol is acetaldehyde whose transformation is mainly carried out by the enzyme alcohol dehydrogenase (ADH). Acetaldehyde is then oxidized to acetate by means of aldehyde dehydrogenase (ALDH). Acetaldehyde causes DNA damage in cultured mammalian cells. It interferes with the DNA synthesis and repair. It also induces sister chromatid exchanges and specific gene mutations.[13] Acetaldehyde inhibits the enzyme 6-methylguanitransferase which is responsible for repairing injuries caused by alkylating agents. With all the above ill-effects of acetaldehyde which initiates or promotes tumor formation, increase in acetaldehyde accumulation in the body either due to increase in its production or due to decrease in its elimination, is considered deleterious. Accumulation of acetaldehyde can occur due to increased activity of ADH enzyme activity which is present in oral microflora and in the oral mucosa.[13] ADH type-3 genotypes cause rapid oxidation of alcohol to acetaldehyde and these individuals are predisposed to oral cancer. Alternately, reduction in ALDH enzyme can also lead to accumulation of acetaldehyde. Genetic polymorphisms have been reported in these two enzymes, ADH and ALDH, which have been related to the increased risk of alcohol-related cancers.[14]
The systemic effects of alcohol are mainly due to the hepatic damage. Alcohol addiction leading to cirrhosis and other diseases (e.g., cardiomyopathy, stroke, and dementia) inhibits the detoxification of carcinogenic compounds such as N-nitrosodiethylamine.[14] Chronic alcoholics tend to have reduced intake of nutrients due to the metabolic processes being occupied in the transformation of ethanol and the proper metabolism of nutrients is altered. This enhances nutritional deficiencies thereby increasing the risk of cancer. Chronic alcohol intake also leads to suppression of immune systemby affecting liver and nutritional status.[15]
Diet and Nutrition
The relationship between diet and nutrition to the risk of cancer development has been established by several epidemiological and laboratory studies.[16] The working group of International Agency for Research on Cancer (IARC) has affirmed that low intake of fruits and vegetables predisposes to increased risk of cancer development. More frequent consumption of fruit and vegetables, particularly of carrots, fresh tomatoes, and green peppers were associated with reduced risk of oral and pharyngeal cancer. Food and food groups other than fruits and raw vegetables that have a protective effect are fish, vegetable oil, olive oil, bread, cereals, legumes, protein, fat, fresh meat, chicken, liver, shrimp, lobster, and fiber.[16]
Certain food groups have been shown to be associated with higher risk of oral cancer namely processed meats, cakes and desserts, butter, eggs, soups, red meat, salted meat, cheese, pulses, polenta, pasta or rice, millet, and corn bread. The evidence from the above studies however does not allow authoritative attribution of either the benefit or the drawback to a specific ingredient in the food.[17]
This has contributed to the significant interest in studies focusing on the macronutrients (proteins, carbohydrates, fat, and cholesterol) and micronutrients (vitamins and their analogs (13-cis retinoic acid and β-D-glucopyranosly ascorbic acid (AA)) and trace elements) present in the food groups that are protective against cancer. Considerable evidence has shown that certain micronutrients decrease the risk of oral cancer development. They include vitamins A (retinol), C (AA), and E (α-tocopherol); carotenoids (β-carotene); potassium; and selenium (38–43). β-carotene, retinol, retinoids, vitamin C (AA), and vitamin E (α-tocopherol) are antioxidants that are essential in reducing free radical reactions that can cause DNA mutations, changes in enzymatic activity, and lipid peroxidation of cellular membranes.[16]
β-carotene, a major form of provitamin A, are converted to vitamin A in the body. There are over 600 carotenoids in the human body of which only 10% are precursors of vitamin A. Although all the mechanisms involved in the anticarcinogenic activity of carotenoids are not known, these agents serve as antioxidants, prooxidants, enhances the immune response, inhibits mutagenesis, reduces the induced nuclear damage (micronuclei), prevents sister chromatid exchanges, protects from various neoplastic events, and protects against photo-induced tissue damage.[18]
A direct cause–effect relationship between β-carotene and risk of oral cancer has not been elucidated. This is not feasible as the cancer prevention activity of any substance could be proven only by large-scale randomized, controlled clinical trial lasting for decades. However, β-carotene supplements have been shown to increase the incidence of lung cancers in smokers[19] Owing to the difficulty in conduction of large-scale prevention trials, considerable interest was shown in the search for intermediate biomarkers which are usually measurable histologic, biochemical, genetic, or other markers that occur during cancer development and which when displayed, places an individual at a higher risk. Several treatment trials with β-carotene have been done in oral precancer and cancer and have shown considerable success rates. Remission or regression of oral leukoplakia using β-carotene only or with vitamin A has been shown in many studies.[20] β-carotene is a nontoxic antioxidant to humansand is highly suitable for chemoprevention trials than retinoids such as 13-cis-retinoic acid which exhibit toxicity.[20]
Vitamin E has been shown to prevent tumor formation in Hamsters and this has been attributed to the stimulation of potent immune response by vitamin E and vitamin E has also been shown to have the potential to reduce oxidative damage caused by hydroxyl radicals. Clinical intervention trials with α-tocopherol, which is a nontoxic antioxidant like β-carotene, have shown much promise with oral cancer and precancer. However, treatment trials with α-tocopherol have to be done with caution as high concentrations (80µmol) of vitamin E has been shown to promote skin tumor formation.[20]
AA, an antioxidant, decreases nitrosation by preventing the formation of nitrosamines, thereby acting as a chemopreventive agent. It also affects the activity of leukocytes and macrophages. AA is also involved in the activity of cytochrome P450 which is important in the inactivation of potent carcinogens and metabolic activation of procarcinogens.[21] There has been no study reported on the sole use of AA in the treatment of oral leukoplakia. The association between AA and oral cancer is based on the dietary assessments that low intake of fruits and vegetables which are usually rich in vitamin C predisposed to increased risk of oral cancer.[21]
Cultural risk factors and dietary factors seem to interplay in the development of oral cancer and precancer. Studies have shown the association between smoking and lowering of serum levels of nutrients.[22] For instance, cigarette smokers had lower levels of β-carotene than nonsmokers and also smoking modified the association between dietary and serum β-carotene. The habit of quid chewing also has been shown to reduce serum levels of vitamins A, C, and B12; folate; and β-carotene in quid chewers than non-quid-chewers.[22]
Mouthwash
The use of mouthwash has also been implicated to cause oral cancer. Mouthwashes usually contains alcohol as a solvent for other ingredients or as a preservative. Epidemiological evidence demonstrates that the risk of mouthwash causing oral cancer is attributed to the frequency and duration of use and its alcohol content. However, there is no cause–effect relationship found between mouthwash and oral cancer. Nevertheless, the dental clinicians must be prudent while advocating mouthwashes/rinses with high alcohol content.[15]
Maté
Maté, which is a tea-like beverage consumed in South America and in parts of Europe has been shown to be an independent cause for development of oral and pharyngeal cancers. The exact pathogenesis of maté predisposing to oral cancer is still unknown. Many reasons that have proposed for maté's carcinogenicity are thermal injury, solvent for other chemical carcinogens, and presence of tannins and N-nitroso compounds.[23]
ENVIRONMENTAL FACTORS
Viral Infections
Viruses have been strongly implicated in the development of malignant tumors of the squamous epithelia including the oral squamous epithelium. Viral infections of latent or chronic nature are usually responsible for inducing malignant transformation by interfering with the host's cell cycle machinery. These viral genes and gene products may affect cell growth and proliferation. Certain viral genes are proto-oncogenes which become oncogenes when inserted into the host's DNA and ultimately resulting in malignant transformation. The prototypic viruses implicated in oral cancer development are human herpes virus (mainly Epstein–Barr virus (EBV)), human papillomavirus (HPV), and herpes simplex virus.[24]
EBV causes oral hairy leukoplakia and “lymphoproliferative disease” in immunosuppressed patients. The causal relationship of EBV with oral squamous cell carcinoma (OSCC) is still unclear. Prevalence studies have shown presence of EBV in OSCC patients, but it does not prove a causal association. One frequently investigated etiologic relationship about the cause of minor salivary gland tumors concerns the association of EBV, with the form of salivary gland carcinoma, often referred to as malignant lymphoepithelial lesion. This type of tumor is extremely rare among people who are not of Asian extraction.[25] One study has demonstrated the presence of DNA from EBV in an adenocarcinoma of the submandibular gland in a Finnish child. As noted by Scully, some spontaneous salivary gland adenocarcinomas in animals reveal the presence of viral particles.[26]
HPV are the most common viruses implicated in oral carcinogenesis. HPV are DNA viruses and are epitheliotropic, especially for squamous epithelia. They cause benign proliferative lesions such as papillomas, condyloma acuminatum, verruca vulgaris, and focal epithelial hyperplasia (Heck's disease). Certain HPV types, referred to as 'high-risk' types are associated with OSCC and oral premalignant lesions. They are HPVs 16, 18, 31, 33, 35, and 39. The major evidence of the role of HPV in cancer development is that their genes and gene products are capable of disturbing the cell cycle machinery. HPV encodes two major oncoproteins namely, E6 and E7. The E6 and E7 proteins have been shown to bind and destroy p53 and Rb tumor suppressor genes, respectively, thereby disrupting the cell cycle with loss of control on DNA replication, DNA repair, and apoptosis. HPV has been detected in OSCC, dysplasia, and other benign lesions using various techniques. Some studies have shown HPV presence in normal oral mucosa making the role of HPV in oral carcinogenesis speculative.[27]
Moreover, HPV 16, which is the most common type found in genital cancers were also the most common in oral cancers, which clearly indicates the possible source of HPV infection in the oral cavity. HSV has not been proven to be the direct cause of oral cancer, although several studies show that oral cancer patients have high serum antibody titers to HSV. The available evidences are circumstantial and are rationalized that reactivation of HSV infection is due to immunosuppression, specifically of natural killer lymphocyte activity. Based on the evidence of in vitro studies, the possible role of HSV in carcinogenesis has been proposed as the enhancement of activation, amplification, and overexpression of preexisting oncogenes such as c-myc and c-erb-B-1.[28]
Fungal Infections
Fungal infections caused by Candida species, in particular, Candida albicans has been implicated in the pathogenesis of oral premalignant lesions. Superficial fungal hyphae of Candida albicans have been found superimposed on leukoplakia, especially nodular leukoplakia, many of which have undergone malignant transformation. The doubt of whether Candida invasion is a secondary event or causal in oral premalignant lesions is still uncertain and debatable. Candida species are commensals in the oral cavity which become opportunistic during host's immunosuppression due to systemic diseases or drug therapy. Besides immunocompromised individuals, Candida infection can coexist or be associated with other risk factors like irondeficiency and in chronic smokers which may prove synergistic in the development of oral cancer. There is evidence that Candida possesses necessary enzymes fromdietary substances to produce nitrosamines and chemicals that have been implicated in carcinogenesis. A recent study showed relationship between oral yeast carriage and epithelial dysplasia yet again, the actual role of yeast in the development of epithelial dysplasia is uncertain.[29]
IMMUNOSUPPRESSION
Immunosuppressed individuals are more prone to develop oral cancers. Human immunodeficiency virus (HIV)-infected patients are predisposed to developing Kaposi's sarcoma and lymphomas, although not to OSCC. Immunosuppressed organ transplant patients have been shown to develop lip cancers and the possible reason was attributed to increased exposure to solar radiation and other risk factors such as smoking. However, the direct role of immunosuppression with lip cancer development was not proven in the studies.[30]
Occupational Risks
Occupational risks, namely exposure to excessive solar radiation/ultraviolet (UV) light is known to cause lip cancers. UV rays also causes actinic cheilitis which may transform to OSCCs. Sulfur dioxide, asbestos, pesticide exposures, and mists from strong inorganic acids and burning of fossil fuels have also been known to cause cancers of posterior mouth, pharynx, and larynx.[31] Certain occupations have been reported to place people at increased risk for the development of salivary gland carcinomas; these include manufacturing of rubber products, plumbing (exposure of metals), and woodworking in an automobile industry.[32]
Dental Factors
Poor oral hygiene, poor dental status (sharp/fractured teeth due to caries/trauma), and chronic ulceration from an ill-fitting denture has been suggested to promote neoplasm in the presence of other risk factors. There has been difficulty in obtaining the evidence whether dental factors influence oral cancer development. This is due to the presence of coexisting risk factors like smoking and alcohol consumption. Nevertheless, an experimental study in hamsters has shown that chronic trauma in addition to carcinogen application could promote tumor development. In this study, mechanical irritation by scratching with a pulp cleaner has been shown to significantly increase the incidence of a chemical carcinogen-induced tongue carcinoma.[33] Therefore, it is prudent to closely monitor patients with known risk factors for signs and symptoms of irritation from teeth and appliances.
Syphilis
Tertiary syphilis had been known to predispose to the development of oral cancer along with other risk factors such as tobacco and alcohol. However, nowadays, tertiary syphilis is rare in clinical practice as the infection is diagnosed and treated before the onset of tertiary stage.[34]
Radiation
Substantial evidence exists for a relationship between exposure to ionizing radiation and the later development of salivary gland tumors. The tumorigenic effects of therapeutic radiation to the head and neck on the salivary gland tissue have been assessed at the Michel Reese Hospital in Chicago. The mean annual incidence per 100,000 people was 48 cases in an early period, but increased to 77 per 100,000 people later in the study.[35]
Hoffman et al., studied a limited number of patients who were treated for hyperthyroidism with radioiodine. They observed an elevated risk of cancer in organs that concentrated iodine (salivary gland, digestive tract, kidney, and bladder). The relative risk in the salivary glands was increased by 6.4-fold.[36]
GENETIC FACTORS
Genetic predisposition has been shown to be an important risk factor in the development of OSCC. A study by Copper et al., who followed up first-degree relatives of 105 head and neck cancer patients, found that 31 of these subjects developed cancers of respiratory tract and upper aerodigestive tract.[37] However, population-based studies to determine the genetic or familial disposition to oral cancers are limited by the coexisting risk factors like smoking and alcohol. It is also believed that certain individuals inherit the susceptibility of inability to metabolize carcinogens or procarcinogens and/or an impaired ability to repair the DNA damage. As discussed earlier about the metabolism of tobacco carcinogens, genetic polymorphisms in the genes coding for the enzymes (P450 enzymes and XMEs) responsible for tobacco carcinogen metabolism are suspected to play key role in the genetic predisposition to tobacco-induced head and neck cancers.[38]
CONCLUSION
It is clear from the above review that several risk factors are implicated in the development of oral cancer, of which the most common and established are tobacco smoking and betel quid chewing. Nevertheless, many patients are diagnosed with oral cancer despite abstaining from known lifestyle or environmental risk factors where factors like genetic susceptibility are believed to play the causative role. Hence, it is important for the public and the clinicians to be completely aware of the risk factors for oral cancer and it is prudent for dentists to look carefully for early signs of oral cancer, while routine examination of the oral cavity especially in patients with history of known risk factors.
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