**4. Risk factors**

Oral cancer usually occurs in people over the age of 40 with an average age of 60, and their risk increases with age. It affects most men, but may increase as women smoke. Racially, black Americans are at higher risk for oral and throat cancer than whites. This increase in risk seems to be due to the influence of environmental factors, because the role of genetic factors in its occurrence has not been determined. Patients who smoke or chew a lot of tobacco and people who drink a lot of alcohol are at higher risk for oral cancer. Exposure to UV rays in people who stay in the sun for long periods of time is more likely to develop lip cancer. This is why the incidence of lip cancer is high in Australia. Other factors such as immunosuppression (such as AIDS and organ transplantation), viral papillomavirus infection (especially type 16, which accounts for 63% of new cases of oral cancer), Plummer–Vinson syndrome, and vitamin A deficiency also increase the risk of oral and pharyngeal cancer. The prevalence of HPV-related oral and pharyngeal cancers (mainly HPV type 16) has been increasing in North America and Northern Europe [11]. Other factors, including arsenic compounds used to treat syphilis, nutritional deficiencies, exposure to compounds such as wood and metal particles, and Candida infection, play a lesser role in cancer [8].

#### **4.1 Hookah**

In recent years, hookah has spread to Europe and the United States. In most countries, the increasing trend of hookah consumption is due to the increase in fruit and flavored tobacco products [12]. In a study conducted in Iran, the prevalence of hookah use among young people was reported to be 33.9%, which is higher than the number of people who smoke [13]. The side effects of hookah are many because the smoke produced from tobacco is composed of 4000 different chemicals and more than 40 carcinogens [14]. Tobacco smoke and hookah use are the most

#### *Oral Cancer: Epidemiology, Prevention, Early Detection, and Treatment DOI: http://dx.doi.org/10.5772/intechopen.99236*

important risk factors for oral cancers and dysplastic lesions [3]. Cigarettes or other tobacco-related compounds are associated with about 75% of oral cancers. Tobacco contains more than 60 known carcinogens. The use of tobacco, whether in a smoky or chewable form alone, and especially with heavy alcohol consumption, is a very important risk factor for oral cancer. Smokers are 7 times more likely to develop oral cancer than non-smokers. The relative risk of developing cancer in people who consume a lot of alcohol is 6 times higher, and this risk is 38 times higher for patients who use alcohol and tobacco together [8].

The association of tobacco with the risk of cancer may differ among the head and neck cancer subtypes [15]. In some studies, it was demonstrated that smoking had a stronger association with larynx and pharynx than the oral cavity. This may be due to the higher exposure of larynx and pharynx to smoke than the oral cavity [15, 16].

The destructive link between tobacco products and human cancers stems from a powerful combination of two factors - nicotine and carcinogens. Nicotine is addictive and toxic, but there is no scientific evidence that nicotine is carcinogenic, and the IARC does not classify nicotine as a carcinogen. However, this addiction causes people to use tobacco products constantly, and these products contain many carcinogens. Cigarette smoke contains more than 60 carcinogens and unburned tobacco contains at least 16 carcinogens. Among these, tobacco-specific nitrosamines such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N′-nitrosonornicotine (NNN), polycyclic aromatic hydrocarbons (such as benzoapyrene) and aromatic amines (such as 4-aminobiphenyl) seem to play an important role as causes of oral cancer [17].

Some believe that filtering hookah smoke through water reduces nicotine. However, contrary to popular belief, studies have shown that only 5% of nicotine is removed by water. In addition, hookah users may tend to increase the duration of smoking, thereby increasing the concentration of nicotine in their bloodstream. Therefore, considering the aforementioned harmful effects of hookah use and the results of a recent study, it seems that the use of this smoking device may cause changes in the oral mucosa [3].

Studies have shown that tobacco users, including slaked lime in the betel quid or with areca nut, experience carcinogenic and genotoxic effects on human oral epithelial cells. These products produce reactive oxygen species (ROS) in the chewing mouth [18]. Areca nut is composed of phenolic compounds and tobacco releases various nitrosamines in the mouth that are responsible for proliferative abrasions and damage to DNA and fibroblasts [19, 20]. The N-nitroso compound extracted from Areca nuts, which contains the active ingredient 3- (methyl nitrosamino) proprionityl, has been shown to cause gene poisoning and cytotoxicity responsible for tumors in the buccal cavity of smokeless smokers [21].

The long-lasting and frequent presence of paan and gutkha in the mouth around the gums leads to inflammation of the oral mucosa, which causes the activation of T-cells and macrophages, and ultimately the release of prostaglandins.

Prostaglandin production in buccal keratinocytes occurs due to Arka nut extract, which plays an important role in oral tissue fibrosis and cancer. Cytokines such as interferon-α, tumor necrosis factor (TNF), interleukin-6, and growth factor-like transforming growth factor-beta have been found to be produced at the sites of irritation [22]. The nitrosamine in tobacco is metabolized by cytochrome P450 enzymes, which may lead to the formation of N-nitrosonornicotine, a major carcinogen, which can lead to DNA damage and eventually oral cancer [23].

The consumption of tobacco is closely associated not only with the development of oral cancer, but also with the course of disease evolving a poor prognosis. The most widespread form of tobacco is chewing of betel-quid with tobacco and this has been demonstrated as a major risk factor of cancer of oral cavity [24].

Evidence from many studies shows that smoking in any way doubles the risk of oral cancer in men and women. The risk increases significantly with the duration and frequency of smoking. The risk among former smokers is consistently lower than current smokers, and the risk decreases as the years of quitting increase [25].

The highest incidence of tobacco related oral cancer is seen in low and middle income countries. People in the lower socioeconomic strata are more commonly affected. In India almost 21 people per 100 000 of the population are affected [26]. Data from a pioneering study by Taiwanese researchers show that people with a habit of smoking, drinking and chewing betel nuts at the same time are 123 times more likely to develop oral cancer than the general population [27]. More than 50 percent of oral cancers in India, Sudan and the Republic of South Sudan and about four percent of oral cancers in the United States are due to smokeless tobacco products. Smoking smokefree tobacco is on the rise among young people in South Asia with the marketing of well-packaged products made from areca nuts and tobacco. As a result, oral precancerous conditions are significantly increased in young adults [28, 29].

#### **4.2 Cigarette**

Smoking helps to spread the tumor by suppressing immunity and tumor suppressor genes, most importantly p53 and PTEN [5]. The benefit of quitting smoking may be a time-dependent advantage. It was found that the risk of oral cancer among non-smokers is similar to that of former smokers after 10 years of smoking cessation. In addition, quitting smoking later or in middle age may significantly reduce the risk of oral cancer [30, 31].

A study in China, which included 210 cases, reported a strong association between long-term smoking and OSCC [32]. In the study by Ahmed et al. they have reported an increase in nuclear size, nuclearcytoplasmic (N/C) ratio and multi-lobed nuclei, while a decrease in size of cytoplasm in smokers as compared to non smokers [33]. The study of Woyceichoski et al. has also revealed an increase in cytoplasmic size and N/C ratio, while a decrease in size of cytoplasm in cocaine users as compared to the control group [34].

#### **4.3 Alcohol**

Tobacco and alcohol are the most well-known reasons for oral and throat cancers [35]. The synergistic effects of alcohol and tobacco smoke increase the risk of OSCC by increasing the permeability of the oral epithelium, tobacco solution, and increasing its permeability [36]. However, chronic alcohol use alone may lead to OSCC through several mechanisms, including the formation of DNA adducts, the production of ethanolrelated reactive oxygen species, and interference with the DNA repair mechanism [37].

#### **4.4 Shammah**

Shamma consumption is increasing in many countries [38]. It is a combination of smokeless powder tobacco with ingredients such as lime, pepper, ash and flavorings, and people use it by placing it in the buccal cavity until the taste penetrates [39]. Another study of Yemeni shammah users found that there was a strong link between daily consumption of leukoplakia [40].

#### **4.5 Chewing of khat**

Khat is a plant that is mostly used for chewing and is amixture of cathine and norephidrine [41]. In an earlier case report of one patient, a strong affiliation

between khat chewing and growth of OSCC was reported [42]. Sawair *et al*. also reported a strong association between khat chewing and OSCC development in their study, which included 649 Yemeni patients [43].
