Tongue cancer (Fig. 1.5a)

Mandibular gingival cancer (Fig. 1.5b)

Buccal mucosa cancer (Fig. 1.5c)

Oral floor cancer (Fig. 1.5d)

Maxillary gingival cancer (Fig. 1.5e) and maxillary sinus cancer

Palate cancer (Fig. 1.5f)

Lip cancer (Fig. 1.5g)

Risk factors of oral cancer

A number of risk factors of oral cancer have been reported [21, 22]. Risk factors of oral cancer reported up to the present are summarized in Fig. 1.6. Surprisingly, however, only few factors have been epidemiologically or experimentally established. In addition, it is widely recognized as an underlying concept that oral cancer is very unlikely to develop with single factor and is caused by overlapping several factors in multistages. Especially smoking and drinking are representative risk factors of oral cancer, which are epidemiologically and experimentally established.

Smoking and oral cancer

There are no other risk factors like smoking in which causal association with cancer has been clearly established. Now, tobacco could be said to be an enemy of every disease to put it in extreme terms. Smoking is a luxury item, which also has the highest causal relation with carcinogenesis in oral cancer.

The occurrence frequency of oral cancer is extremely high in Sri Lanka, India, or Taiwan as compared with Japan, and about 30 % of the entire cancer is oral cancer. It has been epidemiologically shown that such high occurrence of oral cancer is caused by a habit of chewing tobacco and betel nut (Fig. 1.7) [21]. The Declaration of Opposition to Smoking is adopted by about 40 academic societies including the Japanese Society of Oral and Maxillofacial Surgeons at the present day and supports promotion of the antismoking movement in Japan. It is indisputable that smoking is the largest factor for the prevention of oral cancer. A number of studies on carcinogenicity of smoking have been conducted since the mid-1900s, and it has been demonstrated that there are a number of substances that act as initiators or promoters in the carcinogenic process in about 4,000 kinds of chemical substances contained in cigarette smoke [23]. About 40 substances including benzopyrene and nitrosamines have been identified as carcinogenesis-related substances to date [23]. In addition, it is considered that oral cancer, pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer, pancreatic cancer, liver cancer, kidney cancer, bladder cancer, and uterine cancer are associated with smoking. Recently, smoking rate of Japanese is on a declining trend. However, it is pointed out that an increasing tendency is observed in only young females.

Drinking and oral cancer

Drinking is a factor, which causation with oral cancer has been demonstrated similar to smoking. Different from tobacco, alcohol (= ethanol) itself has no carcinogenicity. However, it has been clarified in many studies that alcohol is indirectly associated with carcinogenesis. Moreover, a synergistic effect due to concomitant exposure to drinking and smoking often becomes a problem. Drinking and smoking cause exposure of carcinogenic factors to all pharynx, larynx, esophagus, and stomach in addition to the oral cavity at the same time (field cancerization); therefore, this is also related to the development of double cancer. According to our department, double cancers with upper digestive tract cancer were observed in 10.4 % of the entire oral cancer patients [24]. The carcinogenic mechanism of alcohol was poorly understood until recently in contrast to tobacco. There is no report of carcinogenesis induced by only alcohol administration in animal experiments. However, International Agency for Research on Cancer (IARC) recognized alcohol as a carcinogen because acetaldehyde, which is a metabolic product of alcohol, has carcinogenicity [25]. In other words, the carcinogenic mechanism may directly or indirectly interact with biological reactions. As direct interaction, metabolic enzymes localizing in the oral mucosa degrade alcohol, and it causes exposure of the mucosa to acetaldehyde. Homann et al. [26] reported that bacteria existing inside the oral cavity increase carcinogenic risk of oral cancer by degradation of alcohol to acetaldehyde. As indirect interaction, it is considered that effects of alcohol include effect of acetaldehyde metabolized in the liver on local mucosa, effect as a solvent of carcinogens derived from tobacco and others, decrease of metabolic function of the liver, decrease of immunological capacity due to alcohol ingestion, and lowering of nutritional status.

Epidemiology of smoking and drinking

As the results of a meta-analysis of reports on a large-scale epidemiological studies, IARC concluded that smoking and drinking are distinct risk factors of oral cancer [25]. Of course, the more daily consumption of as well as longer exposure time to smoking and drinking result in increase of carcinogenic risk. Accordingly, an index that takes account of them has an important implication. Brinkman index and Sake index shown in Fig. 1.8 are widely used to express relationship between the amount and duration of smoking and drinking with oral cancer. Sake index that is 60 or higher and Brinkman index that is 1,000 or higher are defined as the risk zones (Fig. 1.8). However, pack-years is used as a new smoking index instead of Brinkman index in recent years. This index is calculated by dividing Brinkman index by 20.

Based on the above findings, we conducted a case–control study in 191 patients with oral cancer and 121 healthy subjects with no oral mucosal diseases who visited our department [27]. The results of multiple logistic analysis on risk for the development of oral cancer are shown in Table 1.4. Risk of developing oral cancer (odds ratio) by smoking alone was 2.5, but it elevated to 4.3 in heavy smokers with Brinkman index 1,000 or higher. In addition, odds ratio of drinking alone was 4.5; however, it elevated to 10.4 in heavy drinker with Sake index 60 or higher. When subjects have a habit of smoking and drinking, the risk of developing oral cancer resulted in 4.8, which was higher than smoking or drinking alone. In other words, it is considered that the risk of oral cancer is high in people with Brinkman index 1,000 or higher and Sake index 60 or higher and especially high in people who have both smoking and drinking habits.

Genotypic analysis of metabolic enzymes related to smoking and drinking

Carcinogens accumulate in the body through tobacco use or alcohol ingestion and then are metabolized and detoxified. Recently, it is revealed that there are differences in individual’s metabolic capability due to genetic variant of metabolic enzymes. In other words, it is speculated that the same loading from smoking and/or drinking may cause different degrees of carcinogenic risk in individuals because metabolic and detoxification capabilities against carcinogens vary considerably from individual to individual. Accordingly, we conducted an analysis of genes related to smoking and drinking in 127 patients with oral cancer and 33 healthy subjects with smoking and drinking habits, who preliminarily gave informed consent (Table 1.2) [27]. As a smoking-related enzyme, gene polymorphism of glutathione S-transferase M1 (GSTM1), which is an enzyme degrading benzopyrene in tobacco, was identified and analyzed with a multiple logistic analysis (Table 1.3) [27]. As a result, the risk of developing oral cancer in smokers with GSTM1 gene mutation was 2.5 times higher. Then aldehyde dehydrogenase 2 (ALDH2), which is an enzyme that degrades acetaldehyde, was identified and analyzed with a multiple logistic analysis. As a result, the risk of developing oral cancer in individuals with drinking habit with ALDH2 gene mutation (hetero deletion) was 2.9 times higher. Furthermore, an Italian research team recently conducted a meta-analysis of papers on ALDH2 gene polymorphism, including our report, and concluded that carcinogenic factor of drinking-related head and neck cancers is acetaldehyde [28]. Moreover, they also reported that higher alcohol consumption causes higher carcinogenic risk in ALDH2-deleted individuals [28].

As mentioned above, the polymorphism pattern of metabolism-related genes may contribute to the identification of risk factors of oral cancer because the polymorphism pattern varies from individual to individual. New biomarkers would be discovered in the future, and the development of tailor-made prevention may be expected in this area.

Virus infection and oral cancer

Several types of carcinogenesis caused by virus infection have been reported. For example, it is famous that hepatitis B virus and hepatitis C virus cause liver cancer and is also well known that adult T-cell leukemia (ATL) is caused by RNA virus (retrovirus). In the head and neck region, EB virus belonging to herpesvirus group causes Burkitt’s lymphoma. In addition, it is reported that human papillomavirus (HPV) is associated with the development of oral cancer [29]. Recently HPV is watched with interest as the cause of oral cancer especially in young individuals with no risk factors of smoking and drinking.

Age and oral cancer

Japan is becoming an unprecedented aging society with a falling birthrate in the world with progress of super-aging society and lowering of birthrate in these years. It is reported that oral cancer appears most frequently at 50 years old and older. However, it is considered that recent increasing tendency is due to the increasing number of the elderly.

Oral cancers in high-risk females (Figs. 1.9, 1.10, and 1.11)

In general, it is believed that oral cancers are often found in middle-aged males and less frequent in females. It is presumed that this is greatly associated with having much stress from work in addition to lifestyle habits such as smoking and drinking. However, increase of female patients is recently being seen as a problem. There are more than a small number of female patients with no smoking/drinking history and no clear carcinogenic cause. There is a report that HPV, which is a cause of cervical cancer, is associated with carcinogenesis; however, concrete conclusion is still not obtained. Especially female patients need attention to aesthetic recovery in addition to functional aspect sufficiently taking into account the social background and living environment.

We compared treatment results of males and females with oral cancer in recent two decades (the first 10 years and later 10 years were analyzed separately) in our department (Fig. 1.9). As a result, 5-year survival rate was lower in females (Fig. 1.10) than males (Fig. 1.11), and it was noted that the number of recurrence and metastasis was increased in females diagnosed with early cancer.

Young patients and oral cancer

It has been known that oral cancer often occurs in males of 60 years and older; however, recently it is pointed out that the rate of oral cancer in young individuals and females is increasing [30–32]. There is no strict definition of “young individuals,” but many reports use 40 years old as a benchmark [30–36]. Our university has also examined for 25 years from 1987 to 2012, and the rate of oral cancer in young individuals below 40 years old was 37/758 cases (5.0 %), which was almost the same rate as reported from other facilities. On the other hand, statistically significant increase was observed in annual changes in the rate of cancer in young individuals (below 40 years old) (Fig. 1.12).

Critical causes include age, sex, smoking, alcohol consumption, virus, and mechanical factors such as poorly fitted prosthesis and sectorial tooth, and genetic abnormality. However, critical causes for young individuals are still unclear [32–34]. Many of the patients in our university had no smoking/drinking history; therefore, it was considered that mechanical factors including odontoparallaxis and malposition of a tooth might cause the cancers.

In addition, it has been known that male-to-female ratios of oral cancer in young individuals come closer to 1 [34]. The majority of primary sites were the tongue [30–34], and well-differentiated squamous cell cancers are often observed in terms of pathological appearance [32]. The male-to-female ratio in our university was 1.38, and a decrease in age was also observed as compared with a group of 40 years and older. Furthermore, the rate of primary sites was significantly high in the tongue, 76.3 %. For the degree of differentiation, the rate of well-differentiated cancers was 39.5 % (Table 1.4).

For prognosis in young individuals, there is not yet a unified view: some reports concluded that it was better in young individuals [34–36], some other reports concluded that it was almost the same [30, 32], and others concluded that it was poor in young individuals [33]. Results in our university indicated that young individuals had good outcome: 5-year overall survival rate was 94.3 %; 5-year relapse-free survival rate was 88.2 %. However, there was no statistically significant difference as compared with a group of 40 years and older, and the rates were equivalent (Fig. 1.13). It is anticipated that pathogenic mechanism would be understood in the future.

Oral cancer and prevention