Betel quid not containing tobacco and oral leukoplakia: a report on a cross-sectional study in Papua New Guinea and a meta-analysis of current evidence

Leukoplakia is an asymptomatic, potentially malignant change in the oral mucosa. Previous studies have reported that smoking and betel quid chewing are associated with increased risk of leukoplakia; few studies have reported on these associations in populations where betel quid does not contain tobacco. We conducted a case-control study nested in a cross-sectional study in Papua New Guinea and a systematic review of studies that included chewers of betel quid without tobacco. Our study recruited 1,670 adults. We recorded betel quid chewing and smoking. The prevalence of leukoplakia was 11.7%. In the nested case-control study of 197 cases and 1,282 controls, current betel chewing was associated with increased risk of leukoplakia with an adjusted odds ratio for current chewers of 3.8 (95% CI 1.7, 8.4) and in the heaviest chewers of 4.1 (95% CI 1.8, 9.1) compared to non-chewers. Current smoking was associated with an increased risk of leukoplakia with an adjusted odds ratio for current smokers of 6.4 (95% CI 4.1, 9.9) and amongst heaviest smokers of 9.8 (95% CI 5.9, 16.4) compared to non-smokers. The systematic review identified 5 studies examining risk of leukoplakia associated with betel quid chewing in populations where betel quid did not contain tobacco and that controlled for smoking. In studies that adjusted for smoking, the combined random effect odds ratio was 7.9 (95% CI 4.3, 14.6) in betel quid chewers. The results of this study and systematic review of similar studies provide evidence of the role of betel quid not containing tobacco and leukoplakia.     

Chewing areca nut, betel quid, oral snuff, cigarette smoking and the risk of oesophageal squamous-cell carcinoma in South Asians: a multicentre case-control study

Oesophageal cancer remains an important public health problem worldwide. This multicentre matched case-control study examined the chewing areca nut alone, betel quid with tobacco, oral snuff (snuff dipping) and cigarette smoking as the risk factors for oesophageal squamous-cell carcinoma. We enrolled 91 cases of oesophageal squamous-cell carcinoma and 364 matched controls from three tertiary-care hospitals in Karachi, Pakistan. A structured questionnaire was used to collect the data through face-to-face interview of the participants. Multivariable conditional logistic regression model showed that after adjusting for the effect of ethnicity, ever chewed areca nut alone (adjusted matched odds ratio (mOR(adj))=3.7; 95% confidence interval (CI): 1.6-8.5), ever chewed betel quid with tobacco (mOR(adj)=12.8; 95% CI: 6.3-26.2), ever practiced snuff dipping (mOR(adj)=4.3; 95% CI: 1.6-11.7) and ever smoked cigarettes (mOR(adj)=2.9; 95% CI: 1.4-5.9) were significantly and independently associated with oesophageal squamous-cell carcinoma status. The adjusted summary population attributable risk (PAR) percent for all four substances together was 67.0. Furthermore, despite incomplete synergy, there was manifold increase in the risk of oesophageal squamous-cell carcinoma, if the respondents ever smoked cigarettes and ever chewed betel quid with tobacco (mOR(adj)=21.4; 95% CI: 6.3-72.4) or if they ever smoked cigarettes and ever practiced snuff dipping (mOR(adj)=14.4; 95% CI: 2.3-91.1). The adjusted PAR (%) was higher for the dual practice of smoking cigarettes and chewing betel quid with tobacco (64.3) than the dual practice of smoking cigarettes and snuff dipping (32.2). Public awareness to curtail the addiction to these substances may result in a substantial reduction in the incidence of oesophageal squamous-cell carcinoma and related mortality in this and similar settings.     

Different impact from betel quid, alcohol and cigarette: risk factors for pharyngeal and laryngeal cancer

The risks of betel quid chewing with or without tobacco, alcohol drinking and cigarette smoking have been well explored in the oral cavity but not in the pharynx and larynx. We conducted a case-control study to investigate the association of these three risk factors to cancers of the pharynx and larynx in Taiwan. A total cases of 148 pharyngeal cancer, 128 laryngeal cancer and 255 hospital controls, all men, were recruited. Betel quid chewing was a significant independent risk factor (adjusted odds ratio [aOR] = 7.7; 95% confidence interval [CI] = 4.1-15.0) similar to that of alcohol drinking (aOR = 6.6; 95% CI = 3.5-13.0) for pharyngeal cancer, but not for laryngeal cancer (aOR = 1.3; 95% CI = 0.7-2.5) on which cigarette smoking (aOR = 7.1) exerts a stronger significant independent risk than alcohol drinking (aOR = 3.8). For pharyngeal cancers, chewers who consumed >20 quid/day, chewed with inflorescence in the quid or swallowed the betel quid juice were at higher risks; significant dose-response effects were found in daily quantity of drinking and chewing, and cumulative quantity of drinking. Synergistic effects from the 3 risk factors existed both on the pharynx (aOR = 96.9) and the larynx (aOR = 40.3), and attributed for 93.1% and 92.9% respectively. Our study is the first evidence to show that betel quid chewing without tobacco has different impact on the pharynx (digestive tract) and the larynx (airway), and supports the concept that exposure quantity and direct mucosal contact with the betel quid juice may contribute to carcinogenesis. Our results show an important insight into the impact of betel quid chewing on other sites of the digestive tract other than the oral cavity.     

Tobacco (Kretek) Smoking,Betel Quid Chewing and Risk of Oral Cancer in a Selected Jakarta Population

Purpose: This study aimed to determine the association between tobacco consumption (kretek) and betel quidchewing with oral cancer risk. Materials and Methods: A total of 81 cases of oral cancers were matched with162 controls in this hospital-based study. Information on sociodemographic characteristics and details of riskhabits (duration, frequency and type of tobacco consumption and betel quid chewing) were collected. Associationbetween smoking and betel quid chewing with oral cancer were analysed using conditional logistic regression.Results: Slightly more than half of the cases (55.6%) were smokers where 88.9% of them smoked kretek. Afteradjusting for confounders, smokers have two fold increased risk, while the risk for kretek consumers and thosesmoking for more than 10 years was increased to almost three-fold. Prevalence of betel quid chewing among casesand controls was low (7.4% and 1.9% respectively). Chewing of at least one quid per day, and quid combinationof betel leaf, areca nut, lime and tobacco conferred a 5-6 fold increased risk. Conclusions: Smoking is positivelyassociated with oral cancer risk. A similar direct association was also seen among betel quid chewers.     

Impact of RECK gene polymorphisms and environmental factors on oral cancer susceptibility and clinicopathologic characteristics in Taiwan

Oral cancer is the fourth common male cancer and causally associated with environmental carcinogens in Taiwan. The reversion-inducing-cysteine-rich protein with Kazal motifs (RECK) has a significant effect on tumorigenesis by limiting angiogenesis and invasion of tumors through the extracellular matrix. RECK downregulation has been confirmed in many human cancers and associated with lymph node metastasis clinically. In the present hospital-based case-controlled study, the demographic, RECK genotype and clinicopathologic data from 341 male oral cancer patients and 415 cancer-free controls were investigated. We found that RECK rs10814325, rs16932912, rs11788747 or rs10972727 polymorphisms were not associated with oral cancer susceptibility. Among 488 smokers, RECK polymorphisms carriers with betel quid chewing have a 7.62-fold [95% confidence interval (CI), 2.96-19.64] to 25.33-fold (95% CI, 9.57-67.02) risk to have oral cancer compared with RECK wild-type carrier without betel quid chewing. Among 352 betel quid chewers, RECK polymorphisms carriers with smoking have a 6.68-fold (95% CI, 1.21-36.93) to 18.57-fold (95% CI, 3.80-90.80) risk to have oral cancer compared with those who carried wild-type without smoking. In 263 betel quid chewing oral cancer patients, RECK rs10814325 polymorphism have a 2.26-fold (95% CI, 1.19-4.29) risk to have neck lymph node metastasis compared with RECK wild-type carrier. These results support that gene-environment interactions between the RECK polymorphisms, smoking and betel quid may alter oral cancer susceptibility and metastasis.     

Betel quid without tobacco as a risk factor for oral precancers

The IARC monographs recently classified chewing betel quid without tobacco as a human carcinogen. Several studies in Taiwan have reported that betel quid without tobacco may increase the risk of oral precancers such as oral leukoplakia and oral submucous fibrosis. However in India, since most betel quid chewers prefer to add tobacco to the quid, the independent effect of betel quid on the risk of oral precancers is difficult to assess and has not yet been fully explored. We conducted a large case-control study in Kerala, India, including 927 oral leukoplakia cases, 170 oral submucous fibrosis cases, 100 erythroplakia cases, 115 multiple oral precancer cases and 47,773 controls. The focus of this reanalysis is on the minority of individuals who chewed betel quid without tobacco. Among nonsmokers and nondrinkers, chewing betel quid without tobacco conferred ORs of 22.2 (95%CI = 11.3, 43.7) for oral leukoplakia, 56.2 (95%CI = 21.8, 144.8) for oral submucous fibrosis, 29.0 (95%CI = 5.63, 149.5) for erythroplakia and 28.3 (95%CI = 6.88, 116.7) for multiple oral precancers, after adjustment for age, sex, education and BMI. Dose-response relationships were observed for both the frequency and duration of betel quid chewing without tobacco on the risk of oral precancers. In conclusion, our study supports the hypothesis that chewing betel quid without tobacco elevates the risks of various oral precancers.     

Expression of p53 in oral squamous cell carcinoma and its association with risk habits in southern Thailand

Tobacco smoking and alcohol drinking are the principal factors associated with p53 expression in oral squamous cell carcinomas (OSCC) in the west, whereas betel quid chewing and smokeless tobacco are important factors in the east. Variable results of p53 expression have been reported and it has been proposed that ethnic difference and a variation in the indigenous oral habit may be responsible for the finding. This study, therefore, investigated p53 expression among 106 OSCC patients from a southern Thailand population in which all four risk behaviours, tobacco smoking, alcohol drinking, betel quid chewing and use of smokeless tobacco, are practised. The associations of p53 expression with lifetime exposure to each risk behaviour were explored. Multivariate modelling showed that lifetime exposure to alcohol drinking was significantly positively associated with p53 expression (likelihood ratio P value 0.01). Betel quid chewing and tobacco smoking habit showed a trend of decreasing risk of p53 expression with increased lifetime exposure (OR 0.62, 95% CI 0.39-1.00 and OR 0.50, 95% CI 0.26-0.98, respectively). No significant association was found between p53 expression and clinico-pathological parameters. Further investigations are needed to study (1) the molecular alteration of p53 in each risk habit and (2) other possible pathways of oral carcinogenesis in betel quid- and tobacco smoking-associated OSCC in these group of patients.     

The Risk of Oral Cancer among Different Categories of Exposure to Tobacco Smoking in Sri Lanka

Background: The global incidence of oral squamous cell carcinoma (OSCC) is on the rise with no improvement seen in survival rates. Tobacco consumption varies depending on geographic location, ethnicity and culture. The present case-controlled study aimed to determine the relative risk of OSCC for different tobacco consumption patterns in a selected Sri Lankan population. Methods: One hundred and five patients with histopathologically confirmed OSCC attending the National Cancer Institute (Apeksha Hospital) of Sri Lanka and 210 age and gender-matched controls from the community responded to an interviewer-administered questionnaire regarding their smoking and betel-quid chewing (with/ without smokeless tobacco) habits were included in the study. The odds ratios (OR) and 95% confidence intervals (CI) were calculated. p<0.05 was considered as statistically significant. Results: The overall risk of OSCC increased 2.93-fold for smokers. Those smoking two packets of cigarettes or more per day (OR=5.56; 95% CI-2.822-10.984; p=0.000) had more than double the risk of OSCC than those smoking 1-2 packets per day. Smoking for more than 20 years had a 3.4-fold risk of OSCC. Consumption of betel quid containing tobacco (smokeless tobacco) had a 4.26-fold higher risk for OSCC (OR=4.26; 95% CI-2.21-8.21; p=0.000), and the risk increased when all four ingredients (betel leaf, slaked lime, areca nut, and tobacco) were consumed together (OR=4.26; 95% CI-2.34-7.74; p=0.000). The combined effect from concurrent smoking and betel chewing emerged as the highest risk for OSCC (OR=15.34) which significantly exceeded the risks evident for the two habits practised in isolation from each other. Conclusions: Use of smokeless tobacco, consumption of all four ingredients together, duration of smoking, the number of cigarettes smoked per day and combined consumption of betel quid and smoking are significant risk factors in the development of OSCC among Sri Lankans.     

Impact of betel quid, tobacco and alcohol on three-stage disease natural history of oral leukoplakia and cancer: implication for prevention of oral cancer.

The natural history of the three-stage process from normal, oral leukoplakia to oral cancer in relation to betel quid chewing, smoking and drinking is rarely addressed. The aim of this study was to simultaneously quantify the effects of three risk factors on occurrence of oral leukoplakia and malignant transformation to oral cancer. A hospital-based case-control study design derived from three retrospective cohorts from 1988 to 1998 was conducted. A total of 74 oral cancer patients, 164 patients with oral leukoplakia and 187 controls were interviewed to collect information on their betel chewing, smoking and drinking habits. The effects of the three risk factors on the progression rates of the three-stage disease process were estimated using the three-state Markov model. Subjects who chewed betel quid were at greater risk of leukoplakia (adjusted odds ratio (OR) 17.7 (9.03-34.5)) but there was no significant effect on malignant transformation (OR 1.04 (0.61-1.76)). Smoking played a major role in the onset of leukoplakia (OR 4.26 (2.21-8.23)) but a minor role in malignant transformation (OR 1.36 (0.69-2.68)). Alcohol was positively associated with malignant transformation (OR 2.37 (1.47-3.82)) but unrelated to occurrence of leukoplakia (OR 0.76 (0.04-1.43)). We concluded that smoking and betel quid were two significant risk factors for the occurrence of leukoplakia, whereas alcohol was significantly responsible for malignant transformation.     

Betel quid chewing and the risk of oral and oropharyngeal cancers: A meta‐analysis with implications for cancer control

We conducted a random‐effects meta‐analysis of 50 publications assessing the relationship between oral/oropharyngeal cancer and chewing betel quid, with (BQ+T) or without added tobacco (BQ‐T), a common practice in many parts of Asia and globally among Asian immigrants. Exposure‐response, by daily amount and years of BQ chewed, was assessed using spline models. Attributable fractions (PAF%) were calculated to estimate the public health impact if BQ were no longer chewed. The meta‐relative risk (mRR) for oral/oropharyngeal cancer in the Indian subcontinent was 2.56 (95%CI, 2.00–3.28; 15 studies) for BQ‐T and 7.74 (95%CI, 5.38–11.13; 31 studies) for BQ+T; in Taiwan, China, the mRR for BQ‐T was 10.98 (95%CI, 4.86–24.84; 13 studies). Restricting to studies that adjusted for tobacco and alcohol use had only a small effect on the risk estimates. For BQ+T in the Indian subcontinent, the mRR was much higher in women (mRR, 14.56; 95%CI, 7.63–27.76) than in men. Exposure‐response analyses showed that the risk of oral/oropharyngeal cancer increased with increasing daily amount and duration (years) of chewing BQ in India and Taiwan, China. Roughly half of oral cancers in these countries could be prevented if BQ were no longer chewed (PAF% = 53.7% for BQ‐T in Taiwan, China; PAF% = 49.5% for BQ+T in India). We demonstrate that betel quid chewing, with or without added tobacco, increases the risk of oral/oropharyngeal cancer in an exposure‐dependent manner, independently of tobacco and alcohol use. Further work is needed to explain the higher risks associated with chewing BQ‐T in Taiwan, China.     

Angiotensin-converting enzyme gene insertion/deletion polymorphism is associated with risk of oral precancerous lesion in betel quid chewers

To investigate whether angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism is related to the risk of oral precancerous lesions (OPL) in Taiwanese subjects who chew betel quid, a total of 61 betel quid chewers having OPL were compared with 61 asymptomatic betel quid chewers matched for betel quid chewing duration and dosage. The frequency of homozygote for ACE D variant is significantly higher in the case subjects than that of the controls (44.3 vs 24.6%; P = 0.0108). The adjusted odds ratio of the D homozygous for the risk of OPL is 8.10 (95% confidence interval (CI) = 2.04-32.19, P = 0.003). In the allelic base analysis, the D allele is also significantly associated with higher risk of OPL. When grouping the study subjects by smoking status, the association between ACE I/D polymorphism and risk of OPL was only observed in nonsmokers. Our results support the theory that genetic factors may contribute to the susceptibility of OPL and suggest that smoking and genetic factors may be differently involved in the development of OPL.     

Interaction of XRCC1 and XPD Gene Polymorphisms with Lifestyle and Environmental Factors Regarding Susceptibility to Lung Cancer in a High Incidence Population in North East India

Background: This study aimed to explore the role of XRCC1 (Arg399Gln) and XPD (Lys751Gln) genepolymorphisms, lifestyle and environmental factors as well as their possible interactions in propensity to developlung cancer in a population with high incidence from North East India. Materials and Methods: A total of 272lung cancer cases and 544 controls were collected and XRCC1 (Arg399Gln) and XPD (Lys751Gln) genotypes wereanalyzed using a polymerase chain reaction based restriction fragment length polymorphism assay. Conditionalmultiple logistic regression analysis was used to calculate adjusted odds ratios and 95% confidence intervalsafter adjusting for confounding factors. Results: The combined Gln/Gln genotype of XRCC1 and XPD genes(OR=2.78, CI=1.05-7.38; p=0.040) was significantly associated with increased risk for lung cancer. Interactionof XRCC1Gln/Gln genotype with exposure of wood combustion (OR=2.56, CI=1.16-5.66; p=0.020), exposure ofcooking oil fumes (OR=3.45, CI=1.39-8.58; p=0.008) and tobacco smoking (OR=2.54, CI=1.21-5.32; p=0.014) andinteraction of XPD with betel quid chewing (OR=2.31, CI=1.23-4.32; p=0.009) and tobacco smoking (OR=2.13,CI=1.12-4.05; p=0.022) were found to be significantly associated with increased risk for lung cancer. Conclusions:Gln/Gln alleles of both XRCC1 and XPD genes appear to amplify the effects of household exposure, smokingand betel quid chewing on lung cancer risk in the study population.     

Assessment of risk factors for oral squamous cell carcinoma in Chidambaram, Southern India: a case-control study.

Oral squamous cell carcinoma, the fifth most common cancer worldwide, is a major cause of morbidity and mortality in India. The effect of lifestyle factors, including tobacco chewing, smoking and alcohol drinking, diet and dental care, on the risk of oral cancer was investigated in a case-control study conducted in Rajah Muthiah Dental College and Hospital, Annamalainagar, Annamalai University, Chidambaram, Tamil Nadu, India during the period 1991-2003. The study included 388 oral squamous cell carcinoma cases and an equal number (388) of age and sex-matched controls. All participants were interviewed using a structured questionnaire that contained data on demographic factors, family history of cancer, tobacco habits, use of alcohol, frequency, duration, cessation of these habits, dietary practices and oral hygiene. The data were analysed using multiple logistic regression model. Among people with chewing habits, those who chewed betel quid with tobacco [odds ratio (OR) 3.19, 95% confidence interval (CI): 0.48-2.13] and tobacco alone (OR 2.89) showed a greater risk than controls. Bidi smoking (OR 4.63) and alcohol drinking (OR 1.65) emerged as significant risk factors for oral cancer. These three habits showed increasing risk with increasing frequency and increase in duration of habits. Addition of alcohol to other habits also enhanced the risk for oral cancer. The combination of chewing and smoking together with alcohol drinking showed very high relative risk (OR 11.34). A positive association was observed between non-vegetarian diet, poor oral hygiene and poor dentition with the risk of oral squamous cell carcinoma. The fact that these risk factors are modifiable emphasizes the need for increasing awareness among the general public and policy makers as a first step in the prevention and control of oral squamous cell carcinoma.     

Betel quid and oral cancer: prospects for prevention.

Betel-quid chewing is an ancient and socially accepted practice. The introduction of tobacco reinforced this practice, and now almost all habitual chewers of betel quids include tobacco. It is well established that chewing of betel quid with tobacco causes oral cancer and is largely responsible for the high incidence of oral cancer in several South Asian countries. The feasibility of primary prevention of oral cancer was studied in a population-based prospective intervention study. A cohort of 12,212 betel-quid chewers and smokers was exposed to a programme of health education for stopping chewing and smoking and subjected to annual examinations for detection of oral precancerous lesions. Evaluations after one, five and eight years showed that primary prevention of oral cancer is feasible and practicable. Early detection of oral cancer is an important control measure. In a secondary prevention study, 53 basic health workers were trained in the detection and referral of lesions suspected of being oral cancer. Over one year, they examined more than 39,000 high-risk individuals, resulting in the detection of 20 cases of oral cancer. The sensitivity and specificity of their diagnoses was assessed through a re-examination of a 5% sample: we concluded that it was possible to incorporate a secondary prevention programme into the existing health care system.     

Lack of association between p53 expression and betel nut chewing in oral cancers from Thailand

To elucidate whether betel-associated oral squamous cell carcinoma is associated with p53 protein expression, tumor samples from 156 patients with detailed histories of exposures were investigated immunohistochemically using CM1 antibody. The expression of p53 (>10% positive cells) was found in 38.5% of the cases. The frequency of expression in betel chewers alone and betel chewer with tobacco use were 37.9% (11/29) and 25%(9/36), respectively, whereas that in betel chewers with smoking/drinking it was 47.2%(17/36) and in smokers or drinkers without chewing was 42.0% (21/50). However, the differences were not statistically significant. Multivariate analysis also revealed with the no independent association of betel chewing with p53 expression (odds ratio [OR] 1.81, 95% confidence interval 0.50-6.49), whereas alcohol drinking and smokeless tobacco use were significant (OR 7.58, 2.01-28.53 and 0.39, 0.16-0.98, respectively). These results suggested that betel chewing with or without smokeless tobacco use may not induce oral cancers via a p53-dependent pathway. However, since this is an immunohistochemical study, further molecular analysis is needed.     

Independent and combined effects of tobacco smoking,chewing and alcohol drinking on the risk of oral,pharyngeal and esophageal cancers in Indian men

Oral, pharyngeal and esophageal cancers are 3 of the 5 most common cancer sites in Indian men. To assess the effect of different patterns of smoking, chewing and alcohol drinking in the development of the above 3 neoplasms and to determine the interaction among these habits, we conducted a case-control study in Chennai and Trivandrum, South India. The cases included 1,563 oral, 636 pharyngeal and 566 esophageal male cancer patients who were compared with 1,711 male disease controls from the 2 centers as well as 1,927 male healthy hospital visitors from Chennai. We observed a significant dose-response relationship for duration and amount of consumption of the 3 habits with the development of the 3 neoplasms. Tobacco chewing emerged as the strongest risk factor for oral cancer, with the highest odds ratio (OR) for chewing products containing tobacco of 5.05 [95% confidence internal (CI) 4.26-5.97]. The strongest risk factor for pharyngeal and esophageal cancers was tobacco smoking, with ORs of 4.00 (95% CI 3.07-5.22) and 2.83 (95% CI 2.18-3.66) in current smokers, respectively. An independent increase in risk was observed for each habit in the absence of the other 2. For example, the OR of oral cancers for alcohol drinking in never smokers and never chewers was 2.56 (95% CI 1.42-4.64) and that of esophageal cancers was 3.41 (95% CI 1.46-7.99). Furthermore, significant decreases in risks for all 3 cancer sites were observed in subjects who quit smoking even among those who had quit smoking 2-4 years before the interview.     

Family History of Cancer and Head and Neck Cancer Risk in a Chinese Population

Background: The aim of this study was to investigate whether family history of cancer is associated with head and neck cancer risk in a Chinese population. Materials and Methods: This case-control study included 921 cases and 806 controls. Recruitment was from December 2010 to January 2015 in eight centers in East Asia. Controls were matched to cases with reference to sex, 5-year age group, ethnicity, and residence area at each of the centers. Results: We observed an increased risk of head and neck cancer due to first degree family history of head and neck cancer, but after adjustment for tobacco smoking, alcohol drinking and betel quid chewing the association was no longer apparent. The adjusted OR were 1.10 (95% CI=0.80-1.50) for family history of tobacco-related cancer and 0.96 (95%CI=0.75-1.24) for family history of any cancer with adjustment for tobacco, betel quid and alcohol habits. The ORs for having a first-degree relative with HNC were higher in all tobacco/ alcohol subgroups. Conclusions: We did not observe a strong association between family history of head and neck cancer and head and neck cancer risk after taking into account lifestyle factors. Our study suggests that an increased risk due to family history of head and neck cancer may be due to shared risk factors. Further studies may be needed to assess the lifestyle factors of the relatives.     

Oral cancer in southern India: the influence of smoking, drinking, paan-chewing and oral hygiene

Between 1996 and 1999 we carried out a case-control study in 3 areas in Southern India (Bangalore, Madras and Trivandrum) including 591 incident cases of cancer of the oral cavity (282 women) and 582 hospital controls (290 women), frequency-matched with cases by age and gender. Odds ratios (ORs) and 95% confidence intervals (CIs) were obtained from unconditional multiple logistic regressions and adjusted for age, gender, center, education, chewing habit and (men only) smoking and drinking habits. Low educational attainment, occupation as a farmer or manual worker and various indicators of poor oral hygiene were associated with significantly increased risk. An OR of 2.5 (95% CI 1.4-4.4) was found in men for smoking > or = 20 bidi or equivalents versus 0/day. The OR for alcohol drinking was 2.2 (95% CI 1.4-3.3). The OR for paan chewing was more elevated among women (OR 42; 95% CI 24-76) than among men (OR 5.1; 95% CI 3.4-7.8). A similar OR was found among chewers of paan with (OR 6.1 in men and 46 in women) and without tobacco (OR 4.2 in men and 16.4 in women). Among men, 35% of oral cancer is attributable to the combination of smoking and alcohol drinking and 49% to pan-tobacco chewing. Among women, chewing and poor oral hygiene explained 95% of oral cancer.     

Genetic cancer susceptibility and DNA adducts: studies in smokers, tobacco chewers, and coke oven workers

Preventive strategies require identification of cancer-susceptible individuals resulting from combinations of carcinogen exposure, cancer-predisposing genes, and lack of protective factors. To this aim, related to tobacco smoking and chewing (betel quid), we measured PAH-DNA adducts as exposure and susceptibility markers together with genetic polymorphism in drug-metabolizing enzymes related to CYP1A1, GSTM1, and GSTT1 genes in case-control studies. (+)-anti-Benzo(a)pyrene diol-epoxide (BPDE)-DNA adduct levels were quantitated in white blood cells (WBCs) and lung tissue DNA. CYP1A1 polymorphism and GSTM1 or GSTT1 gene deletion was analyzed in genomic DNA from lung parenchyma, WBCs, or oral biopsies (leukoplakia patients from India) and from oral exfoliated cells (healthy controls). Results from lung cancer patients and PAH-exposed coke oven workers correlated CYP1A1-GSTM1 genotype combinations with BPDE-DNA adduct levels. Smokers with homozygous CYP1A1 variant and GSTM1 null had the highest adduct levels and were, as shown in Japanese smokers, most susceptible to lung cancer. In oral premalignant leukoplakia cases associated with betel quid/tobacco chewing, the prevalence of the GSTM1 null and GSTT1 null genotypes was significantly higher, as compared to healthy controls. The combined GST null genotypes prevailed in 60% of the cases with none detected in controls. Based on this short review we conclude that (i) BPDE-DNA adduct levels resulting from "at risk" genotype combinations may serve as markers to identify most susceptible individuals; (ii) in Indian betel quid/tobacco chewers, the null genotypes of GSTM1 and GSTT1 greatly increased the risk for developing oral leukoplakia.     

A review of betel quid chewing, oral cancer and precancer in Mainland China

On the Chinese mainland, betel quid (BQ) chewing is common in the Hunan and Hainan provinces. The BQ chewing habit in Hunan consists of dried husks and betel nuts, which are sold as industrially packaged, areca nut-based products. In Hainan, the fresh nut is chewed. Tobacco is not added. Reported prevalence of BQ chewing in Hunan province is high (64.5-82.7%). Oral diseases associated with BQ chewing are oral submucous fibrosis (OSF), oral leukoplakia (OL) and oral cancer. Reported prevalence of OSF among BQ chewers ranges from 0.9% to 4.7%. People most commonly affected are between the ages of 30 and 39 years, and 40 and 49 years. The reported prevalence of OL in Hainan ranges from 2.1% to 2.5%. In BQ chewers who also smoke, the reported prevalence is 20.3%. The prevalence of OL in Hunan province ranges from 0.1% to 0.5%. The prevalence of oral cancer among BQ chewers is low, ranging from 0.02% to 0.05%. In cases of OSF, reported prevalence is 2.6% and 1.2%. Presently, data on prevalence of BQ chewing in southern provinces of Mainland China is limited. BQ chewing habits, however, seem to differ between geographic areas. Future case-control studies are necessary to evaluate the risk for oral cancer and other associated oral mucosal diseases resulting from variations in BQ chewing habits.