Betel quid not containing tobacco and oral cancer: a report on a case-control study in Papua New Guinea and a meta-analysis of current evidence

Smoking and betel quid chewing are associated with increased risk of oral cancer but few studies have reported on associations in populations where betel quid does not contain tobacco. We conducted a case-control study in Papua New Guinea and a systematic review. Our case-control study recruited 143 cases with oral cancer and 477 controls. We collected information on smoking and betel quid chewing. Current smoking was associated with an increased risk of oral cancer with an adjusted odds ratio (OR) for daily smokers of 2.63 (95% confidence intervals (95% CI) 1.32, 5.22) and amongst heaviest smokers of 4.63 (95% CI 2.07, 10.36) compared to never-smokers. Betel chewing was associated with increased risk of oral cancer with an adjusted OR for current chewers of 2.03 (95% CI 1.01, 4.09) and in the heaviest chewers of 2.47 (95% CI 1.13, 5.40) compared to nonchewers. The OR in those who both smoked tobacco and chewed betel quid was 4.85 (95% 1.10, 22.25), relative to those who neither smoked nor chewed. The systematic review identified 10 previous studies that examined risk of oral cancer associated with betel quid chewing that controlled for smoking in populations where betel quid did not contain tobacco. In studies that reported results for non-smokers the combined OR was 2.14 (95% CI 1.06, 4.32) in betel quid chewers and in studies that adjusted for smoking the combined OR was 3.50 (95% CI 2.16, 5.65) in betel quid chewers. Preventive efforts should discourage betel quid chewing as well as smoking.     

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.     

Betel quid chewing as a risk factor for hepatocellular carcinoma: a case-control study

The role of betel quid chewing in the aetiology of hepatocellular carcinoma (HCC) was evaluated in a case-control study including 263 pairs of age- and sex-matched HCC patients and healthy controls. Serum hepatitis B surface antigen (HBsAg), and antibodies to hepatitis C virus (anti-HCV) were determined, and standardized personal interview conducted using a structured questionnaire. Multivariate analysis indicated that betel quid chewing (odds ratio (OR), 3.49; 95% confidence interval (CI), 1.74-6.96), HBsAg (OR, 16.69; 95% CI, 9.92-28.07), anti-HCV (OR, 38.57; 95% CI, 18.15-81.96), and educational duration of less than 10 years (OR, 1.71; 95% CI, 1.05-2.78) are independent risk factors of HCC. In addition, there was an additive interaction between betel quid chewing and chronic infection with either hepatitis B virus (synergy index, 5.37) or hepatitis C virus (synergy index, 1.66). Moreover, risk on HCC increased as duration of betel quid chewing increased, or amount of betel quid consumed (each P for trend < 0.0001).     

Prognostic significance of EGFR and Her-2 in oral cavity cancer in betel quid prevalent area cancer prognosis

Although several studies have found overexpression of epidermal growth factor receptor (EGFR) proteins EGFR and Her-2 in head and neck cancers, the clinical relevance of the finding varies. We examined the expression and clinical association of these molecules with oral squamous cell carcinoma in an area where betel chewing is prevalent. EGFR and Her-2 proteins were measured in 59 paired (grossly normal and cancer) tissues by an enzyme immunoassy method. The cutoff value for gene overexpression was defined as the level of mean expression in normal tissue plus two s.d. A total of 59% of the patients consumed alcohol, 90% smoked tobacco, and 90% chewed betel quid. Of the patients assayed, 34 (58%) and 24 (41%) had EGFR and Her-2 overexpression, with average 3.5- and 1.5-fold elevations. EGFR overexpression has been shown to be statistically associated with T stage, N stage, overall TMN stage, primary tumour depth, lymph node extra-capsular spread, and poor survival. Her-2 overexpression, however, did not demonstrate a similar association with clinicopathological parameters or therapeutic outcome. On multivariant analysis, EGFR overexpression (P=0.041) and N stage (P=0.024) were the only independent factors for overall survival. These results indicate that the molecular targeting therapy to EGFR may be a treatment for oral cavity cancer in the betel quid-chewing prevalent area.     

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.     

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.     

Impact of oral submucous fibrosis on chemotherapy-induced mucositis for head and neck cancer in a geographic area in which betel quid chewing is prevalent.

In Southeast Asia and Taiwan, betel quid chewing is prevalent. Patients with head and neck cancer who chewed betel quid habitually seem to experience more severe chemotherapy-induced mucositis in our clinical practice. To validate this issue, patients with untreated head and neck cancer who received cisplatin (cDDP) plus a 5-fluorouracil (5-FU)-based neoadjuvant chemotherapy were included in this analysis. Information on the consumption of betel quid, tobacco, and alcohol were recorded before chemotherapy. Oral submucous fibrosis (OSF) was diagnosed clinically according to the fibrotic appearance of the mucosa and trismus. Mucositis was scored according to the World Health Organization criteria, and the mucositis score of the first course of chemotherapy was used for analysis. From December 1993 to April 1996, 120 patients were enrolled in this trial. Neither the betel quid chewing nor the cancer of the oral cavity was to be a significant factor for mucositis. However, clinically diagnosed OSF was found to display a significant correlation with more severe mucositis (p = 0.02). We concluded that in betel quid chewing-prevalent areas, OSF was a risk factor of more severe mucositis in head and neck cancer patients treated by CDDP and 5-FU-based regimens.     

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.     

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.     

Univariate and multivariate analysis of prognostic significance of betel quid chewing in squamous cell carcinoma of buccal mucosa in Taiwan

BACKGROUND AND OBJECTIVES: While betel quid (BQ) chewing is clearly the most avoidable risk factor of squamous cell carcinoma of buccal mucosa (BMSCC), little is known about the influence of this habit on the prognosis of BMSCC. METHODS: We surveyed 280 patients with BMSCC who were treated during an 8-year period in a cohort study to assess the independent predictive value of pretreatment BQ chewing habit on the prognosis by univariate and multivariate analysis. RESULTS: We found by univariate analysis that sex, age, clinical stage, smoking, and BQ chewing significantly affected the patients' prognosis and only age, clinical stage, and BQ chewing had significant influence on prognosis by multivariate analysis (P < 0.05). Further analysis revealed that the prognostic effect of BQ chewing changed in a dose- and time-dependent manner. The risk of death was 31.4-fold higher in heavy user (duration >30 years, daily consumption >30 quids, age of start <20 years old) when compared to those who chewed BQ to a milder degree (duration <10 years, daily consumption <15 quids, age of start > or =20 years old ) (P < 0.001). CONCLUSIONS: Pretreatment BQ chewing habit worsens the prognosis of BMSCC in Taiwan. BQ chewing is a prognostic indicator that can be used in conjunction with clinical staging to help plan the treatment for the patients.     

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.     

Ortho- and meta-tyrosine formation from phenylalanine in human saliva as a marker of hydroxyl radical generation during betel quid chewing

The habit of betel quid chewing, common in South-East Asia andthe South Pacific islands, is causally associated with an increasedrisk of oral cancer. Reactive oxygen species formed from polyphenolicbetel quid ingredients and lime at alkaline pH have been implicatedas the agents responsible for DNA and tissue damage. To determinewhether hydroxyl radical (HO) is generated in the human oralcavity during chewing of betel quid, the formation of o- andm-tyrosine from L-phenylalanine was measured, Both o- and m-tyrosinewere formed in vitro in the presence of extracts of areca nutand/or catechu, transition metal ions such as Cu²⁺ and Fe²⁺and lime or sodium carbonate (alkaline pH). Omission of anyof these ingredients from the reaction mixture significantlyreduced the yield of tyrosines. Hydroxyl radical scavengerssuch as ethanol, D-mannitol and dimethylsulfoxide inhibitedthe phenylalanine oxidation in a dose-dependent fashion. Fivevolunteers chewed betel quid consisting of betel leaf, arecanut, catechu and slaked lime (without tobacco). Their saliva,collected after chewing betel quid, contained high concentrationsof p-tyrosine, but no appreciable amounts of o- or m-tyrosine.Saliva samples from the same subjects after chewing betel quidto which 20 mg phenylalanine had been added contained o- andm-tyrosine at concentrations ranging from 1010 to 3000 nM andfrom 1110 to 3140 nM respectively. These levels were significantlyhigher (P< 0.005) than those of subjects who kept phenylalaninein the oral cavity without betel quid, which ranged from 14to 70 nM for o-tyrosine and from 10 to 35 nM for m-tyrosine.These studies clearly demonstrate that the HO radical is formedin the human oral cavity during betel quid chewing and is probablyimplicated in the genetic damage that has been observed in oralepithelial cells of chewers.     

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.     

The precancer risk of betel quid chewing,tobacco use and alcohol consumption in oral leukoplakia and oral submucous fibrosis in southern Taiwan

In areas where the practise of betel quid chewing is widespread and the chewers also often smoke and drink alcohol, the relation between oral precancerous lesion and condition to the three habits is probably complex. To explore such association and their attributable effect on oral leukoplakia (OL) and oral submucous fibrosis (OSF), a gender-age-matched case-control study was conducted at Kaohsiung, southern Taiwan. This study included 219 patients with newly diagnosed and histologically confirmed OL or OSF, and 876 randomly selected community controls. All information was collected by a structured questionnaire through in-person interviews. A preponderance of younger patients had OSF, while a predominance of older patients had OL. Betel quid chewing was strongly associated with both these oral diseases, the attributable fraction of OL being 73.2% and of OSF 85.4%. While the heterogeneity in risk for areca nut chewing across the two diseases was not apparent, betel quid chewing patients with OSF experienced a higher risk at each exposure level of chewing duration, quantity and cumulative measure than those who had OL. Alcohol intake did not appear to be a risk factor. However, cigarette smoking had a significant contribution to the risk of OL, and modified the effect of chewing based on an additive interaction model. For the two oral premalignant diseases combined, 86.5% was attributable to chewing and smoking. Our results suggested that, although betel quid chewing was a major cause for both OL and OSF, its effect might be difference between the two diseases. Cigarette smoking has a modifying effect in the development of 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.     

High Prevalence of Lifestyle Factors Attributable for Oral Cancer,and of Oral Potentially Malignant Disorders in Rural Sri Lanka

Background: Oral Cancer is a major public health problem in most of the South East Asian countries including SriLanka. Use of tobacco in the form of smokeless tobacco and smoking, use of alcohol and betel quid chewing are themajor contributory factors for causation oral cancer. The aim of this study was to investigate the prevalence of lifestylefactors responsible for causation of oral cancer and Oral Potentially Malignant Disorders (OPMD) in the Sabaragamuwaprovince of Sri Lanka. Methods: A cross-sectional community based study was conducted in Sabaragamuwa provinceby interviewing, then conducting an oral examination, on 1029 subjects over 30 years of age, over a one year period fromNovember 2006. The study protocol included an interviewer-administered questionnaire to gather socio-demographicfactors, recording of habits that included areca/betel chewing, smoking, and alcohol consumption. A three-day food diarywas obtained, particularly to assess the consumption of tea, fruits and vegetables. The weight and height of residentswas taken for calculation of Body Mass Index (BMI). Results: One hundred and two individuals with one or moreOPMD were detected among these 1029 subjects. The prevalence of OPMD, weighted according to the estate sector andgender, was estimated as 11.3%. The prevalence of daily betel quid chewing in this study was 53.8%: 15.7% withouttobacco and 47.4% with tobacco. The prevalence of individuals who reported consumption of alcohol at least weeklywas 13.4%. A significant minority, 31.7%, were under nourished, with a BMI < 18.5. Forty six percent of the malespracticed combined habits of betel quid chewing, smoking and regular use of alcohol. Conclusions: This study discloseshigh prevalence of OPMD and of lifestyle factors for oral cancer in these communities. There is an urgent need fora comprehensive strategy to control the use of tobacco, betel quid chewing and alcohol for prevention of oral cancer.     

Elevated frequency of micronucleated cells in the buccal mucosa of individuals at high risk for oral cancer: betel quid chewers

The micronucleus test was applied to buccal mucosa cells of 2 population groups at high risk for oral cancer: Khasis of the northeastern hill region of India, who eat raw betel nuts together with betel leaves and lime, and residents of the state of Orissa (India), who chew betel quids consisting mainly of perfumed tobacco, dried betel nut, betel leaf, lime and several spices. Micronuclei were scored on Feulgen/fast green-stained smear preparations of exfoliated cells obtained by scraping the surface of the buccal mucosa. All 17 raw betel nut eaters and all 20 chewers of betel quids had significantly elevated frequencies of micronucleated mucosa cells over nonchewing controls of comparable ethnic background and dietary habits. The frequencies of micronucleated exfoliated cells were higher at the site within the oral cavity where the quid was kept compared to those at the opposite buccal wall. The micronuclei frequency was lower among individuals chewing a raw betel nut, betel leaf and lime mixture compared to those using tobacco,-betel nut-, lime- and betel leaf-containing quids. Micronuclei frequencies in exfoliated human cells seem to represent a useful 'internal dosimeter' for estimating exposure to genotoxic, and by implication, carcinogenic agents in the tissue from which cancers will develop.     

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.     

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 mRNA profile of genes in betel quid chewing oral cancer patients

Oral cancer is one of the most common types of human cancer in the world. Although the risk factors for oral cancer are well-recognized in different countries, the molecular mechanism responsible for this malignancy remains elusive particularly in the countries where betel quid chewing is prevalent. The cDNA microarray analysis was used to analyse the mRNA expression patterns of 1177 genes in ten oral cancer patients with betel quid chewing history. Eighty-four genes involving cell adhesion, cell shape, growth, apoptosis, angiogenesis, metastasis, and metabolism were deregulated. Although the expression profile of these genes was shared by certain clinical patients, there was no significant association of the expression profile with clinical staging. Functional implication of four validated genes including caspase-1, STAT-1, COX-2 and pleiotrophin was discussed. This study provides pilot data for understanding the pathogenesis of oral cancer in countries like Taiwan where betel quid chewing is prevalent.