Abstract
Purpose
Paan (betel leaf and betel nut quid) used with or without tobacco has been positively associated with oral cancer. Oral submucous fibrosis (OSMF), a precancerous condition caused by paan, lies on the causal pathway between paan use and oral cancer. The purpose of this analysis was to estimate the effect of paan consumption on oral cancer risk when it is mediated by OSMF.
Methods
We used mediation methods proposed by VanderWeele, which are based on causal inference principles, to characterize the total, direct, and indirect effects of paan, consumed with and without tobacco, on oral cancer mediated by OSMF. We reanalyzed case–control data collected from three hospitals in Karachi, Pakistan, between July 1996 and March 1998.
Results
For paan without tobacco, the total effect on oral cancer was OR 7.39, 95 % CI 1.01, 38.11, the natural indirect effect (due to OSMF among paan users) was OR 2.48, 95 % CI 0.99, 10.44, and the natural direct effect (due to paan with OSMF absent) was OR 3.32, 95 % CI 0.68, 10.07. For paan with tobacco, the total direct effect was OR 15.68, 95 % CI 3.00, 54.90, the natural indirect effect was OR 2.18, 95 % CI 0.82, 5.52, and the natural direct effect was OR 7.27, 95 % CI 2.15, 20.43.
Conclusions
Paan, whether or not it contained tobacco, raised oral cancer risk irrespective of OSMF. Oral cancer risk was higher among those who used paan with tobacco.
References
Merchant A, Husain SS, Hosain M, Fikree FF, Pitiphat W, Siddiqui AR, Hayder SJ, Haider SM, Ikram M, Chuang SK, Saeed SA (2000) Paan without tobacco: an independent risk factor for oral cancer. Int J Cancer 86:128–131
International Agency for Research on Cancer (2004) Betel-quid and areca-nut chewing and some areca-nut-derived nitrosamines. IARC Monographs on the evaluation of carcinogenic risks to humans, vol 85. World Health Organization, Geneva
Murti PR, Bhonsle RB, Gupta PC, Daftary DK, Pindborg JJ, Mehta FS (1995) Etiology of oral submucous fibrosis with special reference to the role of areca nut chewing. J Oral Pathol Med 24:145–152
Cole SR, Hernan MA (2002) Fallibility in estimating direct effects. Int J Epidemiol 31:163–165
VanderWeele TJ (2009) Mediation and mechanism. Eur J Epidemiol 24:217–224. doi:10.1007/s10654-009-9331-1
VanderWeele TJ (2013) A three-way decomposition of a total effect into direct, indirect, and interactive effects. Epidemiology 24:224–232. doi:10.1097/EDE.0b013e318281a64e
Valeri L, VanderWeele TJ (2013) Mediation analysis allowing for exposure–mediator interactions and causal interpretation: theoretical assumptions and implementation with SAS and SPSS macros. Psychol Methods 18:137–150. doi:10.1037/a0031034
VanderWeele TJ, Vansteelandt S (2010) Odds ratios for mediation analysis for a dichotomous outcome. Am J Epidemiol 172:1339–1348. doi:10.1093/aje/kwq332
Thomas SJ, Bain CJ, Battistutta D, Ness AR, Paissat D, Maclennan R (2007) 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. Int J Cancer 120:1318–1323. doi:10.1002/ijc.22304
Thomas SJ, Harris R, Ness AR, Taulo J, Maclennan R, Howes N, Bain CJ (2008) 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. Int J Cancer 123:1871–1876. doi:10.1002/ijc.23739
Sharan RN, Mehrotra R, Choudhury Y, Asotra K (2012) Association of betel nut with carcinogenesis: revisit with a clinical perspective. PLoS ONE 7:e42759. doi:10.1371/journal.pone.0042759
Maher R, Lee AJ, Warnakulasuriya KA, Lewis JA, Johnson NW (1994) Role of areca nut in the causation of oral submucous fibrosis: a case–control study in Pakistan. J Oral Pathol Med 23:65–69
Zain RB, Ikeda N, Gupta PC, Warnakulasuriya S, van Wyk CW, Shrestha P, Axell T (1999) Oral mucosal lesions associated with betel quid, areca nut and tobacco chewing habits: consensus from a workshop held in Kuala Lumpur, Malaysia, November 25–27, 1996. J Oral Pathol Med 28:1–4
Lee CH, Chiang SL, Ko AM, Hua CH, Tsai MH, Warnakulasuriya S, Ibrahim SO, Sunarjo, Zain RB, Ling TY, Huang CL, Lane HY, Lin CC, Ko YC (2014) Betel-quid dependence domains and syndrome associated with betel-quid ingredients among chewers: an Asian multi-country evidence. Addiction 109:1194–1204. doi:10.1111/add.12530
Lee CH, Ko AM, Warnakulasuriya S, Yin BL, Sunarjo, Zain RB, Ibrahim SO, Liu ZW, Li WH, Zhang SS, Kuntoro, Utomo B, Rajapakse PS, Warusavithana SA, Razak IA, Abdullah N, Shrestha P, Kwan AL, Shieh TY, Chen MK, Ko YC (2011) Intercountry prevalences and practices of betel-quid use in south, southeast and eastern Asia regions and associated oral preneoplastic disorders: an international collaborative study by Asian betel-quid consortium of south and east Asia. Int J Cancer 129:1741–1751. doi:10.1002/ijc.25809
Murti PR, Gupta PC, Bhonsle RB, Daftary DK, Mehta FS, Pindborg JJ (1990) Effect on the incidence of oral submucous fibrosis of intervention in the areca nut chewing habit. J Oral Pathol Med 19:99–100
Murti PR, Bhonsle RB, Pindborg JJ, Daftary DK, Gupta PC, Mehta FS (1985) Malignant transformation rate in oral submucous fibrosis over a 17-year period. Community Dent Oral Epidemiol 13:340–341
Boffetta P, Hecht S, Gray N, Gupta P, Straif K (2008) Smokeless tobacco and cancer. Lancet Oncol 9:667–675. doi:10.1016/S1470-2045(08)70173-6
Rodu B, Jansson C (2004) Smokeless tobacco and oral cancer: a review of the risks and determinants. Crit Rev Oral Biol Med 15:252–263
Gupta PC, Murti PR, Bhonsle RB, Mehta FS, Pindborg JJ (1995) Effect of cessation of tobacco use on the incidence of oral mucosal lesions in a 10-year follow-up study of 12,212 users. Oral Dis 1:54–58
Sinha DN, Gupta PC, Ray C, Singh PK (2012) Prevalence of smokeless tobacco use among adults in WHO south-east Asia. Indian J Cancer 49:342–346. doi:10.4103/0019-509X.107726
Alam SE (1998) Prevalence and pattern of smoking in Pakistan. J Pak Med Assoc 48:64–66
Merchant AT, Luby SP, Perveen G (1998) Smoking in Pakistan: more than cancer and heart disease. J Pak Med Assoc 48:77–79
Kakde S, Bhopal RS, Jones CM (2012) A systematic review on the social context of smokeless tobacco use in the South Asian population: implications for public health. Public Health 126:635–645. doi:10.1016/j.puhe.2012.05.002
SEER Stat Fact Sheet: Oral Cavity and Pharynx (2014)
Sankaranarayanan R, Swaminathan R, Lucas E (2011) Cancer survival in Africa, Asia, the Caribbean and Central America (SurvCan). IARC Scientific Publications, vol 162. International Agency for Research on Cancer, Lyon
Chaturvedi P, Vaishampayan SS, Nair S, Nair D, Agarwal JP, Kane SV, Pawar P, Datta S (2013) Oral squamous cell carcinoma arising in background of oral submucous fibrosis: a clinicopathologically distinct disease. Head Neck 35:1404–1409. doi:10.1002/hed.23143
Shah SM, Merchant AT, Luby SP, Chotani RA (2002) Addicted schoolchildren: prevalence and characteristics of areca nut chewers among primary school children in Karachi, Pakistan. J Paediatr Child Health 38:507–510
Gupta PC, Ray CS, Sinha DN, Singh PK (2011) Smokeless tobacco: a major public health problem in the SEA region: a review. Indian J Public Health 55:199–209. doi:10.4103/0019-557X.89948
Acknowledgments
We are grateful to Aga Khan University for funding this study and Drs. Mervyn Hosein, Syed Mehmood Haider, Amna Rehana Siddiqui, Fariyal F. Fikree, Stephen P. Luby, and Sung-Kiang Chuang for their contributions to earlier reports from these data.
Conflict of interest
Neither of the authors have any conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Merchant, A.T., Pitiphat, W. Total, direct, and indirect effects of paan on oral cancer. Cancer Causes Control 26, 487–491 (2015). https://doi.org/10.1007/s10552-014-0516-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10552-014-0516-x