PAAN WITHOUT TOBACCO: AN INDEPENDENT RISK FACTOR FOR ORAL CANCER Anwar MERCHANT 1,2,3 * Syed S. M. HUSAIN 4 , Mervyn HOSAIN 5 , Fariyal F. FIKREE 2 , Waranuch PITIPHAT 3,6,7 , Amna Rehana SIDDIQUI 2 , Syed J. HAYDER 4 , Syed M. HAIDER 8 , Mubashir IKRAM 4 , Sung-Kiang CHUANG 3,6 and Shaikh A. SAEED 9 1 Department of Nutrition, Harvard School of Public Health, Boston, MA, USA 2 Department of Community Health Sciences, Aga Khan University, Karachi, Pakistan 3 Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA 4 Department of Surgery, Aga Khan University, Karachi, Pakistan 5 Department of Oral and Maxillofacial Surgery, Civil Hospital Karachi, Pakistan 6 Department of Oral Health Policy and Epidemiology, Harvard School of Dental Medicine, Boston, MA, USA 7 Faculty of Dentistry, Khon Kaen University, Khon Kaen, Thailand 8 Department of Oral and Maxillofacial Surgery, Abbassi Shaheed Hospital, Karachi, Pakistan 9 Department of Pharmacology, Aga Khan University, Karachi, Pakistan Oral cancer is the second most common cancer in women and the third most common in men in Pakistan. Tobacco is smoked and chewed extensively in Pakistan. Paan is a quid of piper betel leaf that contains areca nut, lime, condiment, sweeteners, and sometimes tobacco, which is also used ex- tensively. We did this study to clarify the independent asso- ciation of paan and oral cancer. Between July 1996 and March 1998, we recruited biopsy-proven, primary cases of oral squa- mous-cell carcinoma, from 3 tertiary teaching centers in Karachi, Pakistan, and controls pair-matched for age, gender, hospital and time of occurrence, excluding persons with a past or present history of any malignancy. There were 79 cases and 149 controls. Approximately 68% of the cases were men, 49 years old on average, the youngest being 22 years old and the eldest 80. People with oral submucous fibrosis were 19.1 times more likely to develop oral cancer than those without it, after adjusting for other risk factors. People using paan without tobacco were 9.9 times, those using paan with tobacco 8.4 times, more likely to develop oral cancer as compared with non-users, after adjustment for other co- variates. This study identifies an independent effect of paan without tobacco in the causation of oral cancer. Its findings may be of significance in South Asian communities where paan is used, and among health-care providers who treat persons from South Asia. Int. J. Cancer 86:128 –131, 2000. © 2000 Wiley-Liss, Inc. Oral cancer is the second most common cancer in women and the third most common in men in Pakistan (Jafarey and Zaidi, 1987). Tobacco, chewed or smoked, is a well-established cause of oral squamous-cell carcinoma (Gupta et al., 1982; Jayant and Deo, 1986; Brennan et al., 1995). Alcohol, particularly in association with tobacco, increases the risk of oral cancer. Approximately 40% of men in Pakistan over the age of 15 years smoke cigarettes or bidis (locally cured tobacco rolled in a dry leaf) regularly (National Health Survey of Pakistan, 1997). Tobacco is chewed in Pakistan as paan and as naswar. Paan consists of piper betel leaf containing lime, areca nut, condiments, sweeteners and sometimes tobacco. It is chewed and held in the mouth like a quid. Naswar is a mixture of tobacco and lime (Jayant and Deo, 1986). Areca nut without tobacco is suspected of being associated with oral cancer, but epidemiological studies have not clearly demonstrated its indepen- dent effect (Dave et al., 1992). A study has shown significantly more chromosomal aberrations, sister chromatid exchanges, and genomic damage among areca-nut users than among non-users, independently of tobacco use (Dave et al., 1992). But areca-nut users, independently of tobacco use, are 100 times more likely to get oral submucous fibrosis, which is a pre-cancerous lesion of the mouth (Maher et al., 1994). A study from South Africa showed increased risk of oral cancer from chewing areca nut, but the estimates were not adjusted for all important risk factors (van Wyk et al., 1993). We did this study to clarify the independent associ- ation of paan and oral cancer. MATERIAL AND METHODS Between July 1996 and March 1998, we recruited biopsy- proven primary cases of oral squamous-cell carcinoma, from Aga Khan University Hospital (AKUH), Civil Hospital Karachi (CHK) and Abbassi Shaheed Hospital (ASH). All 3 hospitals are tertiary teaching centers located in Karachi, Pakistan. AKUH and CHK have attached undergraduate medical colleges. Patients attend all 3 hospitals from all over the province. Sindh is Pakistan’s second largest province, with a population of approximately 30 million. Karachi is the largest city in Sindh, with a multi-ethnic population of 9.8 million according to the 1998 census. We pair-matched controls from patients who had been admitted to the orthopedic and general surgical wards of the same hospital at the same time as the corresponding case, were of the same sex, and were aged within 5 years of the cases. We excluded as controls persons with a past or present history of any malignancy. After obtaining verbal consent, a trained interviewer adminis- tered a structured, pre-tested, questionnaire in Urdu (the lingua franca of Pakistan), examined the mouth, and checked for the presence of oral submucous fibrosis (OSMF) on cases and con- trols. This was determined clinically by observation of blanching and by palpation for the presence of fibrous bands. The interviewer was clinically trained to check the clinical signs of the disease. In addition to socio-economic and demographic data, we also col- lected information on the use of cigarettes, bidis, hookah, naswar, paan, areca nut, and alcohol. We defined users of naswar, paan or areca nut as someone who had ever indulged in the habit daily for a month. Smokers were persons who had ever smoked cigarettes, bidis, hookah, cigar, or a pipe daily for at least one month. For each of the substances we asked the date of starting, current use or date of quitting, and average quantity used per day. During anal- Definitions: Oral submucous fibrosis (OSMF), Progressive fibrosis of the oral mucosa resulting in limited mouth opening. Strongly associated with areca nut use; pre-cancerous. Paan without tobacco, Piper betel leaf con- taining lime, areca nut, condiments and sweeteners. It is chewed and held in the mouth like a quid. Paan with tobacco, Piper betel leaf containing lime, areca nut, condiments, sweeteners and tobacco. It is chewed and held in the mouth like a quid. Naswar, Tobacco and lime mixture that is chewed and held in the mouth like a quid. Bidi, Locally cured tobacco rolled in a dry leaf and smoked. Hookah, Hubble-bubble. A pipe for smoking tobacco in which the smoke is filtered through water before inhalation. Grant sponsor: Aga Khan University, Karachi. *Correspondence to: Department of Nutrition, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA. Fax: +1 617 432-2435. E-mail: amerchan@hsph.harvard.edu Received 10 September 1999; Revised 16 November 1999 Int. J. Cancer: 86, 128 –131 (2000) © 2000 Wiley-Liss, Inc. Publication of the International Union Against Cancer