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A pre-existing potentially malignant lesions or conditions, often associated with tobacco and/or areca nut containing quid, may constitute, if not in all cases, pre-malignant stages of oral squamous cell carcinoma. However, their natural history and to what extent these lesions are prevalent and their transformation into a malignant lesion which may vary between different population groups, habit factors and other predisposing or risk factors are difficult to obtain. The present study evaluated the prevalence and characteristics of oral mucosal lesions associated with tobacco and areca nut containing-quid hewing habit in a population based random sample of 1421 individuals in three geographical regions of Nepal, to our knowledge for the first time in the country, and patients presenting with oral mucosal lesions in a hospital setting. Furthermore, to evaluate at least a few aspects of alterations at the molecular level, cellular proliferation and presence of mutant form of p53 oncosupressor gene product, known to affect or contribute in the process of carcinogenesis, in a number of these lesions were assessed by immunohistological methods.

Of the variety of tobacco and areca nut containing quid habit, in the population based survey, the commonest lesions associated with the habit was found to be tobacco pouch associated white or red lesions in 70.4% of tobacco quid users (n=186), leukoplakia in 2.4% of smokers (n=495) and submucous fibrosis in 3 subjects who were all areca nut chewers. All these lesions or conditions were significantly correlated with the duration of more than 5 years (p<0.05) and frequency (p<0.05, at least once a day vs occasional) of the associated habit factor.

In an analysis of the patients presenting with these lesions in a hospital setting – tobacco pouch lesions in tobacco and lime users (n=35) showed complete remission with the discontinuation of the tobacco habit for 1-3 weeks (n=33); betel chewers mucosa (n=12) associated with the areca nut/betel leaves chewing habit, also showed remission with the discontinuation of the habit (n=11) but one patient, 1 36-year-old male, was diagnosed as having multicentric squamous cell carcinoma of left and right lateral border of the tongue. All patients presenting with submucous fibrosis (n=12) had areca nut chewing habit of various duration and may suggest a relationship, yet unknown, with the betel chewers mucosa and one of the patient, a 52-year-old female, was diagnosed as having carcinoma in the buccal mucosa.

Using immunohistological methods, all these tobacco and areca nut quid associated lesions or conditions were found to be hyperproliferative disorder with a statistically significant difference in labeling index of PCNA when compared with clinically healthy mucosa (p<0.001). the epithelial proliferation index assessed on the basis of nuclear immunostaining for proliferating cell nuclear antigen PCNA (mean percentage +/- standard deviation) in the oral mucosa from healthy subjects was 7.2+/-1.96 (n=16) compared with the lesional mucosa of tobacco pouch lesions 21.5+/-1.96 (n=14), submucous fibrosis 28.2+/-4.10 (n=12), betel chewers mucosa 25.4+/-3.20 (n=12), and leukoplakia 18.8+/-4.85 (n=8). Mutant form of p53 was detected in a number of these lesions including nearly 60% of OSF and 25% of clinically healthy oral mucosa restricted to subjects of over 40 years old with some form of tobacco or betel quid habit. The pre-existing oral lesions and SCC, in two patients presenting with betel chewers mucosa and OSF, incidentally were found to express the p53 oncoprotein.

Although a number of factors such as the ethnic variation, geography and lifestyles, nutritional, immune-modulating, and many other factors may affect the ultimate outcome of tobacco and areca nut-quid related lesions, the results presented in the present study reasonably allowed us to conclude that due to a very high incidence of tobacco pouch lesions in tobacco quid users, in order to clarify it nature and potential for malignant transformation, the lesion may be evaluated as a separate lesion from leukoplakia as defined by the WHO criteria. The tobacco and areca nut-quid associated lesions or conditions are indeed hyperproliferative disorders and even clinically healthy oral mucosa in elderly individuals with tobacco or areca nut/betel quid habit, on the basis of detection of mutant form of p53, may be considered as a high rick mucosa.