Bouquot JE, Glover ED, Schroeder KL. Leukoplakia and smokeless tobacco keratosis are two separate precancers. In: Varma AD (ed). Oral oncology. Delhi: MacMillan India, Ltd, 1991; vol 2:67-69.

White keratotic oral mucosal changes resulting from chronic use of smokeless tobacco (ST) have more often than not been referred to in the literature as leukoplakia. This misuse of terminology defeats the very purpose of having different and distinct diagnostic names for various pathologic entities and is, at best, a questionable practice. The authors feel that it is prudent to consider ST keratosis (STK) and leukoplakia as two separate and distinct oral keratotic plaques. While both are undoubtedly premalignant lesions, they have essential and profound differences in etiology, clinical presentation, microscopic features, and prognosis.

Clinical Differences: STK (snuff pouch, snuff dipper's lesion, tobacco pouch) is localized to areas in direct contact with ST. It is often fissured, and is poorly demarcated from surrounding mucosa, but is otherwise quite uniform in consistency. This lesion typically has a soft velvety feel. Inducation, ulceration and pain are not associated with this lesion, but occasional erythema may be noted. This erythema is inflammatory and unrelated to dysplastic change. Once it occurs, STK typically remains unchanged indefinitely unless the daily ST contact increases, in which case it will gradually become thickened to the point of appearing as a distinctly white, leathery or nodular plaque. The latter lesions become clinically indistinguishable from true leukoplakia.

Early and thin leukoplakia may appear similar to STK, i.e. a gray/white soft mucosal plaque which can be semi-translucent. It typically begins, however, as a distinctly outlined white keratosis which extends laterally over time, perhaps also becoming thickened. Some develop irregular thickening and appear nodular, granular, or verruciform. Others develop areas of dysplastic erythema within the white areas. A few in heavy smokers will exhibit an underlying pigmentation (melanoleukoplia), something not yet reported in tobacco chewers.

Age and Gender: Although STK and leukoplakia in Western populations have a similar average age at diagnosis (48-58 years), STK has a biphasic pattern with increased prevalence in young adults and in persons beyond 65 years of age; this prevalence correlates with ST use. Leukoplakia, on the other hand, continues to increase in prevalence throughout life, regardless of the population's tobacco habits. As with age, gender predilection with STK is dependent on the population's use of ST. This usually means a strong male predilection. Leukoplakia also is typically more prevalent among males, especially in older age groups.

Histology: Squamous epithelium in both lesions is hyperplastic and hyperkeratinized, but STK is characterized by intracellular vacuolization or "edema" of superficial layers (perhaps interspersed with streaks of parakeratinized cells, resulting in the typical translucent or edematous clinical appearance. Leukoplakia, on the other hand, is characterized by thickened layers of flattened superficial keratocytes (i.e. excessive parakeratin or orthokeratin) and lacks vacuolization. Both lesions, however, follow a similar chronological pattern of change from normal to mild to severe epithelial dysplasia prior to actual transformation into invasive carcinoma, although the proportion with dysplasia is much greater for leukoplakia than for STK: 13-54% vs. 0-3%, respectively. Both lesions also demonstrate occasional verruciform or chevron structures of superficial epithelium, but such changes in and of themselves are not significant and only the intensity of dysplasia should be considered when determining lesion ‘severity." Hyaline deposition has been noted within connective tissues and salivary glands beneath STK in India, where betel and ereca nut chewing are common habits. Minimal hyalinization is noted in Western ST users, but leukoplakia, even in heavy smokers, never demonstrates such a change.

Etiology: STK is only seen at the site of ST use and routinely disappears after ST habit cessation. The etiology of leukoplakia, however, is entirely unknown. It is true that a high proportion of leukoplakia patients are tobacco smokers, but many are not. Also, actinic rays can produce leukoplakia of the lip vermilion and microorganisms such as candida and human papillomavirus (HPV) have been identified within lesions, although HPV may be more related to the malignant transformation of STK and leukoplakia than to the initial pro9duction of either lesin. Several systemic disease states, such as tertiary syphilis, are associated with leukoplakia but none with STK, except perhaps a deficiency in beta carotene.

Prognosis: The malignant transformation potential of STK has been determined to be only 0.05% per annum in U.S. female textile workers and 0.1% in male Bombay policemen. Previous investigations suggesting malignant potentials as high as 13.8% were based on too few numbewrs of cases to be valid, and larger investigations suggesting an epithelial dysplasia (moderate or severe) rate greater than 16% have used biopsy service samples with their obvious case-selection biases. The largest U.S. STK prevalence study (15,000 persons examined) found not a single malignancy, and the U.S. state with the highest per capita consumption of ST has an oral cancer mortality rate no higher than the national average. A population-based histologic analysis of 1,466 STK lesions among 20,333 ostensibly normal Swedes found no dysplasia in 114 biopsies, likewise for 92 biopsy samples taken from 1109 ST users who were professional U.S. baseball players. No animal investigation has yet produced carcinoma via contact of ST with oral mucosa.

Oral leukoplakia, on the other hand, has a very well-defined malignant potential, ranging from 1-28% (excluding clinical subtypes), with an average of 4% overall. Case-control studies have strongly implicated smoked tobacco and, to a lesser extent, alcohol abuse in the etiology of oral cancer, but such studies have not further correlated white mucosal plaques with malignant transformation. It is not known, then, whether oral cancers in the smokers in epidemiological studies arise from leukoplakias or note. Various clinicopathologic investigations have, however, found leukoplakia in association with 10=60% of oral carcinomas.

           Table 1: Summary of differences between ST keratosis and true leukoplakia.

   * only if patient increases smokeless tobacco use
 ** in Western populations
   # in Indian populations