A novel histopathological subclassification of oral submucous fibrosis based on epithelial keratinization: A proof-of-concept pilot observation

Oral submucous fibrosis (OSMF) is a chronic, progressive oral potentially malignant disorder strongly associated with areca nut consumption. Despite extensive research, a reliable and clinically applicable biomarker for predicting malignant transformation remains unavailable. The present pilot investigation introduces a novel concept by classifying OSMF into two histopathological variants-hyperkeratinized and non-hyperkeratinized-based on epithelial keratinization patterns, a distinction not previously described in the literature. Archival biopsy samples of 51 histologically confirmed OSMF cases from the buccal mucosa were analyzed for keratinization type and epithelial dysplasia. Additionally, 37 cases of oral squamous cell carcinoma arising in the background of OSMF (OSCC-OSMF) were examined for keratinization at surgical margins. Among OSMF cases, 19.6 % exhibited hyperkeratinization, all showing high-risk epithelial dysplasia, whereas 90.2 % of normally keratinized cases demonstrated low-risk dysplasia. In OSCC-OSMF specimens, 60 % of surgical margins revealed hyperkeratinization. These findings suggest that epithelial hyperkeratinization may represent an early histological alteration associated with malignant transformation rather than a protective epithelial response. Although limited by small sample size, this study provides proof-of-concept for a novel histopathological subclassification of OSMF, warranting validation through larger, multicentre longitudinal and molecular correlation studies.