Oral squamous cell carcinoma arising in the background of oral submucous fibrosis: A systematic review of molecular and microenvironmental differences.

OBJECTIVE

This systematic review aimed to synthesize and critically appraise molecular differences between oral squamous cell carcinoma arising in the background of oral submucous fibrosis (OSCC-OSMF) and OSCC without OSMF (OSCC-non-OSMF) across genomic, transcriptomic, proteomic, and immunohistochemical domains.

DESIGN

A comprehensive literature search of PubMed/MEDLINE, Scopus, and Web of Science was conducted from database inception to November 2025 following PRISMA 2020 guidelines (PROSPERO: CRD420251152208). Human observational studies directly comparing molecular biomarkers between OSCC-OSMF and OSCC-non-OSMF were included. Risk of bias was assessed using the Newcastle-Ottawa Scale. Narrative synthesis was performed due to heterogeneity in study design, biomarkers, and analytical methods.

RESULTS

Nineteen studies met inclusion criteria. Core carcinogenic pathways including p53 dysregulation, telomerase activation, and fibrosis-related mediators were largely comparable between OSCC-OSMF and OSCC-non-OSMF. In contrast, OSCC-OSMF consistently demonstrated enhanced epithelial-mesenchymal transition (EMT) and stemness signatures, increased genomic instability, and a markedly immunosuppressive tumor microenvironment characterized by regulatory T-cell predominance, PD-1/PD-L1 upregulation, and dendritic cell depletion. Paradoxically, OSCC-OSMF showed lower proliferative and angiogenic activity compared with OSCC-non-OSMF.

CONCLUSIONS

Available evidence supports OSCC-OSMF as a fibrosis-conditioned clinic-molecular phenotype within the broader spectrum of OSCC. These findings highlight limitations of conventional prognostic markers and underscore the potential utility of immune, EMT, and genomic-related biomarkers for refined risk stratification and targeted therapy.