Malignant Transformation of Oral Leukoplakia and Proliferative Verrucous Leukoplakia and Its Biomarker Predictors: A Systematic Umbrella Review

Abstract

Background: Oral leukoplakia (OL) represents the most common oral potentially malignant disorder globally, with highly variable reported malignant transformation (MT) rates creating challenges for evidence-based clinical management. Objective: To systematically synthesize evidence on MT prevalence in OL and evaluate potential predictive biomarkers through an umbrella review of systematic reviews and meta-analyses. Methods: Following PRISMA guidelines, we searched PubMed, MEDLINE, Scopus, and Embase databases through July 2025. Twenty-seven systematic reviews encompassing more than 125,000 patients were included. Meta-analyses were conducted using random-effects models, with quality assessed using AMSTAR 2 and GRADE approaches. Results: Transformation rates were considerably higher in proliferative verrucous leukoplakia (48%) than in OL (6%). Females exhibited almost twice the MT rate of males (64% vs. 35%), while tongue lesions showed the highest site-specific risk (39%). The most promising predictive biomarker with a moderate level of evidence quality was DNA aneuploidy. Conclusions: Because of its high malignant potential, OL necessitates risk-based surveillance protocols. While the bulk of other predictors requires further investigation, DNA aneuploidy shows potential for clinical application.