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.