Biological Biomarkers in Proliferative Verrucous Leukoplakia: A Systematic Review and Meta‐Analysis

OBJECTIVE: To synthesise biological biomarker evidence in proliferative verrucous leukoplakia/proliferative leukoplakia and quantify malignant transformation using eligible longitudinal evidence. METHODS: Primary human biomarker studies and longitudinal studies reporting extractable malignant-transformation events and denominators were systematically reviewed. Biomarker evidence was synthesised narratively. Malignant-transformation proportions were pooled using a random-effects model, with conservative handling of potentially overlapping cohorts. RESULTS: Forty-one publications contributed to the biomarker synthesis, spanning genetic, genomic, DNA-ploidy, epigenetic, transcriptomic, proteomic, immunohistochemical, immunologic, viral, microbiome, salivary, and circulating markers. No biomarker had sufficient independent validation for clinical diagnostic or prognostic use. Twenty independent or conservatively non-overlapping study estimates comprising 745 patients and 243 malignant-transformation events contributed to the meta-analysis. The pooled malignant-transformation proportion was 34.13% (95% confidence interval 26.62-42.53), with substantial heterogeneity and a 95% prediction interval of 13.85%-62.56%. Results remained stable in sensitivity and leave-one-out analyses. CONCLUSIONS: Diverse biological alterations have been reported, but none currently supports routine biomarker-based diagnosis or individual risk stratification. Malignant transformation is frequent, although substantial between-study variability limits interpretation of the pooled estimate as an individual patient risk.