World Workshop on Oral Medicine VII: Prognostic biomarkers in oral leukoplakia and proliferative verrucous leukoplakia-A systematic review of retrospective studies.

OBJECTIVE: To systematically review retrospective studies examining prognostic potentials of candidate biomarkers to stratify malignant progression of oral leukoplakia (OL) and proliferative verrucous leukoplakia (PVL). MATERIALS AND METHODS: A systematic literature search of PubMed, EMBASE, Evidence-Based Medicine and Web of Science databases targeted literature published through 29 March 2018. Inter-rater agreement was ascertained during title, abstract and full-text reviews. Eligibility evaluation and data abstraction from eligible studies were guided by predefined PICO questions and bias assessment by the Quality in Prognosis Studies tool. Reporting followed Preferred Reporting Items for Systematic Review and Meta-Analysis criteria. Biomarkers were stratified based on cancer hallmarks. RESULTS: Eligible studies (n = 54/3,415) evaluated 109 unique biomarkers in tissue specimens from 2,762 cases (2,713 OL, 49 PVL). No biomarker achieved benchmarks for clinical application to detect malignant transformation. Inter-rater reliability was high, but 65% of included studies had high "Study Confounding" bias risk. CONCLUSION: There was no evidence to support translation of candidate biomarkers predictive of malignant transformation of OL and PVL. Systematically designed, large, optimally controlled, collaborative, prospective and longitudinal studies with a priori-specified methods to identify, recruit, prospectively follow and test for malignant transformation are needed to enhance feasibility of prognostic biomarkers predicting malignant OL or PVL transformation.