Podoplanin and Selected Cancer Stem Cell or Stemness-Associated Markers in Oral Epithelial Dysplasia: A Structured Narrative Review of Their Role in Malignant Transformation and Risk Stratification

Abstract

Background: Oral potentially malignant disorders (OPMDs) comprise clinically and histologically heterogeneous lesions associated with an increased risk of oral squamous cell carcinoma (OSCC). Histopathological grading of oral epithelial dysplasia (OED) remains central to risk estimation but has limited predictive precision. Podoplanin and selected cancer stem cell (CSC) or stemness-associated markers may capture complementary biological processes involved in progression. Objective: To synthesize evidence on podoplanin and selected CSC or stemness-associated markers as indicators of malignant transformation and risk stratification across a prespecified OPMD spectrum, while distinguishing longitudinal prediction from cross-sectional, diagnostic, and mechanistic evidence. Methods: Three original PubMed searches covered database inception to 13 July 2026. A post hoc recall audit against three key evidence syntheses identified one eligible longitudinal report missed during the initial selection; this report was added by backward citation checking. A broader supplementary sensitivity query was run during revision and reported separately without being merged into the original selection counts. In total, 47 publications were included. Study design, effect measure, threshold provenance, internal validation, and possible cohort overlap were charted and synthesized narratively. Results: Among the biomarkers reviewed, podoplanin had the most developed longitudinal evidence, including a pooled hazard ratio (HR) of 3.72 (95% confidence interval [CI] 2.40–5.76) in one meta-analysis. A separate diagnostic-accuracy synthesis reported sensitivity of 78.9% and specificity of 55.0%, corresponding to a positive likelihood ratio (LR+) of 1.75 and a negative likelihood ratio (LR−) of 0.38. Predictive values varied materially with baseline transformation risk. CD133, BMI1, and ABCG2 showed large associations in individual cohorts, but independent replication and external validation were limited. Cross-sectional expression gradients were not treated as evidence of prospective prediction. Conclusions: Within the defined OPMD scope, podoplanin has the most developed longitudinal evidence, but its predictive values are prevalence-dependent and no marker is sufficiently validated for stand-alone clinical use. Prospective multicenter studies should compare prespecified biomarker models with established clinical, histopathological, and molecular predictors and should evaluate calibration, clinical utility, and external validity before management decisions are altered.