# Implications of Podoplanin Overexpression in the Malignant Transformation of Oral Potentially Malignant Disorders: A Systematic Review and Meta-Analysis

## TL;DR

This study finds that high levels of a protein called podoplanin are linked to a higher risk of oral pre-cancerous conditions turning into cancer, especially in a condition called oral leukoplakia.

## Contribution

The study is the first systematic review and meta-analysis to evaluate podoplanin's role in predicting malignant transformation of oral potentially malignant disorders.

## Key findings

- Podoplanin overexpression significantly increases the risk of malignant transformation in oral potentially malignant disorders (RR = 3.64).
- Podoplanin is a strong predictor for malignant transformation in oral leukoplakia and other OPMDs like erythroplakia and oral lichen planus.
- Immunohistochemical evaluation of podoplanin is recommended for assessing cancer risk in OPMD patients.

## Abstract

Oral cancer represents a global health problem, with an estimated annual incidence of 377,713 new cases and 177,757 deaths. Despite advances in oral oncology, its prognosis has remained largely unchanged over the past 40 years, with a 5-year survival rate close to 50%. Oral cancer is often preceded by oral potentially malignant disorders (OPMDs), which are defined by the WHO Collaborating Centre for Oral Cancer as mucosal alterations associated with an elevated risk of progression to oral cancer. At present, no reliable method exists to accurately determine which individuals with OPMDs will undergo malignant progression. Consequently, ongoing research is exploring molecular biomarkers as potential predictive tools for assessing the risk of OPMDs malignant transformation. Among these biomarkers, podoplanin emerges as a promising biomarker with potential predictive value of malignant transformation in oral leukoplakias. Despite the importance of this topic, it is noteworthy that, to date, there is no evidence, in the form of systematic reviews and meta-analyses, on the implications of podoplanin in the malignant transformation of OPMDs.

Objective: To evaluate the degree of current evidence through a systematic review and meta-analysis on the association between podoplanin overexpression and the malignant transformation of oral potentially malignant disorders (OPMDs). Methods: A systematic search was performed in the MEDLINE (through PubMed), Embase, Scopus, and Web of Science databases for primary-level research published before December 2024, strictly designed as longitudinal cohorts with follow up data, and no restrictions by language or publication date. The Quality in Prognosis Studies QUIPS tool (developed by the Cochrane Prognosis Methods Group) was applied in order to assess the methodological quality and risk of bias. Meta-analyses, subgroup meta-analyses, sensitivity, and small-study effects analyses were performed. Results: Twelve primary-level studies met the eligibility criteria and were included, which followed up 857 OPMDs patients over time. Podoplanin overexpression was significantly associated with an increased risk of the malignant transformation of OPMDs (RR = 3.64, 95% CI = 2.18–6.10, p < 0.001). Podoplanin also proved to be a valuable biomarker in the malignant transformation of all investigated OPMDs (oral leukoplakia: p < 0.001; erythroplakia: p = 0.05; oral lichen planus: p = 0.02; discoid lupus erythematosus: p = 0.009). In addition, podoplanin overexpression was significantly associated with an increased risk of cancer development in several study subgroups with methodological implications (anti-podoplanin D2-40 antibody: p < 0.001; membrane and cytoplasm staining: p < 0.001; antibody dilution at 1:100: p < 0.001; overnight incubation: p < 0.001; 4 °C incubation: p < 0.001; cut-off point > 1%: p < 0.001; low risk of bias: p < 0.001). Conclusions: This systematic review and meta-analysis, on the basis of the evidence, indicates that podoplanin overexpression is a predictor of an increased risk of malignant transformation in OPMDs, singularly in oral leukoplakias. Its evaluation using immunohistochemical methods would be advisable in pathology laboratories.