Cancer Hallmarks Expression in Oral Leukoplakia: Systematic Review and Meta‐Analysis

Objectives To assess the available evidence on the expression of hallmarks of cancer and oral leukoplakia (OL) malignant transformation probability, with the goal of identifying the earliest oncogenic molecular events participating in oral cancer carcinogenesis. Methods Embase, MEDLINE/PubMed, Scopus, and Web of Science were searched for primary‐level studies published prior to Sept 24, strictly designed as longitudinal cohorts. Results A total of 60 studies (9758 OLs) fulfilled the eligibility criteria, and the expression of 68 different biomarkers was evaluated using the immunohistochemical technique. Sustaining proliferation hallmark was frequently harbored by OLs (PP = 56.30%, 95% CI = 43.10–69.09), significantly associated with malignant transformation (RR = 1.92, 95% CI = 1.45–2.55, p < 0.001), and markedly more frequent than in normal oral mucosa (OR = 7.70, 95% CI = 2.22–26.65, p = 0.001). Also related, genome instability markers were considerably overexpressed and associated with oral cancer development ( p < 0.05), although resulting from a smaller sample size. Another remarkable finding is related to the activation of proinvasive mechanisms in OLs, representing the epithelial–mesenchymal transition (EMT) phenomenon, which was frequent (PP = 37.30%, 95% CI = 28.21–46.86) and significantly associated with oral cancer (RR = 3.43, 95% CI = 2.67–4.40, p < 0.001). Finally, avoiding immune destruction markers were also overexpressed (PP = 35.77%, 95% CI = 24.66–47.69) and significantly higher in leukoplakias progressing to oral cancer (RR = 3.65, 95% CI = 1.87–7.13, p < 0.001). Conclusions Malignant transformation of OL is significantly increased in hyperproliferative lesions, which develop the EMT phenomenon and avoid immune destruction through oncogenic mechanisms.