Prognostic significance of minor versus major extranodal extension in oral cavity squamous cell carcinoma: a systematic review and meta-analysis

Background Extranodal extension (ENE) is an established adverse prognostic factor in oral cavity squamous cell carcinoma (OCSCC), but the clinical relevance of its extent remains uncertain. This systematic review and meta-analysis evaluated the prognostic impact of quantitatively defined minor versus major ENE, with particular emphasis on the conventional 2-mm threshold. Methods PubMed, Scopus, Embase, and the Cochrane Library were searched from inception to August 2026. Studies of surgically treated OCSCC assessing pathological ENE extent and oncological outcomes were included. Random-effects meta-analyses using restricted maximum likelihood and Hartung-Knapp inference were performed when at least three compatible adjusted hazard ratios (HRs) were available. Risk of bias was assessed using QUIPS. Results Twenty-two reports representing 18 independent cohorts were included. Five studies contributed to the primary overall survival (OS) meta-analysis. Major ENE was associated with significantly worse OS than minor ENE (pooled HR 2.01, 95% CI 1.10–3.66; I 2 = 60.5%). Three studies contributed to the disease-free survival (DFS) meta-analysis, showing a concordant but imprecise association (pooled HR 2.16, 95% CI 0.44–10.66; I 2 = 59.3%). Alternative thresholds and morphological classifications also generally suggested poorer outcomes with increasing ENE extent. Conclusions ENE extent provides prognostic information beyond binary ENE status in OCSCC. Major ENE is associated with worse OS, while evidence for DFS is directionally consistent but less precise. The 2-mm cutoff should be considered clinically useful but not yet biologically definitive.