Prognostic Impact of MYC/TP63 Molecular Subtypes in Adenoid Cystic Carcinoma: A Meta-Analysis

Background: Adenoid cystic carcinoma (ACC) demonstrates marked clinical heterogeneity that is inadequately explained by conventional histopathologic and staging systems alone. Recent studies have identified two molecular subtypes based on transcriptomic profiling and MYC/TP63 expression (ACC I: MYC-high/TP63-low; ACC II: MYC-low/TP63-high) with potential prognostic significance. However, the magnitude and consistency of their survival impact remain uncertain. Methods: A systematic review and meta-analysis were conducted in accordance with PRISMA guidelines. PubMed, Embase, and PubMed Central were searched through January 2026 for studies reporting overall survival in ACC stratified by MYC/TP63 molecular subtype. Hazard ratios (HRs) were pooled using random-effects models. Heterogeneity, subgroup analyses by classification method, sensitivity analyses, cumulative meta-analysis, influence diagnostics, and publication bias assessment were performed. Results: Five independent cohorts from two publications comprising 247 patients (90 ACC I, 157 ACC II) were included. ACC I was associated with significantly worse overall survival compared with ACC II, with a pooled HR of 3.88 (95% CI: 2.55–5.90; p < 0.001). No statistical heterogeneity was observed (I2 = 0%). Prognostic separation was consistent across RNA sequencing and immunohistochemistry-based classification methods. Conclusions: Transcriptomic and MYC/TP63-based molecular subtyping provides strong and reproducible prognostic stratification in ACC. ACC I tumors confer an approximately four-fold higher mortality risk compared with ACC II tumors. Incorporation of molecular subtype into routine diagnostic and clinical decision-making may improve risk stratification, surveillance strategies, and future trial design in ACC.