Mismatch Repair Protein Expression as a Prognostic Factor in Head and Neck Squamous Cell Carcinoma: A Systematic Review.

To evaluate the prognostic significance of mismatch repair (MMR) markers in head and neck squamous cell carcinoma (HNSCC) patients. We performed a systematic review of prognostic factors following PRISMA 2020 using the PI(E)COS framework. Observational studies evaluating MMR protein expression (MSH2, MLH1, MSH6, PMS2) in HNSCC were identified through searches in five databases and gray literature. Eligible studies were qualitatively synthesized. Risk of bias was assessed using the QUIPS tool. Seven observational studies involving 846 HNSCC patients met the eligibility criteria. Most patients were males (78.3%), the age ranged from 59 to 63.6 years, and the oral cavity was the most common tumor site. MMR protein expression associated with clinicopathological features was heterogeneous, with prognostic effects varying according to tumor subsite, HPV/p16 status, and analytical approach. Across the available studies, low or loss of MSH2 expression was consistently associated with poorer overall survival, with reported hazard ratios ranging from 2.75 to 4.38, all indicating a clinically meaningful increased risk of death. In contrast, the prognostic value of MLH1, MSH6, and PMS2 varied by tumor subsite, HPV/p16 status, and patient age, lacking sufficient consistency for quantitative pooling. Due to the limited number of methodologically comparable studies, a quantitative meta-analysis was not appropriate. In conclusion, the pooled results showed that reduced or absent MSH2 expression is linked to poorer outcomes in HNSCC, suggesting that MSH2 may be the most promising prognostic biomarker, pending further validation.