Mismatch repair protein imbalance in head and neck squamous cell carcinoma: associations with clinical features and survival.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) remains a global health challenge with rising incidence, especially in HPV-associated subtypes. The mismatch repair (MMR) system maintains genomic stability, and its deficiency has been linked to tumor immunogenicity and response to immunotherapy in several cancers. However, its role in HNSCC, particularly in the context of HPV status, remains poorly defined. OBJECTIVES: The aim of this study was to compare the imbalance expression of MMR proteins and their association with clinical features and survival in HNSCC. DESIGN: A retrospective, clinicopathological correlation study. METHODS: We retrospectively analyzed 369 HNSCC specimens. Tissue microarrays were constructed and immunohistochemically stained for four key MMR proteins (MSH2, MSH6, PMS2, and MLH1) and p16 (as an HPV surrogate). Expression patterns were correlated with clinicopathological variables, immune cell infiltration, and survival outcomes. RESULTS: Among all HNSCC patients, MMR protein expression was preserved in all but one case. MSH2 and PMS2 showed consistently higher nuclear positivity than their partners, MSH6 and MLH1. These imbalances were more pronounced in p16-negative tumors (p < 0.001), whereas p16-positive tumors showed balanced expression. Expression patterns varied by sex, tumor site, drinking history, and AJCC stage. Moreover, MSH6 was significantly lower than MSH2 in nondrinkers (p = 0.039), and PMS2 was lower in advanced-stage patients (p = 0.023). Immunologically, MSH2 expression positively correlated with CD8⁺ T cells in nontumor tissue, while MSH6 and PMS2/MLH1 ratios were inversely correlated with CD4⁺ T cells in tumor tissue. Kaplan-Meier survival analysis revealed that lower MSH2 expression was significantly associated with improved overall survival (p = 0.030). CONCLUSION: MMR protein expression in HNSCC varies by HPV status and demographic factors and is linked to differential immune infiltration. These findings suggest that MMR protein imbalance may influence tumor immunogenicity and could potentially serve as a biomarker to inform therapeutic strategies in the immunotherapy era, especially in p16-negative tumors.