Clinicopathological significance of deficient DNA mismatch repair and MLH1 promoter methylation in gastric adenosquamous carcinoma

Primary gastric adenosquamous carcinoma (GASC) is a rare tumor that exhibits aggressive behavior and currently lacks standardized therapeutic recommendations. Microsatellite instability (MSI)/mismatch repair deficiency (dMMR) and positive PD-L1 expression confer sensitivity to immune checkpoint inhibitors; however, their statuses in GASC remain uncertain. In this study, clinical features, MMR/MSI status, MLH1 methylation, two T-cell markers, and PD-L1 expression of 30 GASC cases were collected from three institutions. Additionally, 196 gastric adenocarcinomas (GACs) were collected for comparison. The median age of GASC patients was 62 years, with 76.7% being males, and 56.7% at stage III. dMMR/MSI-high with MLH1 hypermethylation was observed in 33.3% GASCs, and was significantly associated with older age, female, distal location, larger size, deeper tumor invasion, and higher CD3 and CD8 densities and PD-L1 expression. Both glandular and squamous components of all dMMR GASCs showed loss of MLH1 and PMS2 expression. No significant difference in overall survival was observed between dMMR and mismatch repair proficiency (pMMR) GASC patients, while inferior overall survival was observed in pMMR GASC treated with surgery alone compared to those receiving chemotherapy. When comparing to GAC, GASC exhibited clinicopathological features indicative of more aggressive behavior (larger size, poorly tumor differentiation, deeper tumor invasion and more lymph node metastases). A significantly higher frequency of dMMR was found in GASC (33.3%) than that in GAC (16.3%). This study offers a comprehensive perspective on the clinicopathological features of GASC, emphasizing a subset of GASC associated with dMMR and MLH1 hypermethylation. Immunotherapy might be a promising strategy for GASC.