Mismatch Repair Deficiency in Upper Gastrointestinal and Pancreaticobiliary Cancers: Integrating Multimodal Molecular Data in Clinical Practice

Context.—: Mismatch repair deficiency (MMRd) is a key diagnostic and predictive biomarker, yet its mechanisms in upper gastrointestinal (UGI) and pancreaticobiliary (PB) malignancies remain incompletely defined. Objective.—: To evaluate real-world clinical practices and multimodal molecular assessments of MMRd UGI and PB malignancies at a tertiary academic medical center. Design.—: We analyzed 91 MMRd UGI and PB cancers from 90 patients. MMRd immunohistochemistry (IHC) patterns and use of ancillary molecular tests (MSI-PCR, MLH1 promoter methylation, germline testing, and tumor next-generation sequencing [NGS]) were reviewed. Results.—: The most common primary sites were stomach (40 of 91; 44%), esophageal (15 of 91; 16%), and small bowel carcinoma (11 of 91; 12%), with pancreatic (8 of 91; 9%), biliary tract (7 of 91; 8%), and ampullary (4 of 91; 4%) carcinomas less frequent. Paired MLH1 of PMS2 loss was the predominant MMRd IHC pattern (71 of 91, 78%), followed by unusual patterns of loss (11 of 91, 12%), and paired MSH2 of MSH6 loss (9 of 91, 10%). Among the subset with MSI testing, MMRd by IHC and MSI were discordant in 16% (3 of 19) of cases. MLH1 promoter methylation was present in 80% (37 of 46) of the tested MLH1 of PMS2-deleted tumors. Lynch syndrome (LS) was identified in 17% (6 of 36) of patients with genetic testing. In addition, somatic MMR gene variants were identified in 43% (9 of 21) of tumors sequenced by NGS. Conclusions.—: MMRd in UGI and PB cancers arises from diverse mechanisms, including MLH1 promoter methylation, somatic MMR gene alterations, and LS. A multimodal approach integrating IHC, MSI-PCR, tumor NGS, and MLH1 promoter methylation is essential for accurate biomarker characterization and optimized LS screening.