# A case report and literature review of duodenal adenocarcinoma with complete loss of mismatch repair proteins

## TL;DR

This paper reports a rare case of duodenal cancer with complete loss of DNA repair proteins, highlighting its unique molecular features and treatment implications.

## Contribution

The study presents a rare, molecularly confirmed case of complete MMR protein loss in duodenal adenocarcinoma.

## Key findings

- The tumor showed complete loss of MLH1, PMS2, MSH2, and MSH6 proteins.
- Molecular profiling confirmed MSI-H, TMB-H, and somatic mutations in MSH2 and MSH6.
- The case suggests a somatic origin distinct from classic hereditary cancer pathways.

## Abstract

Deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) phenotype holds significant prognostic and therapeutic implications in gastrointestinal cancers. While typically characterized by loss of specific MMR protein pairs, the concomitant loss of all four MMR proteins (MLH1, PMS2, MSH2, MSH6) is scarcely documented, with molecularly confirmed cases being exceptionally rare.

We presented a case of duodenal adenocarcinoma whose contrast-enhanced 64-row CT and PET/CT demonstrated characteristic features highly suspicious for malignancy. Subsequently, the patient underwent duodenal resection. Histopathology showed moderately differentiated adenocarcinoma invading the subserosa and immunohistochemical staining revealed MLH1, PMS2, MSH2 and MSH6 were completely lost in tumor cells. Molecular profiling confirmed MSI-H status, high tumor mutational burden (TMB-H), MLH1 promoter hypermethylation and somatic mutations in MSH2 and MSH6 genes, but without pathogenic germline variants.

We represent a molecularly validated case of dMMR duodenal adenocarcinoma, suggesting a somatic molecular pathogenesis distinct from classic intestinal cancer. The findings highlight the critical importance of comprehensive molecular characterization in rare tumors, as accurate identification of these phenotypes are important for optimal treatment selection, particularly immune checkpoint inhibitor therapies for gastrointestinal malignancies.