BackgroundA major molecular pathway of genetic instability in cancer is DNA mismatch repair deficiency. High-level microsatellite instability (MSI-H) is currently the best predictor of responsiveness towards immune checkpoint blockade. Data about the prevalence of high-level microsatellite instability in cholangiocarcinoma (CCA) has been conflicting.MethodsWe employed a cohort comprising 308 Western-world, non-liver fluke-associated CCAs (159 intrahepatic, 106 perihilar, and 43 distal). We analysed the mononucleotide microsatellite instability marker panel consisting of BAT25, BAT26, and CAT25 and detected MSI-H in 4/308 CCAs (1.3%).ResultsPatients affected by MSI-H CCA had mostly an atypical histomorphology (p = 0.004), showed a longer overall survival, although having a high tumour stage, and were of younger age. Correlation analysis of microsatellite instability status with tumour-infiltrating immune cells, MHC I, and PD-L1 expression in the same cholangiocarcinoma cohort showed higher numbers of CD8 + T cells, FOXP3 + regulatory T cells, CD20 + B cells and high or at least moderate MHC I expression levels in MSI-H CCAs.ConclusionsEven though the overall number of MSI-H CCAs is low, the dismal prognosis of the disease and the therapeutic option of immune checkpoint blockade in the respective patients justify MSI testing of cholangiocarcinoma, particularly in younger patients showing an atypical histomorphology.

Perioperative systemic treatment is standard of care for Caucasian patients with locally advanced, resectable gastric adenocarcinoma. The prognostic relevance of the microsatellite instability (MSI) status in patients undergoing neoadjuvant chemotherapy followed by resection is unclear. We analyzed the association of the MSI status with histological regression and clinical outcome in patients undergoing neoadjuvant systemic treatment. Tumor tissue from patients undergoing neoadjuvant chemotherapy followed by resection for gastric or gastroesophageal‐junction adenocarcinoma was analyzed for MSI status using a mononucleotide marker panel encompassing the markers BAT25, BAT26, and CAT25. Histological regression, relapse‐free survival and overall survival were calculated and correlated with MSI status. We identified the MSI‐H phenotype in 9 (8.9%) out of 101 analyzed tumors. Though a poor histological response was observed in eight out of nine MSI‐H patients, overall survival was significantly better for patients with MSI‐H compared to MSS tumors (median overall survival not reached vs. 38.6 months, log‐rank test p = 0.014). Among MSI‐H patients, an unexpected long‐term survival after relapse was observed. Our data indicate that the MSI‐H phenotype is a favorable prognostic marker in gastric cancer patients undergoing neoadjuvant treatment. The benefit of perioperative cytotoxic treatment in patients with MSI‐H gastric cancer, however, remains questionable. Future trials should stratify patients according to their MSI status, and novel treatment modalities focusing on MSI‐H tumors should be considered.