What does the surgeon need to know about microsatellite instability in gastric cancers?

Microsatellite instability (MSI) is a molecular subtype of gastric cancer caused by DNA mismatch repair defects, leading to mutations and neoantigen production. This profile influences tumor behavior, prognosis, and response to therapy, making it important for surgical decision-making. This article reviews the molecular basis of MSI gastric cancer, its clinical relevance, and its impact on management. A narrative analysis integrates evidence on pathophysiology, diagnostic strategies, and treatment implications of MSI in gastric cancer, with a focus on surgical oncology. MSI tumors exhibit a high mutational burden due to impaired DNA repair, resulting in increased immunogenicity and potential responsiveness to programmed death 1/programmed death ligand-1 (PD-L1) inhibitors. Retrospective studies suggest that patients with MSI-high gastric cancer often have a better prognosis and limited benefit from fluoropyrimidine-based chemotherapy, supporting upfront surgical resection in selected cases. Immunohistochemistry for mismatch repair proteins has become the preferred diagnostic tool, replacing microsatellite testing as the primary screening method. For tumors escaping immune surveillance via PD-L1 expression, targeted immunotherapy offers clinical benefit. Integrating MSI status into the treatment algorithm has shifted gastric cancer management, requiring surgeons to apply molecular oncology principles to optimize outcomes and enhance multidisciplinary coordination.