Diagnostic Challenges and Clinical Implications of Microsatellite Instability/Mismatch Repair Deficiency in Solid Tumors

The mismatch repair (MMR) system plays a crucial role in correcting replication errors; when the MMR system is deficient (dMMR), replication errors (particularly within microsatellites) accumulate throughout the genome, leading to microsatellite instability (MSI). The key MMR genes include MLH1, MSH2, MSH6, and PMS2. Germline mutations in these genes are associated with Lynch syndrome, whereas in sporadic solid tumors, dMMR is often caused by hypermethylation of the MLH1 promoter. As the clinical use of dMMR/MSI expands, the importance of reliable testing for dMMR or MSI in companion diagnostics continues to increase. dMMR/MSI is diagnosed using immunohistochemistry (IHC) for MMR proteins, polymerase chain reaction with fragmentation analysis, or next-generation sequencing. Although IHC has technical limitations, it requires less tissue, has a short processing time, and is cost-effective. Experienced or specialized pathologists and educational efforts are helpful for reliable diagnosis, in addition to the technical aspects. Solid tumors with dMMR/MSI exhibit distinct clinicopathological features, including prognostic significance and a predictive role in adjuvant cytotoxic chemotherapy. Solid tumors with dMMR/MSI are also characterized by a higher tumor mutational burden and abundant immune cell infiltration, making them promising candidates for immune checkpoint inhibitor therapy. However, the oncogenic processes and immune microenvironment are not identical across the organs of origin, between patients, and even within the same patient, which should be considered in future studies. This review provides an overview of the practical aspects of dMMR/MSI testing, along with the molecular mechanisms and immune microenvironments associated with dMMR/MSI solid tumors.