In managing patients with solid tumors, the value of detecting the status of tumor DNA mismatch repair function is widely recognized. Mismatch repair protein immunohistochemistry and molecular microsatellite instability testing constitute the two major test modalities currently in use, yet each is associated with caveats and limitations that can be consequential. Most notably, the traditional approach of defining mismatch repair protein immunohistochemistry abnormality by complete loss of staining in all tumor cells is evolving. Partial or clonal loss is becoming recognized as a manifestation of gene abnormality; in some cases, such clonal loss is associated with germline pathogenic variants. The current criteria and cutoff values for defining microsatellite instability-high are developed primarily according to colorectal tumors. Non-colorectal cases, and occasionally even colorectal tumors, that are mismatch repair-deficient by immunohistochemistry but not microsatellite instability-high by current standards are being recognized. Emerging data suggest that these immunohistochemistry abnormal / non-microsatellite instability-high cases warrant further genetic workup for Lynch syndrome detection. Whether these tumors respond to immunotherapy is a question still to be addressed. It is imperative that pathologists as well as clinicians and investigators be aware of such intricacies regarding routine immunohistochemistry and microsatellite instability testing and the results they generate. This review summarizes our current understanding of the advantages and limitations of these tests and offer our view on what constitutes the most optimal strategy in test selection and how best to utilize case context to enhance the interpretation of the test results.
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We thank Dr. Cyriac Kandoth (Director, Clinical Bioinformatics, Molecular Diagnostics at UCLA) for his expert guidance on the NGS-based MSI detection methods.
JS discloses the following relationship: Consultant, Paige.AI, Inc. LZ discloses the following relationship: Family members hold leadership positions and ownership interests in Decipher Medicine. CW: None. EV: None.
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Wang, C., Zhang, L., Vakiani, E. et al. Detecting mismatch repair deficiency in solid neoplasms: immunohistochemistry, microsatellite instability, or both?. Mod Pathol (2022). https://doi.org/10.1038/s41379-022-01109-4