Microsatellite instability and mismatch repair protein deficiency: equal predictive markers?

Abstract

Current clinical guidelines recommend mismatch repair (MMR) protein immunohistochemistry (IHC) or molecular microsatellite instability (MSI) tests as predictive markers of immunotherapies. Most of the pathological guidelines consider MMR protein IHC as the gold standard test to identify cancers with MMR deficiency and recommend molecular MSI tests only in special circumstances or to screen for Lynch syndrome. However, there are data in the literature which suggest that the two test types may not be equal. For example, molecular epidemiology studies reported different rates of deficient MMR (dMMR) and MSI in various cancer types. Additionally, direct comparisons of the two tests revealed relatively frequent discrepancies between MMR IHC and MSI tests, especially in non-colorectal and non-endometrial cancers and in cases with unusual dMMR phenotypes. There are also scattered clinical data showing that the efficacy of immune checkpoint inhibitors is different if the patient selection was based on dMMR versus MSI status of the cancers. All these observations question the current dogma that dMMR phenotype and genetic MSI status are equal predictive markers of the immunotherapies.

Keywords: cancer; immunohistochemistry; microsatellite instability; mismatch repair deficiency; molecular testing.

FIGURE 1

Detection of dMMR by immunohistochemistry. (A,B): Classic two-protein loss in colon cancer. Note the intense labeling of stromal cells. (A): MLH1, (B): PMS2. (C): Focal loss of MSH2 in a colon cancer case. Note the intense staining of stromal normal cells adjacent to the negative tumor cells. (D): Heterogenous loss of MSH6 in a rectal cancer case. Note the intense staining of the stromal cells adjacent to the negative tumor cells.