Microsatellite Instability Assessment by Immunohistochemistry in Acute Myeloid Leukemia: A Reappraisal and Review of the Literature. Microsatellite Instability Assessment by Immunohistochemistry in Acute Myeloid Leukemia

Background: Microsatellite instability (MSI) is caused by deficiency in DNA mismatch repair (MMR) components. Inactivation of any of several MMR genes, including hMLH1, hMSH2, hMSH6, and hPMS2, can result in MSI. Immunohistochemistry is a sensitive and specific screening tool for MSI that can detect loss of expression of one or more MMR components. Of the four MMR markers, hMLH1 and hMSH2 are considered most informative of MSI status. There has been renewed interest in MSI status in cancer in view of its favorable association with response to immune checkpoint inhibitors. No studies have evaluated MMR status by IHC in acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).Methods: We used clinically-validated IHC assays to assess the expression of hMLH1, hMSH2, hMSH6, and/or hPMS2 in formalin-fixed paraffin-embedded tissue sections of bone marrow core biopsies from patients diagnosed with AML/MDS. All assays were confirmed to work optimally in decalcified tissue samples. Staining was done on automated Leica Bond autostainers. Mutation profiling was also conducted using next-generation sequencing to assess for mutations in MMR genes.Results: The study group included 236 patients with AML/MDS, including a cohort treated on a clinical trial of azacitidine and nivolumab (NCT02397720). In addition, hMSH6, and/or hPMS2 expression was assessed in 99 AML patients with diploid karyotype. All patients, except for two, had retained expression of all MMR markers assessed: 1 patient from the azacytidine+nivolumab group had zonal patchy loss of staining of hMLH1 and, to a lesser extent, a similar staining pattern of hMSH2; and 1 patient from the AML with diploid karyotype group had loss of hMSH2 but retained expression of hMLH1, hMSH6 and hPMS2. In addition, a retrospective analysis on a separate cohort of 139 patients with primary AML, on which next generation sequencing profiling was performed, identified 14 cases with alterations in MMR genes.Conclusion and remarks: MMR loss is a rare even in AML/MDS, and thus does not appear to underlie response patterns to anti-PD1 therapy.