743 Frequency and Significance of Unusual Patterns of Abnormal DNA Mismatch Repair (MMR) Immunohistochemistry

Suchet Anand; Matthew Gosse; Anthony Snow; Andrew Bellizzi

doi:10.1016/j.labinv.2025.105030

Background MMR immunohistochemistry (IHC) is performed to screen for Lynch syndrome and to identify tumors likely to respond to checkpoint inhibition. The MMR system functions as a pair of heterodimers, each consisting of a dominant (expressed independent of its partner) and dependent (only expressed in the presence of its partner) protein. MLH1 and MSH2 are dominant, with PMS2 and MSH6 their respective dependent partners. Well-described patterns of abnormal MMR IHC include complete loss of MLH1 and PMS2 (MLH1/PMS2D), MSH2 and MSH6 (MSH2/MSH6D), MSH6 (MSH6D), and PMS2 (PMS2D). MSH6 contains an 8-base mononucleotide C repeat in exon 5 and is subject to "secondary loss” in MLH1/PMS2D and PMS2D tumors. We are frequently consulted on unusual patterns of abnormal MMR IHC. Design We identified all locally tested tumors with abnormal MMR IHC from 10/2015 to 11/2024. The following were recorded: site, MMR pattern, results of MLH1 promoter methylation (PM) and MSI testing (if available). A chi-square test was performed with p<0.05 considered significant. Results 1010 total abnormal MMR IHC were identified (547 endometrium, 310 colon, 153 other); 902 (89.3%) were "canonical” abnormal patterns: 753 MLH1/PMS2D, 82 MSH2/MSH6D, 47 MSH6D, 20 PMS2D. 108 (10.7%) were unusual abnormal patterns (11.6% colon, 8.8% endometrium, 15.7% other; p=0.041). These occurred in 3 main patterns: 1. 43% with presumed secondary loss of MSH6, which was either subclonal (29%) or involved the entire tumor (14%); 2. 38% with staining of reduced intensity relative to internal control in either the dominant or dependent partner with complete loss of the other partner; 3. 14% with a canonical abnormal pattern occurring subclonally. Three (3) tumors demonstrated loss of all 4 MMR proteins; 1 showed MSH6D with subclonal MLH1/PMS2D; 1 showed MSH2/MSH6D with subclonal MLH1/PMS2D. Among MLH1/PMS2D tumors with presumed secondary loss of MSH6, MLH1 PM was detected in 17/20 tumors tested (85%). MSI results were available for 20 tumors with unusual abnormal patterns; 16 were MSI-H, 3 were MSI-L (2 subclonal MLH1/PMS2D, 1 MSH2 reduced/MSH6D), and 1 was MSS. The only MSS tumor showed reduced (though intact) MLH1 and PMS2 staining. Conclusions Unusual patterns constitute ∼10% of abnormal MMR IHC results. Most of these represent secondary loss of MSH6 (supported by frequent MLH1 PM) (∼40%), reduced staining for 1 partner with complete loss of the other partner (∼40%), and otherwise typical abnormal patterns occurring subclonally (∼15%).

743 Frequency and Significance of Unusual Patterns of Abnormal DNA Mismatch Repair (MMR) Immunohistochemistry

View Online

Abstract

Details

Metrics