Mismatch repair immunohistochemistry in endometrial cancer: Intact vs. deficient is insufficient (235)

Abstract

<b>Objectives:</b> Mismatch repair (MMR) and microsatellite instability (MSI) status in endometrial cancer (EC) have been used for Lynch syndrome screening. Recently the utility has expanded to molecular/risk stratification, therapeutic decision making, and clinical trial enrollment. We sought to examine discordance between clinical MMR testing with immunohistochemistry (IHC) and MSI status in a single institution cohort. <b>Methods:</b> A single-institution cohort of EC patients with IHC for <i>MLH1, PMS2, MSH2,</i> and <i>MSH6</i> was performed and scored (intact/deficient) as part of routine clinical care. Tissues appropriate for MSI typing were available for 666 cases. MSI testing using the NCI consensus MSI panel was performed for all 666 cases. Promega V1.2 MSI analysis was performed for cases with discordant IHC and MSI findings. IHC results were re-reviewed using existing archived slides for the discordant cases to evaluate for possible explanations of discordance. We defined a subclonal staining pattern as a strong normal IHC expression seen only in a portion of the tumor whereas the remaining tumor, showing abrupt complete loss of expression, and we defined a heterogeneous staining pattern where there is some patchy staining throughout the tumor rather than large areas of the tumor showing intact or loss of expression. <b>Results:</b> MMR and MSI status was determined for 666 EC cases; 165 (24.8%) had IHC defects, and 183 (27.5%) had MSI. Discordant findings occurred in 24 (3.6%) cases, with the most common discordant result (21 of 24 discordant cases) being intact MMR IHC and the presence of MSI. Upon re-review of IHC, two cases were attributed to inter-observer variability. Of the remaining 19 cases, ten demonstrated subclonal IHC staining (all <i>MLH1/PMS2</i>), seven had heterogeneous staining (six <i>MSH6</i> and one <i>MLH1/PMS2</i>), while only two had no specific IHC abnormality (Table 1). One case of a known Lynch syndrome patient had an <i>MSH6</i> frameshift mutation and heterogeneous IHC staining. Of the 21 tumors with clinically determined intact MMR status and MSI, there were four recurrences leading to EC death. In total, 11.4% of tumors with MSI were not identified with IHC interpretation alone. All three MMR IHC deficient cases without MSI demonstrated protein loss of <i>MLH1/PMS2</i> with evidence of <i>MLH1</i> promoter methylation. <b>Conclusions:</b> Clinical MMR IHC and MSI findings were discordant in 3.6% of tumors in our cohort, consistent with previous reports; however, 11.4% of tumors with MSI were not identified with clinical IHC alone in our cohort. The majority of tumors with normal IHC interpretation and MSI were explained by subclonal or heterogeneous staining patterns of <i>MLH1/PMS2</i>. Given the importance of MMR status in Lynch syndrome screening, clinical trial inclusion, and therapeutic decision making, heterogeneous and subclonal staining patterns should prompt additional molecular testing, and MSI testing should be considered for recurrent EC patients.