Highly sensitive microsatellite instability and immunohistochemistry assessment in endometrial aspirates as a tool for cancer risk individualization in Lynch syndrome

Abstract

Women with Lynch syndrome (LS) are at increased risk of endometrial cancer (EC), among other tumors, and are characterized by mismatch repair (MMR) deficiency and microsatellite instability (MSI). While risk-reducing gynecologic surgeries effectively decrease EC incidence, doubts arise regarding the appropriate timing of the surgery. We explored the usefulness of highly sensitive MSI (hs-MSI) assessment in endometrial aspirates for individualizing gynecologic surveillance in LS carriers. Ninety-three women with LS, 25 sporadic EC patients (9 MMR-proficient and 16 MMR-deficient), and 30 women with benign gynecologic disease were included in this study. hs-MSI was assessed in prospectively collected endometrial aspirates in 67 LS carriers, EC cases, and controls. MMR, PTEN, ARID1A, and PAX2 protein expression patterns were evaluated in the LS samples. Follow-up aspirates from 8 LS carriers were also analyzed. Elevated hs-MSI scores were detected in all aspirates from MMR-deficient EC cases (3 LS and 16 sporadic) and negative in aspirates from controls and MMR-proficient EC cases. Positive hs-MSI scores were also detected in all 4 LS aspirates reported as complex hyperplasia. High hs-MSI was also present in 10 of 49 aspirates (20%) from LS carriers presenting a morphologically normal endometrium, where MMR protein expression loss was detected in 69% of the samples. Interestingly, the hs-MSI score was positively correlated with MMR-deficient gland density and the presence of MMR-deficient clusters, colocalizing PTEN and ARID1A expression loss. High hs-MSI scores and clonality were evidenced in 2 samples collected up to 4 months before EC diagnosis; hs-MSI scores increased over time in 5 LS carriers, whereas they decreased in a patient with endometrial hyperplasia after progestin therapy. In LS carriers, elevated hs-MSI scores were detected in aspirates from premalignant and malignant lesions and normal endometrium, correlating with MMR protein loss. hs-MSI assessment and MMR immunohistochemistry may help individualize EC risk assessment in women with LS.