CTNNB1-Mutant High-Grade Endometrial Carcinoma: Clinical Outcome and Prevalence of Pilomatrix-Like and Corded Hyalinized Morphologies in an Institutional Case-Control Series.

Abstract

The occurrence of somatic CTNNB1 pathogenic mutations has been recently recognized in high-grade endometrial carcinoma (HG-EMC) in association with pilomatrix-like (PM-L) morphology and an aggressive clinical course, highlighting the need for further study on the biologic and clinical importance of CTNNB1 alterations in HG-EMC. Thus, we document the clinical and pathologic characteristics of an institutional cohort of HG-EMC with and without CTNNB1 alterations. Of all the HG-EMCs subjected to next-generation sequencing in a 10-year period, those with pathogenic CTNNB1 alterations were selected (CTNNB1mut), along with a control group matched based on age and histologic type (CTNNB1wt). An additional search for institutional HG-EMCs with abnormal nuclear β-catenin expression and/or related morphologies was performed. All cases with material available were reviewed for the presence of PM-L, solid basaloid morphology with geographic necrosis (SB-GN), and corded and hyalinized characteristics. The following 27 molecularly confirmed CTNNB1mut HG-EMC were identified: 17 of 27 (63%) were of the nonspecific molecular profile (NSMP), 9 of 27 (33%) were mismatch repair deficient (MMRd), and 1 of 27 (4%) were POLE mutant. Five additional HG-EMC cases with abnormal β-catenin were included. All were endometrioid grade 3 (26/32; 81%) or dedifferentiated (6/32; 19%). Compared with CTNNB1wt controls (n = 50), which mostly presented with International Federation of Gynecology and Obstetrics stage I disease, CTNNB1mut HG-EMC were more frequently International Federation of Gynecology and Obstetrics stages III and IV (P = .0005) and NSMP (63% vs 22%; P = .0005). Although there was no statistical difference in survival between CTNNB1mut and CTNNB1wt groups, when separated based on molecular group, MMRd CTNNB1mut showed significantly worse disease-specific survival than MMRd CTNNB1wt HG-EMC. Among cases amenable to morphologic review (CTNNB1mut n = 26; CTNNB1wt n = 37), PM-L features were only seen in 8 CTNNB1mut HG-EMCs and none of the controls. SB-GN features were observed in both the cohorts. Corded and hyalinized morphology was not observed. HG-EMCs with driver CTNNB1 mutations were endometrioid or dedifferentiated and belonged to the NSMP and MMRd molecular groups. Importantly, they were more likely to present at an advanced clinical stage compared with CTNNB1wt tumors. Moreover, we found significant survival differences in MMRd HG-EMC based on CTNNB1 status. SB-GN was common in HG-EMC but not specific. Conversely, PM-L when strictly defined (requiring central keratinization with shadow cells) was specific for CTNNB1mut status.