The aim of this study was to investigate the prognostic value of the Hedgehog (Gli, Patched-1, Shh, Smo) and Notch (Jag1, Notch2, Notch3) pathway members, in comparison to a panel of proteins (ER, PgR, HER2/neu, Ki67, p53, p16, PTEN and MMR) previously suggested to be involved in the pathogenesis of endometrial cancer, in association with clinical outcome and standard clinicopathological characteristics. A total of 204 patients with histological diagnosis of endometrial cancer treated from 2004 to 2013 were included. The evaluation of protein expression was assessed by immunohistochemistry. Univariate analysis showed that higher Ki67 labeling, expression of PTEN, p16, Notch2 and Notch3 proteins, as well as MMR proficiency were associated with increased relapse and mortality rate. Additionally, Patched-1 protein expression was associated with worse DFS, while p53 overexpression was associated with worse OS. In multivariate analyses, patients with MMR proficient tumors had more than double risk for death than patients with MMR deficient (MMRd) tumors (adjusted HR = 2.19, 95% CI 1.05–4.58, p = 0.036). Jag1 positivity conferred reduced mortality risk (HR = 0.48, 95% CI 0.23–0.97, p = 0.042). However, as shown by hierarchical clustering, patients fared better when their tumors expressed high Jag1 protein in the absence of Notch2 and Notch3, while they fared worse when all three proteins were highly expressed. Patched-1 positivity conferred higher risk for relapse (HR = 2.04, 95% CI 1.05–3.96, p = 0.036). Aberrant expression of key components of the Notch and Hedgehog signaling pathways, as well as MMRd may serve as independent prognostic factors for recurrence and survival in patients with endometrial cancer.

Background/Objectives: Lynch syndrome is an inherited autosomal dominant disease that predisposes to a broad spectrum of malignancies. This condition is driven by a germline pathogenic variant in one or more of the mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2, EPCAM) that results in genomic microsatellite instability (MSI-high). However, microsatellite-stable (MSS) tumors in Lynch syndrome patients may occur, but the relevant literature is scant. Our aim is to systematically identify, organize, and characterize the comprehensive available literature for Lynch syndrome-associated gynecological cancers (vulvar, vaginal, cervical, ovarian, endometrial) exhibiting a dMMR/MSS phenotype. Methods: Systematic review of the literature. Three medical databases, major related conferences and relevant oncology journals were scrutinized for relative evidence. Results: Eleven reports were identified comprising 2351 patients, 774 had confirmed Lynch syndrome (LS), of whom MSI results were available for 299 patients. In total, 130 patients developed LS-associated gynecological cancers, for whom MSI results were available. Among them, 36 tumors (27.7%) exhibited a dMMR/MSS molecular phenotype (23 endometrial, 12 ovarian, one synchronous endometrial–ovarian). No data for vulvar, vaginal, or cervical cancers were found. For dMMR/MSS endometrial cancers, the mean age at diagnosis was 50.5 years (range 36–62). dMMR/MSS tumors arose predominantly in MSH6 and, to a lesser extent, PMS2 carriers. No data on selective response to immune checkpoint inhibitors treatment were available. Conclusions: Lynch syndrome-associated gynecological cancers with dMMR/MSS phenotype are strongly underrepresented in the literature. Endometrial and ovarian cancers with dMMR/MSS phenotype are early onset and arise in a small proportion of patients. Better characterization is demanding to unearth whether response to immunotherapy treatment vary across Lynch dMMR/MSS and dMMR/MSI-High phenotypes.