Distinct Molecular Alterations in Complex Endometrial Hyperplasia (CEH) With and Without Immature Squamous Metaplasia (Squamous Morules)

Abstract

Several molecular alterations, most commonly PTEN mutations but also K-ras mutations, microsatellite instability, and beta-catenin mutations have been detected in endometrioid endometrial carcinoma (EEC). Specifically, mutations in the beta-catenin gene are seen in 15% to 20% of EECs, whereas immunohistochemical expression of beta-catenin ranges from 13% to 44%, nuclear staining being concentrated in areas of immature squamous metaplasia (squamous morules). Complex endometrial hyperplasia with atypia (CEH-A) is a well-known precursor of EEC, which can also show immature squamous metaplasia. In this study, we compared the immunohistochemical and molecular profiles of 13 CEH-A with and 11 CEH-A without squamous morules (SM) for mutations of beta-catenin, PTEN, K-ras, and microsatellite instability (MSI). In all cases of CEH-A with SM, beta-catenin immunostaining showed strong and diffuse nuclear expression in areas of SM and weak to moderate nuclear expression in the glandular component. Six different beta-catenin mutations were found in 7 of 13 cases (54%) (G34E, G34V, S33C, D32Y, S33F, D32A); however, no mutations of the PTEN or K-ras genes were identified. beta-Catenin immunostaining showed focal nuclear staining in only 2 cases of CEH-A without SM. Only 1 case had a beta-catenin mutation (S45A), which was associated with a K-ras mutation (G12D). Another 3 cases had both PTEN and K-ras mutations (C296Stop Ex 8 and G12V, 244del C Ex 7 and G12D, 251ins TGAT Ex 7 and G13D), and one had a PTEN mutation (G230E Ex 7) only. Of all 24 cases, only 1 case of CEH-A without SM showed MSI. In conclusion, marked differences in the molecular profiles regarding beta-catenin, PTEN, and K-ras mutations were observed between CEH-A with and without SM. beta-catenin mutations might represent a signaling pathway leading to a distinctive morphology in hyperplastic/neoplastic endometrium with SM. Other molecular events such as K-ras or PTEN mutations are likely to occur in CEH-A independently from beta-catenin. Furthermore, morphologic differences between CEH-A with SM and CEH-A without SM seem to correlate, at least to some extent, with the clinical course of the disease. In our series, cases of CEH-A with SM and beta-catenin alterations appeared to have a less aggressive behavior when compared with CEH-A without SM and with K-ras and PTEN mutations.

Clinicopathological and molecular analysis of endometrial carcinoma associated with tamoxifen

“…8 According to the literature, complex endometrial hyperplasia with immature squamous metaplasia (squamous morules) may be associated with b-catenin mutations and better clinical outcome. 44 Our study supports these results as seven of 13 patients (54%) with endometrial carcinoma and areas of squamous differentiation had evidence of b-catenin mutations. By contrast, only one of 48 patients (2%) without squamous morules had a b-catenin mutation.…”

Low membranous expression of β-catenin and high mitotic count predict poor prognosis in endometrioid carcinoma of the ovary

“…Other studies found that morphologic differences between atypical complex hyperplasia with and without squamous morules seemed to correlate with course of the disease. 47 In our study, mitotic count was the only significant morphologic prognostic factor in both the univariate and multivariate analyses to predict the rate of disease-specific survival and disease-free survival in ovarian endometrioid carcinoma. The analysis of the remaining morphologic characteristics alone or in combination-namely presence of squamous component, glandular pattern, papillary pattern, and nuclear pleomorphismdid not show that they were associated with survival.…”

PIK3CA mutations in the kinase domain (exon 20) of uterine endometrial adenocarcinomas are associated with adverse prognostic parameters

“…Our results are consistent with the finding of CTNNB1 (b-catenin gene) mutations predominantly in early-stage tumors associated with favorable prognosis. 13,21,42 PI3K/AKT and RAS are closely related signaling pathways. RAS can activate PI3K both directly and indirectly.…”

“…19 In contrast, CTNNB1 (b-catenin) mutations are thought to represent a separate pathway in estrogen-driven endometrial carcinogenesis, resulting in low-grade, low-stage endometrioid adenocarcinomas with squamous differentiation and excellent prognosis. 20,21 The phosphatidylinositol 3 0 -kinase (PI3K)/AKT signaling pathway is frequently activated in multiple human epithelial cancers, including endometrioid adenocarcinomas. [22][23][24][25] In response to cell-surface receptor signals, PI3K phosphorylates phosphatidylinositol 4,5-biphosphate to generate the second messenger phosphatidylinositol 3,4,5-triphosphate.…”