title: 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.
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA. ebrachtel@partners.org
authors.forename: Elena F
authors.initials: EF
authors.lastname: Brachtel
authors.forename: Carolina
authors.initials: C
authors.lastname: Sánchez-Estevez
authors.forename: Gema
authors.initials: G
authors.lastname: Moreno-Bueno
authors.forename: Jaime
authors.initials: J
authors.lastname: Prat
authors.forename: José
authors.initials: J
authors.lastname: Palacios
authors.forename: Esther
authors.initials: E
authors.lastname: Oliva
mesh_terms: D000328:Adult; D000368:Aged; D001483:Base Sequence; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics*; D004714:Endometrial Hyperplasia / Q000235:genetics* / Q000473:pathology; D005260:Female; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008679:Metaplasia / Q000235:genetics / Q000473:pathology; D018895:Microsatellite Repeats; D008875:Middle Aged; D009154:Mutation; D016133:Polymerase Chain Reaction; D011230:Precancerous Conditions / Q000235:genetics* / Q000473:pathology; D014599:Uterus / Q000473:pathology*
chemical_list: D004273:DNA, Neoplasm