Expression of cell cycle regulatory proteins in endometrial adenocarcinoma: variations in conventional tumor areas and in microcystic, elongated and fragmented glands

Abstract

Endometrial adenocarcinomas may show a distinctive pattern of invasion characterized by the presence of microcystic, elongated and fragmented glands, often most evident along the advancing tumor margin. Earlier, we have shown that these changes appear restricted to low-grade endometrioid carcinomas, many of which show focal mucinous differentiation and lymphovascular space invasion. However, the molecular alterations associated with this morphological alteration are not known. In this study, we have examined immunoreactivity for the cell cycle regulatory proteins cyclin D1, p16 and b-catenin in 22 endometrial carcinomas, specifically comparing the results in conventional tumor areas and in foci in which the glands exhibited microcystic, elongated and fragmented appearances. The conventional neoplastic glands exhibited cyclin D1 and p16 expression in most cases, with 450% tumor cells positive in 8 cases and 11 tumors, respectively. Membranous expression of b-catenin was usually preserved, with variable cytoplasmic and nuclear staining. Cyclin D1 and b-catenin predominantly stained cells at the peripheral or basal aspect of the conventional glands, whereas p16 was more uniformly expressed centrally. Tumor foci composed of microcystic, fragmented and elongated glands showed strong expression of cyclin D1 and p16, sometimes in contrast to unstained contiguous or adjacent conventional neoplastic elements, and there was also loss or fragmentation of membranous b-catenin staining. Intravascular tumor cells also expressed cyclin D1 and p16 and therefore the immunostains often highlighted subtle foci of lymphovascular invasion. The heterogenous expression of cell cycle regulatory proteins within endometrial adenocarcinoma illustrates the importance of assessing microanatomical variations in immunoreactivity, particularly at the advancing margin of tumors. The upregulation of cyclin D1 and p16, together with loss of membranous b-catenin expression in microcystic, fragmented and elongated glands, is similar to epithelial-mesenchymal transitions observed in other malignancies and suggests that this pattern of invasion represents an active rather than a degenerative cellular process. Modern Pathology (2009) 22, 725-733; doi:10.1038/modpathol.2009 published online 6 March 2009 Keywords: endometrial; carcinoma; invasion; MELF; epithelial-mesenchymal transition; immunohistochemistry Endometrial carcinomas can be divided into two major groups on the basis of clinicopathological, immunohistological and molecular features. 1,2 The more common (type 1) subgroup accounts for 80-85% of cases and mainly comprises endometrioid adenocarcinomas of low-to-intermediate grade. These tumors typically occur in perimenopausal and younger postmenopausal patients, often arise in hyperestrogenic states and are associated with atypical endometrial hyperplasia/endometrial intraepithelial neoplasia. Frequently, type 1 carcinomas are confined to the uterine corpus at the time of diagnosis (stage 1), and the prognosis in such patients is generally ...

KRASmutation and microsatellite instability in endometrial adenocarcinomas showing MELF-type myometrial invasion

“…In addition, MELF-type epithelium frequently exhibits immunophenotypic features distinct from those of adjacent or contiguous conventional neoplastic glands. These include the loss of immunoreactivity for hormone receptors, E-cadherin and β-catenin, but increased expression of cyclin D1 and p16 proteins 18 19. These morphological and immunohistochemical changes are consistent with EMT and suggest that MELF-type invasion represents an active cellular process during EC progression.…”

Cyclin D1 immunoreactivity in normal endocervix and diagnostic value in reactive and neoplastic endocervical lesions

“…16 Further studies are required to determine the significance of focal cyclin D1 expression in cervical adenocarcinoma but the present findings further illustrate the importance of considering microanatomical variations in staining patterns, even if these are restricted to a minority of cells, as they may be relevant to tumor progression. 33,34 Disclosure/conflict of interest…”

How to approach the many faces of endometrioid carcinoma

“…18 Of interest, ECas with a MELF pattern of myometrial invasion may be related to the concept of epithelial mesenchymal transition, as they tend to show greater expression of cytokeratins 7 and 19, cyclin D1, fascin, p16, and loss or reduced expression of ER and PR, galectin-3, CD147, Ki-67, and β-catenin when compared with the usual type of ECa. [21][22][23][24][25][26] ECa with small non-villous papillae. This morphological variant of ECa shows pseudopapillae lacking fibrovascular cores projecting into gland lumens or extending from the surface of the finger-like papillae that characterize villoglandular ECa.…”