Endometrial adenocarcinomas may show a distinctive pattern of invasion characterized by the presence ofmicrocystic, 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 whichshow focal mucinous differentiation and lymphovascular space invasion. However, the molecular alterationsassociated with this morphological alteration are not known. In this study, we have examined immunoreactivityfor the cell cycle regulatory proteins cyclin D1, p16 and b-catenin in 22 endometrial carcinomas, specificallycomparing 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 p16expression in most cases, with 450% tumor cells positive in 8 cases and 11 tumors, respectively. Membranousexpression of b-catenin was usually preserved, with variable cytoplasmic and nuclear staining. Cyclin D1 andb-catenin predominantly stained cells at the peripheral or basal aspect of the conventional glands, whereas p16was more uniformly expressed centrally. Tumor foci composed of microcystic, fragmented and elongatedglands showed strong expression of cyclin D1 and p16, sometimes in contrast to unstained contiguous oradjacent conventional neoplastic elements, and there was also loss or fragmentation of membranous b-cateninstaining. Intravascular tumor cells also expressed cyclin D1 and p16 and therefore the immunostains oftenhighlighted subtle foci of lymphovascular invasion. The heterogenous expression of cell cycle regulatoryproteins within endometrial adenocarcinoma illustrates the importance of assessing microanatomicalvariations in immunoreactivity, particularly at the advancing margin of tumors. The upregulation of cyclin D1and p16, together with loss of membranous b-catenin expression in microcystic, fragmented and elongatedglands, is similar to epithelial–mesenchymal transitions observed in other malignancies and suggests that thispattern of invasion represents an active rather than a degenerative cellular process.