Endometrial Glandular Dysplasia (EmGD): morphologically and biologically distinctive putative precursor lesions of Type II endometrial cancers

Endometrial cancers are the most frequently diagnosed malignancies of the female genital tract in the United States, with 39,080 new cases projected for 2007 [1]. Since 1983, two broad clinicopathologic subtypes of endometrial carcinomas have been recognized [2]. This conceptual classification has largely been supported by subsequent molecular-cytogenetic data, which has facilitated the acceptance of the so-called dualistic model of endometrial carcinogenesis [3-8]. Type I cancers, the prototype of which is the endometrioid histotype, occur in comparatively younger age group [3-8], appear to be related to unopposed estrogen stimulation [9-14], frequently express the estrogen and progesterone receptors [7,13,14], arise in a background of glandular hyperplasia [5,7,13,14], and has a relatively favorable prognostic profile [15]. Genetic alterations in Type 1 cancers include PTEN inactivation [16-19], beta-catenin (CTNNB1) mutations [17], and less frequently, microsatellite instability (related to inactivation of the MLH1 gene) [20,21], and activational mutations of the K-ras gene [22]. Type II cancers, the prototype of which is the endometrial serous carcinoma (ESC), and which was previously termed uterine papillary serous carcinoma (UPSC), typically occur in an older age group [3-8], frequently arise in a background of inactive or resting endometrium [3-8], and display a low frequency of expression of hormonal receptors [13,14,23,24]. Type II cancers also display frequent mutation and overexpression of the p53 [24-26] and HER2/neu [27,28] genes and proteins respectively, and have a comparatively poor prognosis independent of other factors [29-32]. This model has provided a valuable framework for the study of various aspects of endometrial carcinogenesis and for the potential development of therapeutic modalities that are pathway specific. Nonetheless, approximately 7400 deaths attributable to uterine corpus malignancies are projected for 2007 [1]. This relatively high