Based on their etiological and pathological features, sporadic endometrial cancer is classified into two subtypes (2,134). Type I (endometrioid histology) represents the majority of lesions (approximately 80%), whichare mostly low grade, estrogen receptor positive, associated with hyperestrogenism, and arise from atypical complex hyperplasia (196,197). Hyperestrogenism may be attributed to obesity with peripheral conversion of androgens to estrogens, anovulation, or exposure to excessive exogenous estrogen (134,198–202). Obesity, polycystic ovarian syndrome, tamoxifen use, and unopposed estrogen use are all associated with increased risk of endometrial cancer. Other associated findings include late onset of menopause, nulliparity, diabetes mellitus, and hypertension. The molecular basis for the progression from hyperplasia to invasive endometrial carcinoma as a result of hyperestrogenism remains unknown because the involvement of only a minority of factors is reproducible (203). In contrast, type II endometrial cancer (serous, clear cell carcinoma) appears to be unrelated to high estrogen levels and often develops in nonobese women. Type II cancers arise from its precursor, endometrial intraepithelial carcinoma (EIC) adjacent to an atrophic endometrium background in relatively older women (204). Distinct molecular changes are associated with these two subtypes. Common genetic changes in endometrioid endometrial cancer include mutations in PTEN (205–212), or β-catenin genes (213–215). In contrast, type II cancers frequently demonstrate alterations in HER2/neu, p53, p16, e-cadherin, and loss of heterozygosity (LOH) (216–218). These distinct molecular alterations underscore prognostic differences. Type I endometrial cancer is limited to the uterus in 70% of cases with a 5-year survival greater than 85%. Type II endometrial cancer displays a more aggressive clinical course and a poor prognosis; even in tumors with little or no myometrial invasion, more than one in three patients will have extensive extrauterine spread with complete surgical staging, resulting in an overall survival of 20% (106,110,114,219).