Objective. To clarify the hypothesis that there are two pathways of endometrial carcinogenesis we compared the frequency of abnormal p53 protein expression and angiogenesis in endometrial carcinomas with and without hyperplasia. Methods. Specimens obtained from 70 patients with stage I-IV endometrial carcinomas were available for this immunohistochemical study. Immunohistochemical staining for factor VIII-related and p53 antigens was performed using a standard immunoperoxidase technique (Histofine SAB-PO Kit, Nichirei Co., Tokyo, Japan). Microvessels were highlighted by staining endothelial cells for factor VIII-related antigen, and microvessel density (MVD) was counted in a x200 field (0.785 mm(2) per field) in the area of most active neovascularization. p53 protein was detected with monoclonal anti-p53 antibodies (clone DO-7, Dako, Santa Barbara, CA). Results. Twenty-six of 73 (37%) patients had hyperplasia in the endometrium adjacent to the carcinoma. Significantly more patients with low MVD (less than 60) had carcinoma with hyperplasia than those with carcinoma without hyperplasia (P = 0.0053). p53 expression was noted in a carcinomatous area in 8 of 26 patients (30.8%) with hyperplasia compared to 26 of 44 (59.1%) without hyperplasia, and the difference was statistically significant (P = 0.0220). Conclusion. The presence or absence of hyperplasia is a different pathogenesis and important in assessing the biological behavior of endometrial carcinoma, especially concerning angiogenesis and p53 expression. (C) 1999 Academic Press.