Apoptosis, proliferation, and hormone receptors in endometrial carcinoma: results depending on methods of analysis

Abstract

Apoptosis and proliferation were studied in 29 endometrial adenocarcinomas of the endometrioid type and characterized by the immunohisto-chemical pattern of estrogen receptor (ER) alpha and progesterone receptor (PR) expression. Intratumoral heterogeneous distribution of both ER and PR as well as of the proliferation marker Ki-67 was studied and quantified. Both density and heterogeneity of the two steroid receptors and Ki-67 varied, depending on the histological malignancy grade (grades 1-3, or G1-3); interestingly, however, the apoptotic index (Ai) was in the same range for all grades. Receptor staining was evaluated by three different methods: i) counting the percentage of stained cells (staining index), according to stereological principles; ii) the mixed method, a combination of the staining index results and ranking staining intensity; and iii) a superficial and rapid visual scoring. The three methods gave equal results. Apoptotic cells and bodies were generally scattered in the endometrial carcinoma but more frequently observed adjacent to necrotic foci. Bcl-2, known as anti-apoptotic factor, showed no correlation to apoptotic index, Ki-67 expression, ER, or PR. Overexpression of p53 was seen in two tumors of grade 3. In a detailed study of intra-tumoral microfoci performed on consecutively taken tissue sections, a higher staining index of both ER and PR was found in the areas of maximal proliferation compared with the areas of minimal proliferation in tumors of grades 1-2, but not in G3 tumors. Other covariations were also found when non-specified areas were studied. The Ki-67 index was both higher and more heterogeneous in G2-3 tumors than in G1 tumors. Our results indicate that there is an increasing discrepancy between cell death and cell proliferation with progressing tumor grade, which may contribute to the differences in tumor aggressivity.