The Patterns of Expression of an Apoptosis-Related CK18 Neoepitope, the bcl-2 Proto-Oncogene, and the Ki67 Proliferation Marker in Normal, Hyperplastic, and Malignant Endometrium

Abstract

Expression of a neoepitope on cytokeratin 18, recognized by the monoclonal antibody M30, is an early indicator of apoptosis in epithelial cells. The aim of this study was to determine the equilibrium between apoptosis (M30), anti-apoptosis (bcl-2), and proliferation (Ki-67) in different endometrial conditions. Paraffin-embedded samples (n = 107), representing proliferative endometrium (18), secretory endometrium (19), postmenopausal endometrium (15), disordered proliferative endometrium (6), simple hyperplasia (12), complex hyperplasia (8), and endometrial adenocarcinoma (29), were evaluated immunohistochemically. The indirect streptavidin-biotin-horseradish peroxidase technique, with 3-amino-9-ethylcarbazole as the chromogen, was used to visualize the reactions. Proliferative endometrium showed high bcl-2 and Ki-67 expression levels with no M30. In the secretory phase, the balance was tipped in favor of M30 with a decrease of bcl-2 and Ki-67. Postmenopausal endometrium revealed high Ki-67 and bcl-2 expression levels and no M30. In complex hyperplasia, M30, bcl-2, and Ki-67 showed increased expression. In endometrial carcinoma, an increasing reactivity for M30 and Ki-67 was seen as the grade progressed. bcl-2 reacted weakly and only in grade 1 cancer. Immunohistochemistry facilitates the study of the expression of proteins related to cyclic endometrial activity. Interruption of these cyclic events is associated with specific disturbances in the expression patterns of these proteins.

The Expression of Apoptosis-Related Proteins Bcl-2 and Ki67 in Endometrium of Ovulatory Menstrual Cycles

“…Many studies have revealed that tissue degradation associated with menstruation is the result of an active process in which apoptosis is involved [5,[8][9][10]. Studies performed in vitro and in transgenic mice indicate that Bcl-2 could play a role in extending the survival of normal and pathologic cells by preventing apoptosis [5,[8][9][10][11]15]. Bcl-2 can inhibit the apoptosis induced by cmyc [1].…”

“…The histologic appearance of the endometrium was classified as M = menstruation (days 1-5), EP = early proliferative (days 6-9), LP = late proliferative (days [10][11][12][13][14], ES = early secretory (days [15][16][17][18], MS = mid-secretory (days [19][20][21][22] and LS = late secretory (days 23-28) phase. For each of these phases specimens from 5 representative uteri were collected.…”

“…For homeostatic tissue growth, a tight balance must be maintained between cell proliferation and cell loss. The mecha-nism involved in cell proliferation has been studied extensively, cell death has only later been recognized as an important phenomenon [5][6][7][8][9][10][11].…”

“…The protein Bcl-2 has been shown to prolong cell survival by preventing apoptosis [5,10,11,13]. Ki67 is a protein which is expressed in cycling cells from the G 1 to the M phases [10,11].…”

Tubal metaplasia of the endometrium with cytologic atypia: analysis of p53, Ki-67, TERT, and long-term follow-up

“…14 Studies have also shown that Ki-67 proliferation indices are increased in numerous human malignancies, including high-grade endometrial cancer, as compared with post-menopausal (atrophic) endometrium. 15 High proliferation indices with Ki-67 are also seen in invasive 7,16 and intraepithelial serous carcinoma. 12 In contrast, our findings show that the majority of atypical tubal metaplasia is either negative for Ki-67 or shows a low proliferation index, with Ki-67 immunopositivity limited to less than 5% of atypical cells.…”