Progressing Imbalance Between Proliferation and Apoptosis with Increasing Severity of Cervical Intraepithelial Neoplasia

Abstract

The equilibrium between cell proliferation and protection against apoptosis was studied immunohistochemically using monoclonal antibodies against Ki-67-Ag and bcl-2, respectively, in consecutive sections from normal and metaplastic cervical epithelia and cervical intraepithelial neoplasia (CIN) lesions and cervical carcinomas. A high percentage of Ki-67-Ag positive cells was seen in the parabasal cells of normal ectocervical and mature squamous metaplastic epithelium, although the basal cells were virtually negative. In preneoplastic lesions, however, the basal cells showed high proliferative activity and an increasing frequency of Ki-67-Ag positive cells was observed in the higher epithelial layers with increasing severity of CIN. In squamous cell carcinomas, variable numbers of Ki-67-Ag positive cells were observed and in adenocarcinomas expression increased with the degree of anaplasia. bcl-2 expression was observed only in the basal cells of normal endo- and ectocervix including reserve cells. With increasing severity of CIN, staining intensity and number of bcl-2 positive cells gradually increased. Five of eight squamous cell carcinomas were variably positive. All five adenocarcinomas showed extensive bcl-2 expression. Increased expression of both Ki-67-Ag and bcl-2 with increasing severity of CIN indicates an increasing imbalance between cell proliferation and protection from apoptosis. It is therefore proposed that an increasing proliferative fraction combined with a higher number of cells protected from apoptotic cell death contributes to progression of CIN. This phenotype may identify premalignant lesions with the potential to transform to cervical cancer.