Proliferation and DNA Aneuploidy in Mild Dysplasia Imply Early Steps of Cervical Carcinogenesis

Abstract

This project was focused on cellular proliferation relative to the onset of endoreplication and effects of DNA aneuploidy during carcinogenesis in cervical mucosa. Proliferation was monitored with MIB1 antibody, whereas nuclear DNA content was quantified using an image processing microphotometer. For the later procedure, 8 μm sections were of adequate depth with interphases, and lymphocyte nuclei provided an internal standard of the diploid (2c) DNA content. Results from 95 cervical biopsies displaying different types of dysplasia and carcinoma were supplemented with those of cervical smears from 319 cases. The later specimens had been selected from about 30 000 consecutive cases in 1993/94. MIB1-traced proliferation was found in the second cell layer, whereas the bulk of basal cells remained quiescent in normal mucosa. However, predominant MIB1 immunoreactivity was observed with endoreplicated nuclei. A critical 30% of the cases exhibited DNA aneuploidy already in mild dysplasia, which was found in cytological smears and histological sections. The nuclear DNA content of basal cells increased progressively by endoreplication corresponding to the degree of dysplasia. Cases of carcinoma in situ displayed some 18% of non-proliferating diploid cells despite overwhelming endoreplication and DNA aneuploidy. High MIB1 levels combined with DNA aneuploidy unambiguously indicate the beginning of cervical carcinogenesis. The limits of the Bethesda system were discussed.