PROGNOSTIC FACTORS IN INVASIVE CERVICAL CARCINOMAS ASSOCIATED WITH HUMAN PAPILLOMAVIRUS (HPV) - QUANTITATIVE DATA AND CYTOKERATIN EXPRESSION

As a part of a larger programme to search for the prognostic factors in cervical cancer, quantitative morphometry, demonstration of AgNORs and expression of different cytokeratin polypeptides (SK2-27, SK1, A 53-B/A2) were used to study a series of 85 cervical squamous cell carcinomas, previously analysed for the presence of human papillomavirus (HPV) DNA by in situ hybridization and polymerase chain reaction (PCR). The following nuclear profile parameters were calculated: nuclear area, perimeter, maximum diameter, ellipsoidity (form Ell), regularity (form Ar) and roundness (form Pe). In each case, the number of small (<3 mum), large (>3 mum), the total number and the ratio large/small AgNORs were registered. The cancer cell density and the lymphoid cell density were assessed. In the survival analysis, neither the expression of different cytokeratin polypeptides or the pattern of cytokeratin staining proved to be an independent variable. Similarly, none of the nuclear profile parameters analysed possessed an independent prognostic value in the survival analysis. The ratio of large/small AgNORs proved to be a significant independent prognostic predictor (p=0.01 04), second only to the lymphoid cell density. Also the total number of AgNORs was a prognostic indicator. This suggests that AgNOR size and ratio reflect tumor proliferation also in cervical squamous cell carcinoma, as shown in other human malignancies. Similarly, the density of cancer cell nuclei proved to be an independent prognostic predictor (p=0.0601) in that the tumours in patients with longer survival showed lower density of the nuclei. On the contrary, higher density of peritumoral lymphoid cell nuclei was correlated with longer survival up to the point that the intensity of such infiltrate was the most powerful single prognostic factor in the present series (p=0.0026). The mechanism responsible for this prognostic significance of the lymphoid cell infiltration needs further assessment, e.g. subpopulation analysis by monoclonal antibodies, and functional tests of these subpopulations. The results clearly indicate that histoquantitative morphometry and cytokeratin expression seem to be of little or no value as prognostic predictors in cervical cancer, and further work is still needed to elucidate the factors determining the disease outcome more accurately than the currently available means.