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S_ry Clinical data were reviewed in 325 patients with prostatic adenocarcinoma followed up for a mean of 13 years. Paraffin-embedded tumour biopsy specimens from the primary tumours were available for flow cytometry (FCM) in 273 cases. Intra-tumour heterogeneity in DNA index (DI) was found in 4% of the tumours (54 cases were analysed). S-phase fraction (SPF) and DNA ploidy were significantly interrelated. Aneuploidy and high SPF were significantly related to both a high T category and high Gleason score. The progression in TI -2M0 tumours was related to Gleason score (P= 0.009 Prostatic adenocarcinoma is the most common malignancy among elderly men, although only a small fraction of the tumours progress to metastatic disease. The latent cancer is 3-8 times more common than the clinical form of the disease. Accordingly, identification of the malignant subset of prostatic tumours would be of great help in planning treatment and follow-up strategies for the ever-increasing number of men suffering from this age-related disease (Muir et al., 1991). Currently, the prognostic evaluation of prostatic adenocarcinoma is based on tumour staging (UICC, 1978) and on subjective histological grading. Currently, there are several different grading systems for prostatic adenocarcinoma, and most correlate with prognosis (Mostofi, 1975;Gleason 1977;Gaeta et al., 1980). DNA flow cytometry (FCM) provides more objetive prognostic information than grading in several human tumours (Frierson, 1991;Deitch & DeVere White 1992; Lipponen et al., 1993) and measurement of the S-phase fraction (SPF) has given prognostic estimates superior to DNA ploidy alone (Frierson, 1991; Visakorpi et al., 1991; Lipponen et al., 1993). From previous studies we know that DNA ploidy correlates with the histological grade in prostatic adenocarcinoma (Badalament et al., 1991;Robertson & Paulson 1991; Visakorpi et al., 1991;Di Silvero et al., 1992)

Mitotic figures were quantitated by two different methods (number of mitotic figures in 10 high power fields, MI; number of mitotic figures/mm2 of neoplastic epithelium, M/V) in a series of 303 prostatic adenocarcinomas, and the results were related to clinical and histological features as well as to prognosis. Gleason score and mitotic indices were significantly interrelated. Invasive T3-4 tumors showed higher mitosis counts than did the local ones, and metastasis at the time of diagnosis was related to mitotic indices as well. Progression and progression-free survival were related significantly to Gleason score and mitotic indices. In univariate survival analysis, T-category, M-category, Gleason score, MI, and M/V were significant prognostic factors. In multivariate analysis, independent predictors of survival were M-category, T-category, Gleason score, patient age, and the M/V index. If the Gleason score was not included, M/V included all the available prognostic information in T1-2M0 carcinomas. The results show that, in addition to the conventional Gleason grading system, mitotic indices are useful prognostic parameters while evaluating the long-term prognosis in prostatic adenocarcinoma.

The expression of proliferating cell nuclear antigen and p53 protein was analysed by immunocytochemical methods (PC10, CM1 antisera) in 139 patients with T1-2M0 prostatic adenocarcinomas followed-up for > 12 years. p53 protein was expressed in 21 (15%) tumours (15%), the fraction of positive nuclei being very low (mean SE, 1% +/- 0.7%). Accumulation of p53 protein in epithelial cells was independent of tumour stage and Gleason score, and had no effect on prognosis. In 4 cases, p53 protein was expressed only in stromal cells. The fraction of PCNA-positive nuclei (evaluable in 116 cases) was higher in T2 than in T1 tumours (p < 0.001); furthermore, high Gleason score was positively correlated with PCNA positivity (p < 0.001). A finding of over 5% of PCNA-positive nuclei predicted progression in T and M categories and were a sign of poor outcome. The fraction of PCNA-positive stromal-cell nuclei was related to T-category with a borderline significance (p = 0.06). In a multivariate analysis of the prognostic factors, independent predictors of survival included Gleason score (p < 0.001), fraction of PCNA-positive nuclei (p = 0.013), observation before therapy (p = 0.05), and T-category (p = 0.07) in that order of significance. The results suggest that overexpression of p53 protein is of marginal prognostic value in local prostatic adenocarcinomas, whereas direct measurement of cell proliferation by PCNA immunolabelling provides important prognostic information in T1-2M0 tumours, in addition to the Gleason score.

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