CELL-PROLIFERATION IN RENAL-CELL CARCINOMA - A CLINICAL-STUDY WITH SPECIAL REFERENCE TO PROGNOSIS

As the clinical behaviour of renal cell carcinoma (RCC) varies considerably from case to case, it is important to identify variables capable of predicting outcome in the individual patient. DNA ploidy status, analyzed by flow cytometry (FCM) in 59 patients with stage I disease, showed survival to be significantly better in the diploid than in the non-diploid subgroup. The prognostic value of S-phase fraction evaluated from DNA histograms (S-FCM) was studied in 69 RCC patients. The mean S-phase value was 7.5%, the values being significantly lower in the diploid than in the aneuploid subgroup. Both in the group as a whole and among patients with aneuploid tumors, survival was significantly better in the low (<7.5%) than in the high (greater than or equal to 7.5%) S-phase fraction subgroup. Multivariate analysis showed both the S-phase fraction and tumor stage to be significant independent prognostic variables. Immunohistochemistry (IHC) studies with in vivo iododeoxyuridine labeling (IdUrd-IHC) performed in a series of 33 RCC patients, showed a mean labelling index (LI) of 1.06%. The LI values being significantly lower in diploid than in aneuploid tumors. In a series of 29 RCC patients cell kinetic studies with in vivo IdUrd labeling and subsequent FCM analysis (IdUrd-FCM), showed a mean tumor LI of 2.7%, and a mean potential tumor doubling time (T-pot) of 20.3 days (kidney cortex samples 137.7 days). T-pot was found to be a significant prognostic indicator, though as intratumor heterogeneity in T-pot was common it needs to be determined in multiple samples. Proliferating cell nuclear antigen (PCNA) expression evaluated by IHC using the monoclonal antibody PC-10 (PCNA-IHC) in 68 RCC patients, showed the mean PCNA index to be 4.9%, and values being significantly greater in aneuploid than in diploid tumors. Both in the group as a whole and among patients with non-metastatic disease, survival was better in the low (<3.5%) than in the high (greater than or equal to 3.5%) PCNA index subgroup. Four different methods of cell proliferation (S-FCM, IdUrd-IHC, IdUrd-FCM, PCNA-IHC) were compared. Comparative analysis according to the Bland and Altman method, showed a good degree of agreement. The results indicated that the different methods seemed to provide comparable information on proliferative activity, although different cell-cycle compartments were monitored. It's concluded that: DNA-ploidy is a prognostic indicator in low-stage RCC; S-FCM is a significant independent prognostiv variable; Tpot is a significant prognostic variable; the IdUrd-IHC and PCNA-IHC labeling indices may provide useful additional prognostic information; proliferation indices are higher in aneuploid than in diploid tumors; heterogenity in ploidy status and cell kinetics is common in RCC.