Prognostic significance of p53 nuclear accumulation in localized prostate cancer treated with radical prostatectomy

The role of p53 in the pathogenesis of, and as a predictive biomarker for, localized prostate cancer (PCa) is contested. Recent work has suggested tha t patterns of p.53 nuclear accumulation determined by immunohistochemistry are prognostic, whereas studies using other methods question the role of p5 3 mutations in predicting outcome. We studied 263 men with localized PCa tr eated with radical prostatectomy to determine whether p53 nuclear accumulat ion predicts relapse and disease-specific mortality. We combined two p53 im munohistochemistry scoring systems: (a) percentage of p53-positive tumor nu clei in all major foci of cancer within the prostate; and (b) clustering, w here the presence of 12 or more p53-positive cells within a x 200 pow er fi eld was deemed "cluster positive." Analysis was undertaken using chi(2), Kr uskal-Wallis, and Mann-Whitney tests for clinicopathological variables and the Kaplan-Meier method, log-rank test, and univariate and multivariate Cox regression modeling for evaluation of contribution to relapse and disease- specific survival. At mean follow-up of 55.1 months (range, 4.9 -123.0 mont hs), 39 % (102 of 263) of patients had relapsed and 2.3 % (6 of 253) had di ed of PCa, Pretreatment serum prostate-specific antigen concentration, path ological tumor stage, lymph node involvement, Gleason score, and p53 nuclea r accumulation, as determined by either percentage score or cluster status, were independent predictors of relapse in multivariate analysis. Clusterin g of p53-positive cells distinguished between favorable and poor prognosis patients within the lowest p53-positive stratum (>0 to <2%) and was the mos t discriminatory threshold for predicting relapse in the entire cohort. p53 status predicted outcome in patients with a Gleason score of 5 and above b ut not those with a score of 4 and below, In patients treated with neoadjuv ant hormonal therapy, p53 cluster positivity carried a 90% (19 of 21) risk of relapse by 36 months. All six patients who died from PCa in the period o f the study exhibited p53 nuclear accumulation in 20% or more tumor nuclei. This study demonstrates strong relationships between p53 nuclear accumulat ion and relapse and disease-specific mortality in a large series of localiz ed PCas, Furthermore, the presence of clusters of p53-positive nuclei delin eates a group of patients with poor prognosis not identified by traditional scoring methods and supports the hypothesis that p53 dysfunction within PC a may exist in foci of tumor tells that are clonally expanded in metastases .