Prognostic significance of proliferation activity and neuroendocrine differentiation to predict treatment failure after radical prostatectomy

Objectives. Neuroenclocrine (NE) cells in prostate cancer may influence tumor cell proliferation in a paracrine fashion. The aims of this study were to clarify the prognostic value of tumor cell proliferation and NE tumor cell differentiation in prostate cancer after radical prostatectomy, and to compare these parameters with each other. Material and methods. Specimens were pooled from a total of 528 patients treated with radical prostatectomy without neoadjuvant hormonal therapy between 1996 and 2003. NE differentiation (NED) was determined by inummohistochernistry using antibodies directed against chromogranin A (CgA), and was scored as either NE-negative (0 - 1 +) or -positive (2 - 3 +). Tumor cell proliferation was assessed by means of the Ki-67 labeling index (Ki-67 LI). The mean post-surgical follow-up period was 49 months (range 10-116 months). Any subsequent rise in prostate-specific antigen (PSA) level was regarded as reflecting disease progression. The prognostic values of Ki-67 and CgA were comparatively analyzed using multivariate Cox regression. Results. NED was present in 6. 1 % of tumors. The mean Ki-67 LI was significantly higher in the CgA-positive group in comparison with CgA-negative specimens (6.6% vs 5.0%; p =0.029). The Ki-67 LI showed the highest correlations with Gleason score and pathological tumor stage (r=0.31 and r=0.3, respectively). NED was found to have the strongest association with pathological tumor stage (r=0.2). Multivariate analysis determined Gleason score >= 7 (4+3) [hazard ratio (HR) 3.04], NED (HR 1.89), lymph node metastases (HR 1.84), preoperative PSA level > 20 ng/ml (FIR 1.66), and Ki-67 LI >= 5% (HR 1.62) to be significant predictors of biochemical progression. Conclusion. Our results identify Ki-67 LI and NED as additional prognostic markers after radical prostatectomy.