Cell proliferation in prostate cancer patients with lymph node metastasis: a marker for progression

The biological aggressiveness of lymph node-positive prostate cancer is closely linked to cancer volume in nodal metastases. We evaluated MIB-1 (Ki-67) labeling index and bcl-2 expression in primary cancer and matched nodal metastases from 138 node-positive patients treated with radical prostatectomy and bilateral pelvic lymphadenectomy between 1987 and 1992 at the Mayo Clinic. One hundred twenty-eight patients (93%) received androgen deprivation therapy within 90 days after radical prostatectomy. Mean patient age was 66 years (range, 51-78). The median follow-up was 6.7 years (range, 0.03-11). MIB-1 (Ki-67) labeling index was determined by digital image analysis, and nodal cancer volume was determined by the grid method. Systemic progression, defined as the presence of distant metastasis documented by biopsy or radiographic examination, was used as an outcome end point in the Cox proportional hazard models. MIB-1 labeling index in nodal metastases was predictive of systemic progression-free survival (P = 0.001). The 8-year systemic progression-free survival was 100% for those with MIB-1 labeling index <3.5% compared with 78% for those with MIB-1 labeling index > or =7.8%. MIB-1 labeling index correlated with Gleason score, DNA ploidy, and nodal cancer volume (P<0.001, 0.04, and <0.001, respectively). After controlling for nodal cancer volume, MIB-1 labeling index remained significant in predicting systemic progression-free survival (P = 0.047). bcl-2 expression in the primary cancer and lymph node metastasis was associated with systemic progression-free survival in univariate analysis (P = 0.027 and 0.048, respectively) but was not significant after adjusting for nodal cancer volume (P = 0.52 and 0.17, respectively). Our data indicate that assessment of cell proliferation in nodal metastasis is predictive of clinical outcome in prostate cancer patients with regional lymph node metastasis.