Receptor activator of nuclear factor-kappaB ligand (RANKL) as a novel prognostic marker in prostate carcinoma.

Combined immunodetection of parathyroid hormone-related protein (PTHrP) and receptor activator of NF-kappaB ligand (RANKL) has shown to successfully distinguish poorly- and well-differentiated prostate carcinoma (PCa). In the present study, we aimed to assess whether immunohistochemical evaluation of these factors, and also osteoprotegerin (OPG) and Ki67, in radical prostatectomy specimens can predict biochemical recurrence. Fifty nine PCa cases undergoing radical prostatectomy between 1995 and 1998, without history of neoadjuvant hormonal therapy, were studied. Preoperative serum prostate-specific antigen (PSA), Gleason-sum score, pathologic stage, perineural invasion, seminal vesicle involvement, and positive surgical margins were assessed in these patients. Biochemical recurrence, defined by PSA > 0.4 ng/mL at 90 days or later after prostatectomy, occurred in 32/59 patients. In these patients, positivity for OPG and RANKL in the tumoral epithelium was higher than in those patients with no biochemical recurrence. Using univariate analysis, Gleason-sum score, surgical margins, and seminal vesicle involvement, as well as OPG and RANKL immunostaining (using a score value corresponding to moderate staining as cut-off) were significant predictors of biochemical recurrence (p<0.05). Using the multivariate Cox model, among the evaluated factors only RANKL expression (hazard ratio 11.6; p <0.001) was an independent prognostic indicator. Our findings suggest that immunohistochemical evaluation of RANKL in the primary tumor is a potential risk factor in PCa patients.

Immunohistochemical analysis of low-grade and high-grade prostate carcinoma: relative changes of parathyroid hormone-related protein and its parathyroid hormone 1 receptor, osteoprotegerin and receptor activator of nuclear factor-kB ligand.

AIM: To investigate multiple bone cytokines produced by prostate carcinoma (PCa) as a novel strategy to differentiate potential aggressiveness in localised PCa using immunohistochemical analysis. METHODS: A total of 47 cases of PCa undergoing radical prostatectomy or transurethral prostatic resection at our institution (Fundación Jiménez Díaz (Grupo Capio), Madrid, Spain) between January 1991 and June 1998 were identified as low-grade (< or =4; n = 22) or high-grade (> or =7, excluding 7 (3+4) cases; n = 25) PCa according to Gleason grade. PCa specimens were immunostained for: parathyroid hormone (PTH)-related protein (PTHrP), the PTH1 receptor, osteoprotegerin and receptor activator of nuclear factor-kappa B ligand (RANKL), as well as Ki67 (a proliferation marker) and CD34 (an angiogenesis marker). RESULTS: PCa samples showed an increased immunostaining for both osteoprotegerin and RANKL, associated with tumour grade and PTHrP positivity, in the tumoral epithelium. Using a score value of 4-corresponding to moderate staining - as cut-off, the best sensitivity value was for PTHrP (with C-terminal antiserum C6; 100 %); wheras the best specificity value was for RANKL (95 %). CONCLUSIONS: All the evaluated factors are overexpressed mainly in the high-grade tumours. Our findings indicate that, in most patients with PCa (with Ki67 values between 1% and 9%), sequential determination of C-terminal PTHrP and RANKL immunoreactivities is a useful approach to discriminate low-grade and high-grade tumours.