BERKELEY, CA (UroToday.com) - This study pertained to our initial observation of biochemical-free survival rates (BCR) between patients with positive and negative surgical margins after an open retropubic radical prostatectomy, correlating clinical and pathologic variables with the results of follow-up. Prostate cancer volume and Gleason score in surgical specimen were, at multivariate analysis, the significant risk factors for BCR (p = 0,022 and p < 0,005).
There are well-established clinical, surgical, and anatomo-pathological parameters currently used to allow us to predict the evolution to biochemical recurrence of adenocarcinoma of the prostate. However, after surgical treatment, especially when in the presence of positive surgical margins, immunohistochemical tests have become very important tools to support the indication of adjuvant therapies, either precociously or not, based on the expression of certain markers that signal the tumor’s aggressiveness. The iNOS (inducible nitric oxide synthase) synthesizes nitric oxide (NO) which plays an important role in the tumor’s growth and in the angiogenesis. It affects the macrophage’s cytotoxicity and tumor-induced immunosuppression as well. Being a marker very commonly found in prostate adenocarcinoma cells, it thus differentiates this from benign hyperplasia. COX-2, the production of which is stimulated by the NO, has also been associated with various neoplasias due to its angiogenic action and to its influence on the inflammation process as well, being then studied as a therapeutic target via. GLUT1 is an active glucose transporter expressed in normal tissues and expressed at high levels in numerous tumors, playing the role as intrinsic and mediator hypoxia marker, reducing oxidative phosphorylation, and acting on the oxygen-dependent signalizing via through hypoxia inducible factor (HIF-1). Nitrotyrosine is a product of tyrosine nitration mediated by reactive nitrogen species such as peroxynitrite anion and nitrogen dioxide, being detect in pathological conditions such as in neoplasias, it is thus considered a marker of NO-dependent oxidative stress. The objectives were to evaluate the expressions of those markers in surgical specimens of prostates with adenocarcinoma, as well as to evaluate their relation with prognosis after radical prostatectomy in patients with positive surgical margins, a factor that has been considered in the literature significant for biochemical recurrence.
As we cannot obtain from all patients from the first study the histological blocks necessary to evaluate the presence of these biomarkers, a smaller number of medical records - 162 patients - with prostatic adenocarcinoma who were submitted to radical prostatectomy, were retrospectively checked and analyzed. Of those, 110 cases presented positive surgical margins. For comparison purposes, we have also studied another group consisting of 52 patients with negative surgical margins. The microscope slides and corresponding histological blocks were reviewed, and by using the tissue microarray technique, we appraised iNOS, COX-2, GLUT1 and nitrotyrosine expressions. The objectives of this work were to evaluate the expressions of those markers in surgical specimens of prostates with adenocarcinoma, as well as to evaluate their relation with prognosis after radical prostatectomy in patients with positive surgical margins. The microscope slides and corresponding histological blocks were revised, and by using the tissue microarray technique, we appraised iNOS, COX-2, GLUT1 and nitrotyrosine expressions. These expression values were associated with the patients’ biochemical recurrence-free survival for a follow-up period of greater than two years, with those results being reappraised after 5 and 10 years of postoperative survival. The association between the clinical variables or the anatomo-pathological variables with the presence or absence of positive margins was checked using the chi-square test or the Fisher’s exact test. The elapsed times for biochemical recurrence and disease-free survival were assessed using the Kaplan-Meier estimator. For graphics comparison, the non-parametric LogRank test was used. The significance level assumed was 5%, and calculations, graphics, and tests were developed with the aid of the ‘R Project for Statistical Computing’ free software (www.r-project.org). Multiple logistic regression analyses were used to assess the predictive factors for CaP biochemical recurrence. The risk for recurrence was estimated through the “hazard ratio” obtained from the Cox model. This work demonstrates that the Gleason score, the PSA level, the tumor volume, the pathological stage, the capsular invasion, and positive surgical margins showed a significant association with lower biochemical recurrence-free survival rates (p < 0.001).
The iNOS, COX-2, GLUT1, and nitrotyrosine immunoexpressions did not present association to biochemical recurrence in patients with positive surgical margins (p=0.3646; p=0.1457; p=0.4414 and p=0.0806, respectively). Multivariate analysis in the 110 patients with positive surgical margins provided evidence that the tumor volume, when higher than 30% of total volume of the specimen (HR 12.13; 95%CI = 4.208 – 34.965; p < 0.001 and the presence of capsular invasion (HR 3.106; 95%CI = 1.249 – 7.277; p=0.014), was an independent prognostic factor for CaP biochemical recurrence
Ricardo L.R. Felts de la Roca,a Isabela Werneck da Cunha,c Stephania Martins Bezerra,c and Francisco Paulo da Fonsecab as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
aDepartment of Oncology; bDivision of Urology; cDepartment of Pelvic Surgery and Department of Pathology, Fundação Antonio Prudente A. C. Camargo Cancer Center, São Paulo - SP, Brazil