Clinical and Pathological Parameters Predicting Extracapsular Disease in Patients Undergoing a Radical Prostatectomy for Clinically Localized Prostate Cancer

To determine the epidemiological, clinical and pathological factors that can potentially predict extracapsular extension of prostate cancer in patients undergoing radical prostatectomy for clinically localized disease. We retrospectively analyzed the medical records of patients who undergone radical prostatectomy from January 2001 until November 2010. Patients age, prostate volume, PSA, PSA density, percent of cancer in prostate biopsy material, presence of cancer in biopsy cores of the right lobe or the left lobe or both lobes, Gleason summary, 1 Gleason pattern and 2 Gleason pattern were analyzed for their predictive ability. From 187 studied patients, 44 of them (23.5%) had extracapsular disease. Multivariate analyses revealed that smaller prostate volumes and the presence of malignancy in both lobes after prostate biopsy were significant predictors for non-organ confined disease in the total population and in patients with Gleason score ≥7. Presence of malignancy in both lobes was the only significant predictive factor in patients with PSA ≤10 and in those with Gleason score ≤6. Prostate volume and positive cores for malignancy from both lobes after prostate biopsy are preoperative data that can be used for prediction of extracapsular disease. This information can be valuable in cases a nerve sparing radical prostatectomy is planned. © Charl s University in Pr gue – Karolinum Press, Prague 2012 Mailing Address: Stavros Sfoungaristos, MD., Department of Urology, University Hospital of Patras, Building A, 4 Floor, Rion, 26500 Patras, Greece; Phone: +302 610 999 367; Fax: +302 610 993 981; e-mail: [email protected] PMR_2012_01.indd 5 10.2.12 10:42 Sfoungaristos S.; Perimenis P. 6) Prague Medical Report / Vol. 113 (2012) No. 1, p. 5–15 Introduction The introduction of prostate-specific antigen (PSA) and other circulating biomarkers in addition to transrectal ultrasound has revolutionized prostate cancer (PCa) screening. These factors have resulted in early detection and increased incidence of the disease (Bensalah et al., 2008). Radical prostatectomy is the gold standard for the treatment of clinical localized PCa. However, histopathological examination of the surgical specimen not rarely reveals, that the disease extends outside of the prostatic capsule border. Extracapsular extension is classified as T3a disease, based on 2009 TNM (tumor, node and metastasis) classification and represents a negative pathological factor. These patients have an increased risk for local or systemic disease recurrence and biochemical failure (Lu-Yao et al., 1996). For this reason, preoperative estimation of each patient specific risk for extracapsular disease (ECD), based on epidemiological, clinical and pathological data, would be helpful for the selection of candidates for more aggressive surgical modalities, like neurovascular bundle wide excision, during radical prostatectomy (Smith et al., 1996). The aim of this study was to analyze several preoperative factors and evaluate their predictive potential for ECD in patients undergoing radical prostatectomy for clinically localized PCa. Material and Methods We performed a retrospective analysis of the medical records from patients who undergone a radical prostatectomy with the diagnosis of organ-confined PCa from January of 2001 until November of 2010. The study protocol had been approved by Ethics Committee of our institution and it conformed to the provisions of the Declaration of Helsinki in 1995 (as revised in Edinburgh 2000). Exclusion criteria from the study was any preoperative therapy for PCa (hormone therapy, radiation therapy) and patients that found to have seminal vesicle invasion (stage T3b) or invasion of adjacent structures like bladder neck and external sphincter (stage T4). Patients diagnosed after transurethral resection of the prostate were excluded. Patients with incomplete medical records were excluded, as well. The analysis comprised preoperative 1 and 2 Gleason pattern and Gleason summary, age, preoperative value of PSA, prostate volume, PSA density, the presence of positive cores for malignancy after prostate biopsy in right (R+) or left (L+) or both (RL+) prostatic lobes and percentage of cancer in biopsy material (% CM). Preoperative PSA was measured before digital rectal examination, transrectal ultrasound or biopsy. In all patients cancer suspicion, because of PSA elevation, abnormal digital rectal examination or hypoechoic and hypervascular areas in Doppler transrectal ultrasound, was confirmed by transrectal ultrasound biopsy and positive for malignancy histological examination of the obtained cores. An open retropubic or laparoscopic extraperitoneal radical prostatectomy was performed in all patients by 4 experienced surgeons. The surgical specimen was PMR_2012_01.indd 6 10.2.12 10:42 Parameters Predicting Extracapsular Prostate Cancer Prague Medical Report / Vol. 113 (2012) No. 1, p. 5–15 7) sent for pathological examination and a histological report concerning the prostate dimensions, GS and 1 and 2 pattern and pathological stage was obtained. As stage T3a was considered disease extension outside of the prostate capsule. When the disease had penetrated the prostate capsule but was not extended outside this, the disease was staged as T2c. Prostate volume was calculated according to the information of the maximum transverse diameter (D1), the maximum anteroposterior diameter (D2) and the maximum longitudinal diameter (D3) and by using the formula D1×D2×D3×π/6 based on the prostate ellipse dimension theory. PSA density was calculated by dividing the preoperative PSA value and prostate volume. Even thought prostate volume was calculated postoperatively according to the prostate dimensions given by the pathologists report, there is a great positive correlation between preoperative (during transrectal ultrasound) and postoperative calculation of prostate volume (Wolff et al., 1995). The study design had 5 objectives. The first one was to analyze the above mentioned parameters as predictors for ECD in the total population of patients. Next, we analyze the same factors and their predictive ability for ECD in patients with PSA ≤10 ng/ml (subgroup 1), in patients with PSA >10 ng/ml (subgroup 2), in patients with preoperative Gleason score ≤6 (subgroup 3) and in patients with preoperative Gleason score ≥7 (subgroup 4). Statistical analysis All analyses were performed by using SPSS version 17 (SPSS Inc., Chicago, IL, USA). The descriptive statistics are presented as the mean ± standard deviation (SD) and interquartile range (IQR) for continuous variables and as the absolute and percent frequency for categorical variables. The normality condition of the numerical variables was studied by means of the Kolmogorov-Smirnov test. None of them had normal distribution. For this reason, the Mann-Whitney test was used to compare means between numerical groups. The chi-square χ test was used for categorical variables. A univariate analysis was performed to identify the predictive significance of age, preoperative PSA, prostate volume, PSA density, preoperative Gleason score, R+, L+, RL+ and % CM in prediction of ECD. A multivariate analysis was performed then for the variables identified as statistically important in univariate analysis, using logistic regression. The same statistical concatenation was used for subgroups data analysis, as well. By using receiver operating curve (ROC curve), the area under the curve (AUC) was derived. The optimal cutoff value and sensitivity and specificity for quantitative variables were estimated by using ROC curve, as well. In case of quantitative variables, cross tabulation was used for calculation of sensitivity [number of true positive/ (number of true positive + number of false negative)] and specificity [number of true negative/(number of true negative + number of false positive)]. Positive [true positive/(true positive + false positive)] and negative predictive value [true negative/ PMR_2012_01.indd 7 10.2.12 10:42 Sfoungaristos S.; Perimenis P. 8) Prague Medical Report / Vol. 113 (2012) No. 1, p. 5–15 (true negative + false negative)] were estimated as well. All tests were 2-tailed with α of p-value of less than 0.05 to be considered as statistically significant. Results A total of 187 patients were reviewed finally. Patients’ age were ranged from 46–78 years (66.8 ± 6.3, 9). Preoperative PSA value ranged from 3.3–41.8 ng/ml (9.9 ± 5.8, 5.2), PSA density from 0.01–1.85 (0.26 ± 0.24, 0.16) and prostate volume from 7–140 ml (45.34 ± 22.01, 28). After a median number of 12.00 cores (12.79 ± 6.70, 10) obtained during prostate biopsy procedures, 39 patients (20.9%) had R+, 44 patients (23.5%) had L+ and 104 patients (55.6%) had RL+. The % CM was ranged from 0.04–90% (26.75 ± 23.43, 31). Preoperative Gleason score ≤6 was found in 108 patients (57.8%) and 79 patients (42.2%) had Gleason score ≥7. The pathological examination of the surgical specimens revealed that 44 patients (23.5%) had ECD. The characteristics of the patients with and without ECD are seen in Table 1. A lymphadenectomy procedure was performed in 124 patients (66.3%) and positive lymph node metastasis was observed in 13 of them (10.5%). In multivariate analysis of the variables found to be statistically significant in univariate analysis (prostate volume, PSA density, R+, RL+, % CM, Gleason score and 1 pattern of Gleason score), we found that only prostate volume (p=0.028) and RL+ (p=0.034) were significant for prediction of ECD (Table 2). By using ROC curve, the AUC for prostate volume and LR+ were 0.666 (p=0.001, 95% CI 0.578–0.753) and 0.686 (p<0.001, 95% CI 0.602–0.770), respectively. Sensitivity and specificity of RL+ to predict ECD were 84.1% and 53.1%, respectively. ROC curve analysis showed that an optimal cut off value for prostate volume is ≤40 ml which is correlated with ECD with 77.3% sensitivity and 52.4% specificity. Subgroup 1 analysis One hundred and thirty one patients (70.05%) had PSA ≤10 ng/ml and 25 of them (19.1%) had ECD. In univariate analysis of preoperative variables for prediction of ECD in this group of patients, we found that prostate volume (p=0.001), PSA density (p=0.003), RL+ (p<0.001), R+ (p=0.025), L+ (p=0.042), % CM (p=0.008), Gleason score (p=0.026) and 2 Gleason pattern (p=0.031) were statistically significant, while age (p=0.404), PSA (p=0.731) and 1 Gleason pattern (p=0.098) were not. The multivariate analysis is seen in Table 3. The only factor found to be significant was RL+ (p=0.005). AUC was 0.737 (p<0.001, 95% CI 0.639–0.836). RL+ can predict ECD in patients with PSA ≤10 ng/ml with 88.0% sensitivity and 59.4% specificity. Subgroup 2 analysis Fifty six patients (29.95%) had PSA >10 ng/ml and 19 of them (33.9%) had ECD. Interestingly, as the results of the univariate analysis shown, none of the PMR_2012_01.indd 8 10.2.12 10:42 Parameters Predicting Extracapsular Prostate Cancer Prague Medical Report / Vol. 113 (2012) No. 1, p. 5–15 9) Table 1 – Patients’ characteristics