Rolf-Peter Henke

A VALIDATED STRATEGY FOR SIDE SPECIFIC PREDICTION OF ORGAN CONFINED PROSTATE CANCER: A TOOL TO SELECT FOR NERVE SPARING RADICAL PROSTATECTOMY

PURPOSE Nerve sparing radical prostatectomy for prostate cancer should be restricted to patients who harbor tumors without capsular penetration. To our knowledge the selection criteria for nerve sparing radical prostatectomy are not clearly defined. We investigated a panel of preoperative tumor characteristics with respect to their ability to predict organ confined tumor growth for each lobe of the prostate to indicate unilateral or bilateral nerve sparing radical prostatectomy. MATERIALS AND METHODS Nine preoperative tumor characteristics in 278 patients with clinically localized prostate cancer were included in retrospective univariate and multivariate tree structured regression analysis. The association of clinical stage, serum prostate specific antigen (PSA), PSA density, and results of transrectal ultrasound and systematic sextant biopsy, including a quantitative assessment of cancer in the biopsies with organ confined tumor growth, was statistically evaluated. Except for serum PSA and PSA density preoperative characteristics were considered separately for each prostate lobe. Multivariate analysis results were validated prospectively in 353 patients. RESULTS On univariate analysis the number of positive biopsies was the most useful single parameter with a positive predictive value of 83% in 274 lobes and a negative predictive value of 55%, followed by mm. of tumor in the biopsy. Of all characteristics included in multivariate analysis only the number of biopsies with high grade cancer, the number of positive biopsies and serum PSA were independent for predicting organ confined cancer. When PSA was less than 10 ng./ml. and not more than 1 biopsy with high grade cancer was identified in a lobe, organ confined tumor growth was present in 86.1% of cases. On prospective validation the same criteria led to an 88.5% incidence of organ confined prostate cancer. Pooling the 2 most favorable groups led to 391 prostate lobes (70.8% of those investigated) with a positive predictive value of 82.1% (95% confidence interval 77.9% to 85.8%). Using the multivariate approach more prostate lobes were assigned to a favorable risk group than on univariate analysis. Clinical stage and simple Gleason grade did not contribute independent information for predicting organ confined disease. CONCLUSIONS Quantifying cancer and high grade cancer by systematic biopsy and serum PSA concentration are useful preoperative characteristics for predicting organ confined prostate cancer. Side specific analysis of these parameters is a flexible and reliable tool for selecting patients for nerve sparing radical prostatectomy.

Early Prostate-Specific Antigen Relapse after Radical Retropubic Prostatectomy:Prediction on the Basis of Preoperative andPostoperative Tumor Characteristics

Objectives: This study was undertaken to distinguish between patients who will and will not benefit from a retropubic radical prostatectomy (RRP) for clinically localized prostatic carcinoma (PCa) on the basis of preoperative and postoperative tumor characteristics. Methods: Data of 318 consecutive patients who underwent RRP for clinically localized PCa were reviewed. Preoperative characteristics used included clinical stage, findings on transrectal ultrasonography, prostate-specific antigen (PSA) values, Gleason grade, number of positive biopsies, number of biopsies containing any Gleason grade 4 and/or 5 cancer, and number of biopsies with predominant (>50% of cancerous tissue) Gleason grade 4 and/or 5 cancer. Postoperative characteristics included pathologic stage, Gleason grade, margin status, cancer volume, and volume of Gleason grade 4 and/or 5 cancer. The impact on biochemical relapse after RRP were calculated by Cox regression and CART (classification and regression tree) analysis to establish low, intermediate, and high risk of recurrence. Results: Of patients who underwent RRP, 66% showed no evidence of relapse after a follow-up of 42 months. All preoperative and postoperative characteristics showed a significant association with biochemical relapse. Cox regression of preoperative characteristics showed the number of positive biopsies with predominant Gleason grade 4 and/or 5 cancer to be the most accurate predictor of failure (p < 0.0001), followed by the number of positive biopsies and PSA. CART analysis distinguished between four risk groups on the basis of the same characteristics as in the Cox regression. The low-risk group consisted of 232 patients (75.1%) and the high-risk group of 17 patients (5.5%); corresponding Kaplan-Meier curves showed a 2-year PSA-free survival rate of 97% for the low-risk group and 20% for the high-risk group. Cox regression of postoperative characteristics recognized the volume of Gleason grade 4 and/or 5 as the characteristic with the strongest association with biochemical failure. CART analysis distinguished between four risk groups, using the volume of high-grade cancer as the most influential characteristic. The corresponding Kaplan-Meier curves showed for the low-risk group (n = 79; 29.6%) a PSA-free survival rate of 96% after 42 months and for the high-risk group (n = 47; 17.6%) a 21% PSA-free survival rate after 42 months. Conclusion: For preoperative and postoperative estimation of biochemical recurrence after RRP, a quantitative analysis of high-grade cancer, expressed by the number of preoperative biopsy cores containing high-grade cancer and the volume of cancer, proved to be the best predictor of relapse. CART analysis might be useful in advising patients for their best therapy options. However, defined characteristics of risk groups should be evaluated with new prospective data before they are used routinely.

Stage Migration in Clinically Localized Prostate Cancer

Objectives: To determine whether migration of pathological tumor stages in patients with clinically localized prostate cancer exists and whether this is due to an increasing frequency of treating patients with clinically insignificant cancer.Methods: 1,063 radical retropubic prostatectomies were performed in patients with clinically localized prostate cancer in one institution within 7.5 years (from 1992 until June 1999). All specimens were prospectively processed according to the Stanford protocol. These were then analyzed regarding the migration of pathological tumor stages and cancer volumes.Results: Within the observation period, the annual rate of radical retropubic prostatectomies increased by 225% from 69 to 224 cases. The authors noted a decline of advanced tumor stages (from 65 to 40%) and an increase in pathological T2 tumors (from 30 to 55%). The rate of small cancers (<0.5 cm3) remained stable between 2 and 5% over the last 5 years.Conclusion: The data confirm trends which were observed in large US centers with increasing detection and treatment of localized prostate cancer without unnecessary treatment of clinically insignificant cancers.

Preoperative Prediction of Tumor Heterogeneity and Recurrence After Radical Prostatectomy for Localized Prostatic Carcinoma with Digital Rectal Examination, Prostate Specific Antigen and the Results of 6 Systematic Biopsies

PURPOSE Digital rectal examination, preoperative serum prostate specific antigen (PSA) concentration and results of 6 ultrasound guided systematic sextant biopsies in 257 consecutive patients with clinical stages T2 and T1c prostatic carcinoma were evaluated for their use in predicting pathological stage and tumor recurrence. MATERIALS AND METHODS Each of the 257 consecutive specimens was examined using the 3 mm. step section technique. Results of preoperative digital rectal examination, PSA and 6 systematic sextant biopsies were correlated with pathological stage, margin status and postoperative PSA during a mean followup of 2 years. Patients were considered to have disease progression based on elevated PSA level by a supersensitive assay. RESULTS Digital rectal examination could not predict pathological stage and tumor recurrence. Preoperative PSA concentration, number of positive biopsies and tumor grade in the biopsy specimens correlated well with pathological stage. The best predictor of tumor recurrence was the biopsy result. However, a precise prediction of outcome (87% probability of being PSA negative versus 0%) was possible only in a third of the patients if the biopsy results were used. Use of preoperative PSA concentration did not improve this probability. CONCLUSIONS Preoperative PSA concentration and/or biopsy results correlate significantly with pathological stage and margin status. Precise prediction of tumor recurrence is possible in only approximately a third of the patients with clinical stage T2 prostatic carcinoma.

SYSTEMATIC SEXTANT BIOPSIES IMPROVE PREOPERATIVE PREDICTION OF PELVIC LYMPH NODE METASTASES IN PATIENTS WITH CLINICALLY LOCALIZED PROSTATIC CARCINOMA

PURPOSE An algorithm including the results of systematic sextant biopsies was statistically developed and evaluated to predict the probability of pelvic lymph node metastases in patients with clinically localized carcinoma of the prostate. MATERIALS AND METHODS Clinical stage, serum prostate specific antigen concentration, Gleason score, number of positive biopsies, number of biopsies containing any Gleason grade 4 or 5 cancer and number of biopsies predominated by Gleason grade 4 or 5 cancer were recorded in 345 patients undergoing pelvic lymph node dissection and correlated with the incidence of lymph node metastases. Multivariate logistic regression, and classification and regression trees analyses were performed. RESULTS In univariate analysis all variables had a statistically significant influence on lymph node status. Logistic regression showed that the amount and distribution of undifferentiated Gleason grade 4 and 5 cancer in the biopsies were the best predictors of lymphatic spread followed by serum prostate specific antigen. Classification and regression trees analysis classified 79.9% of patients who had 3 or fewer biopsies with Gleason grade 4 or 5 cancer and no biopsies predominated by undifferentiated cancer as a low risk group. In this group positive lymph nodes occurred in only 2.2% (95% confidence interval 0.8 to 4.7%). CONCLUSIONS Including the results of systematic sextant biopsies substantially enhances the predictive accuracy of algorithms that define the probability of lymph node metastases in prostatic cancer. Patients thus defined as having no lymphatic spread could potentially be spared pelvic lymph node dissection before definitive local treatment.

PROSPECTIVE VALIDATION OF AN ALGORITHM WITH SYSTEMATIC SEXTANT BIOPSY TO PREDICT PELVIC LYMPH NODE METASTASIS IN PATIENTS WITH CLINICALLY LOCALIZED PROSTATIC CARCINOMA

PURPOSE We prospectively validate an algorithm to predict pelvic lymph node metastasis in patients with clinically localized prostatic carcinoma. MATERIAL AND METHODS A total of 293 patients with prostatic cancer were identified before pelvic lymph node dissection according to an algorithm developed with the classification and regression tree analysis as high-greater than 3 sextant biopsies containing any Gleason grade 4 or 5 cancer, intermediate-at least 1 biopsy dominated by Gleason grade 4 or 5 cancer but not high risk and low risk-all other patients. Observed and predicted frequencies of pelvic lymph node metastasis were compared. RESULTS The observed frequencies of lymph node metastasis were remarkably similar to the predicted frequencies, including 2.8% versus 2.2% in 85.7% of patients in the low risk group, 16.7% versus 19.4% in 10.2% intermediate and 41.7% versus 45.5% in 4.1% high, respectively. If patients in the low risk group were considered to have node negative disease the specificity and negative predictive value of the algorithm were 88.4% and 97.2%, respectively. CONCLUSIONS Our algorithm is valid as a simple and accurate tool for the prediction of pelvic lymph node metastasis in patients with clinically localized prostatic cancer. Those 85.7% of patients classified by the algorithm to have a low risk of lymphatic spread should not undergo pelvic lymph node dissection before definitive local treatment.

Immunohistochemical detection of p53 protein in human prostatic cancer.

Tissue sections from 73 radical-prostatectomy specimens were studied immunohistochemically for the presence of p53 protein. In seven specimens numerous tumor cells showed a strong nuclear immunostaining. An additional 27 revealed a more discrete and focal accumulation of p53 protein. Comparison of the pathologic characteristics of the p53-negative and -positive groups showed that the presence of p53 protein closely correlated with more advanced tumor stages (p < 0.00001), with higher primary (p = 0.0004), combined (p < 0.0001) and worst (p < 0.0001) Gleason grades, and with larger total (p = 0.0001) and high-grade (p < 0.0001) tumor volumes. No staining was found in areas of benign hyperplasia or in well-differentiated tumor zones. Our results suggest that the accumulation of p53 protein to immunohistochemically detectable concentrations is not a feature of low-grade cancer. This finding implies that abnormal p53 accumulation might be involved in the process of prostatic cancer progression.

In situ hybridization to detect Epstein-Barr virus DNA in oral tissues of HIV-infected patients

Thirty biopsies of oral mucosal lesions and normal oral mucosa were obtained from 26 HIV-seropositive individuals and studied for virus infections with Epstein-Barr virus-specific DNA probes (EBV). In situ DNA hybridization was carried out on frozen and formalin-fixed, paraffin-embedded tissues. Specifically bound biotinylated virus probes were detected with the streptavidin-gold-silver technique and visualized by standard and interference reflection microscopy. In 9/30 biopsies, EBV DNA was clearly demonstrated in the upper two thirds of oral epithelia. This finding corresponded to peculiar cytopathic effects including ground glass nuclei, basophilic nuclear inclusions, and ballooning of the cytoplasm, which were concentrated in the upper two or three layers of the stratum spinosum. Cytopathic effects together with the demonstration of EBV DNA were demonstrated in seven cases of tongue mucosa, and two cases derived from the gingiva. When comparing clinical and pathological findings with DNA detection rates, we saw 5/9 hairy leukoplakias associated with EBV infections. Four positive cases (two samples from the tongue, two gingival specimens) had not been regarded as hairy leukoplakia clinically. EBV infection of the oral epithelium occurred in male homosexuals (7 cases) and in male/ female intravenous drug abusers (2 cases). Among the nine EBV-positive cases, 2 patients were asymptomatic, 4 patients were grouped into the ARC-, and 3 individuals into the AIDS-category. We conclude that HIV-seropositive patients are particularly prone to develop productive EBV infections in oral epithelia. This infection most frequently appears at the lateral border of the tongue, but may also occur at other sites of the oral cavity, and may already exist in a preclinical stage prior to the development of oral white lesions (hairy leukoplakia).

Assessment of clinical and pathologic characteristics predisposing to disease recurrence following radical prostatectomy in men with pathologically organ-confined prostate cancer.

OBJECTIVE To identify risk factors for biochemical failure after radical prostatectomy (RP) in men with pathologically organ-confined (OC) prostate cancer (PCa). METHODS Clinical and pathological characteristics of 331 consecutive men with pT2N0 PCa treated solely with RP were used in Cox proportional hazard models to identify independent predictors of prostate specific antigen (PSA) failure (PSA > or = 0.1 ng/ml). All pathologic specimens were step sectioned at 3 mm. RESULTS Twelve patients (3.6%) failed at a median follow-up of 26 months (range 0.2-99.6 months) and 120 men remained at risk 3 years after RP. In univariate Cox models PSA (P < 0.001), percentage of high-grade cancer (P < 0.001) total and high-grade cancer volume (P = 0.001 and P < 0.0001, respectively) and RP Gleason sum (P = 0.003) represented significant predictors of PSA failure. Clinical stage (P = 0.4), surgical margin status (P = 0.3), age (P = 0.2), and pathologic evidence of unilateral versus bilateral PCa (P = 0.6) failed to reveal significance. In receiver operator curve (ROC) analyses, high-grade cancer volume achieved highest outcome predictive accuracy (area under the curve (AUC 0.93)), which was not exceeded by Cox regression-based nomogram combining serum PSA, RP Gleason sum, margin status and pathologic evidence of unilateral versus bilateral PCa (AUC 091). Predictive accuracy of this multivariate nomogram was not enhanced by adding total cancer volume (AUC 0.93), high-grade cancer volume (AUC 0.90), or percentage of high-grade cancer (AUC 0.90). CONCLUSIONS In pT2N0 PCa high-grade cancer volume appears to represent the most important pathologic factor for prediction of outcome following RP. However, similar predictive accuracy may be achieved by combining routinely available tumor characteristics.

Incidence of positive surgical margins after biopsy-selected nerve-sparing radical prostatectomy.

OBJECTIVES The selection criteria for a nerve-sparing radical prostatectomy (NSRP) are not thoroughly investigated and are based mainly on preoperative digital rectal examinations and intraoperative findings. At our institution NSRP is performed only on patients whose preoperative systematic sextant biopsy of the prostate showed only unilateral cancer. To prove the safety of these criteria, we analyzed the incidence of positive surgical margins and tumor progression rate in patients who were selected for an NSRP only by the result of the biopsy. METHODS Preoperative systematic sextant biopsies revealed unilateral cancer in 69 preoperatively potent men of 289 consecutive prostatic cancer patients (23.9%); contralateral NSRP was performed on these 69 patients. The prostate specimens were investigated by using a 3-mm step-section technique to identify positive surgical margins. Tumor progression was defined as a prostate-specific antigen (PSA) level greater than 0.4 ng/mL in the native and greater than 0.025 ng/mL in the suprasensitive postoperative blood test. Mean follow-up was 15 months (range 6 to 24). RESULTS In 69 patients who underwent NSRP, 11 positive margins (15.9%) were found. Only 3 patients (4.3%) had a positive margin on the nerve-sparing side. In 220 patients who underwent non-NSRP 59 positive margins (26.8%) were detected. PSA recurrence rate after 12 months was similar in patients with NSRP and non-NSRP. Analysis of systematic sextant biopsies gives safe selection criteria because in approximately 95% the surgical margin on the nerve-sparing side will be negative. CONCLUSIONS Basing the indication for an NSRP on the results of preoperative systematic biopsies was safe according to margin status and postoperative PSA, when all patients with tumor in one of the three biopsy cores of each side of the prostate were excluded from an NS technique on that side. Such a strict approach will exclude approximately 30% of patients from NSRP unnecessarily because of tumor findings on a prostate side where the cancer is still organ-confined. Less strict criteria, including patients with only well-differentiated cancer and a maximum of one positive biopsy on the evaluated side, seem to be as safe as the described selection. However, data on these patients need further evaluation.