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The detection of prostate cancer relies primarily on abnormal digital rectal examination or increased serum prostate specific antigen concentration. However, low positive predictive values result in many men with increased prostate specific antigen and/or suspicious digital rectal examination having a negative biopsy. We investigated the value of the PCA3 (prostate cancer gene 3) urine test in predicting the likelihood of diagnosis of cancer before biopsy.We performed a prospective, community based clinical trial to evaluate PCA3 score before any biopsy. This trial was conducted at 50 urology practices in the United States. Samples were obtained from 1,962 men with increased serum prostate specific antigen (greater than 2.5 ng/ml) and/or abnormal digital rectal examination before transrectal prostate needle biopsy. Study samples (urinary PCA3 and biopsies) were processed and analyzed by a central laboratory. Sensitivity-specificity analyses were conducted.A total of 1,913 urine samples (97.5%) were adequate for PCA3 testing. Of 802 cases diagnosed with prostate cancer 222 had high grade prostatic intraepithelial neoplasia or atypical small acinar proliferation and were suspicious for cancer, whereas 889 cases were benign. The traditional PCA3 cutoff of 35 reduced the number of false-positives from 1,089 to 249, a 77.1% reduction. However, false-negatives (missed cancers) increased significantly from 17 to 413, an increase of more than 2,300%. Lowering the PCA3 cutoff to 10 reduced the number of false-positives 35.4% and false-negatives only increased 5.6%.Urinary PCA3 testing in conjunction with prostate specific antigen has the potential to significantly decrease the number of unnecessary prostate biopsies.

A randomized, double-blind, dose finding, placebo controlled, parallel group clinical study was done to determine the incidence of prostate cancer in men with high grade prostatic intraepithelial neoplasia treated with toremifene.A total of 514 patients with high grade prostatic intraepithelial neoplasia and no evidence of prostate cancer on screening biopsy were randomized to 20, 40 or 60 mg toremifene, or placebo daily for 12 months. Patients underwent re-biopsy at 6 and 12 months.The number of evaluable patients, that is those with 1 on study biopsy who were compliant, was 447. The cumulative risk of prostate cancer was decreased in patients on 20 mg toremifene compared with placebo (24.4% vs 31.2%, p0.05). The annualized rate of prevention was 6.8 cancers per 100 men treated. In patients with no biopsy evidence of cancer at baseline and 6 months, the 12-month incidence of prostate cancer was decreased by 48.2% with 20 mg toremifene compared with placebo (9.1% vs 17.4%, p0.05). The 20 mg dose was most effective but cumulative and 12-month incidences of prostate cancer were lower for each toremifene dose vs placebo with a cumulative risk of 29.2% and 28.1%, and a 12-month incidence of 14.3% and 13.0% for 40 and 60 mg, respectively. Gleason scores were similar across treatments. The overall incidence of drug related and serious adverse events did not differ between any of the toremifene groups and the placebo group.Toremifene decreased the incidence of prostate cancer by 1 year and had a tolerability profile comparable to that of placebo in a high risk population.

Purpose:: We assess temporal trends in prostate biopsy incidence, utilization and cancer yield in the community before and after the introduction of serum prostate specific antigen (PSA) to the community medical practiceMaterials and Methods:: Study subjects comprised all Olmsted County men with a first prostate biopsy performed between January 1, 1980 and December 31, 1997. Medical records of all study subjects (1,729) were reviewed for clinical information from the first and all subsequent biopsies.Results:: Annual age adjusted prostate biopsy incidence increased from 113/100,000 (95% confidence interval 76, 150) in 1980 to 487/100,000 (421, 554) in 1992 and decreased to 264/100,000 (219, 309) in 1997. For men 50 to 59 years old biopsy incidence increased 400% from 137/100,000 in 1980 to 1986 to 686/100,000 in 1993 to 1997. Overall, there were 93/100,000 more negative biopsies and 49/100,000 more positive biopsies in 1993 to 1997 than in 1980 to 1986. The overall cancer yield of 36% was essentially unch...

Purpose: The monoclonal antibody (mAb) 323/A3, a second generation high affinity antibody of the 17-1A antibody family, recognizes a 40 kDa transmembrane glycoprotein that has been referred to as Ep-CAM, 17-1A recognized antigen, or EGP40. While Ep-CAM is expressed on the basolateral surface of a variety of epithelia, the strongest expression is frequently detected among several types of carcinoma. In this regard, Ep-CAM may be useful in therapy, in diagnosis, and/or in prognosis. We examined the distribution of Ep-CAM in normal, dysplastic, and malignant prostatic epithelium.Materials and Methods: Paraffin sections of prostate tissue from 76 patients with clinically localized (pT2) prostatic adenocarcinoma were immunostained with mouse mAb 323/A3 using the avidin-biotin horseradish peroxidase method.Results: Within benign prostatic epithelium, immunoreactivity typically was low and frequently was restricted to the luminal cells. In contrast, moderate to strong immunostaining was detected frequent...

The pleotropic cytokine TGF-beta1 which induces connective tissue synthesis, and inhibits the growth of smooth muscle cells, has been implicated in corpus cavernosum fibrosis. The objective of this study was to determine the dose and time dependence of TGF-beta1 as an active agent in penile corporal fibrosis in an animal model.A time release method of delivery was developed using sodium alginate microspheres containing recombinant human (rh) TGF-beta1. New Zealand White rabbits were injected intracorporally with a single alginate microsphere either with or without rh-TGF-beta1. Dosage was varied from 325 to 1500 ng./bead. Animals were sacrificed at either three or five days post injection and the penises removed en bloc, examined, and processed for quantitative histomorphometric analysis, staining the sections with Masson's trichrome.Alginate microspheres containing [125I]-rh-TGF-beta1 showed slow-release kinetics (t1/2 = 10.5 hours). Histomorphometric analysis of 60 sets of high powered fields/treatment/ animal showed dose dependent decreases in percentage of corporal smooth muscle with TGF-beta1 treatment (750 to 1500 ng./bead). Placebo (alginate microspheres alone) had trabecular smooth muscle content comparable to values previously reported for untreated rabbit corpus cavernosum.This study confirms that TGF-beta1 induces fibrosis in situ by altering connective tissue synthesis and hence the structure of the corpus cavernosum. Injection of rh-TGF-beta1 impregnated alginate microspheres into the corpus cavernosum resulted in dose-dependent decreases in percentage of corporal smooth muscle.

Purpose: To perform loss of heterozygosity (LOH) analysis on chromosome 16 in 102 highly purified DNA samples isolated from one or more adenocarcinomas, prostatic intraepithelial neoplasia (PIN), and matched benign prostatic epithelium from 95 radical prostatectomy patients.Materials and Methods: Specimens were procured by microdissection of frozen tissue samples, thus ensuring that highly select pure populations of cells were obtained for DNA extraction and LOH analysis. Multiple microsatellite markers were used to determine allelic loss on chromosome 16q.Results: Overall loss on 16q was seen in 31% of the cancers, and occurred more frequently in high stage cancers than low stage cancers. In contrast, allelic loss in PIN failed to exceed 6% at any of the loci that were examined.Conclusions: These results suggest that inactivation of a putative tumor suppressor gene on 16q may be involved in the progression of some prostate cancers.

Purpose: Previous studies have suggested that central zone prostatic volume may be more strongly correlated with lower urinary tract symptom severity and peak urinary flow rates than total prostatic volume. We determine whether prostatic central zone volume and central zone index volume correlate better with these measures than total prostate volume in an age stratified, community based random sample of healthy white men.Materials and Methods: A cohort of 474 men were randomly selected from the 2,115 community dwelling men, 40 to 79 years old, who participated in the Olmsted County study of urinary symptoms and health status among men. All men had undergone transrectal ultrasound of the prostate. The total prostate and hypoechoic central zone volumes were caliper measured by 1 operator on static ultrasounds from baseline. Volumes were calculated with the prolate ellipsoid formula. The operator was blinded to clinical information and outcome. The associations between total prostate volume and centr...

Carcinosarcoma of the bladder is a rare neoplasm characterized by an intimate admixture of carcinoma and malignant soft tissue neoplasm. The clinical usefulness of separating carcinosarcoma (carcinoma with sarcomatous component) from sarcomatoid carcinoma (carcinoma with spindle cell carcinomatous component) is uncertain, and it comprises the subject of this report.We reviewed the clinical and pathological records of 10 men and 5 women a mean of 66 years old with carcinosarcoma, and 21 men and 5 women a mean of 66.5 years old with sarcomatoid carcinoma of the bladder, as documented in the files of the Mayo Clinic between 1936 and 1995.Of the 15 patients in the carcinosarcoma group 9 had urothelial carcinoma, small cell carcinoma, 3 had squamous cell carcinoma and 2 had more than 1 type. The sarcomatous component included chondrosarcoma in 3 cases, leiomyosarcoma in 3, malignant fibrous histiocytoma in 3, osteosarcoma in 2, fibrosarcoma in 1, rhabdomyosarcoma in 1 and more than 1 type in 2. All disease was high stage at presentation. Treatment included cystectomy in 11 patients with (4) and without (7) radiation therapy, and transurethral resection in 4 with (1) and without (3) radiation therapy. Mean followup available in 14 cases was 34 months (range 1 to 144). A total of 11 patients died of cancer at 1 to 48 months (mean 17.2) and 2 survived for 8 to 131 months. Of the 26 patients in the sarcomatoid carcinoma group 18 had urothelial carcinoma, 1 had squamous carcinoma, 2 had urothelial carcinoma combined with squamous cell carcinoma and 5 had spindle cells only with no recognizable epithelium. All but 1 case was high stage at diagnosis. Treatment included transurethral resection in 17 patients with (7) and without (10) radiation therapy, including 1 who also received chemotherapy, and only cystectomy in 5, including 2 who also underwent radiation therapy and 1 who also received chemotherapy. Mean followup available in 21 cases was 49 months (range 1 to 420). A total of 17 patients died of cancer at 1 to 73 months (mean 9.8), 1 was alive at 140 months and 3 died of unrelated causes.Carcinosarcoma and sarcomatoid carcinoma of the bladder are highly aggressive malignancies with a similar outcome regardless of histological findings and treatment. Pathological stage is the best predictor of survival.

Purpose: Metanephric adenoma has recently been recognized as a unique renal tumor characterized by an unusual degree of cellular differentiation and maturation. We recently studied metanephric adenoma using metaphase analysis and observed concomitant chromosome Y loss and chromosome 7 and 17 gain. To determine if these chromosomal anomalies are consistently present in renal metanephric adenoma, we studied all 11 tumors in the pathology tissue registry at our institution using fluorescence in situ hybridization (FISH).Materials and Methods: FISH, using deoxyribonucleic acid probes for chromosomes 1, 7, 8, 17, × and Y, was performed in isolated nuclei from 11 paraffin embedded renal metanephric adenoma specimens.Results: Of the 11 tumors (73%) 8 demonstrated chromosome 7 and 17 gain by FISH, and the remaining 3 were found to have an apparently normal chromosomal content. Of the 8 tumors (75%) from men showed 6 chromosome 7 and 17 gain with Y chromosome loss. Of the 3 tumors (33%) from women 1 had ch...

Published data over the past decade suggesting that prostate cancer detection rates are enhanced with additional sampling of the prostate have resulted in modifications to the traditional 6-core (sextant) biopsy regimen1,2 such that recent clinical guidelines recommend that extended biopsy schemes with 10 to 12 specimens be obtained.3–5 There are also data that suggest that segregation of prostate biopsy tissue specimens into individual vials improves specimen handling, enhances tissue representation, and improves diagnostic accuracy.6–8 Furthermore, focal prostate cancer treatment strategies gaining recent popularity are dependent on more precise tumor mapping, requiring even greater tissue sampling.9 Over approximately the same time frame, there has been an increase in consolidation of medical practices into larger single- or multispecialty group practices. By incorporating efficiencies of scale, these groups afford physicians the opportunity to retain the characteristics of traditional medical practices while improving their ability to adapt to changing health care circumstances.10 These groups often integrate additional capabilities beyond professional services, including anatomic and clinical pathology, diagnostic imaging, and radiation therapy. Proponents of these arrangements argue that integration of medical services facilitates the development of coordinated clinical pathways, improves communication between specialists, offers better quality control of ancillary services, and enhances data collection—all of which can improve patient care and lead to lower costs.11–13 Specifically with regard to anatomic pathology, recent data suggest that certain specimen handling errors are significantly lower (P = .018) at urology practices with integrated in-house pathology laboratories (urology practice laboratories [UPLs]) than at other sites of service14; however, some contend that group practice integration creates conflicts of interest and self-referral issues, which ultimately leads to increased utilization of services.15–19 A recent study based on analysis of Medicare claims data purported that positive prostate biopsy rates and the number of samples submitted per biopsy are significantly different across sites of service20; however, this study has been criticized as both methodologically flawed and scientifically inaccurate.21 Also problematic is the fact that calculation of prostate cancer incidence has been identified as particularly susceptible to error when determined by analysis of outpatient claims data alone.22 We sought to determine positive biopsy rates and utilization trends in the United States via direct analysis of laboratory records from both a national reference laboratory (NRL) and UPLs, and to determine if there was a correlation between positive biopsy rates and number of specimen vials submitted.

Purpose: Up to 26 percent of patients with pathologically organ confined prostate cancer will experience clinical progression after radical prostatectomy. We attempted to identify patients at greatest risk for future clinical failure despite a favorable pathological outcome.Materials and Methods: The study group included 904 patients treated with bilateral pelvic lymphadenectomy and radical retropubic prostatectomy for disease confined to the prostate gland. Preoperative serum prostate specific antigen (PSA), clinical stage, pathological grade and stage, and deoxyribonucleic acid (DNA) ploidy were evaluated by multivariate analysis to determine relative value in predicting treatment failure. A prognostic scoring system was created using the regression coefficients from the Cox multivariate model to classify patients further according to risk of progression.Results: Preoperative PSA concentration, clinical stage, grade and DNA ploidy were significant univariate predictors of progression (p less tha...

Purpose: Cytogenetic studies of a small number of renal oncocytomas have indicated that loss of chromosomes 1 and Y may be involved in the pathogenesis of this tumor. To evaluate these observations further we selected paraffin embedded renal oncocytoma specimens from 20 male and 10 female patients for fluorescence in situ hybridization analysis.Materials and Methods: Isolated nuclei were prepared from paraffin embedded specimens, and fluorescence in situ hybridization was performed with enumeration probes for chromosomes 1, 12, × and Y.Results: Tumors from 10 male (50 percent) and 4 female (40 percent) patients demonstrated chromosomal alterations. Loss of chromosome Y was observed in specimens from all 10 male patients, and loss of chromosome 1 or gain of chromosome 12 was noted in 5 and 2 of these specimens, respectively. Of the 4 female patients with chromosomal abnormalities 2 had loss of chromosome 1, 1 had gain of chromosome 1 and 1 had gain of chromosome 12.Conclusions: Our results confirm ...

Previous studies suggest that prostate cancer with a volume of 0.5 ml. or less and a Gleason score of less than 7 may be clinically insignificant and may be managed with watchful waiting. A proposed method of determining the volume of cancer in the prostate gland has been the grade and volume of cancer present in the transrectal needle biopsy specimen. Volume of cancer in the biopsy specimen as a predictor of volume of cancer in the prostate gland was studied in 130 men who underwent radical retropubic prostatectomy for adenocarcinoma. Of the men 46 (35 percent) had clinical stage T1c (nonpalpable) disease, while 84 (65 percent) had clinical stage T2 (palpable) disease. Each radical prostatectomy specimen was whole-mounted and step-sectioned for accurate cancer volume determination. Three parameters for measuring volume of cancer in the biopsy specimen (percentage of biopsy cores involved, millimeters of cancer per biopsy core and percentage of cancer in the biopsy specimen) were determined and co...

The serum prostate specific antigen (PSA) level was determined in 311 men with documented prostate cancer (stages T1cN0, T2N0 and T3N0) before bilateral pelvic lymphadenectomy and radical retropubic prostatectomy. The prostates were whole mounted, serially sectioned, and examined for cancer volume, capsular perforation, seminal vesicle invasion, lymph node involvement, Gleason grade, nuclear grade and nuclear deoxyribonucleic acid content. Median serum PSA level was significantly different between cancers that were organ confined, those that had capsular perforation or seminal vesicle invasion and those with positive lymph nodes (p0.001). Median serum PSA level was also significantly different between tumors with Gleason scores of less than 6 and those with higher Gleason scores (p0.001), and between tumors with greater than 30% of poorly differentiated cancer (Gleason primary grades 4 and 5) and those with 30% or less poorly differentiated cancer (p0.001). Bivariate analysis revealed that the strongest correlations of serum PSA level were with cancer volume (r = 0.56), per cent of poorly differentiated cancer (r = 0.42), positive surgical margins (r = 0.39) and pathological stage (r = 0.38), for all p0.001. Multivariate analysis showed that cancer volume was the major contributor to serum PSA level. The derivative, PSA-cancer density (serum PSA times cancer volume divided by prostate volume), accounted for the effects of prostate volume and cancer volume on serum PSA. PSA-cancer density showed a significant correlation with pathological stage (r = 0.56), Gleason score (r = 0.53) and per cent of poorly differentiated cancer (r = 0.49, for all p0.001), and these correlations were significantly stronger than serum PSA level alone or PSA density (serum PSA divided by prostate volume; volume determined from tissue specimens) for all variables. These results indicate that preoperative serum PSA level has significant predictive value in determining tumor burden and pathological stage, and this predictive value is increased by accounting for cancer and gland volume with PSA-cancer density.

To determine if the preoperative variables of serum prostate specific antigen (PSA), primary Gleason grade from the biopsy specimen and local clinical stage as determined from digital rectal examination can accurately predict the pelvic lymph node status in patients with clinically localized prostate cancer, we reviewed the medical records of 1,632 patients who underwent bilateral pelvic lymphadenectomy at our institution between January 1988 and December 1991. Using logistic regression analysis, serum PSA was found to be the best predictor of pelvic lymph node metastases (p0.0001). The predictive power of serum PSA could be enhanced considerably by taking into account the Gleason grade (p0.001) and local clinical stage (p0.001). A statistical model using all 3 variables was developed that allows the practicing urologist to estimate on an individual basis the probability of pelvic lymph node involvement. Using a conservative cutoff point of less than 3% as an acceptable false-negative rate, 61% of the patients with clinical stages T1a to T2b (A1 to B1) disease and 29% of those with clinical stages T1a to T2c (A1 to B2) prostate cancer may be spared an open or laparoscopic staging bilateral pelvic lymphadenectomy. As a result, patient morbidity can be decreased and a significant economic savings to the health care system can be realized. This observation has particular importance for prostate cancer patients being managed with radical perineal prostatectomy or definitive radiation therapy.

in Men with Elevated PSA ED Crawford, J Qian, K Drewnowska, S Varvel, M Wilk, L Mason, J Kaminetsky, T Huisman, M Bilowus, S Freedman, DG Bostwick 1. University of Colorado, Denver, Co 80045 2. Bostwick Laboratories, Glen Allen, VA 23060 3. University Urology Associates, New York, NY 10016 4. Chiramonte Huisman Zorn Urology, Clinton, MD, 20735 5. Bilowus Medical, Reston, VA, 20190 6. Sheldon J. Freedman M.D., LTD, Las Vegas, NV 89148

We analyzed a large series of cases of renal oncocytoma to define the incidence of coexistent renal cell carcinoma, multifocality, bilateralism and metachronous tumor development.Between 1980 and 1997, 100 men and 38 women with a mean age of 68 years with oncocytoma, were treated surgically at our institution. We analyzed tumor characteristics and reviewed specimens for coexistent renal cell carcinoma.Tumors were discovered incidentally in 58% of the cases. Specimens were obtained from 84 radical and 70 partial nephrectomies. Tumor size ranged from 0.3 to 14.5 cm. (median 3.2). Oncocytoma was unilateral in 131 cases (95%) and bilateral in 7 (5%), while there were multiple oncocytomas in 8 (6%). Mean followup was 41 months (range 0 to 200). The disease specific survival rate was 100% and no patient had metastasis. In 6 patients (4%) metachronous oncocytoma developed during followup. No patient had locally recurrent oncocytoma after partial nephrectomy for a solitary renal oncocytoma. Renal cell carcinoma and oncocytoma were found in 14 patients (10%), including unilateral synchronous disease in 9 and bilateral synchronous disease in 5.Our data support the benign nature of renal oncocytoma. Multifocality, bilateralism and metachronous tumor develop in approximately 4 to 6% of all cases. Renal cell carcinoma coexisted in 10% of oncocytoma cases.

In an effort to characterize more fully multifocal renal cell carcinoma, 100 radical nephrectomy specimens with localized renal cell carcinoma were analyzed in a prospective fashion. Analysis of each specimen consisted of preoperative computerized tomography or magnetic resonance imaging, standard pathological examination with frozen section and 3 mm. step sectioning under magnification. Multifocal renal cell carcinoma was found in 16 specimens. Multifocal disease was suspected by preoperative imaging in 7 specimens (44%) and confirmed after standard pathological investigation in 10 (63%). Papillary and mixed histological patterns occurred at a significantly increased rate in specimens with multifocal disease (p = 0.011). Other parameters, such as stage, tumor size and volume, histological grade and deoxyribonucleic acid ploidy were evaluated and did not correlate with the presence or extent of multifocality. The number of secondary tumors per specimen varied from 1 to 50 (median 2) and were of hi...

the 10 year follow-up. The cancer-free survival rate after a single cryoablation procedure was 92.2%, this improved to 96.6% after a secondary cryoablation procedure (n = 8). Median preoperative renal mass size was 2.49 cm (range, 0.7cm-8.4cm). In tumors with T1N0M0 (n = 171) disease-free survival (recurrence and death) and recurrencefree survival were significantly different between pT1a and pT1b when stratified by tumor size, 97.5% of mass size 4cm remained disease free up to 10.5 years compared to 71.4% of those with tumor mass size greater than 4cm (Hazard risk ratio 37.5; 95% confidence interval [CI] 3.4 to 414.1; p = 0.003). Recurrence-free survival showed similar pattern between pT1a and pT1b (p = 0.04). Disease-free survival or recurrence-free survival was not significantly modified by gender, age, tumor position, ECOG status, or treatment approach. CONCLUSIONS: Disease-free survival and recurrence-free survival are significantly better in patients undergoing cryoablation for renal neoplasm mass 4 cm or less compared to those with larger tumors. The current T1N0M0 substratification, based on the 2002 TNM criteria, is an effective predictor of the disease-free survival or recurrence-free survival in patients undergoing cryoablation for renal neoplasm.