Prostate cancers detected by saturation repeat biopsy impairs the Partin tables' accuracy to predict final pathological stage.

OBJECTIVE: • To analyse the overall accuracy of Partin tables, with special emphasis to potential limitations resulting from differences between prostate cancers detected by different biopsy schedules. PATIENTS AND METHODS: • Clinical characteristics from 599 patients treated with radical prostatectomy defined the 2007 Partin probabilities of organ confinement (OC), seminal vesicle invasion (SVI) and extracapsular extension (ECE). Prostate cancers were detected by initial biopsy (IBx) with ≤12 cores in 405 patients (67.6%), by conventional repeat biopsy (CRBx) with ≤12 cores in 99 (16.5%) and by saturation repeat biopsy (SRBx) with ≥20 cores in 95 patients (15.9%). • The area under the curve (AUC) estimated by the receiver operating characteristic curve, assessed the predictive accuracy of the 2007 Partin tables. RESULTS: • The Partin tables AUC of the IBx, CRBx and the SRBx groups were 0.730 vs 0.701 vs 0.585 for OC, 0.631 vs 0.689 vs 0.547 for ECE, and 0.775 vs 0.755 vs 0.641 for SVI, respectively. CONCLUSIONS: • The overall accuracy of the 2007 Partin tables was clearly inferior in patients with prostate cancers detected by SRBx. • Prostate cancers detected by SRBx undermine the Partin tables' overall accuracy, and this group of patients may be miscounselled by vague predictions.

A comparative performance analysis of total prostate-specific antigen, percentage free prostate-specific antigen, prostate-specific antigen velocity and urinary prostate cancer gene 3 in the first, second and third repeat prostate biopsy.

UNLABELLED: Study Type - Diagnosis (exploratory cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Risk factor assessment in the repeat biopsy setting is affected by a decreasing diagnostic accuracy of each single risk factor (e.g. DRE, tPSA, %fPSA, complexed PSA, PSA density or PSAV] with increasing number of prostate biopsy sessions. PCA3 shows impressive diagnostic performance in the initial and early repeat biopsy settings. In a head-to-head comparison we demonstrate the concept that the number of previous repeat biopsy session strongly influences performance characteristics of biopsy risk factors, including PCA3. While the novel diagnostic marker would have avoided a considerable number of unnecessary biopsies in the first repeat biopsy scenario, its effects dissipated at second and ≥ third repeat biopsies. OBJECTIVE: To compare the performance characteristics of prostate cancer risk factors such as total prostate-specific antigen (tPSA), percentage free PSA (%fPSA), PSA velocity (PSAV) and urinary prostate cancer gene 3 (PCA3) at first, second and ≥ third repeat biopsy session. PATIENTS AND METHODS: Patients (n= 127) aged ≤70 years, with suspicious digital rectal examination (DRE) and/or persistently elevated age-specific total PSA levels (2.5-6.5 ng/mL) and/or suspicious prior histology (atypical small acinar proliferations [ASAPs]≥ two cores affected by high-grade prostatic intra-epithelial neoplasia [HGPIN]) undergoing either a first, second, or ≥ third repeat biopsy were investigated using a 12- or 24-core biopsy scheme. PSAV (≥ three values collected over ≥12 months) was calculated using the log-slope method. PCA3 scores were assessed using the Progensa assay®. After stratification according to the number of previous biopsies (first, second and ≥ third), calculation of specificity, positive and negative predictive values (PPV, NPV) and the proportion of avoided unnecessary repeat biopsies (PAB) compared with tPSA at fixed sensitivity thresholds (75, 85 and 95%) were performed. Finally, accuracy estimates (area under the curve [AUC]) were quantified for each repeat biopsy scenario. RESULTS: At repeat biopsy, overall prostate cancer (PCa) detection was 34.6%. At first repeat biopsy, PCA3 predicted PCa best (AUC = 0.80) and would have avoided 72.2% of repeat biopsies (75% sensitivity) compared with tPSA. At second repeat biopsy, %fPSA demonstrated the highest accuracy (AUC = 0.82) and would have avoided 66.7% of repeat biopsies (75% sensitivity) compared with tPSA. At ≥ third repeat biopsy, again %fPSA demonstrated the highest accuracy (AUC = 0.70) and would have avoided 45.0% of repeat biopsies (75% sensitivity) compared with tPSA. The main limitation of our study resides in its small sample size. CONCLUSIONS: The findings of the present study promote the concept that the number of previous repeat biopsy sessions strongly influences the performance characteristics of biopsy risk factors. Total PSA was no significant risk factor in the entire analysis. By contrast, %fPSA performed best at second and ≥ third repeat biopsy. PSAV's diagnostic potential was reserved to patients at second and ≥ third repeat biopsy. Finally, PCA3 demonstrated the highest diagnostic accuracy and potential to reduce unnecessary biopsies at first repeat biopsy. However, this advantage dissipated at second and ≥ third repeat biopsy.

Diagnostic yield of touch imprint cytology of prostate core needle biopsies.

Touch imprint cytology may provide additional information to core needle biopsy interpretation according to previous reports. The aim of this study was to investigate the diagnostic yield of this method in the diagnosis of prostate carcinoma. For this purpose, 452 transrectal prostate needle biopsies were evaluated from 56 patients. All patients were clinically suspicious of having prostate carcinoma. Two touch imprints were prepared from each fresh biopsy cylinder. Results of the standard histology and of the touch imprint evaluation were compared. Histologically negative biopsy cylinders were further evaluated for prostate carcinoma by fine step serial sectioning. The standard histological examination showed adenocarcinoma in 27 patients. Touch imprint cytology revealed atypical cells suspicious of carcinoma in 38 patients. This group included all 27 patients with positive standard histology and further 11 patients with initially negative core biopsy. Following serial sectioning, in three out of these 11 samples, histological evidence of a carcinoma could be proven. Fine step serial sectioning of all 29 core biopsies negative for carcinoma by standard histological examination, 26 patients remained negative. All three core biopsies initially negative by standard histology but positive after serial sectioning had cytology findings suspicious of carcinoma. We conclude, that in problematic cases the additional use of touch imprint cytology and serial sectioning of prostate core needle biopsies significantly improve the diagnostic accuracy.

Shift of tumor features in patients with clinically localized prostate cancer undergoing radical prostatectomy since the beginning of the PSA era.

AIM: To analyze trends of clinical and tumor characteristics over a 12-year period since the beginning of the prostate-specific antigen (PSA) era in a consecutive series of radical prostatectomies. PATIENTS AND METHODS: Between 1993 and 2004 a consecutive series of 1351 patients underwent radical prostatectomy for clinically localized prostate cancer (PC) in a single institution. Clinical and histopathological information was entered into our computer database and analyzed for changes over time. RESULTS: The annual frequency of surgical interventions increased from 43 to 160 (272%) during the observation period (r = 0.930; p < 0.01). The detection of PC based solely on pathological PSA levels rose impressively from 7% to 70% (r = 0.986; p < 0.01). The rates of organ-confined disease also increased significantly from 47% to 79% (r = 0.774; p < 0.01). Stage pT3a decreased somewhat from 28% to 18% (r = -0.389; n.s.) whereas pT3b decreased significantly from 26% to 3% (r = -0.729; p < 0.01). CONCLUSION: During the 12-year period, PC was increasingly detected on the basis of a pathological PSA level only and shifted significantly to more organ-confined stages. With a time delay, these findings are consistent with trends observed in large centers in the USA.

Initial prostate biopsy: development and internal validation of a biopsy-specific nomogram based on the prostate cancer antigen 3 assay.

BACKGROUND: Urinary prostate cancer antigen 3 (PCA3) assay in combination with established clinical risk factors improves the identification of men at risk of harboring prostate cancer (PCa) at initial biopsy (IBX). OBJECTIVE: To develop and validate internally the first IBX-specific PCA3-based nomogram that allows an individual assessment of a man's risk of harboring any PCa and high-grade PCa (HGPCa). DESIGN, SETTING, AND PARTICIPANTS: Clinical and biopsy data including urinary PCA3 score of 692 referred IBX men at risk of PCa were collected within two prospective multi-institutional studies. INTERVENTION: IBX (≥ 10 biopsy cores) with standard risk factor assessment including prebiopsy urinary PCA3 measurement. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: PCA3 assay cut-off thresholds were investigated. Regression coefficients of logistic risk factor analyses were used to construct specific sets of PCA3-based nomograms to predict any PCa and HGPCa at IBX. Accuracy estimates for the presence of any PCa and HGPCa were quantified using area under the curve of the receiver operator characteristic analysis and compared with a clinical model. Bootstrap resamples were used for internal validation. Decision curve analyses quantified the clinical net benefit related to the novel PCA3-based IBX nomogram versus the clinical model. RESULTS AND LIMITATIONS: Any PCa and HGPCa were diagnosed in 46% (n=318) and 20% (n=137), respectively. Age, prostate-specific antigen, digital rectal examination, prostate volume, and PCA3 were independent predictors of PCa at IBX (all p<0.001). The PCA3-based IBX nomograms significantly outperformed the clinical models without PCA3 (all p<0.001). Accuracy was increased by 4.5-7.1% related to PCA3 inclusion. When applying nomogram-derived PCa probability thresholds ≤ 30%, only a few patients with HGPCa (≤ 2%) will be missed while avoiding up to 55% of unnecessary biopsies. External validation of the PCA3-based IBX-specific nomogram is warranted. CONCLUSIONS: The internally validated PCA3-based IBX-specific nomogram outperforms a clinical prediction model without PCA3 for the prediction of any PCa, leading to the avoidance of unnecessary biopsies while missing only a few cases of HGPCa. Our findings support the concepts of a combination of novel markers with established clinical risk factors and the superiority of decision tools that are specific to a clinical scenario.

Contemporary role of prostate cancer antigen 3 in the management of prostate cancer.

CONTEXT: Newly discovered biomarkers ideally should prove clinical usefulness, provide additional detection, staging, and prognosis information to improve individual risk assessment, and potentially permit targeted cancer therapy. OBJECTIVE: To review, display, and evaluate the current evidence regarding the biologic and analytic approach of urinary prostate cancer gene 3 (PCA3) in prostate cancer (PCa) detection, staging, and prognosis, and its therapeutic potential. EVIDENCE ACQUISITION: A systematic and comprehensive Medline search was performed using the Medical Subject Headings search terms PCA3, DD3, UPM3, prostate cancer, cell-lines, prostate tissue, prostate biopsy, detection, diagnosis, radical prostatectomy, staging, grading, progression, and gene therapy. Results were restricted to English-language papers published within the period 1999-2011. EVIDENCE SYNTHESIS: The PCA3 gene is highly overexpressed in specific PCa cell lines and prostatic tumours. In 2006, a simple and robust urine test (Progensa) became commercially available. Despite its costs, prostate cancer antigen 3 (PCA3) is superior to prostate-specific antigen (PSA) and percent free PSA in the early detection of PCa. PCA3 improves the diagnostic accuracy of externally validated nomograms among men with an elevated PSA undergoing biopsy. PCA3 independently predicts low-volume disease and pathologically insignificant PCa but is not associated with locally advanced disease and is limited in the prediction of aggressive cancer. Preliminary data demonstrate that combining PCA3 with other new biomarkers further improves diagnostic and prognostic accuracy. Finally, findings of the first PCA3-Gene-ViroTherapy study suggest therapeutic potential by exploiting PCA3 overexpression. CONCLUSIONS: PCA3, integrated in novel biopsy nomograms or risk stratification tools, can be used to counsel or confirm biopsy indications. If confirmed in further studies, using PCA3 together with established staging risk factors could assist clinicians in specific pretreatment decision making. So far no evidence for the usefulness of PCA3 in active surveillance programs has been presented.

Critical assessment of preoperative urinary prostate cancer antigen 3 on the accuracy of prostate cancer staging.

BACKGROUND: Knowledge about the staging significance of the prostate cancer antigen 3 (PCA3) score to better identify pathologic features after radical prostatectomy (RP) is limited and controversial. OBJECTIVE: Our aim was to study the clinical staging significance of PCA3 to identify pathologic favorable and/or unfavorable features in the RP specimen. DESIGN, SETTING, AND PARTICIPANTS: Complete retrospective clinical and pathologic data of consecutive men who had undergone RP from three tertiary referral centers including preoperative PCA3 scores (n=305) and computer-assisted planimetrically measured tumor volume data (n=160) were available. INTERVENTION: All patients were treated with RP. MEASUREMENTS: PCA3 scores were assessed using the PROGENSA assay (Gen-Probe, San Diego, CA, USA). Beyond standard risk factors (age, digital rectal examination, prostate-specific antigen, prostate volume, biopsy Gleason score, percentage of positive cores), five different PCA3 codings were used in logistic regression models to identify five distinct pathologic end points: (1) low-volume disease (<0.5 ml), (2) insignificant prostate cancer (PCa) according to the Epstein criteria, (3) extracapsular extension (ECE), (4) seminal vesicle invasion (SVI), and (5) aggressive disease defined as Gleason sum ≥7. Accuracy estimates of each end point were quantified using the area under the curve (AUC) of the receiver operator characteristic analysis in models with and without PCA3. RESULTS AND LIMITATIONS: PCA3 scores were significantly lower in low-volume disease and insignificant PCa (p ≤ 0.001). AUC of multivariable low-volume disease (+2.4 to +5.5%) and insignificant PCa models (+3 to +3.9%) increased when PCA3 was added to standard clinical risk factors. In contradistinction, regardless of its coding, PCA3 scores were not significantly elevated in pathologically confirmed ECE (p=0.4) or SVI (p=0.5), respectively. Higher PCA3 scores were associated with aggressive disease (p<0.001). Importantly, the addition of PCA3 to multivariable intermediate- and high-grade models did not improve prediction. Despite reporting the largest pathologic PCA3 study, the main limitation resides in its small sample size. CONCLUSIONS: PCA3 was confirmed as a valuable predictor of pathologically confirmed low-volume disease and insignificant PCa. Further exploration of its role as an additional marker to select patients for active surveillance may be warranted. In contradistinction, assessment of pathologically advanced or aggressive PCa is not improved using PCA3.

Head to head comparison of three generations of Partin tables to predict final pathological stage in clinically localised prostate cancer.

OBJECTIVE: To perform a head to head comparison between three generations of Partin tables, namely from 1997, 2001 and the last updated version of 2007. MATERIAL AND METHODS: The external validations were based on clinical and pathological data of 687 consecutive patients undergoing radical prostatectomy for clinically localised prostate cancer between 2003 and 2008. Three versions of the Partin tables were compared for their accuracy and performance to predict final pathological stage using receiver operating characteristic (ROC) curve and Loess plots analyses. RESULTS: Of the whole cohort, 76.2% of men were presented with organ-confined disease (OC), 17.0% had extraprostatic extension (ECE), 6.0% showed seminal vesicle involvement (SVI) and 1.2% had lymph node involvement (LNI). The area under the receiver operating characteristic curve (AUC) of the Partin Tables 1997, 2001 and 2007 was 0.731, 0.727 and 0.722 for OC; 0.671, 0.662 and 0.650 for ECE; 0.795, 0.788 and 0.779 for SVI as well as 0.826, 0.786 and 0.746 for LNI, respectively. CONCLUSION: All three generations of the Partin tables showed a good accuracy to predict OC, SVI and LNI. However, the predictive accuracy for ECE was only modest. Overall, the newer versions of the Partin tables could not exceed the version of 1997 in their predictive accuracy for any pathological stage and they failed to demonstrate a clear advantage. Our results underline the necessity to perform external validations before the implementation of a new predicting tool.

External validation of urinary PCA3-based nomograms to individually predict prostate biopsy outcome.

BACKGROUND: Prior to safely adopting risk stratification tools, their performance must be tested in an external patient cohort. OBJECTIVE: To assess accuracy and generalizability of previously reported, internally validated, prebiopsy prostate cancer antigen 3 (PCA3) gene-based nomograms when applied to a large, external, European cohort of men at risk of prostate cancer (PCa). DESIGN, SETTING, AND PARTICIPANTS: Biopsy data, including urinary PCA3 score, were available for 621 men at risk of PCa who were participating in a European multi-institutional study. INTERVENTION: All patients underwent a ≥10-core prostate biopsy. Biopsy indication was based on suspicious digital rectal examination, persistently elevated prostate-specific antigen level (2.5-10 ng/ml) and/or suspicious histology (atypical small acinar proliferation of the prostate, >/= two cores affected by high-grade prostatic intraepithelial neoplasia in first set of biopsies). MEASUREMENTS: PCA3 scores were assessed using the Progensa assay (Gen-Probe Inc, San Diego, CA, USA). According to the previously reported nomograms, different PCA3 score codings were used. The probability of a positive biopsy was calculated using previously published logistic regression coefficients. Predicted outcomes were compared to the actual biopsy results. Accuracy was calculated using the area under the curve as a measure of discrimination; calibration was explored graphically. RESULTS AND LIMITATIONS: Biopsy-confirmed PCa was detected in 255 (41.1%) men. Median PCA3 score of biopsy-negative versus biopsy-positive men was 20 versus 48 in the total cohort, 17 versus 47 at initial biopsy, and 37 versus 53 at repeat biopsy (all p≤0.002). External validation of all four previously reported PCA3-based nomograms demonstrated equally high accuracy (0.73-0.75) and excellent calibration. The main limitations of the study reside in its early detection setting, referral scenario, and participation of only tertiary-care centers. CONCLUSIONS: In accordance with the original publication, previously developed PCA3-based nomograms achieved high accuracy and sufficient calibration. These novel nomograms represent robust tools and are thus generalizable to European men at risk of harboring PCa. Consequently, in presence of a PCA3 score, these nomograms may be safely used to assist clinicians when prostate biopsy is contemplated.

Development of a multiplexed urine assay for prostate cancer diagnosis.

BACKGROUND: Several studies have demonstrated the value of DNA methylation in urine-based assays for prostate cancer diagnosis. However, a multicenter validation with a clinical prototype has not been published. METHODS: We developed a multiplexed, quantitative methylation-specific polymerase chain reaction (MSP) assay consisting of 3 methylation markers, GSTP1, RARB, and APC, and an endogenous control, ACTB, in a closed-tube, homogeneous assay format. We tested this format with urine samples collected after digital rectal examination from 234 patients with prostate-specific antigen (PSA) concentrations > or =2.5 microg/L in 2 independent patient cohorts from 9 clinical sites. RESULTS: In the first cohort of 121 patients, we demonstrated 55% sensitivity and 80% specificity, with area under the curve (AUC) 0.69. In the second independent cohort of 113 patients, we found a comparable sensitivity of 53% and specificity of 76% (AUC 0.65). In the first cohort, as well as in a combined cohort, the MSP assay in conjunction with total PSA, digital rectal examination status, and age improved the AUC without MSP, although the difference was not statistically significant. Importantly, the GSTP1 cycle threshold value demonstrated a good correlation (R = 0.84) with the number of cores found to contain prostate cancer or premalignant lesions on biopsy. Moreover, samples that exhibited methylation for either GSTP1 or RARB typically contained higher tumor volumes at prostatectomy than those samples that did not exhibit methylation. CONCLUSIONS: These data confirm and extend previously reported studies and demonstrate the performance of a clinical prototype assay that should aid urologists in identifying men who should undergo biopsy.

Prostatic phyto-oestrogen tissue levels in different Austrian regions.

INTRODUCTION: A number of studies suggest that the low incidence of prostate cancer as well as benign prostatic enlargement in Asia depends on the extended consumption of phyto-oestrogens in these parts of the world. In most Asian men, phyto-oestrogen levels are multiple higher compared to Austrian (European) men. The aim of our study was to evaluate, according to the East-West decline, whether there were significant differences within the Austrian population. We compared prostate phyto-oestrogen tissue levels of men living in three different geographical regions of Austria. We further compared men living in rural and urban environments. MATERIAL AND METHODS: Prostatic tissue samples of 103 men undergoing surgery for benign prostatic hyperplasia or prostate cancer were collected and frozen at -40 degrees C. In tissue samples, enterolactone (representative for lignans) and genistein levels (representative for isoflavones) were determined in duplicate by monoclonal antibody-based immunoassays. We subsequently compared tissue levels of men living in rural and urban environments and different geographical regions of Austria. RESULTS: Prostatic enterolactone tissue levels were similar in men living in an urban (median 19.1 ng/g dry weight, range 1.5-76.4) or rural environment (median 15.7 range 0.6-140.6) p = 0.99. The respective values for genistein were 20.5 ng/g dry weight (range 4.6-47.4) and 9.3 (range 0.1-156.7) p = 0.77. Furthermore, enterolactone (p = 0.1) and genistein (p = 0.65) levels were similar in three different geographic regions in Austria. CONCLUSION: No significant differences regarding genistein and enterolactone were found between our study populations. However, we found a wide variation between individual patients.

Phytoestrogen tissue levels in benign prostatic hyperplasia and prostate cancer and their association with prostatic diseases.

OBJECTIVES: To compare phytoestrogen tissue levels in men with small-volume benign prostatic hyperplasia (BPH), large-volume BPH, and prostate cancer (PCa). METHODS: Prostatic tissue samples of men consuming a Western diet who underwent surgery for BPH (n = 63) or PCa (n = 31) were collected and frozen at -40 degrees C. In the tissue samples, the enterolactone and genistein levels were determined in duplicate by monoclonal antibody-based immunoassays. We subsequently compared the tissue levels in patients with BPH and PCa and studied the impact of enterolactone and genistein on prostate volume. RESULTS: The enterolactone tissue levels were comparable in patients with BPH and PCa and revealed no correlation to prostate volume. The genistein tissue levels tended to be lower in patients with PCa (median 8.4 ng/g dry weight) compared with the entire BPH group (11.0 ng/g dry weight; P = 0.072). In addition, the genistein tissue levels were significantly greater in men with small-volume BPH (median 20.9 ng/g dry weight) compared with those with large-volume BPH (8.8 ng/g dry weight; P = 0.023). CONCLUSIONS: Our data suggest an involvement of genistein in the pathogenesis of BPH and, possibly, of PCa. The impact of enterolactone is currently unknown.

Did the rate of incidental prostate cancer change in the era of PSA testing? A retrospective study of 1127 patients.

OBJECTIVES: To evaluate, in a retrospective study, the impact of routine prostate-specific antigen (PSA) testing on the rate of incidental prostate cancer in patients undergoing surgery for obstructive symptoms caused by presumed benign prostatic enlargement (BPE) and to investigate the indication of a routine biopsy before alternative treatment procedures for BPE. In the pre-PSA era, the diagnosis of incidental carcinoma was exclusively based on normal digital rectal examination (DRE) findings. METHODS: Since January 1993, 2422 operations (2283 transurethral resection of the prostate, 139 retropubic adenoma enucleations) for BPE were performed at our institution. The preoperative DRE findings and PSA level were evaluated, and patients with any suspicion for cancer were excluded. The pathologic reports of all patients were reviewed. A diagnosis of incidental carcinoma of the prostate required histologic evidence of cancer and negative DRE findings and a PSA level within age-specific reference ranges preoperatively. RESULTS: Of 2422 patients, 1127 (46.5%) had both negative DRE findings and an age-specific PSA level and were evaluated for our study. Overall, prostate cancer was diagnosed by surgery in 314 (13%) of 2422 patients. The rate of incidental prostate cancer in patients with both negative age-specific PSA levels and negative DRE findings was 6.4% (72 of 1127). CONCLUSIONS: In our series, the likelihood of detecting incidental prostate cancer by surgery was 6.4%. In the PSA era, the rate of incidental prostate cancer has been decreased by more than 50%. Today, the low rate of incidental carcinoma does not warrant routine histologic evaluation of the prostate if PSA testing and DRE are negative when alternative treatment modalities without tissue sampling are offered for the treatment of BPE.