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Aims: There is strong evidence that cribriform morphology indicates a worse prognosis of prostatic adenocarcinoma. Our aim was to investigate its interobserver reproducibility in prostate needle biopsies. Methods and results: A panel of nine prostate pathology experts from five continents independently reviewed 304 digitised biopsies for cribriform cancer according to recent International Society of Urological Pathology criteria. The biopsies were collected from a series of 702 biopsies that were reviewed by one of the panellists for enrichment of high-grade cancer and potentially cribriform structures. A 2/3 consensus diagnosis of cribriform and noncribriform cancer was reached in 90% (272/304) of the biopsies with a mean kappa value of 0.56 (95% confidence interval 0.52–0.61). The prevalence of consensus cribriform cancers was estimated to 4%, 12%, 21%, and 20% of Gleason scores 7 (3 + 4), 7 (4 + 3), 8, and 9–10, respectively. More than two cribriform structures per level or a largest cribriform mass with ≥9 lumina or a diameter of ≥0.5 mm predicted a consensus diagnosis of cribriform cancer in 88% (70/80), 84% (87/103), and 90% (56/62), respectively, and noncribriform cancer in 3% (2/80), 5% (5/103), and 2% (1/62), respectively (all P < 0.01). Conclusion: Cribriform prostate cancer was seen in a minority of needle biopsies with high-grade cancer. Stringent diagnostic criteria enabled the identification of cribriform patterns and the generation of a large set of consensus cases for standardisation. publishedVersion

PDF file - 41K, Percentage genome alteration (PGA) levels are displayed for patient biopsies categorized as per their NKX3.1/T-category status (a), NKX3.1/PSA status (b), NKX3.1/Gleason-score status (c), NKX3.1/c-MYC/T-category status (d) and NKX3.1/c-MYC/PSA status (e). The median PGA for each group is represented by the black line. (GS=Gleason-score, *=significantly different). Patients with NKX3.1 allelic loss have a significant increase in PGA as compared to patients with a normal status of NKX3.1 in T-category groups pT1=0.00045 and pT210=0.0012 (b). Patients with NKX3.1 allelic loss have a significant increase in PGA as compared to patients with a normal status of NKX3.1 in Gleason-scores pGS6=0.0015 and pGS710=0.001 (e).

Supplementary Figure Legends 1-2, Tables 1-6 from NKX3.1 Haploinsufficiency Is Prognostic for Prostate Cancer Relapse following Surgery or Image-Guided Radiotherapy

Background: Despite the use of prostate specific antigen (PSA), Gleason-score, and T-category as prognostic factors, up to 40% of patients with intermediate-risk prostate cancer will fail radical prostatectomy or precision image-guided radiotherapy (IGRT). Additional genetic prognosticators are needed to triage these patients toward intensified combination therapy with novel targeted therapeutics. We tested the role of the NKX3.1 gene as a determinant of treatment outcome given its reported roles in tumor initiating cell (TIC) renewal, the DNA damage response, and cooperation with c-MYC during prostate cancer progression.Methods: Using high-resolution array comparative genomic hybridization (aCGH), we profiled the copy number alterations in TIC genes using tumor DNA from frozen needle biopsies derived from 126 intermediate-risk patients who underwent IGRT. These data were correlated to biochemical relapse-free rate (bRFR) by the Kaplan–Meier method and Cox proportional hazards models.Results: A screen of the aCGH-IGRT data for TIC genes showed frequent copy number alterations for NKX3.1, PSCA, and c-MYC. NKX3.1 haploinsufficiency was associated with increased genomic instability independent of PSA, T-category, and Gleason-score. After adjusting for clinical factors in a multivariate model, NKX3.1 haploinsufficiency was associated with bRFR when tested alone (HR = 3.05, 95% CI: 1.46–6.39, P = 0.0030) or when combined with c-MYC gain (HR = 3.88, 95% CI: 1.78–8.49, P = 0.00067). A similar association was observed for patients following radical prostatectomy with a public aCGH database. NKX3.1 status was associated with positive biopsies post-IGRT and increased clonogen radioresistance in vitro.Conclusions: Our results support the use of genomic predictors, such as NKX3.1 status, in needle biopsies for personalized approaches to prostate cancer management. Clin Cancer Res; 18(1); 308–16. ©2011 AACR.

Take Home Messages Among men with low- or intermediate-risk prostate cancer who choose active surveillance, those with suspicious magnetic resonance imaging (MRI) at the time of inclusion in active surveillance are more likely to show switch to treatment than men with nonsuspicious MRI., Background The inclusion criterion for active surveillance (AS) is low- or intermediate-risk prostate cancer. The predictive value of the presence of a suspicious lesion at magnetic resonance imaging (MRI) at the time of inclusion is insufficiently known. Objective To evaluate the percentage of patients needing active treatment stratified by the presence or absence of a suspicious lesion at baseline MRI. Design, setting, and participants A retrospective analysis of the data from the multicentric AS GAP3 Consortium database was conducted. The inclusion criteria were men with grade group (GG) 1 or GG 2 prostate cancer combined with prostate-specific antigen

BackgroundActive surveillance (AS) is a management option for men diagnosed with low-risk prostate cancer. Opinions differ on whether it is safe to include young men (≤60 yr) or men with intermediate-risk disease.ObjectiveTo assess whether reasons for discontinuation, treatment choice after AS, and adverse pathology at radical prostatectomy (RP; N1, or ≥GG3, or ≥pT3) differ for men ≤60 yr or those with European Association of Urology (EAU) intermediate-risk disease from those for men >60 yr or those with EAU low-risk disease.Design setting and participantsWe analyzed data from 5411 men ≤60 yr and 14959 men >60 yr, 14064 men with low-risk cancer, and 2441 men with intermediate-risk cancer, originating from the GAP3 database (21169 patients/27 cohorts worldwide).Outcome measurements and statistical analysisCumulative incidence curves were used to estimate the rates of AS discontinuation and treatment choice.Results and limitationsThe probability of discontinuation of AS due to disease progression at 5 yr was similar for men aged ≤60 yr (22%) and those >60 yr (25%), as well as those of any age with low-risk disease (24%) versus those with intermediate-risk disease (24%). Men with intermediate-risk disease are more prone to discontinue AS without evidence of progression than men with low-risk disease (at 1/5 yr: 5.9%/14.2% vs 2.0%/8.8%). Adverse pathology at RP was observed in 32% of men ≤60 yr compared with 36% of men >60 yr (p=0.029), and in 34% with low-risk disease compared with 40% with intermediate-risk disease (p=0.048).ConclusionsOur descriptive analysis of AS practices worldwide showed that the risk of progression during AS is similar across the age and risk groups studied. The proportion of adverse pathology was higher among men >60 yr than among men ≤60 yr. These results suggest that men ≤60 yr and those with EAU intermediate-risk disease should not be excluded from opting for AS as initial management.Patient summaryData from 27 international centers reflecting daily clinical practice suggest that younger men or men with intermediate-risk prostate cancer do not hold greater risk for disease progression during active surveillance.

Fibroblast growth factor receptor 3 (FGFR3) is an actionable target in bladder cancer (BC). FGFR3 mutations are common in noninvasive BC and associated with favorable BC prognosis. Overexpression was reported in up to 40% of FGFR3 wild-type muscle-invasive BC. We analyzed FGFR3 mutations, FGFR3, and p53 protein expression and assessed their prognostic value in a cohort of 1000 chemotherapy-naive radical cystectomy specimens. FGFR3 mutations were found in 11%, FGFR3 overexpression was found in 28%, and p53 overexpression was found in 69% of tumors. Among FGFR3 mutant tumors, 73% had FGFR3 overexpression versus 22% among FGFR3 wild-type tumors. FGFR3 mutations were significantly associated with lower pT stage, tumor grade, absence of carcinoma in situ, pN0, low-level p53, and longer disease-specific survival (DSS). FGFR3 overexpression was associated only with lower pT stage and tumor grade. Moreover, FGFR3 overexpression was not associated with DSS in patients with FGFR3 wild-type tumors. In conclusion, FGFR3 mutations identified patients with favorable BC at cystectomy. Our results suggest that FGFR3 mutations have a driver role and are functionally distinct from FGFR3 overexpression. Hence, patients with FGFR3 mutations would be more likely to benefit from anti-FGFR3 therapy. Ideally, further research is needed to test this hypothesis. Patient summary: Oncogenic fibroblast growth factor receptor 3 (FGFR3) mutations are very common in bladder cancer. In this report, we found that these FGFR3 mutations were associated with favorable features and prognosis of bladder cancer compared with patients with FGFR3 overexpressed tumors only. As a consequence, patients with FGFR3 mutant tumors would be more likely to benefit from anti-FGFR3 therapy than patients with FGFR3 protein overexpression only.

Background The initial report from the ASIST trial showed little benefit from targeted biopsy for men on active surveillance (AS) for prostate cancer. Data after 2-yr follow-up are now available for analysis. Objective To determine if there was a difference in the AS failure rate in a 2-yr follow-up period among men undergoing magnetic resonance imaging (MRI) before initial confirmatory biopsy (CBx) compared to those who did not. Design, setting, and participants This is the 2-yr post-CBx follow-up for the ASIST trial, a prospective, randomized, multicenter, open-label study for men with Gleason grade group (GG) 1 cancer eligible for AS. Patients were randomized to CBx with 12-core systematic sampling or MRI with systematic and targeted sampling. Outcome measurements and statistical analysis Patients with GG ≤ 1 on CBx were followed for 2 yr and had MRI and biopsy at that time point. Patients failed AS if they were no longer under AS because of grade progression, clinical progression, subject choice, clinical judgment, treatment, or lost to follow-up. Clinically significant cancer (CSC) was defined as GG ≥ 2. Results and limitations In total, 259 men underwent CBx, 132 in the non-MRI and 127 in the MRI arm. After biopsy, 101 men in the non-MRI arm (76%) and 98 in the MRI arm (77%) continued AS. There were fewer men with AS failures in the MRI (19/98, 19%) compared to the non-MRI group (35/101, 35%; p = 0.017). At 2-yr biopsy there were fewer men with CSC in the MRI arm (9.9%, 8/81) than in the non-MRI arm (23%, 17/75; p = 0.048). Significant differences in AS failure rates were detected across the three centers in the MRI arm only (4.2% [2/48] vs 17% [4/24] vs 27% [7/26]; p = 0.019). Conclusions Baseline MRI before CBx during AS results in 50% fewer AS failures and less grade progression over 2 yr. The center where MRI and targeted biopsy is performed may influence AS failure rates. Patient summary The ASIST trial randomized 273 men on active surveillance with low-grade prostate cancer diagnosed within the last year to systematic biopsy or magnetic resonance imaging (MRI) with systematic and targeted biopsy. The initial report showed little benefit from targeted biopsy. However, after 2 yr of follow-up we found that baseline MRI before confirmatory biopsy resulted in 50% fewer failures of surveillance and less progression to higher-grade cancer. This confirms the value of MRI in men on surveillance. This study is registered at ClinicalTrials.gov (NCT01354171).

During the 2019 International Society of Urological Pathology Consultation Conference on Molecular Pathology of Urogenital Cancer, the Working Group on Bladder Cancer presented the current status and made recommendations on the diagnostic use of molecular pathology, incorporating a premeeting survey. Bladder cancers are biologically diverse and can be separated into "molecular subtypes," based on expression profiling. These subtypes associate with clinical behavior, histology, and molecular alterations, though their clinical utility has not been demonstrated at present and use in bladder cancer is not recommended. Mutations in the TERT promoter are present in the majority of bladder cancers, including the noninvasive stage of tumor evolution, but not in reactive conditions. Mutational analysis of the TERT promoter thus distinguishes histologically deceptive cancers from their benign mimics in some cases. A minority of pathologists employ this test. FGFR3 mutations are common in bladder cancer, and metastatic urothelial carcinoma (UC) with such mutations frequently responds to erdafitinib, an FGFR inhibitor. Testing for FGFR3 alterations is required before using this drug. Metastatic UC responds to immune-oncology (IO) agents in 20% of cases. These are approved as first and second-line treatments in metastatic UC. Several biological parameters associate with response to IO agents, including tumor mutational burden, molecular subtype, and infiltration by programmed death-ligand 1-positive lymphocytes, detected by immunohistochemistry. Programmed death-ligand 1 immunohistochemistry is mandatory before administering IO agents in the first-line setting. In conclusion, much has been learned about the biology of bladder cancer, and this understanding has improved the care of patients with the disease.

Purpose: To evaluate the risk factors associated with positive surgical margins' (PSMs) location and their impact on disease-specific survival (DSS) in patients with bladder cancer (BCa) undergoing radical cystectomy (RC). Methods: We analyzed a large multi-institutional cohort of patients treated with upfront RC for non-metastatic (cT1-4aN0M0) BCa. Multivariable binomial logistic regression analyses were used to assess the risk of PSMs at RC for each location after adjusting for clinicopathological covariates. The Kaplan–Meier method was used to estimate DSS stratified by margins’ status and location. Log-rank statistics and Cox’ regression models were used to determine significance. Results: A total of 1058 patients were included and 108 (10.2%) patients had PSMs. PSMs were located at soft-tissue, ureter(s), and urethra in 57 (5.4%), 30 (2.8%) and 21 (2.0%) patients, respectively. At multivariable analysis, soft-tissue PSMs were independently associated with pathological stage T4 (pT4) (Odds ratio (OR) 6.20, p < 0.001) and lymph-node metastases (OR 1.86, p = 0.04). Concomitant carcinoma-in-situ (CIS) was an independent risk factor for ureteric PSMs (OR 6.31, p = 0.003). Finally, urethral PSMs were independently correlated with pT4-stage (OR 5.10, p = 0.01). The estimated 3-years DSS rates were 58.2%, 32.4%, 50.1%, and 40.3% for negative SMs, soft-tissue-, ureteric- and urethral PSMs, respectively (log-rank; p < 0.001). Conclusions: PSMs’ location represents distinct risk factors’ patterns. Concomitant CIS was associated with ureteric PSMs. Urethral and soft-tissue PSM showed worse DSS rates. Our results suggest that clinical decision-making paradigms on adjuvant treatment and surveillance might be adapted based on PSM and their location.

Background Active surveillance (AS) enrolment criteria and follow-up schedules for low-risk prostate cancer vary between institutions. However, uncertainty remains about adherence to these protocols. Objective To determine adherence to institution-specific AS inclusion criteria and follow-up schedules within the Movember Foundation’s Global Action Plan Prostate Cancer Active Surveillance (GAP3) initiative. Design, setting, and participants We retrospectively assessed the data of 15 101 patients from 25 established AS cohorts worldwide between 2014 and 2016. Outcome measurements and statistical analysis Adherence to individual AS inclusion criteria was rated on a five-point Likert scale ranging from poor to excellent. Nonadherence to follow-up schedules was defined as absence of repeat biopsy 1 yr after the scheduled date. Cohorts were pooled into annual and Prostate Cancer Research International: Active Surveillance (PRIAS)-based biopsy schedules, and a generalised linear mixed model was constructed to test for nonadherence. Results and limitations Serum prostate-specific antigen (PSA) inclusion criteria were followed in 92%, Gleason score (GS) criteria were followed in 97%, and the number of positive biopsy cores was followed in 94% of men. Both age and tumour stage (T stage) criteria had 99% adherence overall. Pooled nonadherence rates increased over time—8%, 16%, and 34% for annual schedules and 11%, 30%, and 29% for PRIAS-based schedules at 1, 4, and 7 yr, respectively—and did not differ between biopsy schedules. A limitation is that our results do not consider the use of multiparametric magnetic resonance imaging. Conclusions In on-going development of evidence-based AS protocols, variable adherence to PSA and GS inclusion criteria should be considered. Repeat biopsy adherence reduces with increased duration of surveillance, independent of biopsy frequency. This emphasises the importance of risk stratification at the commencement of AS. Patient summary We studied adherence to active surveillance protocols for prostate cancer worldwide. We found that inclusion criteria were generally followed well, but adherence to repeat biopsy reduced with time. This should be considered when optimising future active surveillance protocols.

Aims Lymph node metastases at the time of prostatectomy are an infrequent finding. The correlation of the pattern of nodal metastases with patient outcome has yet to be explored. Methods and results Lymph node-positive prostatectomies were retrospectively reviewed. The presence of cribriform carcinoma (CC), intraductal carcinoma (IDC) and ISUP grade (G) were documented. The largest nodal metastasis was assessed for the morphological patterns present. G was assigned to the metastasis based on percentage morphological patterns present. Statistical analysis used spss to assess disease-specific survival (DSS), disease-free survival (DFS) and distant metastasis-free survival (DMFS). One hundred and ten cases were identified: G5 (n = 52), G4 (n = 8), G3 (n = 34), G2 (n = 10) and no G (n = 6; treatment effect). IDC or CC was present in 103 (94%) specimens. More than one positive node correlated with worse DFS [P = 0.012, hazard ratio (HR) = 1.951, 95% confidence interval (CI) = 1.142-3.331] and DMFS (P = 0.009, HR = 2.647, 95% CI = 1.239-5.651). G in the prostate and nodal metastasis were poorly correlated (kappa = 0.073, P = 0.195). The presence of pattern 5 was seen in 33 nodes (30%) and correlated with DFS (P = 0.020, HR = 1.903, 95% CI = 1.091-3.320), DSS (P = 0.021, HR = 5.937, 95% CI = 1.084-32.533) and DMFS (P = 0.007, HR = 2.695, 95% CI = 1.269-5.726). Nodal cribriform pattern showed no prognostic correlation and pattern 3 metastasis showed a significant trend towards better outcome (DMFS P = 0.033, HR = 0.431, 95% CI = 0.194-0.958). Conclusions IDC or CC is identified in 94% of node-positive prostate cancers. Although G in the largest nodal metastasis has prognostic significance, its G does not reflect that of the primary prostatic adenocarcinoma.

The International Collaboration on Cancer Reporting (ICCR) is a not-for-profit organisation sponsored by the Royal Colleges of Pathologists of Australasia and the United Kingdom, the College of American Pathologists, the Canadian Association of Pathologists in association with the Canadian Partnership Against Cancer, the European Society of Pathology, the American Society of Clinical Pathology and the Faculty of Pathology, Royal College of Physicians of Ireland. Its goal is to produce standardised, internationally agreed-upon, evidence-based datasets for cancer pathology reporting throughout the world. This paper describes the development of a cancer dataset by the multidisciplinary ICCR expert panel for the reporting of carcinoma of the urethra in urethrectomy specimens. The dataset is composed of 'required' (mandatory) and 'recommended' (non-mandatory) elements, which are based on a review of the most recent evidence and supported by explanatory commentary. Fourteen required elements and eight recommended elements were agreed by the international dataset authoring committee to represent the essential/required (core) and recommended (non-core) information for the reporting of carcinoma of the urethra in urethrectomy specimens. Use of an internationally agreed, structured pathology dataset for reporting carcinoma of the urethra (in urethrectomy specimens) will provide the necessary information for optimal patient management, will facilitate consistent data collection and will provide valuable data for research and international benchmarking. The dataset will be valuable for those countries and institutions that are not in a position to develop their own datasets.

Within the Movember Foundation's Global Action Plan Prostate Cancer Active Surveillance (GAP3) initiative, 25 centers across the globe collaborate to standardize active surveillance (AS) protocols for men with low-risk prostate cancer (PCa). A centralized PCa AS database, comprising data of more than 15000 patients worldwide, was created. Comparability of the histopathology between the different cohorts was assessed by a centralized pathology review of 445 biopsies from 15 GAP3 centers. Grade group 1 (Gleason score 6) in 85% and grade group ≥2 (Gleason score ≥7) in 15% showed 89% concordance at review with moderate agreement (κ=0.56). Average biopsy core length was similar among the analyzed cohorts. Recently established highly adverse pathologies, including cribriform and/or intraductal carcinoma, were observed in 3.6% of the reviewed biopsies. In conclusion, the centralized pathology review of 445 biopsies revealed comparable histopathology among the 15 GAP3 centers with a low frequency of high-risk features. This enables further data analyses-without correction-toward uniform global AS guidelines for men with low-risk PCa. PATIENT SUMMARY: Movember Foundation's Global Action Plan Prostate Cancer Active Surveillance (GAP3) initiative combines data from 15000 men with low-risk prostate cancer (PCa) across the globe to standardize active surveillance protocols. Histopathology review confirmed that the histopathology was consistent with low-risk PCa in most men and comparable between different centers.

Background: The European Association of Urology (EAU) prognostic factor risk groups for non–muscle-invasive bladder cancer (NMIBC) are used to provide recommendations for patient treatment after transurethral resection of bladder tumor (TURBT). They do not, however, take into account the widely used World Health Organization (WHO) 2004/2016 grading classification and are based on patients treated in the 1980s. Objective: To update EAU prognostic factor risk groups using the WHO 1973 and 2004/2016 grading classifications and identify patients with the lowest and highest probabilities of progression. Design, setting, and participants: Individual patient data for primary NMIBC patients were collected from the institutions of the members of the EAU NMIBC guidelines panel. Intervention: Patients underwent TURBT followed by intravesical instillations at the physician's discretion. Outcome measurements and statistical analysis: Multivariable Cox proportional-hazards regression models were fitted to the primary endpoint, the time to progression to muscle-invasive disease or distant metastases. Patients were divided into four risk groups: low-, intermediate-, high-, and a new, very high-risk group. The probabilities of progression were estimated using Kaplan-Meier curves. Results and limitations: A total of 3401 patients treated with TURBT ± intravesical chemotherapy were included. From the multivariable analyses, tumor stage, WHO 1973/2004–2016 grade, concomitant carcinoma in situ, number of tumors, tumor size, and age were used to form four risk groups for which the probability of progression at 5 yr varied from 40%. Limitations include the retrospective collection of data and the lack of central pathology review. Conclusions: This study provides updated EAU prognostic factor risk groups that can be used to inform patient treatment and follow-up. Incorporating the WHO 2004/2016 and 1973 grading classifications, a new, very high-risk group has been identified for which urologists should be prompt to assess and adapt their therapeutic strategy when necessary. Patient summary: The newly updated European Association of Urology prognostic factor risk groups for non–muscle-invasive bladder cancer provide an improved basis for recommending a patient's treatment and follow-up schedule. The updated European Association of Urology prognostic factor risk groups for patients with non–muscle-invasive bladder cancer provide urologists with information that they should take into account when choosing a patient's treatment and scheduling follow-up.

Take Home Message Risks of upgrading and disease progression were higher among African than among Caucasian men on active surveillance for prostate cancer. Transitioning to treatment without progression was highest among Asian men. Understanding of the reasons for these differences requires further investigation., Background Studies of active surveillance (AS) for prostate cancer (PCa) have focussed predominantly on Caucasian populations. Little is known about the experience of Asian men, while suitability for men of African descent has been questioned. Objective To compare baseline characteristics, follow-up, and outcomes for men on AS for PCa, according to ethnicity. Design, setting, and participants The study cohort included 13 centres from the GAP3 consortium that record ethnicity (categorised broadly as Caucasian/white, African/Afro-Caribbean/black, Asian, mixed/other, and unknown). Men with biopsy grade group >2, prostate-specific antigen (PSA) >20 ng/ml, T stage ≥cT3, or age >80 yr were excluded. Outcome measurements and statistical analysis Clinical characteristics, follow-up schedules, outcome status, and reasons for discontinuation were compared across ethnic groups. Risk of upgrading, potential disease progression (grade group ≥3 or T stage ≥3), suspicious indications (any upgrading, number of positive cores >3, T stage ≥cT3, PSA >20 ng/ml, or PSA density >0.2 ng/ml/cc2), and conversion to treatment were assessed using mixed-effect regression models. Results and limitations The eligible cohort (n = 9158) comprised 83% Caucasian men, 6% men of African descent, 5% Asian men, 2% men of mixed/other ethnicity, and 4% men of unknown ethnicity. Risks of suspicious indicators (hazard ratio = 1.27; 95% confidence interval [CI] 1.12–1.45), upgrading (odds ratio [OR] = 1.40; 95% CI 1.14–1.71), and potential progression (OR = 1.46; 95% CI 1.06–2.01) were higher among African/black than among Caucasian/white men. Risk of transitioning to treatment did not differ by ethnicity. More Asian than Caucasian men converted without progression (42% vs 26%, p < 0.001). Heterogeneity in surveillance protocols and racial makeup limit interpretation. Conclusions This multinational study found differences in the risk of disease progression and transitioning to treatment without signs of progression between ethnic groups. Further research is required to determine whether differences are due to biology, sociocultural factors, and/or clinical practice. Patient summary This international study compared prostate cancer active surveillance outcomes by ethnicity. Risks of upgrading and disease progression were higher among African than among Caucasian men. Transitioning to treatment without progression was highest among Asian men. Understanding of these differences requires further investigation.

The International Society of Urological Pathology (ISUP) hosts a reference image database supervised by experts with the purpose of establishing an international standard in prostate cancer grading. Here, we aimed to identify areas of grading difficulties and compare the results with those obtained from an artificial intelligence system trained in grading. In a series of 87 needle biopsies of cancers selected to include problematic cases, experts failed to reach a 2/3 consensus in 41.4% (36/87). Among consensus and non-consensus cases, the weighted kappa was 0.77 (range 0.68–0.84) and 0.50 (range 0.40–0.57), respectively. Among the non-consensus cases, four main causes of disagreement were identified: the distinction between Gleason score 3 + 3 with tangential cutting artifacts vs. Gleason score 3 + 4 with poorly formed or fused glands (13 cases), Gleason score 3 + 4 vs. 4 + 3 (7 cases), Gleason score 4 + 3 vs. 4 + 4 (8 cases) and the identification of a small component of Gleason pattern 5 (6 cases). The AI system obtained a weighted kappa value of 0.53 among the non-consensus cases, placing it as the observer with the sixth best reproducibility out of a total of 24. AI may serve as a decision support and decrease inter-observer variability by its ability to make consistent decisions. The grading of these cancer patterns that best predicts outcome and guides treatment warrants further clinical and genetic studies. Results of such investigations should be used to improve calibration of AI systems.

Background Men with prostate cancer (PCa) on active surveillance (AS) are followed through regular prostate biopsies, a burdensome and often unnecessary intervention, not without risks. Identifying men with at a low risk of disease reclassification may help reduce the number of biopsies. Objective To assess the external validity of two Canary Prostate Active Surveillance Study Risk Calculators (PASS-RCs), which estimate the probability of reclassification (Gleason grade ≥7 with or without >34% of biopsy cores positive for PCa) on a surveillance biopsy, using a mix of months since last biopsy, age, body mass index, prostate-specific antigen, prostate volume, number of prior negative biopsies, and percentage (or ratio) of positive cores on last biopsy. Design, setting, and participants We used data up to November 2017 from the Movember Foundation’s Global Action Plan (GAP3) consortium, a global collaboration between AS studies. Outcome measurements and statistical analysis External validity of the PASS-RCs for estimating reclassification on biopsy was assessed by calibration, discrimination, and decision curve analyses. Results and limitations Five validation cohorts (Prostate Cancer Research International: Active Surveillance, Johns Hopkins, Toronto, Memorial Sloan Kettering Cancer Center, and University of California San Francisco), comprising 5105 men on AS, were eligible for analysis. The individual cohorts comprised 429–2416 men, with a median follow-up between 36 and 84 mo, in both community and academic practices mainly from western countries. Abilities of the PASS-RCs to discriminate between men with and without reclassification on biopsy were reasonably good (area under the receiver operating characteristic curve values 0.68 and 0.65). The PASS-RCs were moderately well calibrated, and had a greater net benefit than most default strategies between a predicted 10% and 30% risk of reclassification. Conclusions Both PASS-RCs improved the balance between detecting reclassification and performing surveillance biopsies by reducing unnecessary biopsies. Recalibration to the local setting will increase their clinical usefulness and is therefore required before implementation. Patient summary Unnecessary prostate biopsies while on active surveillance (AS) should be avoided as much as possible. The ability of two calculators to selectively identify men at risk of progression was tested in a large cohort of men with low-risk prostate cancer on AS. The calculators were able to prevent unnecessary biopsies in some men. Usefulness of the calculators can be increased by adjusting them to the characteristics of the population of the clinic in which the calculators will be used.

We assessed the effect of screening in the European Randomized study of Screening for Prostate Cancer (ERSPC) Rotterdam pilot 1 study cohort with men randomized in 1991-1992. A total of 1134 men were randomized on a 1:1 basis to a screening (S) and control (C) arm after prostate-specific antigen (PSA) testing (PSA ≥10.0ng/ml was excluded from randomization). Further PSA testing was offered to all men in the S-arm with 4-yr intervals starting at age 55yr and screened up to the age of 74yr. Overall, a PSA level of ≥3.0ng/ml triggered biopsy. At time of analysis, 63% of men had died. Overall relative risk of metastatic (M+) disease and prostate cancer (PCa) death was 0.46 (95% confidence interval [CI]: 0.19-1.11) and 0.48 (95% CI: 0.17-1.36), respectively, in favor of screening. This ERSPC Rotterdam pilot 1 study cohort, screened in a period without noteworthy contamination, shows that PSA-based screening could result in considerable reductions of M+ disease and mortality which if confirmed in larger datasets should trigger further discussion on pros/cons of PCa screening. PATIENT SUMMARY: In a cohort with 19yr of follow-up, we found indications for a more substantial reduction in metastatic disease and cancer-specific mortality in favor of prostate cancer screening than previously reported. If confirmed in larger cohorts, these findings should be considered in the ongoing discussion on harms and benefits of prostate cancer screening.

Aims: Pathological evaluation of lymphadenectomy specimens plays a pivotal role in accurate lymph node (LN) staging. Guidelines standardising the gross handling and reporting of pelvic LN dissection (PLND) in prostate (PCa) and bladder (BCa) cancer are currently lacking. This study aimed to establish current practice patterns of PLND evaluation among pathologists. Methods and results: A web-based survey was circulated to all members of the European Network of Uropathology (ENUP), comprising 29 questions focusing on the macroscopic handling, LN enumeration and reporting of PLND in PCa and BCa. Two hundred and eighty responses were received from pathologists throughout 23 countries. Only LNs palpable at grossing were submitted by 58%, while 39% routinely embedded the entire specimen. Average LN yield from PLND was ≥10 LNs in 56% and

Many changes have been made during these last years and concepts for understanding bladder cancer have evolved. We make an update with the latest findings of the WHO (World Health Organistaion) 2016, ICCR (International Collaboration on Cancer Reporting) and other official organisms and try to show the latest developments. In this document we provide new consensus guidelines and insights. We kept this document short and concise providing consensus guidelines to clinicians for the best patient care, it should be easy to understand for a non pathologists. We focussed on several burning issues, such as the anatomical and histological understanding of the bladder wall, the prognostic significance of grading and the most challenging problems in staging, we underline our needs from the clinicians such as clinical information, we further discuss the histological subtypes of bladder cancer, which is an extremely important issue in the light of molecular classifications and give prognostic insights. Furthermore, we discuss the ICCR worldwide consensus reporting, urinary cytology with the Paris system and several issues such as frozen section specimen.

MRI is under evaluation for image-guided intervention for prostate cancer. The sensitivity and specificity of MRI parameters is determined via correlation with the gold-standard of histopathology. Whole-mount histopathology of prostatectomy specimens can be digitally registered to in vivo imaging for correlation. When biomechanical-based deformable registration is employed to account for deformation during histopathology processing, the ex vivo biomechanical properties are required. However, these properties are altered by pathology fixation, and vary with disease. Hence, this study employs magnetic resonance elastography (MRE) to measure ex vivo prostate biomechanical properties before and after fixation. A quasi-static MRE method was employed to measure high resolution maps of Young's modulus (E) before and after fixation of canine prostate and prostatectomy specimens (n = 4) from prostate cancer patients who had previously received radiation therapy. For comparison, T 1, T 2 and apparent diffusion coefficient (ADC) were measured in parallel. E (kPa) varied across clinical anatomy and for histopathology-identified tumor: peripheral zone: 99(±22), central gland: 48(±37), tumor: 85(±53), and increased consistently with fixation (factor of 11 ± 5; p

Objectives A total of 15 men who died of prostate cancer had cT1/2 biopsy Gleason score ≤6 prostate cancer at prevalence screening in the European Randomized study of Screening for Prostate Cancer Rotterdam. Our objective was to explain (part of) these prostate cancer deaths by undergrading with the classical Gleason score. Methods Biopsy specimens of 98 men with classical Gleason score ≤6 or 3 + 4 = 7 at prevalence screening in the European Randomized study of Screening for Prostate Cancer Rotterdam were retrospectively reviewed by two pathologists using the International Society of Urological Pathology 2014 modified Gleason score. These 98 men included 15 men with cT1/2 classical Gleason score ≤6 who died of prostate cancer (cases) and 83 randomly selected men with classical Gleason score ≤6 or 3 + 4 = 7 (controls). The primary outcome was the reclassification rate from classical Gleason score ≤6 to modified classical Gleason score 3 + 4 = 7 (grade group 2) stratified for prostate cancer death. The secondary outcome was the rate of cribriform/intraductal carcinoma in Gleason score-reclassified men stratified for prostate cancer death. Results A total of 79 out of 98 men had classical Gleason score ≤6 prostate cancer. A total of eight out of 15 (53%) prostate cancer deaths with classical Gleason score ≤6 were reclassified to modified Gleason score 3 + 4 = 7, compared with 16 out of 64 (25%) men with non-fatal prostate cancer (P = 0.017). A total of five out of eight (63%) Gleason score-reclassified men with fatal prostate cancer had cribriform/intraductal carcinoma, compared with two out of 16 (13%) Gleason score-reclassified men with non-fatal prostate cancer (P = 0.011). Conclusions Part of the prostate cancer deaths with Gleason score ≤6 at prevalence screening in the European Randomized study of Screening for Prostate Cancer Rotterdam could be explained by biopsy undergrading. The present study confirms that the International Society of Urological Pathology 2014 modified Gleason score is more accurate for prognostic assessment based on prostate biopsy than the classical Gleason score.

ERG and PTEN have been suggested as potential prognostic markers in prostatic adenocarcinoma. We assessed the relationship between ERG and PTEN protein expression in cribriform architecture prostatic carcinomas and adjacent acinar non-cribriform carcinoma and determined the interobserver variability in assessment of these markers. A contemporary cohort of radical prostatectomy cases (n=246) were reviewed and cribriform architecture carcinomas (intraductal carcinoma and cribriform Gleason 4 carcinomas) were identified and confirmed with triple cocktail immunostaining. ERG and PTEN protein expression were independently examined across all carcinoma components by two pathologists. 57 cases were available for immunohistochemistry. ERG protein expression was concordant between the cribriform and non-cribriform acinar carcinomas in 56/57 cases. There was no interobserver discrepancy in ERG assessment. PTEN staining was concordant in 53/57 cases however 33 cases showed heterogeneous staining, most marked in the non-cribriform acinar component. The kappa value for interobserver assessment of PTEN scoring was 0.787 (moderate) with discrepant cases resolved by cooperative review. ERG protein expression shows almost complete concordance (98.2%) across cribriform and non-cribriform prostatic carcinomas. Assessment of this staining is straightforward and consistent between observers. PTEN protein expression is heterogeneous and results in only moderate interobserver agreement. Both staining heterogeneity and interpretation present challenges in analyzing PTEN protein expression.

The study aimed to determine the relationship between T2-weighted magnetic resonance imaging (MRI) signal and histologic sub-patterns in prostate cancer areas with different Gleason grades.MR images of prostates (n = 25) were obtained prior to radical prostatectomy. These were processed as whole-mount specimens with tumors and the peripheral zone was annotated digitally by two pathologists. Gleason grade 3 was the most prevalent grade and was subdivided into packed, intermediate, and sparse based on gland-to-stroma ratio. Large cribriform, intraductal carcinoma, and small cribriform glands (grade 4 group) were separately annotated but grouped together for statistical analysis. The log MRI signal intensity for each contoured region (n = 809) was measured, and pairwise comparisons were performed using the open-source software R version 3.0.1.Packed grade 3 sub-pattern has a significantly lower MRI intensity than the grade 4 group (P 0.00001). Sparse grade 3 has a significantly higher MRI intensity than the packed grade 3 sub-pattern (P 0.0001). No significant difference in MRI intensity was observed between the Gleason grade 4 group and the sparse sub-pattern grade 3 group (P = 0.54). In multivariable analysis adjusting for peripheral zone, the P values maintained significance (packed grade 3 group vs grade 4 group, P 0.001; and sparse grade 3 sub-pattern vs packed grade 3 sub-pattern, P 0.001).This study demonstrated that T2-weighted MRI signal is dependent on histologic sub-patterns within Gleason grades 3 and 4 cancers, which may have implications for directed biopsy sampling and patient management.

Objective: Fibroblast growth factor receptor 3 (FGFR3) is a potentially actionable target in bladder cancer (BC). FGFR3 mutations are associated with favorable prognosis in non-muscle invasive (NMI) BC and MIBC. Overexpression of FGFR3 was reported in up to 40% of FGFR3 wild-type MIBC. p53 alterations rarely coincide with FGFR3 mutations. We analyzed FGFR3 mutations and protein-expression of FGFR3 and p53 and assessed their prognostic value in a multicenter, multilaboratory setting. Methods: We included 1,000 cN0M0, chemotherapy-naive patients who underwent radical cystectomy (RC) with pelvic node dissection. Specimens were reviewed by eight uropathologists. At seven laboratories, FGFR3 mutation status was examined using PCR-SNaPshot. p53 and FGFR3 expression were determined by immunohistochemistry (IHC). FGFR3 mutation status, p53 and FGFR3 protein expression were correlated to each other, clinicopathologic parameters, and disease-specific survival (DSS). Results: FGFR3 mutations were found in 107/1,000 RCs (11%), of which 67 were S249C. Overexpression of FGFR3 was found in 279/1,000 (28%) of tumors. p53 overexpression (cut-off>10%) was found in 638/926 (69%) of available cases. Among FGFR3 mutant tumors, 73% had FGFR3 overexpression. Among FGFR3 wild-type tumors, 22% had FGFR3 overexpression. FGFR3 mutations were associated with lower pT-stage (P Conclusions: FGFR3 mutations identified patients with favorable BC with fewer p53 alterations at RC. FGFR3 overexpression was not associated with DSS in patients with FGFR3 wild-type tumors. Our results suggest that FGFR3 mutations (driver effect) have a distinct functional role than FGFR3 overexpression (passenger effect). Hence, patients with FGFR3 mutations may be more likely to benefit from anti-FGFR3 therapy than patients with only overexpression of FGFR3. Citation Format: Bas van Rhijn, Laura Mertens, Roman Mayr, Peter Bostrom, Mirari Marques, Geert van Leenders, Stefanie Gotz, Michiel van der Heijden, Michael Jewett, Francisco Real, Robert Stohr, Alexandre Zlotta, Markus Eckstein, Yanish Soorojebally, Max Burger, Wolfgang Otto, Francois Radvanyi, Damien Pouessel, Theo van der Kwast, Nuria Malats, Arndt Hartmann, Yves Allory, Deric van der Schoot, Ellen Zwarthoff, Tahlita Zuiverloon. FGFR3 mutations and their relation to FGFR3 expression and clinical outcome in a large radical cystectomy cohort: Implications for anti-FGFR3 bladder cancer treatment? [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr B23.

Background: Careful assessment of the reasons for discontinuation of active surveillance (AS) is required for men with prostate cancer (PCa). Objective: Using Movember's Global Action Plan Prostate Cancer Active Surveillance initiative (GAP3) database, we report on reasons for AS discontinuation. Design, setting, and participants: We compared data from 10 296 men on AS from 21 centres across 12 countries. Outcome measurements and statistical analysis: Cumulative incidence methods were used to estimate the cumulative incidence rates of AS discontinuation. Results and limitations: During 5-yr follow-up, 27.5% (95% confidence interval [CI]: 26.4–28.6%) men showed signs of disease progression, 12.8% (95% CI: 12.0–13.6%) converted to active treatment without evidence of progression, 1.7% (95% CI: 1.5–2.0%) continued to watchful waiting, and 1.7% (95% CI: 1.4–2.1%) died from other causes. Of the 7049 men who remained on AS, 2339 had follow-up for >5 yr, 4561 had follow-up for

Longitudinal cohort studies and guidelines demonstrate that prostate specific antigen 1 ng/ml or greater in younger patients confers an increased risk of delayed prostate cancer death. At our institution we have used an aggressive biopsy strategy in younger patients with prostate specific antigen 1 ng/ml or greater. Our objective was to determine the proportion of detected cancer and specifically clinically significant cancer by this strategy.The prostate biopsy database at Princess Margaret Cancer Centre was queried for patients younger than 50 years who underwent a first prostate biopsy between 2000 and 2016. We included only patients who underwent prostate biopsy due to prostate specific antigen 1 ng/ml or greater and those with a suspicious digital rectal examination, a positive family history or a suspicious lesion on transrectal ultrasound. All clinical and pathological parameters were analyzed. Patients were stratified according to specific prostate specific antigen values. Multivariable logistic regression was performed to ascertain predictors of any prostate cancer diagnosis and of clinically significant prostate cancer.Of the 199 patients who met study inclusion criteria 37 (19%) were diagnosed with prostate cancer and 8 (22%) had a Gleason score of 7 or greater. Of those diagnosed with prostate cancer 25 (68%) had prostate specific antigen 1.5 ng/ml or greater and all men with a Gleason score of 7 or greater had prostate specific antigen 1.5 ng/ml or greater. Notably 19 patients (51%) had prostate cancer exceeding the Epstein criteria for active surveillance. Factors predicting prostate cancer included a positive family history, rising prostate specific antigen and lower prostate volume.Our results justify adopting an aggressive prostate biopsy strategy in men younger than 50 years with prostate specific antigen 1.5 ng/ml or greater while patients with prostate specific antigen less than 1.5 ng/ml are unlikely to have significant cancer. Special attention should be given to patients with a smaller prostate and a positive family history.

Aims: Despite efforts to standardise grading of prostate cancer, even among experts there is still a considerable variation in grading practices. In this study we describe the use of Pathology Imagebase, a novel reference image library, for setting an international standard in prostate cancer grading. Methods and results: The International Society of Urological Pathology (ISUP) recently launched a reference image database supervised by experts. A panel of 24 international experts in prostate pathology reviewed independently microphotographs of 90 cases of prostate needle biopsies with cancer. A linear weighted kappa of 0.67 (95% confidence interval = 0.62-0.72) and consensus was reached in 50 cases. The interobserver weighted kappa varied from 0.48 to 0.89. The highest level of agreement was seen for Gleason score (GS) 3 + 3 = 6 (ISUP grade 1), while higher grades and particularly GS 4 + 3 = 7 (ISUP grade 3) showed considerable disagreement. Once a two-thirds majority was reached, images were moved automatically into a public database available for all ISUP members at www.isupweb.org. Non-members are able to access a limited number of cases. Conclusions: It is anticipated that the database will assist pathologists to calibrate their grading and, hence, decrease interobserver variability. It will also help to identify instances where definitions of grades need to be clarified.

Cribriform and intraductal prostate cancer are both associated with an adverse outcome after radical prostatectomy. We included all patients with prostate cancer from the first screening round of the European Randomized Study of Screening for Prostate Cancer (ERSPC). All available slides were revised and scored for presence of cribriform and/or intraductal prostate cancer. Outcome measurements were biochemical recurrence and disease-specific survival. In total, 486 patients had Gleason score (GS) 6 (47%) and 545 GS ≥7 (53%). The disease-specific survival and biochemical-recurrence-free survival of CR/IDC−-GS3+4 patients did not differ significantly from those with GS 6, while patients with CR/IDC+-GS3+4-patients had a significant poorer outcome. Conclusion: The presence of cribriform and intraductal growth in prostate cancer, is a strong clinical prognostic marker with potential. The use of this variable in a clinical setting could contribute to reducing overtreatment of prostate cancer.

Background and objective This study aimed to determine, in men recently diagnosed with grade group 1 (GG1) prostate cancer, if magnetic resonance imaging (MRI) with targeted biopsy could identify a greater proportion of men with GG ≥2 cancer on their confirmatory biopsy compared with systematic biopsies. The study was registered with www.clinicaltrials.gov (NCT01354171). Design, setting, and participants This study is a prospective, randomized, multicenter, open-label trial. Eligible patients were men diagnosed with GG1 cancer within 1 yr prior to study entry in whom a confirmatory biopsy was indicated. Patients were randomized to 12-core systematic biopsy or MRI with systematic and targeted biopsy using the Artemis fusion targeting system. The primary end point was the proportion upgraded to GG ≥2 in each arm. Results and limitations In total, 296 men were registered and 273 randomized. Of the MRI group, 64% had a region of interest. No difference was observed in the rate of GG ≥2 upgrading (the intent-to-treat population, p=0.7, and per-protocol [PP] population, p=0.4), GG ≥2 upgrading within each stratum separately, or GG ≥3. After central pathology review, upgrading was observed in 36/132 (27%) men in the systematic biopsy arm and 42/127 (33%) men in the MRI arm (p=0.3). Upgrading was seen in 19/137 (14%) patients in the MRI arm on targeted biopsy alone (median, 2 cores) compared with 31/136 (23%) in the systematic biopsy arm (median, 12 cores; p=0.09). In the MRI arm, 8/127 (6.5%) patients had GG ≥2 disease identified on targeted biopsy, but ≤GG1 on the systematic biopsy, and 10/127 (7.9%) patients had GG ≥2 disease identified by systematic biopsy but ≤GG1 on targeted biopsy. Significant differences in upgrading on targeted biopsies were seen between sites, likely reflecting different levels of expertise with the targeted biopsy technique. Conclusions The addition of MRI with targeted biopsies to systematic biopsies did not significantly increase the upgrading rate compared with systematic biopsy alone. Furthermore, 2-core targeted biopsies alone resulted in a nonsignificant trend to less upgrading than 12-core systematic biopsy (p=0.09). In men on active surveillance, targeted biopsies identify most, but not all, clinically significant cancers.

The current definition of clinically significant prostate cancer includes an indirect measure of the volume of prostate cancer in addition to Gleason score based on biopsy findings. This biopsy-based tumor volume measure lacks accuracy, and therefore assessment by MRI of prostate cancer tumor volume could have a beneficial role for men on active surveillance. Despite the advances in interpretation and reporting on prostate cancer identified on MRI, limited evidence is available on tumor volume measurements on MRI. Although the PI-RADS version 2 has made some effort to define lesion measurements, many factors may influence these measurements. The robustness of tumor size or tumor volume assessment is reduced especially in small lesions visible on MRI. Furthermore, the overlap of benign and malignant tissue may hamper the accuracy of volume measurements. Even more, the heterogeneity of the prostate cancer, as also shown by the different Gleason patterns within the tumor, may demonstrate differences in tumor visualization on MRI. Moreover, differences in MRI hardware, software, imaging protocols, the chosen sequence, and the chosen slice may each have some effect on the robustness of tumor volume measurements.

BACKGROUND Stem cells are postulated to mediate prostate cancer progression, and represent a small fraction of the entire tumor. Various proteins (α2-integrin, α6-integrin, CD117, CD133, EZH2, OCT3/4) are associated with a prostate cancer stem cell phenotype in cell lines and xenografts. Our objective was to investigate expression of stem cell markers in clinical prostate cancer in relation to outcome. METHODS We validated immunohistochemical expression of stem cell markers in 481 prostate cancer patients and correlated expression with clinicopathologic parameters. RESULTS Sporadic expression of α2-integrin was present in a fraction of tumor cells ( 10 ng/ml (P = 0.04). α6-Integrin expression (

Resume La Societe internationale d’uropathologie (ISUP) a organise en 2009 une conference de consensus pour la prise en charge et la stadification d’une piece de prostatectomie. Les resultats de cette conference sont resumes dans cette revue. Elle precise les recommandations concernant l’analyse macroscopique, la macroscopie, la sous-stadification pT2, le volume tumoral, l’envahissement extraprostatique, l’infiltration des vesicules seminales, l’envahissement ganglionnaire et des marges chirurgicales. Ces recommandations forment la base d’une analyse des pieces de prostatectomie necessaire a une prise en charge consensuelle et optimale.

Context: The Gleason grading system is one of the most powerful predictors of outcome in prostate cancer and a cornerstone in counseling and treating patients. Since its inception, it has undergone several modifications triggered by a change in clinical practice and a better understanding of the cancer’s histologic spectrum and variants and their prognostic significance. Objective: To provide an overview of the implementation and the impact of the Gleason system as a predictive and prognostic tool in all available treatment modalities, and to compare the original and modified Gleason systems in major pathologic and clinical outcome data sets. Evidence acquisition: A comprehensive nonsystematic Medline search was performed using multiple Medical Subject Headings such as Gleason, modified, system, outcome, biopsy, prostatectomy, recurrence, prognosis, radiotherapy, and focal therapy, with restriction to the English language and a preference for publications within the last 10 yr. All Gleason grade–related studies in the last 3 yr were reviewed. For studies before this date, we relied on prior culling of the literature for various recent books, chapters, and original articles on this topic. Evidence synthesis: Using the modified grading system resulted in disease upgrading with more cancers assigned a Gleason score � 7 than in the past. It also resulted in a more homogeneous Gleason score 6, which has an excellent prognosis when the disease is organ confined. The vast majority of studies using both systems showed that Gleason grading of adenocarcinomas on needle biopsies and radical prostatectomies was strongly associated with pathologic stage, status of surgical margins, metastatic disease, biochemical recurrence, and cancer-specific survival, with the modified system outperforming the original one in some large series. A description of the continuous incorporation of this parameter in the clinical decision making for treating prostate cancer using all currently used treatment modalities is presented, and the findings of studies before and after the inception of the modified grading system, if available, are compared. The proposed contemporary grading prognostic categories are 3 + 3, 3 + 4, 4 + 3, 8, and 9–10. Conclusions: The Gleason score is one of the most critical predictive factors of prostate cancer regardless of the therapy used. Modernization of the Gleason grading system has resulted in a more accurate grading system for radical prostatectomy (RP) but has complicated the comparison of data before and after the updating. A better prognostication with the updated Gleason grading system for patients treated with modalities other than surgery can only be postulated at this time because there are limited conflicting data on radiation and no studies on other treatment modalities. Its greatest impact is the uniformly excellent prognosis associated with Gleason score 6 in RPs.

Cellular immunotherapy targeting human tumor antigens is a promising strategy to treat solid tumors. Yet clinical results of cellular immunotherapy are disappointing. Moreover, the currently available in vitro human tumor models are not designed to study the optimization of T-cell therapies of solid tumors. Here, we describe a novel assay for multiparametric in situ analysis of therapeutic effects on individual human three-dimensional (3D) tumors. In this assay, tumors of several millimeter diameter are generated from human cancer cell lines of different tumor entities in a collagen type I microenvironment. A newly developed approach for efficient morphological analysis reveals that these in vitro tumors resemble many characteristics of the corresponding clinical cancers such as histological features, immunohistochemical staining patterns, distinct tumor growth compartments and heterogeneous protein expression. To assess the response to therapy with tumor antigen specific T-cells, standardized protocols are described to determine T-cell infiltration and tumor destruction by monitoring soluble factors and tumor growth. Human tumors engineered in 3D collagen scaffolds are excellent in vitro surrogates for avascular tumor stages allowing integrated analyses of the antitumor efficacy of cancer specific immunotherapy in situ.

Purpose: Validation of MRI-guided tumor boundary delineation for targeted prostate cancer therapy is achieved via correlation with gold-standard histopathology of radical prostatectomy specimens. Challenges to accurate correlation include matching the pathology sectioning plane with the in vivoimaging slice plane and correction for the deformation that occurs between in vivoimaging and histology. A methodology is presented for matching of the histological sectioning angle and position to the in vivoimaging slices. Methods: Patients (n = 4) with biochemical failure following external beam radiotherapy underwent diagnostic MRI to confirm localized recurrence of prostate cancer, followed by salvage radical prostatectomy. High-resolution 3-D MRI of the ex vivo specimens was acquired to determine the pathology sectioning angle that best matched the in vivoimaging slice plane, using matching anatomical features and implanted fiducials. A novel sectioning device was developed to guide sectioning at the correct angle, and to assist the insertion of reference dye marks to aid in histopathology reconstruction. Results: The percentage difference in the positioning of the urethra in the ex vivopathology sections compared to the positioning in in vivoimages was reduced from 34% to 7% through slicing at the best match angle. Reference dye marks were generated, which were visible in ex vivoimaging, in the tissue sections before and after processing, and in histology sections. Conclusions: The method achieved an almost fivefold reduction in the slice-matching error and is readily implementable in combination with standard MRI technology. The technique will be employed to generate datasets for correlation of whole-specimen prostate histopathology with in vivo diagnostic MRI using 3-D deformable registration, allowing assessment of the sensitivity and specificity of MRI parameters for prostate cancer. Although developed specifically for prostate, the method is readily adaptable to other types of whole tissue specimen, such as mastectomy or liver resection.

UNLABELLED: What's known on the subject? and What does the study add? The reported discordance between staging on transurethral bladder resection and on radical cystectomy pathology in the literature ranges from 20 to 80%.Correct staging in bladder cancer has direct implications for its management. The upstaging from organ-confined (OC) to non-organ-confined (nOC) disease has been reported in 40% of cases. Lymphovascular invasion (LVI) is a factor known to be associated with poor clinical outcome. Pathological upstaging was observed in our cohort in 40% of cases and most cases (80%) were upstaged from OC to nOC disease. During the study period the frequency of upstaging observed increased. We found LVI (hazard ratio [HR]= 5.07, 95% CI = 3.0-8.3, P < 0.001) and any histological variant variant (HR = 2.77, 95% CI = 1.6-4.8, P < 0.001) to be strong independent predictors of upstaging. Patients with clinical T2 bladder cancer found with upstaging at the time of radical cystectomy had a poorer outcome than patients with no upstaging. Identification of patients at high risk of upstaging at radical cystectomy is key to improving their management and outcome. OBJECTIVES: To analyse the details of bladder cancer (BC) staging in a large combined radical cystectomy (RC) database from two academic centres. To study rate and time trends, as well as risk factors for upstaging, especially clinical factors associated with staging errors after RC. PATIENTS AND METHODS: Characteristics of patients undergoing RC at University Health Network, Toronto, Canada (1992-2010) and University of Turku, Turku, Finland (1986-2005) were analysed. RESULTS: Among 602 patients undergoing RC, 306 (51%) had a discordance in clinical and pathological stages. Upstaging occurred in 240 (40%) patients and 192 (32%) patients were upstaged from organ-confined (OC) to non-organ-confined (nOC) disease. During the study period, upstaging became more common in both centres. In multivariate analyses, T2 disease at initial presentation (P= 0.001, odds ratio [OR]= 2.62, 95% confidence interval [CI]: 1.44-4.77), high grade disease (P= 0.01, OR = 2.85, 95% CI: 1.21-6.7), lymphovascular invasion (LVI) (P < 0.001, OR = 5.17, 95% CI: 3.48-7.68), female gender (P= 0.038, OR = 0.6, 95% CI: 0.38-0.97, and histological variants (P < 0.001, OR = 2.77, 95% CI: 1.6-4.8) were associated with a risk of upstaging from OC to nOC disease. Upstaged patients had worse survival rates than patients with correct staging. This was especially significant among patients with carcinoma invading bladder muscle before undergoing RC (16% vs 46% 10-year disease-specific mortality, P < 0.001). CONCLUSIONS: Upstaging is a common problem and unfortunately no improvements have been observed during the last two decades. LVI and the presence of histological variants are strong predictors of upstaging at the time of RC. Pathologists should be encouraged to report LVI and any histological variant at the time of TURBT.

Study Type – Aetiology (individual cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Smoking is well described among the most important risk factors for bladder cancer. It is also known that higher quantity of tobacco exposure is associated with higher bladder cancer risk and that smoking cessation is known to be associated with lower risk of bladder cancer. Furthermore, among patients with non-muscle invasive bladder cancer, smoking cessation decreases the risk of tumour recurrence. On the other hand, the effect of smoking on tumour stages at presentation and especially on prognosis is not well studied. The current study describes the presentation and outcome of 564 patients (64% smokers, 36% non-smokers) treated with radical cystectomy. Patients with smoking history have more advanced outcome at the time of radical surgery and significantly worse outcome after surgery when compared to non-smokers, although the effect of smoking was not significant when survival was studied in multivariable analysis including classic prognostic parameters such as tumour grade, stage and adjuvant chemotherapy. Finally, there was a surprising finding that history of smoking affected outcome among male patients but such effect was not noted among female patients. OBJECTIVE • To study the effect of smoking on bladder cancer presentation and outcome in a large cystectomy population. PATIENTS AND METHODS • A database including 546 patients from the University Health Network (Toronto, Canada) and Turku University Hospital (Turku, Finland) was studied. • In addition to the association of smoking with clinicopathological parameters, the effect of smoking on survival was analyzed. • Categorical data were analyzed by the chi-squared test and numerical data were analyzed by Student's t-test. • The Kaplan–Meier method, log-rank test and a proportional hazards model were used to estimate the effect of smoking on survival. RESULTS • In total, 352 patients (64%) were smokers and 194 (36%) were non-smokers. • Smokers had more frequently advanced tumours and nodal metastasis. • The 10-year disease-specific survival (DSS) was 52% vs 66% for smokers and non-smokers, respectively (P= 0.039). • Smokers also had significantly worse overall survival (10-year overall survival 37% vs 62%; P= 0.015). • Smoking affected significant DSS among men (P= 0.012), although no effect was observed among women. • In a univariate model smoking was associated with a hazard ratio (HR) of 1.4 (95% confidence interval, CI, 1.0–1.9) for bladder cancer specific mortality and 1.4 (95% CI, 1.1–1.8) for overall mortality. • In a multivariate model, smoking did not impact on DSS (HR, 1.1; 95% CI, 0.8–1.6; P= 0.41). • In addition to advanced stage and nodal metastasis, female sex was an independent risk factor for DSS (HR, 1.6; 95% CI, 1.1–2.3; P= 0.007). CONCLUSIONS • Smokers appear to have worse outcomes after radical cystectomy for bladder cancer; however, it does not appear to be an independent prognostic factor for survival. • Smoking affected survival only among men. • Women had poorer survival but smoking was not a contributing factor to this.

This article reviews the proceedings of the cause and risk session of the recently held BCAN Bladder Think Tank in 2009. Understanding associations between specific genetic changes and development of particular forms of bladder cancer, whether low-grade or more invasive forms, may justify screening programs for earlier detection. A fundamental epidemiological issue is causation. Associations are supported by high rates in industrialized regions and parallel associations with cigarette smoking. The evolution to molecular and integrative epidemiology incorporates molecular and cytogenetic markers in host and tumor tissue with classic epidemiology to develop risk assessment models to identify high-risk populations. Animal models can teach us something about human bladder cancer and address the issue of the differentiation between papillary low-grade and invasive high-grade tumors. After the diagnosis of a bladder tumor, pathological risk stratification becomes important but there are weaknesses in the current grading systems. Molecular grading may provide a new, simple, and highly reproducible tool to determine bladder cancer prognosis. Based on our current knowledge, including gaps in that knowledge, education is the immediate top-priority action item. The promotion of smoking cessation is also a high priority action. The symptoms of bladder cancer, particularly hematuria, must be emphasized to both the medical and lay. Given the costs associated with the treatment and surveillance of bladder cancer, a comprehensive program supported by governmental funding sources to identify the risks associated with bladder cancer development would seem prudent.

Primary detection and follow-up of patients with non–muscle-invasive (NMI) bladder cancer (BC) is done by urethro-cystoscopy (UCS) and, in most cases, cytology. Many urine-based tests have been developed, and in general, these tests have a higher sensitivity than cytology but a lower specificity. In this review, we assessed the value of urine tests for screening, primary detection, and surveillance of NMIBC. Considering the frequency of UCS for follow-up, having markers for recurrent BC would be especially useful. Therefore, we updated our systematic review to include five commonly studied urine markers (BTA stat, NMP22, uCyt+/Immunocyt, FISH UroVysion, and microsatellite analysis) and cytology for surveillance. The sensitivity and/or specificity of cytology and these five markers were more than 5% lower for patients under surveillance compared to the numbers reported in other reviews, confirming that the performance of urine markers and cytology is lower for the detection of recurrent BC than is UCS. Recent data from the first randomized trial to investigate the possibility of lowering UCS frequency with urinary microsatellite analysis showed substantial underestimation of sensitivity and specificity if the urologist was not aware of the urine test outcome. These results question but do not replace UCS as the gold standard for NMIBC surveillance. In conclusion, cytology is still important as an adjunct for the evaluation of patients with hematuria and the surveillance of patients with high-risk NMIBC. Urine markers other than cytology may play a role in future screening studies and the follow-up of patients with low-grade (G1–2) NMIBC.

Accurate prediction of progression is an urgent unmet need in T1 bladder cancer (BCa) because the stakes are high for this disease. Approximately one-third of patients never recur after initial treatment, one-third have cancer that recurs as non–muscle invasive BCa (NMIBC), and one-third progress to muscle-invasive BCa with significantly worse clinical outcome. Optimal treatment for the individual patient is still lacking [1,2]. Conservative management with maintenance bacillus Calmette-Guerin (BCG) instillations may lead to progression and possibly death. Conversely, radical cystectomy is considered overtreatment for many patients with nonprogressive T1 BCa. To complicatematters even further, considerable interobserver variability exists among pathologists for T1 BCa staging [3]. In thismonth’s issueofEuropeanUrology, Patschanetal [4] report a potentially important study bringing the field a few steps forward to predict progression in T1 BCa. They identified 254 patients with primary T1 BCa in the Swedish population-based registry. After exclusion of 105 cases because of pathology review and other reasons, 149 cases could be molecularly subtyped with multiple immunohistochemical (IHC) markers: urobasal, 32%; genomically unstable, 58%; and squamous cell carcinoma (SCC)-like, 10%. Univariable and multivariable models were constructed to analyze progression. Median follow-up was 6.5 yr. Clinicopathologic variables such as European Organisation for Research and Treatment of Cancer (EORTC) risk score, multifocality, lymphovascular invasion, World Health Organisation (WHO; 1999) grade, T1 substage (T1a–T1c) and CD3 lymphocyte score, age, sex, adjuvant BCG treatment, and carcinoma in situ (CIS)were also available. The authors found that urobasal tumors generally have favorable T1 BCa characteristics and favorable clinical outcome, whereas genomically unstable and SCC-like tumors are associated with worse T1 BCa characteristics and progressive disease [4]. Rapidly progressing cases were characterized by high EORTC risk scores, high CD3 scores, and an unfavorable molecular subtype (genomically unstable or SCC-like). The main clinical prognostic factors for predicting NMIBC progression include presence of CIS, histologic grade, and T1 stage [1,2]. In stage T1 BCa, a recent metaanalysis of clinicopathologic variables reported T1 substage (T1a–T1c), lymphovascular invasion, CIS, size, age, and adjuvant BCG treatment as important prognostic factors in high-grade T1 BCa [5]. T1 substage (T1a–T1c) was found to be the most important prognostic variable in this metaanalysis [5]. Most studies have reported on T1 substage according to invasion above (T1a), in (T1b), or beyond (T1c) the muscularis mucosae and vascular plexus (MM-VP). However, T1a–T1c substages have not been recommended in clinical guidelines or classification systems for stage [1,2,5]. Themain reasonwas lack of consensus regarding the identification of the MM-VP at the invasion front of the tumor and the inability to substage patients in a significant percentage (up to 42%) of cases [1,5–7]. To circumvent this problem, new reproducible and user-friendly systems for T1 substage were developed, for example, the system that discerns T1-microinvasive (T1m) and T1-extensive-invasive (T1e) tumors [1,6–8]. In two head-to-head comparisons, T1m and T1e provedmore user friendly, could be used in 100% of cases, and predicted progression in multivariable analyses,making themmore robust tools to substage T1 BCa EU RO P E AN URO LOGY 6 8 ( 2 0 1 5 ) 8 3 3 – 8 3 6

for cancer. I was one of the architects of the National Health Service Breast Screening Programme (NHSBSP) in the United Kingdom in the late 1980s and also have enjoyed the privilege of acting as independent chairman of the Prostate Testing for Cancer and Treatment (ProtecT) trial of PCa screening in the United Kingdom for the last 12 yr [3]. I was also one of the first to break ranks with the NHSBSP as emergingdata started to suggest that breast cancer screening was failing to liveup to itspromise.Most recently, I published a paper in the BMJ inwhich I returned to basics and posed the question in the introduction of the editorial, ‘‘Does screening for breast cancer improve LoL andorQoL?’’ The answerwas a resounding no [4]. If we are not to repeat the errors of the past, then all cancer-screening trials must be reported using absolute numbers, numbers needed to screen to avoid a causespecific death, all-cause mortality, and some measure of QoL. Impotence and incontinence might be good surrogates for the latter. Some biostatisticians get very cross with me when they argue that the trials were not powered to determine any impact on all-cause deaths. Yet hundreds of thousands of men have been randomised in screening trials, so if the signal has been lost in the background noise, it must be a very small signal. If that is indeed the case, there is the issue of opportunity costs when the same money might be used with greater wisdom to save more lives. I am confident that the ProtecT trial will not repeat the mistakes of the past.