Predicting non-muscle invasive bladder cancer outcomes using artificial intelligence: a systematic review using APPRAISE-AI.

Accurate prediction of recurrence and progression in non-muscle invasive bladder cancer (NMIBC) is essential to inform management and eligibility for clinical trials. Despite substantial interest in developing artificial intelligence (AI) applications in NMIBC, their clinical readiness remains unclear. This systematic review aimed to critically appraise AI studies predicting NMIBC outcomes, and to identify common methodological and reporting pitfalls. MEDLINE, EMBASE, Web of Science, and Scopus were searched from inception to February 5th, 2024 for AI studies predicting NMIBC recurrence or progression. APPRAISE-AI was used to assess methodological and reporting quality of these studies. Performance between AI and non-AI approaches included within these studies were compared. A total of 15 studies (five on recurrence, four on progression, and six on both) were included. All studies were retrospective, with a median follow-up of 71 months (IQR 32-93) and median cohort size of 125 (IQR 93-309). Most studies were low quality, with only one classified as high quality. While AI models generally outperformed non-AI approaches with respect to accuracy, c-index, sensitivity, and specificity, this margin of benefit varied with study quality (median absolute performance difference was 10 for low, 22 for moderate, and 4 for high quality studies). Common pitfalls included dataset limitations, heterogeneous outcome definitions, methodological flaws, suboptimal model evaluation, and reproducibility issues. Recommendations to address these challenges are proposed. These findings emphasise the need for collaborative efforts between urological and AI communities paired with rigorous methodologies to develop higher quality models, enabling AI to reach its potential in enhancing NMIBC care.

MRI-guided Focused Ultrasound Focal Therapy for Intermediate-Risk Prostate Cancer: Final Results from a 2-year Phase II Clinical Trial.

Background MRI-guided focal therapy (FT) allows for accurate targeting of localized clinically significant prostate cancer (csPCa) while preserving healthy prostate tissue, but the long-term outcomes of this approach require more study. Purpose To assess the 2-year oncological and functional outcomes of men with intermediate-risk prostate cancer (PCa) treated with targeted FT. Materials and Methods In this single-center prospective phase II trial, men with localized unifocal intermediate-risk PCa underwent transrectal MRI-guided focused ultrasound between July 2016 and July 2019. Planned ablation volumes included 10-mm margins when possible. Data regarding adverse events were collected and quality-of-life questionnaires were completed by participants at 6 weeks and at 5, 12, 18, and 24 months after treatment. Multiparametric MRI and targeted and systematic biopsies were performed at 24 months. Ablation volumes were determined by manual contouring of nonperfused volumes on immediate contrast-enhanced images. Generalized estimating equations were used to model trends in quality-of-life measures. Results Treatment was successfully completed in the 44 participants (median age, 67 years; IQR, 62-70 years; 36 patients with grade group [GG] 2; eight patients with GG 3). No major adverse events from treatment were recorded. One participant refused biopsy at 24 months. After 2 years, 39 of 43 participants (91%) had no csPCa at the treatment site and 36 of 43 (84%) had no cancer in the entire gland. No changes in International Index of Erectile Function-15 score or International Prostate Symptom Score were observed during 2-year follow-up (P = .73 and .39, respectively). Conclusion The majority of men treated with MRI-guided focused ultrasound for intermediate risk PCa had negative results for csPCa at biopsy 2 years after treatment. Additionally, there was no significant decline in quality of life per the validated questionnaires. Clinical trial registration no. NCT02968784 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Woodrum in this issue.

International Society of Urological Pathology Consensus Conference on Current Issues in Bladder Cancer: Main Conclusions and Recommendations.

The 2022 International Society of Urological Pathology consensus conference on current issues in bladder cancer made recommendations regarding adoption of a three-tier grading system, grading of cancers with grade heterogeneity, grading and reporting of bladder cancers with subtype/divergent differentiation, and mandatory subcategorisation of T1 bladder cancers.

Addition of cribriform pattern 4 and intraductal prostatic carcinoma into the CAPRA-S tool improves post-radical prostatectomy patient stratification in a multi-institutional cohort.

AIMS: Pre-surgical risk classification tools for prostate cancer have shown better patient stratification with the addition of cribriform pattern 4 (CC) and intraductal prostatic carcinoma (IDC) identified in biopsies. Here, we analyse the additional prognostic impact of CC/IDC observed in prostatectomies using Cancer of Prostate Risk Assessment post-surgical (CAPRA-S) stratification. METHODS: A retrospective cohort of treatment-naïve radical prostatectomy specimens from three North American academic institutions (2010-2018) was assessed for the presence of CC/IDC. Patients were classified, after calculating the CAPRA-S scores, into low-risk (0-2), intermediate-risk (3-5) and high-risk (6-12) groups. Kaplan-Meier curves were created to estimate biochemical recurrence (BCR)-free survival. Prognostic performance was examined using Harrell's concordance index, and the effects of CC/IDC within each risk group were evaluated using the Cox proportional hazards models. RESULTS: Our cohort included 825 prostatectomies (grade group (GG)1, n=94; GG2, n=475; GG3, n=185; GG4, n=13; GG5, n=58). CC/IDC was present in 341 (41%) prostatectomies. With a median follow-up of 4.2 years (range 2.9-6.4), 166 (20%) patients experienced BCR. The CAPRA-S low-risk, intermediate-risk and high-risk groups comprised 357 (43%), 328 (40%) and 140 (17%) patients, and discriminated for BCR-free survival (p<0.0001). For CAPRA-S scores 3-5, the addition of CC/IDC status improved stratification for BCR (HR 2.27, 95% CI 1.41 to 3.66, p<0.001) and improved the overall c-index (0.689 vs 0.667, analysis of variance p<0.001). CONCLUSION: The addition of CC/IDC into the CAPRA-S classification significantly improved post-radical prostatectomy patient stratification for BCR among the intermediate-risk group (CAPRA-S scores 3-5). The reporting of CC and IDC should be included in future prostate cancer stratification tools for improved outcome prediction.

Aggressive prostatic adenocarcinoma with urothelial-like morphology, with frequent CK7/CK20/HMWK expression and occasional diffuse neuroendocrine features: A clinicopathologic study of 12 cases.

INTRODUCTION: Prostatic adenocarcinoma can occasionally display urothelial carcinoma morphology, which prompts immunohistochemistry (IHC) studies to determine its lineage. Typically, prostate cancer is characterized by the lack of cytokeratin (CK) 7, CK20 and high molecular weight keratin (HMWK) expression, as opposed to bladder cancer. METHODS: We report a series of 12 prostatic adenocarcinoma cases with unusual urothelial-like morphology, diagnosed at two academic institutions in Toronto between 2018 and 2023, and analyzed by immunohistochemistry for prostatic, urothelial, and neuroendocrine marker expression. We collected patient age, androgen deprivation therapy (ADT) status, tumour site, histomorphology, Grade group (GG) and results of genetic testing. RESULTS: The median age of the 12 patients included in this case series was 75.5 years (range 41-85). A history of prostatic cancer was noted in 7/12 (58%) patients. Five of nine (56%) patients had elevated serum PSA level at diagnosis. Six of eleven (55%) patients had prior ADT. Tumour sites were prostate (n = 6), bladder (n = 3), liver metastases (n = 2), and lung metastasis (n = 1). GGs of the primary tumours were GG3 (n = 1) and GG5 (n = 8). The observed urothelial-like morphology was diffuse in ten cases, and focal in two cases. CK7 was strong/diffuse in 8/11 tested cases, and focal weak in one case. CK20, HMWK, p63 and GATA3 were patchy/focal/weak/moderate in 3/6, 4/7, 4/8 and 2/9 cases, respectively. Ten (83%) cases were positive for at least one prostatic marker; eight (67%) cases had loss/weak staining of at least one prostatic marker. AR loss was seen in 2/7 (29%) cases. Seven of ten (70%) cases had diffuse/strong expression of at least one neuroendocrine marker. No trend was evident between prior ADT/AR status and any IHC result. Molecular analyses for DNA damage repair (DDR) genes (n = 6) demonstrated one ATM deletion (bladder). In addition, one TMPRSS2:ERG fusion (lung metastasis) was identified. CONCLUSION: This series comprises high-grade and/or metastatic prostatic adenocarcinoma cases with distinctive urothelial-like morphology and frequent aberrant CK7/CK20/HMWK expression. Their histomorphology, highly suggestive of an urothelial origin, represents a diagnostic pitfall that can lead to considerable management repercussions. The fact that a high proportion of the reported cases had loss/weak expression of at least one of the tested prostatic-specific markers, and occasionally a diffuse positivity for neuroendocrine markers highlights the importance of (1) clinical history and (2) utilization of broad IHC panels to correctly diagnose such unusual prostate cancer cases.

International Society of Urological Pathology Consensus Conference on Current Issues in Bladder Cancer. Working Group 4: Molecular Subtypes of Bladder Cancer-Principles of Classification and Emerging Clinical Utility.

Molecular subtyping has been a major focus of bladder cancer research over the past decade. Despite many promising associations with clinical outcomes and treatment response, its clinical impact has yet to be defined. As part of the 2022 International Society of Urological Pathology Conference on Bladder Cancer, we reviewed the current state of the science for bladder cancer molecular subtyping. Our review included several different subtyping systems. We derived the following 7 principles, which summarize progress and challenges of molecular subtyping: (1) bladder cancer has 3 major molecular subtypes: luminal, basal-squamous, and neuroendocrine; (2) signatures of the tumor microenvironment differ greatly among bladder cancers, particularly among luminal tumors; (3) luminal bladder cancers are biologically diverse, and much of this diversity results from differences in features unrelated to the tumor microenvironment, such as FGFR3 signaling and RB1 inactivation; (4) molecular subtype of bladder cancer associates with tumor stage and histomorphology; (5) many subtyping systems include idiosyncrasies, such as subtypes recognized by no other system; (6) there are broad fuzzy borders between molecular subtypes, and cases that fall on these fuzzy borders are often classified differently by different subtyping systems; and (7) when there are histomorphologically distinct regions within a single tumor, the molecular subtypes of these regions are often discordant. We reviewed several use cases for molecular subtyping, highlighting their promise as clinical biomarkers. Finally, we conclude that data are currently insufficient to support the routine use of molecular subtyping to guide bladder cancer management, an opinion shared with the majority of conference attendees. We also conclude that molecular subtype should not be considered an "intrinsic" property of a tumor but should instead be considered the result of a specific laboratory test, performed using a specific testing platform and classification algorithm, validated for a specific clinical application.

International Society of Urological Pathology (ISUP) Consensus Conference on Current Issues in Bladder Cancer. Working Group 1: Comparison of Bladder Cancer Grading System Performance.

Grade is a key prognostic factor in determining progression in nonmuscle invasive papillary urothelial carcinomas. The 2 most common grading methods in use worldwide are the World Health Organization (WHO) 2004 and 1973 schemes. The International Society of Urological Pathology (ISUP) organized the 2022 consensus conference in Basel, Switzerland on current issues in bladder cancer and tasked working group 1 to make recommendations for future iterations of bladder cancer grading. For this purpose, the ISUP developed in collaboration with the European Association of Urology a 10-question survey for their memberships to understand the current use of grading schemes by pathologists and urologists and to ascertain the areas of potential improvements. An additional survey was circulated to the ISUP membership for their opinion on interobserver variability in grading, reporting of urine cytology, and challenges encountered in grade assignment. Comprehensive literature reviews were performed on bladder cancer grading prognosis and interobserver variability along with The Paris System for urine cytology. There are notable differences in practice patterns between North American and European pathologists in terms of used grading scheme and diagnosis of papillary urothelial neoplasm of low malignant potential. Areas of common ground include difficulty in grade assignment, a desire to improve grading criteria, and a move towards subclassifying high-grade urothelial carcinomas. The surveys and in-person voting demonstrated a strong preference to refine current grading into a 3-tier scheme with the division of WHO 2004 high grade into clinically relevant categories. More variable opinions were voiced regarding the use of papillary urothelial carcinoma with low malignant potential.

International Society of Urological Pathology (ISUP) Consensus Conference on Current Issues in Bladder Cancer. Working Group 2: Grading of Mixed Grade, Invasive Urothelial Carcinoma Including Histologic Subtypes and Divergent Differentiations, and Non-Urothelial Carcinomas.

The 2022 International Society of Urological Pathology (ISUP) Consensus Conference on Urinary Bladder Cancer Working Group 2 was tasked to provide evidence-based proposals on the applications of grading in noninvasive urothelial carcinoma with mixed grades, invasive urothelial carcinoma including subtypes (variants) and divergent differentiations, and in pure non-urothelial carcinomas. Studies suggested that predominantly low-grade noninvasive papillary urothelial carcinoma with focal high-grade component has intermediate outcome between low- and high-grade tumors. However, no consensus was reached on how to define a focal high-grade component. By 2004 WHO grading, the vast majority of lamina propria-invasive (T1) urothelial carcinomas are high-grade, and the rare invasive low-grade tumors show only limited superficial invasion. While by 1973 WHO grading, the vast majority of T1 urothelial carcinomas are G2 and G3 and show significant differences in outcome based on tumor grade. No consensus was reached if T1 tumors should be graded either by the 2004 WHO system or by the 1973 WHO system. Because of the concern for underdiagnosis and underreporting with potential undertreatment, participants unanimously recommended that the presence of urothelial carcinoma subtypes and divergent differentiations should be reported. There was consensus that the extent of these subtypes and divergent differentiations should also be documented in biopsy, transurethral resection, and cystectomy specimens. Any distinct subtype and divergent differentiation should be diagnosed without a threshold cutoff, and each type should be enumerated in tumors with combined morphologies. The participants agreed that all subtypes and divergent differentiations should be considered high-grade according to the 2004 WHO grading system. However, participants strongly acknowledged that subtypes and divergent differentiations should not be considered as a homogenous group in terms of behavior. Thus, future studies should focus on individual subtypes and divergent differentiations rather than lumping these different entities into a single clinicopathological group. Likewise, clinical recommendations should pay attention to the potential heterogeneity of subtypes and divergent differentiations in terms of behavior and response to therapy. There was consensus that invasive pure squamous cell carcinoma and pure adenocarcinoma of the bladder should be graded according to the degree of differentiation. In conclusion, this summary of the International Society of Urological Pathology Working Group 2 proceedings addresses some of the issues on grading beyond its traditional application, including for papillary urothelial carcinomas with mixed grades and with invasive components. Reporting of subtypes and divergent differentiation is also addressed in detail, acknowledging their role in risk stratification. This report could serve as a guide for best practices and may advise future research and proposals on the prognostication of these tumors.

International Society of Urological Pathology (ISUP) Consensus Conference on Current Issues in Bladder Cancer: Working Group 3: Subcategorization of T1 Bladder Cancer.

Emerging data on T1 bladder cancer subcategorization (aka substaging) suggests a correlation with oncological outcomes. The International Society of Urological Pathology (ISUP) organized the 2022 consensus conference in Basel, Switzerland to focus on current issues in bladder cancer and tasked working group 3 to make recommendations for T1 subcategorization in transurethral bladder resections. For this purpose, the ISUP developed and circulated a survey to their membership querying approaches to T1 bladder cancer subcategorization. In particular, clinical relevance, pathological reporting, and endorsement of T1 subcategorization in the daily practice of pathology were surveyed. Of the respondents of the premeeting survey, about 40% do not routinely report T1 subcategory. We reviewed literature on bladder T1 subcategorization, and screened selected articles for clinical performance and practicality of T1 subcategorization methods. Published literature offered evidence of the clinical rationale for T1 subcategorization and at the conference consensus (83% of conference attendants) was obtained to report routinely T1 subcategorization of transurethral resections. Semiquantitative T1 subcategorization was favored (37%) over histoanatomic methods (4%). This is in line with literature findings on practicality and prognostic impact, that is, a shift of publications from histoanatomic to semiquantitative methods or by reports incorporating both methodologies is apparent over the last decade. However, 59% of participants had no preference for either methodology. They would add a comment in the report briefly stating applied method, interpretation criteria (including cutoff), and potential limitations. When queried on the terminology of T1 subcategorization, 34% and 20% of participants were in favor of T1 (microinvasive) versus T1 (extensive) or T1 (focal) versus T1 (nonfocal), respectively.

Addition of Cribriform and Intraductal Carcinoma Presence to Prostate Biopsy Reporting Strengthens Pretreatment Risk Stratification Using CAPRA and NCCN Tools.

BACKGROUND: Pretreatment stratification tools can help in clinical decision making in prostate cancer. To date, none incorporates well-established routinely reported adverse prognostic pathologic features such as intraductal carcinoma of prostate (IDC) or cribriform pattern 4 (CC). OBJECTIVE: To assess the impact of addition of CC and/or IDC on the Cancer of Prostate Risk Assessment (CAPRA) and National Cancer Comprehensive Network (NCCN) tools for predicting biochemical recurrence free survival (BCR-FS) and event-free survival (EFS) across multiple patient cohorts. DESIGN, SETTING, AND PARTICIPANTS: Matched prostate biopsies and radical prostatectomies from institutions in Toronto, Wisconsin and Rotterdam. The presence/absence of CC/IDC was recorded on all biopsies. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Relationship to outcome was assessed using Cox proportional hazard models, ANOVA and Harrell's concordance index. RESULTS AND LIMITATIONS: We included 1326 patients (Toronto- 612, Wisconsin- 542, Rotterdam- 172) with median follow up of 4.2 years (IQR 2.9-6.4 years); 306 (23.1%) had CC/IDC on biopsy with 207 (20.9%) BCR and 154 (11.6%) events (metastases/death). Addition of CC/IDC improved stratification in CAPRA scores 3 to 5 for BCR-FS (c-index increase 0.633-0.658, P < .001) and scores 6-10 for EFS (c-index increase 0.653-0.697, P < .001). For NCCN, all risk groups apart from score 1 to 2 showed improvement in BCR-FS (c-index increase 0.599-0.636, P < 0.001) and EFS prediction (c-index increase 0.648-0.697, P < .001). Sub-analysis of grade group (GG) 2 biopsies showed similar findings. The retrospective nature and inclusion of cases only reported by genitourinary pathologists are study limitations. CONCLUSIONS: The clinical benefit of the addition of CC/IDC to both CAPRA and NCCN pretreatment tools was validated in 3 cohorts, including the subset of biopsy GG2 prostate cancer patients. PATIENT SUMMARY: Including additional pathologic features to existing pretreatment, clinical decision making tools improves the ability to predict prostate cancer recurrence, cancer spread and death of disease.

Long-term outcomes and cost savings of office fulguration of papillary Ta low-grade bladder cancer.

OBJECTIVES: To assess whether office-based fulguration (OF) under local anaesthesia for small, recurrent, pathological Ta low-grade (LG) non-muscle-invasive bladder cancer (NMIBC) is an effective alternative to transurethral resection of bladder tumour (TURBT), avoiding the costs and risks of procedure, and anesthesia. PATIENTS AND METHODS: Of 521 patients with primary TaLG NMIBC, this retrospective study included 270 patients who underwent OF during follow-up for recurrent, small, papillary LG-appearing tumours at a university centre (University Health Network, University of Toronto, Canada). We assessed the cumulative incidence of cancer-specific mortality (CSM) and disease progression (to MIBC or metastases), as well as possible direct cost savings. RESULTS: In the 270 patients with recurrent TaLG NMIBC treated with OF, the mean (sd) age was 64.9 (13.3) years, 70.8% were men, and 60.3% had single tumours. The mean (sd, range) number of OF procedures per patient was 3.1 (3.2, 1-22). The median (interquartile range) follow-up was 10.1 (5.8-16.2) years. Patients also underwent a mean (sd) of 3.6 (3.0) TURBTs during follow-up in case of numerous or bulkier recurrence. In all, 44.4% of patients never received intravesical therapy. The 10-year incidence of CSM and progression were 0% and 3.1% (95% confidence interval 0.8-5.4%), respectively. Direct cost savings in Ontario were estimated at $6994.14 (Canadian dollars) per patient over the study follow-up. CONCLUSIONS: This study supports that properly selected patients with recurrent, apparent TaLG NMIBC can be safely managed with OF under local anaesthesia with occasional TURBT for larger or numerous recurrent tumours, without compromising long-term oncological outcomes. This approach could generate substantial cost-saving to healthcare systems, is patient-friendly, and could be adopted more widely.

Transposable Elements Are Co-opted as Oncogenic Regulatory Elements by Lineage-Specific Transcription Factors in Prostate Cancer.

Transposable elements hold regulatory functions that impact cell fate determination by controlling gene expression. However, little is known about the transcriptional machinery engaged at transposable elements in pluripotent and mature versus oncogenic cell states. Through positional analysis over repetitive DNA sequences of H3K27ac chromatin immunoprecipitation sequencing data from 32 normal cell states, we report pluripotent/stem and mature cell state-specific "regulatory transposable elements." Pluripotent/stem elements are binding sites for pluripotency factors (e.g., NANOG, SOX2, OCT4). Mature cell elements are docking sites for lineage-specific transcription factors, including AR and FOXA1 in prostate epithelium. Expanding the analysis to prostate tumors, we identify a subset of regulatory transposable elements shared with pluripotent/stem cells, including Tigger3a. Using chromatin editing technology, we show how such elements promote prostate cancer growth by regulating AR transcriptional activity. Collectively, our results suggest that oncogenesis arises from lineage-specific transcription factors hijacking pluripotent/stem cell regulatory transposable elements. SIGNIFICANCE: We show that oncogenesis relies on co-opting transposable elements from pluripotent stem cells as regulatory elements altering the recruitment of lineage-specific transcription factors. We further discover how co-option is dependent on active chromatin states with important implications for developing treatment options against drivers of oncogenesis across the repetitive DNA. This article is featured in Selected Articles from This Issue, p. 2293.

Development, multi-institutional external validation, and algorithmic audit of an artificial intelligence-based Side-specific Extra-Prostatic Extension Risk Assessment tool (SEPERA) for patients undergoing radical prostatectomy: a retrospective cohort study.

BACKGROUND: Accurate prediction of side-specific extraprostatic extension (ssEPE) is essential for performing nerve-sparing surgery to mitigate treatment-related side-effects such as impotence and incontinence in patients with localised prostate cancer. Artificial intelligence (AI) might provide robust and personalised ssEPE predictions to better inform nerve-sparing strategy during radical prostatectomy. We aimed to develop, externally validate, and perform an algorithmic audit of an AI-based Side-specific Extra-Prostatic Extension Risk Assessment tool (SEPERA). METHODS: Each prostatic lobe was treated as an individual case such that each patient contributed two cases to the overall cohort. SEPERA was trained on 1022 cases from a community hospital network (Trillium Health Partners; Mississauga, ON, Canada) between 2010 and 2020. Subsequently, SEPERA was externally validated on 3914 cases across three academic centres: Princess Margaret Cancer Centre (Toronto, ON, Canada) from 2008 to 2020; L'Institut Mutualiste Montsouris (Paris, France) from 2010 to 2020; and Jules Bordet Institute (Brussels, Belgium) from 2015 to 2020. Model performance was characterised by area under the receiver operating characteristic curve (AUROC), area under the precision recall curve (AUPRC), calibration, and net benefit. SEPERA was compared against contemporary nomograms (ie, Sayyid nomogram, Soeterik nomogram [non-MRI and MRI]), as well as a separate logistic regression model using the same variables included in SEPERA. An algorithmic audit was performed to assess model bias and identify common patient characteristics among predictive errors. FINDINGS: Overall, 2468 patients comprising 4936 cases (ie, prostatic lobes) were included in this study. SEPERA was well calibrated and had the best performance across all validation cohorts (pooled AUROC of 0·77 [95% CI 0·75-0·78] and pooled AUPRC of 0·61 [0·58-0·63]). In patients with pathological ssEPE despite benign ipsilateral biopsies, SEPERA correctly predicted ssEPE in 72 (68%) of 106 cases compared with the other models (47 [44%] in the logistic regression model, none in the Sayyid model, 13 [12%] in the Soeterik non-MRI model, and five [5%] in the Soeterik MRI model). SEPERA had higher net benefit than the other models to predict ssEPE, enabling more patients to safely undergo nerve-sparing. In the algorithmic audit, no evidence of model bias was observed, with no significant difference in AUROC when stratified by race, biopsy year, age, biopsy type (systematic only vs systematic and MRI-targeted biopsy), biopsy location (academic vs community), and D'Amico risk group. According to the audit, the most common errors were false positives, particularly for older patients with high-risk disease. No aggressive tumours (ie, grade >2 or high-risk disease) were found among false negatives. INTERPRETATION: We demonstrated the accuracy, safety, and generalisability of using SEPERA to personalise nerve-sparing approaches during radical prostatectomy. FUNDING: None.

Use of the ISUP e-learning module improves interrater reliability in prostate cancer grading.

AIMS: Prostate cancer (PCa) grading is an important prognostic parameter, but is subject to considerable observer variation. Previous studies have shown that interobserver variability decreases after participants were trained using an e-learning module. However, since the publication of these studies, grading of PCa has been enhanced by adopting the International Society of Urological Pathology (ISUP) 2014 grading classification. This study investigates the effect of training on interobserver variability of PCa grading, using the ISUP Education web e-learning on Gleason grading. METHODS: The ISUP Education Prostate Test B Module was distributed among Dutch pathologists. The module uses images graded by the ISUP consensus panel consisting of 24 expert uropathologists. Participants graded the same 10 images before and after e-learning. We included those who completed the tests before and after training. We evaluated variation in PCa grading in a fully crossed study design, using linearly weighted kappa values for each pathologist, comparing them to other pathologists and to the ISUP consensus panel. We analysed the improvement in median weighted kappas before and after training, using Wilcoxon's signed rank-test. RESULTS: We included 42 pathologists. Inter-rater reliability between pathologists improved from 0.70 before training to 0.74 after training (p=0.01). When compared with the ISUP consensus panel, five pathologists improved significantly, whereas the kappa of one pathologist was significantly lower after training. All pathologists who improved significantly, graded with less than substantial agreement before training. CONCLUSIONS: ISUP Prostate Test B e-learning reduces variability in PCa grading. E-learning is a cost-effective method for standardisation of pathology.

Predictive Value of Cribriform and Intraductal Carcinoma for the Nomogram-based Selection of Prostate Cancer Patients for Pelvic Lymph Node Dissection.

OBJECTIVE: To assess the predictive value of biopsy-identified cribriform carcinoma and/or intraductal carcinoma (CR/IDC) within the Briganti and MSKCC nomograms predicting lymph node metastasis (LNM) in patients with primary prostate cancer (PCa). METHODS: We retrospectively included 393 PCa patients who underwent radical prostatectomy with extended pelvic lymph node dissection at 3 tertiary referral centers. We externally validated 2 prediction tools: the Briganti 2012 nomogram and the Memorial Sloan Kettering Cancer Center (MSKCC) nomogram. Both nomograms were augmented with CR/IDC. The original model was compared with the CR/IDC-updated model using the likelihood ratio test. The performance of the prediction tools was assessed using calibration, discrimination, and clinical utility. RESULTS: Overall, 109 (28%) men were diagnosed with LNM. Calibration plots of the Briganti and MSKCC nomograms demonstrated an underestimation of the LNM risk across clinically relevant thresholds (≤15%). The addition of CR/IDC to the Briganti nomogram increased the fit of the data (χ2(1) = 4.30, P = .04), but did not improve the area under the curve (AUC) (0.69, 95% CI 0.63-0.75 vs 0.69, 95% CI 0.64-0.75). Incorporation of CR/IDC in the MSKCC nomogram resulted in an increased fit on the data (χ2(1) = 10.04, P <.01), but did not increase the AUC (0.66, 95% CI 0.60-0.72 vs 0.68, 95% CI 0.62-0.74). The addition of CR/IDC to the Briganti and MSKCC nomograms did not improve the clinical risk prediction. CONCLUSION: Incorporation of CR/IDC into the 2 clinically most used pre-radical prostatectomy nomograms does not improve LNM prediction in a multinational, contemporary PCa cohort.

Comparison of Micro-US and Multiparametric MRI for Prostate Cancer Detection in Biopsy-Naive Men.

Background Multiparametric MRI has led to increased detection of clinically significant prostate cancer (csPCa). Micro-US is being investigated for csPCa detection. Purpose To compare multiparametric MRI and micro-US in detecting csPCa (grade group ≥2) and to determine the proportion of MRI nodules visible at micro-US for real-time targeted biopsy. Materials and methods This prospective, single-center trial enrolled biopsy-naive men with suspected prostate cancer (PCa) between May 2019 and September 2020. All patients underwent multiparametric MRI followed by micro-US; findings at both were interpreted in a blinded fashion, followed by targeted biopsy and nontargeted systematic biopsy using micro-US. Proportions were compared using the exact McNemar test. The differences in proportions were calculated. Results Ninety-four men (median age, 61 years; IQR, 57-68 years) were included. MRI- and micro-US-targeted biopsy depicted csPCa in 37 (39%) and 33 (35%) of the 94 men, respectively (P = .22); clinically insignificant PCa in 14 (15%) and 15 (16%) (P > .99); and cribriform and/or intraductal PCa in 14 (15%) and 13 (14%) (P > .99). The MRI- plus micro-US-targeted biopsy pathway depicted csPCa in 38 of the 94 (40%) men. The addition of nontargeted systematic biopsy to MRI- plus micro-US-targeted biopsy did not enable identification of any additional men with csPCa but did help identify nine additional men with clinically insignificant PCa (P = .04). Biopsy was avoided in 32 of the 94 men (34%) with MRI and nine of the 94 men (10%) with micro-US (P < .001). Among 93 MRI targets, 62 (67%) were prospectively visible at micro-US. Conclusion MRI and micro-US showed similar rates of prostate cancer detection, but more biopsies were avoided with the MRI pathway than with micro-US, with no benefit of adding nontargeted systematic biopsy to the MRI- plus micro-US-targeted biopsy pathway. Most MRI lesions were prospectively visible at micro-US, allowing real-time targeted biopsy. ClinicalTrials.gov registration no.: NCT03938376 © RSNA, 2022 Online supplemental material is available for this article.

Impact of cribriform pattern 4 and intraductal prostatic carcinoma on National Comprehensive Cancer Network (NCCN) and Cancer of Prostate Risk Assessment (CAPRA) patient stratification.

Pretreatment classification tools are used in prostate cancer to inform patient management. The effect of cribriform pattern 4 (CC) and intraductal carcinoma (IDC) on such nomograms is still underexplored. We analyzed the Cancer of Prostate Risk Assessment (CAPRA) and National Comprehensive Cancer Network (NCCN) risk scores in cases with and without CC/IDC to assess impact on biochemical recurrence (BCR) and metastases/death of prostate cancer (event free survival-EFS) after prostatectomy. A matched biopsy- prostatectomy cohort (2010-2017) was reviewed for CC/IDC. CAPRA and NCCN scores were calculated. CAPRA score 0-2 were deemed "low", 3-5 "intermediate" and 6-10 "high". NCCN scores 1-2 "very low/low", 3 "favorable intermediate", 4 "unfavorable intermediate", 5-6 "high/very high". Cases were stratified by presence of CC/IDC. BCR and EFS probabilities were estimated using the Kaplan-Meier method. Prognostic performance was evaluated using log-rank tests and Harrell's concordance index. 612 patients with mean age 63.1 years were included with mean follow up of 5.3 (range 0-10.8) years. CC/IDC was noted in 159/612 (26%) biopsies. There were 101 (17%) BCR and 36 (6%) events. CAPRA discriminated three distinct risk categories for BCR (p < 0.001) while only high risk separated significantly for EFS (p < 0.001). NCCN distinguished two prognostic groups for BCR (p < 0.0001) and three for EFS (p < 0.0001). Addition of CC/IDC to CAPRA impacted scores 3-5 for BCR and scores 3-5 and 6-10 for EFS and improved the overall concordance index (BCR: 0.66 vs. 0.71; EFS: 0.74 vs. 0.80). Addition of CC/IDC to NCCN impacted scores 4 and 5-6 and also improved the concordance index for BCR (0.62 vs. 0.68). Regarding EFS, NCCN scores 4 and 5-6 demonstrated markedly different outcomes with the addition of CC/IDC. The CAPRA nomogram allows better outcome stratification than NCCN. Addition of CC/IDC status particularly improves patient stratification for CAPRA scores 3-5, 6-10, and for NCCN scores 4 and 5-6.