Widespread and Functional RNA Circularization in Localized Prostate Cancer.

The cancer transcriptome is remarkably complex, including low-abundance transcripts, many not polyadenylated. To fully characterize the transcriptome of localized prostate cancer, we performed ultra-deep total RNA-seq on 144 tumors with rich clinical annotation. This revealed a linear transcriptomic subtype associated with the aggressive intraductal carcinoma sub-histology and a fusion profile that differentiates localized from metastatic disease. Analysis of back-splicing events showed widespread RNA circularization, with the average tumor expressing 7,232 circular RNAs (circRNAs). The degree of circRNA production was correlated to disease progression in multiple patient cohorts. Loss-of-function screening identified 11.3% of highly abundant circRNAs as essential for cell proliferation; for ∼90% of these, their parental linear transcripts were not essential. Individual circRNAs can have distinct functions, with circCSNK1G3 promoting cell growth by interacting with miR-181. These data advocate for adoption of ultra-deep RNA-seq without poly-A selection to interrogate both linear and circular transcriptomes.

Risk SNP-Mediated Promoter-Enhancer Switching Drives Prostate Cancer through lncRNA PCAT19.

The prostate cancer (PCa) risk-associated SNP rs11672691 is positively associated with aggressive disease at diagnosis. We showed that rs11672691 maps to the promoter of a short isoform of long noncoding RNA PCAT19 (PCAT19-short), which is in the third intron of the long isoform (PCAT19-long). The risk variant is associated with decreased and increased levels of PCAT19-short and PCAT19-long, respectively. Mechanistically, the risk SNP region is bifunctional with both promoter and enhancer activity. The risk variants of rs11672691 and its LD SNP rs887391 decrease binding of transcription factors NKX3.1 and YY1 to the promoter of PCAT19-short, resulting in weaker promoter but stronger enhancer activity that subsequently activates PCAT19-long. PCAT19-long interacts with HNRNPAB to activate a subset of cell-cycle genes associated with PCa progression, thereby promoting PCa tumor growth and metastasis. Taken together, these findings reveal a risk SNP-mediated promoter-enhancer switching mechanism underlying both initiation and progression of aggressive PCa.

The Evolutionary Landscape of Localized Prostate Cancers Drives Clinical Aggression.

The majority of newly diagnosed prostate cancers are slow growing, with a long natural life history. Yet a subset can metastasize with lethal consequences. We reconstructed the phylogenies of 293 localized prostate tumors linked to clinical outcome data. Multiple subclones were detected in 59% of patients, and specific subclonal architectures associate with adverse clinicopathological features. Early tumor development is characterized by point mutations and deletions followed by later subclonal amplifications and changes in trinucleotide mutational signatures. Specific genes are selectively mutated prior to or following subclonal diversification, including MTOR, NKX3-1, and RB1. Patients with low-risk monoclonal tumors rarely relapse after primary therapy (7%), while those with high-risk polyclonal tumors frequently do (61%). The presence of multiple subclones in an index biopsy may be necessary, but not sufficient, for relapse of localized prostate cancer, suggesting that evolution-aware biomarkers should be studied in prospective studies of low-risk tumors suitable for active surveillance.

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.

Somatic Tumor Testing in Prostate Cancer: Experience of a Tertiary Care Center Including Pathologist-Driven Reflex Testing of Localized Tumors at Diagnosis.

Somatic tumor testing in prostate cancer (PCa) can guide treatment options by identifying clinically actionable variants in DNA damage repair genes, including acquired variants not detected using germline testing alone. Guidelines currently recommend performing somatic tumor testing in metastatic PCa, whereas there is no consensus on the role of testing in regional disease, and the optimal testing strategy is only evolving. This study evaluates the frequency, distribution, and pathologic correlates of somatic DNA damage repair mutations in metastatic and localized PCa following the implementation of pathologist-driven reflex testing at diagnosis. A cohort of 516 PCa samples were sequenced using a custom next-generation sequencing panel including homologous recombination repair and mismatch repair genes. Variants were classified based on the Association for Molecular Pathology/American Society of Clinical Oncology/College of American Pathologists guidelines. In total, 183 (35.5%) patients had at least one variant, which is as follows: 72 of 516 (13.9%) patients had at least 1 tier I or tier II variant, whereas 111 of 516 (21.5%) patients had a tier III variant. Tier I/II variant(s) were identified in 27% (12/44) of metastatic biopsy samples and 13% (61/472) of primary samples. Overall, 12% (62/516) of patients had at least 1 tier I/II variant in a homologous recombination repair gene, whereas 2.9% (10/516) had at least 1 tier I/II variant in a mismatch repair gene. The presence of a tier I/II variant was not significantly associated with the grade group (GG) or presence of intraductal/cribriform carcinoma in the primary tumor. Among the 309 reflex-tested hormone-naive primary tumors, tier I/II variants were identified in 10% (31/309) of cases, which is as follows: 9.2% (9/98) GG2; 9% (9/100) GG3; 9.1% (4/44) GG4; and 13.4% (9/67) GG5 cases. Our findings confirm the use of somatic tumor testing in detecting variants of clinical significance in PCa and provide insights that can inform the design of testing strategies. Pathologist-initiated reflex testing streamlines the availability of the results for clinical decision-making; however, pathologic parameters such as GG and the presence of intraductal/cribriform carcinoma may not be reliable to guide patient selection.

Intraductal Prostate Cancer Affinity for Lymphatic-Predominant Metastases Through 18F-DCFPyL‒Prostate-Specific Membrane Antigen‒Positron Emission Tomography/CT Scans in Pretreatment Prostate Cancer Patients.

PURPOSE: Intraductal prostate cancer (IDC) is linked to unfavorable oncologic outcomes, marked by distinctive cellular intrinsic pathway changes and intricate immunosuppressive microenvironments that could impact the way cancer spreads. The aim of this study was to determine whether the presence of IDC in prostate biopsy specimens obtained from patients before primary prostate cancer (PCa) treatment is associated with a lymph node metastatic propensity in prostate-specific membrane antigen (PSMA)‒positron emission tomography (PET)/CT. MATERIALS AND METHODS: This was a cross-sectional analysis of all PCa patients undergoing a pretreatment 18F-DCFPyL-PSMA-PET/CT between January 1, 2016, and August 2021 at The Princess Margaret Cancer Centre. Outcomes were presence of any metastasis in the overall cohort, presence of lymphatic vs no metastases, and presence of lymphatic vs bone metastasis among patients who underwent PSMA-PET/CT as PCa primary staging. The associations between IDC presence on the prostate biopsy and the study outcomes were evaluated using univariable and multivariable logistic regression analyses. RESULTS: The cohort consisted of 120 patients. IDC and cribriform pattern were observed in 55 (46%) and 48 (40%) prostate biopsies, respectively. Overall, 52 patients (43%) had evidence of metastasis. Presence of IDC on biopsy was associated with increased odds of overall metastasis (odds ratio: 2.47, 95% CI: 1.09-5.61, P = .03). Of the 52 patients with evidence of metastasis, 41 (79%) had evidence of lymphatic metastasis. Presence of IDC on biopsy was associated with significantly increased odds of lymphatic metastasis vs nonmetastases (odds ratio: 3.03, 95% CI: 1.24-7.40, P = .01). CONCLUSIONS: The identification of IDC morphology in prostate biopsy specimens has been observed to be significantly linked with lymph node metastasis on 18F-DCFPyL-PET/CT imaging in a PCa pretreatment staging setting. We found that presence of IDC in prostate biopsy appears to be a marker for lymph node metastasis on 18F-DCFPyL-PET/CT.

Head-to-head: how many categories for grading urothelial carcinoma?

Tumour grade is a critical prognostic parameter for guiding the management of patients with non-muscle invasive bladder cancer. In 2004, the World Health Organisation (WHO) adopted a binary (low-grade/high-grade) grading system to replace the three-tier (grades 1-3) system used to grade urothelial carcinoma since 1973. However, there is significant global variation in the grading of urothelial carcinoma. Some pathology and clinical guidelines recommend reporting of the WHO 1973 and 2004 grades in parallel, while others require reporting only of the WHO 2004 grade. This variation in pathology practice is clinically significant, because the two grading systems are not readily translatable. Some experts have proposed novel systems for grading urothelial carcinoma that involve splitting of the WHO 1973 and 2004 grade categories. The arguments for and against splitting urothelial carcinomas into two-, three- and four-grade categories are independently discussed by the three authors.

Oral pimonidazole unveils clinicopathologic and epigenetic features of hypoxic tumour aggressiveness in localized prostate cancer.

BACKGROUND: Tumor hypoxia is associated with prostate cancer (PCa) treatment resistance and poor prognosis. Pimonidazole (PIMO) is an investigational hypoxia probe used in clinical trials. A better understanding of the clinical significance and molecular alterations underpinning PIMO-labeled tumor hypoxia is needed for future clinical application. Here, we investigated the clinical significance and molecular alterations underpinning PIMO-labeled tumor hypoxia in patients with localized PCa, in order to apply PIMO as a prognostic tool and to identify potential biomarkers for future clinical translation. METHODS: A total of 39 patients with localized PCa were recruited and administered oral PIMO before undergoing radical prostatectomy (RadP). Immunohistochemical staining for PIMO was performed on 37 prostatectomy specimens with staining patterns evaluated and clinical association analyzed. Whole genome bisulfite sequencing was performed using laser-capture of microdissected specimen sections comparing PIMO positive and negative tumor areas. A hypoxia related methylation molecular signature was generated by integrating the differentially methylated regions with previously established RNA-seq datasets. RESULTS: Three PIMO staining patterns were distinguished: diffuse, focal, and comedo-like. The comedo-like staining pattern was more commonly associated with adverse pathology. PIMO-defined hypoxia intensity was positively correlated with advanced pathologic stage, tumor invasion, and cribriform and intraductal carcinoma morphology. The generated DNA methylation signature was found to be a robust hypoxia biomarker, which could risk-stratify PCa patients across multiple clinical datasets, as well as be applicable in other cancer types. CONCLUSIONS: Oral PIMO unveiled clinicopathologic features of disease aggressiveness in localized PCa. The generated DNA methylation signature is a novel and robust hypoxia biomarker that has the potential for future clinical translation.

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.

Papillary renal neoplasm with reverse polarity is biologically and clinically distinct from eosinophilic papillary renal cell carcinoma.

Papillary renal neoplasm with reverse polarity (PRNRP) is a recently described indolent entity with distinct features and its recognition from other oncocytic/eosinophilic papillary renal cell carcinoma (ePRCC) has important prognostic implications. ABCC2, a renal drug transporter, is overexpressed in aggressive PRCCs. In this study, we compared the clinicopathological parameters and the biological ABCC2 expression between PRNRP and ePRCC. PRNRP (n = 8) and ePRCC (n = 21) cases were selected from resection specimens and corresponding clinicopathological data were collected. ABCC2 immunohistochemical (IHC) staining was performed and ABCC2 staining patterns were classified as negative, cytoplasmic, and brush-border. RNA in-situ hybridization (ISH) was used to assess ABCC2 transcript levels. All eight PRNRP cases had weak cytoplasmic ABCC2 IHC reactivity; however, they showed no detectable ABCC2 transcripts on RNA ISH. In comparison, 76% (16/21) of ePRCCs showed ABCC2 IHC brush-border expression and significantly higher ABCC2 RNA ISH transcript levels (p < 0.001). Additionally, the ePRCC group showed a significantly larger tumor size (p = 0.004), higher WHO/ISUP grade (p < 0.001), and stage (p = 0.044). None of the PRNRP cases showed disease progression, while 9.5% (2/21) ePRCCs had disease progression. PRNRP is clinically and biologically distinct from ePRCC. Hence, it is crucial to differentiate between these two entities, particularly in needle core biopsies.

Prostate Cancer Screening With PSA, Kallikrein Panel, and MRI: The ProScreen Randomized Trial.

Importance: Prostate-specific antigen (PSA) screening has potential to reduce prostate cancer mortality but frequently detects prostate cancer that is not clinically important. Objective: To describe rates of low-grade (grade group 1) and high-grade (grade groups 2-5) prostate cancer identified among men invited to participate in a prostate cancer screening protocol consisting of a PSA test, a 4-kallikrein panel, and a magnetic resonance imaging (MRI) scan. Design, Setting, and Participants: The ProScreen trial is a clinical trial conducted in Helsinki and Tampere, Finland, that randomized 61 193 men aged 50 through 63 years who were free of prostate cancer in a 1:3 ratio to either be invited or not be invited to undergo screening for prostate cancer between February 2018 and July 2020. Interventions: Participating men randomized to the intervention underwent PSA testing. Those with a PSA level of 3.0 ng/mL or higher underwent additional testing for high-grade prostate cancer with a 4-kallikrein panel risk score. Those with a kallikrein panel score of 7.5% or higher underwent an MRI of the prostate gland, followed by targeted biopsies for those with abnormal prostate gland MRI findings. Final data collection occurred through June 31, 2023. Main Outcomes and Measures: In descriptive exploratory analyses, the cumulative incidence of low-grade and high-grade prostate cancer after the first screening round were compared between the group invited to undergo prostate cancer screening and the control group. Results: Of 60 745 eligible men (mean [SD] age, 57.2 [4.0] years), 15 201 were randomized to be invited and 45 544 were randomized not to be invited to undergo prostate cancer screening. Of 15 201 eligible males invited to undergo screening, 7744 (51%) participated. Among them, 32 low-grade prostate cancers (cumulative incidence, 0.41%) and 128 high-grade prostate cancers (cumulative incidence, 1.65%) were detected, with 1 cancer grade group result missing. Among the 7457 invited men (49%) who refused participation, 7 low-grade prostate cancers (cumulative incidence, 0.1%) and 44 high-grade prostate cancers (cumulative incidence, 0.6%) were detected, with 7 cancer grade groups missing. For the entire invited screening group, 39 low-grade prostate cancers (cumulative incidence, 0.26%) and 172 high-grade prostate cancers (cumulative incidence, 1.13%) were detected. During a median follow-up of 3.2 years, in the group not invited to undergo screening, 65 low-grade prostate cancers (cumulative incidence, 0.14%) and 282 high-grade prostate cancers (cumulative incidence, 0.62%) were detected. The risk difference for the entire group randomized to the screening invitation vs the control group was 0.11% (95% CI, 0.03%-0.20%) for low-grade and 0.51% (95% CI, 0.33%-0.70%) for high-grade cancer. Conclusions and Relevance: In this preliminary descriptive report from an ongoing randomized clinical trial, 1 additional high-grade cancer per 196 men and 1 low-grade cancer per 909 men were detected among those randomized to be invited to undergo a single prostate cancer screening intervention compared with those not invited to undergo screening. These preliminary findings from a single round of screening should be interpreted cautiously, pending results of the study's primary mortality outcome. Trial Registration: ClinicalTrials.gov Identifier: NCT03423303.

Quantitative Nuclear Grading: An Objective, Artificial Intelligence-Facilitated Foundation for Grading Noninvasive Papillary Urothelial Carcinoma.

In nonmuscle invasive bladder cancer, grade drives important treatment and management decisions. However, grading is complex and qualitative, and it has considerable interobserver and intraobserver variability. Previous literature showed that nuclear features quantitatively differ between bladder cancer grades, but these studies were limited in size and scope. In this study, we aimed to measure morphometric features relevant to grading criteria and build simplified classification models that objectively distinguish between the grades of noninvasive papillary urothelial carcinoma (NPUC). We analyzed 516 low-grade and 125 high-grade 1.0-mm diameter image samples from a cohort of 371 NPUC cases. All images underwent World Health Organization/International Society of Urological Pathology 2004 consensus pathologist grading at our institution that was subsequently validated by expert genitourinary pathologists from 2 additional institutions. Automated software segmented the tissue regions and measured the nuclear features of size, shape, and mitotic rate for millions of nuclei. Then, we analyzed differences between grades and constructed classification models, which had accuracies up to 88% and areas under the curve as high as 0.94. Variation in the nuclear area was the best univariate discriminator and was prioritized, along with the mitotic index, in the top-performing classifiers. Adding shape-related variables improved accuracy further. These findings indicate that nuclear morphometry and automated mitotic figure counts can be used to objectively differentiate between grades of NPUC. Future efforts will adapt the workflow to whole slides and tune grading thresholds to best reflect time to recurrence and progression. Defining these essential quantitative elements of grading has the potential to revolutionize pathologic assessment and provide a starting point from which to improve the prognostic utility of grade.

ABCC2 brush-border expression predicts outcome in papillary renal cell carcinoma: a multi-institutional study of 254 cases.

AIMS: Papillary renal cell carcinoma (PRCC) histologic subtyping is no longer recommended in the 2022 WHO classification. Currently, WHO/ISUP nucleolar grade is the only accepted prognostic histologic parameter for PRCC. ABCC2, a renal drug transporter, has been shown to significantly predict outcomes in PRCC. In this study we evaluated the prognostic significance of ABCC2 IHC staining patterns in a large, multi-institutional PRCC cohort and assessed the association of these patterns with ABCC2 mRNA expression. METHODS AND RESULTS: We assessed 254 PRCCs for ABCC2 IHC reactivity patterns that were stratified into negative, cytoplasmic, brush-border <50%, and brush-border ≥50%. RNA in situ hybridization (ISH) was used to determine the transcript level of each group. Survival analysis was performed with SPSS and GraphPad software. RNA-ISH showed that the ABCC2 group with any brush-border staining was associated with a significant increase in the transcript level, when compared to the negative/cytoplasmic group (P = 0.034). Both ABCC2 groups with brush-border <50% (P = 0.024) and brush-border ≥50% (P < 0.001) were also associated with worse disease-free survival (DFS) in univariate analysis. Multivariate analysis showed that only ABCC2 IHC brush-border (<50% and ≥50%) reactivity groups (P = 0.037 and P = 0.003, respectively), and high-stage disease (P < 0.001) had a DFS of prognostic significance. In addition, ABCC2 brush-border showed significantly worse DFS in pT1a (P = 0.014), pT1 (P = 0.013), ≤4 cm tumour (P = 0.041) and high stage (P = 0.014) groups, while a similar analysis with high WHO/ISUP grade in these groups was not significant. CONCLUSION: ABCC2 IHC brush-border expression in PRCC correlates with significantly higher gene expression and also independently predicts survival outcomes.

The role of [18F]-DCFPyL PET/MRI radiomics for pathological grade group prediction in prostate cancer.

PURPOSE: To evaluate the diagnostic accuracy of [18F]-DCFPyL PET/MRI radiomics for the prediction of pathological grade group in prostate cancer (PCa) in therapy-naïve patients. METHODS: Patients with confirmed or suspected PCa, who underwent [18F]-DCFPyL PET/MRI (n = 105), were included in this retrospective analysis of two prospective clinical trials. Radiomic features were extracted from the segmented volumes following the image biomarker standardization initiative (IBSI) guidelines. Histopathology obtained from systematic and targeted biopsies of the PET/MRI-detected lesions was the reference standard. Histopathology patterns were dichotomized as ISUP GG 1-2 vs. ISUP GG ≥ 3 categories. Different single-modality models were defined for feature extraction, including PET- and MRI-derived radiomic features. The clinical model included age, PSA, and lesions' PROMISE classification. Single models, as well as different combinations of them, were generated to calculate their performances. A cross-validation approach was used to evaluate the internal validity of the models. RESULTS: All radiomic models outperformed the clinical models. The best model for grade group prediction was the combination of PET + ADC + T2w radiomic features, showing sensitivity, specificity, accuracy, and AUC of 0.85, 0.83, 0.84, and 0.85, respectively. The MRI-derived (ADC + T2w) features showed sensitivity, specificity, accuracy, and AUC of 0.88, 0.78, 0.83, and 0.84, respectively. PET-derived features showed 0.83, 0.68, 0.76, and 0.79, respectively. The baseline clinical model showed 0.73, 0.44, 0.60, and 0.58, respectively. The addition of the clinical model to the best radiomic model did not improve the diagnostic performance. The performances of MRI and PET/MRI radiomic models as per the cross-validation scheme yielded an accuracy of 0.80 (AUC = 0.79), whereas clinical models presented an accuracy of 0.60 (AUC = 0.60). CONCLUSION: The combined [18F]-DCFPyL PET/MRI radiomic model was the best-performing model and outperformed the clinical model for pathological grade group prediction, indicating a complementary value of the hybrid PET/MRI model for non-invasive risk stratification of PCa. Further prospective studies are required to confirm the reproducibility and clinical utility of this approach.

Renaming Grade Group 1 Prostate "Cancer" From a Pathology Perspective: A Call for Multidisciplinary Discussion.

Despite the innovations made to enhance smarter screening and conservative management for low-grade prostate cancer, overdiagnosis, and overtreatment remains a major health care problem. Driven by the primary goal of reducing harm to the patients, relabeling of nonlethal grade group 1 (GG 1) prostate cancer has been proposed but faced varying degrees of support and objection from clinicians and pathologists. GG 1 tumor exhibits histologic (invasive) and molecular features of cancer but paradoxically, if pure, is unable to metastasize, rarely extends out of the prostate, and if resected, has a cancer-specific survival approaching 100%. Most of the arguments against relabeling GG 1 relate to concerns of missing a higher-grade component through the unsampled area at biopsy. However, the designation of tumor benignity or malignancy should not be based on the shortcomings of a diagnostic procedure and sampling errors. This review explores possible solutions, mainly the feasibility of renaming GG 1 in radical prostatectomy (RP) with ramifications in biopsy diagnosis, acceptable for both pathologists and clinicians. One workable approach is to rename GG 1 in RP with a cautious neutral or nonbenign non-cancer term (eg, acinar neoplasm) using "defined criteria" that will stop the indiscriminate reporting of every GG 1 in biopsy as carcinoma including eventual insignificant microtumors in RPs. Use of a corresponding noncommittal term at biopsy while commenting on the possibility of an undersampled nonindolent cancer, might reduce the pathologist's concerns about upgrading. Dropping the word "carcinoma" in biopsy preempts the negative consequences of labeling the patient with cancer, including unnecessary definitive therapy (the root cause of overtreatment). Renaming should retain the status quo of contemporary grading and risk stratifications for management algorithms while trying to minimize overtreatment. However, the optimal approach to find answers to this issue is through multidisciplinary discussions of key stakeholders with a specific focus on patient-centered concerns and their ramifications in our practices. GG 1 renaming has been brought up in the past and came up again despite the continued counterarguments, and if not addressed more comprehensively will likely continue to reemerge as overdiagnosis, overtreatment, and patient's sufferings persist.

Predicting the recurrence risk of renal cell carcinoma after nephrectomy: potential role of CT-radiomics for adjuvant treatment decisions.

OBJECTIVES: Previous trial results suggest that only a small number of patients with non-metastatic renal cell carcinoma (RCC) benefit from adjuvant therapy. We assessed whether the addition of CT-based radiomics to established clinico-pathological biomarkers improves recurrence risk prediction for adjuvant treatment decisions. METHODS: This retrospective study included 453 patients with non-metastatic RCC undergoing nephrectomy. Cox models were trained to predict disease-free survival (DFS) using post-operative biomarkers (age, stage, tumor size and grade) with and without radiomics selected on pre-operative CT. Models were assessed using C-statistic, calibration, and decision curve analyses (repeated tenfold cross-validation). RESULTS: At multivariable analysis, one of four selected radiomic features (wavelet-HHL_glcm_ClusterShade) was prognostic for DFS with an adjusted hazard ratio (HR) of 0.44 (p = 0.02), along with American Joint Committee on Cancer (AJCC) stage group (III versus I, HR 2.90; p = 0.002), grade 4 (versus grade 1, HR 8.90; p = 0.001), age (per 10 years HR 1.29; p = 0.03), and tumor size (per cm HR 1.13; p = 0.003). The discriminatory ability of the combined clinical-radiomic model (C = 0.80) was superior to that of the clinical model (C = 0.78; p < 0.001). Decision curve analysis revealed a net benefit of the combined model when used for adjuvant treatment decisions. At an exemplary threshold probability of ≥ 25% for disease recurrence within 5 years, using the combined versus the clinical model was equivalent to treating 9 additional patients (per 1000 assessed) who would recur without treatment (i.e., true-positive predictions) with no increase in false-positive predictions. CONCLUSION: Adding CT-based radiomic features to established prognostic biomarkers improved post-operative recurrence risk assessment in our internal validation study and may help guide decisions regarding adjuvant therapy. KEY POINTS: In patients with non-metastatic renal cell carcinoma undergoing nephrectomy, CT-based radiomics combined with established clinical and pathological biomarkers improved recurrence risk assessment. Compared to a clinical base model, the combined risk model enabled superior clinical utility if used to guide decisions on adjuvant treatment.

Prevalence of adverse pathology features in grade group 2 prostatectomy specimens with syn- or metachronous metastatic disease.

BACKGROUND: To validate the importance of recently established adverse histopathology features (cribriform pattern and intraductal carcinoma) as contra-indication for deferred treatment of Gleason score 7 (3 + 4) (grade group [GG] 2) prostate cancer, we investigated their frequency in GG2 radical prostatectomies with syn- or metachronous metastatic disease. METHODS: GG2 prostatectomy specimens of patients with concomitant lymph node metastasis or distant metastasis at follow-up were identified in a clinical database of a tertiary care center and their pathology was reviewed for pathological stage, lymphovascular invasion, Gleason grade 4 subpatterns, presence of tertiary grade 5, and ductal adenocarcinoma histology. A control group of 99 GG2 prostatectomy specimens who had no metastatic disease (controls) was reviewed for the same adverse pathological features. RESULTS: Of 1860 GG2 prostatectomy specimens (operated between 2002 and 2020), 45 (2.4%) had concurrent regional lymph node metastases or distant metastases at follow-up. Pathological stage distribution of cases and controls was 24% and 79% pT2, 42% and 15% pT3a, 33% and 6.1% pT3b -T4, respectively (p < 0.001). Eleven of 45 cases (24%) had ≤10% Gleason grade 4 component. Cribriform pattern or intraductal carcinoma was present in 84% of cases versus 34% of controls (p < 0.001), tertiary grade 5 in 16% of cases versus 5% controls (p = 0.05) and ductal adenocarcinoma in 16% of cases versus 2% of controls (p = 0.004). Among the seven cases without cribriform or intraductal carcinoma, two displayed ductal adenocarcinoma features. CONCLUSIONS: Well-established unfavorable histopathologic features (intraductal and cribriform pattern carcinoma, ductal adenocarcinoma) are represented in about 90% of GG2 prostate cancers with local or distant metastatic disease and are much less common (38%) in those without metastatic disease. Strikingly, about 25% of GG2 prostatectomy cases with metastatic disease had an organ-confined disease and/or a small percentage of Gleason grade 4 pattern. This further emphasizes the relative importance of these adverse histopathological features (cribriform, intraductal, and ductal adenocarcinoma) rather than percentage Gleason grade 4 as contra-indicator of deferred treatment for patients with GG2 prostate cancer.

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.

Factors Associated with Re-Resection in T1 Bladder Cancer: Identifying Patients Who Do Not Receive Guideline-Concordant Care at the Population Level.

PURPOSE: Prior research has shown that concordance with the guideline-endorsed recommendation to re-resect patients diagnosed with primary T1 bladder cancer (BC) is suboptimal. Therefore, the aim of this population-based study was to identify factors associated with re-resection in T1 BC. MATERIALS AND METHODS: We linked province-wide BC pathology reports (January 2001 to December 2015) with health administrative data sources to derive an incident cohort of patients diagnosed with T1 BC in the province of Ontario, Canada. Re-resection was ascertained by a billing claim for transurethral resection within 2 to 8 weeks after the initial resection, accounting for system-related wait times. Multivariable logistic regression analysis accounting for the clustered nature of the data was used to identify various patient-level and surgeon-level factors associated with re-resection. P values <0.05 were considered statistically significant (2-sided). RESULTS: We identified 7,373 patients who fulfilled the inclusion criteria. Overall, 1,678 patients (23%) underwent re-resection. Patients with a more aggressive tumor profile and individuals without sufficiently sampled muscularis propria as well as younger, healthier and socioeconomically advantaged patients were more likely to receive re-resection (all p <0.05). In addition, more senior, lower volume and male surgeons were less likely to perform re-resection for their patients (all p <0.05). CONCLUSIONS: Only a minority of all patients received re-resection within 2 to 8 weeks after initial resection. To improve the access to care for potentially underserved patients, we suggest specific knowledge translation/exchange interventions that also include equity aspects besides further promotion of evidence-based instead of eminence-based medicine.