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Adenoid cystic carcinomas (AdCC) of salivary gland origin have long been categorized as fusion-defined carcinomas owing to the almost universal presence of the gene fusion MYB::NFIB, or less commonly MYBL1::NFIB. Sinonasal AdCC is an aggressive salivary gland malignancy with no effective systemic therapy. Therefore, it is urgent to search for potentially targetable genetic alterations associated with AdCC. We have searched the authors' registries and selected all AdCCs arising in the sinonasal tract. The tumors were examined histologically, immunohistochemically, by next generation sequencing (NGS) and/or fluorescence in situ hybridization (FISH) looking for MYB/MYBL1 and/or NFIB gene fusions or any novel gene fusions and/or mutations. In addition, all tumors were tested for HPV by genotyping using (q)PCR. Our cohort comprised 88 cases of sinonasal AdCC, predominantly characterized by canonical MYB::NFIB (49 cases) and MYBL1::NFIB (9 cases) fusions. In addition, noncanonical fusions EWSR1::MYB; ACTB::MYB; ESRRG::DNM3, and ACTN4::MYB were identified by NGS, each of them in 1 case. Among nine fusion-negative AdCCs, FISH detected rearrangements in MYB (7 cases), NFIB (1 case), and EWSR1 (1 case). Six AdCCs lacked fusions or gene rearrangements, while 11 cases were unanalyzable. Mutational analysis was performed by NGS in 31/88 (35%) AdCCs. Mutations in genes with established roles in oncogenesis were identified in 21/31 tumors (68%), including BCOR (4/21; 19%), NOTCH1 (3/21; 14%), EP300 (3/21; 14%), SMARCA4 (2/21; 9%), RUNX1 (2/21; 9%), KDM6A (2/21; 9%), SPEN (2/21; 9%), and RIT1, MGA, RB1, PHF6, PTEN, CREBBP, DDX41, CHD2, ROS1, TAF1, CCD1, NF1, PALB2, AVCR1B, ARID1A, PPM1D, LZTR1, GEN1, PDGFRA, each in 1 case (1/21; 5%). Additional 24 cases exhibited a spectrum of gene mutations of uncertain pathogenetic significance. No morphologic differences were observed between AdCCs with MYBL1::NFIB and MYB::NFIB fusions. Interestingly, mutations in the NOTCH genes were seen in connection with both canonical and noncanonical fusions, and often associated with high-grade histology or metatypical phenotype, as well as with poorer clinical outcome. Noncanonical fusions were predominantly observed in metatypical AdCCs. These findings emphasize the value of comprehensive molecular profiling in correlating morphologic characteristics, genetic landscape, and clinical behavior in AdCC., (Copyright © 2025 The Author(s). Published by Wolters Kluwer Health, Inc.)

The pathological assessment of cystectomy specimens is important for accurate prognostic information and to inform adjuvant therapy decisions. However, there is limited evidence regarding the best approach to fixation, dissection, block selection and microscopic assessment of cystectomies. We report the results of an international survey of 212 pathologists and their approach to cystectomy pathology. There is variation at all stages of the specimen journey including in fixation and dissection techniques, and in the approach to evaluating residual tumour. This is particularly evident in the post-neoadjuvant chemotherapy setting where there is variable use of response scoring systems and differing approaches to sampling. We also find variation in the use of digital and molecular pathology in cystectomy specimens. Finally, we have suggested areas for future research in cystectomy pathological assessment., Competing Interests: Declarations All participants gave informed consent to complete the questionnaire and the study received ethical approval from the University of Sheffield (UK) Ethics Committee on 24th July 2023 (approval number: 054611). Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background and Objective: Failure rates after first-line treatment of localized prostate cancer (PCa) treatment remain high; therefore, it is essential to improve the selection and identification of at-risk patients to reduce mortality. The aim of the ANDROCAN study was to evaluate the biochemical recurrence (BCR) in patients with localized PCa treated by total prostatectomy at 5 yr after surgery, according to their presurgery gonadal status., Methods: A prospective cohort study was conducted including 1318 patients undergoing total prostatectomy for localized PCa with a 5-yr postoperative follow-up. Clinical and hormonal data (assays of total testosterone [TT], bioavailable testosterone [BT], dihydrotestosterone, estrone, and estradiol were performed by gas chromatography/mass spectrometry) as well as metabolic syndrome parameters were collected at baseline before surgery. Pathological data (predominant Gleason grade 4 and stage) were collected and cross-referenced centrally. Factors associated with BCR were assessed by a multivariate analysis, and BCR-free survival was assessed by a Kaplan-Meier analysis., Key Findings and Limitations: Among the 1318 patients, 237 had BCR of PCa. Considering demographic characteristics, populations with and without BCR were similar. However, patients with BCR had cancers with a higher Gleason score (p = 0.0001) and higher prostate-specific antigen (PSA) values (p = 0.0005) at baseline. Gleason score, pT >3a, and PSA level at baseline were positively correlated with BCR (p < 0.0001, p < 0.0001, and p = 0.0048, respectively), while BT and TT levels were not associated with BCR. This study includes patients with varying clinical characteristics, such as cancer history and metabolic syndrome, introducing variability that makes it challenging to isolate the specific effects of gonadal status on BCR. Another limitation is the lack of evaluation of long-term BCR beyond 5 yr, potentially overlooking recurrences that occur between 5 and 15 yr after surgery. This could lead to an underestimation of the actual long-term recurrence rates., Conclusions and Clinical Implications: Overall, PSA levels, high Gleason score, and pT >3a are associated with a greater likelihood of disease recurrence following initial treatment and could serve as important prognostic indicators for predicting the risk of BCR. In this prospective study, biochemical hypogonadism was not associated with a higher occurrence of BCR within 5 yr of prostatectomy. The biological gonadal status of preoperative patients could potentially be useful for therapeutic decisions but does not provide an indication for the oncological follow-up., Patient Summary: Five-year follow up of patients after surgery showed that there is no association between hypogonadism (low levels of total testosterone and bioavailable testosterone) and cancer recurrence. However, cancer recurrence seems to be more associated with aggressiveness of cancer at the time of detection., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Sarcomatoid urothelial cancer of the bladder (SBC) is a rare, but aggressive histological subtype for which novel treatments are needed., Objective: We evaluated the clinical activity and safety of neoadjuvant cisplatin plus gemcitabine plus docetaxel (CGD) in muscle-invasive patients with SBC and assessed SBC tumor biology by whole transcriptome RNA sequencing., Methods: A single-institution, retrospective analysis of muscle-invasive SBC patients treated with neoadjuvant CGD with molecular analysis. Patients received cisplatin 35 mg/m2 + gemcitabine 800 mg/m2 + docetaxel 35 mg/m2 intravenously on days 1 and 8 + pegfilgrastim 6 mg subcutaneously on day 9 every 3 weeks for 4 cycles followed by cystectomy. The primary endpoint was pathologic complete response (ypCR) rate., Results: Sixteen patients with SBC received neoadjuvant CGD with a ypCR rate of 38% and a  < ypT2 rate of 50%. Grade 3 and 4 toxicity occurred in 80% and 40% of patients, but was manageable with 81% of patients completing > 3 CGD cycles. Whole transcriptome RNA sequencing demonstrates co-clustering of SBC with conventional urothelial tumors. SBC tumors are characterized by basal-squamous and stroma rich gene signatures with frequent increased expression of immune checkpoint ( CD274 (PD-L1)), chemokine ( CXCL9 ), and T-cell ( CD8A ) genes., Conclusions: SBC is a chemosensitive subtype, with ypCR rate similar to urothelial bladder cancer following CGD neoadjuvant therapy. Whole transcriptome tissue analyses demonstrate increased expression of immune checkpoint and T-cell genes with therapeutic implications., Competing Interests: Noah Hahn discloses consulting compensation from AstraZeneca, Merck, BioGears, Seattle Genetics, Mirati, Incyte, RemGen, Janssen, Pfizer, EMD Serono, Verity Pharmaceuticals, Huron Consulting, Guidepoint, Natera, Protara Therapeutics, Astellas Pharma, Trya Biosciences; research support to the institution from HTG Molecular Diagnostics, AstraZeneca, Bristol Myers-Squibb, Genentech, Seattle Genetics, Pieris, Inovio, Principia Biopharm, Incyte, Loxo Oncology, and Ikena Oncology; speaking honorarium from Medscape. Max Kates discloses consulting compensation from Genesis Biotech, Janssen, Pacific Edge, and FerGene. Andres Matoso discloses consulting compensation from PathAI. Burles A. Johnson III discloses serving as an unpaid member of Seattle Genetics Emerging Thought Leaders Advisory Board. Burles A. Johnson III, Noah Hahn, Jean Hoffman-Censits, and David McConkey are co-authors on a provisional US patent for an immune-based biomarker to predict response to immunotherapy in patients with advanced bladder cancer. T.J.B., J.H-C., N.M.H., and D.J.M. are on the Editorial Board of this journal, but these individuals were not involved in the peer-review process nor had access to any information regarding its peer-review., (© 2024 – The authors. Published by IOS Press.)

Competing Interests: Disclosure TP reports personal fees for advisory board membership from Astellas, AstraZeneca, Bristol Myers Squibb (BMS), Eisai, Exelixis, Incyte, Ipsen, Johnson & Johnson, Merck, Merck Serono, MSD, Novartis, Pfizer, Roche and Seattle Genetics; personal travel grants from AstraZeneca, Ipsen, MSD, Pfizer and Roche; personal sponsorship for the Uromigos Podcast from Mashup Ltd; institutional honoraria from Gilead; and institutional research grants from Astellas, AstraZeneca, BMS, Eisai, Exelixis, Ipsen, Johnson & Johnson, Merck, Merck Serono, MSD, Novartis, Pfizer, Roche and Seattle Genetics. JB reports personal fees for advisory board membership from AstraZeneca (bladder cancer), BMS (adjuvant study CM 247), Merck (bladder cancer) and Pfizer (global); personal fees as an invited speaker from Merck (lectures in national meetings) and MSD (ESMO Asia Congress 2020); personal stocks/shares in Bicycle; personal royalties as Section Editor for bladder cancer from UpToDate; institutional fees as coordinating principal investigator (PI) of the INDUCOMAIN trial from MSD and of a prostate cancer study of avelumab plus carboplatin from Pfizer, both through the Asia Pacific Regional Office (APRO) Association; and non-renumerated membership of the IMvigor011 study Steering Committee (Genentech) and the American Society of Clinical Oncology (ASCO). EC reports personal fees as an invited speaker from Janssen; and a non-renumerated advisory role as a consulting pathologist for the European Association of Urology (EAU) guidelines for bladder cancer. MDS reports fees from 4D (personal for advisory board membership; personal and institutional for Steering Committee membership and an advisory function), AAA (personal for advisory board and Steering Committee memberships), Amgen (personal for advisory board and Steering Committee memberships and an advisory function), Astellas (personal for advisory board membership, an advisory function and as an invited speaker; personal and institutional for Steering Committee membership and an advisory function), AstraZeneca (personal for advisory board and Steering Committee memberships and as an invited speaker; personal and institutional as coordinating PI and for an advisory function), Basilea (personal for advisory board membership; personal and institutional for Steering Committee membership, an advisory function, clinical trials and as local PI), Bayer (personal for advisory board membership; personal and institutional for Steering Committee membership and an advisory function), Bioclin (personal for advisory board membership, advisory functions and as an invited speaker), BMS (personal for advisory board membership; personal and institutional for Steering Committee membership, an advisory function and travel grants), Calithera (institutional as local PI), Eisai (personal for advisory board membership; personal and institutional as local PI, for an advisory function and clinical trials), Ferring (personal for advisory board membership and an advisory function), Gilead (personal for advisory board membership; personal and institutional for Steering Committee membership), Immunomedics/Gilead (personal for advisory board membership; personal and institutional for Steering Committee membership, an advisory function and as local PI), Ipsen (personal for advisory board membership; personal and institutional for Steering Committee membership and an advisory function), Janssen (personal as an invited speaker; personal and institutional for Steering Committee membership and an advisory function), Merck/Serono (personal for advisory board membership; personal and institutional for Steering Committee membership and an advisory function), MSD (personal for advisory board membership and as an invited speaker; personal and institutional for Steering Committee membership, an advisory function, clinical trials and as local PI), Nektar (institutional for clinical trials and as local PI), Novartis/Sandoz (personal for advisory board membership; personal and institutional for Steering Committee membership and advisory function), Pierre Fabre (personal for advisory board membership and as an invited speaker personal and institutional for Steering Committee membership, an advisory function and as local and coordinating PI), Roche (personal for advisory board membership), Roche/Genentech (personal and institutional for Steering Committee membership and an advisory function), Sandoz (personal for Steering Committee membership and an advisory function), Sanofi (personal for advisory board membership; personal and institutional for Steering Committee membership and an advisory function), Seagen (personal for advisory board membership; personal and institutional for Steering Committee membership, an advisory function and as local PI); and non-renumerated membership of the EAU guidelines group for prostate cancer (writing and discussing guidelines for treatment and diagnostics), the ESMO CPGs author group for bladder cancer and the S3-Leitlinie Blasenkrebs (guidelines for the treatment of bladder cancer). RH reports personal fees for advisory board membership from Astellas, BioNTech, BMS, Merck, MSD, Nektar and Roche; personal fees as an invited speaker from Pfizer and Roche; personal fees for expert testimony from the National Institute of Clinical Excellence; personal and institutional fees for Steering Committee membership from Janssen and Nektar; personal fees for consultancy from Roche; personal fees for a limited liability partnership from the Cancer Centre London; institutional royalties from Janssen; institutional fees as a local PI from Astellas, Basilea, Bicycle, Gilead, Janssen, MSD, Nektar and Roche; institutional fees as a coordinating PI from Cancer Research UK (CRUK); institutional research grants from MSD and Roche; non-renumerated roles as chief investigator or co-investigator on CRUK-funded studies; non-renumerated roles as educational secretary and trustee of the British Uro-oncology group; a non-renumerated role as chair of the NCRI Clinical and Translational Radiotherapy Research Working Group (CTRad); and non-renumerated membership of the consensus guideline group of the Royal College of Radiologists. YL reports personal fees for advisory board membership from Gilead, Merck KGaA, Pfizer, Seattle Genetics and Taiho; personal fees for advisory board membership and lectures from Astellas, AstraZeneca, BMS, Janssen, MSD and Roche; personal fees for Steering Committee membership from Basilea; institutional fees as a local PI from Astellas, AstraZeneca, BMS, Exelixis, Gilead, Incyte, Janssen, Merck KGaA, MSD and Pfizer; institutional fees for Steering Committee membership and as a coordinating PI from Janssen; institutional research grants from Celsius, Janssen, MSD, Roche and Sanofi; Steering Committee membership for Astellas, Gilead/Immunomedics, MSD and Taiho; and non-renumerated memberships of the American Association for Cancer Research (AACR), the Scientific Committee of Fondation ARC, ASCO and ESMO. AN reports personal fees for Steering Committee membership from Astellas, AstraZeneca, Bayer, Clovis Oncology, Janssen, Merck and Roche; institutional research grants from AstraZeneca, BMS, Gilead, Ipsen and Merck; a role as coordinating PI for Incyte; a role as local PI for Pfizer; and a non-renumerated leadership role for the Global Society of Rare Genitourinary Tumors (GSRGT). BPV reports personal fees for advisory board membership from AAA, Astellas Pharma, AstraZeneca, BMS, EUSA Pharma, Ipsen, Merck, MSD, Pfizer and Recordati; personal fees as an invited speaker from AAA, Almirall Pharma, Astellas Pharma, Bayer, BMS, Merck, MSD and Pfizer; and travel grants from BMS and Pfizer. AR reports personal fees for advisory board membership from AstraZeneca, BMS, Ipsen, Merck GA and Pfizer; institutional research grants from Ipsen, Merck GA and Pfizer; institutional fees as local PI from AstraZeneca, BMS, Ipsen, Merck GA and Pfizer; travel grants/accommodation compensation for meetings/conferences from BMS, Ipsen, Merck GA and Pfizer; and a non-renumerated role as affiliate of ASCO. SFS reports personal fees for advisory board membership from Astellas, AstraZeneca, Bayer, BMS, Cepheid, Ferring, Ipsen, Janssen, Lilly, MSD, Olympus, Pfizer, Pierre Fabre, Richard Wolf, Roche, Sanochemia, Sanofi, Takeda and UroGen. BS reports personal fees for advisory board membership from Merck KGaA; personal fees as an invited speaker from MSD and Pfizer; personal fees for expert testimony from Ellipses and Ipsen; and personal travel grants from Photocure and Roche/Genentech. MSvdH reports institutional fees for advisory board membership from AstraZeneca, BMS, Janssen, MSD, Pfizer and Seagen; institutional funding for investigator-initiated trials from 4SC, AstraZeneca, BMS and Roche; institutional fees for Steering Committee membership and as local PI from AstraZeneca, BMS, MSD and Seagen; and institutional fees as local and study co-PI from Janssen. SG reports personal fees as an invited speaker for DESO, ESMO, Meister ConCept GmbH and the Swiss Group for Clinical Cancer Research (SAKK); personal travel grants from AstraZeneca, Bayer, Gilead and Intellisphere LLC; a patent for a biomarker of Proteomedix/Onconetix; institutional fees for advisory board membership from Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Daiichi Sankyo, Innomedica, Ipsen, Macrogenics, MSD Merck Sharp & Dohme, Myriad Genetics and Orion; institutional fees as an invited speaker for AdMeTech Foundation, ASCO GU, EPG Health, ESMO, Intellisphere LLC, Meister ConCept GmbH, S. Grasso Consulting, SAKK and Silvio Grasso Consulting; institutional funding as a co-investigator from Astellas; other institutional fees from PeerVoice (interview), Pfizer (Scientific Committee Pfizer Forschungspreis), TOLREMO (consulting) and WebMD-Medscape (faculty activity); and a non-remunerated advisory role for ProteoMediX.

Background: Visceral metastases are known to occur in advanced prostate cancer, usually when the tumour is resistant to androgen deprivation and, have worse outcomes regardless of therapies., Objective: To analyse genomic alterations in tumour samples according to their lymphatic, bone, and visceral metastatic stages and overall survival., Design, Setting, and Participants: We selected 200 patients with metastatic prostate cancer. Genomic profiling of 111 genes and molecular signatures (homologous recombination deficiency [HRD], microsatellite instability, and tumour burden mutation) was performed with the MyChoice test (Myriad Genetics, Inc, Salt Lake City, UT, USA)., Outcome Measurements and Statistical Analysis: The association between genomic profiles and visceral metastatic evolution was evaluated using logistic regression. Kaplan-Meier and Cox proportional hazard analyses were used for analyses of early death., Results and Limitations: A total of 173 (87%) genomic profiles were obtained. Eighty-four (49%) patients died during the follow-up period (median duration = 76 mo). TP53 was the most frequently mutated gene, followed by FANC genes, including BRCA2, and those of the Wnt-pathway (APC/CTNNB1). TP53 gene mutations were more frequent in patients of European (42%) than in those of African (16%) ancestry. An HRD score of >25 was predictive of FANC gene mutations. The mutational status of TP53 (p < 0.001) and APC (p = 0.002) genes were significantly associated with the risk of visceral metastases. The mutational status of CTNNB1 (p = 0.001), TP53 (p = 0.015), BRCA2 (p = 0.027), and FANC (p = 0.005) genes were significantly associated with an earlier age at death. The limitations are the retrospective study design based on a selection of genes and the low frequency of certain molecular events., Conclusions: Mutations in the TP53 gene and genes (APC/CTNNB1) related to the Wnt pathway are associated with metastatic visceral dissemination and early death. These genomic alterations could be considered as markers to identify prostate cancer patients at a high risk of life-threatening disease who might benefit from more intensified treatment or new targeted therapies., Patient Summary: In this report, we evaluated the relationships between genomic profiles (gene mutations and molecular signatures) of tumour samples from patients with metastatic prostate cancer and early death. We found that mutations of specific genes, notably TP53 and APC/CTNNB1 related to the Wnt pathway, are associated with visceral metastatic progression and an earlier age at death., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Fasciitis ossificans is a rare subtype of nodular fasciitis, a benign soft tissue tumor with reactive characteristics. Due to its rapid growth, it is often misdiagnosed as a malignant tumor. While fasciitis ossificans commonly originates from the subcutaneous tissue and can appear throughout the body, it may also arise from extraordinary sites., Case Presentation: We report the first-ever documented case of fasciitis ossificans arising from the penis in a male patient who presented with a tumor on the glans penis. The tumor was surgically resected due to suspicion of penile cancer. Initial histopathological analysis led to a misdiagnosis of squamous cell carcinoma. However, pathological consultation ultimately confirmed the diagnosis of fasciitis ossificans of the penis originating from the glans penis by demonstrating ossification., Conclusion: This case underscores the importance of considering fasciitis ossificans in the differential diagnosis of soft tissue tumors, even in unusual locations such as penile soft tissue., (© 2024. The Author(s).)

Background: Depending on the risk of LN metastasis ePLND at RP is recommended. As ePLND has potential side effects, and diagnostics have improved substantially, our objective was to evaluate the performance of the Briganti 2019 nomogram in a contemporary cohort with preoperative negative PSMA-PET., Methods: Patients with intermediate- and high-risk prostate cancer (CaP), undergoing RP and ePND at our center with preoperative negative [ 68 Ga]Ga-PSMA-11 PET were included. The Accuracy of the nomogram was assessed using ROC analysis. The association of clinical parameters with the presence of LN metastasis was assessed using logistic regression. Specimen of prostate and LNs in patients with false negative PSMA-PET were additionally stained for AR and PSMA expression and assessed by IHC., Results: The study included 108 patients, 28% intermediate- and 72% high-risk. Twelve patients harbored occult LN metastasis. Accuracy of the nomogram was 0.62. [ 68 Ga]Ga-PSMA-11 PET showed a NPV of 89%. IHC showed expression of PSMA and AR in the primary and LN metastasis in all patients. On logistic regression analysis only DRE (OR 2.72; 95%CI 1.01-7.35; P = 0.05) and percentage of cores with significant CaP (OR 1.29; 95%CI 1.05-1.60; P = 0.02) showed a significant association with LN metastasis., Conclusion: The currently used nomogram is suboptimal in detecting patients with occult LNM. While the cut-off value to perform ePLND can be increased slightly following a negative PSMA-PET scan, more accurate methods of identifying these patients are needed. Whether ePLND can have a therapeutic benefit, as opposed to a diagnostic only, needs to be re-evaluated in the PSMA-PET era., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Diagnostic work-up and risk stratification in patients with bladder cancer before and after treatment must be refined to optimize management and improve outcomes. MRI has been suggested as a non-invasive technique for bladder cancer staging and assessment of response to systemic therapy. The Vesical Imaging-Reporting And Data System (VI-RADS) was developed to standardize bladder MRI image acquisition, interpretation and reporting and enables accurate prediction of muscle-wall invasion of bladder cancer. MRI is available in many centres but is not yet recommended as a first-line test for bladder cancer owing to a lack of high-quality evidence. Consensus-based evidence on the use of MRI-VI-RADS for bladder cancer care is needed to serve as a benchmark for formulating guidelines and research agendas until further evidence from randomized trials becomes available., (© 2023. Springer Nature Limited.)

Urothelial carcinoma in situ (CIS) is an aggressive phenotype of non-muscle-invasive bladder cancer. Molecular features unique to CIS compared to high-grade papillary tumors are underexplored. RNA sequencing of CIS, papillary tumors, and normal urothelium showed lower immune marker expression in CIS compared to papillary tumors. We identified a 46-gene expression signature in CIS samples including selectively upregulated known druggable targets MTOR , TYK2 , AXIN1 , CPT1B , GAK , and PIEZO1 and selectively downregulated BRD2 and NDUFB2 . High expression of selected genes was significantly associated with CIS in an independent dataset. Mutation analysis of matched CIS and papillary tumors revealed shared mutations between samples across time points and mutational heterogeneity. CCDC138 was the most frequently mutated gene in CIS. The immunological landscape showed higher levels of PD-1-positive cells in CIS lesions compared to papillary tumors. We identified CIS lesions to have distinct characteristics compared to papillary tumors potentially contributing to the aggressive phenotype., Competing Interests: L.D. has sponsored research agreements with C2i Genomics, Natera, AstraZeneca, Photocure, and Ferring and has an advisory/consulting role at Ferring, MSD, and UroGen. L.D. has received speaker honoraria from AstraZeneca, Pfizer, and Roche and received travel support from MSD. L.D. is a board member at BioXpedia. S.P.L. has funding for clinical trials from Aura Bioscience, FKD, JBL (SWOG), Genentech (SWOG), Merck (Alliance), QED Therapeutics, Surge Therapeutics, Vaxiion, and Viventia; is a consultant/Advisory Board member for Aura Bioscience, BMS, Pfizer/EMD Serono, Protara, Surge Therapeutics, Vaxiion, and Verity; has a patent for the TCGA classifier; and received honoraria from Grand Rounds Urology and UroToday. J.B.J. is a member of Advisory Boards at Ferring, Roche, Cepheid, Urotech, Olympus, AMBU, Janssen, and Cystotech; is a speaker at medac, Olympus, Intuitive Surgery, and Photocure ASA; and has research collaborations with Medac, Photocure ASA, Roche, Ferring, Olympus, Intuitive Surgery, Astellas, Cepheid, Nucleix, Urotech, Pfizer, AstraZenica, MeqNordic, Laborie, VingMed, AMBU, and Cystotech. H.A.-A. provides consultation to AstaZeneca and Paige.AI. B.I. runs clinical trials or scientific studies in collaboration with FKD Therapies, Taris Biomedical, CG Oncology, Genentech Inc, Janssen, Medtronic, and Profound Medical and has consultant or advisory roles at Seattle Genetics, Combat Medical, and Johnson & Johnson., (© 2024 The Authors.)

Background: A growing number of centers worldwide are preserving testicular tissue (TT) of young boys at risk of fertility loss to preserve their fertility. Data in this regard are scarce and experience sharing is essential to the optimization of the process., Objectives: This report of our 10-year activity of pediatric fertility preservation (FP) has the objective to (1) improve knowledge regarding the feasibility, acceptability, safety, and potential usefulness of the procedure; (2) analyze the impact of chemotherapy on spermatogonia in the cryopreserved TT., Materials and Methods: For this retrospective study of data prospectively recorded, we included all boys under 18 years of age referred to the FP consultation of our academic network between October 2009 and December 2019. Characteristics of patients and cryopreservation of testicular tissue (CTT) were extracted from the clinical database. Univariate and multivariate analyses were used to assess factors associated with the risk of absence of spermatogonia in the TT., Results: Three hundred and sixty-nine patients (7.2 years; 0.5-17.0) were referred to the FP consultation for malignant (70%) or non-malignant (30%) disease, of whom 88% were candidates for CTT, after a previous chemotherapy exposure (78%). The rate of recorded immediate adverse events was 3.5%, with painful episodes dominating. Spermatogonia were detected in the majority of TTs: 91.1% of those exposed to chemotherapy and 92.3% of those not exposed (p = 0.962). In multivariate analysis, the risk of absence of spermatogonia was almost three-fold higher in boys > 10 years of age ([OR] 2.74, 95% CI 1.09-7.26, p = 0.035) and four-fold higher in boys exposed to alkylating agents prior to CTT ([OR] 4.09, 95% CI 1.32-17.94, p = 0.028)., Discussion/conclusion: This large series of pediatric FP shows that this procedure is well accepted, feasible, and safe in the short term, strengthening its place in the clinical care pathway of young patients requiring a highly gonadotoxic treatment. Our results demonstrate that CTT post-chemotherapy does not impair the chance to preserve spermatogonia in the TT except when the treatment includes alkylating agents. More data on post-CTT follow-up are still required to ensure the long-term safety and usefulness of the procedure., (© 2023 The Authors. Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology.)

Aims: Small cell bladder carcinoma (SCBC) is a rare, divergent form of urothelial carcinoma (UC). We aimed to determine whether pure (n = 16) and mixed (SCBC and UC; n = 30) tumours differed in pathology, gene expression characteristics, genetic alterations, and clinical outcomes., Methods and Results: Forty (87%) patients received first-line chemotherapy. Twenty-nine patients had no metastatic disease at diagnosis and underwent radical cystectomy. There were no differences in age, sex, race distribution, tumour size, stage at presentation, therapy response with pathological downstaging to ≤ypT1N0, or overall or progression-free survival (PFS) between pure and mixed tumours. There was a longer PFS among downstaged chemotherapy-responding tumours ≤ypT2N0M0 than among unresponsive tumours ≥ypT2 ≥ yN1M1 (P = 0.001). Patients who achieved pathological downstaging with neoadjuvant chemotherapy (n = 10) were stage cT2N0M0 at the time of diagnosis and were alive at the last follow-up (median 37 months), while 46% of patients who failed to achieve pathological downstaging were alive at the last follow-up (median 38 months; P = 0.008). RNA sequencing showed that the UC of mixed SCBC had similar neural expression signatures to pure SCBC. DNA sequencing revealed alterations in TERT (83%), P53 (56%), ARID1A (28%), RB1 (22%), and BRCA2 (11%). Immunohistochemistry for RB1 showed loss of expression in 18/19 (95%) patients, suggesting frequent pathway downregulation despite a low prevalence of RB1 mutation., Conclusion: Patients with pure and mixed SCBC have similar outcomes and these outcomes are determined by the pathological stage at RC and are best among patients who have pathological downstaging after NAC., (© 2023 John Wiley & Sons Ltd.)

Objectives: To evaluate different scenarios for the management of early diagnosis of cancer (PCa) in men at high genetic risk, using recently developed blood and urinary molecular biomarkers in combination with clinical information alongside multiparametric magnetic resonance imaging (mpMRI)., Patients and Methods: A total of 322 patients with a high genetic risk (familial or personal history of cancers or a predisposing germline variant) were included in this study. The primary outcome was the detection rates of PCa (positive biopsy) or clinically significant PCa (biopsy with International Society of Urological Pathology [ISUP] grade >1). Clinical parameters included age, body mass index, ancestry, and germline mutational status, mpMRI, prostate-specific antigen density (PSAD), Prostate Health Index and urinary markers (Prostate Cancer Associated 3, SelectMdx™ and T2:ERG score) were assessed. Sensitivity (Se) and specificity (Sp) for each marker at their recommended cut-off for clinical practice were calculated. Comparison between diagnoses accuracy of each procedure and scenario was computed using mutual information based and direct effect contribution using a supervised Bayesian network approach., Results: A mpMRI Prostate Imaging-Reporting and Data System (PI-RADS) score ≥3 showed higher Se than mpMRI PI-RADS score ≥4 for detection of PCa (82% vs 61%) and for the detection of ISUP grade >1 lesions (96% vs 80%). mpMRI PI-RADS score ≥3 performed better than a PSA level of ≥3 ng/mL (Se 96%, Sp 53% vs Se 91%, Sp 8%) for detection of clinically significant PCa. In case of negative mpMRI results, the supervised Bayesian network approach showed that urinary markers (with the same accuracy for all) and PSAD of ≥0.10 ng/mL/mL were the most useful indicators of decision to biopsy., Conclusions: We found that screening men at high genetic risk of PCa must be based on mpMRI without pre-screening based on a PSA level of >3 ng/mL, to avoid missing too many ISUP grade >1 tumours and to significantly reduce the number of unnecessary biopsies. However, urinary markers or a PSAD of ≥0.10 ng/mL/mL when mpMRI was negative increased the detection of ISUP grade >1 cancers. We suggest that a baseline mpMRI be discussed for men at high genetic risk from the age of 40 years., (© 2023 BJU International.)

Background: While family history (FHx) of prostate cancer (PCa) increases the risk of PCa, comparably less is known regarding the impact of FHx on pathologic and oncologic outcomes after radical prostatectomy (RP)., Methods: We retrospectively reviewed our multicenter database comprising 6,041 nonmetastatic PCa patients treated with RP. Patients with a FHx of PCa in one or more first-degree relatives were considered as FHx positive. We examined the association of FHx with pathologic outcomes and biochemical recurrence (BCR) using logistic and Cox regression models, respectively., Results: In total, 1,677 (28%) patients reported a FHx of PCa. Compared to patients without FHx, those with, were younger at RP (median age of 59 vs. 62 years, p  < 0.01), and had significantlymore favorable biopsy and RP histopathologic findings. On multivariable logistic regression analysis, positive FHx was associated with extracapsular extension (odds ratio [OR] 0.77, 95% confidence interval [CI] 0.66-0.90, p  < 0.01; model AUC 0.73) and upgrading (OR 0.70, 95% CI 0.62-0.80, p  < 0.01; model AUC 0.68). Incorporating FHx significantly improved the AUC of the base model for upgrading ( p  < 0.01). Positive FHx was not associated with BCR in pre- and postoperative multivariable models ( p  = 0.1 and p  = 0.7); c-indexes of Cox multivariable models were: 0.73 and 0.82, respectively., Conclusions: We found that patients with clinically nonmetastatic PCa who have positive FHx of PCa undergo RP at a younger age and have more favorable pathologic outcomes. Nevertheless, FHx of PCa did not confer better BCR rates, suggesting that FHx leads to potentially early detection and treatment without impact on BCR., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Myoid gonadal stromal tumours (MGST) represent a rare type of testicular sex cord-stromal tumour that has recently been recognised as a distinct entity by the World Health Organization (WHO) classification of genitourinary tumours. MGSTs affect adult men and have been reported to behave in an indolent fashion. Histologically, MGSTs are pure spindle cell neoplasms that coexpress SMA and S100 protein. Given that the molecular features of these neoplasms remain largely undescribed, we evaluated a multi-institutional series of MGSTs using DNA and RNA sequencing. This study included 12 tumours from 12 patients aged 28 to 57 years. Tumour sizes ranged from 0.6 to 4.3 cm. Aggressive histologic features, such as vascular invasion, necrosis, invasive growth, and atypical mitoses were invariably absent. Mitotic activity was low, with a median of less than 1 mitosis per 10 high power fields (HPF; maximum: 3 mitoses per 10 HPF). Molecular analyses did not identify recurrent mutations or gene fusions. All cases with interpretable copy number variant data (9/10 cases sequenced successfully) demonstrated a consistent pattern of chromosome arm-level and whole-chromosome-level copy number gains indicative of ploidy shifts, with recurrent gains involving chromosomes 3, 6, 7, 8, 9, 11, 12, 14q, 15q, 17, 18q, 20, and 21q. Similar findings have also been recognised in pure spindle cell and spindle-cell predominant sex cord-stromal tumours without S100 protein expression. MGSTs are characterised by ploidy shifts and may be part of a larger spectrum of spindle cell-predominant sex cord-stromal tumours, including cases without S100 protein expression., (© 2022 John Wiley & Sons Ltd.)

Low-grade oncocytic tumour (LOT) of the kidney has recently emerged as a potential novel tumour type. Despite similarity to oncocytoma or eosinophilic chromophobe renal cell carcinoma, it shows diffuse keratin 7 immunohistochemistry (IHC) and negative KIT (CD117), which differs from both. We aimed to identify the molecular characteristics of these tumours. Seventeen tumours (one male, 16 female, nine previously published) fitting the original description of this entity (solid eosinophilic cell morphology, often with areas of tumour cells loosely stretched in oedematous stroma, and the above IHC features) were analysed with a next-generation sequencing panel of 324 cancer-associated genes from formalin-fixed, paraffin-embedded tissue. All tumours harboured at least one alteration in either TSC1 (n = 7, 41%), TSC2 (n = 2, 12%), MTOR (n = 5, 29%) or PIK3CA (n = 4, 24%). Four tumours harboured a second alteration, including two NF2, one each in conjunction with MTOR and TSC2 alterations, one PTEN with TSC1 alteration and one tumour with both MTOR and TSC1 alterations. No other renal cancer-related or recurring gene alterations were identified. In addition to the previously described IHC findings, 16 of 16 were positive for GATA3. Eleven patients with follow-up had no metastases or recurrent tumours. Recurrent tuberous sclerosis/MTOR pathway gene alterations in LOT support its consideration as a distinct morphological, immunohistochemical and genetic entity. PIK3CA is another pathway member that may be altered in these tumours. Further study will be necessary to determine whether tumour behaviour or syndromic associations differ from those of oncocytoma and chromophobe carcinoma, warranting different clinical consideration., (© 2022 John Wiley & Sons Ltd.)

Predicting the clinical behavior and trajectory of chromophobe renal cell carcinoma (ChRCC) by histologic features has so far proven to be challenging. It is known that ChRCC represents a heterogeneous group of neoplasms demonstrating variable, yet distinctive morphologic and genetic profiles. In this international multi-institutional study, we aimed to assess the impact of histologic diversity in ChRCC (classic/eosinophilic versus rare subtypes) on survival outcome. This is an international multi-institutional matched case-control study including 14 institutions, examining the impact of histologic subtypes of ChRCC on survival outcome. The study group (cases) included 89 rare subtypes of ChRCC. The control group consisted of 70 cases of ChRCC including classic and eosinophilic features, age- and tumor size-matched. Most of the rare subtypes were adenomatoid cystic/pigmented ChRCC (66/89, 74.2%), followed by multicystic ChRCC (10/89, 11.2%), and papillary ChRCC (9/89, 10.1%). In the control group, there were 62 (88.6%) classic and 8 (11.4%) eosinophilic ChRCC. There were no statistically significant differences between the study and control groups for age at diagnosis, gender distribution, tumor size, presence of tumor necrosis, presence of sarcomatoid differentiation, and adverse outcomes. No statistically significant differences were found in clinical outcome between the rare subtypes and classic/eosinophilic groups by tumor size, necrosis, and sarcomatoid differentiation. Further, no statistically significant differences were found in clinical outcome between the two groups, stratified by tumor size, necrosis, and sarcomatoid differentiation. Our findings corroborated previous studies that both sarcomatoid differentiation and tumor necrosis were significantly associated with poor clinical outcome in classic/eosinophilic ChRCC, and this was proven to be true for ChRCC with rare histologic subtypes as well. This study suggests that rare morphologic patterns in ChRCC without other aggressive features play no role in determining the clinical behavior of the tumor., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Renal cell carcinoma (RCC) is a heterogeneous disease comprising histologically defined subtypes. For therapy selection, precise subtype identification and individualized prognosis are mandatory, but currently limited. Our aim was to refine subtyping and outcome prediction across main subtypes, assuming that a tumor is composed of molecular features present in distinct pathological subtypes., Methods: Individual RCC samples were modeled as linear combination of the main subtypes (clear cell (ccRCC), papillary (pRCC), chromophobe (chRCC)) using computational gene expression deconvolution. The new molecular subtyping was compared with histological classification of RCC using the Cancer Genome Atlas (TCGA) cohort (n = 864; ccRCC: 512; pRCC: 287; chRCC: 65) as well as 92 independent histopathologically well-characterized RCC. Predicted continuous subtypes were correlated to cancer-specific survival (CSS) in the TCGA cohort and validated in 242 independent RCC. Association with treatment-related progression-free survival (PFS) was studied in the JAVELIN Renal 101 (n = 726) and IMmotion151 trials (n = 823). CSS and PFS were analyzed using the Kaplan-Meier and Cox regression analysis., Results: One hundred seventy-four signature genes enabled reference-free molecular classification of individual RCC. We unambiguously assign tumors to either ccRCC, pRCC, or chRCC and uncover molecularly heterogeneous tumors (e.g., with ccRCC and pRCC features), which are at risk of worse outcome. Assigned proportions of molecular subtype-features significantly correlated with CSS (ccRCC (P = 4.1E - 10), pRCC (P = 6.5E - 10), chRCC (P = 8.6E - 06)) in TCGA. Translation into a numerical RCC-R(isk) score enabled prognosis in TCGA (P = 9.5E - 11). Survival modeling based on the RCC-R score compared to pathological categories was significantly improved (P = 3.6E - 11). The RCC-R score was validated in univariate (P = 3.2E - 05; HR = 3.02, 95% CI: 1.8-5.08) and multivariate analyses including clinicopathological factors (P = 0.018; HR = 2.14, 95% CI: 1.14-4.04). Heterogeneous PD-L1-positive RCC determined by molecular subtyping showed increased PFS with checkpoint inhibition versus sunitinib in the JAVELIN Renal 101 (P = 3.3E - 04; HR = 0.52, 95% CI: 0.36 - 0.75) and IMmotion151 trials (P = 0.047; HR = 0.69, 95% CI: 0.48 - 1). The prediction of PFS significantly benefits from classification into heterogeneous and unambiguous subtypes in both cohorts (P = 0.013 and P = 0.032)., Conclusion: Switching from categorical to continuous subtype classification across most frequent RCC subtypes enables outcome prediction and fosters personalized treatment strategies., (© 2022. The Author(s).)

Purpose: The aim of our study was to evaluate and compare the expression of different immunohistochemical markers in Bladder Carcinomas (BC) in patients with Neurogenic Bladder (NB) and Urinary Schistosomiasis (US) infection., Materials and Methods: We collected tissue samples from patients with Neurogenic Bladder and Bladder Carcinoma (NBC Group) and from patients with Urinary Schistosomiasis infection and Bladder Carcinoma (SBC Group). We compared to these two groups to control samples from resection from patients with Urinary Schistosomiasis without Bladder Carcinoma (US Group); we also investigate patients' characteristics according to urothelial transitional cell carcinoma (TCC), and squamous cell carcinoma (SCC) histopathological differentiation. The expression of markers in all groups (CK7, CK14, CK20, FoxP3, GATA3, STAG2, CD3, CD8, Ki67, and P53) was analyzed using immunohistochemistry of tissue micro-array sections (TMA)., Results: Overall, 136 patients were included in the study (n = 72 in the NBC group, n = 33 in the SBC group, and n = 31 in the US group). In the TCC subgroup, the expression of CK7, CK14, CK20, and Ki67 was significantly higher compared to US controls (p 0.002; p < 0.001; p 0.036; p < 0.001). In the SCC subgroup, the expression of CK7, CK14, and CK20 was significantly higher compared to US controls (p 0.007; p < 0.001; p 0.005). Both in TCC and SCC subgroups, no difference in the expression of any tested markers was found comparing NBC and SBC groups. In US group, a significant higher expression of STAG2 was found compared to SCC subgroup (p 0.005)., Conclusion: Based on our results, the profile of immunohistochemical biomarkers' expression in both NBC and SBC groups is similar., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: To establish whether the expression of markers of cell differentiation (CK7, CK14, CK20, GATA3), apoptosis (p53), proliferation (Ki67, STAG2) and peri-tumoural lymphocytes (CD3, CD8), provides specific information about urothelial carcinogenesis in neuro-urological patients with bladder cancer (NBC)., Methods: Tissue samples from NBC were retrieved from 15 centres in France and compared to control samples from non neuro-urological patients with bladder cancer (NNBC) and from neuro-urological patients without bladder cancer (NB). The expression of CK7, CK14, CK20, GATA3, p53, Ki67, STAG2, CD3 and CD8 markers was analysed using immunohistochemistry of tissue microarray sections., Results: Overall, tissue samples from 124 patients were included in the study (n = 72 NBC, n = 26 NNBC and n = 26 NB). Muscle invasive bladder cancer (MIBC) was found in 52 NBC patients (72.2%) and squamous cell differentiation in 9 (12.5%). In NBC samples, the expression of CK20 and GATA3 was significantly more frequent in NMIBC compared to MIBC (p = 0.015 and p = 0.004, respectively). CK20 and GATA3 were significantly more expressed in NBC compared to NNBC (p < 0.001 and p = 0.010, respectively). The expression of CK14, Ki67, CD3 and CD8 was significantly more frequent in NBC than in NNBC samples (p = 0.005, p < 0.001, p < 0.001 and p < 0.001, respectively). The expression of CD3 and CD8 was similar in NBC and NB samples., Conclusion: In NBC, markers of basal differentiation, proliferation and peri-tumoural lymphocytes were significantly more expressed compared to NNBC controls. These results suggest the aggressiveness of NBC and the role of chronic inflammation in the carcinogenesis of bladder cancer in neuro-urological patients., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Squamous cell carcinoma of the penis (PSC) is a rare disease with limited information on the molecular events leading to malignant transformation. In a third of PSC cases, presence of human papilloma virus (HPV) is found. The APOBEC3 family of proteins is known to play a significant role in defense against HPV infection, but their role in PSC is largely unknown. In this study, we aim to assess mRNA expression levels of APOBEC3 family members in HPV+ and HPV- PSC to get insight into their association with clinicopathological features and to evaluate their prognostic impact. Expression levels of six APOBEC3 family members in tissue from 50 patients with PSC were determined by RT-PCR and correlated with clinical and histopathological features. Lower expression of APOBEC3A, APOBEC3B, and APOBEC3C was observed in advanced PSC stages. Except for APOBEC3D, HPV+ samples showed higher expression of APOBEC3s compared to HPV- samples. In univariate analyses, APOBEC3A and APOBEC3C expression tended to be associated with disease-free survival and APOBEC3A expression with overall survival; however, multivariable analyses failed to confirm these associations with outcome. More extensive external validation and functional laboratory studies are needed to evaluate further their role in PSC development and progression., (© 2022. The Author(s).)

Purpose: To perform a dynamic evaluation of the prostate cancer (PCa) detection rate according to the biopsy strategy over 10 years of practice in a single institution that pioneered MRI-targeted fusion biopsy (MRI-TB)., Methods: This stage 4 IDEAL study prospectively included all consecutive patients who underwent transrectal prostate biopsy for clinically suspected PCa between January 2010 and November 2020. Patients with positive MRI (PIRADS score ≥ 3) underwent both MRI-TB and systematic biopsy (SB) while those with negative MRI (PIRADS score < 3) underwent SB only. The main outcome was the evolution of the detection rate of clinically relevant PCa (csPCa; grade ≥ 2). The secondary outcome was the change in PCa detection rate according to the biopsy method., Results: A total of 2942 men underwent prostate MRI and a prostate biopsy: 2322 underwent MRI-TB and 620 had SB only. The detection rate of csPCa increased 2.5-fold from 23 to 58%. The detection rate of PCa and csPCa was significantly higher in patients who underwent MRI-TB compared to those who underwent SB only (67% vs. 52% and 40% vs. 32%, respectively (P < 0.001 for both comparisons)). The number of csPCa diagnosed by MRI-TB increased linearly over the study period and represented the majority of PCa diagnoses after 2016., Conclusion: Implementation of MRI-TB in patients with positive MRI led to improved detection of csPCa., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Patients with upper tract urothelial carcinoma (UTUC) often have a delayed diagnosis and by then, present with advanced disease which has been shown to be associated with lymphovascular invasion (LVI). It has been suggested to be involved in the metastatic cascade of the disease. In this review, we provide an extensive up-to-date summary of the current knowledge about the prognostic impact of LVI in patients undergoing radical nephroureterectomy (RNU). A systematic search of PubMed/MEDLINE, Scopus, EMBASE, and Web of Science for all reports published from 2010 through 2021 was performed. We performed pooled analyses of hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) of series that evaluated LVI as a prognostic factor in adults with UTUC who underwent RNU. The assessed oncological outcomes were disease recurrence, cancer-specific and overall survival. A meta-regression analysis was used to explore potential heterogeneity. A total of 58 series met the eligibility criteria for qualitative and quantitative synthesis. We included 29,829 patients, ranging from 101 to 2492 per study. All series were retrospective. LVI was present in 7,818 patients (26.2%). The median age of the patients was 69 years and the median follow-up was 40 months. In 40 of 58 studies (68.9%), adjuvant chemotherapy was given. The pooled HRs show that LVI predicts a greater risk of recurrence of the disease (pooled HR 1.43, 95% CI: 1.31-1.55, P = 0.000; I 2  = 76.3%), and decreases cancer-specific survival (pooled HR 1.53, 95% CI: 1.41-1.66, P = 0.000; I 2  = 72.3%) and overall survival (HR 1.56, 95% CI 1.45-1.69, P = 0.000; I 2  = 62.9%). It can be concluded that LVI is a common histologic pattern in surgical specimen in patients undergoing RNU for UTUC. LVI predicts a greater risk of recurrence and mortality, thus it should be carefully assessed in clinical practice to determine prognosis, and for optimal decision-making within the concept of personalized therapies., (Copyright © 2022 Elsevier Inc. All rights reserved.)

A distinct renal tumor has recently been described as "high-grade oncocytic renal tumor" and "sporadic renal cell carcinoma with eosinophilic and vacuolated cytoplasm". The Genitourinary Pathology Society (GUPS) consensus proposed a unifying name "eosinophilic vacuolated tumor" (EVT) for this emerging entity. In this multi-institutional study, we evaluated 19 EVTs, particularly their molecular features and mutation profile, using next-generation sequencing. All cases were sporadic and none of the patients had a tuberous sclerosis complex. There were 8 men and 11 women, with a mean age of 47 years (median 50; range 15-72 years). Average tumor size was 4.3 cm (median 3.8 cm; range 1.5-11.5 cm). All patients with available follow-up data (18/19) were alive and without evidence of disease recurrence or progression during the follow-up, ranging from 12 to 198 months (mean 56.3, median 41.5 months). The tumors were well circumscribed, but lacked a well-formed capsule, had nested to solid growth, focal tubular architecture, and showed ubiquitous, large intracytoplasmic vacuoles, round to oval nuclei, and prominent nucleoli. Immunohistochemically, cathepsin K, CD117, CD10, and antimitochondrial antigen were expressed in all cases. Other positive stains included: PAX8, AE1/AE3 and CK18. CK7 was typically restricted only to rare scattered cells. Vimentin, HMB45, melan-A, and TFE3 were negative in all cases. All tumors showed retained SDHB. All cases (19/19) showed non-overlapping mutations of the mTOR pathway genes: TSC1 (4), TSC2 (7), and MTOR (8); one case with MTOR mutation showed a coexistent RICTOR missense mutation. Low mutational rates were found in all samples (ranged from 0 to 6 mutations/Mbp). Microsatellite instability and copy number variations were not found in any of the 17 analyzable cases. EVT represents an emerging renal entity that shows a characteristic and readily identifiable morphology, consistent immunohistochemical profile, indolent behavior, and mutations in either TSC1, TSC2, or MTOR genes., (© 2021. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

Competing Interests: Disclosure TP has received research funding from Merck Serono, Merck, Sharp & Dohme (MSD), Roche, Bristol Myers Squibb (BMS), AstraZeneca, Astellas, Novartis, Johnson and Johnson, Seattle Genetics, Pfizer, Exelixis and Eisai and honoraria from Merck Serono, MSD, Roche, BMS, AstraZeneca, Astellas, Novartis, Johnson and Johnson, Seattle Genetics, Pfizer, Exelixis and Eisai; JB has received honoraria for participation in advisory boards from Pfizer, AstraZeneca, Merck and BMS, invited speaker fees from Merck, Genentech and MSD, royalties from UpToDate, institutional research funding as principal investigator (PI) for MSD and Pfizer, research funding from Takeda and non-remunerated activities as steering committee member of the IMvigor 011 study; EC has received honoraria from Jansen for invited speaker and non-remunerated activities in an advisory role for the EAU guidelines; MDS has received honoraria for participation in advisory boards and as an invited speaker for 4D, AAA, Amgen, Astellas, AstraZeneca, Basilea, Bayer, Bioclin, BMS, EISAI, Ferring, Immunomedics, Ipsen, Janssen, MSD, Merck Serono, Novartis, Pfizer, Pierre Fabre Oncology, Roche, Sandoz, Sanofi, SeaGen and Amgen and institutional research as PI and steering committee member for Basilea, AstraZeneca, MSD, Merck, EISAI, Astellas, SeaGen, Exelixis, Ipsen, Roche, Immunomedics, Janssen and Calithera; RH has received honoraria for participation in advisory boards for Roche, Nektar, BMS, MSD and Astellas, expert testimony for National Institute of Clinical Excellence and partnership in the Cancer Centre London, institutional royalties received from Janssen, research grants from MSD and Roche, local PI for Roche, MSD, Basilea and Cancer Research UK; patient funding from Astellas and steering committee member with Cancer Research UK; YL has received honoraria for lectures, presentations, speaker’s bureau, manuscript writing or educational events from BMS, Pfizer, Merck KGaA, MSD, AstraZeneca, Roche, Jansen, Astellas, Seattle Genetics and Immunomedics and support for attending meetings and/or travel grants from BMS, Roche, AstraZeneca, MSD and Pfizer; AN has received institutional research grants from Merck, AstraZeneca, Ipsen and BMS and has undertaken personal research as a steering committee member for Roche, Janssen, Bayer, Astellas, AstraZeneca, Merck and Clovis Oncology; BPV has received honoraria for advisory boards for Pfizer, Astellas Pharma, BMS, Ipsen, EUSA Pharma, Sanofi-Aventis and Merck and has been an invited speaker for Janssen, Pfizer, BMS, Roche, Bayer, EUSA Pharma, MSD and Merck; AR has received honoraria for advisory boards for Pfizer, Merck GA, BMS, Ipsen, MSD and AstraZeneca and has been an invited speaker for Pfizer, Merck GA, BMS, Ipsen and MSD and has received institutional grants from Pfizer, Merck GA and Ipsen; SFS has received honoraria for participation in advisory boards for Astellas, Janssen, MSD, AstraZeneca, Bayer, BMS, Cepheid, Ferring Pharmaceuticals, Ipsen, Lilly, Olympus, Pfizer, Pierre Fabre, Richard Wolf, Roche, Sanochemia, Sanofi, Takeda and UroGen; BS has received honoraria from Ellipses, Ipsen, Merck, Pfizer and Roche and has received travel and research funding from BMS, Genentech, MSD, Pfizer and Roche; MSvdH has received honoraria (paid to institute) for participation in advisory boards for BMS, Roche, Seagen, AstraZeneca, Janssen, Pfizer and MSD, stock ownership with Gilead; and institutional research funding from BMS, Roche, AstraZeneca and 4SC; SG has received personal honoraria for participation in advisory boards for Sanofi, Orion, Roche, Amgen, MSD and Aranda; other honoraria from RSI Televisione Svizzera Italiana); has been an invited speaker for ESMO, SAKK, SAMO, Orikata and CACA-GU, speaker’s bureau for Janssen Cilag; travel grant from ProteoMEdiX, institutional honoraria for advisory boards for Bayer, Janssen Cilag, Roche and AAA International including Independent Data Monitoring Committee; steering committee for Amgen, Menarini Silicon Biosystems, Astellas Pharma, Tolero Pharmaceuticals, MSD, Pfizer, Telixpharma, BMS and Orion and has received a patent, royalties and other intellectual property from Method for Biomarker WO2009138392.

Background: Nephrectomy is the management of choice for the treatment of renal tumors. Surgical pathologists primarily focus on tumor diagnosis and investigations relating to prognosis or therapy. Pathological changes in non-neoplastic tissue may, however, be relevant for further management and should be thoroughly assessed., Methods: Here, we examined the non-neoplastic renal parenchyma in 206 tumor nephrectomy specimens for the presence of glomerular, tubulo-interstitial, or vascular lesions, and correlated them with clinical parameters and outcome of renal function., Results: We analyzed 188 malignant and 18 benign or pseudo-tumorous lesions. The most common tumor type was clear cell renal cell carcinoma (CCRCC, n = 106) followed by papillary or urothelial carcinomas (n = 25). Renal pathology examination revealed the presence of kidney disease in 39 cases (18.9%). Glomerulonephritis was found in 15 cases (7.3%), and the most frequent was IgA nephropathy (n = 6; 2.9%). Vasculitis was found in two cases (0.9%). In 15 cases we found tubulo-interstitial nephritis, and in 9 severe diabetic or hypertensive nephropathy. Partial nephrectomy was not linked to better eGFR at follow-up. Age, vascular nephropathy, glomerular scarring and interstitial fibrosis were the leading independent negative factors influencing eGFR at time of surgery, whereas proteinuria was associated with reduced eGFR at 1 year., Conclusion: Our large study population indicates a high incidence of renal diseases potentially relevant for the postoperative management of patients with renal neoplasia. Consistent and systematic reporting of non-neoplastic renal pathology in tumor nephrectomy specimens should therefore be mandatory., (© 2021. The Author(s).)

The Genitourinary Pathology Society (GUPS) reviewed recent advances in renal neoplasia, particularly post-2016 World Health Organization (WHO) classification, to provide an update on existing entities, including diagnostic criteria, molecular correlates, and updated nomenclature. Key prognostic features for clear cell renal cell carcinoma (RCC) remain WHO/ISUP grade, AJCC/pTNM stage, coagulative necrosis, and rhabdoid and sarcomatoid differentiation. Accrual of subclonal genetic alterations in clear cell RCC including SETD2, PBRM1, BAP1, loss of chromosome 14q and 9p are associated with variable prognosis, patterns of metastasis, and vulnerability to therapies. Recent National Comprehensive Cancer Network (NCCN) guidelines increasingly adopt immunotherapeutic agents in advanced RCC, including RCC with rhabdoid and sarcomatoid changes. Papillary RCC subtyping is no longer recommended, as WHO/ISUP grade and tumor architecture better predict outcome. New papillary RCC variants/patterns include biphasic, solid, Warthin-like, and papillary renal neoplasm with reverse polarity. For tumors with 'borderline' features between oncocytoma and chromophobe RCC, a term "oncocytic renal neoplasm of low malignant potential, not further classified" is proposed. Clear cell papillary RCC may warrant reclassification as a tumor of low malignant potential. Tubulocystic RCC should only be diagnosed when morphologically pure. MiTF family translocation RCCs exhibit varied morphologic patterns and fusion partners. TFEB-amplified RCC occurs in older patients and is associated with more aggressive behavior. Acquired cystic disease (ACD) RCC-like cysts are likely precursors of ACD-RCC. The diagnosis of renal medullary carcinoma requires a negative SMARCB1 (INI-1) expression and sickle cell trait/disease. Mucinous tubular and spindle cell carcinoma (MTSCC) can be distinguished from papillary RCC with overlapping morphology by losses of chromosomes 1, 4, 6, 8, 9, 13, 14, 15, and 22. MTSCC with adverse histologic features shows frequent CDKN2A/2B (9p) deletions. BRAF mutations unify the metanephric family of tumors. The term "fumarate hydratase deficient RCC" ("FH-deficient RCC") is preferred over "hereditary leiomyomatosis and RCC syndrome-associated RCC". A low threshold for FH, 2SC, and SDHB immunohistochemistry is recommended in difficult to classify RCCs, particularly those with eosinophilic morphology, occurring in younger patients. Current evidence does not support existence of a unique tumor subtype occurring after chemotherapy/radiation in early childhood.

The Genitourinary Pathology Society (GUPS) undertook a critical review of the recent advances in bladder neoplasia with a focus on issues relevant to the practicing surgical pathologist for the understanding and effective reporting of bladder cancer, emphasizing particularly on the newly accumulated evidence post-2016 World Health Organization (WHO) classification. The work is presented in 2 manuscripts. Here, in the first, we revisit the nomenclature and classification system used for grading flat and papillary urothelial lesions centering on clinical relevance, and on dilemmas related to application in routine reporting. As patients of noninvasive bladder cancer frequently undergo cystoscopy and biopsy in their typically prolonged clinical course and for surveillance of disease, we discuss morphologies presented in these scenarios which may not have readily applicable diagnostic terms in the WHO classification. The topic of inverted patterns in urothelial neoplasia, particularly when prominent or exclusive, and beyond inverted papilloma has not been addressed formally in the WHO classification. Herein we provide a through review and suggest guidelines for when and how to report such lesions. In promulgating these GUPS recommendations, we aim to provide clarity on the clinical application of these not so uncommon diagnostically challenging situations encountered in routine practice, while also importantly advocating consistent terminology which would inform future work., Competing Interests: The authors have no funding or conflicts of interests to disclose relevant to this work., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Initial reports of a clinical response in patients treated with the radioligand [ 177 Lu]-PSMA-617 for castration-resistant prostate cancer (CRPC) are promising, despite known inter- and intrapatient heterogeneity. In metastatic CRPC, we examined the association of baseline immunohistochemical (IHC) expression of prostate-specific membrane antigen (PSMA) in a single lesion and responsiveness to [ 177 Lu]-PSMA-617 therapy, measured as the PSMA maximum standardized uptake value (SUV max ). Between 2015 and 2020, 19 patients with multiple metastases underwent single-lesion biopsy, [ 68 Ga]-PSMA positron emission tomography (PET) imaging, and treatment with [ 177 Lu]-PSMA-617. A monoclonal anti-PSMA antibody was used to semiquantitatively assess PSMA IHC in the biopsy specimen. Imaging evaluation of the biopsied single lesion and overall response was performed according to Positron Emission Tomography Response Criteria in Solid Tumors. The PSMA IHC histoscore correlated positively with pretreatment same-site PSMA SUV max ( r s  = 0.6). Nine patients had imaging after three cycles of [ 177 Lu]-PSMA-617 and were included in the lesion-specific analysis. Of these, five patients (55.6%) had an SUV max response at the biopsy site, but three experienced overall progression. The histoscore was unable to predict the lesion-specific change in SUV max (95% confidence interval [CI] -44.2 to 69.2) or PSA (95% CI-125.2 to 17.2). There was no correlation between single-lesion SUV max and overall progression ( r s  = 0.1) on [ 68 Ga]-PSMA PET imaging. Additional studies need to interrogate the clinical consequence of PSMA expression heterogeneity in metastases and the association with response to [ 177 Lu]-PSMA-671., Patient Summary: Treatment with a radioactive binding molecule called [ 177 Lu]-PSMA-617 for men with prostate cancer resistant to castration (CRPC) is showing promise. We investigated the association between the presence of PSMA protein in metastatic lesions at biopsy and response to [ 177 Lu]-PSMA-617 among men with metastatic CRPC. We found that assessment of PSMA presence at biopsy is not a reliable predictor of response to [ 177 Lu]-PSMA-617. Additional studies are needed to better determine which CRPC metastatic sites will respond to this therapy., (© 2021 The Authors.)

The Genitourinary Pathology Society (GUPS) undertook a critical review of the recent advances in renal neoplasia, particularly focusing on the newly accumulated evidence post-2016 World Health Organization (WHO) classification. In the era of evolving histo-molecular classification of renal neoplasia, morphology is still key. However, entities (or groups of entities) are increasingly characterized by specific molecular features, often associated either with recognizable, specific morphologies or constellations of morphologies and corresponding immunohistochemical profiles. The correct diagnosis has clinical implications leading to better prognosis, potential clinical management with targeted therapies, may identify hereditary or syndromic associations, which may necessitate appropriate genetic testing. We hope that this undertaking will further facilitate the identification of these entities in practice. We also hope that this update will bring more clarity regarding the evolving classification of renal neoplasia and will further reduce the category of "unclassifiable renal carcinomas/tumors". We propose three categories of novel entities: (1) "Novel entity", validated by multiple independent studies; (2) "Emerging entity", good compelling data available from at least two or more independent studies, but additional validation is needed; and (3) "Provisional entity", limited data available from one or two studies, with more work required to validate them. For some entities initially described using different names, we propose new terminologies, to facilitate their recognition and to avoid further diagnostic dilemmas. Following these criteria, we propose as novel entities: eosinophilic solid and cystic renal cell carcinoma (ESC RCC), renal cell carcinoma with fibromyomatous stroma (RCC FMS) (formerly RCC with leiomyomatous or smooth muscle stroma), and anaplastic lymphoma kinase rearrangement-associated renal cell carcinoma (ALK-RCC). Emerging entities include: eosinophilic vacuolated tumor (EVT) and thyroid-like follicular renal cell carcinoma (TLFRCC). Finally, as provisional entities, we propose low-grade oncocytic tumor (LOT), atrophic kidney-like lesion (AKLL), and biphasic hyalinizing psammomatous renal cell carcinoma (BHP RCC).

To evaluate oncological outcomes of primary versus secondary muscle-invasive bladder cancer treated with radical cystectomy. Medline, Embase, Scopus and Cochrane Library were searched for eligible studies. Hazard ratios for overall survival (OS), cancer specific survival (CSS) and progression free survival (PFS) were calculated using survival data extracted from Kaplan-Meier curves. A total of 16 studies with 5270 patients were included. Pooled analysis showed similar 5-year and 10-year OS (HR 1, p = 0.96 and HR 1, p = 0.14) and CSS (HR 1.02, p = 0.85 and HR 0.99, p = 0.93) between primMIBC and secMIBC. Subgroup analyses according to starting point of follow-up and second-look transurethral resection revealed similar results. Subgroup analyses of studies in which neoadjuvant chemotherapy was administered demonstrated significantly worse 5-year CSS (HR 1.5, p = 0.04) but not 10-year CSS (HR 1.36, p = 0.13) in patients with secMIBC. Patients with secMIBC had significantly worse PFS at 5-year (HR 1.41, p = 0.002) but not at 10-year follow-up (HR 1.25, p = 0.34). This review found comparable oncologic outcomes between primMIBC and secMIBC patients treated with RC regarding OS and CSS. Subgroup analysis showed worse 5-year CSS but not 10-year CSS for neoadjuvant chemotherapy in the secMIBC group. Prospective clinical trials incorporating molecular markers, that allow precise risk stratification of secMIBC and further research uncovering underlying molecular and clinical drivers of the heterogeneous group of secMIBC is needed.

Purpose: To survey urologic clinicians regarding interpretation of and practice patterns in relation to emerging aspects of prostate cancer grading, including quantification of high-grade disease, cribriform/intraductal carcinoma, and impact of magnetic resonance imaging-targeted needle biopsy., Materials and Methods: The Genitourinary Pathology Society distributed a survey to urology and urologic oncology-focused societies and hospital departments. Eight hundred and thirty four responses were collected and analyzed using descriptive statistics., Results: Eighty percent of survey participants use quantity of Gleason pattern 4 on needle biopsy for clinical decisions, less frequently with higher Grade Groups. Fifty percent interpret "tertiary" grade as a minor/<5% component. Seventy percent of respondents would prefer per core grading as well as a global/overall score per set of biopsies, but 70% would consider highest Gleason score in any single core as the grade for management. Seventy five percent utilize Grade Group terminology in patient discussions. For 45%, cribriform pattern would affect management, while for 70% the presence of intraductal carcinoma would preclude active surveillance., Conclusion: This survey of practice patterns in relationship to prostate cancer grading highlights similarities and differences between contemporary pathology reporting and its clinical application. As utilization of Gleason pattern 4 quantification, minor tertiary pattern, cribriform/intraductal carcinoma, and the incorporation of magnetic resonance imaging-based strategies evolve, these findings may serve as a basis for more nuanced communication and guide research efforts involving pathologists and clinicians., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Although predominantly urothelial, some bladder cancer and upper tract urothelial cancer (BC/UTUC) harbor histologic variants. Small cell BC (SCBC) variants comprised ˜5% of The Cancer Genome Atlas BC cohort, with a poor prognosis. We describe genomic profiles of BC/UTUC with small cell/neuroendocrine features identified in the Foundation Medicine database from June 2012 to September 2018. Of 3368 BC/UTUC samples, 3.92% (132) harbored small cell/neuroendocrine features by immunohistochemistry. Mutations were noted in: TP53 (92%), RB1 (75%), combined TP53/RB1 (72%), and TERT promoter (68%). Of the samples, 6.5% had TMB ≥ 10 mutations/Mb. RNA expression profiling of 24 pure SCBC and 51 urothelial BC (UBC) muscle-invasive samples evaluated from a separate cohort revealed a large number of differentially expressed genes with suppression of several inflammatory pathways in SCBC compared with UBC. This largest reported SCBC dataset to date confirms enrichment of signatures in SCBC similar to small cell lung cancer and describes unique gene expression compared with UBC. These findings may explain aggressive SCBC phenotype. PATIENT SUMMARY: Small cell bladder cancer (SCBC) is an aggressive subtype that microscopically resembles aggressive small cell lung cancer (SCLC). This study confirms that SCBC shares DNA changes similar to SCLC and that SCBC expresses many genes that urothelial bladder cancer does not, possibly explaining aggressive SCBC activity., (Copyright © 2019. Published by Elsevier B.V.)

Context.—: Controversies and uncertainty persist in prostate cancer grading., Objective.—: To update grading recommendations., Data Sources.—: Critical review of the literature along with pathology and clinician surveys., Conclusions.—: Percent Gleason pattern 4 (%GP4) is as follows: (1) report %GP4 in needle biopsy with Grade Groups (GrGp) 2 and 3, and in needle biopsy on other parts (jars) of lower grade in cases with at least 1 part showing Gleason score (GS) 4 + 4 = 8; and (2) report %GP4: less than 5% or less than 10% and 10% increments thereafter. Tertiary grade patterns are as follows: (1) replace "tertiary grade pattern" in radical prostatectomy (RP) with "minor tertiary pattern 5 (TP5)," and only use in RP with GrGp 2 or 3 with less than 5% Gleason pattern 5; and (2) minor TP5 is noted along with the GS, with the GrGp based on the GS. Global score and magnetic resonance imaging (MRI)-targeted biopsies are as follows: (1) when multiple undesignated cores are taken from a single MRI-targeted lesion, an overall grade for that lesion is given as if all the involved cores were one long core; and (2) if providing a global score, when different scores are found in the standard and the MRI-targeted biopsy, give a single global score (factoring both the systematic standard and the MRI-targeted positive cores). Grade Groups are as follows: (1) Grade Groups (GrGp) is the terminology adopted by major world organizations; and (2) retain GS 3 + 5 = 8 in GrGp 4. Cribriform carcinoma is as follows: (1) report the presence or absence of cribriform glands in biopsy and RP with Gleason pattern 4 carcinoma. Intraductal carcinoma (IDC-P) is as follows: (1) report IDC-P in biopsy and RP; (2) use criteria based on dense cribriform glands (>50% of the gland is composed of epithelium relative to luminal spaces) and/or solid nests and/or marked pleomorphism/necrosis; (3) it is not necessary to perform basal cell immunostains on biopsy and RP to identify IDC-P if the results would not change the overall (highest) GS/GrGp part per case; (4) do not include IDC-P in determining the final GS/GrGp on biopsy and/or RP; and (5) "atypical intraductal proliferation (AIP)" is preferred for an intraductal proliferation of prostatic secretory cells which shows a greater degree of architectural complexity and/or cytological atypia than typical high-grade prostatic intraepithelial neoplasia, yet falling short of the strict diagnostic threshold for IDC-P. Molecular testing is as follows: (1) Ki67 is not ready for routine clinical use; (2) additional studies of active surveillance cohorts are needed to establish the utility of PTEN in this setting; and (3) dedicated studies of RNA-based assays in active surveillance populations are needed to substantiate the utility of these expensive tests in this setting. Artificial intelligence and novel grading schema are as follows: (1) incorporating reactive stromal grade, percent GP4, minor tertiary GP5, and cribriform/intraductal carcinoma are not ready for adoption in current practice., (© 2021 College of American Pathologists.)

Although Bacillus Calmette Guérin (BCG) remains a mainstay of adjuvant treatment in high-risk, non-muscle-invasive bladder cancer, BCG failure occurs in up to 40% of patients, with radical cystectomy (RC) as the inevitable therapeutic consequence. Current data suggest that PD-L1 immunosuppressive signaling is responsible for BCG failure, supporting the therapeutic rationale of combining checkpoint inhibitors with BCG. To address the immune cascade in 19 RC specimens obtained after BCG failure, we applied a small immunohistochemical (IHC) panel consisting of selected markers (PD-L1, GATA-3, a disintegrin and metalloproteinase (ADAM) proteases, IL-10/IL-10R). A modified quick score was used for IHC semi-quantification of these markers in tumor cells (TC) and immune cells (IC) within two different regions: muscle-invasive bladder cancer (MIBC) and primary/concurrent carcinoma in situ (CIS). Contrary to expectation, PD-L1 was consistently low, irrespective of tumor region and cell type. Intriguingly, expression of ADAM17, which has been reported to release membrane-bound PD-L1, was high in both tumor regions and cell types. Moreover, expression of GATA3, IL-10, and IL-10R was also increased, indicative of a generally immunosuppressive tumor microenvironment in BCG failure. ADAM10 expression was associated with advanced tumor disease at RC. Our findings raise the possibility that ADAM proteases may cleave PD-L1 from the surface of bladder TC and possibly also from IC. Therefore, IHC assessment of PD-L1 expression seems to be insufficient and should be supplemented by ADAM10/17 in patients with BCG failure.

Introduction: This systematic review and meta-analysis was conducted to assess the prognostic differences between different Gleason patterns in patients with prostate cancer (PC) within Internal Society of Urological Pathology (ISUP) grade group 4 (GG 4)., Evidence Acquisition: PUBMED and Scopus databases were searched for articles published prior to December 2019 according to the Preferred Reporting Items for Systematic Review and Meta-analysis statement. Studies were deemed eligible if they compared overall survival (OS), cancer-specific survival (CSS), and surgical pathological outcomes in PC patients categorized as ISUP GG 4 (Gleason Score [GS] 4+4 vs. GS 3+5 or GS 5+3). Formal meta-analyses were performed for these outcomes., Evidence Synthesis: Ten studies with 42,041 patients were eligible for the systematic review and eight studies with 36,250 patients for meta-analysis. The treatment type of included study was three surgery and three radiotherapy. The other four studies included many kinds of treatments such as surgery, radiotherapy, androgen deprivation therapy, and chemotherapy. GS 4+4 was significantly associated with better OS (pooled hazard ratio (HR): 0.52, 95% confidential interval (CI): 0.29-0.91) than GS 3+5 or GS 5+3. Positive surgical margin rates were significantly lower with GS 4+4 than GS 3+5 and GS 5+3 (odds ratio [OR] 0.70/95% CI 0.64-0.77 and OR 0.70/95% CI 0.56-0.87, respectively). In contrast, different Gleason patterns in ISUP GG 4 were not significantly associated with CSS (pooled HR: 0.77, 95% CI: 0.56-1.06)., Conclusions: GS 4+4 in patients with PC was associated with better OS and positive surgical margin rates. It seems likely that there is heterogeneity within ISUP GG 4. However, caution should be exercised in interpreting the conclusions drawn from this study, given the limitations of the study, which include the heterogeneity of the population of interest and the retrospective nature of the primary data evaluated.

Purpose: The value of adding dynamic contrast-enhanced (DCE) imaging to T2-weighted (T2W) magnetic resonance imaging (MRI) and diffusion-weighted imaging (DWI) to improve the detection and staging of prostate cancer (PCa) is unclear. The aim of this retrospective study was to compare the diagnostic performance of non-contrast biparametric MRI (bpMRI) with multiparametric MRI (mpMRI), for local staging of PCa., Methods: Ninety-two patients who underwent prostate MRI on a 3-Tesla MRI system before radical prostatectomy for PCa were included retrospectively. Four readers independently assigned a Likert score (ranging from 1 to 5) for predicting extra-prostatic extension (EPE) on T2W + DWI (bpMRI) and then on T2W + DWI + DCE imaging (mpMRI). MRI-based staging results were compared with radical prostatectomy histology. A prediction of EPE generalized linear mixed model was used to assess the added-value of DCE and discriminative power of staging accuracy by area under the receiver-operating curve (AUC ROC)., Results: AUC was not significantly improved by DCE (mpMRI, AUC = 0.73 [95%CI: 0.655‒0.827] vs. bpMRI, AUC = 0.76 [95%CI: 0.681‒0.846]). After applying a selection procedure, only MRI criteria were retained in a multivariate model. The following criteria were significantly associated with local extension: localization in the peripheral zone (p < 0.001), maximal diameter of the lesion (<0.0001), curvilinear capsular contact on T2W (p < 0.0001), capsular irregularity on T2W (p < 0.0001), bulging on T2W (p < 0.001) and seminal vesicle hypo-signal (p < 0.001)., Conclusion: Use of bpMRI did not result in a decrease in local staging accuracy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose of Review: Pathomics, the fusion of digitalized pathology and artificial intelligence, is currently changing the landscape of medical pathology and biologic disease classification. In this review, we give an overview of Pathomics and summarize its most relevant applications in urology., Recent Findings: There is a steady rise in the number of studies employing Pathomics, and especially deep learning, in urology. In prostate cancer, several algorithms have been developed for the automatic differentiation between benign and malignant lesions and to differentiate Gleason scores. Furthermore, several applications have been developed for the automatic cancer cell detection in urine and for tumor assessment in renal cancer. Despite the explosion in research, Pathomics is not fully ready yet for widespread clinical application., Summary: In prostate cancer and other urologic pathologies, Pathomics is avidly being researched with commercial applications on the close horizon. Pathomics is set to improve the accuracy, speed, reliability, cost-effectiveness and generalizability of pathology, especially in uro-oncology.

Objective: To evaluate the clinical features, pathologic features, and prevalence of human papilloma virus (HPV) in squamous cell carcinoma (SCC) of the bladder. SCC of the bladder is known to be associated with conditions that cause chronic inflammation/irritation. The literature is inconsistent regarding the association of HPV with pure SCC of the bladder., Methods: A multi-institutional study identified cases of SCC of the bladder. Pure squamous histology and the absence of urothelial carcinoma in situ were required for inclusion. Clinical and pathologic features were collected, and tissues were evaluated for high-risk HPV using p16 immunohistochemistry and in situ hybridization., Results: We identified 207 cases of SCC of the bladder. Risk factors for bladder cancer included smoking (133/207, 64%) and chronic bladder irritation (83/207, 40%). The majority (155/207, 75%) of patients had > pT2 disease. Mean tumor size was 5.6 ± 3.0 cm and 36/207 (17%) patients had lymph node positive disease. p16 immunohistochemistry was positive in 52/204 (25%) cases but high-risk HPV was identified with in situ hybridization in only 1 (0.5%) case. Tumor size, stage, number of lymph nodes removed, number of positive lymph nodes, lymphovascular invasion, perineural invasion, and positive margins each were associated with cancer-specific mortality when adjusted for demographic factors. A multivariate analysis of variable importance further revealed sex and race as important factors in predicting cancer-specific mortality., Conclusion: SCC of the bladder is an aggressive histologic subtype. Although bladder SCC can express p16, it is not typically associated with high-risk HPV, although rare cases can occur., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Renal oncocytoma is an uncommon tumor that exhibits numerous features which are characteristic but not necessarily unique. Percutaneous biopsy is a safe method of diagnosis. However, differentiation from other tumor subtypes often requires sophisticated analysis and is not universally feasible. This is why, surgical management can be considered as a first-line treatment or after surveillance. Potential triggers for change in management are: tumor size >3 cm, stage progression, kinetics of size progression (>5 mm/y), and clinical change in patient or tumor factors. Long-term follow-up data are lacking and greater centralization should be considered to reach adequate management., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Peptide-based imaging agents targeting prostate-specific membrane antigen (PSMA) have revolutionized the evaluation of biochemical recurrence of prostate cancer (PCa) but lacks sensitivity at very low serum prostate specific antigen (PSA) levels. Once recurrence is suspected, other positron emission tomography (PET) radiotracers could be of interest to discriminate between local and distant relapse. We studied [ 18 F]fluorodeoxyglucose ([ 18 F]FDG) targeting glucose metabolism, [ 18 F]fluorocholine ([ 18 F]FCH) targeting membrane metabolism and peptide-based imaging agents [ 68 Ga]Ga-PSMA-11, [ 68 Ga]Ga-AMBA, [ 68 Ga]Ga-NODAGA-RGD and [ 68 Ga]Ga-DOTA-NT-20.3 targeting PSMA, gastrin releasing peptide receptor (GRPr), αvβ3 integrin and neurotensin type 1 receptor (NTSR1) respectively, in different PCa tumour models., Methods: Mice were xenografted with 22Rv1, an androgen-receptor (AR)-positive, PCa cell line that expresses PSMA and PC3, an AR-negative one that does not express PSMA. PET imaging using the different radiotracers was performed sequentially and the uptake characteristics compared to one other. NTSR1 and PSMA expression levels were analysed in tumours by immunohistochemistry., Results: [ 18 F]FDG displayed low but sufficient uptake to visualize PC3 and 22Rv1 derived tumours. We also observed a low efficacy of [ 18 F]FCH PET imaging and a low [ 68 Ga]Ga-NODAGA-RGD tumour uptake in those tumours. As expected, an elevated tumour uptake was obtained for [ 68 Ga]Ga-PSMA-11 in 22Rv1 derived tumour although no uptake was measured in the androgen independent cell line PC3, derived from a bone metastasis of a high-grade PCa. Moreover, in PC3 cell line, we obtained good tumour uptake, high tumour-to-background contrast using [ 68 Ga]Ga-AMBA and [ 68 Ga]Ga-DOTA-NT-20.3. Immunohistochemistry analysis confirmed high NTSR1 expression in PC3 derived tumours and conversely high PSMA expression in 22Rv1 derived tumours., Conclusion: PET imaging using [ 68 Ga]Ga-AMBA and [ 68 Ga]Ga-DOTA-NT-20.3 demonstrates that GRPr and NTSR1 could represent viable alternative targets for diagnostic or therapeutic applications in PCa with limited PSMA expression levels. More preclinical and clinical studies will follow to explore this potential., Advances in Knowledge and Implications for Patient: Peptide-based imaging agents targeting PSMA represent a major progress in the evaluation of biochemical recurrence of PCa but sometimes yield false negative results in some lesions. Continuing efforts have thus been made to evaluate other radiotracers. Our preclinical results suggest that [ 68 Ga]labelled bombesin and neurotensin analogues could serve as alternative PET radiopharmaceuticals for diagnostic or therapy in cases of PSMA-negative PCa., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)