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Aims: Urothelial carcinoma (UC) demonstrates significant molecular and histologic heterogeneity. The WHO 2022 classification has hinted at adding molecular signatures to the morphologic diagnosis. As morphology and associated molecular repertoire may potentially translate to choices of and response to therapy and relapse rate, broader acceptability of recognizing these key features among uropathologists is needed. This prompted an international survey to ascertain the practice patterns in classical/subtype UC among uropathologists across the globe., Methods and Results: A survey instrument was shared among 98 uropathologists using SurveyMonkey software. Anonymized respondent data were analysed. The response rate was 85%. A majority were in concordance with the profiles of luminal (93%) and basal (82%) types. Opinion on the FGFR3 testing platform was variable. While 95% concurred that TERT promoter mutation is the key driver in UC, 72% had the opinion that APOBEC mutagenesis is the main signature in muscle invasive bladder cancer (MIBC). Uropathologists have divergent opinions on MIBC and ERCC2 mutations. Among the participants, 94% would quantify aggressive micropapillary and sarcomatoid histology, while 88% would reevaluate another transurethral resection of the bladder tumour specimen in nonmuscle invasive tumour with micropapillary, small cell, or sarcomatoid histology. A leading number agreed to specific molecular signatures of micropapillary (93%), plasmacytoid (97%), and small cell (86%) subtypes. Ninety-six percent of participants agreed that a small-cell component portends a more aggressive course and should be treated with neoadjuvant chemotherapy and 63% would perform HER2/neu testing only on oncologist's request in advanced tumours. Ninety percent agreed that microsatellite instability testing, although not a standard protocol, should be considered in young patients with upper tract UC. Eighty-six percent agreed that UC with high tumour mutational burden would be a better candidate for immunotherapy., Conclusion: In the era of precision medicine, enhanced understanding of molecular heterogeneity of UC will contribute to better therapeutic options, novel biomarker discovery, innovative management protocols, and outcomes. Our survey provides a broad perspective of pathologists' perceptions and experience regarding incorporation of histomolecular approaches to "personalize" therapy. Due to variable clinical adoption, there is a need for additional data using uniform study criteria. This will drive generation of best practice guidelines in this area for widespread and consistent clinical utility., (© 2024 John Wiley & Sons Ltd.)

Juxtaglomerular cell tumor (JGCT) is a rare neoplasm, part of the family of mesenchymal tumors of the kidney. Although the pathophysiological and clinical correlates of JGCT are well known, as these tumors are an important cause of early-onset arterial hypertension refractory to medical treatment, their molecular background is unknown, with only few small studies investigating their karyotype. Herein we describe a multi-institutional cohort of JGCTs diagnosed by experienced genitourinary pathologists, evaluating clinical presentation and outcome, morphologic diversity, and, importantly, the molecular features. Ten JGCTs were collected from 9 institutions, studied by immunohistochemistry, and submitted to whole exome sequencing. Our findings highlight the morphologic heterogeneity of JGCT, which can mimic several kidney tumor entities. Three cases showed concerning histologic features, but the patient course was unremarkable, which suggests that morphologic evaluation alone cannot reliably predict the clinical behavior. Gain-of-function variants in RAS GTPases were detected in JGCTs, with no evidence of additional recurrent genomic alterations. In conclusion, we present the largest series of JGCT characterized by whole exome sequencing, highlighting the putative role of the MAPK-RAS pathway., (Copyright © 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Objectives: To evaluate the added benefit of integrating features from pre-treatment MRI (radiomics) and digitized post-surgical pathology slides (pathomics) in prostate cancer (PCa) patients for prognosticating outcomes post radical-prostatectomy (RP) including a) rising prostate specific antigen (PSA), and b) extraprostatic-extension (EPE)., Methods: Multi-institutional data (N = 58) of PCa patients who underwent pre-treatment 3-T MRI prior to RP were included in this retrospective study. Radiomic and pathomic features were extracted from PCa regions on MRI and RP specimens delineated by expert clinicians. On training set (D1, N = 44), Cox Proportional-Hazards models M R , M P and M RaP were trained using radiomics, pathomics, and their combination, respectively, to prognosticate rising PSA (PSA > 0.03 ng/mL). Top features from M RaP were used to train a model to predict EPE on D1 and test on external dataset (D2, N = 14). C-index, Kalplan-Meier curves were used for survival analysis, and area under ROC (AUC) was used for EPE. M RaP was compared with the existing post-treatment risk-calculator, CAPRA (M C )., Results: Patients had median follow-up of 34 months. M RaP (c-index = 0.685 ± 0.05) significantly outperformed M R (c-index = 0.646 ± 0.05), M P (c-index = 0.631 ± 0.06) and M C (c-index = 0.601 ± 0.071) (p < 0.0001). Cross-validated Kaplan-Meier curves showed significant separation among risk groups for rising PSA for M RaP (p < 0.005, Hazard Ratio (HR) = 11.36) as compared to M R (p = 0.64, HR = 1.33), M P (p = 0.19, HR = 2.82) and M C (p = 0.10, HR = 3.05). Integrated radio-pathomic model M RaP (AUC = 0.80) outperformed M R (AUC = 0.57) and M P (AUC = 0.76) in predicting EPE on external-data (D2)., Conclusions: Results from this preliminary study suggest that a combination of radiomic and pathomic features can better predict post-surgical outcomes (rising PSA and EPE) compared to either of them individually as well as extant prognostic nomogram (CAPRA)., Competing Interests: Dr. Anant Madabhushi is an equity holder in Elucid Bioimaging and in Inspirata Inc. In addition, he has served as a scientific advisory board member for Inspirata Inc, Astrazeneca, Bristol Meyers-Squibb and Merck. Currently he serves on the advisory board of Aiforia Inc. He also has sponsored research agreements with Philips, AstraZeneca and Bristol Meyers-Squibb. His technology has been licensed to Elucid Bioimaging. He is also involved in a NIH U24 grant with PathCore Inc, and 3 different R01 grants with Inspirata Inc (NIH 1R01CA202752-01A1: Computerized histologic image predictor of cancer outcome, NIH 1 R01 CA216579-01A1: Computerized Histologic Risk Predictor (CHiRP) for Early Stage Lung Cancers, NIH 1 R01 CA220581-01A1: Quantitative Histomorphometric Risk Classifier (QuHbIC) in HPV + Oropharyngeal Carcinoma). Dr. Andrei Purysko: service contract with Profound Medical and Research support from RSNA R&E foundation. Dr. Patrick Leo is employed in Genentech and have Roche group stock., (© 2024 The Authors.)

Background: Accurate delineations of regions of interest (ROIs) on multi-parametric magnetic resonance imaging (mpMRI) are crucial for development of automated, machine learning-based prostate cancer (PCa) detection and segmentation models. However, manual ROI delineations are labor-intensive and susceptible to inter-reader variability. Histopathology images from radical prostatectomy (RP) represent the "gold standard" in terms of the delineation of disease extents, for example, PCa, prostatitis, and benign prostatic hyperplasia (BPH). Co-registering digitized histopathology images onto pre-operative mpMRI enables automated mapping of the ground truth disease extents onto mpMRI, thus enabling the development of machine learning tools for PCa detection and risk stratification. Still, MRI-histopathology co-registration is challenging due to various artifacts and large deformation between in vivo MRI and ex vivo whole-mount histopathology images (WMHs). Furthermore, the artifacts on WMHs, such as tissue loss, may introduce unrealistic deformation during co-registration., Purpose: This study presents a new registration pipeline, MSERgSDM, a multi-scale feature-based registration (MSERg) with a statistical deformation (SDM) constraint, which aims to improve accuracy of MRI-histopathology co-registration., Methods: In this study, we collected 85 pairs of MRI and WMHs from 48 patients across three cohorts. Cohort 1 (D 1 ), comprised of a unique set of 3D printed mold data from six patients, facilitated the generation of ground truth deformations between ex vivo WMHs and in vivo MRI. The other two clinically acquired cohorts (D 2 and D 3 ) included 42 patients. Affine and nonrigid registrations were employed to minimize the deformation between ex vivo WMH and ex vivo T2-weighted MRI (T2WI) in D 1 . Subsequently, ground truth deformation between in vivo T2WI and ex vivo WMH was approximated as the deformation between in vivo T2WI and ex vivo T2WI. In D 2 and D 3 , the prostate anatomical annotations, for example, tumor and urethra, were made by a pathologist and a radiologist in collaboration. These annotations included ROI boundary contours and landmark points. Before applying the registration, manual corrections were made for flipping and rotation of WMHs. MSERgSDM comprises two main components: (1) multi-scale representation construction, and (2) SDM construction. For the SDM construction, we collected N = 200 reasonable deformation fields generated using MSERg, verified through visual inspection. Three additional methods, including intensity-based registration, ProsRegNet, and MSERg, were also employed for comparison against MSERgSDM., Results: Our results suggest that MSERgSDM performed comparably to the ground truth (p > 0.05). Additionally, MSERgSDM (ROI Dice ratio = 0.61, landmark distance = 3.26 mm) exhibited significant improvement over MSERg (ROI Dice ratio = 0.59, landmark distance = 3.69 mm) and ProsRegNet (ROI Dice ratio = 0.56, landmark distance = 4.00 mm) in local alignment., Conclusions: This study presents a novel registration method, MSERgSDM, for mapping ex vivo WMH onto in vivo prostate MRI. Our preliminary results demonstrate that MSERgSDM can serve as a valuable tool to map ground truth disease annotations from histopathology images onto MRI, thereby assisting in the development of machine learning models for PCa detection on MRI., (© 2023 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Solitary fibrous tumour (SFT) is a mesenchymal neoplasm with variable behaviour, very rarely involving the genitourinary (GU) tract. Most reported cases correspond to isolated case reports. STAT6 immunohistochemistry is a more recent and reliable diagnostic marker. The pathology database of two tertiary institutes was searched for SFTs involving the GU tract. STAT6 strong diffuse nuclear staining confirmed the diagnosis in all four cases, and the NAB2::STAT6 fusion was demonstrated by NGS in one case. Two cases were diagnosed in needle biopsy, one involving the prostate and the other involving the seminal vesicle. One case corresponded to a pelvic mass inseparable from and infiltrating the prostate and bladder. The remainder represented an exceedingly rare involvement of the spermatic cord. Involvement by a SFT should be considered in the differential diagnosis of spindle cell lesions involving GU organs. STAT6 strong diffuse nuclear staining is an important ancillary tool, particularly in a biopsy., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aims: The distinction of high-grade prostate cancer (PCa) from poorly differentiated urothelial carcinoma (UC) can be somewhat challenging on clinical and morphological grounds alone, yet it is of great importance for prognostication and choice of treatment. GATA3 is a useful immunohistochemical marker to confirm urothelial origin. However, recent works report strong GATA3 immunoexpression in primary high-grade PCa. The aim of this study was to explore GATA3 expression specifically in metastatic PCa., Methods and Results: The pathology databases of four tertiary institutions were queried for cases of metastatic PCa. Available slides and clinical records were reviewed by experienced genitourinary pathologists. Prostatic markers (PSA, PSAP, NKX3.1) and GATA3 immunohistochemistry were performed. A total of 163 metastatic PCa cases were included. At least one prostate marker was positive in each case of non-regional distant metastasis, confirming prostatic origin. GATA3 strong staining was found in four (2.5%) cases: two liver, one bone and one non-regional lymph-node metastases. All four patients had Grade Group 5 PCa at the initial diagnosis. The metastatic prostatic adenocarcinomas were solid, either with no gland formation (n = 3) or with only focal cribriforming (n = 1)., Conclusions: To our knowledge, this is the first study exploring GATA3 expression specifically in metastatic PCa. Despite being infrequent, GATA3 positivity in high-grade PCa may lead to misdiagnosis, with clinical implications. We recommend a panel of immunohistochemical markers, both prostatic and urothelial, for ruling out UC, either in primary tumour samples or in the event of metastases of unknown primary, when a genitourinary origin is suspected., (© 2023 John Wiley & Sons Ltd.)

Prostate cancer remains the second leading cause of cancer death in men in Western cultures. A deeper understanding of the mechanisms by which prostate cancer cells divide to support tumor growth could help devise strategies to overcome treatment resistance and improve survival. Here, we identified that the mitotic AGC family protein kinase citron kinase (CIT) is a pivotal regulator of prostate cancer growth that mediates prostate cancer cell interphase progression. Increased CIT expression correlated with prostate cancer growth induction and aggressive prostate cancer progression, and CIT was overexpressed in prostate cancer compared with benign prostate tissue. CIT overexpression was controlled by an E2F2-Skp2-p27 signaling axis and conferred resistance to androgen-targeted treatment strategies. The effects of CIT relied entirely on its kinase activity. Conversely, CIT silencing inhibited the growth of cell lines and xenografts representing different stages of prostate cancer progression and treatment resistance but did not affect benign epithelial prostate cells or nonprostatic normal cells, indicating a potential therapeutic window for CIT inhibition. CIT kinase activity was identified as druggable and was potently inhibited by the multikinase inhibitor OTS-167, which decreased the proliferation of treatment-resistant prostate cancer cells and patient-derived organoids. Isolation of the in vivo CIT substrates identified proteins involved in diverse cellular functions ranging from proliferation to alternative splicing events that are enriched in treatment-resistant prostate cancer. These findings provide insights into the regulation of aggressive prostate cancer cell behavior by CIT and identify CIT as a functionally diverse and druggable driver of prostate cancer progression., Significance: The poorly characterized protein kinase citron kinase is a therapeutic target in prostate cancer that drives tumor growth by regulating diverse substrates, which control several hallmarks of aggressive prostate cancer progression. See related commentary by Mishra et al., p. 4008., (©2023 American Association for Cancer Research.)

Background. Neuroendocrine differentiation in the prostate gland ranges from clinically insignificant neuroendocrine differentiation detected with markers in an otherwise conventional prostatic adenocarcinoma to a lethal high-grade small/large cell neuroendocrine carcinoma. The concept of neuroendocrine differentiation in prostatic adenocarcinoma has gained considerable importance due to its prognostic and therapeutic ramifications and pathologists play a pivotal role in its recognition. However, its awareness, reporting, and resource utilization practice patterns among pathologists are largely unknown. Methods. Representative examples of different spectrums of neuroendocrine differentiation along with a detailed questionnaire were shared among 39 urologic pathologists using the survey monkey software. Participants were specifically questioned about the use and awareness of the 2016 WHO classification of neuroendocrine tumors of the prostate, understanding of the clinical significance of each entity, and use of different immunohistochemical (IHC) markers. De-identified respondent data were analyzed. Results. A vast majority (90%) of the participants utilize IHC markers to confirm the diagnosis of small cell neuroendocrine carcinoma. A majority (87%) of the respondents were in agreement regarding the utilization of type of IHC markers for small cell neuroendocrine carcinoma for which 85% of the pathologists agreed that determination of the site of origin of a high-grade neuroendocrine carcinoma is not critical, as these are treated similarly. In the setting of mixed carcinomas, 62% of respondents indicated that they provide quantification and grading of the acinar component. There were varied responses regarding the prognostic implication of focal neuroendocrine cells in an otherwise conventional acinar adenocarcinoma and for Paneth cell-like differentiation. The classification of large cell neuroendocrine carcinoma was highly varied, with only 38% agreement in the illustrated case. Finally, despite the recommendation not to perform neuroendocrine markers in the absence of morphologic evidence of neuroendocrine differentiation, 62% would routinely utilize IHC in the work-up of a Gleason score 5 + 5 = 10 acinar adenocarcinoma and its differentiation from high-grade neuroendocrine carcinoma. Conclusion. There is a disparity in the practice utilization patterns among the urologic pathologists with regard to diagnosing high-grade neuroendocrine carcinoma and in understanding the clinical significance of focal neuroendocrine cells in an otherwise conventional acinar adenocarcinoma and Paneth cell-like neuroendocrine differentiation. There seems to have a trend towards overutilization of IHC to determine neuroendocrine differentiation in the absence of neuroendocrine features on morphology. The survey results suggest a need for further refinement and development of standardized guidelines for the classification and reporting of neuroendocrine differentiation in the prostate gland.

Background: around one third of clinically significant prostate cancer (CsPCa) foci are reported to be MRI non-visible (MRI─)., Objective: To quantify the differences between MR visible (MRI+) and MRI ─ CsPCa using intra- and peri-lesional radiomic features on bi-parametric MRI (bpMRI)., Methods: This retrospective and multi-institutional study comprised 164 patients with pre-biopsy 3T prostate multi-parametric MRI from 2014 to 2017. The MRI ─ CsPCa referred to lesions with PI-RADS v2 score < 3 but ISUP grade group > 1. Three experienced radiologists were involved in annotating lesions and PI-RADS assignment. The validation set (D v ) comprised 52 patients from a single institution, the remaining 112 patients were used for training (D t ). 200 radiomic features were extracted from intra-lesional and peri-lesional regions on bpMRI.Logistic regression with least absolute shrinkage and selection operator (LASSO) and 10-fold cross-validation was applied on D t to identify radiomic features associated with MRI ─ and MRI + CsPCa to generate corresponding risk scores R MRI─ and R MRI+ . R bpMRI was further generated by integrating R MRI─ and R MRI+ . Statistical significance was determined using the Wilcoxon signed-rank test., Results: Both intra-lesional and peri-lesional bpMRI Haralick and CoLlAGe radiomic features were significantly associated with MRI ─ CsPCa (p < 0.05). Intra-lesional ADC Haralick and CoLlAGe radiomic features were significantly different among MRI ─ and MRI + CsPCa (p < 0.05). R bpMRI yielded the highest AUC of 0.82 (95 % CI 0.72-0.91) compared to AUCs of R MRI+ 0.76 (95 % CI 0.63-0.89), and PI-RADS 0.58 (95 % CI 0.50-0.72) on D v . R bpMRI correctly reclassified 10 out of 14 MRI ─ CsPCa on D v ., Conclusion: Our preliminary results demonstrated that both intra-lesional and peri-lesional bpMRI radiomic features were significantly associated with MRI ─ CsPCa. These features could assist in CsPCa identification on bpMRI., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Anant Madabhushi reports a relationship with Picture Health that includes: consulting or advisory and equity or stocks. Anant Madabhushi reports a relationship with Elucid Bioimaging that includes: equity or stocks. Anant Madabhushi reports a relationship with Inspirata Inc that includes: equity or stocks. Anant Madabhushi reports a relationship with Aiforia Inc that includes: consulting or advisory. Anant Madabhushi reports a relationship with SimBioSys Inc that includes: consulting or advisory. Anant Madabhushi reports a relationship with Biohme that includes: consulting or advisory. Anant Madabhushi reports a relationship with Castle Biosciences Inc that includes: consulting or advisory. Anant Madabhushi reports a relationship with AstraZeneca that includes: funding grants. Anant Madabhushi reports a relationship with Boehringer Ingelheim Pharmaceuticals Inc that includes: funding grants. Anant Madabhushi reports a relationship with Eli Lilly and Company that includes: funding grants. Anant Madabhushi reports a relationship with Bristol Myers Squibb Co that includes: funding grants. Andrei S Purysko reports a relationship with American College of Radiology that includes: funding grants. Andrei S Purysko reports a relationship with Blue Earth Diagnostics that includes: consulting or advisory, funding grants, and travel reimbursement. Andrei S Purysko reports a relationship with University of Missouri that includes: consulting or advisory. Andrei S Purysko reports a relationship with Koelis that includes: consulting or advisory. Andrei S Purysko reports a relationship with Profound Medical that includes: travel reimbursement. Sree Harsha Tirumani reports a relationship with Radiological Society of North America that includes: funding grants. Andrei S Purysko has patent #Radiomic features of prostate bi-parametric magnetic resonance imaging (BPMRI) associate with decipher score Patent number: 11017896 issued to UNIV CASE WESTERN RESERVE (US) CLEVELAND CLINIC FOUND (US). Anant Madabhushi has patent #US9235887B2 issued to Boston University Rutgers State University of New Jersey University of Pennsylvania Penn Elucid Bioimaging Inc., (© 2023 The Authors.)

Poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPis) have demonstrated antitumor activity in cancers with a homologous recombination deficiency (HRD) and have recently been approved by the FDA for the treatment of germline BRCA1/2- mutation-associated breast cancer. PARPis have also been found to be efficacious in BRCA wild-type ( BRCAwt ) lesions with high genomic loss of heterozygosity (LOH-high). The goal of this study was to retrospectively investigate the tumor mutations in homologous recombination (HRR) genes and the LOH score in advanced-stage breast carcinomas (BCs). Sixty-three patients were included in our study, 25% of whom had HRR gene mutations in their tumors, including 6% BRCA1/2 and 19% non- BRCA -containing gene mutations. An HRR gene mutation was associated with a triple-negative phenotype. Twenty-eight percent of the patients had an LOH-high score, which, in turn, was associated with a high histological grade, a triple-negative phenotype, and a high tumor mutational burden (TMB). Among the six patients who received PARPi therapy, one had a tumor with a PALB2 mutation other than BRCA and had a clinical partial response. Twenty-two percent of the LOH-low tumors had BRCAwt -HRR gene mutations, compared with 11% of the LOH-high tumors. Comprehensive genomic profiling revealed a subset of breast cancer patients with a BRCAwt -HRR gene mutation that would be missed by an LOH test. The necessity of next-generation sequencing coupled with HRR gene analysis for PARPi therapy requires further investigation in clinical trials.

Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is an aggressive, rare genetic disease affecting the kidney and other organ systems. We constructed a specialized multi-institutional cohort of 20 primary FH-deficient RCC cases with aims of characterizing a new commercially available antibody, S-(2-succino)-cysteine (2SC). Herein, we present our findings on the biomarker characterization and performance of 2SC expression by immunohistochemistry (IHC) in FH-deficient RCC and other common and rare RCC subtypes. Morphological assessment revealed characteristic cytomorphologic features and a majority (55%) of FH-deficient RCC had mixed architectural growth patterns. We observed predominantly diffuse and strong cytoplasmic staining with limited nuclear positivity for 2SC staining on IHC. Receiver operating characteristic curves (ROC) for 2SC identified the threshold IHC score (cutoff) as 90, with the sensitivity and specificity being 100% and 91%, respectively. The findings of the present study along with the prior evidence in literature encourage utilization of 2SC as a positive marker along with the loss of FH expression by anti-FH IHC staining as a negative marker, in clinical and/or pathologic scenarios when considering FH-deficient RCC in the differential diagnosis. FH - /2SC + may serve as a comprehensive IHC panel in identifying such cases and excluding morphologically similar entities., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Testicular cancer is the most common solid neoplasm of adult men between the ages of 20 and 40 years. Germ cell tumors account for 95% of all testicular tumors. The assessment of staging is essential to guide further management of patients with testicular cancer and to prognosticate cancer-related outcomes. Postradical orchiectomy treatment options, including adjuvant therapy and active surveillance, vary based on the anatomical extent of disease, serum tumor markers, pathologic diagnosis, and imaging. This review provides an update on the germ cell tumor staging system adopted by the 8th edition of the American Joint Commission on Cancer (AJCC) Staging Manual, treatment implications, risk factors, and predictors of outcomes., (Published by Elsevier Inc.)

A subset of testicular sex cord-stromal tumors (SCST), which includes neoplasms with mixed histology, cannot be classified into a specific histologic subtype. This study evaluated the clinicopathologic, immunophenotypic and molecular features of 26 SCST not amenable to specific classification by expert uropathologists. Median age at diagnosis was 43 years and median tumor size was 2.4 cm. Follow-up information was available for 18 (69%) patients, with evidence of an aggressive clinical course in 6 patients (4 alive with disease, 2 dead of disease 3 months and 6 months after orchiectomy). Microscopically, SCST not amenable to specific classification demonstrated monophasic epithelioid (9/26, 35%), monophasic spindle cell (5/26, 19%), and biphasic or mixed histology (12/26, 46%). One or more aggressive histopathologic features were seen in 11 cases. DNA sequencing was successful in 22 tumors. Pathogenic CTNNB1 and APC alterations were seen in 7 (33%) and 2 (10%) cases, respectively, with additional variants (e.g., CDKN2A, RB1, TP53, BRCA2) being identified in individual cases. Combined evaluation of morphology, sequencing data and beta-catenin immunohistochemistry resulted in reclassification of 6 (23%) tumors as Sertoli cell tumor, not otherwise specified. This was supported by comparing the methylation profiles of a subset of these tumors and those of typical Sertoli cell tumors. Additionally, a subset of 5 neoplasms (19%) with spindle cell or biphasic histology and SMA expression was characterized by hyperdiploid genomes with recurrent chromosomal gains and absence of driver mutations, possibly representing a distinct tumor type. The SCST that remained not amenable to specific histologic classification (15/26, 58%) were enriched for aggressive histologic features and malignant clinical behavior. In conclusion, this study demonstrated that a subset of testicular SCST that were originally not amenable to specific classification could be reclassified by combined evaluation of morphology, immunohistochemistry and molecular data., (© 2022. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

Context.—: The US Food and Drug Administration (FDA) approved immune checkpoint inhibitor therapy for patients with advanced solid tumors that have DNA mismatch repair defects or high levels of microsatellite instability; however, the FDA provided no guidance on which specific clinical assays should be used to determine mismatch repair status., Objective.—: To develop an evidence-based guideline to identify the optimal clinical laboratory test to identify defects in DNA mismatch repair in patients with solid tumor malignancies who are being considered for immune checkpoint inhibitor therapy., Design.—: The College of American Pathologists convened an expert panel to perform a systematic review of the literature and develop recommendations. Using the National Academy of Medicine-endorsed Grading of Recommendations Assessment, Development and Evaluation approach, the recommendations were derived from available evidence, strength of that evidence, open comment feedback, and expert panel consensus. Mismatch repair immunohistochemistry, microsatellite instability derived from both polymerase chain reaction and next-generation sequencing, and tumor mutation burden derived from large panel next-generation sequencing were within scope., Results.—: Six recommendations and 3 good practice statements were developed. More evidence and evidence of higher quality were identified for colorectal cancer and other cancers of the gastrointestinal (GI) tract than for cancers arising outside the GI tract., Conclusions.—: An optimal assay depends on cancer type. For most cancer types outside of the GI tract and the endometrium, there was insufficient published evidence to recommend a specific clinical assay. Absent published evidence, immunohistochemistry is an acceptable approach readily available in most clinical laboratories., Competing Interests: Authors' disclosures of potential conflicts of interest and author contributions are found in the Appendix at the end of this article.

Testicular cancer is the most common solid neoplasm of adult men between the ages of 20 and 40 years. Germ cell tumors account for 95% of all testicular tumors. The assessment of staging is essential to guide further management of patients with testicular cancer and to prognosticate cancer-related outcomes. Postradical orchiectomy treatment options, including adjuvant therapy and active surveillance, vary based on the anatomical extent of disease, serum tumor markers, pathologic diagnosis, and imaging. This review provides an update on the germ cell tumor staging system adopted by the 8th edition of the American Joint Commission on Cancer (AJCC) Staging Manual, treatment implications, risk factors, and predictors of outcomes., (Published by Elsevier Inc.)

Penile intraepithelial neoplasia (PeIN) is classified as human papillomavirus (HPV)- and non-HPV-related. This classification is associated with distinct morphologic subtypes. The natural history and prognosis of PeIN subtypes are not well known. This study aims to evaluate clinicopathological features, HPV status, and outcome of PeIN subtypes. Eighty-two lesions from 64 patients with isolated PeIN were retrospectively reviewed. Mean age was 59 years. Lesions were multicentric in 34% of patients and affected glans (33%), shaft (26%), and foreskin (20%). Histologically, 22% of patients had coexisting lesions, classified as hybrid and mixed. HPV-related PeIN (97%) included basaloid (59%), warty (8%), warty-basaloid (8%), hybrid (19%) and mixed (3%) types. P16 and HPV positivity occurred in 99% and 82% of lesions, respectively. HPV 16 was more common in basaloid PeIN. Multiple genotypes were detected in 35%, more commonly in hybrid PeIN (P = 0.051). Positive margins occurred in 63% of excisions. PeIN recurred in 48% of excisions and 30% of overall repeated procedures, and progression to invasive carcinoma occurred in 2%. At follow-up, 86% of patients had no evidence of disease and 12% were alive with disease. Lichen sclerosus occurred in non-HPV and HPV-related PeIN (100% and 47%).In conclusion, HPV-related and, more specifically basaloid PeIN were the predominant types and preferentially associated with HPV 16. While PeIN had a high recurrence rate, there was a slow and infrequent progression to invasive or metastatic carcinoma with multimodal treatments. Additional studies are needed to understand biology and natural history of PeIN., (© 2022. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

Evidence supporting the safe use of the single-port (SP) robot for partial nephrectomy is scarce. The purpose of this study was to compare perioperative outcomes for patients undergoing robotic assisted SP vs multi-port (MP) partial nephrectomy (PN) in a time-matched cohort. All patients with clinically localized renal masses who underwent robotic PN from January 2019 to March 2020 were evaluated. Patients were stratified according to SP vs MP approach. Postoperative analgesia was administered in accordance with department-wide opioid stewardship protocol and outpatient opioid use was tracked. Total of 78 patients underwent robotic PN with 26 patients in the SP cohort. The majority of renal masses had low-complexity (53, 67.9%) R.E.N.A.L. nephrometry scores, without a significant difference between the two cohorts (p = 0.19). A retroperitoneal approach was performed in 16 (20.5%) patients overall, though more commonly via the SP robotic approach (13 vs 3, p < 0.001). Mean operative time for SP cases was 183.9 ± 63.5 min vs 208.6 ± 65.0 min in the MP cohort (p = 0.12). Rate of conversion to radical nephrectomy was 3.8% vs 9.6% for SP vs MP cases, respectively, (p = 0.37). The majority of patients were discharged on postoperative day one (67.9%) irrespective of operative approach (p = 0.60). There were no differences in inpatient milligram morphine equivalents administered (MME, p = 0.08) or outpatient postoperative MME prescribed (p = 0.21) between the two cohorts. In this retrospective single-institution study, SP robotic approach offers similar short-term perioperative outcomes to MP platforms for minimally invasive, nephron-sparing surgery. Using the SP system was not associated with a reduction in postoperative opioid analgesic requirements., (© 2021. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Aims: Formal depiction of granulomatous inflammation associated with renal neoplasms has mainly consisted of case reports. Herein, we investigate the clinicopathological features and potential significance of granulomas associated with renal tumours from a large multi-institutional cohort., Methods and Results: One hundred and eleven study cases were collected from 22 institutions, including 57 partial nephrectomies and 54 radical nephrectomies. Patient ages ranged from 27 to 85 years (average = 60.1 years; male = 61%). Renal neoplasms included clear cell renal cell carcinoma (RCC; 86%), papillary RCC (8%), chromophobe RCC (3%), clear cell papillary RCC (1%), mixed epithelial stromal tumour (1%) and oncocytoma (1%). Granulomas were peritumoral in 36%, intratumoral in 24% and both in 40% of cases. Total granuloma count per case ranged from one to 300 (median = 15) with sizes ranging from 0.15 to 15 mm (mean = 1.9 mm). Necrotising granulomas were seen in 14% of cases. Histochemical stains for organisms were performed on 45% of cases (all negative). Sixteen cases (14%) had a prior biopsy/procedure performed, and eight patients had neoadjuvant immunotherapy or chemotherapy. Eleven patients (10%) had a confirmed diagnosis of sarcoidosis, including five in whom sarcoidosis was diagnosed after nephrectomy., Conclusion: Based on this largest case-series to date, peri-/intratumoral granulomas associated with renal neoplasms may be more common than initially perceived. The extent of granulomatous inflammation can vary widely and may or may not have necrosis with possible aetiologies, including prior procedure or immunotherapy/chemotherapy. Although a clinical association with sarcoidosis is infrequent it can still occur, and the presence of granulomas warrants mention in pathology reports., (© 2022 John Wiley & Sons Ltd.)

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.)

Purpose: To assess the association of adverse pathology (AP), defined as high-grade (≥ Gleason Grade Group 3) and/or non-organ confined disease, with long-term oncologic outcomes after radical prostatectomy (RP)., Materials and Methods: Using a stratified cohort sampling design, we evaluated the association of AP with the risk of distant metastasis (DM) and prostate cancer-specific mortality (PCSM) up to 20 years after RP in 428 patients treated between 1987 to 2004. Cox regression of cause-specific hazards was used to estimate the absolute risk of both endpoints, with death from other causes treated as a competing risk. Additionally, subgroup analysis in patients with low and/or intermediate-risk disease, who are potentially eligible for active surveillance (AS), was performed., Results: Within the cohort sample, 53% of men exhibited AP at time of RP, with median follow up of 15.5 years (IQR 14.6-16.6 years) thereafter. Adverse pathology was highly associated with DM and PCSM in the overall cohort (HR 12.30, 95% confidence interval [CI] 5.30-28.55, and HR 10.03, 95% CI 3.42-29.47, respectively, both P < 0.001). Adverse pathology was also highly associated with DM and PCSM in the low/intermediate-risk subgroup (HR 10.48, 95% CI 4.18-26.28, and 8.60, 95% CI 2.40-30.48, respectively, both P < 0.001)., Conclusions: Adverse pathology at the time of RP is highly associated with future development of DM and PCSM. Accurate prediction of AP may thus be useful for individualizing risk-based surveillance and treatment strategies., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The 8th Edition of the American Joint Committee on Cancer (AJCC) Staging Manual designates discontinuous involvement of spermatic cord soft tissue by testicular germ cell tumors as a metastatic deposit. We conducted a retrospective international multi-institutional study to validate the current recommendations. Thirty-three (72%) nonseminomatous and 13 (28%) seminomatous testicular germ cell tumors were collected from 15 institutions in America, Europe, and Asia. Testicular tumor size ranged from 1.3 to 18.0 cm (mean: 6.1). Cases were classified as discontinuous involvement of spermatic cord soft tissue (n = 26), continuous cord involvement (n = 17), or cord lymphovascular invasion (n = 3). The mean follow-up was 39 months. Clinical stage for discontinuous involvement of spermatic cord soft-tissue patients was I (local disease) in 2/24 (8%), II (regional disease) in 6/24 (25%), and III (distant disease) in 16/24 (67%) cases; 16 (67%) patients presented with distant metastasis. Clinical stage for continuous cord involvement patients was I in 9/17 (53%), II in 4/17 (23%), and III in 4/17 (23%); 4 (23%) patients presented with distant metastasis. Disease progression was seen in 4 patients with discontinuous involvement of spermatic cord soft tissue and 5 with continuous cord-involvement (p = 0.699). When comparing discontinuous and continuous cord involvement, a significant difference was found in cord margin status (p = 0.044), spermatic cord tumor size (p = 0.016), lymph-node involvement (p = 0.037), distant metastasis (p = 0.010), individual clinical stage (p = 0.003), and nonadvanced vs. advanced disease (p = 0.003) at presentation. In multivariate analysis, after adjusting for age, histology, testicular tumor size, percent of embryonal carcinoma, lymphovascular invasion, and cord margin status, discontinuous involvement of spermatic cord soft tissue was significantly associated (p = 0.011) with advanced clinical stage at presentation. Our findings support the designation of metastatic disease for discontinuous involvement of spermatic cord soft tissue, as introduced by the 8th edition of the AJCC staging., (© 2021. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)