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Ovarian-type (ie, Mullerian) epithelial tumors occurring in the testicular and paratesticular regions are exceptionally rare, with only a handful reported worldwide. Serous tumors are the most frequently encountered subtype among these rare tumors. The pathogenesis of these tumors within the testicular and paratesticular regions remains a subject of intrigue and debate, with various hypotheses attempting to explain their presence in the paratestis region, where most tumors occur. However, our understanding of the pathogenesis of intratesticular tumors is limited. To date, 11 known examples of intratesticular serous Mullerian tumors have been reported globally. In this report, we present an extraordinary tumor, an intratesticular Mullerian serous borderline tumor with foci of microinvasion, in a 38-year-old male patient. This tumor exhibits histological features similar to their ovarian counterparts and is confirmed through an immunohistochemical panel. Our report underscores the extreme rarity of these tumors, emphasizes the importance of heightened awareness among clinicians and pathologists, and provides valuable insights into their complex development and histogenesis. This contribution aims to enhance diagnostic precision and optimize therapeutic strategies for similar tumors., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Oncocytic renal neoplasms are a major source of diagnostic challenge in genitourinary pathology; however, they are typically nonaggressive in general, raising the question of whether distinguishing different subtypes, including emerging entities, is necessary. Emerging entities recently described include eosinophilic solid and cystic renal cell carcinoma (ESC RCC), low-grade oncocytic tumor (LOT), eosinophilic vacuolated tumor (EVT), and papillary renal neoplasm with reverse polarity (PRNRP). A survey was shared among 65 urologic pathologists using SurveyMonkey.com (Survey Monkey, Santa Clara, CA, USA). De-identified and anonymized respondent data were analyzed. Sixty-three participants completed the survey and contributed to the study. Participants were from Asia (n = 21; 35%), North America (n = 31; 52%), Europe (n = 6; 10%), and Australia (n = 2; 3%). Half encounter oncocytic renal neoplasms that are difficult to classify monthly or more frequently. Most (70%) indicated that there is enough evidence to consider ESC RCC as a distinct entity now, whereas there was less certainty for LOT (27%), EVT (29%), and PRNRP (37%). However, when combining the responses for sufficient evidence currently and likely in the future, LOT and EVT yielded > 70% and > 60% for PRNRP. Most (60%) would not render an outright diagnosis of oncocytoma on needle core biopsy. There was a dichotomy in the routine use of immunohistochemistry (IHC) in the evaluation of oncocytoma (yes = 52%; no = 48%). The most utilized IHC markers included keratin 7 and 20, KIT, AMACR, PAX8, CA9, melan A, succinate dehydrogenase (SDH)B, and fumarate hydratase (FH). Genetic techniques used included TSC1/TSC2/MTOR (67%) or TFE3 (74%) genes and pathways; however, the majority reported using these very rarely. Only 40% have encountered low-grade oncocytic renal neoplasms that are deficient for FH. Increasing experience with the spectrum of oncocytic renal neoplasms will likely yield further insights into the most appropriate work-up, classification, and clinical management for these entities., Competing Interests: Declarations Conflict of interest The authors declare no competing interests., (© 2024. The Author(s).)

Aims: Recently, SOX17 has emerged as a promising biomarker for non-mucinous Müllerian (ovarian and endometrial) carcinomas, demonstrating increased specificity in comparison to PAX8 while maintaining similar sensitivity. However, expression of SOX17 in mesonephric-like adenocarcinoma (MLA), a carcinoma of the female genital tract with uncertain, but probably Müllerian histogenesis, remains unexplored. This study aims to address this gap., Methods and Results: SOX17 immunohistochemistry was performed on whole tissue sections from 68 MLAs originating from the endometrium or ovary and seven cervical mesonephric carcinomas, as well as six mesonephric remnants/hyperplasias. Using a four-tiered scoring system based on distribution and intensity of staining, 68% of MLA displayed a negative/low (< 10%) SOX17 expression pattern, which contrasts with the high expression observed in most Müllerian carcinomas. However, 22% of MLA demonstrated high SOX17 expression, similar to other endometrial and ovarian carcinomas. Similarly, five of seven (72%) mesonephric carcinomas of the cervix were SOX17-negative, but two cases (28%) were positive. All mesonephric remnants/hyperplasias were SOX17 negative., Conclusions: The majority of MLA are negative or exhibit low SOX17 expression, in contrast to the diffuse and strong expression commonly seen in other types of Müllerian carcinoma. However, a subset of MLAs demonstrate high SOX17 expression. Therefore, absence of SOX17 staining is supportive for MLA when the differential includes another non-mucinous Müllerian carcinoma. SOX17 may also be useful for differentiating mesonephric remnants/hyperplasias from Müllerian malignancies and benign Müllerian glandular lesions., (© 2024 John Wiley & Sons Ltd.)

Spindle cell-rich testicular sex cord-stromal tumors (TSCSTs) comprise a group that includes mostly (but not exclusively): myoid gonadal stromal tumor (MGST), adult granulosa cell tumor (AGCT), and unclassified TSCST. These entities demonstrate histopathologic overlap, and prior genomic studies have failed to identify specific oncogenic drivers. Results of DNA sequencing suggest that different types of spindle cell-rich TSCSTs harbor a recurrent pattern of chromosomal gains. However, these results have not been validated by alternative methods and the extent of these changes within individual tumors remains unknown. We used a combination of commercially available fluorescence in-situ hybridization (FISH) probes (3q11.2, 6p24.3, 6q11.1, 6q23, 7q11.21-q11.22, 9p21.3, 11q13.3, 17p11.2) to enumerate a subset of chromosomes identified as altered (gained) in prior studies. We analyzed 10 cases (3 MGST, 4 unclassified TSCST, 3 AGCT), including 7 that had been previously sequenced. FISH demonstrated gains of chromosomes 3, 6, 7, 9, and 11 above the pre-established threshold (25%) in 50%, 80%, 70%, 20%, and 40% of cases, respectively, with gains of chromosome 17 being present in only 1 unclassified TSCST. The proportion of cells with chromosomal gains ranged from 26% to 60%. Tumors with available copy number data from prior genomic analyses showed a partial discordance between FISH and sequencing results. This study demonstrates that spindle-cell rich TSCSTs harbor a recurrent pattern of chromosomal gains, which are present in variable subsets of neoplastic cells. Further studies are needed to determine if these chromosomal changes represent a mechanism relevant for oncogenesis or a secondary event., Competing Interests: Declaration of competing interest The authors declare that they have no financial or intellectual conflicts of interest pertaining to the contents of this manuscript., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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.)

Background: Papillary renal neoplasm with reverse polarity is a recently recognized low-grade neoplasm with a favorable prognosis. To date, its cytologic features have not been well documented., Methods: Two patients with papillary renal neoplasm with reverse polarity sampled by fine needle aspiration and core needle biopsy are described, one of whom is under active surveillance without clinical progression and the other is alive and well 16 years after partial nephrectomy., Results: The cytologic features included a mix of papillae and dispersed cells with abundant oncocytic cytoplasm and round, bland nuclei apically displaced away from the papillary core. Immunohistochemistry showed positive staining for GATA3 in both cases. Molecular studies on one of the cases showed a KRAS p.G12V mutation., Conclusions: The cytologic features of this distinctive, indolent neoplasm are important to recognize because patients with papillary renal neoplasm with reverse polarity may be excellent candidates for partial nephrectomy or even active surveillance., (© 2024 American Cancer Society.)

Prepubertal-type teratomas are uncommon, especially in postpubertal male patients. We document a case of a 28-year-old man with a lifelong history of bilateral testicular masses who presented with scrotal fistulas and no clinical evidence of extratesticular disease. Bilateral radical orchiectomies demonstrated large bilateral solid and cystic masses that contained grossly visible hairs. Microscopically, both tumors consisted of pure teratomas comprising a mixture of mature tissues derived from the three embryonic layers. Germ cell neoplasia in situ was not identified, and fluorescence in situ hybridization studies demonstrated the absence of i(12p), supporting a diagnosis of prepubertal-type teratoma. The absence of metastases in this patient with longstanding tumors highlights the benign nature of prepubertal-type teratomas affecting postpubertal patients. Furthermore, this case illustrates that at least a subset of prepubertal-type teratomas seen in adult men represent a late diagnosis of a largely pediatric entity. Additionally, we performed a comprehensive review of the literature on this topic., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aims: The 2022 WHO classification for kidney tumours recently downgraded clear cell tubulopapillary (also known as clear cell papillary) renal cell carcinoma (RCC) to a benign neoplasm (i.e. clear cell tubulopapillary renal cell tumour) based on the overwhelmingly banal nature of this neoplasm. However, it has been recognized that some clear cell tubulopapillary renal cell tumours demonstrate vascular, adipose or pelvicalyceal invasion, raising the possibility of more aggressive behaviour. The goal of this study was to determine if these 'high stage' features have an effect on tumour prognosis, warranting a carcinoma designation., Methods and Results: After excluding cases with tissue artefact (i.e. prior core biopsy track changes) and other RCC subtypes with next-generation sequencing, nine clear cell tubulopapillary renal cell tumours with these so-called 'high stage' features, and otherwise classic morphologic and immunophenotypic findings, including low-grade cytology and 'cup-like' CA9 expression, were evaluated. Median tumour size was 2.2 cm with a range of 0.8 to 6.7 cm. Eight cases (89%) demonstrated perinephric or hilar adipose tissue invasion, although most of these cases showed a bulging (in contrast to an infiltrative) growth pattern. One case demonstrated renal vascular invasion in addition to hilar adipose tissue invasion, and one case demonstrated extension into the pelvicalyceal system. There were no recurrences or evidence of metastatic disease., Conclusion: These overall findings continue to support the benign designation for clear cell tubulopapillary renal cell tumours, despite morphologic features that might raise the possibility of a 'higher stage' neoplasm., (© 2024 John Wiley & Sons Ltd.)

Purpose: The 2022 World Health Organization classification of renal neoplasia expanded the spectrum of oncocytic neoplasms to encompass newly established and emerging entities; one of the latter is the low-grade oncocytic tumor (LOT). This study reports the radiologic appearance and clinical behavior of LOT., Methods: In this IRB-approved, HIPPA-compliant retrospective study, our institution's pathology database was searched for low-grade oncocytic tumors or neoplasms. Patient age, gender, and comorbidities were obtained from a review of electronic medical records, and imaging characteristics of the tumors were assessed through an imaging platform., Results: The pathology database search yielded 14 tumors in 14 patients. Four patients were excluded, as radiologic images were not available in three, and one did not fulfill diagnostic criteria after pathology re-review. The resulting cohort consisted of 10 tumors (median diameter 2.3 cm, range 0.7-5.1) in 10 patients (median age 68 years, range 53-91, six women). All tumors presented as a solitary, well-circumscribed, mass with solid components. All enhanced as much or almost as much as adjacent renal parenchyma; all but one enhanced heterogeneously. None had lymphadenopathy, venous invasion, or metastatic disease at presentation or at clinical follow-up (median, 22.2 months, range 3.4-71.6). Among five tumors undergoing active surveillance, mean increase in size was 0.4 cm/year at imaging follow-up (median 16.7 months, range 8.9-25.4)., Conclusion: LOT, a recently described pathologic entity in the kidney, can be considered in the differential diagnosis of an avidly and typically heterogeneously enhancing solid renal mass in an adult patient., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction/background: Immune checkpoint inhibitors (ICIs) have limited efficacy in prostate cancer (PCa). Better biomarkers are needed to predict responses to ICIs. We sought to demonstrate that a panel-based mutational signature identifies mismatch repair (MMR) deficient (MMRd) PCa and is a biomarker of response to pembrolizumab., Patients and Methods: Clinico-genomic data was obtained for 2664 patients with PCa sequenced at Dana-Farber Cancer Institute (DFCI) and Memorial Sloan Kettering (MSK). Clinical outcomes were collected for patients with metastatic castration-resistant PCa (mCRPC) treated with pembrolizumab at DFCI. SigMA was used to characterize tumors as MMRd or MMR proficient (MMRp). The concordance between MMRd with microsatellite instability (MSI-H) was assessed. Radiographic progression-free survival (rPFS) and overall survival (OS) were collected for patients treated with pembrolizumab. Event-time distributions were estimated using Kaplan-Meier methodology., Results: Across both cohorts, 100% (DFCI: 12/12; MSK: 43/43) of MSI-H tumors were MMRd. However, 14% (2/14) and 9.1% (6/66) of MMRd tumors in the DFCI and MSK cohorts respectively were microsatellite stable (MSS), and 26% (17/66) were MSI-indeterminate in the MSK cohort. Among patients treated with pembrolizumab, those with MMRd (n = 5) versus MMRp (n = 14) mCRPC experienced markedly improved rPFS (HR = 0.088, 95% CI: 0.011-0.70; P = .0064) and OS (HR = 0.11, 95% CI: 0.014-0.80; P = .010) from start of treatment. Four patients with MMRd experienced remissions of >= 2.5 years., Conclusion: SigMA detects additional cases of MMRd as compared to MSI testing in PCa and identifies patients likely to experience durable response to pembrolizumab., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The differential diagnosis for oncocytic renal tumors spans the spectrum from benign entities to more aggressive renal cell carcinomas (RCC). Recent work has characterized a provisional renal oncocytic neoplasm, namely the low-grade oncocytic tumor (LOT), which demonstrates overlapping morphologic features with oncocytoma and chromophobe RCC, but also has a unique immunoprofile (ie, diffusely positive for KRT7, negative for KIT) and a high rate (80% to 100%) of mTOR pathway gene alterations. Given the diagnostic overlap among oncocytic tumors, we looked for concordance between mTOR pathway mutations and LOT. Thirty low-grade renal oncocytic neoplasms underwent histologic review and immunohistochemistry for KRT7 and KIT. Tumors were classified as "determinate" (eg, LOT) for tumors with solid, nested or vaguely tubular growth and diffuse KRT7 staining and negative KIT, or "indeterminate" if the morphology and/or immunostains did not fully support a definitive LOT diagnosis. Next-generation sequencing was performed without any knowledge of the diagnoses, and identified mTOR pathway mutations in 80% (12/15) of the determinate tumors, compared with 7% (1/15) in the indeterminate group. One determinate tumor was reclassified as papillary RCC ( MTOR mutation negative) and 6 indeterminate tumors were confirmed to be oncocytoma (N = 4), clear cell RCC or papillary RCC with reverse polarity, respectively. Overall, integration of morphology, immunohistochemistry, and molecular data enabled a final definitive diagnosis for 70% of tumors (21 of the total 30), with a high concordance (93%) for LOT specifically in the determinate group; the remaining 9 tumors (30%) were classified as renal oncocytic neoplasm, not otherwise specified., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ovarian immature teratoma (IT) is a rare neoplasm comprising ∼3% of ovarian cancers, occurring primarily in young females. Management presents several challenges, including those with elevated serum alpha-fetoprotein, potential confusion regarding pathology interpretation, and paucity of data to support decision-making. MaGIC (https://magicconsortium.com/) is an interdisciplinary international consortium of GCT experts from multiple subspecialties, with members receiving frequent queries regarding IT patient management. With evidence from published literature where available, we summarise consensus management of such patients. Given lack of published data, controversy in certain areas remains. The most obvious variance in practice is between paediatric and adult teams, despite very similar outcomes. Paediatric teams typically employ a surgery-only approach, whereas in adult practice, all patients, except those with stage IA, grade 1 (low-grade) tumours, still generally receive adjuvant chemotherapy. Given the rarity of ovarian IT and lack of published data, discussion with GCT experts and/or national advisory panels is recommended., Competing Interests: The authors have no conflicts to declare., (© 2024 The Author(s).)

Sarcomatoid transformation occurs in ∼8% of chromophobe renal cell carcinoma (chRCC) and is associated with aggressive clinical behavior. In recent years, several studies have identified genomic, transcriptomic, and epigenomic correlates of aggressive behavior in chRCC; however, the molecular mechanisms associated with sarcomatoid transformation remain incompletely understood. In this study, we analyzed paired conventional and sarcomatoid histologic components of individual chRCC to elucidate the genomic alterations that underlie sarcomatoid transformation in this tumor type. Massively parallel sequencing was performed on paired (conventional and sarcomatoid) components from 8 chRCCs. All cases harbored TP53 variants (87.5% showing TP53 variants in both components and 12.5% only in the sarcomatoid component). Intratumor comparisons revealed that TP53 variants were concordant in 71% and discordant in 29% of cases. Additional recurrent single-nucleotide variants were found in RB1 (37.5% of cases) and PTEN (25% of cases), with the remaining single-nucleotide variants detected in these tumors (PBRM1, NF1, and ASXL1) being nonrecurrent. Copy number variant analysis showed the characteristic pattern of chromosomal losses associated with chRCC (1, 2, 6, 10, 13, 17, and 21) in the conventional histologic components only. Interestingly, the sarcomatoid components of these tumors demonstrated widespread loss of heterozygosity but lacked the above chromosomal losses, likely as a consequence of whole-genome duplication/imbalanced chromosomal duplication events. Overall, the findings suggest that TP53 variants followed by whole-genome duplication/imbalanced chromosomal duplication events underlie sarcomatoid transformation in chRCC., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Spermatocytic tumor (ST) is a rare type of germ cell tumor that occurs exclusively in the postpubertal testis and typically affects elderly men. Most STs are benign, but rare cases exhibit aggressive clinical behavior, often in association with transition to sarcomatoid histology. Limited molecular analyses have been performed on STs; therefore, their genomic and epigenomic features remain incompletely described. Twenty-seven samples from 25 individual patients were analyzed with a combination of DNA sequencing panels, genomic methylation profiling, SNP array, isochromosome (12p) [i(12p)] FISH, and immunohistochemistry. The series included five metastasizing tumors (three with sarcomatoid transformation, one anaplastic, and one conventional) and 20 non-metastasizing tumors (14 anaplastic and six conventional). Anaplastic tumors comprised a monomorphic population of intermediate-sized neoplastic cells, as previously described. Multiomic analyses demonstrated that there were two genomic subgroups of STs: one with diploid genomes and hotspot RAS/RAF variants and the other with global ploidy shift and absence of recurrent mutations. Relative gain of chromosome 9 was a consistent finding in both subgroups. A comparison of metastasizing and non-metastasizing cases demonstrated that aggressive behavior was associated with the acquisition of pathogenic TP53 mutations and/or relative gains of 12p/i(12p). In cases with sarcomatoid transformation, TP53 mutations seem to underlie the transition to sarcomatoid histology. Genomic methylation analysis demonstrated that aggressive cases with gains of 12p cluster closer to pure seminomas than to STs without gains of 12p. In conclusion, STs include two genomic subgroups, characterized by global ploidy shifts without recurrent mutations and diploid genomes with RAS/RAF hotspot mutations, respectively. Biologic progression was associated with relative gains of 12p and TP53 mutations. The findings in STs with relative gains of 12p suggest that they may exhibit biologic characteristics akin to those seen in germ cell neoplasia in situ-related germ cell tumors rather than non-germ cell neoplasia in situ-derived STs. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

Sertoli cell tumor (SCT) is the second most common type of sex cord-stromal tumor in men, and ∼10% exhibit malignant behavior. Although CTNNB1 variants have been described in SCTs, only a limited number of metastatic cases have been analyzed, and the molecular alterations associated with aggressive behavior remain largely unexplored. This study evaluated a series of nonmetastasizing and metastasizing SCTs using next-generation DNA sequencing to further characterize their genomic landscape. Twenty-two tumors from 21 patients were analyzed. Cases were divided into metastasizing SCTs and nonmetastasizing SCTs. Nonmetastasizing tumors were considered to have aggressive histopathologic features if they exhibited ≥1 of the following: size >2.4 cm, necrosis, lymphovascular invasion, ≥3 mitoses per 10 high-power fields, severe nuclear atypia, or invasive growth. Six patients had metastasizing SCTs, and the remaining 15 patients had nonmetastasizing SCTs; 5 nonmetastasizing tumors had ≥1 aggressive histopathologic feature(s). Gain-of-function CTNNB1 or inactivating APC variants were highly recurrent in nonmetastasizing SCTs (combined frequency >90%), with arm-level/chromosome-level copy number variants, loss of 1p, and CTNNB1 loss of heterozygosity occurring exclusively in CTNNB1-mutant tumors with aggressive histopathologic features or size >1.5 cm. Nonmetastasizing SCTs were almost invariably driven by WNT pathway activation. In contrast, only 50% of metastasizing SCTs harbored gain-of-function CTNNB1 variants. The remaining 50% of metastasizing SCTs were CTNNB1-wild-type and harbored alterations in the TP53, MDM2, CDKN2A/CDKN2B, and TERT pathways. These findings suggest that ∼50% of aggressive SCTs represent progression of CTNNB1-mutant benign SCTs, whereas the remaining ones are CTNNB1-wild-type neoplasms that exhibit alterations in genes of the TP53, cell cycle regulation, and telomere maintenance pathways., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Aims: Extramammary Paget disease (EMPD) is an epithelial neoplasm that can occur at many sites, including the vulva and scrotum. EMPD is characterised by the presence of neoplastic cells, in single cells and clusters, that infiltrate all layers of non-neoplastic squamous epithelium. The differential diagnosis for EMPD includes melanoma in situ and secondary involvement of tumours from other sites, such as urothelial or cervical; pagetoid spread of tumor cells can also been seen at other sites, such as anorectal mucosa. The most frequently utilised biomarkers for confirming the diagnosis of EMPD include CK7 and GATA3; however, these biomarkers lack specificity. The purpose of this study was to evaluate TRPS1, a newly described breast biomarker, in pagetoid neoplasms of the vulva, scrotum and anorectum., Methods and Results: Fifteen cases of primary EMPD of the vulva (two with associated invasive carcinoma) and four primary EMPD of the scrotum showed strong nuclear immunoreactivity for TRPS1. In contrast, five cases of vulvar melanoma in situ, one case of urothelial carcinoma with secondary pagetoid spread into the vulva and two anorectal adenocarcinomas with pagetoid spread into anal skin (one with associated invasive carcinoma) were negative for TRPS1. Additionally, weak nuclear TRPS1 staining was observed in non-neoplastic tissues (e.g. keratinocytes), but always with less intensity when compared to tumour cells., Conclusions: These results demonstrate that TRPS1 is a sensitive and specific biomarker for EMPD, and may be especially useful for excluding secondary involvement of the vulva by urothelial and anorectal carcinomas., (© 2023 John Wiley & Sons Ltd.)

Perivascular epithelioid cell tumors (PEComas) are a distinctive group of mesenchymal neoplasms that demonstrate features of smooth muscle and melanocytic differentiation. Here, we present the clinicopathologic, immunohistochemical, and molecular features of 15 uterine sarcomas diagnosed as malignant PEComa. The median patient age was 56 years (range: 27 to 86 y). The median tumor size was 8.0 cm (range: 5.0 to 14.0 cm). All tumors were classified as malignant based on the presence of mitoses (15/15; 100%), necrosis (15/15; 100%), lymphovascular invasion (8/15; 53%), and high nuclear grade (13/15; 87%). Molecular analysis revealed the mammalian target of rapamycin pathway gene mutations in 7 cases (47%), including mutually exclusive variants in TSC1 (27%) and TSC2 (20%). Recurrent alterations were also identified in TP53 (53%), RB1 (30%), ATRX (33%), and BRCA2 (13%). Tumors with inactivating ATRX mutations all demonstrated loss of ATRX expression by immunohistochemistry. Loss of expression was also observed in 2 tumors without demonstrable ATRX alterations. Clinical follow-up was available for 14 patients (range: 5 to 92 mo; median: 15 mo). Five patients developed local recurrence and 9 developed metastases; 2 patients died of their disease. Our series expands the spectrum of molecular events in tumors diagnosed as malignant PEComa and further highlights the important role of targeted sequencing in tumors with focal melanocytic marker expression., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Rationale and Objectives: The study aims to propose an optimal workflow in patients with a PI-RADS 3 (PR-3) assessment category (AC) through determining the timing and type of pathology interrogation used for the detection of clinically significant prostate cancer (csPCa) in these men based upon a 5-year retrospective review in a large academic medical center., Materials and Methods: This United States Health Insurance Probability and Accountability Act (HIPAA)-compliant, institutional review board-approved retrospective study included men without prior csPCa diagnosis who received PR-3 AC on magnetic resonance (MR) imaging (MRI). Subsequent incidence and time to csPCa diagnosis and number/type of prostate interventions was recorded. Categorical data were compared using Fisher's exact test and continuous data using ANOVA omnibus F -test., Results: Our cohort of 3238 men identified 332 who received PR-3 as their highest AC on MRI, 240 (72.3%) of whom had pathology follow-up within 5 years. csPCa was detected in 76/240 (32%) and non-csPCa in 109/240 (45%) within 9.0 ± 10.6 months. Using a non-targeted trans-rectal ultrasound biopsy as the initial approach ( n  = 55), another diagnostic procedure was required to diagnose csPCa in 42/55 (76.4%) of men, compared with 3/21(14.3%) men with an initial MR targeted-biopsy approach ( n  = 21); ( p  < 0.0001). Those with csPCa had higher median serum prostate-specific antigen (PSA) and PSA density, and lower median prostate volume ( p  < 0.003) compared with non-csPCa/no PCa., Conclusion: Most patients with PR-3 AC underwent prostate pathology exams within 5 years, 32% of whom were found to have csPCa within 1 year of MRI, most often with a higher PSA density and a prior non-csPCa diagnosis. Addition of a targeted biopsy approach initially reduced the need for a second biopsy to reach a for csPCa diagnosis. Thus, a combination of systematic and targeted biopsy is advised in men with PR-3 and a co-existing abnormal PSA and PSA density., Competing Interests: Grant disclosures are added at the beginning of the article. The remaining authors have no disclosures or possible conflict of interest and/or commercial involvement related to contents of his manuscript., (© 2023 The Authors. BJUI Compass published by John Wiley & Sons Ltd on behalf of BJU International Company.)

Background There is uncertainty in the management of renal masses diagnosed as oncocytomas with image-guided percutaneous biopsy. Purpose To assess the reliability of a diagnosis of oncocytoma based on image-guided percutaneous renal mass biopsy and evaluate patient outcomes following different management strategies. Materials and Methods In this retrospective study, image-guided percutaneous biopsy pathology reports from April 2004 to April 2019 were searched for keywords "oncocytoma" and "oncocytic neoplasm" and compared with surgical pathology or repeat biopsy results. Patients with at least 12 months of clinical follow-up and known cause of death were grouped according to management strategies, and disease-specific survival and metastatic renal cell carcinoma (RCC)-free survival were compared. Mass growth rates were calculated with use of a normal linear mixed model. Results The database yielded 160 biopsy reports of 149 renal masses in 139 patients; 149 masses were categorized as oncocytoma ( n = 107), likely oncocytoma ( n = 12), oncocytic neoplasm ( n = 28), and indeterminate with oncocytoma in differential ( n = 2). Biopsied masses categorized as oncocytoma or likely oncocytoma were oncocytomas in 16 of 17 masses (94%) based on surgical pathology or repeat biopsy; four of eight masses (50%) categorized as oncocytic neoplasms were low-grade RCCs. Outcome analysis included 121 patients (mean age ± SD, 68 years ± 9.1; 82 men); 80 patients initially underwent active surveillance (11 were later treated), 33 underwent ablation, and eight underwent surgery. Disease-specific survival and metastatic-free survival were 100% after each management strategy (median follow-up, 86.6 months; range, 14.2-207.9 months). Mass growth rate (mean, 1.7 mm per year) showed no evidence of a significant difference among biopsy result categories ( P = .37) or initial ( P = .84) or final management strategies ( P = .11). Conclusion Image-guided percutaneous biopsy diagnosis of renal oncocytoma was reliable. Although some masses diagnosed as oncocytic neoplasms were low-grade renal cell carcinomas (RCCs) at final diagnosis, no patients died of RCC, including those managed with active surveillance. © RSNA, 2023 See also the editorial by Lockhart in this issue.

Long interspersed element 1 (LINE-1) open reading frame 1 protein (ORF1p) expression is a common feature of many cancer types, including high-grade serous ovarian carcinoma (HGSOC). Here, we report that ORF1p is not only expressed but also released by ovarian cancer and primary tumor cells. Immuno-multiple reaction monitoring-mass spectrometry assays showed that released ORF1p is confidently detectable in conditioned media, ascites, and patients' plasma, implicating ORF1p as a potential biomarker. Interestingly, ORF1p expression is detectable in fallopian tube (FT) epithelial precursors of HGSOC but not in benign FT, suggesting that ORF1p expression in an early event in HGSOC development. Finally, treatment of FT cells with DNA methyltransferase inhibitors led to robust expression and release of ORF1p, validating the regulatory role of DNA methylation in LINE-1 repression in non-tumorigenic tissue., (© 2023. The Author(s).)

While the mutational and transcriptional landscapes of renal cell carcinoma (RCC) are well-known, the epigenome is poorly understood. We characterize the epigenome of clear cell (ccRCC), papillary (pRCC), and chromophobe RCC (chRCC) by using ChIP-seq, ATAC-Seq, RNA-seq, and SNP arrays. We integrate 153 individual data sets from 42 patients and nominate 50 histology-specific master transcription factors (MTF) to define RCC histologic subtypes, including EPAS1 and ETS-1 in ccRCC, HNF1B in pRCC, and FOXI1 in chRCC. We confirm histology-specific MTFs via immunohistochemistry including a ccRCC-specific TF, BHLHE41. FOXI1 overexpression with knock-down of EPAS1 in the 786-O ccRCC cell line induces transcriptional upregulation of chRCC-specific genes, TFCP2L1, ATP6V0D2, KIT, and INSRR, implicating FOXI1 as a MTF for chRCC. Integrating RCC GWAS risk SNPs with H3K27ac ChIP-seq and ATAC-seq data reveals that risk-variants are significantly enriched in allelically-imbalanced peaks. This epigenomic atlas in primary human samples provides a resource for future investigation., (© 2023. The Author(s).)

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.)

A small subset of male germ cell tumors (GCT) demonstrates overgrowth of histologic components that resemble somatic malignancies (e.g., sarcoma, carcinoma). The presence of so-called "somatic-type" malignancies (SM) in GCT has been associated with chemotherapy-resistance and poor clinical outcomes in prior studies. However, the molecular characteristics of these tumors remain largely undescribed. In this study, we performed a multi-platform molecular analysis of GCTs with SM diagnosed in 36 male patients (primary site: testis, 29 and mediastinum, 7). The most common histologic types of SM were sarcoma and embryonic-type neuroectodermal tumor (ENT, formerly known as "PNET"), present in 61% and 31% of cases, respectively. KRAS and TP53 mutations were identified by DNA sequencing in 28% of cases each, with enrichment of TP53 mutations in mediastinal tumors (86%). Gains in the short arm of chromosome 12 were seen in 91% of cases, likely reflecting the presence of isochromosome 12p. Numerous copy number changes indicative of widespread aneuploidy were found in 94% of cases. Focal homozygous deletions and amplifications were also detected, including MDM2 amplifications in 16% of cases. Sequencing of paired samples in 8 patients revealed similar mutational and copy number profiles in the conventional GCT and SM components. Oncogenic gene fusions were not detected using RNA sequencing of SM components from 9 cases. DNA methylation analysis highlighted the distinct methylation profile of SM components that sets them apart from conventional GCT components. In conclusion, GCT with SM are characterized by widespread aneuploidy, a distinct epigenetic signature and the presence of mutations that are otherwise rare in testicular GCT without SM. The similarity of the mutational and DNA methylation profiles of different histologic types of SM suggests that the identification of SM components could be more important than their precise histologic subclassification, pending confirmation by further studies., (© 2022. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

Aims: Biphasic hyalinizing psammomatous (BHP) renal cell carcinoma (RCC) is a newly described emerging entity within the spectrum of papillary RCC in the WHO 2022 classification. Molecular analyses have discovered that BHP RCC consistently harbour somatic mutations in the neurofibromin 2 (NF2) gene. The NF2 gene product, merlin, is known to primarily function as a tumour suppressor. Merlin protein loss correlates closely with the presence of NF2 mutations in benign and malignant tumours arising in different sites. In the present study we explored the role of merlin immunohistochemistry (IHC) in tumours within the spectrum of BHP RCC to determine the diagnostic utility of this marker., Materials and Methods: We performed merlin IHC in 13 BHP RCC, 18 papillary RCC, 10 TFE3-translocation RCC, 15 TFEB-altered RCC (including 13 TFEB-rearranged and 2 TFEB-amplified), and 10 mucinous tubular and spindle cell carcinomas of unknown mutational status., Results: Unequivocal loss of merlin expression in >90% of the tumour cells was observed in 12/13 BHP-RCC (92%), with the remaining tumour demonstrating weak focal cytoplasmic expression in ~10% of the tumour. In contrast, merlin was diffusely or multifocally expressed in all papillary RCC, TFE3-translocation RCC, and TFEB-altered RCC, as well as in 70% of mucinous tubular and spindle carcinomas., Conclusions: In this study, merlin IHC was ~92% sensitive and ~94% specific for BHP RCC. These data suggest that merlin IHC is a reliable surrogate marker for the presence of underlying NF2 gene inactivation, being diagnostically useful to identify BHP RCC., Conclusions: In this study, merlin IHC was ~92% sensitive and ~94% specific for BHP RCC. These data suggest that merlin IHC is a reliable surrogate marker for the presence of underlying NF2 gene inactivation, being diagnostically useful to identify BHP RCC., (© 2022 John Wiley & Sons Ltd.)

Prostatic malakoplakia (MP) is rare, with only case reports and small series (< five patients) available in the literature. In this study we analysed an international multi-institutional series of 49 patients with prostatic MP to more clearly define its clinicopathological features. The median age was 67 years and the median serum prostate-specific antigen (PSA) was 7.5 ng/ml. MP was clinically manifest in most cases (28 of 45 patients with data available, 62%). Of 43 patients with detailed clinical history available, 21 (49%) had concurrent or metachronous malignancies (including prostate cancer). Diabetes or insulin resistance was present in 11 patients (26%). Additionally, three patients had a history of solid organ transplantation and one had HIV. Of note, six of 34 patients (18%) without concurrent prostate cancer had an abnormal digital rectal examination and/or lesions on magnetic resonance imaging (MRI) with prostate imaging reporting and data system (PIRADS) scores 4-5. The initial diagnosis was made on core biopsies (25 of 49, 51%), transurethal resection specimens (12 of 49, 24%), radical prostatectomies (10 of 49, 20%), Holmium-laser enucleation (one of 49, 2%) and cystoprostatectomy (one of 49, 2%). Tissue involvement was more commonly diffuse or multifocal (40 of 49, 82%). Von Kossa and periodic acid-Schiff stains were positive in 35 of 38 (92%) and 26 of 27 lesions (96%), respectively. Of note, two cases were received in consultation by the authors with a preliminary diagnosis of mesenchymal tumour/tumour of the specialised prostatic stroma. The present study suggests that prostatic MP is often associated with clinical findings that may mimic those of prostate cancer in a subset of patients. Moreover, MP may be found incidentally in patients with concurrent prostate cancer., (© 2022 John Wiley & Sons Ltd.)

Secondary involvement of the prostate by urothelial or hematolymphoid neoplasms is relatively common and well-described. In contrast, less is known about the clinicopathologic spectrum of secondary solid tumors of the prostate of nonurothelial origin. This study evaluated a series of secondary nonurothelial solid tumors of the prostate diagnosed at 21 institutions. Eighty-five patients with a median age at diagnosis of 64 years were included. Sixty-two patients had clinically manifest disease (62/85, 73%), 10 were diagnosed incidentally (10/85, 12%), and 13 (13/85, 15%) had no detailed clinical data available about symptomatology at presentation. Among patients with clinically manifest disease, the most common symptoms and signs were lower urinary tract symptoms (either obstructive of irritative; 36/62, 58%), abdominal or pelvic pain or discomfort (16/62, 26%), and hematuria (12/62, 19%). Metastasis and direct invasion occurred at roughly similar frequencies (47% vs. 42%) in this series, and in 11% of the cases, the mechanism of spread to the prostate was unclear/uncertain. Overall, among tumors with confirmed sites of origin, the most common primary sites were gastrointestinal tract (53/85, 62%), lung (9/85, 11%), skin (6/85, 7%), and testis (4/85, 5%). Among metastases, the most common tumor types were lung carcinomas (9/40, 23%), colorectal adenocarcinomas (7/40, 18%), melanoma (6/40, 15%), and germ cell tumors (6/40, 15%). This study demonstrated that secondary involvement of the prostate by solid tumors of nonurothelial origin is commonly symptomatic and that the most frequent sites of origin are the gastrointestinal tract, lung, skin, and testis. These findings are worth considering when lesions with unusual cytomorphology and/or architecture are encountered in prostate specimens., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Ovarian immature teratoma is a rare subtype of germ cell tumour that can be pure or associated with non-teratomatous germ cell tumour elements and is graded based on extent of the immature neuroectodermal component. Immature teratoma (IT) can also be associated with somatic differentiation in the form of sarcoma, carcinoma, or extensive immature neuroectodermal elements and may produce low levels of serum alpha-fetoprotein. Variable interpretation of these issues underlies diagnostic and management dilemmas, resulting in substantial practice differences between paediatric and adult women with IT. The Malignant Germ Cell International Consortium (MaGIC) convened oncologists, surgeons, and pathologists to address the following crucial clinicopathologic issues related to IT: (1) grading of IT, (2) definition and significance of 'microscopic' yolk sac tumour, (3) transformation to a somatic malignancy, and (4) interpretation of serum tumour biomarkers. This review highlights the discussion, conclusions, and suggested next steps from this clinicopathologic conference., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Aims . Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is a rare aggressive renal malignancy associated with hereditary leiomyomatosis and RCC syndrome (HLRCC). Tumors exhibiting heterogeneous (ie, patchy) FH loss by immunohistochemistry have rarely been described, may be diagnostically challenging, and have never been the focus of a study. We aimed to investigate the FH mutational status of FH-deficient RCC with heterogeneous versus complete FH loss, to characterize additional genetic drivers, and to evaluate 2SC immunohistochemistry in this setting. Methods and Results . We studied FH-deficient RCC with heterogeneous ( n  = 3) and complete ( n  = 4) FH loss. Targeted next-generation sequencing (NGS) was performed on all tumors. No patients had a known history of HLRCC. All tumors had histological features within the morphologic spectrum described for FH-deficient RCC. All 7 tumors were immunoreactive for 2SC. Molecularly, all 7 tumors revealed multiple hits involving the FH locus resulting in complete loss of wild-type alleles. All tumors with heterogeneous FH loss harbored FH missense variants within domain 2 of the protein, and each had concomitant copy neutral loss of heterozygosity (CN-LOH). In complete FH loss tumors, FH alterations included splice variants with concomitant loss of heterozygosity ( n  = 2) and homozygous gene deletions ( n  = 2). Other non-recurrent alterations included biallelic alterations of TP53 , NF2 , SMAD4 and activation of PIK3CA . Conclusions . Our series highlights how heterogeneous FH loss (patchy positive staining) is an important staining pattern to recognize since it is compatible with a diagnosis of FH-deficient RCC and should prompt additional ancillary studies (confirmatory 2SC immunohistochemistry and/or molecular testing) and genetic evaluation.

Aims: Malignant mesothelioma (MM) of the tunica vaginalis (TV) is a rare and aggressive tumour, and the molecular features and staining profile with contemporary immunohistochemical (IHC) biomarkers are largely unexplored. We characterise the clinicopathological, molecular and IHC features of MM (n = 13) and mesothelial neoplasms of uncertain malignant potential (MUMP) (n = 4)., Methods and Results: Targeted next-generation sequencing was performed on seven MMs and two MUMPs. IHC was performed for methylthioadenosine phosphorylase (MTAP), BRCA1-associated protein 1 (BAP1) and SRY-box transcription factor 6 (SOX6). Thirteen adenomatoid tumours were also assessed with SOX6. MM were epithelioid (seven of 13) or biphasic (six of 13). In MM, NF2 (five of seven; 71%), CDKN2A (three of seven; 43%) and BAP1 (two of seven; 29%) were most frequently altered. Non-recurrent driver events were identified in PTCH1 and TSC1. In contrast, none of these alterations were identified in MUMPs; however, one MUMP harboured a TRAF7 missense mutation. By IHC, loss of MTAP (two of 12; 17%) and BAP1 (two of nine; 22%) was infrequent in MM, whereas both were retained in the MUMPs. SOX6 was positive in nine of 11 (82%) MMs and negative in all MUMPs and adenomatoid tumours., Conclusions: Testicular MM exhibit a similar mutational profile to those of the pleura/peritoneum; however, alterations in CDKN2A and BAP1 are less common. These findings suggest that although MTAP and BAP1 IHC are specific for MM, their sensitivity in testicular MMs appears lower. In addition, rare tumours may harbour targetable alterations in driver genes (PTCH1 and TSC1) that are unusual in MMs at other anatomical sites. SOX6 is sensitive for MM; accordingly, the presence of SOX6 expression argues against a benign neoplastic process., (© 2022 John Wiley & Sons Ltd.)

Aims: Mismatch repair (MMR) deficiency is commonly caused by functional inactivation of MLH1, PMS2, MSH2 or MSH6. The morphological and molecular correlates of MMR deficiency have been extensively characterized in certain tumour types such as colorectal and endometrial adenocarcinoma. In contrast, the histological and molecular features of MMR-deficient prostate cancer remain incompletely described. In this study, we evaluated 19 MMR-deficient prostate cancers, including 11 cases without prior systemic treatment., Methods and Results: All treatment-naive cases (11 of 11, 100%) were grade group 4-5 and had predominant cribriform and/or solid growth patterns. Solid components (any amount) and tumour infiltrating lymphocytes were 7 cases each (7 of 11, 64%). In 68 MMR-proficient grade group 5 prostate cancers, predominant cribriform or solid growth patterns, solid components (any amount) and tumour infiltrating lymphocytes were seen at significantly lower frequencies (31 of 68, 46%; 9 of 68, 13% and 6 of 62, 9%, respectively; P < 0.001 for all comparisons). Molecular evaluation of 19 cases demonstrated that MMR-deficiency was secondary to functional loss of MSH2/MSH6 and MLH1/PMS2 in 15 (79%) and 4 cases (21%), respectively. Definite or probable germline mutations were present in 4 cases (4 of 19, 21%). TMPRSS2::ERG rearrangements were identified in 2 cases (2 of 19, 11%). Recurrent cancer-relevant somatic mutations included (but were not limited to) ATM, TP53, FOXA1, RB1, BRCA2 and PTEN., Conclusions: MMR deficiency was most commonly secondary to inactivation of MSH2/MSH6 in this study. Importantly, MMR-deficient high-grade prostatic adenocarcinomas had morphological features that might be useful to identify selected cases for MMR immunohistochemistry., (© 2022 John Wiley & Sons Ltd.)

Most succinate dehydrogenase (SDH)-deficient renal cell carcinomas (RCCs) demonstrate stereotypical morphology characterized by bland eosinophilic cells with frequent intracytoplasmic inclusions. However, variant morphologic features have been increasingly recognized. We therefore sought to investigate the incidence and characteristics of SDH-deficient RCC with variant morphologies. We studied a multi-institutional cohort of 62 new SDH-deficient RCCs from 59 patients. The median age at presentation was 39 years (range 19-80), with a slight male predominance (M:F = 1.6:1). A relevant family history was reported in 9 patients (15%). Multifocal or bilateral tumors were identified radiologically in 5 patients (8%). Typical morphology was present at least focally in 59 tumors (95%). Variant morphologies were seen in 13 (21%) and included high-grade nuclear features and various combinations of papillary, solid, and tubular architecture. Necrosis was present in 13 tumors, 7 of which showed variant morphology. All 62 tumors demonstrated loss of SDHB expression by immunohistochemistry. None showed loss of SDHA expression. Germline SDH mutations were reported in all 18 patients for whom the results of testing were known. Among patients for whom follow-up data was available, metastatic disease was reported in 9 cases, 8 of whom had necrosis and/or variant morphology in their primary tumor. Three patients died of disease. In conclusion, variant morphologies and high-grade nuclear features occur in a subset of SDH-deficient RCCs and are associated with more aggressive behavior. We therefore recommend grading all SDH-deficient RCCs and emphasize the need for a low threshold for performing SDHB immunohistochemistry in any difficult to classify renal tumor, particularly if occurring at a younger age., (© 2021. Crown.)

Testicular adult granulosa cell tumor (AGCT) is a rare type of sex-cord stromal tumor that affects patients of a wide age range and has the potential for late metastasis. In the testis, the diagnosis of AGCTs often requires the exclusion of other more common types of sex-cord stromal tumors. Immunohistochemistry is of limited utility, being used mostly to confirm sex-cord lineage and to exclude other entities when morphology is not typical. Unlike ovarian AGCTs, which are molecularly homogeneous and harbor a specific activating FOXL2 mutation (c.7558C > T p.C134W) in >90% of cases, the molecular characteristics of testicular AGCTs remain largely unknown. In the current study, we analyzed 13 testicular AGCTs diagnosed at multiple institutions using massively parallel DNA sequencing to evaluate single nucleotide variants, copy number alterations, and structural variants. In all, 10/13 cases were sequenced successfully. Notably, the FOXL2 c.7558C > T (p.C134W) mutation was identified in only a single case (1/10, 10%). The remaining cases were molecularly heterogeneous, with largely nonrecurrent genetic variants. Putative driver events in individual cases included a well-characterized gain-of-function NRAS mutation, as well as inactivation of ATM and TP53, among others. The only highly recurrent finding was single copy loss of 22q (7/10 cases, 70%). Comparatively, the frequencies of FOXL2 c.7558C > T (p.C134W) and 22q loss in 12 metastatic ovarian AGCTs identified in our database were 92% (11/12) and 42% (5/12), respectively. The results of the present study suggest that testicular AGCTs are different from their ovarian counterparts in that they appear to be molecularly heterogeneous and only rarely harbor FOXL2 mutations., (© 2021. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

In testicular germ cell tumors (TGCTs), components with nonspecific sarcomatous features that express keratins and glypican 3 are classified as sarcomatoid yolk sac tumor (SYST). SYST is most frequently seen in metastatic sites after chemotherapy. Like so-called "somatic-type" malignancies arising in TGCTs, SYST is markedly resistant to systemic therapy and has a more aggressive clinical course than conventional types of TGCT. However, the clinicopathologic and molecular features of SYST remain incompletely described. This study evaluated a multi-institutional series of 20 SYSTs using massively parallel sequencing and p53 immunohistochemistry. The histologic and clinical characteristics of the cases were also assessed, including analyses of disease-specific outcomes. DNA sequencing identified somatic mutations in 12/20 cases (60%), including recurrent TP53 and RIF1 mutations (present in 4/20 cases, 20% each). In 3 of the 4 SYST with TP53 mutations, there was molecular evidence of loss of heterozygosity. Immunohistochemistry demonstrated diffuse overexpression of p53 protein in 3/4 (75%) cases with TP53 mutations. The remaining TP53-mutant case demonstrated multifocal overexpression of p53, suggestive of subclonal inactivation of the gene. Overexpression of p53 protein was not seen in any of 15 TP53 wild-type cases evaluated by immunohistochemistry. A subset of 4 cases underwent RNA sequencing (fusion panel), which demonstrated the absence of oncogenic gene fusions. A 2-tiered grading system based on 3 histologic parameters (cellularity, number of mitoses, and necrosis) demonstrated that high-grade SYSTs have a higher risk of disease-specific death compared to low-grade tumors. The risk of disease-specific mortality was also higher in SYSTs with somatic mutations. In conclusion, this study demonstrated that 60% of SYSTs harbor somatic oncogenic mutations that are otherwise rare in TGCTs, and the presence of these mutations is associated with an aggressive clinical course. In addition, the results presented herein suggest that grading SYSTs may be clinically relevant., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is a rare and clinically aggressive RCC subtype that is commonly associated with the hereditary leiomyomatosis and renal cell carcinoma syndrome. The diagnostic hallmark of FH-deficient RCC is a high-grade microscopic appearance with prominent inclusion-like eosinophilic nucleoli and perinucleolar halos. Herein we report a case of an FH-deficient RCC in a 30-year-old female that exhibited low-grade nuclei and abundant eosinophilic cytoplasm, reminiscent of the clinically more indolent succinate dehydrogenase-deficient RCC subtype and the newly described eintity, eosinophilic, solid and cystic RCC. This case illustrates that FH-deficient RCC can have a wide spectrum of microscopic appearances, including low-grade eosinophilic RCC. In addition, it highlights that a low threshold to perform the immunohistochemical stains for FH and S-(2-succino) cysteine is warranted in RCC cases with unusual and even low-grade eosinophilic morphology.

Aims: Large cell calcifying Sertoli cell tumour (LCCSCT) is a rare testicular sex cord-stromal tumour that primarily affects young patients and is associated with Carney complex. We sought to characterise the clinicopathological features of a series of LCCSCT and evaluate the diagnostic utility of PRKAR1A immunohistochemistry (IHC)., Methods and Results: The LCCSCT cohort (n = 15) had a median age of 16 years (range = 2-30 years). Four patients were known to have Carney complex. PRKAR1A IHC was performed in each case. For comparison, PRKAR1A IHC was also assessed in other sex cord-stromal tumours, including Sertoli cell tumour, not otherwise specified (SCT, NOS; n = 10), intratubular large cell hyalinising Sertoli cell tumour (n = 1) and Leydig cell tumour (n = 23). Loss of cytoplasmic PRKAR1A expression was observed in all but one LCCSCT (14 of 15; 93%). PRKAR1A expression was retained in all SCTs, NOS (10 of 10; 100%), the majority of Leydig cell tumours (22 of 23; 96%) and an intratubular large cell hyalinising Sertoli cell tumour (1 of 1; 100%). One Leydig cell tumour showed equivocal staining (multifocal weak expression)., Conclusions: Overall, PRKAR1A loss is both sensitive (93%) and highly specific (97%) for the diagnosis of LCCSCT. PRKAR1A loss may aid its diagnosis, particularly in sporadic cases and those that are the first presentation of Carney complex., (© 2021 John Wiley & Sons Ltd.)

Purpose: Neuroendocrine prostate cancer (NEPC) is a resistance phenotype that emerges in men with metastatic castration-resistant prostate adenocarcinoma (CR-PRAD) and has important clinical implications, but is challenging to detect in practice. Herein, we report a novel tissue-informed epigenetic approach to noninvasively detect NEPC., Experimental Design: We first performed methylated immunoprecipitation and high-throughput sequencing (MeDIP-seq) on a training set of tumors, identified differentially methylated regions between NEPC and CR-PRAD, and built a model to predict the presence of NEPC (termed NEPC Risk Score). We then performed MeDIP-seq on cell-free DNA (cfDNA) from two independent cohorts of men with NEPC or CR-PRAD and assessed the accuracy of the model to predict the presence NEPC., Results: The test cohort comprised cfDNA samples from 48 men, 9 with NEPC and 39 with CR-PRAD. NEPC Risk Scores were significantly higher in men with NEPC than CR-PRAD (P = 4.3 × 10-7) and discriminated between NEPC and CR-PRAD with high accuracy (AUROC 0.96). The optimal NEPC Risk Score cutoff demonstrated 100% sensitivity and 90% specificity for detecting NEPC. The independent, multi-institutional validation cohort included cfDNA from 53 men, including 12 with NEPC and 41 with CR-PRAD. NEPC Risk Scores were significantly higher in men with NEPC than CR-PRAD (P = 7.5×10-12) and perfectly discriminated NEPC from CR-PRAD (AUROC 1.0). Applying the predefined NEPC Risk Score cutoff to the validation cohort resulted in 100% sensitivity and 95% specificity for detecting NEPC., Conclusions: Tissue-informed cfDNA methylation analysis is a promising approach for noninvasive detection of NEPC in men with advanced prostate cancer., (©2021 American Association for Cancer Research.)

Primary peritoneal malignant mesothelioma (MM) can demonstrate morphologic overlap with low-grade and high-grade tubo-ovarian serous neoplasms; it is also biologically and prognostically distinct from benign mesothelial proliferations. Currently, there is no single biomarker that can definitively distinguish these neoplasms. Sex-determining region Y box 6 (SOX6) immunohistochemistry has been recently described to differentiate pleural epithelioid MM from lung adenocarcinoma, but it has not been evaluated in the peritoneum. SOX6 immunohistochemistry was performed on 43 peritoneal epithelioid MM, 7 peritoneal biphasic MM, 5 well-differentiated papillary mesotheliomas, 5 serous borderline tumors, 29 low-grade serous carcinomas (LGSCs), 20 high-grade serous carcinomas (HGSCs), and 25 cases of peritoneal reactive mesothelial hyperplasia. Quantitative SOX6 expression in epithelioid MM (median, 100% of tumor cells) was significantly greater than in LGSC/serous borderline tumor (median, 90%; P=0.004) and HGSC (median, 45%; P=0.0001). However, when SOX6 is expression is defined as ≥10% of tumor cells, there was no significant difference in the rate of SOX6 positivity between epithelioid MM (41/43, 95%), LGSC (28/29, 97%; P=1.0), and HGSC (17/20, 85%; P=0.16). Quantitative extent of SOX6 expression in epithelioid MM was significantly greater than in biphasic MM (median, 0%; P=0.0001), well-differentiated papillary mesothelioma (median, 20%; P=0.001), and reactive mesothelial hyperplasia (median, 20%; P=0.0001), but not significantly different from flat quiescent mesothelium (median, 90%; P=0.82). SOX6 immunohistochemistry is 95% sensitive for peritoneal epithelioid MM, but is also consistently expressed in LGSC and HGSC, negating its usefulness in this common differential diagnosis. SOX6 also shows variable expression across the spectrum of reactive, benign neoplastic, and malignant mesothelial lesions of the peritoneum, and does not appear to be diagnostically useful in distinguishing benign from malignant mesothelial proliferations., Competing Interests: Conflicts of Interest and Source of Funding: D.B.C.’s work is supported by the Ovarian Cancer Research Alliance (Ann Schreiber Mentored Investigator Award; grant no. 650320). For M.S.H. none were declared., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Translocation renal cell carcinoma (tRCC) is a poorly characterized subtype of kidney cancer driven by MiT/TFE gene fusions. Here, we define the landmarks of tRCC through an integrative analysis of 152 patients with tRCC identified across genomic, clinical trial, and retrospective cohorts. Most tRCCs harbor few somatic alterations apart from MiT/TFE fusions and homozygous deletions at chromosome 9p21.3 (19.2% of cases). Transcriptionally, tRCCs display a heightened NRF2-driven antioxidant response that is associated with resistance to targeted therapies. Consistently, we find that outcomes for patients with tRCC treated with vascular endothelial growth factor receptor inhibitors (VEGFR-TKIs) are worse than those treated with immune checkpoint inhibitors (ICI). Using multiparametric immunofluorescence, we find that the tumors are infiltrated with CD8 + T cells, though the T cells harbor an exhaustion immunophenotype distinct from that of clear cell RCC. Our findings comprehensively define the clinical and molecular features of tRCC and may inspire new therapeutic hypotheses., Competing Interests: Declaration of interests Z.B.: research funding from Bristol-Myers Squibb & Genentech/imCORE; honoraria from UpToDate. X.G.: advisory board for Exelixis, Bayer and Guardant Health. D.A.B.: non-financial support from Bristol Myers Squibb, honoraria from LM Education/Exchange Services, advisory board fees from Exelixis and Aveo, and consulting/personal fees from Octane Global, Defined Health, Dedham Group, Adept Field Solutions, Slingshot Insights, Blueprint Partnerships, Charles River Associates, Trinity Group, and Insight Strategy outside of the submitted work. N.I.V.: advisory board to Sanofi/Genzyme, Oncocyte, and Lilly. M.S.H.: consultant, Janssen Pharmaceuticals and UpToDate. R.H.: research funding from Novartis. B.A.M.: consultant for Bayer, Astellas, AstraZeneca, Seattle Genetics, Exelixis, Nektar, Pfizer, Janssen, Genentech, Eisai, Dendreon, Bristol Myers Squibb, Calithera, and EMD Serono; research funding to the institution from Bristol Myers Squibb, Calithera, Exelixis, and Seattle Genetics. A.S.F.: consultant, Olympus America, Inc.; honoraria, Roche, Janssen; advisory board, Vessi Medical. C.J.W.: equity holder of BioNTech, Inc; research funding from Pharmacyclics. D.F.M.: honoraria from BMS, Pfizer, Merck, Alkermes, Inc., EMD Serono, Eli Lilly and Company, Iovance, Eisai, Inc., Werewolf Therapeutics, and Calithera Biosciences; research support from BMS, Merck, Genentech, Pfizer, Exelixis, X4 Pharma, and Alkermes, Inc. D.Y.C.H.: consultancies and research funding from Pfizer, Novartis, BMS, Merck, Eisai, Ipsen, and Exelixis. S.S.: grants from Exelixis, grants from Bristol-Myers Squibb, personal fees from Merck, grants and personal fees from AstraZeneca, personal fees from CRISPR Therapeutics, personal fees from NCI, and personal fees from AACR; a patent for Biogenex with royalties paid. E.M.V.A.: advisory/consulting, Tango Therapeutics, Genome Medical, Invitae, Enara Bio, Janssen, Manifold Bio, Monte Rosa; research support, Novartis, BMS; equity, Tango Therapeutics, Genome Medical, Syapse, Enara Bio, Manifold Bio, Microsoft, Monte Rosa; patents, institutional patents filed on chromatin mutations and immunotherapy response and methods for clinical interpretation. T.K.C.: research (institutional and personal), Alexion, Analysis Group, AstraZeneca, Aveo, Bayer, Bristol Myers-Squibb/ER Squibb and Sons, LLC, Calithera, Cerulean, Corvus, Eisai, Exelixis, F. Hoffmann-La Roche, Foundation Medicine, Inc., Genentech, GlaxoSmithKline, Ipsen, Lilly, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Roche, Roche Products Limited, Sanofi/Aventis, Takeda, and Tracon; consulting/honoraria or advisory role, Alexion, Analysis Group, AstraZeneca, Aveo, Bayer, Bristol Myers-Squibb/ER Squibb and Sons, LLC, Cerulean, Corvus, Eisai, EMD Serono, Exelixis, Foundation Medicine, Inc., Genentech, GlaxoSmithKline, Heron Therapeutics, Infinity Pharma, Ipsen, Jansen Oncology, IQVIA, Lilly, Merck, NCCN, Novartis, Nuscan, Peloton, Pfizer, Pionyr, Prometheus Labs, Roche, Sanofi/Aventis, Surface Oncology, Tempest, and Up-to-Date; CME-related events (e.g., OncLIve, PVI, MJH Life Sciences); NCI GU Steering Committee; stock ownership, Pionyr and Tempest; patents filed, royalties, or other intellectual properties, related to biomarkers of immune checkpoint blockers and ctDNA; travel, accommodations, expenses, medical writing in relation to consulting, advisory roles, or honoraria; no speaker’s bureau. S.R.V.: consulting, MPM Capital and Vida Ventures; spouse is an employee of and holds equity in Kojin Therapeutics. All other authors report no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Most vulvar squamous cell carcinomas are human papillomavirus (HPV)-associated or TP53-mutant. A third category of HPV-independent TP53-wild-type lesions is uncommon and not fully understood. Differentiated exophytic vulvar intraepithelial lesion (DEVIL) has been characterised as a precursor of this latter category. The reproducibility of the diagnosis of DEVIL and its distinction from lesions with overlapping morphology has not been studied. Our aim was to establish the interobserver agreement in the diagnosis of DEVIL and its distinction from neoplastic and reactive conditions of the vulva on haematoxylin and eosin evaluation., Methods and Results: A set of 35 slides was evaluated by eight reviewers (two trainees and six practising gynaecological pathologists). The set included DEVIL, condyloma, established vulvar precursors [high-grade squamous intraepithelial lesion (HSIL) and differentiated vulvar intraepithelial neoplasia (dVIN)] with superimposed acanthosis or verruciform growth, lichen simplex chronicus (LSC), and psoriasis. Kappa (κ) values were calculated. Overall, interobserver agreement was moderate (κ = 0.56), improving to substantial (κ = 0.7) when evaluation was performed by practising pathologists. Agreement was strong for the diagnosis of HSIL (κ = 0.88), and substantial for the diagnosis of DEVIL (κ = 0.61), condyloma (κ = 0.79), and LSC (κ = 0.72). Agreement was moderate for the diagnosis of dVIN (κ = 0.59) and psoriasis (κ = 0.53). Perfect agreement (6/6) among practising pathologists was observed in 43% of cases, and majority agreement (5/6 or 4/6) was observed in 48% of cases., Conclusions: Reproducibility in the diagnosis of verruciform vulvar lesions, including the novel DEVIL, is acceptable overall. Reproducibility is higher for well-known lesions such as HSIL and condyloma than for more challenging diagnoses such as DEVIL, dVIN, and psoriasis. Agreement is higher among practising gynaecological pathologists, suggesting that training and experience improve reproducibility. Our findings support the inclusion of DEVIL as a diagnostic entity in the classification of vulvar squamous lesions., (© 2021 John Wiley & Sons Ltd.)

Aims: Spermatocytic tumour (ST) is a rare testicular germ cell neoplasm with few confirmatory biomarkers that can be challenging to diagnose. Like normal spermatogonia, STs are known to express SSX proteins. Recently, a novel SSX antibody directed against a conserved C-terminal region of SSX1, SSX2 and SSX4 (SSX&#95;CT) has emerged as a reliable biomarker for these SSX proteins and synovial sarcoma. However, SSX&#95;CT immunostaining has not been demonstrated in ST. The aim of this study was to assess the diagnostic utility of SSX&#95;CT immunohistochemistry in ST and other tumours in the differential diagnosis with ST., Methods and Results: SSX&#95;CT, OCT3/4 and c-KIT immunohistochemistry was performed on 15 STs, 38 seminomas, 13 embryonal carcinomas, 12 yolk sac tumours, six choriocarcinomas, four teratomas, seven Sertoli cell tumours, and six lymphomas. Staining was scored as negative, rare, focal, or diffuse. SSX&#95;CT was positive in all (15/15) STs, and diffusely positive in 14 of 15 (93%). SSX&#95;CT was positive in 22 of 38 (58%) seminomas; however, only two cases showed diffuse expression. SSX&#95;CT was negative in all other tumours. OCT3/4 was negative in all STs, but positive in all seminomas and embryonal carcinomas. c-KIT was frequently positive in both STs (12/15; 80%) and seminomas (33/38; 87%). OCT3/4 and c-KIT were negative in all other tumours., Conclusions: SSX&#95;CT is a valuable and highly sensitive biomarker that supports the diagnosis of ST. Diffuse expression of SSX-CT in STs is also highly specific for ST. Nevertheless, SSX&#95;CT is best used in combination with OCT3/4 when ST is in the differential diagnosis., (© 2021 John Wiley & Sons Ltd.)

Testicular Leydig cell tumor (LCT), the most common sex-cord stromal tumor in men, represents a small fraction of all testicular tumors (~1 to 3%). Although most testicular LCTs are indolent and cured by radical orchiectomy, 5-10% have aggressive biology and metastatic potential. In primary LCTs, large size, cytologic atypia, necrosis, increased mitotic activity, and vascular invasion have been associated with clinically aggressive tumors. From a molecular perspective, the characteristics of aggressive LCTs and the differences between aggressive and nonaggressive LCTs remain largely unexplored. This study compares the genomic landscape of aggressive and nonaggressive testicular LCTs. Twenty-six cases were analyzed using next-generation DNA sequencing (NGS) and immunohistochemistry. Cases were classified as aggressive LCT if they met published criteria for malignancy in primary (i.e., testicular) tumors or if they had pathology-proven metastatic disease; otherwise, cases were considered nonaggressive. This multi-institutional series included 18 aggressive LCTs (14 primary/testicular, 4 metastatic) and 8 nonaggressive LCTs. Two cases (2/26, 8%; both aggressive LCTs) failed sequencing and had negative (i.e., uninformative) FH immunohistochemistry results. One additional primary aggressive LCT failed sequencing but had informative FH immunohistochemistry results. Combined NGS and immunohistochemical analysis demonstrated FH inactivation in 5/26 cases (19%). In addition, NGS demonstrated CTNNB1 mutations or biallelic APC inactivation in 9/23 cases (39%), copy number changes without recurrent mutations in 6/23 (26%) cases, and no alterations in 4/23 cases (17%). CTNNB1 mutations were present in both aggressive and nonaggressive LCTs. In contrast, FH inactivation and multiple copy number changes were only identified in aggressive LCTs. In conclusion, three distinct subgroups of aggressive LCTs were characterized by FH inactivation, Wnt pathway activation, and copy number changes without recurrent mutations, respectively. Nuclear translocation of β-catenin and Wnt pathway activation appear to be early driver events that provide an environment conducive for progression to aggressive biology in a subset of LCTs., (© 2021. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

Purpose: We performed a systematic review to assess the clinical features of cyclophosphamide-associated bladder cancer., Materials and Methods: MEDLINE, Web of Science, and Cochrane Library were searched from inception to August 2020 according to PRISMA guidelines. Studies that associated bladder cancer with prior cyclophosphamide use on an individual level were included., Results: We identified 121 studies spanning over a 50-year period with 285 patients. The most common malignant indication for cyclophosphamide was lymphoma (25%), while the most common non-malignant indication was ANCA-associated vasculitides (26%). Hematuria and dysuria were the most prevalent symptoms prior to a cyclophosphamide-associated bladder cancer diagnosis, and median age at diagnosis was 55 years. Conventional urothelial carcinoma (UC) was the most common bladder-associated diagnosis (74%), although a broad range of cancer types were represented, notably leiomyosarcoma and squamous cell carcinoma. About half of bladder cancers were muscle invasive at diagnosis and median latency time was 10.0 years; 33% of patients had a bladder cancer related death., Conclusions: We describe the largest pooled analysis of patients with cyclophosphamide-associated bladder cancer. These bladder cancers have a propensity for younger age at diagnosis, more advanced stage at diagnosis, and variant histology. There was a substantial number of patients with latency time of ≥20 years independent of cumulative cyclophosphamide dose. These findings support consideration of screening and long-term surveillance of cancer survivors with a history of cyclophosphamide therapy for bladder cancer., (Copyright © 2021. Published by Elsevier Inc.)

Context.—: Renal malignancies can be divided into cortical- and medullary-based tumors, the latter of which classically infiltrate the renal parenchyma by extending between nonneoplastic structures. Although high-grade cortical tumors can rarely exhibit the same growth pattern, the infiltrative morphology should elicit a differential diagnosis to be considered in each case. However, these diagnoses can be challenging to distinguish, especially on small renal biopsy samples., Objective.—: To provide an overview of the clinical, gross, and microscopic findings; genetic and molecular alterations; and immunohistochemical evaluation of medullary-based renal tumors and other tumor types with overlapping morphologies and growth patterns., Data Sources.—: Literature review and personal observations were used to compile the information in this review., Conclusions.—: Collecting duct carcinoma is a prototypical medullary-based tumor, and although diagnostic criteria exist, it remains a diagnosis of exclusion, especially with ancillary techniques aiding the recognition of established as well as more recently described neoplasms. Other medullary-based malignancies included in the differential diagnosis include renal medullary carcinoma/renal cell carcinoma unclassified with medullary phenotype, fumarate hydratase-deficient renal cell carcinoma, and upper tract urothelial carcinoma. Moreover, other rare entities should be excluded, including metastatic carcinoma, lymphoma, and melanoma. In addition to potential prognostic differences, accurate diagnoses can have important surgical and clinical management implications.

Accurate diagnosis of cribriform Gleason pattern 4 (CrP4) prostate adenocarcinoma (PCa) is important due to its independent association with adverse clinical outcomes and as a growing body of evidence suggests that it impacts clinical decision making in PCa management. To identify reproducible features for diagnosis of CrP4, we assessed interobserver agreement among 27 experienced urologic pathologists of 60 digital images from 44 radical prostatectomies (RP) that represented a broad spectrum of potential CrP4. The following morphologic features were correlated with the consensus diagnosis (defined as 75% agreement) for each image: partial vs. transluminal glandular bridging, intraglandular stroma, <12 vs. ≥12 lumina, well vs. poorly formed lumina, mucin (mucinous fibroplasia, extravasation, or extracellular pool), size (compared to benign glands and number of lumina), number of attachments with gland border by tumor cells forming a "glomeruloid-like" pattern, a clear luminal space along the periphery of gland occupying <50% of glandular circumference, central nerve, dense (cell mass occupying >50% of luminal space) vs. loose, and regular vs. irregular contour. Interobserver reproducibility for the overall diagnostic agreement was fair (k=0.40). Large CrP4 had better agreement (k=0.49) compared to small CrP4 (k=0.40). Transluminal bridging, dense cellular proliferation, a clear luminal space along the periphery of gland occupying <50% of gland circumference, lack of intraglandular mucin, and lack of contact between the majority of intraglandular cells with stroma were significantly associated with consensus for CrP4. In contrast, partial bridging, majority of intraglandular cells in contact with stroma, mucinous fibroplasia, only one attachment to the gland border by tumor cells forming a "glomeruloid-like" pattern, and a clear luminal space along the periphery of gland accounting for >50% of the glandular circumference were associated with consensus against CrP4. In summary, we identified reproducible morphological features for and against CrP4 diagnosis, which could be used to refine and standardize the diagnostic criteria for CrP4., Competing Interests: None., (AJCR Copyright © 2021.)

Context.—: Plasmacytoid urothelial carcinoma (PC-UC) is an aggressive variant of urothelial carcinoma (UC), characterized by loss of E-cadherin (E-Cad)-mediated intercellular adhesion. Loss of E-Cad by immunohistochemistry can help diagnose PC-UC; however, sensitivity is limited. Expression of other cadherin-catenin adhesion complex members, that is, p-120 catenin (p-120) and β-catenin (B-Cat), which are diagnostically useful for lobular breast carcinoma, remains unknown in UC., Objective.—: To determine the utility of p-120 and B-Cat in conventional and variant UC., Design.—: E-cadherin, B-Cat, and p-120 immunohistochemistry was performed in 25 conventional UCs and 33 variant UCs, including 22 PC-UCs, 6 sarcomatoid UCs (SUCs), and 5 micropapillary UCs. Membranous staining for all biomarkers was considered normal; however, any cytoplasmic staining or an absence of staining was considered diagnostically abnormal. Next-generation sequencing was performed on 8 PC-UC cases., Results.—: E-cadherin, B-Cat, and p-120 showed membranous staining in all conventional and micropapillary UCs. In contrast, most PC-UCs were negative for E-Cad (17 of 22; 77%) with an additional 2 of 22 cases (9%) showing cytoplasmic with partial membranous staining. p-120 catenin demonstrated cytoplasmic or negative staining in 21 of 22 cases (95%). Most SUCs showed an absence of E-Cad (5 of 6; 83%) and cytoplasmic or negative p-120 in 5 of 6 cases (83%). Staining for B-Cat was also abnormal in a subset of PC-UCs and SUCs. Five PC-UC cases that harbored CDH1 gene variants were p-120 cytoplasmic positive., Conclusions.—: p-120 catenin is a useful adjunct biomarker to E-Cad in the clinically important distinction of PC-UC and SUC from conventional UC. In particular, the combination of cytoplasmic p-120 and loss of E-Cad is strongly supportive of PC-UC and SUC., Competing Interests: The authors have no relevant financial interest in the products or companies described in this article.

Objective: To characterize the presentation, patterns of care, and outcomes of radiation-associated muscle-invasive bladder cancer (RA-MIBC) compared to primary (non-radiation associated) MIBC. RA-MIBC has been suggested to represent a more aggressive disease variant and be more difficult to treat compared to primary (non-radiation associated) MIBC., Methods: We identified 60,090 patients diagnosed with MIBC between 1988-2015 using the Surveillance, Epidemiology, and End Results database and stratified patients based on whether radiation had been administered to a prior pelvic primary cancer. We used Fine-Gray competing risks regression to compare adjusted bladder cancer-specific mortality (BCSM) for RA-MIBC compared to primary MIBC., Results: There were 1,093 patients with RA-MIBC and 58,997 patients with primary MIBC. RA-MIBCs were more likely to be T4 at diagnosis (21.0% vs 17.3%, P < .001), and less likely to be node-positive (10.3% vs 17.1%, P < .001). The rate of 5-year BCSM was significantly higher for patients with RA-MIBC vs primary MIBC (56.1% vs 35.3%, AHR 1.24, P < .001), even after stratification by other tumor, treatment and patient-specific factors., Conclusion: RA-MIBCs tended to present with higher grade and T stage disease and were less likely to receive curative treatment. Even when accounting for stage, grade, and receipt of treatment, patients with RA-MIBC had worse survival compared to those with primary MIBC. These findings suggest that RA-MIBC present unique clinical challenges and may also represent a biologically more aggressive disease compared to primary MIBC. Future research is needed to better understand the biology of RA-MIBC and develop improved treatment approaches., (Copyright © 2021 Elsevier Inc. All rights reserved.)