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Najla Aldaoud,1,2 Ashley Graboski-Bauer,3 Nour Abdo,4 Samir Al Bashir,1,2 Ashraf O Oweis,5 Hanadi Ebwaini,1 Yousef Hasen,1–2,6 Rami Alazab,7 Kiril Trpkov81Department of Pathology and Microbiology, King Abdullah University Hospital, Irbid, Jordan; 2Jordan University of Science and Technology, Irbid, Jordan; 3Department of Teacher Education, University of Texas, El Paso, TX, USA; 4Department of Public Health, Jordan University of Science and Technology, Irbid, Jordan; 5Division of Nephrology, Department of Medicine, Jordan University of Science and Technology, Irbid, Jordan; 6Attasami Diagnostic Center, Tripoli, Libya; 7Division of Urology, Jordan University of Science and Technology, Irbid, Irbid; 8Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, CanadaBackground: High-grade prostatic intraepithelial neoplasia (HGPIN) is the most likely precancerous lesion for prostatic adenocarcinoma (PCa). Recent molecular studies have shown that HGPIN can harbor TMPRSS2-ERG fusion, a genetic marker also associated with PCa, which may provide an additional risk stratification tool for HGPIN, especially when present as an isolated lesion. Our aim was to assess the frequency of HGPIN and ERG expression in a cohort of prostatic needle core biopsies from Jordanian-Arab patients with PCa.Materials and methods: We studied 109 needle core biopsies from patients with PCa. Clinical data, including age and preoperative prostate specific antigen (PSA) level, were obtained from patients’ medical records.Results: HGPIN was present in 31 (28.4 %) of the 109 cases. Of the HGPIN cases, 13 (41.9%) expressed ERG immunostain. ERG expression in HGPIN was independent of patient age at presentation (P=0.4), pre-operative PSA (P=0.9), and the grade, using the novel Grade Groups (P=0.5).Conclusion: The frequency of HGPIN in our cohort appears similar to the one found in the Western patient populations and demonstrates a comparable frequency of ERG expression in these lesions.Keywords: high-grade prostatic intraepithelial neoplasia, prostate carcinoma, ERG, immunohistochemistry

Premal Patel,1 Ryan Sun,1 Benjamin Shiff,1 Kiril Trpkov,2 Geoffrey Thomas Gotto3 1Section of Urology, University of Manitoba, Winnipeg, MB, Canada; 2Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada; 3Department of Surgery, University of Calgary, Calgary, AB, Canada Objective: To assess the impact of time between prostate cancer diagnosis on biopsy and definitive intervention with radical prostatectomy (RP) in regard to adverse pathologic outcomes using a large multi-surgeon database.Materials and methods: We retrospectively reviewed 2,728 patients who underwent RP between 2005 and 2014. Patients were stratified according to biopsy Grade Group (GG). Pathologic outcomes were evaluated for patients with Results: In total 2,310 patients met the inclusion criteria. Median time from biopsy to surgery was 83 days (range: 61–109 days). No difference was observed for patients in any risk category regarding the adverse pathologic outcomes, including GG upgrade from biopsy to prostatectomy, presence of EPE, SVI, positive surgical margins, and positive lymph node involvement, with delays of up to 6 months between biopsy and RP. Surgical margins were positive in 25% of cases with pT2 disease and 50.2% of cases with pT3 and greater disease. EPE and SVI were present in 24.5% and 7.5% of specimens, respectively.Conclusion: Surgical delays of up to 6 months following prostate biopsy were not associated with an increased risk of GG upgrading, EPE, SVI, positive surgical margins, or lymph node involvement. Keywords: radical prostatectomy, prostate cancer, surgical wait time, surgical delay, pathologic outcomes, prostate biopsy

Benjamin Shiff,1 Premal Patel,1 Kiril Trpkov,2 Geoffrey T Gotto3 1Division of Urology, Department of Surgery, University of Manitoba, Winnipeg, MB, Canada; 2Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada; 3Division of Urology, Department of Surgery, University of Calgary, Calgary, AB, Canada Introduction: Prostate cancer is the most common cancer among men, but overall mortality rates remain low, due to the preponderance of low-risk disease. Over the last decade, there has been a shift toward more conservative management in low-risk prostate cancer, in order to minimize unnecessary intervention. This study aimed to evaluate the number of low-risk radical prostatectomies (RPs) being performed at the Southern Alberta Institute of Urology over a 10-year period. Methods: We retrospectively reviewed all patients who underwent RP from 2005 to 2014 at our institution. Patients were stratified by D’Amico risk classification and grade group based on 12-core transrectal ultrasound–guided biopsy (TRUS-bx) results. RP findings are reported from February 2005 to October 2014 to describe concordance between TRUS-bx and RPs. Basic descriptive analyses were used for this study. Results: Over the study period, 2,310 RPs were performed in our institution. Overall, 35.2% of these were performed on men with low-risk prostate cancer. From 2005 to 2014, the proportion of RPs performed for low-risk prostate cancer dropped from 54.0% to 8.9%, and 49.8% of patients who underwent RP for low-risk disease experienced pathologic upgrading, though only 3.8% were upgraded to grade group 3 or greater. Other adverse pathological findings were uniformly low among the low-risk group. Conclusion: The proportion of patients undergoing RP at our center for low-risk prostate cancer decreased significantly over the 10 years evaluated in this study, reflecting current global trends toward active surveillance in the management of low-risk prostate cancer. Keywords: radical prostatectomy, prostate cancer, active surveillance

Aims: A subset of exceptionally rare primary renal perivascular epithelioid cell tumours (PEComas) that harbour Xp11.2 translocation have been reported, but no larger series devoted to this topic have been published., Methods and Results: We describe the clinicopathological and molecular features of 10 renal PEComas, collected from our routine and consultation files. There were five female and five male patients aged 14-65 (median: 32 years). One patient had a history of childhood neuroblastoma, but no patients were known to have a tuberous sclerosis complex or other hereditary disorder. Complete surgical excision was the treatment for all patients. The available follow-up in five patients indicated a favourable outcome in 4/5 cases. Tumour size ranged from 2.8 to 15.2 cm (median, 5.2 cm). Immunohistochemistry revealed consistently strong TFE3 expression in all tumours, whereas PAX8 and keratin cocktails were uniformly negative. Other positive markers included HMB45 (7/9 tumours), CathepsinK (7/9 tumours), and CD117 (KIT) (3/5 tumours). TFE3 rearrangements were detected in 8/9 tumours (by targeted RNA sequencing in seven and by FISH in one). The identified fusion partners included SFPQ (n = 2) and one tumour each with ASPSCR1, ZC3H4, MED15, RBMX, and PRCC. One tumour that lacked TFE3 rearrangement by next-generation sequencing (NGS) and fluorescence in situ hybridization (FISH) revealed a large intrachromosomal deletion involving PKD1 and TSC2 by DNA-based NGS., Conclusion: This study highlights the morphologic and genetic diversity of TFE3-rearranged primary renal PEComas and underlines the value of surrogate TFE3 immunohistochemistry in identifying them. The lack of PAX8 and keratin expression represents the mainstay for distinguishing these tumours from MiTF-associated renal cell carcinomas. In addition, we report rare (ZC3H4, RBMX) and novel (MED15) TFE3 fusion partners in PEComa., (© 2024 The Author(s). Histopathology published by John Wiley & Sons Ltd.)

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.)

Autosomal dominant polycystic kidney disease (ADPKD) may be associated with various epithelial malignancies. The most reported ones are papillary renal cell carcinoma (RCC) and clear cell RCC. Only one noninvasive urothelial carcinoma arising in the renal pelvis has been previously reported in the setting of ADPKD in the English literature. A 52-year-old patient with ADPKD and a history of renal transplant presented with a poorly differentiated sarcomatoid neoplasm in his native left polycystic kidney. A recognizable urothelial or renal cell carcinoma differentiation was not identified in the resected neoplasm microscopically. The initial diagnosis for this specimen was challenging on morphology and immunohistochemistry, but targeted next-generation sequencing provided molecular evidence in support of urothelial origin, indicating a hotspot mutation -124 C > T in the TERT promoter (C228 T) and loss of heterozygosity on chromosomes 9p and 8p. This tumor is unique because, to our knowledge, this is the first report of upper tract sarcomatoid urothelial carcinoma in a patient with ADPKD., 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.

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., (© 2024. The Author(s).)

Historically, papillary renal cell carcinoma (PRCC) was divided into two types, type 1 and type 2, based solely on morphology. However, it is apparent that PRCC is far more complex and represents a histological, clinical, and molecular spectrum. There has been a significant evolution in our understanding of PRCC, highlighted by the recognition of new and molecularly defined entities that were previously included in PRCC type 2. This contemporary review addresses the evolving concepts regarding the PRCC, including why it is no longer needed to subtype PRCC, the current molecular landscape, prognostic parameters, and PRCC variants, including biphasic PRCC, papillary renal neoplasm with reverse polarity, and Warthin-like PRCC. Pathologists should also be aware of the potential mimickers of both low-grade and high-grade PRCCs as well as some new and emerging entities that may show papillary growth that should be excluded in the diagnostic workup. The evolving knowledge of PRCC biomarkers, morphologic patterns, and PRCC variants could also have important implications for clinical management. Lastly, the heterogeneity within the PRCC spectrum needs to be further studied, aiming to better stratify PRCC for appropriate clinical management and systemic therapy., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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.)

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.)

Papillary renal neoplasm with reverse polarity (PRNRP) is a recently described indolent entity with distinct features and its recognition from other oncocytic/eosinophilic papillary renal cell carcinoma (ePRCC) has important prognostic implications. ABCC2, a renal drug transporter, is overexpressed in aggressive PRCCs. In this study, we compared the clinicopathological parameters and the biological ABCC2 expression between PRNRP and ePRCC. PRNRP (n = 8) and ePRCC (n = 21) cases were selected from resection specimens and corresponding clinicopathological data were collected. ABCC2 immunohistochemical (IHC) staining was performed and ABCC2 staining patterns were classified as negative, cytoplasmic, and brush-border. RNA in-situ hybridization (ISH) was used to assess ABCC2 transcript levels. All eight PRNRP cases had weak cytoplasmic ABCC2 IHC reactivity; however, they showed no detectable ABCC2 transcripts on RNA ISH. In comparison, 76% (16/21) of ePRCCs showed ABCC2 IHC brush-border expression and significantly higher ABCC2 RNA ISH transcript levels (p < 0.001). Additionally, the ePRCC group showed a significantly larger tumor size (p = 0.004), higher WHO/ISUP grade (p < 0.001), and stage (p = 0.044). None of the PRNRP cases showed disease progression, while 9.5% (2/21) ePRCCs had disease progression. PRNRP is clinically and biologically distinct from ePRCC. Hence, it is crucial to differentiate between these two entities, particularly in needle core biopsies., (© 2024 The Authors. Pathology International published by Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Aims: Papillary renal cell carcinoma (PRCC) histologic subtyping is no longer recommended in the 2022 WHO classification. Currently, WHO/ISUP nucleolar grade is the only accepted prognostic histologic parameter for PRCC. ABCC2, a renal drug transporter, has been shown to significantly predict outcomes in PRCC. In this study we evaluated the prognostic significance of ABCC2 IHC staining patterns in a large, multi-institutional PRCC cohort and assessed the association of these patterns with ABCC2 mRNA expression., Methods and Results: We assessed 254 PRCCs for ABCC2 IHC reactivity patterns that were stratified into negative, cytoplasmic, brush-border <50%, and brush-border ≥50%. RNA in situ hybridization (ISH) was used to determine the transcript level of each group. Survival analysis was performed with SPSS and GraphPad software. RNA-ISH showed that the ABCC2 group with any brush-border staining was associated with a significant increase in the transcript level, when compared to the negative/cytoplasmic group (P = 0.034). Both ABCC2 groups with brush-border <50% (P = 0.024) and brush-border ≥50% (P < 0.001) were also associated with worse disease-free survival (DFS) in univariate analysis. Multivariate analysis showed that only ABCC2 IHC brush-border (<50% and ≥50%) reactivity groups (P = 0.037 and P = 0.003, respectively), and high-stage disease (P < 0.001) had a DFS of prognostic significance. In addition, ABCC2 brush-border showed significantly worse DFS in pT1a (P = 0.014), pT1 (P = 0.013), ≤4 cm tumour (P = 0.041) and high stage (P = 0.014) groups, while a similar analysis with high WHO/ISUP grade in these groups was not significant., Conclusion: ABCC2 IHC brush-border expression in PRCC correlates with significantly higher gene expression and also independently predicts survival outcomes., (© 2023 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Diffuse large B-cell lymphoma (DLBCL) shows a high degree of clinical and biological heterogeneity. Primary testicular lymphoma (PTL) is an extranodal variant of DLBCL associated with a higher risk of recurrence, including contralateral testicles and central nervous system sanctuary sites. Several molecular aberrations, including somatic mutation of MYD88, CD79B, and upregulation of NF-kB, PDL-1, and PDL-2, are thought to contribute to the pathogenesis and poor prognosis of PTL. However, additional biomarkers are needed that may improve the prognosis and help understand the PTL biology and lead to new therapeutic targets. RNA from diagnostic tissue biopsies of the PTL-ABC subtype and matched nodal DLBCL-ABC subtype patients was evaluated by mRNA and miRNA expression. Screening of 730 essential oncogenic genes was performed, and their epigenetic connections were examined using the nCounter PAN-cancer pathway, and Human miRNA assays with the nCounter System (NanoString Technologies). PTL and nodal DLBCL patients were comparable in age, gender, and putative cell of origin (p > 0.05). Wilms tumor 1 (WT1) expression in PTL exceeded that in nodal DLBCL (>6-fold; p = 0.01, FDR <0.01) and WT1 associated pathway genes THBS4, PTPN5, PLA2G2A, and IFNA17 were upregulated in PTL (>2.0-fold, p < 0.01, FDR <0.01). Additionally, miRNAs targeting WT1 (hsa15a-5p, hsa-miR-16-5p, has-miR-361-5p, has-miR-27b-3p, has-miR-199a-5p, has-miR-199b-5p, has-miR-132-3p, and hsa-miR-128-3p) showed higher expression in PTL compared to nodal DLBCL (≥2.0-fold; FDR 0.01). Lower expression of BMP7, LAMB3, GAS1, MMP7, and LAMC2 (>2.0-fold, p < 0.01) was observed in PTL compared to nodal DLBCL. This research revealed higher WT1 expression in PTL relative to nodal DLBCL, suggesting that a specific miRNA subset may target WT1 expression and impact the PI3k/Akt pathway in PTL. Further investigation is needed to explore WT1's biological role in PTL and its potential as a therapeutic target., (© 2023 John Wiley & Sons Ltd.)

The 2022 WHO classification of urinary and male genital tumors introduced several novel kidney entities exhibiting eosinophilic/oncocytic features with specific mutational backgrounds. Thus, molecular techniques, such as next-generation sequencing (NGS), became more commonly used for their evaluation. We studied 12 low-grade oncocytic tumors (LOT) of the kidney (from 11 patients), identified in a cohort of 210 eosinophilic/oncocytic renal tumors, diagnosed in our institution between October 2019 and May 2023, which represented 5.7% (12/210) of all eosinophilic/oncocytic renal tumors during this period. We reviewed their clinicopathologic, histologic, and immunohistochemical features, as well as their mutational profiles. We also reviewed the literature on NGS-derived data of LOT, by selecting papers in which LOT diagnosis was rendered according to the criteria proposed initially. Median age was 65 years (mean: 63.5; range 43-79) and median tumor size was 2.0 cm (mean: 2.2; range: 0.9-3.1). All tumors were positive for PAX8, CK7, and GATA3, and negative or focally positive for CD117/KIT. We found the following gene mutations: MTOR ((6/11), 54.5%)), TSC1 ((2/11), 18.2%)), and 1 had both NOTCH1 and NOTCH4 ((1/11), 9.1%)). Wild-type status was found in 2/11 (18.2%) patients and one tumor was not analyzable. A review of 8 previous studies that included 79 LOTs revealed frequent mutations in the genes that regulate the mammalian target of rapamycin (mTOR) pathway: MTOR (32/79 (40.5%)), TSC1 (21/79 (26.6%)), and TSC2 (9/79 (11.4%)). Other mutated genes included PIK3CA, NF2, and PTEN, not typically known to affect the mTOR pathway, but potentially acting as upstream and downstream effectors. Our study shows that LOT is increasingly diagnosed in routine practice when applying the appropriate diagnostic criteria. We also confirm that the mTOR pathway is strongly implicated in the pathogenesis of this tumor mainly through MTOR, TCS1, and TSC2 mutations, but other genes could also be involved in the pathway activation, especially in LOTs without "canonical" mutations., (© 2023. The Author(s).)

Lipoblastoma-like tumor (LLT) is a rare adipocytic neoplasm with a predilection for the vulva. Since 2002, <30 cases have been reported, characterizing it as an indolent tumor that may sometimes recur locally. Diagnosis can be challenging due to its rarity and morphologic overlap with other adipocytic tumors. Thus far, there are no specific molecular or immunohistochemical features to aid in the diagnosis of LLT. Recent case reports have described LLT arising at other sites, including the spermatic cord and gluteal region, suggesting wider anatomical distribution. We present a large series of LLT to further characterize its clinicopathologic and molecular features. Twenty-eight cases of LLT were retrieved from departmental and consult archives (including 8 from a prior series). The cohort comprised 28 patients (8 males, 20 females) with a median age of 28 years (range: 1-80 years). There were 17 primary LLT of the vulva. Other anatomical sites included the scrotum (n = 3), spermatic cord (n = 2), inguinal region (n = 2), limbs (n = 2), pelvis (n = 1), and retroperitoneum (n = 1). Median tumor size was 6.0 cm (range: 1.8-30.0 cm). The tumors had a lobulated architecture and were typically composed of adipocytes, lipoblasts, and spindle cells in a myxoid stroma with prominent thin-walled vessels. Using immunohistochemistry, a subset showed loss of Rb expression (12/23 of samples). Follow-up in 15 patients (median: 56 months) revealed 8 patients with local recurrence and 1 patient with metastases to the lung/pleura and breasts. Targeted DNA sequencing revealed a simple genomic profile with limited copy number alterations and low mutational burden. No alterations in RB1 were identified. The metastatic LLT showed concurrent pathogenic PIK3CA and MTOR activating mutations, both in the primary and in the lung/pleural metastasis; the latter also harbored TERT promoter mutation. One tumor had a pathogenic TSC1 mutation, and one tumor showed 2-copy deletion of CDKN2A, CDKN2B, and MTAP. No biologically significant variants were identified in 8 tumors. No gene fusions were identified by RNA sequencing in 4 tumors successfully sequenced. This study expands the clinicopathologic spectrum of LLT, highlighting its wider anatomical distribution and potential for occasional metastasis. Molecularly, we identified activating mutations in the PI3K-MTOR signaling pathway in 2 tumors, which may contribute to exceptional aggressive behavior., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

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.

To elucidate the spectrum of metastatic solid tumors to the testis and their clinicopathologic features. The databases and files of 26 pathology departments from 9 countries on 3 continents were surveyed to identify metastatic solid tumors to the testis and to characterize their clinicopathologic features in detail. We compiled a series of 157 cases of metastatic solid tumors that secondarily involved the testis. The mean patient age at diagnosis was 64 years (range, 12-93 years). Most patients (127/144; 88%) had clinical manifestation of the disease, with testicular mass/nodule (89/127; 70%) being the most common finding. The main mechanism of testicular involvement was metastasis in 154/157 (98%) cases. Bilateral testicular involvement was present in 12/157 (8%) patients. Concurrent or prior extratesticular metastases were present in 78/101 (77%) patients. The diagnosis was made mainly in orchiectomy specimens (150/157; 95%). Different types of carcinomas (138/157; 87%), most commonly adenocarcinoma (72/157; 46%), were the most common malignancies. The most common primary carcinomas included prostatic (51/149; 34%), renal (29/149; 20%), and colorectal (13/149; 9%). Intratubular growth was identified in 13/124 (11%) cases and paratesticular involvement was found in 73/152 (48%) cases. In patients with available follow-up (110/157; 70%), more than half (58/110; 53%) died of disease. In this largest series compiled to date, we found that most secondary tumors of the testis represent metastases from the genitourinary and gastrointestinal tract carcinomas and typically occur in the setting of disseminated disease., (Copyright © 2023 Elsevier Inc. All rights reserved.)

A spectrum of renal tumors associated with frequent TSC/mTOR (tuberous sclerosis complex/mechanistic target of rapamycin) pathway gene alterations (in both the germline and sporadic settings) have recently been described. These include renal cell carcinoma with fibromyomatous stroma (RCC FMS), eosinophilic solid and cystic renal cell carcinoma (ESC RCC), eosinophilic vacuolated tumor (EVT), and low-grade oncocytic tumor (LOT). Most of these entities have characteristic morphologic and immunohistochemical features that enable their recognition without the need for molecular studies. In this report, we summarize recent advances and discuss their evolving complexity.

Differentiating benign renal oncocytic tumors and malignant renal cell carcinoma (RCC) on imaging and histopathology is a critical problem that presents an everyday clinical challenge. This manuscript aims to demonstrate a novel methodology integrating metabolomics with radiomics features (RF) to differentiate between benign oncocytic neoplasia and malignant renal tumors. For this purpose, thirty-three renal tumors (14 renal oncocytic tumors and 19 RCC) were prospectively collected and histopathologically characterised. Matrix-assisted laser desorption/ionisation mass spectrometry imaging (MALDI-MSI) was used to extract metabolomics data, while RF were extracted from CT scans of the same tumors. Statistical integration was used to generate multilevel network communities of -omics features. Metabolites and RF critical for the differentiation between the two groups (delta centrality > 0.1) were used for pathway enrichment analysis and machine learning classifier (XGboost) development. Receiver operating characteristics (ROC) curves and areas under the curve (AUC) were used to assess classifier performance. Radiometabolomics analysis demonstrated differential network node configuration between benign and malignant renal tumors. Fourteen nodes (6 RF and 8 metabolites) were crucial in distinguishing between the two groups. The combined radiometabolomics model achieved an AUC of 86.4%, whereas metabolomics-only and radiomics-only classifiers achieved AUC of 72.7% and 68.2%, respectively. Analysis of significant metabolite nodes identified three distinct tumour clusters (malignant, benign, and mixed) and differentially enriched metabolic pathways. In conclusion, radiometabolomics integration has been presented as an approach to evaluate disease entities. In our case study, the method identified RF and metabolites important in differentiating between benign oncocytic neoplasia and malignant renal tumors, highlighting pathways differentially expressed between the two groups. Key metabolites and RF identified by radiometabolomics can be used to improve the identification and differentiation between renal neoplasms., (© 2023. Springer Nature Limited.)

The increasing evidence of oncocytic renal tumors positive in 99m Tc Sestamibi Single Photon Emission Tomography/Computed Tomography (SPECT/CT) examination calls for the development of diagnostic tools to differentiate these tumors from more aggressive forms. This study combined radiomics analysis with the uptake of 99m Tc Sestamibi on SPECT/CT to differentiate benign renal oncocytic neoplasms from renal cell carcinoma. A total of 57 renal tumors were prospectively collected. Histopathological analysis and radiomics data extraction were performed. XGBoost classifiers were trained using the radiomics features alone and combined with the results from the visual evaluation of 99m Tc Sestamibi SPECT/CT examination. The combined SPECT/radiomics model achieved higher accuracy (95%) with an area under the curve (AUC) of 98.3% (95% CI 93.7-100%) than the radiomics-only model (71.67%) with an AUC of 75% (95% CI 49.7-100%) and visual evaluation of 99m Tc Sestamibi SPECT/CT alone (90.8%) with an AUC of 90.8% (95%CI 82.5-99.1%). The positive predictive values of SPECT/radiomics, radiomics-only, and 99m Tc Sestamibi SPECT/CT-only models were 100%, 85.71%, and 85%, respectively, whereas the negative predictive values were 85.71%, 55.56%, and 94.6%, respectively. Feature importance analysis revealed that 99m Tc Sestamibi uptake was the most influential attribute in the combined model. This study highlights the potential of combining radiomics analysis with 99m Tc Sestamibi SPECT/CT to improve the preoperative characterization of benign renal oncocytic neoplasms. The proposed SPECT/radiomics classifier outperformed the visual evaluation of 99m Tc Sestamibii SPECT/CT and the radiomics-only model, demonstrating that the integration of 99m Tc Sestamibi SPECT/CT and radiomics data provides improved diagnostic performance, with minimal false positive and false negative results.

Aims: To elucidate the spectrum of metastatic tumours to the penis and their clinicopathologic features., Methods: The databases and files of 22 pathology departments from eight countries on three continents were queried to identify metastatic solid tumours of the penis and to characterize their clinical and pathologic features., Results: We compiled a series of 109 cases of metastatic solid tumours that secondarily involved the penis. The mean patient age at diagnosis was 71 years (range, 7-94 years). Clinical presentation commonly included a penile nodule/mass (48/95; 51%) and localised pain (14/95; 15%). A prior history of malignancy was known in 92/104 (89%) patients. Diagnosis was made mainly on biopsy (82/109; 75%), or penectomy (21/109; 19%) specimens. The most common penile locations were the glans (45/98; 46%) and corpus cavernosum (39/98; 39%). The most frequent histologic type was adenocarcinoma (56%). Most primary carcinomas originated in the genitourinary (76/108; 70%) and gastrointestinal (20/108; 18%) tracts, including prostate (38/108; 35%), urinary bladder (27/108; 25%), and colon/rectum (18/108; 17%). Concurrent or prior extrapenile metastases were identified in 50/78 (64%) patients. Clinical follow-up (mean 22 months, range 0-171 months) was available for 87/109 (80%) patients, of whom 46 (53%) died of disease., Conclusion: This is the largest study to date of metastatic solid tumours secondarily involving the penis. The most frequent primaries originated from the genitourinary and gastrointestinal tracts. Metastatic penile tumours usually presented with penile nodules/masses and pain, and they often occurred in the setting of advanced metastatic disease, portending poor clinical outcomes., (© 2023 John Wiley & Sons Ltd.)

This review summarizes current knowledge on several novel and emerging renal entities, including eosinophilic solid and cystic renal cell carcinoma (RCC), RCC with fibromyomatous stroma, anaplastic lymphoma kinase-rearranged RCC, low-grade oncocytic renal tumor, eosinophilic vacuolated tumor, thyroidlike follicular RCC, and biphasic hyalinizing psammomatous RCC. Their clinical features, gross and microscopic morphology, immunohistochemistry, and molecular and genetic features are described. The diagnosis of most of them rests on recognizing their morphologic features using immunohistochemistry. Accurate diagnosis of these entitles will further reduce the category of "unclassifiable renal carcinomas/tumors" and will lead to better clinical management and improved patient prognostication., (Copyright © 2023 Elsevier Inc. All rights reserved.)