Molecular Characterization of Juxtaglomerular Cell Tumors: Evidence of Alterations in MAPK-RAS Pathway.

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.

Proposal for an optimised definition of adverse pathology (unfavourable histology) that predicts metastatic risk in prostatic adenocarcinoma independent of grade group and pathological stage.

AIMS: Histological grading of prostate cancer is a powerful prognostic tool, but current criteria for grade assignment are not fully optimised. Our goal was to develop and test a simplified histological grading model, based heavily on large cribriform/intraductal carcinoma, with optimised sensitivity for predicting metastatic potential. METHODS AND RESULTS: Two separate non-overlapping cohorts were identified: a 419-patient post-radical prostatectomy cohort with long term clinical follow-up and a 209-patient post-radical prostatectomy cohort in which all patients had pathologically confirmed metastatic disease. All prostatectomies were re-reviewed for high-risk histological patterns of carcinoma termed 'unfavourable histology'. Unfavourable histology is defined by any classic Gleason pattern 5 component, any large cribriform morphology (> 0.25 mm) or intraductal carcinoma, complex intraluminal papillary architecture, grade 3 stromogenic carcinoma and complex anastomosing cord-like growth. For the outcome cohort, Kaplan-Meier analysis compared biochemical recurrence, metastasis and death between subjects with favourable and unfavourable histology, stratified by pathological stage and grade group. Multivariable Cox proportional hazards models evaluated adding unfavourable histology to the Memorial Sloan Kettering Cancer Center (MSKCC) post-prostatectomy nomogram and stratification by percentage of unfavourable histology. At 15 years unfavourable histology predicted biochemical recurrence, with sensitivity of 93% and specificity of 88%, metastatic disease at 100 and 48% and death at 100 and 46%. Grade group 2 prostate cancers with unfavourable histology were associated with metastasis independent of pathological stage, while those without had no risk. Histological models for prediction of metastasis based on only large cribriform/intraductal carcinoma or increasing diameter of cribriform size improved specificity, but with lower sensitivity. Multivariable Cox proportional hazards models demonstrated that unfavourable histology significantly improved discriminatory power of the MSKCC post-prostatectomy nomogram for biochemical failure (likelihood ratio test P < 0.001). In the retrospective review of a separate RP cohort in which all patients had confirmed metastatic disease, none had unequivocal favourable histology. CONCLUSIONS: Unfavourable histology at radical prostatectomy is associated with metastatic risk, predicted adverse outcomes better than current grading and staging systems and improved the MSKCC post-prostatectomy nomogram. Most importantly, unfavourable histology stratified grade group 2 prostate cancers into those with and without metastatic potential, independent of stage. While unfavourable histology is driven predominantly by large cribriform/intraductal carcinoma, the recognition and inclusion of other specific architectural patterns add to the sensitivity for predicting metastatic disease. Moreover, a simplified dichotomous model improves communication and could increase implementation.

Prostate cancer - major changes in the American Joint Committee on Cancer eighth edition cancer staging manual.

Answer questions and earn CME/CNE The eighth edition of the American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) Staging Manual has been updated and improved to ensure the highest degree of clinical relevance and to improve its utility for patient evaluation and clinical research. Major changes include: 1) pathologically organ-confined disease is now considered pT2 and is no longer subclassified by extent of involvement or laterality, 2) tumor grading now includes both the Gleason score (as in the seventh edition criteria) and the grade group (introduced in the eighth edition criteria), 3) prognostic stage group III includes select, organ-confined disease based on prostate-specific antigen and Gleason/grade group status, and 4) 2 statistical prediction models are included in the staging manual. The AJCC will continue to critically analyze emerging prostate cancer biomarkers and tools for their ability to prognosticate and guide treatment decision making with the highest level of accuracy and confidence for patients and physicians. CA Cancer J Clin 2017;67:245-253. © 2017 American Cancer Society.

Long-Term Outcomes in Patients Using Protocol-Directed Active Surveillance for Prostate Cancer.

Importance: Outcomes from protocol-directed active surveillance for favorable-risk prostate cancers are needed to support decision-making. Objective: To characterize the long-term oncological outcomes of patients receiving active surveillance in a multicenter, protocol-directed cohort. Design, Setting, and Participants: The Canary Prostate Active Surveillance Study (PASS) is a prospective cohort study initiated in 2008. A cohort of 2155 men with favorable-risk prostate cancer and no prior treatment were enrolled at 10 North American centers through August 2022. Exposure: Active surveillance for prostate cancer. Main Outcomes and Measures: Cumulative incidence of biopsy grade reclassification, treatment, metastasis, prostate cancer mortality, overall mortality, and recurrence after treatment in patients treated after the first or subsequent surveillance biopsies. Results: Among 2155 patients with localized prostate cancer, the median follow-up was 7.2 years, median age was 63 years, 83% were White, 7% were Black, 90% were diagnosed with grade group 1 cancer, and median prostate-specific antigen (PSA) was 5.2 ng/mL. Ten years after diagnosis, the incidence of biopsy grade reclassification and treatment were 43% (95% CI, 40%-45%) and 49% (95% CI, 47%-52%), respectively. There were 425 and 396 patients treated after confirmatory or subsequent surveillance biopsies (median of 1.5 and 4.6 years after diagnosis, respectively) and the 5-year rates of recurrence were 11% (95% CI, 7%-15%) and 8% (95% CI, 5%-11%), respectively. Progression to metastatic cancer occurred in 21 participants and there were 3 prostate cancer-related deaths. The estimated rates of metastasis or prostate cancer-specific mortality at 10 years after diagnosis were 1.4% (95% CI, 0.7%-2%) and 0.1% (95% CI, 0%-0.4%), respectively; overall mortality in the same time period was 5.1% (95% CI, 3.8%-6.4%). Conclusions and Relevance: In this study, 10 years after diagnosis, 49% of men remained free of progression or treatment, less than 2% developed metastatic disease, and less than 1% died of their disease. Later progression and treatment during surveillance were not associated with worse outcomes. These results demonstrate active surveillance as an effective management strategy for patients diagnosed with favorable-risk prostate cancer.

Artificial Intelligence-Based PTEN Loss Assessment as an Early Predictor of Prostate Cancer Metastasis After Surgery: A Multicenter Retrospective Study.

Phosphatase and tensin homolog (PTEN) loss is associated with adverse outcomes in prostate cancer and can be measured via immunohistochemistry. The purpose of the study was to establish the clinical application of an in-house developed artificial intelligence (AI) image analysis workflow for automated detection of PTEN loss on digital images for identifying patients at risk of early recurrence and metastasis. Postsurgical tissue microarray sections from the Canary Foundation (n = 1264) stained with anti-PTEN antibody were evaluated independently by pathologist conventional visual scoring (cPTEN) and an automated AI-based image analysis pipeline (AI-PTEN). The relationship of PTEN evaluation methods with cancer recurrence and metastasis was analyzed using multivariable Cox proportional hazard and decision curve models. Both cPTEN scoring by the pathologist and quantification of PTEN loss by AI (high-risk AI-qPTEN) were significantly associated with shorter metastasis-free survival (MFS) in univariable analysis (cPTEN hazard ratio [HR], 1.54; CI, 1.07-2.21; P = .019; AI-qPTEN HR, 2.55; CI, 1.83-3.56; P < .001). In multivariable analyses, AI-qPTEN showed a statistically significant association with shorter MFS (HR, 2.17; CI, 1.49-3.17; P < .001) and recurrence-free survival (HR, 1.36; CI, 1.06-1.75; P = .016) when adjusting for relevant postsurgical clinical nomogram (Cancer of the Prostate Risk Assessment [CAPRA] postsurgical score [CAPRA-S]), whereas cPTEN does not show a statistically significant association (HR, 1.33; CI, 0.89-2; P = .2 and HR, 1.26; CI, 0.99-1.62; P = .063, respectively) when adjusting for CAPRA-S risk stratification. More importantly, AI-qPTEN was associated with shorter MFS in patients with favorable pathological stage and negative surgical margins (HR, 2.72; CI, 1.46-5.06; P = .002). Workflow also demonstrated enhanced clinical utility in decision curve analysis, more accurately identifying men who might benefit from adjuvant therapy postsurgery. This study demonstrates the clinical value of an affordable and fully automated AI-powered PTEN assessment for evaluating the risk of developing metastasis or disease recurrence after radical prostatectomy. Adding the AI-qPTEN assessment workflow to clinical variables may affect postoperative surveillance or management options, particularly in low-risk patients.

Anastomosing haemangioma of the adrenal gland: A clinicopathological series of seven cases.

AIMS: Anastomosing haemangioma is a rare benign vascular neoplasm that may histologically mimic angiosarcoma. We report the largest single institution series of anastomosing haemangioma in the adrenal gland with emphasis on clinical and radiological features. METHODS AND RESULTS: Our laboratory information system was searched for a 25-year period (1999-2023), yielding seven cases confirmed as anastomosing haemangioma of the adrenal gland after pathological re-review. Clinical, radiological and pathological information was obtained from medical charts and submitting pathologists. Of a total of seven patients, four (57.1%) were men and three women, ranging in age from 37 to 75 years (mean = 61). Six of seven patients underwent adrenalectomies and one had radical nephrectomy. Tumours ranged from 0.7 to 6.4 cm (mean = 2.1 cm) and five of seven (71%) were grossly well-circumscribed. Five of seven lesions were found incidentally at imaging for other indications. All tumours were unifocal except one, which presented with multifocal disease with a concurrent adjacent retroperitoneal anastomosing haemangioma. Three of five tumours imaged with contrast enhancement were almost completely hyperenhancing with a small central non-enhancing portion, features overlapping with pheochromocytoma. One of seven tumours involved the peri-adrenal adipose tissue with a focally infiltrative pattern. There were no recurrences or metastases in six patients with available follow-up data (median = 95 months). CONCLUSIONS: Benign anastomosing haemangiomas of the adrenal gland tend to occur in older patients, may mimic pheochromocytoma on imaging and must be distinguished from angiosarcoma pathologically. Better awareness of this entity by pathologists, radiologists and surgeons is crucial to appropriate work-up, diagnosis and management.

Low-grade oncocytic tumour of the kidney is characterised by genetic alterations of TSC1, TSC2, MTOR or PIK3CA and consistent GATA3 positivity.

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

Evaluation of Lineage/Site-specific Nuclear Immunohistochemical Markers SATB2, Cyclin D1, SALL4, and BCOR in High-grade Endometrial Carcinomas.

Poorly differentiated malignant neoplasms involving the gynecologic tract routinely include a poorly differentiated endometrial carcinoma (EC) in the differential diagnosis. Some nuclear lineage/site-specific immunohistochemical markers are utilized in this diagnostic setting including SATB2, cyclin D1, SALL4, and BCOR, but their specificity and use in small samples are not clear across the spectrum of ECs. Cases of undifferentiated/dedifferentiated endometrial carcinomas (UEC/DDEC), clear cell carcinoma (CCC), uterine serous carcinoma (USC), FIGO grade 3 endometrial endometrioid carcinoma (EEC), and uterine carcinosarcoma (UCS) were identified and diagnoses confirmed. Whole-section immunohistochemical stains for SATB2, cyclin D1, SALL4, BCOR, and PAX8 were performed. A total of 113 cases were utilized: 15 CCC, 26 EEC, 19 UCS, 22 USC, and 31 UEC/DDEC. Cases were distributed across both low (49%) and high (51%) FIGO clinical stages. SATB2 was expressed by UCS (8/19, 42%), EEC (10/26, 38%), UEC/DDEC (11/30, 37%), and USC (6/22, 27%). Cyclin D1 was expressed by EEC (24/26, 92%), USC (17/22, 77%), UEC/DDEC (15/20 EEC component, 75%; 22/30 UEC, 73%), UCS (10/16 carcinoma, 63%; 11/19 sarcoma, 58%), and CCC (8/15, 53%). SALL4 was expressed most frequently by UEC/DDEC (12/30, 40%), but also USC (7/22, 32%), EEC (5/26, 19%), and UCS (4/16 carcinoma, 25%; 3/19 sarcoma, 16%). BCOR was expressed at low levels in 2 USC, 2 UEC/DDEC, and 2 UCS. PAX8 was generally positive but showed lower expression in UEC/DDEC (17/30, 57%) and in the sarcomatous portions of UCS (6/19, 32%). SATB2, cyclin D1, SALL4, and BCOR stain variable numbers of poorly-differentiated EC and must be carefully interpreted within morphologic and clinical context.

Treatment in the absence of disease reclassification among men on active surveillance for prostate cancer.

BACKGROUND: Maintaining men on active surveillance for prostate cancer can be challenging. Although most men who eventually undergo treatment have experienced clinical progression, a smaller subset elects treatment in the absence of disease reclassification. This study sought to understand factors associated with treatment in a large, contemporary, prospective cohort. METHODS: This study identified 1789 men in the Canary Prostate Cancer Active Surveillance Study cohort enrolled as of 2020 with a median follow-up of 5.6 years. Clinical and demographic data as well as information on patient-reported quality of life and urinary symptoms were used in multivariable Cox proportional hazards regression models to identify factors associated with the time to treatment RESULTS: Within 4 years of their diagnosis, 33% of men (95% confidence interval [CI], 30%-35%) underwent treatment, and 10% (95% CI, 9%-12%) were treated in the absence of reclassification. The most significant factor associated with any treatment was an increasing Gleason grade group (adjusted hazard ratio [aHR], 14.5; 95% CI, 11.7-17.9). Urinary quality-of-life scores were associated with treatment without reclassification (aHR comparing "mostly dissatisfied/terrible" with "pleased/mixed," 2.65; 95% CI, 1.54-4.59). In a subset analysis (n = 692), married men, compared with single men, were more likely to undergo treatment in the absence of reclassification (aHR, 2.63; 95% CI, 1.04-6.66). CONCLUSIONS: A substantial number of men with prostate cancer undergo treatment in the absence of clinical changes in their cancers, and quality-of-life changes and marital status may be important factors in these decisions. LAY SUMMARY: This analysis of men on active surveillance for prostate cancer shows that approximately 1 in 10 men will decide to be treated within 4 years of their diagnosis even if their cancer is stable. These choices may be related in part to quality-or-life or spousal concerns.

Low grade oncocytic tumors of the kidney: a clinically relevant approach for the workup and accurate diagnosis.

Renal oncocytoma and chromophobe renal cell carcinoma were accepted as unique renal tumors in the late 1990s. Since their formal description, criteria for diagnosis have evolved and additional distinct tumor subtypes originally considered as one these two entities are now recognized. The last two decades have witnessed unprecedented interest in the spectrum of low grade oncocytic renal neoplasms in three specific areas: (1) histologic characterization of tumors with overlapping morphologic features between oncocytoma and chromophobe renal cell carcinoma; (2) description of potentially unique entities within this spectrum, such as eosinophilic vacuolated tumor and low-grade oncocytic tumor; and (3) better appreciation of the association between a subset of low grade oncocytic tumors and hereditary renal neoplasia. While this important work has been academically rewarding, the proposal of several histologic entities with overlapping morphologic and immunophenotypic features (which may require esoteric adjunctive immunohistochemical and/or molecular techniques for confirmation) has created frustration in the diagnostic pathology and urology community as information evolves regarding classification within this spectrum of renal neoplasia. Pathologists, including genitourinary subspecialists, are often uncertain as to the "best practice" diagnostic approach to such tumors. In this review, we present a practical clinically relevant algorithmic approach to classifying tumors within the low grade oncocytic family of renal neoplasia, including a proposal for compressing terminology for evolving categories where appropriate without sacrificing prognostic relevance.

Molecular assessment of paratesticular rhabdomyomas demonstrates recurrent findings, including a novel H3C2 p.K37I mutation.

Rhabdomyomas are benign tumors with skeletal muscle differentiation that are broadly divided into cardiac and extracardiac types. The latter demonstrate a predilection for head and neck and genital locations and are further subclassified into adult-type rhabdomyoma (ATRM), fetal-type rhabdomyoma (FTRM) and genital rhabdomyoma (GRM). Most extracardiac rhabdomyomas that arise in paratesticular tissues have a somewhat distinctive morphology and have been termed sclerosing rhabdomyomas (SRM). Therefore, we hypothesized that these tumors may harbor recurrent genetic alterations. In this study, we assessed 15 paratesticular rhabdomyomas (11 initially classified as SRM, 2 cellular FTRM and 2 ATRM) using massively parallel DNA and RNA sequencing. Five of 14 successfully sequenced cases harbored a novel H3C2 p.K37I mutation (4 SRM and 1 ATRM). This mutation replaced a highly conserved lysine residue that is a target for epigenetic modifications and plays a role in regulation of DNA replication. Moreover, 4 tumors (2 cellular FTRM, 1 case initially diagnosed as SRM and 1 ATRM) had complex copy number profiles characterized by numerous chromosome-level and arm-level copy number gains, consistent with a ploidy shift. Rereview of the SRM with copy number gains demonstrated that it was significantly more cellular and had a more prominent fascicular architecture than the rest of the SRMs included in this series. Therefore, it was retrospectively reclassified as a cellular FTRM. In conclusion, this study demonstrated that paratesticular rhabdomyomas harbor recurrent somatic H3C2 p.K37I mutations and ploidy shifts.

Analysis of separate training and validation radical prostatectomy cohorts identifies 0.25 mm diameter as an optimal definition for "large" cribriform prostatic adenocarcinoma.

Cribriform growth pattern is well-established as an adverse pathologic feature in prostate cancer. The literature suggests "large" cribriform glands associate with aggressive behavior; however, published studies use varying definitions for "large". We aimed to identify an outcome-based quantitative cut-off for "large" vs "small" cribriform glands. We conducted an initial training phase using the tissue microarray based Canary retrospective radical prostatectomy cohort. Of 1287 patients analyzed, cribriform growth was observed in 307 (24%). Using Kaplan-Meier estimates of recurrence-free survival curves (RFS) that were stratified by cribriform gland size, we identified 0.25 mm as the optimal cutoff to identify more aggressive disease. In univariable and multivariable Cox proportional hazard analyses, size >0.25 mm was a significant predictor of worse RFS compared to patients with cribriform glands ≤0.25 mm, independent of pre-operative PSA, grade, stage and margin status (p < 0.001). In addition, two different subset analyses of low-intermediate risk cases (cases with Gleason score ≤ 3 + 4 = 7; and cases with Gleason score = 3 + 4 = 7/4 + 3 = 7) likewise demonstrated patients with largest cribriform diameter >0.25 mm had a significantly lower RFS relative to patients with cribriform glands ≤0.25 mm (each subset p = 0.004). Furthermore, there was no significant difference in outcomes between patients with cribriform glands ≤ 0.25 mm and patients without cribriform glands. The >0.25 mm cut-off was validated as statistically significant in a separate 419 patient, completely embedded whole-section radical prostatectomy cohort by biochemical recurrence, metastasis-free survival, and disease specific death, even when cases with admixed Gleason pattern 5 carcinoma were excluded. In summary, our findings support reporting cribriform gland size and identify 0.25 mm as an optimal outcome-based quantitative measure for defining "large" cribriform glands. Moreover, cribriform glands >0.25 mm are associated with potential for metastatic disease independent of Gleason pattern 5 adenocarcinoma.

Evaluating the Outcomes of Active Surveillance in Grade Group 2 Prostate Cancer: Prospective Results from the Canary PASS Cohort.

PURPOSE: Active surveillance (AS) for grade group (GG) 2 patients is not yet well defined. We sought to compare clinical outcomes of men with GG1 and GG2 prostate cancer undergoing AS in a large prospective North American cohort. MATERIALS AND METHODS: Participants were prospectively enrolled in an AS study with protocol-directed followup at 10 centers in the U.S. and Canada. We evaluated time from diagnosis to biopsy grade reclassification and time to treatment. In men treated after initial surveillance, adverse pathology and recurrence were also analyzed. RESULTS: At diagnosis, 154 (9%) had GG2 and 1,574 (91%) had GG1. Five-year reclassification rates were similar between GG2 and GG1 (30% vs 37%, p=0.11). However, more patients with GG2 were treated at 5 years (58% vs 34%, p <0.001) and GG at diagnosis was associated with time to treatment (HR=1.41; p=0.01). Treatment rates were similar in patients who reclassified during AS, but in patients who did not reclassify, those diagnosed with GG2 underwent definitive treatment more often than GG1 (5-year treatment rates 52% and 12%, p <0.0001). In participants who underwent radical prostatectomy after initial surveillance, the adjusted risk of adverse pathology was similar (HR=1.26; p=0.4). Biochemical recurrence within 3 years of treatment for GG2 and GG1 patients was 6% for both groups. CONCLUSIONS: In patients on AS, the rate of definitive treatment is higher after an initial diagnosis of GG2 than GG1. Adverse pathology after radical prostatectomy and short-term biochemical recurrence after definitive treatment were similar between GG2 and GG1.

Impact of Prostate Health Index Results for Prediction of Biopsy Grade Reclassification During Active Surveillance.

PURPOSE: We assessed whether Prostate Health Index results improve prediction of grade reclassification for men on active surveillance. METHODS AND MATERIALS: We identified men in Canary Prostate Active Surveillance Study with Grade Group 1 cancer. Outcome was grade reclassification to Grade Group 2+ cancer. We considered decision rules to maximize specificity with sensitivity set at 95%. We derived rules based on clinical data (R1) vs clinical data+Prostate Health Index (R3). We considered an "or"-logic rule combining clinical score and Prostate Health Index (R4), and a "2-step" rule using clinical data followed by risk stratification based on Prostate Health Index (R2). Rules were applied to a validation set, where values of R2-R4 vs R1 for specificity and sensitivity were evaluated. RESULTS: We included 1,532 biopsies (n = 610 discovery; n = 922 validation) among 1,142 men. Grade reclassification was seen in 27% of biopsies (23% discovery, 29% validation). Among the discovery set, at 95% sensitivity, R2 yielded highest specificity at 27% vs 17% for R1. In the validation set, R3 had best performance vs R1 with Δsensitivity = -4% and Δspecificity = +6%. There was slight improvement for R3 vs R1 for confirmatory biopsy (AUC 0.745 vs R1 0.724, ΔAUC 0.021, 95% CI 0.002-0.041) but not for subsequent biopsies (ΔAUC -0.012, 95% CI -0.031-0.006). R3 did not have better discrimination vs R1 among the biopsy cohort overall (ΔAUC 0.007, 95% CI -0.007-0.020). CONCLUSIONS: Among active surveillance patients, using Prostate Health Index with clinical data modestly improved prediction of grade reclassification on confirmatory biopsy and did not improve prediction on subsequent biopsies.

The Histologic Diversity of Chromophobe Renal Cell Carcinoma With Emphasis on Challenges Encountered in Daily Practice.

Chromophobe renal cell carcinoma (ChRCC) is the third most common renal cell carcinoma in adults. The aim of this review is to provide a comprehensive overview highlighting the broad morphologic spectrum of ChRCC, and offer a practical approach for handling cases in daily practice. For the purpose of this review, we classify ChRCC subtypes as (1) classic, (2) eosinophilic, (3) sarcomatoid, and (4) other rare patterns. The concept of eosinophilic ChRCC has significantly evolved, yet it still is one of the major diagnostic challenges pathologists face in routine practice due to its morphologic overlap with renal oncocytoma. Rare patterns of ChRCC have been described over the last few decades, showing a wide histologic spectrum including those with adenomatoid microcystic pigmented, multicystic, neuroendocrine, small cell, and papillary features. ChRCC represents a heterogenous group of neoplasms, demonstrating varied but unique morphologic and genetic profiles. Although the field of ChRCC knowledge is still evolving, rare patterns can present diagnostic challenges if they are not known to pathologists and/or clinicians. Proper and generous tumor sampling along with careful histologic examination allow for recognition of these rare morphologies. The role of routine molecular testing appears to be limited. From a clinical management standpoint, the rare patterns of ChRCC seem to have no definite clinical implications at present and likely can be managed similarly to usual ChRCC. Finally, we will discuss distinctive novel/emerging renal neoplasms previously considered under the spectrum of ChRCC, low-grade oncocytic renal tumor and eosinophilic vacuolated tumor, with regard to their current significance and implications for future classification strategies.

Re-evaluating tumors of purported specialized prostatic stromal origin reveals molecular heterogeneity, including non-recurring gene fusions characteristic of uterine and soft tissue sarcoma subtypes.

Tumors of purported specialized prostatic stromal origin comprise prostatic stromal sarcomas (PSS) and stromal tumors of uncertain malignant potential (STUMP). Prior studies have described their clinicopathologic characteristics, but the molecular features remain incompletely understood. Moreover, these neoplasms are morphologically heterogeneous and the lack of specific adjunctive markers of prostatic stromal lineage make precise definition more difficult, leading some to question whether they represent a specific tumor type. In this study, we used next-generation DNA and RNA sequencing to profile 25 primary prostatic mesenchymal neoplasms of possible specialized prostatic stromal origin, including cases originally diagnosed as PSS (11) and STUMP (14). Morphologically, the series comprised 20 cases with solid architecture (11 PSS and 9 STUMP) and 5 cases with phyllodes-like growth pattern (all STUMP). Combined DNA and RNA sequencing results demonstrated that 19/22 (86%) cases that underwent successful sequencing (either DNA or RNA) harbored pathogenic somatic variants. Except for TP53 alterations (6 cases), ATRX mutations (2 cases), and a few copy number variants (-13q, -14q, -16q and +8/8p), the findings were largely nonrecurrent. Eight gene rearrangements were found, and 4 (NAB2-STAT6, JAZF1-SUZ12, TPM3-NTRK1 and BCOR-MAML3) were useful for reclassification of the cases as specific entities. The present study shows that mesenchymal neoplasms of the prostate are morphologically and molecularly heterogeneous and include neoplasms that harbor genetic aberrations seen in specific mesenchymal tumors arising in other anatomic sites, including soft tissue and the uterus. These data suggest that tumors of purported specialized prostatic stromal origin may perhaps not represent a single diagnostic entity or specific disease group and that alternative diagnoses should be carefully considered.

TRIM63 is a sensitive and specific biomarker for MiT family aberration-associated renal cell carcinoma.

Microphthalmia-associated transcription factor (MiT) family aberration-associated renal cell carcinoma (MiTF-RCC) is a subtype of renal cell carcinoma harboring recurrent chromosomal rearrangements involving TFE3 or TFEB genes. MiTF-RCC is morphologically diverse, can histologically resemble common RCC subtypes like clear cell RCC and papillary RCC, and often poses a diagnostic challenge in genitourinary clinical and pathology practice. To characterize the MiTF-RCC at the molecular level and identify biomarker signatures associated with MiTF-RCC, we analyzed RNAseq data from MiTF-RCC, other RCC subtypes and benign kidney. Upon identifying TRIM63 as a cancer-specific biomarker in MiTF-RCC, we evaluated its expression independently by RNA in situ hybridization (RNA-ISH) in whole tissue sections from 177 RCC cases. We specifically included 31 cytogenetically confirmed MiTF-RCC cases and 70 RCC cases suspicious for MiTF-RCC in terms of clinical and morphological features, to evaluate and compare TRIM63 RNA-ISH results with the results from TFE3/TFEB fluorescence in situ hybridization (FISH), which is the current clinical standard. We confirmed that TRIM63 mRNA was highly expressed in all classes of MiTF-RCC compared to other renal tumor categories, where it was mostly absent to low. While the TRIM63 RNA-ISH and TFE3/TFEB FISH results were largely concordant, importantly, TRIM63 RNA-ISH was strongly positive in TFE3 FISH false-negative cases with RBM10-TFE3 inversion. In conclusion, TRIM63 can serve as a diagnostic marker to distinguish MiTF-RCC from other renal tumor subtypes with overlapping morphology. We suggest a combination of TFE3/TFEB FISH and TRIM63 RNA-ISH assays to improve the accuracy and efficiency of MiTF-RCC diagnosis. Accurate diagnosis of MiTF-RCC and other RCC subtypes would enable effective targeted therapy and avoid poor therapeutic response due to tumor misclassification.

EWSR1-PATZ1-rearranged sarcoma: a report of nine cases of spindle and round cell neoplasms with predilection for thoracoabdominal soft tissues and frequent expression of neural and skeletal muscle markers.

The knowledge of clinical features and, particularly, histopathological spectrum of EWSR1-PATZ1-rearranged spindle and round cell sarcomas (EPS) remains limited. For this reason, we report the largest clinicopathological study of EPS to date. Nine cases were collected, consisting of four males and five females ranging in age from 10 to 81 years (average: 49 years). Five tumors occurred in abdominal wall soft tissues, three in the thorax, and one in the back of the neck. Tumor sizes ranged from 2.5 to 18 cm (average 6.6 cm). Five patients had follow-up with an average of 38 months (range: 18-60 months). Two patients had no recurrence or metastasis 19 months after diagnosis. Four patients developed multifocal pleural or pulmonary metastasis and were treated variably by surgery, radiotherapy, and chemotherapy. The latter seemed to have little to no clinical benefit. One of the four patients was free of disease 60 months after diagnosis, two patients were alive with disease at 18 and 60 months, respectively. Morphologically, low, intermediate, and high-grade sarcomas composed of a variable mixture of spindled, ovoid, epithelioid, and round cells were seen. The architectural and stromal features also varied, resulting in a broad morphologic spectrum. Immunohistochemically, the following markers were most consistently expressed: S100-protein (7/9 cases), GFAP (7/8), MyoD1 (8/9), Pax-7 (4/5), desmin (7/9), and AE1/3 (4/9). By next-generation sequencing, all cases revealed EWSR1-PATZ1 gene fusion. In addition, 3/6 cases tested harbored CDKN2A deletion, while CDKN2B deletion and TP53 mutation were detected in one case each. Our findings confirm that EPS is a clinicopathologic entity, albeit with a broad morphologic spectrum. The uneventful outcome in some of our cases indicates that a subset of EPS might follow a more indolent clinical course than previously appreciated. Additional studies are needed to validate whether any morphological and/or molecular attributes have a prognostic impact.

New developments in existing WHO entities and evolving molecular concepts: The Genitourinary Pathology Society (GUPS) update on renal neoplasia.

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

Novel, emerging and provisional renal entities: The Genitourinary Pathology Society (GUPS) update on renal neoplasia.

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