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.

Significance of caveolin-1 immunohistochemical staining differences in biopsy samples from kidney recipients with BK virus viremia.

BK virus infections which usually remains asymptomatic in healthy adults may have different clinical manifestations in immunocompromised patient population. BK virus reactivation can cause BK virus nephropathy in 8% of kidney transplant patients and graft loss may be seen if not treated. Clathrin or Caveolar system is known to be required for the transport of many viruses from Polyomaviruses family including BK viruses. In this study, kidney transplant patients with BK virus viremia were divided into two groups according to the BK virus nephropathy found in kidney biopsy (Group I: Viremia+, Nephropathy+ / Group II: Viremia+, Nephropathy-). Kidney biopsies were examined with immunohistochemical staining to determine the distribution and density of the Caveolin-1 and Clathrin molecules. Immunohistochemical staining of the 31 pathologic specimens with anti-caveolin-1 immunoglobulin revealed statistically significant difference between group-I and group-II. The number of the specimens stained with anti-caveolin-1 was less in group I. On the other hand, we did not find any difference between the groups regarding the anti-clathrin immunochemical analysis. According to these findings, caveolin-1 expression differences in kidney transplant patients may be important in disease progression.

Prognostic significance of pre- and post-treatment PD-L1 expression in patients with primary high-grade non-muscle-invasive bladder cancer treated with BCG immunotherapy.

PURPOSE: Programmed cell death-1 ligand-1 (PD-L1) expression has been associated with prognostic implications in urologic malignancies. We aimed to investigate prognostic significance of pre- and post-treatment PD-L1 expression in patients treated with BCG for high-grade non-muscle-invasive bladder cancer (NMIBC). METHODS: We reviewed a total of 141 high-grade NMIBC cases treated with transurethral resection + ≥ 6 BCG instillations between 2004 and 2017. PD-L1 immunohistochemistry (IHC) scoring was done on 0-3 scale, and cut-off for positive and high-level PD-L1 expression was set to ≥ 1% and ≥ 5% staining of tumor-infiltrating immune cells (IC), respectively. Clinicopathologic characteristics and oncologic outcomes [recurrence-free (RFS) and progression-free survival (PFS)] were compared, stratified by PD-L1 positivity. The prognostic role of PD-L1 was assessed using Kaplan-Meier, and univariate and multivariate Cox regression analyses. RESULTS: Pre-treatment, 46.2% and 6.8% of high-grade NMIBC demonstrated positive and high-level PD-L1 expression, respectively. Positive PD-L1 expression was associated with submucosal invasion and refractory-tumor recurrence. PD-L1 expression was not associated with RFS or PFS in regression analysis. Post-treatment, 55.1% and 11.6% of recurrent tumors demonstrated positive and high-level PD-L1 expression, respectively. Down-regulation of PD-L1 expression was noted in patients with refractory recurrence (p = 0.012). CONCLUSION: Pre-treatment PD-L1 expression was associated with unfavorable pathological features in primary high-grade NMIBC and its expression level after BCG immunotherapy was significantly decreased in patients with refractory recurrence. PD-L1 expression did not have prognostic value for PFS or RFS; therefore, further research is necessary to identify novel biomarkers for prediction of disease outcomes in high-grade NMIBC.

Prostatitis, the Great Mimicker of Prostate Cancer: Can We Differentiate Them Quantitatively With Multiparametric MRI?

OBJECTIVE. The purpose of this study was to investigate the diagnostic performance of semiquantitative and quantitative pharmacokinetic parameters and quantitative apparent diffusion coefficient (ADC) values obtained from prostate multiparametric MRI (mpMRI) to differentiate prostate cancer (PCa) and prostatitis objectively. MATERIALS AND METHODS. We conducted a retrospective review of patients with biopsy-proven PCa or prostatitis who underwent mpMRI study between January 2015 and February 2018. Mean ADC, forward volume transfer constant (Ktrans), reverse volume transfer constant (kep), plasma volume fraction (Vp), extravascular extracellular space volume fraction (Ve), and time to peak (TTP) values were calculated for both lesions and contralateral normal prostate tissue. Signal intensity-time curves were analyzed. Lesion-to-normal prostate tissue ratios of pharmacokinetic parameters were also calculated. The diagnostic accuracy and cutoff points of all parameters were analyzed to differentiate PCa from prostatitis. RESULTS. A total of 138 patients (94 with PCa and 44 with prostatitis) were included in the study. Statistically, ADC, quantitative pharmacokinetic parameters (Ktrans, kep, Ve, and Vp), their lesion-to-normal prostate tissue ratios, and TTP values successfully differentiated PCa and prostatitis. Surprisingly, we found that Ve values were significantly higher in prostatitis lesions. The combination of these parameters had 92.7% overall diagnostic accuracy. ADC, kep, and TTP made up the most successful combination for differential diagnosis. Analysis of the signal intensity-time curves showed mostly type 2 and type 3 enhancement curve patterns for patients with PCa. Type 3 curves were not seen in any prostatitis cases. CONCLUSION. Quantitative analysis of mpMRI differentiates PCa from prostatitis with high sensitivity and specificity, appears to have significant potential, and may improve diagnostic accuracy. In addition, evaluating these parameters does not cause any extra burden to the patients.

Practice patterns related to prostate cancer grading: results of a 2019 Genitourinary Pathology Society clinician survey.

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

The 2019 Genitourinary Pathology Society (GUPS) White Paper on Contemporary Grading of Prostate Cancer.

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

Prognostic significance of lymphovascular invasion in clinically localized prostate cancer after radical prostatectomy.

Whether lymphovascular invasion (LVI) is an independent prognostic factor in prostate cancer is still controversial. We retrospectively investigated its predictive role in disease progression following radical prostatectomy. The histological sections of radical prostatectomies from 71 clinically localized, prostatic adenocarcinoma patients were reviewed for LVI. Pre- and postoperative follow-up data were collected. LVI was identified in 15.5% of cases. Univariate analysis showed a significant association between LVI and advanced pathological stage, higher Gleason score, positive surgical margins, extraprostatic extension, seminal vesicle invasion, and lymph node metastasis (each p < 0.05). Multivariate analyses pointed to vascular involvement as a strong and independent predictor for PSA failure (p = 0.023), and reduced biochemical progression-free survival (p = 0.019). LVI in radical prostatectomy is an adverse prognostic finding that must be recorded in the pathology report.

Long-standing aggressive angiomyxoma as a paratesticular mass: A case report and review of literature.

OBJECTIVES: Aggressive angiomyxoma is known as a mesenchymal tumor of premenopausal women and it is extremely rare in men. METHODS: Herein, we report a 66-year-old male with a firm scrotal mass that had gradually enlarged over 20 years. RESULTS: Radiological studies revealed 10 x 15 cm mass lesion confined to right scrotum with neither local invasion nor distant metastasis. Inguinal orchiectomy was performed and histopathology showed characteristic features of an aggressive angiomyxoma occupying paratesticular region, which was a challenging diagnosis due to its unexpected occurrence in the male gender. CONCLUSION: Aggressive angiomyxoma is mostly considered as a benign tumor in females despite its propensity for local recurrence. Whether it may show a divergent biological behavior in men is unknown as the reported cases are too few.

Small Cell Carcinomas of the Bladder Highly Express Somatostatin Receptor Type 2A: Impact on Prognosis and Treatment--A Multicenter Study of Urooncology Society, Turkey.

Small cell carcinoma (SmCC) is a rare and aggressive neuroendocrine carcinoma of the bladder. Neuroendocrine carcinomas expressing somatostatin receptors (SSTR) in other viscera such as lung, pancreas, and gastrointestinal system respond to therapy with somatostatin analogs. In the present study, expressions of SSTRs 1 to 5 including type 2A are investigated by immunohistochemistry (IHC) and their relationship with clinicopathologic factors was evaluated. Hundred primary bladder SmCC cases were collected from 12 centers in Turkey. Forty-three cases were pure SmCC. Other cases had mostly papillary urothelial carcinoma as a second component. The percentage of the SmCC component ranged from 5% to 100%. SSTR-2A expression was membranous, whereas the other receptors showed cytoplasmic staining. The percentages of positive cases for SSTR-1, SSTR-2A, SSTR-3, SSTR-4, and SSTR-5 were 4% (3/75), 61.4% (54/88), 2.4% (2/84), 24.4% (20/82), and 6.25% (5/80), respectively. The percentage of SmCC component was positively correlated with the percentage of SSTR-2A expression (P=0.003) while negatively correlated with patient age (P=0.032). SSTR-2A expression was correlated with survival as a bad prognostic factor (P=0.018). SSTR-1, SSTR-3, SSTR-4, and SSTR-5 expressions did not show any statistical significance with any parameter. In conclusion, although the limited number of cases with adequate term follow-up, SSTR-2A expression could be a prognostic factor and somatostatin analogs therapeutic candidate for SmCCs of the bladder as these tumors show high percentage of SSTR-2A expression.

Immunohistochemical analysis of SMARCB1/INI-1 expression in collecting duct carcinoma.

OBJECTIVES: Collecting duct carcinoma (CDC) is a rare and aggressive renal tumor with a tendency to involve the renal sinus. CDC displays variable morphologic features that can overlap with those of renal medullary carcinoma. The loss of SMARCB1/INI1 tumor suppressor gene, initially found in pediatric malignant rhabdoid tumors of the central nervous system, kidneys, and soft tissues, was also recently described in renal medullary carcinoma. The current immunohistochemical study assessed SMARCB1/INI1 expression in a series of CDCs. METHODS: A total of 20 archival cases of CDC were used to construct a tissue microarray. Each tumor was spotted 3-7 times; benign tissue from the same specimen was also included when available. The immunoexpression of SMARCB1/INI1 was evaluated using BAF47, a monoclonal mouse antibody directed against the SMARCB1/INI1 gene product. Nuclear staining was considered as indicative of SMARCB1/INI1 expression. RESULTS: The complete loss of SMARCB1/INI1 expression was observed in 3 of 20 cases of CDC. Another 3 cases revealed focal and weak intensity staining. The remaining tumors showed multifocal or diffuse SMARCB1/INI1 expression with variable staining intensity. No significant differences were found in the clinicopathologic and outcome features regarding SMARCB1/INI1 status. CONCLUSIONS: The complete loss of SMARCB1/INI1 immunoexpression was found in 15% of CDC. No differences were found between the SMARCB1/INI1 positive and negative cases regarding the clinicopathologic and outcome features. Our results suggest that some CDC cases might be associated with genetic alterations involving the SMARCB1/INI1 gene. In addition, SMARCB1/INI1 immunoexpression seems to be of limited value in the differential diagnosis of CDC versus renal medullary carcinoma, although these results require additional validation.