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AIMS Cribriform morphology, which includes intraductal carcinoma (IDCP) and invasive cribriform carcinoma, is an indicator of poor prognosis in prostate cancer. Phosphatase and tensin homologue (PTEN) loss is a predictor of adverse clinical outcomes. The association between PTEN expression and morphological patterns of prostate cancer is unclear. METHODS AND RESULTS We explored the association between PTEN expression by immunohistochemistry, Gleason pattern 4 morphologies, IDCP and biochemical recurrence (BCR) in 163 radical prostatectomy specimens. IDCP was delineated from invasive cribriform carcinoma by p63 positive immunohistochemical staining in basal cells. Combined invasive cribriform carcinoma and IDCP were associated with a higher cumulative incidence of BCR [hazard ratio (HR) = 5.06; 2.21, 11.6, P

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.

Intraductal cribriform (IDC) and invasive cribriform morphologies are associated with worse prostate cancer outcomes. Limited retrospective studies have associated IDC and cribriform morphology with germline mutations in DNA repair genes, particularly BRCA2. These findings, which prompted the National Comprehensive Cancer Network® (NCCN) Guidelines for Prostate Cancer and Genetic/Familial High- Risk Assessment to consider germline testing for individuals with IDC/cribriform histology, have been questioned in a recent prospective study. A deepened understanding of the molecular mechanisms driving disease aggressiveness in cribriform morphology is critical to provide more clarity in clinical decision making. This review summarizes the current understanding of IDC and cribriform prostate cancer, with an emphasis on clinical outcomes and molecular alterations.

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.

Objectives. To compare the clinicopathologic characteristics of urothelial carcinoma (UC), urothelial carcinoma with squamous differentiation (UCSD), and squamous cell carcinoma (SCC) of the bladder, which have been suggested to differ in terms of risk factors, immunophenotype, and prognosis. Methods. We evaluated the clinicopathologic features of radical cystectomy specimens between 1980 and 2015 with a diagnosis of SCC, UCSD, and UC. PD-L1 immunohistochemistry (clinically available clones 22C3, SP142, and SP263) was performed on SCC and UCSD. Multivariate Cox regression was used to identify prognostic factors. Kaplan–Meier curves were plotted to assess cancer-specific survival (CSS). Results. Of the 1478 cases, there were 1126 UC (76%), 217 UCSD (15%), and 135 SCC (9%). Bladder cancer was more common in men than women (80% vs 20%, P pT2) at the time of cystectomy (UCSD-74%, SCC 71%, UC-44%, P

Excessive intake of animal fat and resultant obesity are major risk factors for prostate cancer. Because the composition of the gut microbiota is known to change with dietary composition and body type, we used prostate-specific Pten knockout mice as a prostate cancer model to investigate whether there is a gut microbiota–mediated connection between animal fat intake and prostate cancer. Oral administration of an antibiotic mixture (Abx) in prostate cancer–bearing mice fed a high-fat diet containing a large proportion of lard drastically altered the composition of the gut microbiota including Rikenellaceae and Clostridiales, inhibited prostate cancer cell proliferation, and reduced prostate Igf1 expression and circulating insulin-like growth factor-1 (IGF1) levels. In prostate cancer tissue, MAPK and PI3K activities, both downstream of the IGF1 receptor, were suppressed by Abx administration. IGF1 directly promoted the proliferation of prostate cancer cell lines DU145 and 22Rv1 in vitro. Abx administration also reduced fecal levels of short-chain fatty acids (SCFA) produced by intestinal bacteria. Supplementation with SCFAs promoted tumor growth by increasing IGF1 levels. In humans, IGF1 was found to be highly expressed in prostate cancer tissue from obese patients. In conclusion, IGF1 production stimulated by SCFAs from gut microbes influences the growth of prostate cancer via activating local prostate MAPK and PI3K signaling, indicating the existence of a gut microbiota-IGF1-prostate axis. Disrupting this axis by modulating the gut microbiota may aid in prostate cancer prevention and treatment. Significance: These results suggest that intestinal bacteria, acting through short-chain fatty acids, regulate systemic and local prostate IGF1 in the host, which can promote proliferation of prostate cancer cells.

Outcomes for men with localized prostate cancer vary widely, with some men effectively managed without treatment on active surveillance, while other men rapidly progress to metastatic disease despite curative‐intent therapies. One of the strongest prognostic indicators of outcome is grade groups based on the Gleason grading system. Gleason grade 4 prostate cancer with cribriform morphology is associated with adverse outcomes and can be utilized clinically to improve risk stratification. The underpinnings of disease aggressiveness associated with cribriform architecture are not fully understood. Most studies have focused on genetic and molecular alterations in cribriform tumor cells; however, less is known about the tumor microenvironment in cribriform prostate cancer. Cancer‐associated fibroblasts (CAFs) are a heterogeneous population of fibroblasts in the tumor microenvironment that impact cancer aggressiveness. The overall goal of this study was to determine if cribriform prostate cancers are associated with a unique repertoire of CAFs. Radical prostatectomy whole‐tissue sections were analyzed for the expression of fibroblast markers (ASPN in combination with FAP, THY1, ENG, NT5E, TNC, and PDGFRβ) in stroma adjacent to benign glands and in Gleason grade 3, Gleason grade 4 cribriform, and Gleason grade 4 noncribriform prostate cancer by RNAscope®. Halo® Software was used to quantify percent positive stromal cells and expression per positive cell. The fibroblast subtypes enriched in prostate cancer were highly heterogeneous. Both overlapping and distinct populations of low abundant fibroblast subtypes in benign prostate stroma were enriched in Gleason grade 4 prostate cancer with cribriform morphology compared to Gleason grade 4 prostate cancer with noncribriform morphology and Gleason grade 3 prostate cancer. In addition, gene expression was distinctly altered in CAF subtypes adjacent to cribriform prostate cancer. Overall, these studies suggest that cribriform prostate cancer has a unique tumor microenvironment that may distinguish it from other Gleason grade 4 morphologies and lower Gleason grades.

Objective To evaluate the clinical features, pathologic features, and prevalence of human papilloma virus (HPV) in squamous cell carcinoma (SCC) of the bladder. SCC of the bladder is known to be associated with conditions that cause chronic inflammation/irritation. The literature is inconsistent regarding the association of HPV with pure SCC of the bladder. Methods A multi-institutional study identified cases of SCC of the bladder. Pure squamous histology and the absence of urothelial carcinoma in situ were required for inclusion. Clinical and pathologic features were collected, and tissues were evaluated for high-risk HPV using p16 immunohistochemistry and in situ hybridization. Results We identified 207 cases of SCC of the bladder. Risk factors for bladder cancer included smoking (133/207, 64%) and chronic bladder irritation (83/207, 40%). The majority (155/207, 75%) of patients had > pT2 disease. Mean tumor size was 5.6 ± 3.0 cm and 36/207 (17%) patients had lymph node positive disease. p16 immunohistochemistry was positive in 52/204 (25%) cases but high-risk HPV was identified with in situ hybridization in only 1 (0.5%) case. Tumor size, stage, number of lymph nodes removed, number of positive lymph nodes, lymphovascular invasion, perineural invasion, and positive margins each were associated with cancer-specific mortality when adjusted for demographic factors. A multivariate analysis of variable importance further revealed sex and race as important factors in predicting cancer-specific mortality. Conclusion SCC of the bladder is an aggressive histologic subtype. Although bladder SCC can express p16, it is not typically associated with high-risk HPV, although rare cases can occur.

We discuss the role of the pathologist for MRI-targeted prostate biopsy with a focus on specimen processing, reporting of pathological findings and quality assurance in establishing a successful MRI-targeted biopsy programme. The authors discuss the current issues relevant to pathologists regarding MRI-targeted prostate biopsy. In addition, a brief review of the recently published literature was performed using an English literature search on PubMed with a focus on original investigations related to MRI-targeted prostate biopsy. Our search terms included the following: 'prostate cancer', 'pathology', 'histology', 'reporting', 'cores', 'imaging', 'MRI' and 'mpMRI'. Prostate multiparametric magnetic resonance imaging (mp-MRI) and MRI-targeted biopsy has been shown to improve the diagnosis of clinically significant prostatic adenocarcinoma and can affect the management of patients with prostate cancer. The current active surveillance guidelines were based on data from TRUS biopsies and not MRI-targeted biopsies. MRI-targeted biopsy acquires multiple cores of tissue from one or more suspicious lesions found on mp-MRI. The way in which multiple targeted core biopsies obtained from a single image-directed region of interest are analysed and reported can potentially alter the Gleason score and tumour burden as reported on biopsy, which could undoubtedly alter patient management. Pathologists play an important role in the reporting of MRI-targeted prostate biopsies. How we report prostate cancer grade and extent on these biopsies can influence patient management. In addition, the pathologist should be involved in the quality assurance for patients undergoing MRI-targeted prostate biopsy.

While multiple studies have demonstrated that minimally invasive surgical (MIS) techniques are a safe and efficacious approach to adrenalectomy for pheochromocytomas (PC), these studies have only been small comparative studies. The aim of this multi-institutional study is to compare perioperative outcomes between open and MIS, stratified by robotic and conventional laparoscopic, techniques in the surgical management of PC. We retrospectively evaluated patients who underwent adrenalectomy for PCs from 2000 to 2017 at three different institutions. Clinical, perioperative, and pathologic parameters were analyzed using t test, Chi square, and Fisher exact statistical measures. Of the 156 adrenalectomy cases performed, 26 (16.7%) were with an open approach and 130 (83.3%) using MIS techniques. Of the MIS procedures, 41 (31.5%) were performed robotically and 89 (68.5%) performed laparoscopically without robotic assistance. Demographic and clinical parameters were similar between the open and MIS groups. Patients, who underwent MIS procedure had a lower complication rate (p = 0.04), shorter hospitalization (p = 0.02), shorter operative time (p < 0.001), and less blood loss (p = 0.002) than those who underwent open surgical resection. Conventional laparoscopic and robotic operative approaches resulted in similar complication rates, length of hospitalization, and blood loss. Our study is one of the largest cohorts comparing the perioperative outcomes between conventional laparoscopic and robotic adrenalectomies in patients with PC. Our results support that MIS techniques have potentially lower morbidity compared to open techniques, while laparoscopic and robotic approaches have similar perioperative outcomes.

The Genitourinary Pathology Society (GUPS) undertook a critical review of the recent advances in bladder cancer focusing on important topics of high interest for the practicing surgical pathologist and urologist. This review represents the second of 2 manuscripts ensuing from this effort. Herein, we address the effective reporting of bladder cancer, focusing particularly on newly published data since the last 2016 World Health Organization (WHO) classification. In addition, this review focuses on the importance of reporting bladder cancer with divergent differentiation and variant (subtypes of urothelial carcinoma) histologies and the potential impact on patient care. We provide new recommendations for reporting pT1 staging in diagnostic pathology. Furthermore, we explore molecular evolution and classification, emphasizing aspects that impact the understanding of important concepts relevant to reporting and management of patients.

Urinary diversion and reconstructive urologic procedures are most often performed by incorporating various intestinal segments into the urinary tract. Although the risk of malignancy, among other complications, is well recognized and occurs most frequently after ureterosigmoidostomies and cystoplasties, data on the histopathologic and immunohistochemical characteristics of these tumors are scant. This study aims to evaluate the clinicopathological features of secondary tumors arising after urologic reconstruction procedures. Eleven cases were identified among five collaborating academic institutions. The average age was 51.7 years, and the M:F ratio was 8:3. Surgical procedures included 7 ileal conduits, 2 gastrocystoplasties, 1 augmentation cystoplasty not otherwise specified (NOS), and 1 Indiana pouch. Median time from reconstruction to malignancy was 36 years. Malignancy included adenocarcinoma in 10 patients (intestinal type in 6, gastric in 2, signet-ring cell in 1, undetermined type after neoadjuvant treatment in 1) and squamous cell carcinoma in 1. By immunohistochemistry, the adenocarcinomas were CK7 (45%), CK20 (89%), CK903 (78%), CDX2 (89%), SATB2 (67%), and beta-catenin (100%) positive. GATA-3 was negative in all cases. Pathologic stage was T1 (30%), T2 (40%), T3 (20%), and T4 (10%). Regional lymph node and distant metastasis were present in 60% and 20%, respectively. Treatment included multimodality therapy in most patients. On follow-up (mean, 27.4 months), 2 patients were dead (1 of disease), 3 were alive with disease, 4 were alive without disease, and 2 were lost to follow-up. Secondary malignancy arising within urologic reconstruction is rare, most frequently has adenocarcinoma morphology, presents late, and behaves aggressively.

Summary Men diagnosed with low-risk prostate cancer (PC) are increasingly electing active surveillance (AS) as their initial management strategy. While this may reduce the side effects of treatment for PC, many men on AS eventually convert to active treatment. PC is one of the most heritable cancers, and genetic factors that predispose to aggressive tumors may help distinguish men who are more likely to discontinue AS. To investigate this, we undertook a multi-institutional genome-wide association study (GWAS) of 5,222 PC patients and 1,139 other patients from replication cohorts, all of whom initially elected AS and were followed over time for the potential outcome of conversion from AS to active treatment. In the GWAS we detected 18 variants associated with conversion, 15 of which were not previously associated with PC risk. With a transcriptome-wide association study (TWAS), we found two genes associated with conversion (MAST3, p = 6.9 × 10−7 and GAB2, p = 2.0 × 10−6). Moreover, increasing values of a previously validated 269-variant genetic risk score (GRS) for PC was positively associated with conversion (e.g., comparing the highest to the two middle deciles gave a hazard ratio [HR] = 1.13; 95% confidence interval [CI] = 0.94–1.36); whereas decreasing values of a 36-variant GRS for prostate-specific antigen (PSA) levels were positively associated with conversion (e.g., comparing the lowest to the two middle deciles gave a HR = 1.25; 95% CI, 1.04–1.50). These results suggest that germline genetics may help inform and individualize the decision of AS—or the intensity of monitoring on AS—versus treatment for the initial management of patients with low-risk PC., Genetic factors may distinguish who should receive active surveillance (AS) versus treatment following prostate cancer diagnosis. We undertook the first study to investigate this and report novel variants, genes, and risk scores associated with AS outcomes. These findings could help inform and individualize the decision of AS.

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

Prostate cancer is well known to metastasize to the testis and is not an uncommon finding on castration performed for advanced disease. Although germ cell tumors make up the majority of testis neoplasms, there are more rare tumors, such as rete testis adenocarcinoma, that can mimic metastatic disease. NKX3.1 and prostein (P501S) are antibodies highly specific for prostate origin. Relatively little is known of the expression of these markers in testicular tissue. We investigated the expression of NKX3.1 and P501S in testicular tissues, sex cord-stromal tumors, germ cell tumors, and rete testis adenocarcinoma. We found strong diffuse nuclear staining for NKX3.1 in Sertoli cells of the testis. Expression of NKX3.1 was seen in 0/3 ovarian Sertoli cell tumors, 1/4 testicular Sertoli cell tumors, and in the Sertoli cell component of 1/12 ovarian Sertoli-Leydig cell tumors. We found moderate, diffuse cytoplasmic positivity for P501S in rete testis epithelium and in testicular Leydig cells. P501S also highlighted Leydig cells in 9/12 Sertoli-Leydig cell tumors of the ovary. Two of 3 Leydig cell tumors of the testis showed weak to moderate, diffuse cytoplasmic staining for P501S. All cases of embryonal carcinoma and pure seminoma were negative for both NKX3.1 and P501S. One case of rete testis adenocarcinoma showed patchy positivity for both NKX3.1 and P501S. In conclusion, NKX3.1 shows routine expression in Sertoli cells and P501S shows routine expression in Leydig cells and rete testis epithelium. In addition, these markers can be positive in sex cord-stromal tumors and rete testis adenocarcinoma.

Cancer cells utilize vitamin folate to fulfill their excessive demand for nucleotides and amino acids. Dihydrofolate reductase (DHFR), an enzyme involved in folate metabolism converts dihydrofolate into tetrahydrofolate, which is required for the de novo synthesis of purines, and certain amino acids. DHFR inhibitors are used as a chemotherapeutic agent. Cancer sequencing analysis has identified additional enzymes in folate metabolism that are dysregulated in cancer. Methylenetetrahydrofolate dehydrogenase 1 like (MTHFD1L), one such enzyme is overexpressed in bladder cancer. MTHFD1L is a mitochondrial enzyme involved in the folate cycle by catalyzing the reaction of formyl-tetrahydrofolate to formate and tetrahydrofolate (THF). THF is crucial for de novo purine and thymidylate synthesis and is also involved in the regeneration of methionine. Cancer cells rely on purines derived from the de novo pathway for the nucleotides whereas normal cells favor the salvage pathway. In this study we examined MTHFD1L expression in bladder cancer. By using publicly available cancer transcriptome data analysis web-portal UALCAN, we found overexpression of MTHFD1L in bladder cancer and expression was associated with overall survival. RT-PCR and immunoblot analysis confirmed the overexpression of MTHFD1L in muscle invasive bladder cancer tissues compared to normal urothelium. Furthermore, our investigations suggested a critical role for MTHFD1L in bladder cancer cell proliferation, colony formation and invasion. Thus, in this study, we show the significance of the folate metabolic enzyme MTHFD1L in aggressive bladder cancers and suggest that being an enzyme, MTHFD1L serves as a valuable therapeutic target.

Summary Multiparametric magnetic resonance imaging (MRI)/ultrasound fusion targeted prostate biopsy has been shown to outperform systematic biopsy in the detection of clinically significant prostate cancer. Aside from tumor grade, tumor biomarkers such as phosphatase and tensin homolog (PTEN) and ETS-related gene (ERG) have prognostic significance in prostate cancer and may help direct management of patients with low-grade tumors. Our objective was to compare the detection of PTEN and ERG expression in MRI-targeted versus systematic prostate biopsies. We compared immunohistochemical expression for PTEN and ERG on prostate biopsy cores from patients with Grade Group (GG) 1 or GG2 prostate cancer who had undergone systematic biopsy with concurrent targeted biopsy. Fifty-three cases had both systematic and MRI-targeted prostate tissue available for staining for PTEN; and 52 cases, for ERG. ERG positivity was seen in 37/52 (71.2%) cases, and PTEN loss was seen in 15/53 (28.3%) cases. The detection of ERG expression was not significantly different between MRI-targeted and systematic biopsy (P = .4). Targeted biopsy was superior to systematic biopsy in the detection of PTEN loss (P = .02). MRI-targeted cores detected 14/15 (93.3%) cases of PTEN loss compared to 7/15 (46.7%) cases detected by systematic cores. Most cases with PTEN loss showed heterogeneous expression in both systematic and targeted cores. In 14/15 (93.3%) cases with PTEN loss, GG was the same between targeted and systematic biopsy. Targeted biopsy is superior to systematic biopsy in the detection of PTEN loss in GG1 and GG2 tumors. Inclusion of targeted cores may be helpful for evaluation of certain prognostic biomarkers.

Prostate cancer can be difficult to appreciate grossly and therefore partial sampling of the gland can lead to incorrect grading, staging, or margin status. However, submitting the entire prostate is more time consuming and costly. We investigated the use of magnetic resonance imaging/ultrasound-targeted biopsy for the selective submission of prostatectomy specimens. We performed a retrospective review for patients with cancer on targeted prostate biopsy who underwent subsequent radical prostatectomy. Prostatectomy specimens were submitted in their entirety and assessed for Grade Group, extraprostatic extension (EPE), margins, and number of blocks. For Targeted-Grossing (TG) assessment, apex margin, bladder neck margin, seminal vesicles, and vas deferens sections were included. For the remainder of the prostate, only sections from areas shown to be positive for cancer on targeted biopsy were included in the analysis. With total tissue submission, EPE was found in 39/81 (48.1%) cases and positive margins in 19/81 (23.5%) cases. The TG method required significantly fewer blocks: 15.8 ± 5.9 versus 44.9 ± 11.9 ( P < .0001). The TG method would have diagnosed the correct stage in 73/81 (90.1%) cases, Grade Group in 74/81 (91.4%) cases, and margin status in 79/81 (97.5%) cases. EPE was missed completely by the TG method in 7 cases ( P = .008), of which 5/7 (71.4%) had focal EPE. There was no significant difference in stage ( P = .24), Grade Group ( P = .95), or margin status ( P = .16) between the 2 methods. Grossing utilizing selective tissue submission from areas found to be positive for prostate cancer on magnetic resonance imaging/ultrasound-targeted prostate biopsy remains inferior to complete submission of tissue for radical prostatectomy specimens.

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. (C) 2020 Elsevier Inc. All rights reserved.

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).

Some observational studies have implied a link between vasectomy and an elevated risk of prostate cancer. We investigated the impact of vasectomy on prostate cancer outgrowth, mainly using preclinical models. Neoplastic changes in the prostate were compared in transgenic TRAMP mice that underwent vasectomy vs. sham surgery performed at 4 weeks of age. One of the molecules identified by DNA microarray (i.e., ZKSCAN3) was then assessed in radical prostatectomy specimens and human prostate cancer lines. At 24 weeks, gross tumor (p = 0.089) and poorly differentiated adenocarcinoma (p = 0.036) occurred more often in vasectomized mice. Vasectomy significantly induced ZKSCAN3 expression in prostate tissues from C57BL/6 mice and prostate cancers from TRAMP mice. Immunohistochemistry showed increased ZKSCAN3 expression in adenocarcinoma vs. prostatic intraepithelial neoplasia (PIN), PIN vs. non-neoplastic prostate, Grade Group &ge, 3 vs. &le, 2 tumors, pT3 vs. pT2 tumors, pN1 vs. pN0 tumors, and prostate cancer from patients with a history of vasectomy. Additionally, strong (2+/3+) ZKSCAN3 expression (p = 0.002), as an independent prognosticator, or vasectomy (p = 0.072) was associated with the risk of tumor recurrence. In prostate cancer lines, ZKSCAN3 silencing resulted in significant decreases in cell proliferation/migration/invasion. These findings suggest that there might be an association between vasectomy and the development and progression of prostate cancer, with up-regulation of ZKSCAN3 expression as a potential underlying mechanism.

OBJECTIVE. The purpose of this study was to evaluate in a multicenter dataset the performance of an artificial intelligence (AI) detection system with attention mapping compared with multiparametric MRI (mpMRI) interpretation in the detection of prostate cancer. MATERIALS AND METHODS. MRI examinations from five institutions were included in this study and were evaluated by nine readers. In the first round, readers evaluated mpMRI studies using the Prostate Imaging Reporting and Data System version 2. After 4 weeks, images were again presented to readers along with the AI-based detection system output. Readers accepted or rejected lesions within four AI-generated attention map boxes. Additional lesions outside of boxes were excluded from detection and categorization. The performances of readers using the mpMRI-only and AI-assisted approaches were compared. RESULTS. The study population included 152 case patients and 84 control patients with 274 pathologically proven cancer lesions. The lesion-based AUC was 74.9% for MRI and 77.5% for AI with no significant difference (p = 0.095). The sensitivity for overall detection of cancer lesions was higher for AI than for mpMRI but did not reach statistical significance (57.4% vs 53.6%, p = 0.073). However, for transition zone lesions, sensitivity was higher for AI than for MRI (61.8% vs 50.8%, p = 0.001). Reading time was longer for AI than for MRI (4.66 vs 4.03 minutes, p < 0.001). There was moderate interreader agreement for AI and MRI with no significant difference (58.7% vs 58.5%, p = 0.966). CONCLUSION. Overall sensitivity was only minimally improved by use of the AI system. Significant improvement was achieved, however, in the detection of transition zone lesions with use of the AI system at the cost of a mean of 40 seconds of additional reading time.

BackgroundObesity is a major risk factor for renal cancer, yet our understanding of its effects on antitumor immunity and immunotherapy outcomes remains incomplete. Deciphering these associations is critical, given the growing clinical use of immune checkpoint inhibitors for metastatic disease and mounting evidence for an obesity paradox in the context of cancer immunotherapies, wherein obese patients with cancer have improved outcomes.MethodsWe investigated associations between host obesity and anti-programmed cell death (PD-1)-based outcomes in both renal cell carcinoma (RCC) subjects and orthotopic murine renal tumors. Overall survival (OS) and progression-free survival (PFS) were determined for advanced RCC subjects receiving standard of care anti-PD-1 who had ≥6 months of follow-up from treatment initiation (n=73). Renal tumor tissues were collected from treatment-naive subjects categorized as obese (body mass index, ‘BMI’ ≥30 kg/m2) or non-obese (BMI 2) undergoing partial or full nephrectomy (n=19) then used to evaluate the frequency and phenotype of intratumoral CD8+ T cells, including PD-1 status, by flow cytometry. In mice, antitumor immunity and excised renal tumor weights were evaluated ±administration of a combinatorial anti-PD-1 therapy. For a subset of murine renal tumors, immunophenotyping was performed by flow cytometry and immunogenetic profiles were evaluated via nanoString.ResultsWith obesity, RCC patients receiving anti-PD-1 administration exhibited shorter PFS (p=0.0448) and OS (p=0.0288). Treatment-naive renal cancer subjects had decreased frequencies of tumor-infiltrating PD-1highCD8+ T cells, a finding recapitulated in our murine model. Following anti-PD-1-based immunotherapy, both lean and obese mice possessed distinct populations of treatment responders versus non-responders; however, obesity reduced the frequency of treatment responders (73% lean vs 44% obese). Tumors from lean and obese treatment responders displayed similar immunogenetic profiles, robust infiltration by PD-1int interferon (IFN)γ+CD8+ T cells and reduced myeloid-derived suppressor cells (MDSC), yielding favorable CD44+CD8+ T cell to MDSC ratios. Neutralizing interleukin (IL)-1β in obese mice improved treatment response rates to 58% and reduced MDSC accumulation in tumors.ConclusionsWe find that obesity is associated with diminished efficacy of anti-PD-1-based therapies in renal cancer, due in part to increased inflammatory IL-1β levels, highlighting the need for continued study of this critical issue.

In the urinary tract, there is an uncertain relationship between intestinal metaplasia (IM), primary adenocarcinoma, and urothelial carcinoma. Although IM is usually found adjacent to concurrent urothelial carcinoma or adenocarcinoma, small retrospective series have shown that most bladder biopsies with only IM do not subsequently develop cancer. However, IM with dysplasia does seem to be associated with a higher risk of concurrent malignancy or progressing to cancer. Since the molecular landscape of these lesions has remained largely unexplored, there are significant uncertainties about the oncogenic potential of IM in the bladder and urethra. This study investigated the presence of potentially oncogenic genetic variants in cases of IM with and without dysplasia. Twenty-three (23) cases of IM (3 urethra, 20 bladder) were sequenced using a solid tumor next-generation sequencing panel. Of these, five contained IM with high-grade dysplasia (including a case with paired IM-adenocarcinoma and another with paired IM-urothelial carcinoma) and 18 lacked dysplasia. Oncogenic genetic variants were found in all cases of IM with high-grade dysplasia and in five non-dysplastic IM cases, including mutations and copy number variants commonly seen in primary adenocarcinoma of the bladder and urothelial carcinoma. This study demonstrates that IM can harbor potentially oncogenic genetic variants, suggesting that it might represent a cancer precursor or a marker of increased cancer risk in a subset of cases.

Despite the improvement in survival for patients with liver cancer (LCa) in recent decades, only one in five patients survive for 5 years after diagnosis. Thus, there is an urgent need to find new treatment options to improve patient survival. For various cancers, including LCa, the chemokine CCL5 (RANTES) facilitates tumor progression and metastasis. Since the function of the CCR5/CCL5 interaction in LCa cell proliferation and migration is poorly understood, the present study was undertaken to investigate the role of the CCR5/CCL5 axis in these processes. Flow cytometry, RT-PCR, Western blot, and immunofluorescence techniques were used to quantify the expression of CCR5 and CCL5 in LCa cells. To determine the biological significance of CCR5 expressed by LCa cell lines, a tissue microarray of LCas stained for CCR5 and CCL5 was analyzed. The results showed higher expression (p &lt, 0.001) of CCR5 and CCL5 in hepatocellular carcinoma (HCC) tissues compared to non-neoplastic liver tissues. Furthermore, to delineate the role of the CCR5/CCL5 interaction in LCa cell proliferation and migration, various LCa cells were treated with maraviroc, a CCR5 antagonist, in the presence of CCL5. These data demonstrated the biological and clinical significance of the CCR5/CCL5 axis in LCa progression. The targeting of this axis is a promising avenue for the treatment of LCa.

A 65-year-old male presented with a cystic scrotal mass that fluctuated in size. The cyst was associated with aberrant epididymal tissue and was found to have benign epithelial proliferations, with immunohistochemistry supporting a mesonephric origin (GATA3, CD10, and WT1 positive). Clinical presentation, imaging, and pathologic findings are described.

Aims Reports of respiratory illnesses among soldiers returning from Southwest Asia have been described. During deployment to Southwest Asia, soldiers are exposed to various respiratory hazards, including dust storms, smoke from burn pits and industrial air pollutants. A few studies have reported increased rates of constrictive bronchiolitis and asthma in these patients. We sought to expand upon the pathological findings in this cohort. Methods and results Lung biopsies from veterans of Southwest Asia were identified and re-reviewed. All patients had undergone pulmonary function tests and chest high-resolution CT imaging with no significant findings. Overall, 59 patients with a history of inhalational exposure to at least one of the following were identified: smoke from burn pit, dust storm and sulphur plant fire. Samples included video-assisted thoracoscopic lung biopsies (57 of 59, 96.6%) and cryobiopsies (two of 59, 3.4%). Patients were predominantly male (54 of 59, 91.5%) with an age range of 24-55 years (mean and median = 35). Non-necrotising, poorly formed granulomas were identified in 22 cases (22 of 59, 37.2%). The granulomas were mainly bronchiolocentric and were associated with chronic lymphoplasmacytic bronchiolitis, similar to hypersensitivity pneumonitis (HP). Pleural reaction in the form of focal chronic lymphocytic pleuritis and/or focal pleural adhesions were seen in 43 of 57 (75.4%) biopsies. Conclusions To our knowledge, this is the first study to report pleural reaction as well as features of HP in this population, suggesting that pleural reaction and HP may be part of the spectrum of Southwest Asia deployment-related lung diseases.

No well-established staging system exists for bladder leiomyosarcoma (LMS), and the current staging system does not include tumor size, a thoroughly validated prognostic parameter for sarcomas. Uterine and extremity/trunk LMS are more common than those in the bladder and have well-established staging systems incorporating tumor size. We aim to improve the understanding of LMS of the urinary bladder by assessing cancer-specific survival (CSS) and comparing LMS at this unusual anatomic site to those arising at other sites using the Surveillance, Epidemiology, and End Results (SEER) database. The SEER database (1973-2013) was queried for bladder, uterus, and trunk/extremity LMS. Multivariable Cox proportional hazard regression was performed to identify predictors of CSS for each anatomic location and used to compare outcomes at different sites. We identified 165 bladder, 4987 uterus, and 2536 extremity/trunk LMS cases. Five-year CSS was 52% for uterus, 73% for bladder, and 82% for extremity/trunk LMS. For LMS at all sites, uterine location (HR = 2.14, P 0.001) and increasing tumor size (HR = 1.05, P 0.001) were significant predictors of worse CSS on multivariate analysis. For bladder LMS, increasing tumor size (HR = 1.18, P = 0.003) was an independent prognostic factor and the conventional staging cut-off threshold of 5 cm for sarcomas outside the head/neck showed statistical significance in stratifying patient risk of cancer-related death. Bladder LMS appears to have clinical behavior intermediate between those of the extremities/trunk and uterus. We suggest that the conventional sarcoma staging protocols based on tumor size be applied to LMS of the urinary bladder.

Angiomyolipomas (AMLs) are triphasic tumors (smooth muscle, vascular and adipocytic components) with myomelanocytic differentiation, arising most commonly in the kidneys, which can show predominant epithelioid morphology and fat-predominant or fat-poor variants. Fat-predominant AMLs can show areas of hypercellularity and lipoblast-like cells, and these features can mimic well-differentiated liposarcoma (WDLS). To date, only one documented metastatic epithelioid AML showed unequivocal MDM2 amplification by fluorescence in situ hybridization. We describe our findings in a series of 35 AMLs including epithelioid, fat-poor, and fat-predominant variants, following interrogation of the MDM2 locus by FISH and CISH assays. MDM2 amplification was detected in 1 fat-predominant AML. Our findings demonstrate that rare MDM2 amplifications can occur in AMLs. We favor that this finding likely represents a "molecular bystander" event since these tumors are mainly driven by aberrations in the TSC1/TSC2 genes. Nevertheless, the presence of MDM2 amplification in a fat-predominant AML could present a potential diagnostic pitfall, particularly when confronted with the differential diagnosis of fat-predominant AML and WDLS in limited material from the retroperitoneum.

Understanding the effects of obesity on the immune profile of renal cell carcinoma (RCC) patients is critical, given the rising use of immunotherapies to treat advanced disease and recent reports of differential cancer immunotherapy outcomes with obesity. Here, we evaluated multiple immune parameters at the genetic, soluble protein, and cellular levels in peripheral blood and renal tumors from treatment-naive clear cell RCC (ccRCC) subjects (n = 69), to better understand the effects of host obesity (Body Mass Index "BMI" ≥ 30 kg/m2) in the absence of immunotherapy. Tumor-free donors (n = 38) with or without obesity were used as controls. In our ccRCC cohort, increasing BMI was associated with decreased percentages of circulating activated PD-1+CD8+ T cells, CD14+CD16neg classical monocytes, and Foxp3+ regulatory T cells (Tregs). Only CD14+CD16neg classical monocytes and Tregs were reduced when obesity was examined as a categorical variable. Obesity did not alter the percentages of circulating IFNγ+ CD8 T cells or IFNγ+, IL-4+, or IL-17A+ CD4 T cells in ccRCC subjects. Of 38 plasma proteins analyzed, six (CCL3, IL-1β, IL-1RA, IL-10, IL-17, and TNFα) were upregulated specifically in ccRCC subjects with obesity versus tumor-free controls with obesity. IGFBP-1 was uniquely decreased in ccRCC subjects with obesity versus non-obese ccRCC subjects. Immunogenetic profiling of ccRCC tumors revealed that 93% of examined genes were equivalently expressed and no changes in cell type scores were found in stage-matched tumors from obesity category II/III versus normal weight (BMI ≥ 35 kg/m2 versus 18.5-24.9 kg/m2, respectively) subjects. Intratumoral PLGF and VEGF-A proteins were elevated in ccRCC subjects with obesity. Thus, in ccRCC patients with localized disease, obesity is not associated with widespread detrimental alterations in systemic or intratumoral immune profiles. The effects of combined obesity and immunotherapy administration on immune parameters remains to be determined.

Clear cell papillary renal cell carcinoma (CCP-RCC) is a recently recognized tumor that shares morphologic features of both clear cell renal cell carcinoma and papillary renal cell carcinoma but behaves in a more indolent fashion. To date, there is little molecular information available on CCP-RCC. DNA was extracted from formalin-fixed, paraffin-embedded tissue blocks of 22 cases of CCP-RCC at the University of Alabama at Birmingham. Targeted next-generation sequencing and single-nucleotide polymorphism array were performed on all cases. Next-generation sequencing analysis found 30 somatic variants across 63.3% of cases. Seventeen variants (56.7%) were predicted to be deleterious or possibly/probably damaging. Single-nucleotide polymorphism array analysis found copy number abnormalities and/or loss of heterozygosity in 22.7% of cases. We analyzed the genetic characteristics of a group of CCP-RCCs cases and found them to be genetically different from one another. Some cases were genetically similar to clear cell renal cell carcinoma.

An abnormality in hedgehog (Hh) signaling has been implicated in the progression of prostate cancer (PCa) to a more aggressive and therapy-resistant disease. Our assessments of human PCa tissues have shown an overexpression of the Hh pathway molecules, glioma-associated oncogene homolog 1 (GLI-1), and sonic hedgehog (SHH). The effect of the natural compound thymoquinone (TQ) in controlling the expression of Hh signaling molecules in PCa was investigated in this study. We generated planetary ball-milled nanoparticles (PBM-NPs) made with a natural polysaccharide, containing TQ, and coated with an RNA aptamer, A10, which binds to prostate-specific membrane antigen (PSMA). We prepared docetaxel-resistant C4-2B-R and LNCaP-R cells with a high expression of Hh, showing the integration of drug resistance and Hh signaling. Compared to free TQ, A10-TQ-PBM-NPs were more effective in controlling the Hh pathway. Our findings reveal an effective treatment strategy to inhibit the Hh signaling pathway, thereby suppressing PCa progression.

Current imaging and biopsy practices offer limited insight into preoperative detection of seminal vesicle invasion despite the implications for treatment decisions and patient prognoses. We identified magnetic resonance imaging features to assess the risk of seminal vesicle invasion and inform the inclusion of seminal vesicle sampling during biopsy.Patients underwent multiparametric magnetic resonance imaging and fusion targeted biopsy with or without seminal vesicle biopsy. Magnetic resonance imaging suspicion of seminal vesicle invasion, multiparametric magnetic resonance imaging of prostate base lesions of moderate or greater suspicion, extraprostatic extension, anatomical zone and biopsy data were used to generate multivariable logistic regression models. One model without and 1 with biopsy data were externally validated in a multi-institutional cohort. Decision curve analyses were done to determine net benefit of the 2 models.The training and validation cohorts comprised 564 and 250 patients, respectively. In the training cohort 55 patients (9.8%) had pathologically confirmed seminal vesicle invasion. In the prebiopsy model magnetic resonance imaging suspicion of seminal vesicle invasion (OR 9.5, 95% CI 4.0-22.4, p0.001), multiparametric magnetic resonance imaging base lesions of moderate or greater suspicion with extraprostatic extension (OR 13.6, 95% CI 4.0-46.5, p0.001) and a transition and/or central zone location (OR 11.6, 95% CI 3.5-38.3, p0.001) showed strong correlations. In the post-biopsy model the risk of pathologically confirmed seminal vesicle invasion increased with the base Gleason Group (Gleason Group 5 OR 85.3, 95% CI 11.8-619.1, p0.001). In the validation cohort the AUC of the prebiopsy and post-biopsy models was 0.84 and 0.93, respectively (p = 0.030).Magnetic resonance imaging evidence of seminal vesicle invasion or extraprostatic extension at the prostate base transition and/or central zone and high grade prostate cancer from the prostate base are significant features associated with an increased risk of pathologically confirmed seminal vesicle invasion. Our models successfully incorporated these features to predict seminal vesicle invasion and inform when to biopsy the seminal vesicles.

Background Active surveillance (AS) is a widely adopted strategy to monitor men with low-risk, localized prostate cancer (PCa). Current AS inclusion criteria may misclassify as many as 1 in 4 patients. The advent of multiparametric magnetic resonance imaging (mpMRI) and novel PCa biomarkers may offer improved risk stratification. We performed a review of recently published literature to characterize emerging evidence in support of these novel modalities. Methods An English literature search was conducted on PubMed for available original investigations on localized PCa, AS, imaging and biomarkers published within the past three years. Our Boolean criteria included the following terms: prostate cancer, active surveillance, imaging, biomarker, genetic, genomic, prospective, retrospective and comparative. The bibliographies and diagnostic modalities of the identified studies were used to expand our search. Results Our review identified 222 original studies. Our expanded search yielded 244 studies. Among these, 70 met our inclusion criteria. Evidence suggests mpMRI offers improved detection of clinically significant PCa, and MRI-fusion technology enhances the sensitivity of surveillance biopsies. Multiple studies demonstrate the promise of commercially available screening assays for prediction of AS failure, and several novel biomarkers show promise in this setting. Conclusions In the era of AS for men with low-risk PCa, improved strategies for proper stratification are needed. mpMRI has dramatically enhanced the detection of clinically significant PCa. The advent of novel biomarkers for prediction of aggressive disease and AS failure have shown some initial promise, but further validation is warranted.