Objective: Active surveillance (AS) offers a strategy to reduce overtreatment and now is a widely accepted treatment option for low-risk prostate cancer. An ideal tool for risk-stratification would detect aggressive cancers and exclude such men from taking up AS in the first place. We evaluate if a combination of transperineal template biopsy with magnetic resonance imaging (MRI)-targeted biopsy identifies significant prostate cancer amongst men initially diagnosed with low-risk prostate cancer. Methods: This prospective, single-blinded study included men with low-risk prostate cancer (D'Amico's Criteria) diagnosed on conventional transrectal ultrasound-guided biopsy. Patients first underwent multiparametric MRI of the prostate >= 6 weeks after initial biopsy. Each suspicious lesion is mapped and assigned a Prostate Imaging Reporting and Data System (PIRADS) score. Template biopsy is first performed with the surgeon blinded to MRI findings followed by MRI-targeted biopsy using a robotic transperineal biopsy platform. Results: The age of the 19 men included is 65.4 +/- 4.9 years (mean +/- SD). Prostate specific antigen (PSA) at diagnosis and at the time of transperineal biopsy were comparable (7.3 +/- 1.7 ng/mL and 7.0 +/- 1.8 ng/mL, p = 0.67), so were prostate volumes (34.2 +/- 8.9 mL and 32.1 +/- 13.4 mL, p = 0.28). MRI-targeted biopsy had a higher percentage of cancer detection per core compared to template biopsy (11.7% vs. 6.5%, p = 0.02), this was more than 3 times superior for Gleason 7 disease (5.9% vs. 1.6%, p < 0.01). Four of 18 (22.2%) patients with MRI lesions had significant disease with MRI-targeted biopsy alone. Three of 19 patients (15.8%) had significant disease with template biopsy alone. In combination, both techniques upclassified five patients (26.3%), all of whom underwent radical prostatectomy. Whole mount histology confirmed tumour location and grade. All six patients with PIRADS 5 lesions had cancer detected (66.6% significant disease). Conclusion: A combination of MRI-targeted and template biopsy may optimally risk-classify "low-risk" patients diagnosed on initial conventional transrectal ultrasonography (TRUS) prostate biopsy. (C) 2018 Editorial Office of Asian Journal of Urology. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Testicular metastasis is rare with the prostate being the most common site of primary cancer. We report a case of a 72-year-old man with castration-resistant prostate cancer (CRPC) and known metastases to bone and lymph nodes, who developed bilateral painful swollen testes 3 years after the initial diagnosis of prostate cancer. He had first presented with lower urinary tract symptoms (LUTS) with suspicious findings on digital rectal examination of the prostate, and an elevated serum prostate specific antigen (PSA) level of 129 ng/mL. Transrectal prostate biopsy revealed Gleason 4 + 5 adenocarcinoma. Radiological staging showed locally advanced prostate cancer with extensive metastases to bone and pelvic and retroperitoneal lymph nodes. He was given hormonal therapy for over 2 years until progression to CRPC. Six months later he developed painful bilateral testicular swellings, and serum markers for testicular germ cell cancer were normal. Bilateral orchiectomy was performed, showing metastatic prostate cancer (Gleason 4 + 5) on histology. One month postoperatively his PSA level dropped to 0.1 ng/mL from a presurgery level of 6.24 ng/mL.

DOI: 10.4328/JCAM.1759 Received: 25.03.2013 Accepted: 24.04.2013 Publihed Online: 25.04.2013 Corresponding Author: Nazim Emrah Kocer, Baskent Universitesi Adana Uygulama ve Arastirma Merkezi Patoloji bolumu, Dadaloglu Mah. 39 Sok. No:6 01250, Yuregir, Adana, Turkiye. T.: +905052730578 F.: +90 3223271276 E-Mail: nemrahkocer@yahoo.com Ozet Prostatin inflamatuar myofibroblastik tumorleri (IMT), sarkomlar ve igsi hucreli karsinomlari klinik ve histopatolojik olarak taklit edebilen nadir lezyonlardir. Burada sunulan olgu, normal prostat spesifik antijen duzeyleri ve kronik yakinmalari olan, tibbi tedaviye yanitsiz infravezikal tikanma bulgulari nedeni ile suprapubik prostatektomi uygulanan 63 yasinda bir hastadir. Eksizyon materyalinin histopatolojik incelenmesi fokal nukleer pleomorfizm, hiperkromazi gosteren, mononukleer iltihabi infiltrasyon ve miksoid degisiklikler iceren, duzgun sinirli, igsi hucreli bir lezyonu ortaya koydu. Mitoz nadirdi. Immunhistokimyasal calismada duz kas aktini ve vimentin pozitif, anaplastik lenfoma kinaz -1 fokal pozitif, S-100 ve pansitokeratin negatifti. Lezyon inflamatuar myofibroblastik tumor olarak tani aldi. IMT’nin prostatin malign igsi hucreli lezyonlarindan ayrimi gereksiz ileri tedavi islemlerinin onune gecilmesi icin sarttir.

OBJECTIVE:End-stage renal disease (ESRD) patients with acquired cystic kidney disease are at higher risk of developing renal cell carcinoma (RCC) than the general population. The aim of this study was to investigate the clinical and histopathological differences between ESRD patients and the general population with RCC. MATERIALS AND METHODS:Data were retrospectively collected from all nephrectomies performed for localized RCC from 2000 to 2010. Age at nephrectomy, gender, race, symptoms, baseline Eastern Cooperative Oncology Group (ECOG) performance status, Charlson Comorbidity Index score and histological data were extracted. Independent-samples t test and Mann-Whitney test were used for quantitative data, while chi-squared (two-sided) and Fisher's exact tests were used for qualitative data. RESULTS:This study included 627 patients: 73 with and 554 without ESRD. The majority of patients were Chinese. The male to female ratio of 2:1 was identical in both groups. Baseline ECOG performance status and Charlson Comorbidity score were higher in the ESRD group. RCC in ESRD patients was more frequently asymptomatic (56.2% vs 44.9%, p = 0.071), diagnosed earlier (53.6 ± 11.8 years vs 57.9 ± 12.2 years, p = 0.004) and of lower stage (p < 0.001). The ESRD cohort had a higher proportion of the papillary histological subtype (21.9% vs 9.7%, p < 0.001). Importantly, there was a trend towards more favourable outcomes in ESRD patients in terms of cancer-specific (p = 0.203) and relapse-free survival (p = 0.096). CONCLUSION:This study suggests that RCC in ESRD patients is associated with more favourable clinical and histological features and oncological outcome compared with that in patients with normal renal function.

Ketamine is a short-acting anaesthetic agent that has gained popularity as a 'club drug' due to its hallucinogenic effects. Substance abuse should be considered in young adult patients who present with severe debilitating symptoms such as lower urinary tract symptoms, even though the use of controlled substances is rare in Singapore. Although the natural history of disease varies from person to person, a relationship between symptom severity and frequency/dosage of abuse has been established. It is important to be aware of this condition and have a high degree of clinical suspicion to enable early diagnosis and immediate initiation of multidisciplinary and holistic treatment. A delayed diagnosis can lead to irreversible pathological changes and increased morbidity among ketamine abusers.

Background Insulin-like growth factor 2 mRNA binding protein 3 (IMP3) is expressed in metastatic and a subset of primary renal cell carcinoma (RCC). However, the role of IMP3 in RCC progression was poorly understood. We aim to uncover the mechanism of IMP3 in regulating clear cell RCC (CCRCC) progression and validate the prognostic significance of IMP3 in localized CCRCC. Methods Caki-1 cells stably overexpressing IMP3 and Achn cells with knockdown of IMP3 were analyzed for cell migration and invasion by Transwell assay. RNA-seq was used to profile gene expression in IMP3-expressing Caki-1 cells. A cohort of 469 localized CCRCC patients were examined for IMP3 expression by immunohistochemistry using tumor tissue array. Results IMP3 promoted Caki-1 cell migration and invasion, whereas knockdown of IMP3 by RNAi inhibited Achn cell migration and invasion. Enhanced IMP3 expression activated NF-кB pathway and through which, it functioned in promoting the RCC cell migration. IMP3 expression in localized CCRCC was found to be associated with higher nuclear grade, higher T stage, necrosis and sarcomatoid differentiation (p< 0.001). Enhanced IMP3 expression was correlated with shorter recurrence-free and overall survivals. Multivariable analysis validated IMP3 as an independent prognostic factor for localized CCRCC patients. Conclusion IMP3 promotes RCC cell migration and invasion by activation of NF-кB pathway. IMP3 is validated to be an independent prognostic marker for localized CCRCC.

Background The likelihood of tumour recurrence after nephrectomy in localised clear cell renal cell carcinoma is well characterised by clinical and pathological parameters. However, these assessments can be improved and personalised by the addition of molecular characteristics of each patient's tumour. We aimed to develop and validate a prognostic multigene signature to improve prediction of recurrence risk in clear cell renal cell carcinoma.Methods In the development stage, we investigated the association between expression of 732 genes, measured by reverse-transcription PCR, and clinical outcome in 942 patients with stage I-III clear cell renal cell carcinoma who had undergone a nephrectomy at the Cleveland Clinic (OH, USA). 516 genes were associated with recurrence-free interval. 11 of these genes were selected by further statistical analyses, and were combined with five reference genes (ie, 16 genes in total), from which a recurrence score algorithm was developed. The recurrence score was then validated in an independent cohort of 626 patients from France with stage I-III clear cell renal cell carcinoma who had also undergone nephrectomy. The association between the recurrence score and the risk of recurrence and cancer-specific survival in the first 5 years after surgery was assessed using Cox proportional hazard regression, stratified by tumour stage (stage I vs stage II vs III).Findings In our primary univariate analysis, the continuous recurrence score (median 37, IQR 31-45) was significantly associated with recurrence-free interval (hazard ratio 3.91 [95% CI 2.63-5.79] for a 25-unit increase in score, p<0.0001). In multivariable analyses, the recurrence score was significantly associated with the risk of tumour recurrence (hazard ratio per 25-unit increase in the score 3.37 [95% CI 2.23-5.08], p<0.0001) after stratification by stage and adjustment for tumour size, grade, or Leibovich score. The recurrence score was able to identify a clinically significant number of both high-risk stage I and low-risk stage II-III patients. A heterogeneity study on separate samples showed little to no intratumoural variability among the 16 genes.Interpretation Our findings validate the recurrence score as a predictor of clinical outcome in patients with stage I-III clear cell renal cell carcinoma, providing a more accurate and individualised risk assessment beyond existing clinical and pathological parameters.

Background Adenocarcinoma of urothelial tract is considered primary when conventional urothelial carcinoma component is not identified. Cases with co-existing urothelial carcinoma are regarded as differentiation of urothelial origin. Clear cell adenocarcinoma is a rare variant that needs to be discriminated from primary adenocarcinoma of urinary tract, urothelial carcinoma with glandular differentiation and metastatic tumours. Methods We report two cases of clear cell adenocarcinoma of urinary tract, involving urethra (Case 1) and urinary bladder (Case 2). Histological features, immunohistochemical profile and clinical outcome are summarised. Results Case 1 (urethral tumour): A 64-year-old Chinese female presented with anterior vaginal wall mass. Biopsy showed clear cell adenocarcinoma and she underwent neoadjuvant chemotherapy. Resection showed urethral tumour involving bladder neck and one lymph node. Histologically, tumour showed tubulopapillary and glandular architecture, hobnail nuclei and clear cytoplasm. Immunohistochemically, tumour cells were CK7 and CA125 positive, thrombomodulin and HMWCK weak positive, and CK20 and p63 negative. Patient is under follow-up. Case 2 (bladder tumour): A 56-year-old Chinese female underwent surgery for bladder mass. Tumour showed tubulopapillary and glandular architecture, hobnail nuclei and clear cytoplasm. Two lymph nodes were positive. Immunohistochemical profile was CK7 positive and CK20 negative. Patient expired following peritoneal carcinomatosis. Conclusions: Clear cell adenocarcinoma of urinary tract can be identified by a constellation of features: (1) presence of tubulo-papillary/glandular architecture, high grade hobnail nuclei and clear cytoplasm, (2) absence of primary adenocarcinoma of urinary tract, conventional urothelial carcinoma with glandular differentiation and metastasis, and (3) immunohistochemical profile of positive CK7 and CA125, weak positive HMWCK and CK5/6, negative CK20 and p63 and negative staining for potential metastatic tumour (e.g., CDX2 negative). Clinical behaviour is aggressive. Correct identification can aid in trial of neoadjuvant chemotherapy. Adenocarcinoma of urothelial tract is considered primary when conventional urothelial carcinoma component is not identified. Cases with co-existing urothelial carcinoma are regarded as differentiation of urothelial origin. Clear cell adenocarcinoma is a rare variant that needs to be discriminated from primary adenocarcinoma of urinary tract, urothelial carcinoma with glandular differentiation and metastatic tumours. We report two cases of clear cell adenocarcinoma of urinary tract, involving urethra (Case 1) and urinary bladder (Case 2). Histological features, immunohistochemical profile and clinical outcome are summarised. Case 1 (urethral tumour): A 64-year-old Chinese female presented with anterior vaginal wall mass. Biopsy showed clear cell adenocarcinoma and she underwent neoadjuvant chemotherapy. Resection showed urethral tumour involving bladder neck and one lymph node. Histologically, tumour showed tubulopapillary and glandular architecture, hobnail nuclei and clear cytoplasm. Immunohistochemically, tumour cells were CK7 and CA125 positive, thrombomodulin and HMWCK weak positive, and CK20 and p63 negative. Patient is under follow-up. Case 2 (bladder tumour): A 56-year-old Chinese female underwent surgery for bladder mass. Tumour showed tubulopapillary and glandular architecture, hobnail nuclei and clear cytoplasm. Two lymph nodes were positive. Immunohistochemical profile was CK7 positive and CK20 negative. Patient expired following peritoneal carcinomatosis. Conclusions: Clear cell adenocarcinoma of urinary tract can be identified by a constellation of features: (1) presence of tubulo-papillary/glandular architecture, high grade hobnail nuclei and clear cytoplasm, (2) absence of primary adenocarcinoma of urinary tract, conventional urothelial carcinoma with glandular differentiation and metastasis, and (3) immunohistochemical profile of positive CK7 and CA125, weak positive HMWCK and CK5/6, negative CK20 and p63 and negative staining for potential metastatic tumour (e.g., CDX2 negative). Clinical behaviour is aggressive. Correct identification can aid in trial of neoadjuvant chemotherapy.

Background Presence of multiple nodules in lung is concerning for metastatic tumour and triggers prompt evaluation. Such scenario in a transplant/immunocomprimsed patient is further complicated since infectious aetiology and secondary malignancy need to be considered. Epstein-Barr Virus (EBV) associated smooth muscle tumours are rare lesions that occur in immuno-comprimsed patients. They are typically well-differentiated with low mitotic activity and little cytological atypia. They are believed to represent consequence of multiple infection events rather than metastasis. Methods We report a 51-year-old patient with a history renal transplant and immunosuppression whose surveillance showed multiple bilateral lung nodules. Transthoracic, CT guided fine needle aspiration smears and core biopsy materials were evaluated using light microscopy, immunohistochemistry and in situ hybridisation for EBV associated RNA. Results The fine needle aspiration smears showed rare, inconclusive stromal pieces. The core biopsy samples displayed spindle cell lesion with smooth-muscle features. There was mild cytological atypia without necrosis or mitotic activity. Immunohisto-chemical stains showed spindle cells were positive for SMA (smooth muscle actin), desmin, and vimentin. S-100 and MNF-116 (cytokeratin stain) were negative. In situ hybridisation for EBER showed nuclear positivity. Conclusions: EBV associated smooth muscle tumours can present as multiple bilateral lung nodules mimicking metastatic tumour. Histologically, they show spindle cell lesion with bland cytological features and low mitotic activity. Supportive ancillary findings by immunohistochemistry and in situ hybridization are as follows: (1) positive for SMA, desmin and vimentin, (2) negative for S-100 and epithelial marker MNF-116, and (3) positive for EBER. Presence of multiple nodules in lung is concerning for metastatic tumour and triggers prompt evaluation. Such scenario in a transplant/immunocomprimsed patient is further complicated since infectious aetiology and secondary malignancy need to be considered. Epstein-Barr Virus (EBV) associated smooth muscle tumours are rare lesions that occur in immuno-comprimsed patients. They are typically well-differentiated with low mitotic activity and little cytological atypia. They are believed to represent consequence of multiple infection events rather than metastasis. We report a 51-year-old patient with a history renal transplant and immunosuppression whose surveillance showed multiple bilateral lung nodules. Transthoracic, CT guided fine needle aspiration smears and core biopsy materials were evaluated using light microscopy, immunohistochemistry and in situ hybridisation for EBV associated RNA. The fine needle aspiration smears showed rare, inconclusive stromal pieces. The core biopsy samples displayed spindle cell lesion with smooth-muscle features. There was mild cytological atypia without necrosis or mitotic activity. Immunohisto-chemical stains showed spindle cells were positive for SMA (smooth muscle actin), desmin, and vimentin. S-100 and MNF-116 (cytokeratin stain) were negative. In situ hybridisation for EBER showed nuclear positivity. Conclusions: EBV associated smooth muscle tumours can present as multiple bilateral lung nodules mimicking metastatic tumour. Histologically, they show spindle cell lesion with bland cytological features and low mitotic activity. Supportive ancillary findings by immunohistochemistry and in situ hybridization are as follows: (1) positive for SMA, desmin and vimentin, (2) negative for S-100 and epithelial marker MNF-116, and (3) positive for EBER.

BACKGROUND. The objective of this study was to evaluate the effect of pericyte coverage (PC) of differentiated tumor microvessels on the prognosis of patients with clear cell renal cell carcinoma (CCRCC). METHODS. Samples from 2 cohorts of patients with CCRCC (101 Asian patients and 524 US patients) were prepared using 2 different histologic approaches: routine sectioning versus tissue microarray. Then, the samples were immunohistochemically doubled-stained for a pericyte marker (alpha smooth muscle actin [a-SMA]) and a differentiated vessel marker (cluster of differentiation 34 [CD34]), followed by multispectral image capturing and computerized image analyses to quantify the microvessel density (MVD) and the PC of differentiated vessels. The correlations of PC and the MVD:PC ratio with clinicopathologic characteristics were analyzed. RESULTS. There was an inverse correlation between differentiated MVD and PC. Higher PC correlated with more aggressive clinicopathologic characteristics of CCRCC in both cohorts, including more advanced T-classification, higher pathologic grades, and the occurrence of tumor necrosis. The MVD:PC ratio was an independent favorable prognostic factor for overall and recurrence-free survival in the Asian cohort and for recurrence-free survival in the US cohort. PC also was an independent prognostic factor, with higher PC predicting a poorer outcome. The combination of PC and MVD was better at distinguishing the outcome of patients with CCRCC. PC combined with differentiated MVD or with the MVD:PC ratio provided additional, independent prognostic information to the Leibovich risk model, and that information was used to generate improved risk models. CONCLUSIONS. The authors consistently observed that higher PC was correlated with more aggressive clinicopathologic characteristics. PC was an independent unfavorable prognostic factor. The authors concluded that pericytes should be considered for therapeutic targeting. Cancer 2013. (c) 2012 American Cancer Society.

338 Background: Current pathology and clinical methods do not accurately estimate risk of recurrence in all patients with pT1 ccRCC. Quantitative RT-PCR (qPCR) analysis was performed on resected ccRCC tumors to identify genes associated with recurrence that significantly augment current prognostic tools. Methods: A retrospective observational cohort consisting of 931 patients (434 T1a, 201 T1b, 296 T2/3) with ccRCC was evaluated. All patients underwent nephrectomy between 1985 and 2003 at Cleveland Clinic and had paraffin-embedded tumor blocks. Patients with inherited ccRCC or inadequate follow-up (< 6 months or no recurrence data) were excluded. qPCR analysis of 732 genes was performed on all patients. Cox Proportional Hazards regression models were used to evaluate the association between gene expression and recurrence-free interval (RFI). Results: 448 genes were significantly (unadj. p < 0.05) associated with RFI, from which 72 genes were carried forward for further study (Rini, ASCO 2010, #4501). Angiogenesis is the strongest among the pathways represented, from which 3 genes (AQP1, NOS3, PPAP2B) were selected for this analysis. Incorporating these 3 genes, a subset of higher risk patients among those classified as low risk by Leibovich criteria was identified. By Leibovich criteria, 85% of the patients in the cohort with pT1 tumors (< 7.0 cm) were identified as low risk - 7% recurrence at 5 years (95% CI: 5%, 9%). Incorporating these 3 genes, 9% of these patients were found to be at increased risk for recurrence - 19% at 5 years (95% CI: 7%, 21%). For the subset of T1a patients (< 4.0 cm), 98.6% were low risk according to the Leibovich criteria - 7% recurrence at 5 years (95% CI: 4%, 10%). Incorporating the 3 genes, 11% of these patients were found to be at increased risk - 20% at 5 years (95% CI: 7%, 31%). Conclusions: Addition of 3 angiogenesis-related genes to the Leibovich criteria in patients with pT1 tumors refines stratification of patient risk in a subset of patients. More precise estimation of recurrence risk will help to tailor surveillance and refine inclusion into clinical trials. These genes will be incorporated into an algorithm that requires validation in an external data set. [Table: see text]

Recently several low-grade renal cell tumors, distinct from those recognized by the 2004 World Health Organization classification of renal tumors, have been described. These tumors had similar clinicopathologic features, being low-stage tumors with cystic, tubuloacinar, and/or papillary architecture. The tumor cells were low grade with variable amounts of clear cytoplasm that was positive for cytokeratin 7 (CK7), but negative for CD10. Genetic changes characteristic of clear cell or papillary renal cell carcinoma were not seen in these tumors. We investigated the morphologic, immunohistochemical, and genetic features of 36 additional tumors. Immunohistochemistry was carried out for CK7, carbonic anhydrase 9, α-methylacyl-CoA racemase, CD10, TFE-3, and desmin. Interphase fluorescence in situ hybridization was carried out with centromeric probes for chromosomes 3, 7, 17, and a subtelomeric probe for 3p25. Sequencing of von Hippel-Lindau gene and analysis of the methylation status of the promoter region was also carried out in 2 tumors. Thirty-six tumors from 33 patients (mean age: 60.4 , range: 26 to 88; 17 men and 16 women) were studied. Three patients had bilateral tumors and 1 patient had von Hippel-Lindau disease. Follow-up was available in 60% (20/33) of the patients for a mean of 27.4 (range 1 to 85) months. No patient had evidence of the disease after surgery except for the patient with von Hippel-Lindau disease, who was alive with stable disease in the contralateral kidney. All 36 tumors were small (mean size 2.4 cm; range 0.9 to 4.5 cm) and low stage (pT1). The majority was cystic and had prominent fibrous capsule and stroma. The tumors were composed of variable amount of cysts, papillae, tubules, acini, and solid nests. The most characteristic histologic features were branching tubules and acini and anastomosing clear cell ribbons with low-grade nuclei. All tumors were strongly positive for CK7 and variably positive for CA9, but largely negative for CD10, and negative for α-methylacyl-CoA racemase and TFE-3. All but 1 tumor had no gains of chromosomes 7 and 17 and deletion of 3p. Only 1 tumor had low copy number gains of chromosomes 7 and 17. VHL gene mutation and promoter methylation were negative in 2 tumors analyzed. We show that these tumors, which we term as “clear cell tubulopapillary renal cell carcinoma,” constitute a unique subtype in the spectrum of renal epithelial neoplasia based on their characteristic morphologic and immunohistochemical features.