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BACKGROUND Urinary cytology is a noninvasive and cost-effective diagnostic and surveillance test in the clinical management of urothelial carcinoma (UC). The Paris System for Reporting Urinary Cytology (TPS), published in 2016, introduced definite diagnostic criteria aimed at improving performance in detecting high-grade UC (HGUC) and decreasing the indeterminate (atypical) diagnosis. METHODS The authors retrospectively reviewed and compared urinary cytology diagnoses reported between January 2013 and December 2014 (pre-TPS, 7658 cases) and between May 2016 and April 2018 (post-TPS, 20,026 cases) to assess the influence of TPS in their practice. The time in between was used as a learning period. Follow-up information and correlation with the UroVysion fluorescence in situ hybridization test were obtained when available. RESULTS Urinary cytology diagnoses pre-TPS included negative for UC (NUC) (n = 5293; 69.2%), atypical urothelial cells (AUC) (n = 2227; 29%), and suspicious/positive for HGUC (SHGUC/HGUC) (n = 138; 1.8%). Diagnoses post-TPS included negative for HGUC (NHGUC) (n = 18,507; 92.4%), AUC (n = 1237; 6.2%), and SHGUC/HGUC (n = 282; 1.4%). Comparing the pre-TPS and post-TPS periods, AUC diagnoses decreased from 29% to 6.2% (P < .00001), and the specificity and positive predictive value of AUC to detect HGUC significantly improved from 49% to 86% (P < .00001) and from 9% to 39% (P = .002), respectively. The correlation of an AUC diagnosis with a positive UroVysion test improved from 17% to 38% (P < .00001), whereas overall use of the UroVysion test was decreased. CONCLUSIONS Implementation of TPS resulted in a significant reduction in AUC diagnoses that had a superior correlation with a subsequent biopsy and a UroVysion test, resulting in potential reductions in test use and medical cost.

BACKGROUND The loss of PTEN tumor suppressor gene is one of the most common somatic genetic aberrations in prostate cancer (PCa) and is frequently associated with high-risk disease. Deletion or mutation of at least one PTEN allele has been reported to occur in 20% to 40% of localized PCa and up to 60% of metastases. The goal of this study was to determine if somatic alteration detected by PTEN immunohistochemical loss of expression is associated with specific histologic features. METHODS Two hundred sixty prostate core needle biopsies with PCa were assessed for PTEN loss using an analytically validated immunohistochemical assay. Blinded to PTEN status, each tumor was assessed for the Grade Group (GG) and the presence or absence of nine epithelial features. Presence of stromogenic PCa was also assessed and defined as grade 3 reactive tumor stroma as previously described: the presence of carcinoma associated stromal response with epithelial to stroma ratio of greater than 50% reactive stroma. RESULTS Eight-eight (34%) cases exhibited PTEN loss while 172 (66%) had intact PTEN. PTEN loss was significantly (P

AIMS Atypical intraductal proliferation (AIP) of the prostate is histologically worse than high-grade prostate intraepithelial neoplasia, but lacks the diagnostic criteria of intraductal carcinoma of the prostate (IDC-P). The aim of this study was to compare the clinicopathological and molecular characteristics (ERG overexpression and PTEN loss) of AIP and IDC-P in core needle biopsies. METHODS AND RESULTS One hundred and six [84 (5.6%) of 1480 consecutive and 22 retrospectively collected] cases met the criteria: AIP only (2.4%), IDC-P only (1.3%), and IDC-P coexisting with AIP (2%). Invasive adenocarcinoma [prostate adenocarcinoma (PCa)] was present in 96% and 97% cases of AIP and IDC-P, respectively. The mean number of glands/focus and the largest gland diameter for AIP and IDC-P were 7.6 (range, 2-27) and 11.7 (range, 1-51), and 0.59 mm (range, 0.2-1.1 mm) and 0.75 mm (range, 0.2-1.8 mm), respectively. For AIP, loose cribriform architecture was the most common (93%) morphology. IDC-P-associated PCa had more aggressive pathology, including the highest combined Gleason score (GS), high-grade GS ≥ 4 + 3, and largest percentage involvement of core by PCa and percentage positive cores, than AIP-associated PCa (P

Since its initial description in 1966 by Dr Donald Gleason, Gleason grading has become the cornerstone in the management of prostate cancer (PCa). With widespread use of Prostate Specific Antigen (PSA) screening and needle core biopsy, the diagnosis and management of PCa have dramatically evolved. In addition, better understanding of the morphological spectrum of prostate cancer and its clinical significance have prompted the refinement of the grading criteria and reporting guidelines commensurate to contemporary practice. The modification of the Gleason grading system implemented by the International Society of Urological Pathology in 2005 and subsequent revision in 2014 has profoundly impacted how PCa is graded and managed. This review aims to provide a concise update on the refinement of the histological criteria for various Gleason patterns and problem areas of Gleason grading, and provide recommendations on how to improve the grading reproducibility. The new proposal to group Gleason scores into clinically meaningful "grade groups" will also be discussed. Finally, we will discuss how magnetic resonance imaging (MRI)-targeted biopsy and emerging genetic markers may help improve the Gleason grading accuracy and risk stratification currently based on clinicopathological parameters.

Carvalho J C, Thomas D G, McHugh J B, Shah R B & Kunju L P (2012) Histopathology 60, 597–608 p63, CK7, PAX8 and INI-1: an optimal immunohistochemical panel to distinguish poorly differentiated urothelial cell carcinoma from high-grade tumours of the renal collecting system Aims: High-grade, poorly differentiated, infiltrative carcinomas involving the renal sinus region often pose challenging differential diagnostic considerations, specifically differentiation of urothelial carcinoma (UC) from renal cell carcinoma (RCC) subtypes. Accurate classification, especially the distinction of UC from RCC, is critical, as therapeutic approaches differ. Methods and results: Cluster analysis was performed on immunohistochemical data from 18 invasive UCs, six CDCs, two RMCs, 18 type 2 papillary renal cell carcinomas (PRCCs) and 20 high-grade clear cell renal cell carcinomas (CRCCs) using a broad panel of traditional and novel immunohistochemical markers. The initial analysis with all antibodies segregates almost all the RCCs (45 of 46, 98%) from all the UCs based on the lack of expression of p63 in all (100%) RCCs, along with predominant strong expression of paired box gene 8 (PAX8) and vimentin, predominant lack of expression of high molecular weight cytokeratin (HMCK) and CK7 and variable expression of RCC, CD10, CA1X and PAX2. All the UCs cluster together with strong, diffuse reactivity for p63, predominant reactivity for CK7 and high molecular weight kininogen (HMWK), and absent to minimal staining with PAX8, RCC antigen, PAX2, alpha-methylacyl-CoA racemase (AMACR), carbonic anhydrase IX (CAIX) and vimentin. After removing antibodies with significant overlap and/or minimal impact, a second analysis with a limited panel including p63, CK7, vimentin, integrase interactor 1 (INI-1) and PAX8 was performed. Again, the majority of UCs cluster into one group and p63 positivity separates all UCs from RCCs. Conclusions: Lack of INI-1 expression, noted exclusively in RMCs, segregates RMCs into a separate cluster. PAX8 is rarely positive (17%) in UC, is commonly expressed in CDC, RMC, PRCC and CRCC and is superior to PAX2.

Carvalho J C, Wasco M J, Kunju L P, Thomas D G & Shah R B (2011) Histopathology58, 169–179 Cluster analysis of immunohistochemical profiles delineates CK7, vimentin, S100A1 and C-kit (CD117) as an optimal panel in the differential diagnosis of renal oncocytoma from its mimics Aims: To develop an immunohistochemical strategy for distinguishing renal oncocytoma (RO) from the eosinophilic variant of chromophobe (ChRCC), and papillary (PRCC) and clear cell (CRCC) renal cell carcinoma containing eosinophilic cytoplasm in core biopsy specimens. Methods and results: Cluster analysis was performed on immunohistochemical data from 21 RO, 16 ChRCC, 16 CRCC and 20 PRCC patients. A panel of CK7, C-kit, S100A1 and vimentin clustered into four groups. Cluster A (94% ChRCC) expressed C-kit and CK7 and lacked S100A1 and vimentin. Cluster B (95% RO) expressed C-kit, S100A1, focal CK7 (single or small clusters of cells) and lacked vimentin. Cluster C comprised a mixture of PRCC and CRCC with no expression of C-kit or CK7 and variable S100A1 and vimentin. PRCC with strong expression of CK7 clustered into group D. A panel of S100A1 (positive) and focal CK7 expression distinguished RO from ChRCC with 91% sensitivity and 93% specificity. A panel of vimentin (negative) and C-kit (positive) distinguished RO from CRCC with 83% sensitivity and 86% specificity and RO from PRCC with 79% sensitivity and 88% specificity. Conclusions: Hierarchical cluster analysis is an effective approach to analyse high-volume immunohistochemical data to generate an optimal panel in the differential diagnosis of oncocytoma from its mimics.

BACKGROUND. Focal targeted therapy has been proposed as a potential treatment for localized prostate cancer in an attempt to reduce morbidity. However, these modalities rely heavily on accurate tumor localization to achieve total tumor ablation. In the current study, we sought to examine the ability of contemporary extended pattern prostate biopsy to predict the location of tumors. METHODS. A total of 281 men with prostate cancer detected via a standardized extended pattern biopsy template with at least 12 cores and who subsequently underwent radical prostatectomy were evaluated. Tumor location on biopsy, stratified by laterality and by site (apex vs mid-base prostate), was compared with corresponding locations on the prostatectomy specimen. Generalized estimating equation models were developed to assess the effects of clinical variables on pathologic agreement between biopsy and prostatectomy specimens. RESULTS. Of the 281 prostate biopsies, the positive predictive value (PPV) of right and left needle biopsy was high at 97.3% and 96.7%, respectively. However, the negative predictive value (NPV) was low at 24.7% and 31.3%, respectively. When more specific locations were considered, the NPV improved at the apex. However, this came at a cost to the PPV. Tumor focality on prostatectomy specimen was the only clinical feature found to be significantly and consistently related to pathologic agreement. CONCLUSIONS. Contemporary extended pattern prostate biopsy, although able to diagnose cancers, fails to provide reliable localization of tumors to specific areas of the prostate. Focal therapy, which relies heavily on localization, should only be performed with this caveat in mind. Cancer 2008;113:1559-65. � 2008 American Cancer Society.

BACKGROUND Prostate cancer (PCa) frequently metastasizes to the bone and induces osteoblastic lesions. We previously demonstrated through over-expression of the Wnt inhibitor dickkopf-1 (DKK-1) that Wnts contribute to the osteoblastic component of PCa osseous lesions in vivo. METHODS To test the clinical significance of DKK-1 expression during PCa progression, tissue microarrays were stained for DKK-1 protein by immunohistochemistry. RESULTS DKK-1 expression index (EI) was found to increase in PIN and primary lesions compared to non-neoplastic tissue (106 ± 10 vs. 19 ± 6, respectively, where the EI is the product of the percent expression and staining intensity). DKK-1 expression was also found to be higher in all PCa metastatic lesions (56 ± 21 EI) compared to non-neoplastic tissues but was significantly decreased versus primary PCa lesions (P

BACKGROUND. The role of the epidermal growth factor receptor (ErbB1) in the progression of prostate cancer is incompletely understood. METHODS. Tissue microarrays from hormone-naive and advanced androgen-independent tumors were used to investigate the role of ErbB1 in prostate cancer progression. RESULTS. ErbB1 expression in tumor tissues was strongly associated with hormonerefractory status (odds ratio ¼6.67, 95% CI ¼(2.6, 17.4), P ¼0.0001). However, ErbB1 overexpression was not a statistically significant covariate in a multivariate proportional hazards

BACKGROUND. DiminishedexpressionofRafkinaseinhibitorprotein(RKIP),aninhibitorof the Raf signaling cascade, promotes prostate cancer (PCa) metastasis in a murine model, suggestingthatitisametastasissuppressorgene.However,theprognosticsignificanceofRKIP expression and its association with metastasis in PCa patients is unknown. METHODS. To investigate RKIP protein expression is a prognostic marker in PCa we performedimmunohistochemicalstainingforRKIPexpressionintissuemicroarraysconsisting of 758 non-neoplastic prostate tissues, primary tumors and metastases from 134 PCa patients. TheCoxproportional-hazardsmodelwasusedtoadjustforcovariatesincludingGleasonscore, tumor volume, tumor weight, clinical stage, digital rectal exam findings, serum PSA level and surgical margins. RESULTS. RKIP expression was low in approximately 5%, 48%, and 89%of non-neoplastic prostate,primarytumorsandmetastases,respectively.LowRKIPexpressioninprimarytumors was a strong positive predictive factor for PCa recurrence based on PSA levels. In patients whose primary tumors expressed high RKIP levels, the 7-year PSA recurrence rate was

The direct relationship between the aging process and the incidence and prevalence of both benign prostatic hyperplasia (BPH) and prostate cancer (PCa) implies that certain risk factors associated with the development of both diseases increase with the aging process. In particular, both diseases share an overly proliferative phenotype, suggesting that mechanisms that normally act to suppress cellular proliferation are disrupted or rendered dysfunctional as a consequence of the aging process. We propose that one such mechanism involves changes in the prostate microenvironment, which 'evolves' during the aging process and disrupts paracrine interactions between epithelial and associated stromal fibroblasts. We show that stromal fibroblasts isolated from the prostates of men 63-81 years of age at the time of surgery express and secrete higher levels of the CXCL12 chemokine compared with those isolated from younger men, and stimulate CXCR4-mediated signaling pathways that induce cellular proliferation. These studies represent an important first step towards a mechanistic elucidation of the role of aging in the etiology of benign and malignant prostatic diseases.

Aim : Studies using a monoclonal (P504S) and a polyclonal antibody (p-AMACR) to α-methylacyl-CoA racemase (AMACR) have shown variable expression in prostate cancer (PCa). The goal is to compare the sensitivity of both antibodies in PCa and evaluate their utility in the work-up of atypical prostate needle biopsies (NBXs). Methods and results : A tissue microarray (TMA) with 248 samples of benign prostate, high-grade prostatic intraepithelial neoplasia (HGPIN) and PCa samples, 20 NBXs with minute PCa and 32 NBXs with ‘atypical’ foci were stained with P504S and p-AMACR. Ninety percent of PCa (76/76 TMA, 16/20 NBXs) showed predominantly strong p-AMACR expression while 87% (65/69 TMA, 16/20 NBXs) showed variable P504S expression (sensitivity 90% versus 87%, P = 0.10). In HGPIN, P504S and p-AMACR were positive in 77% and 91% of samples, respectively. In the ‘atypical’ NBXs group, 53% were classified as PCa, 12% benign and 35% atypical, suspicious for PCa, after review of the basal marker. Of atypical, suspicious for PCa, P504S/p-AMACR helped convert the diagnosis to PCa in 5/11 (45%) cases, where, despite negative basal cell markers, morphology was less than optimal. Conclusions : Differences between P504S and p-AMACR appear marginal and clinically insignificant. AMACR is negative in a subset of unequivocal minute PCa with both antibodies. However, when utilized in proper context, AMACR may offer significant advantage in converting an ‘atypical’ diagnosis to PCa where morphology and basal markers are less than optimal in resolving the diagnosis.