The International Society of Urological Pathology 2012 Consensus Conference made recommendations regarding classification, prognostic factors, staging, and immunohistochemical and molecular assessment of adult renal tumors. Issues relating to prognostic factors were coordinated by a workgroup who identified tumor morphotype, sarcomatoid/rhabdoid differentiation, tumor necrosis, grading, and microvascular invasion as potential prognostic parameters. There was consensus that the main morphotypes of renal cell carcinoma (RCC) were of prognostic significance, that subtyping of papillary RCC (types 1 and 2) provided additional prognostic information, and that clear cell tubulopapillary RCC was associated with a more favorable outcome. For tumors showing sarcomatoid or rhabdoid differentiation, there was consensus that a minimum proportion of tumor was not required for diagnostic purposes. It was also agreed upon that the underlying subtype of carcinoma should be reported. For sarcomatoid carcinoma, it was further agreed upon that if the underlying carcinoma subtype was absent the tumor should be classified as a grade 4 unclassified carcinoma with a sarcomatoid component. Tumor necrosis was considered to have prognostic significance, with assessment based on macroscopic and microscopic examination of the tumor. It was recommended that for clear cell RCC the amount of necrosis should be quantified. There was consensus that nucleolar prominence defined grades 1 to 3 of clear cell and papillary RCCs, whereas extreme nuclear pleomorphism or sarcomatoid and/or rhabdoid differentiation defined grade 4 tumors. It was agreed upon that chromophobe RCC should not be graded. There was consensus that microvascular invasion should not be included as a staging criterion for RCC.

BackgroundAlthough androgens are depleted in castration resistant prostate cancer (CRPC), metastases still express nuclear androgen receptor (AR) and androgen regulated genes. We recently reported that C-terminal truncated constitutively active AR splice variants contribute to CRPC development. Since specific antibodies detecting all C-terminal truncated AR variants are not available, our aim was to develop an approach to assess the prevalence and function of AR variants in prostate cancer (PCa).Methodology/Principal FindingsUsing 2 antibodies against different regions of AR protein (N- or C-terminus), we successfully showed the existence of AR variant in the LuCaP 86.2 xenograft. To evaluate the prevalence of AR variants in human PCa tissue, we used this method on tissue microarrays including 50 primary PCa and 162 metastatic CRPC tissues. RT-PCR was used to confirm AR variants. We observed a significant decrease in nuclear C-terminal AR staining in CRPC but no difference between N- and C-terminal AR nuclear staining in primary PCa. The expression of the AR regulated proteins PSA and PSMA were marginally affected by the decrease in C-terminal staining in CRPC samples. These data suggest that there is an increase in the prevalence of AR variants in CRPC based on our ability to differentiate nuclear AR expression using N- and C-terminal AR antibodies. These findings were validated using RT-PCR. Importantly, the loss of C-terminal immunoreactivity and the identification of AR variants were different depending on the site of metastasis in the same patient.ConclusionsWe successfully developed a novel immunohistochemical approach which was used to ascertain the prevalence of AR variants in a large number of primary PCa and metastatic CRPC. Our results showed a snapshot of overall high frequency of C-terminal truncated AR splice variants and site specific AR loss in CRPC, which could have utility in stratifying patients for AR targeted therapeutics.

STK15 gene amplification and associated increased expression of the mitotic kinase it encodes are associated with aneuploidy and aggressive clinical behavior in human bladder cancer.

Purpose Active surveillance represents a strategy to address the overtreatment of prostate cancer, yet uncertainty regarding individual patient outcomes remains a concern. We evaluated outcomes in a prospective multi-center study of active surveillance. Methods We studied 905 men in the prospective Canary Prostate cancer Active Surveillance Study (PASS) enrolled between 2008 to 2013. We collected clinical data at study entry and at pre-specified intervals and determined associations with adverse reclassification defined as increased Gleason grade or greater cancer volume on follow-up biopsy. We also evaluated the relationships of clinical parameters with pathology findings in participants who underwent surgery after a period of active surveillance. Results During a median follow-up of 28 months, 24% of participants experienced adverse reclassification, of whom 53% underwent treatment while 31% continued active surveillance. Overall, 19% of participants received treatment, 68% with adverse reclassification while 32% opted for treatment without disease reclassification. In multivariate Cox proportional hazards modeling, percent of biopsy cores with cancer, BMI, and PSA density were associated with adverse reclassification (P = 0.01, 0.04, 0.04). Of 103 participants subsequently treated by radical prostatectomy, 34% had adverse pathology, defined as primary pattern 4–5 or non-organ confined disease, including two with positive lymph nodes, with no significant relationship between risk category at diagnosis and findings at surgery (P = 0.76). Conclusion Most men remain on active surveillance at five years without adverse reclassification or adverse pathology at surgery. However, clinical factors had only modest association with disease reclassification, supporting the need for approaches that improve prediction of this outcome.

Introduction and Objectives The clinical significance of ductal prostatic carcinoma has not been well defined. We utilized a population-based cancer registry to identify a large group of ductal carcinoma cases to characterize the impact of the ductal subtype on the presentation and survival of men with prostate cancer. Methods A national cancer registry was used to identify incident cases of ductal and acinar adenocarcinomas from 1996–2006. Clinicopathologic variables were analyzed and Cox multivariate survival analysis performed. PSA values were available for the years 2004–2006, and these were used to assess for differences in Gleason grade and serum PSA levels between ductal and acinar cancers at the time of diagnosis. Results A total of 442,881 acinar cases and 371 ductal cases were identified. Ductal cases were more likely to present with distant disease (12% vs. 4%, p<0.001) and to be poorly differentiated (50% vs. 32%; p<0.001). Ductal histology was associated with a 30% lowering of the geometric mean PSA (adjusted coeff.=0.7, 95% CI 0.6–0.8) and a more than two-fold increased odds of having a PSA<4.0 ng/ml (OR 2.4, 95% CI 1.4–4.0) independent of other clinicopathologic variables. For those with non-distant disease at diagnosis, ductal histology was associated with a 2.4-fold (CI 1.5–3.8) increased disease-specific mortality. Conclusions In the largest series of this histologic subtype, ductal cancers were more likely to present with advanced stage cancer and a lower PSA, suggesting that timely detection of the disease is a significant challenge. In addition, those with loco regional disease were more likely to die of their disease.

Kinases can phosphorylate and regulate androgen receptor activity during prostate cancer progression. In particular, we showed that glycogen synthase kinase-3␤ phosphorylates the androgen receptor, thereby inhibiting androgen receptor-driven transcription. Conversely, the glycogen synthase kinase-3␤ inhibitor lithium chloride suppressed the glycogen synthase kinase-3␤-mediated phosphorylation of the androgen receptor, thereby enabling androgen receptor-driven transcription to occur. The androgen receptor hinge and ligandbinding domains were important for both the phosphorylation and the inhibition of transcriptional activity of the receptor by glycogen synthase kinase-3␤. Furthermore, androgen receptor phosphorylation was augmented by LY294002, an indirect inhibitor of protein kinase B/Akt that inhibits glycogen synthase kinase-3␤. We also showed that the mutation of various phosphorylation sites on glycogen synthase kinase-3␤ affected the ability of these mutants to co-distribute with the androgen receptor in the cell nucleus, also that both glycogen synthase kinase-3␤ and androgen receptor proteins can be found in cell nuclei of prostate cancer tissue samples. Because glycogen synthase kinase-3␤ activity is suppressed after the enzyme is phosphorylated by protein kinase B/Akt and Akt activity frequently increases during the progression of prostate cancer, nullification of the glycogen synthase kinase-3␤-mediated suppression of androgen receptor activity by Akt likely contributes to prostate cancer progression.

BackgroundAdvancing age is associated with substantial increases in the incidence rates of common diseases affecting the prostate gland including benign prostatic hyperplasia (BPH) and prostate carcinoma. The prostate is comprised of a functional secretory epithelium, a basal epithelium, and a supporting stroma comprised of structural elements, and a spectrum of cell types that includes smooth muscle cells, fibroblasts, and inflammatory cells. As reciprocal interactions between epithelium and stromal constituents are essential for normal organogenesis and serve to maintain normal functions, discordance within the stroma could permit or promote disease processes. In this study we sought to identify aging-associated alterations in the mouse prostate microenvironment that could influence pathology.Methodology/Principal FindingsWe quantitated transcript levels in microdissected glandular-adjacent stroma from young (age 4 months) and old (age 20–24 months) C57BL/6 mice, and identified a significant change in the expression of 1259 genes (p<0.05). These included increases in transcripts encoding proteins associated with inflammation (e.g., Ccl8, Ccl12), genotoxic/oxidative stress (e.g., Apod, Serpinb5) and other paracrine-acting effects (e.g., Cyr61). The expression of several collagen genes (e.g., Col1a1 and Col3a1) exhibited age-associated declines. By histology, immunofluorescence, and electron microscopy we determined that the collagen matrix is abundant and disorganized, smooth muscle cell orientation is disordered, and inflammatory infiltrates are significantly increased, and are comprised of macrophages, T cells and, to a lesser extent, B cells.Conclusion/SignificanceThese findings demonstrate that during normal aging the prostate stroma exhibits phenotypic and molecular characteristics plausibly contributing to the striking age associated pathologies affecting the prostate.

Objective To assess the prevalence and pattern of myocardial fibrosis as detected by delayed enhanced magnetic resonance imaging (DE‐MRI) in patients with systemic sclerosis (SSc), and to evaluate a possible association between myocardial fibrosis and cardiac arrhythmias. Methods Forty‐one patients with SSc underwent 24‐hour Holter monitoring, Doppler echocardiography, and DE‐MRI following gadolinium administration. Results Technically acceptable DE‐MRIs were obtained in 36 patients with SSc. Enhancement on DE‐MRI, consistent with myocardial fibrosis, was observed in 24 of these patients (66%), and it was invariably midwall with a linear pattern, mostly involving basal and midcavity segments of the left ventricle. The volume of enhancement (total volume percentage index [TVPI]) did not differ between patients with diffuse SSc and those with limited SSc (mean ± SD 1.46 ± 1.73% versus 1.44 ± 1.77%; P = 0.98). Patients with a long duration (≥15 years) of Raynaud's phenomenon had a greater number of enhancing segments (mean ± SD 6.55 ± 4.93 versus 2.96 ± 3.46; P = 0.017) and a greater TVPI (mean ± SD 2.44 ± 1.97% versus 1.02 ± 1.43%; P = 0.02) than those with a duration of Raynaud's phenomenon <15 years. Nineteen patients with SSc (53%) had abnormal Holter study results. Compared with patients with normal Holter study results, those with abnormal results had a greater number of enhancing segments (mean ± SD 5.4 ± 4.8 versus 2.5 ± 2.9; P < 0.05) and a greater TVPI (mean ± SD 2.1 ± 1.9% versus 0.8 ± 1.2%; P < 0.05). Conclusion DE‐MRI can identify myocardial fibrosis in a significant percentage of patients with SSc and may be a useful noninvasive tool for determining cardiac involvement.