Bladder Cancer
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Bladder cancer is a disease in which malignant cells arise in the bladder. Symptoms can include blood in the urine, pain during urination, increased frequency of passing urine, or feeling the need to urinate but with nothing coming out. The bulk of bladder cancers are histlogically classed as transitional cell carcinomas which arise in the uroepithelium (lining of the bladder). Other types include squamous cell carcinomas, and adenocarcinomas. Treatment will depend on how far the tumour has invaded the surrounding tissues, and if it has spread to other parts of the body. World-wide about 260,000 people are diagnosed with bladder cancer each year.

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Information for Patients and the Public
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Latest Research Publications
Molecular Biology of Bladder Cancer
Urinary System Cancers

Information Patients and the Public (16 links)

Information for Health Professionals / Researchers (8 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Garg M
Prognostic and therapeutic applications of the molecular events in clinical management of urothelial carcinoma of bladder.
J Exp Ther Oncol. 2014; 10(4):301-16 [PubMed] Related Publications
Urothelial carcinoma of bladder being the commonest malignancy of the urinary tract progresses through successive accumulation of genetic alterations and bears high metastatic potential. Despite significant advances in its prognosis and treatment, including surgical techniques, various adjuvant therapies, radical cystectomy and robot-assisted radical cystectomy, tumor recurs with a poor 5 year survival rate thereby necessitating the need to institute an additional form of novel target based therapies to improve the overall outcome. Improved understanding of the molecular pathways critical for both early and late stage disease not only leads to better prognostication but may also enhance therapeutic index. This review article highlights the recent progress in the development of novel anti-cancer targeted therapies that may modulate clinical response of cytotoxic drugs with minimal adverse side effects and provide insight for the potential reversion of the resistance in patients failing therapy.

Li W, Liang Y, Deavers MT, et al.
Uroplakin II is a more sensitive immunohistochemical marker than uroplakin III in urothelial carcinoma and its variants.
Am J Clin Pathol. 2014; 142(6):864-71 [PubMed] Related Publications
OBJECTIVES: Uroplakin (UP) II and UPIII are highly specific immunohistochemical markers for urothelial differentiation. Here we studied the sensitivity of UPII and UPIII in conventional and variant urothelial carcinomas (UCs).
METHODS: Immunohistochemical staining for UPII and UPIII was performed on tissue microarray slides, including 105 conventional bladder UCs (BUCs), 90 upper urinary tract UCs (UUTUCs), and 47 micropapillary, 16 plasmacytoid, 22 small cell carcinoma, and 41 sarcomatoid UC variants.
RESULTS: UPII expression was significantly higher than UPIII expression in conventional BUC (44% vs 17%, P < .001) and UUTUC (67% vs 46%, P = .045). UPIII expression was significantly higher in UUTUC than in BUC (P < .001). In UC variants, UPII expression was significantly higher than UPIII expression in micropapillary (91% vs 25%, P < .001), plasmacytoid (63% vs 6%, P < .001), and sarcomatoid (29% vs 5%, P = .032) variants. Only rare cases of the small cell carcinoma variant had focal UPII and UPIII expression. Compared with conventional UC, the sarcomatoid variant had significantly lower UPII expression, whereas the micropapillary variant had significantly higher UPII expression (P < .001).
CONCLUSIONS: UPII demonstrates a significantly higher sensitivity than UPIII in conventional and variant UCs. Thus, UPII is a more valuable marker than UPIII in immunohistochemical analyses for confirming the urothelial origin of carcinomas.

Related: Transitional Cell Cancer of the Renal Pelvis and Ureter

Klopfer K, Delahunt B, Adamson M, Samaratunga H
Value of uroplakin III in distinguishing variants of primary bladder urothelial carcinoma from malignancy metastatic to the urinary bladder.
Anticancer Res. 2014; 34(11):6779-84 [PubMed] Related Publications
BACKGROUND: Urothelial carcinoma (UC) variants can be difficult to differentiate from carcinoma metastatic to the bladder.
MATERIALS AND METHODS: We examined immunostaining for uroplakin III in 43 cases of primary bladder UC variants including micropapillary UC (n=19), nested variant of UC (n=2), pleomorphic giant-cell carcinoma (n=8), plasmacytoid UC (n=4), lymphoepithelioma-like carcinoma (n=2), large cell undifferentiated carcinoma (n=2), UC with abundant myxoid stroma (n=3) and lipid cell variant (n=3) and in 11 tumors from other organs metastatic to the bladder. These tumors included invasive ductal carcinoma of the breast (n=2), colorectal adenocarcinoma (n=4), endometrioid adenocarcinoma (n=1) and serous papillary carcinoma of the uterus (n=1) melanoma (n=1), embryonal carcinoma of the testis (n=1), and renal clear cell carcinoma (n=1).
RESULTS: Out of the 43 UC variants, 35 (81%) were positive for uroplakin III, including micropapillary, lipid cell variant and UC with abundant myxoid stroma. Pleomorphic giant cell carcinoma, plasmacytoid UC and nested variant of UC were less commonly positive. Of the 11 metastatic tumors, six were found to be positive for uropIakin III: metastatic colorectal adenocarcinoma, clear cell carcinoma of the kidney and embryonal carcinoma of testis.
CONCLUSION: UP III Positivity for uroplakin III is not found only in primary bladder UC variants, but in some tumors that have metastatized to the bladder. Staining for uroplakin III alone should not be taken as evidence of UC.

Fu YP, Kohaar I, Moore LE, et al.
The 19q12 bladder cancer GWAS signal: association with cyclin E function and aggressive disease.
Cancer Res. 2014; 74(20):5808-18 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
A genome-wide association study (GWAS) of bladder cancer identified a genetic marker rs8102137 within the 19q12 region as a novel susceptibility variant. This marker is located upstream of the CCNE1 gene, which encodes cyclin E, a cell-cycle protein. We performed genetic fine-mapping analysis of the CCNE1 region using data from two bladder cancer GWAS (5,942 cases and 10,857 controls). We found that the original GWAS marker rs8102137 represents a group of 47 linked SNPs (with r(2) ≥ 0.7) associated with increased bladder cancer risk. From this group, we selected a functional promoter variant rs7257330, which showed strong allele-specific binding of nuclear proteins in several cell lines. In both GWASs, rs7257330 was associated only with aggressive bladder cancer, with a combined per-allele OR = 1.18 [95% confidence interval (CI), 1.09-1.27, P = 4.67 × 10(-5)] versus OR = 1.01 (95% CI, 0.93-1.10, P = 0.79) for nonaggressive disease, with P = 0.0015 for case-only analysis. Cyclin E protein expression analyzed in 265 bladder tumors was increased in aggressive tumors (P = 0.013) and, independently, with each rs7257330-A risk allele (P(trend) = 0.024). Overexpression of recombinant cyclin E in cell lines caused significant acceleration of cell cycle. In conclusion, we defined the 19q12 signal as the first GWAS signal specific for aggressive bladder cancer. Molecular mechanisms of this genetic association may be related to cyclin E overexpression and alteration of cell cycle in carriers of CCNE1 risk variants. In combination with established bladder cancer risk factors and other somatic and germline genetic markers, the CCNE1 variants could be useful for inclusion into bladder cancer risk prediction models.

Related: Chromosome 19 CCNE1 gene

Giedl J, Schneckenpointner R, Filbeck T, et al.
Low frequency of HNPCC-associated microsatellite instability and aberrant MMR protein expression in early-onset bladder cancer.
Am J Clin Pathol. 2014; 142(5):634-9 [PubMed] Related Publications
OBJECTIVES: Recently, it was shown that patients with Lynch syndrome due to an MSH2 mutation are at increased risk for the development of bladder cancer. To further this discussion, we screened the largest investigated cohort of patients with early-onset bladder cancer for microsatellite instability (MSI) and mismatch repair (MMR) deficiency to determine a possible role of Lynch syndrome in young patients with bladder cancer.
METHODS: A total of 109 cases of bladder tumors from young patients (aged <45 years) were examined for MSI (Bethesda consensus panel). Expression of MMR proteins (hMLH1, hMSH2, and hMSH6) was evaluated by immunohistochemistry using a tissue microarray. Results were compared with a series of unselected consecutive bladder tumors (n = 95).
RESULTS: Regarding the frequency of MSI high (1% vs 0%) or abnormal expression of MMR proteins (2% vs 6.5%), no significant difference between the early-onset and unselected patient group was found.
CONCLUSIONS: In young patients with bladder tumors, MSI and defects in MMR protein expression were not more frequent than in a series of consecutive bladder tumors. Most bladder tumors in young patients are not to be attributed to Lynch syndrome.

Related: Lynch Syndrome - HNPCC

Shin K, Lim A, Zhao C, et al.
Hedgehog signaling restrains bladder cancer progression by eliciting stromal production of urothelial differentiation factors.
Cancer Cell. 2014; 26(4):521-33 [PubMed] Related Publications
Hedgehog (Hh) pathway inhibitors are clinically effective in treatment of basal cell carcinoma and medulloblastoma, but fail therapeutically or accelerate progression in treatment of endodermally derived colon and pancreatic cancers. In bladder, another organ of endodermal origin, we find that despite its initial presence in the cancer cell of origin Sonic hedgehog (Shh) expression is invariably lost during progression to invasive urothelial carcinoma. Genetic blockade of stromal response to Shh furthermore dramatically accelerates progression and decreases survival time. This cancer-restraining effect of Hh pathway activity is associated with stromal expression of BMP signals, which stimulate urothelial differentiation. Progression is dramatically reduced by pharmacological activation of BMP pathway activity with low-dose FK506, suggesting an approach to management of human bladder cancer.

Related: Signal Transduction

Xu K, Bägli DJ, Egan SE
NOTch just a bladder control problem.
Cancer Cell. 2014; 26(4):452-4 [PubMed] Related Publications
Human bladder cancers harbor deletions and point mutations in genes coding for Notch receptors and proteins involved in Notch signaling. This leads to elevated MAPK pathway activation, as direct Notch-mediated transcription of MAPK phosphatase DUSP is lost. These bladder tumors, with impaired Notch signaling, also show basal differentiation.

Raza SJ, Tawfeeq M, Al-Daghmin A, Guru KA
Robot-assisted intracorporeal urinary diversion: where do we stand in 2014?
Urol Clin North Am. 2014; 41(4):503-9 [PubMed] Related Publications
Radical cystectomy can only be considered as minimally invasive when both extirpative and reconstructive part of the procedure are performed with an intracorporeal approach. Robot-assisted radical cystectomy makes it possible to achieve this task, which seemed difficult with conventional laparoscopy. Intracorporeal urinary diversion (ICUD) is associated with better perioperative outcomes. Quality-of-life assessments and functional outcomes from continent ICUD are encouraging. Working in high-volumes center with mentored training can help robotic surgeons to learn the techniques of ICUD in conjunction with robot-assisted radical cystectomy. This article discusses the perioperative and functional outcomes of ICUD with a review of literature.

Inoue M, Koga F, Yoshida S, et al.
Significance of ERBB2 overexpression in therapeutic resistance and cancer-specific survival in muscle-invasive bladder cancer patients treated with chemoradiation-based selective bladder-sparing approach.
Int J Radiat Oncol Biol Phys. 2014; 90(2):303-11 [PubMed] Related Publications
PURPOSE: To investigate the associations of ERBB 2 overexpression with chemoradiation therapy (CRT) resistance and cancer-specific survival (CSS) in muscle-invasive bladder cancer (MIBC) patients treated with the CRT-based bladder-sparing protocol.
METHODS AND MATERIALS: From 1997 to 2012, 201 patients with cT2-4aN0M0 bladder cancer were treated with CRT (40 Gy with concurrent cisplatin) following transurethral resection of bladder tumor (TURBT). Basically, patients with tumors that showed good CRT response and were amenable to segmental resection underwent partial cystectomy (PC) with pelvic lymph node dissection for bladder preservation; otherwise, radical cystectomy (RC) was recommended. Included in this study were 119 patients in whom TURBT specimens were available for immunohistochemical analysis of ERBB 2 expression. Following CRT, 30 and 65 patients underwent PC or RC, respectively; the remaining 24 patients did not undergo cystectomy. Tumors were defined as CRT-resistant when patients did not achieve complete response after CRT. Associations of ERBB 2 overexpression with CRT resistance and CSS were evaluated.
RESULTS: CRT resistance was observed clinically in 56% (67 of 119 patients) and pathologically (in cystectomy specimens) in 55% (52 of 95 patients). ERBB 2 overexpression was observed in 45 patients (38%). On multivariate analysis, ERBB 2 overexpression was an independent predictor for CRT resistance clinically (odds ratio, 3.6; P=.002) and pathologically (odds ratio, 2.9; P=.031). ERBB 2 overexpression was associated with shorter CSS (5-year CSS rates, 56% vs 87% for the ERBB 2 overexpression group vs the others; P=.001). ERBB 2 overexpression was also an independent risk factor for bladder cancer death at all time points of our bladder-sparing protocol (pre-CRT, post-CRT, and post-cystectomy).
CONCLUSIONS: ERBB 2 overexpression appears relevant to CRT resistance and unfavorable CSS in MIBC patients treated with the CRT-based bladder-sparing protocol. ERBB 2-targeting treatment may improve the outcomes of such patients.

Related: Cisplatin

Pusiol T, Morichetti D, Zorzi MG
"Pure" primary large cell neuroendocrine carcinoma of the urinary bladder: case report, literature review and diagnostic criteria.
Pathologica. 2014; 106(2):82-5 [PubMed] Related Publications
INTRODUCTION: Large cell neuroendocrine carcinoma (LCNC) is defined in the urinary bladder, as in other sites, as a high-grade neoplasm exhibiting neuroendocrine features at the H&E level, high mitotic activity and evidence of neuroendocrine differentiation by immunohistochemistry. We report a case of pure bladder LCNC with review of the literature.
METHODS: A 68-year-old male presented with gross haematuria of two weeks' duration in October 2011. Transurethral resection and subsequently radical cystoprostatectomy (CP) with bilateral lymphadenectomy (L) were performed in December 2012.
RESULTS: Urinary cytology identified malignant cells. Histologically, the tumour showed organoid nesting, trabecular growth, rosettes and perilobular palisading patterns, suggesting neuroendocrine differentiation. Immunohistochemical staining showed intense positivity for CD56.
DISCUSSION: We examined all published pure bladder LCNC (12 cases) excluding mixed neoplasms. Small cell carcinoma of the urinary bladder pure LCNC of the bladder is a very aggressive malignancy, unresponsive to therapy, presents in an advanced stage and has a propensity for early metastasis. Prior to the advent of immunohistochemistry, such cases would most likely have been categorised as poorly differentiated, high-grade urothelial carcinomas.

Related: NCAM1

Alderman M, Kunju LP
Inflammatory myofibroblastic tumor of the bladder.
Arch Pathol Lab Med. 2014; 138(10):1272-7 [PubMed] Related Publications
We illustrate a case of an inflammatory myofibroblastic tumor (IMT) involving the bladder in a woman with dysuria and review the literature and differential diagnosis. Inflammatory myofibroblastic tumor, also referred to as pseudosarcomatous myofibroblastic proliferation, is a rare lesion that can arise in the genitourinary system and is characterized by a fascicular arrangement of myofibroblasts with admixed inflammatory cells and slitlike vessels. Urinary bladder IMT can be a diagnostic pitfall because its histologic features (brisk mitoses, invasion into muscularis propria, and prominent nucleoli) can mimic malignancy. The differential diagnosis of urinary bladder IMT includes sarcomatoid carcinoma and leiomyosarcoma. Diagnostic features such as bland nuclear chromatin, ganglion-like cells, pale eosinophilic cytoplasm with long processes, overexpression of anaplastic lymphoma kinase (immunohistochemistry or gene rearrangement studies), and the absence of atypical mitoses help distinguish IMT from its malignant mimics. Current controversies regarding postoperative spindle cell nodule and IMT are discussed.

Ostenfeld MS, Jeppesen DK, Laurberg JR, et al.
Cellular disposal of miR23b by RAB27-dependent exosome release is linked to acquisition of metastatic properties.
Cancer Res. 2014; 74(20):5758-71 [PubMed] Related Publications
Exosomes are small secreted vesicles that can transfer their content to recipient cells. In cancer, exosome secretion has been implicated in tumor growth and metastatic spread. In this study, we explored the possibility that exosomal pathways might discard tumor-suppressor miRNA that restricts metastatic progression. Secreted miRNA characterized from isogenic bladder carcinoma cell lines with differing metastatic potential were uncoupled from binding to target transcripts or the AGO2-miRISC complex. In metastatic cells, we observed a relative increase in secretion of miRNA with tumor-suppressor functions, including miR23b, miR224, and miR921. Ectopic expression of miR23b inhibited invasion, anoikis, angiogenesis, and pulmonary metastasis. Silencing of the exocytotic RAB family members RAB27A or RAB27B halted miR23b and miR921 secretion and reduced cellular invasion. Clinically, elevated levels of RAB27B expression were linked to poor prognosis in two independent cohorts of patients with bladder cancer. Moreover, highly exocytosed miRNA from metastatic cells, such as miR23b, were reduced in lymph node metastases compared with patient-matched primary tumors and were correlated with increments in miRNA-targeted RNA. Taken together, our results suggested that exosome-mediated secretion of tumor-suppressor miRNA is selected during tumor progression as a mechanism to coordinate activation of a metastatic cascade.

Related: MicroRNAs

Van Batavia J, Yamany T, Molotkov A, et al.
Bladder cancers arise from distinct urothelial sub-populations.
Nat Cell Biol. 2014; 16(10):982-91, 1-5 [PubMed] Related Publications
Bladder cancer is the sixth most common cancer in humans. This heterogeneous set of lesions including urothelial carcinoma (Uca) and squamous cell carcinoma (SCC) arise from the urothelium, a stratified epithelium composed of K5-expressing basal cells, intermediate cells and umbrella cells. Superficial Uca lesions are morphologically distinct and exhibit different clinical behaviours: carcinoma in situ (CIS) is a flat aggressive lesion, whereas papillary carcinomas are generally low-grade and non-invasive. Whether these distinct characteristics reflect different cell types of origin is unknown. Here we show using lineage tracing in a murine model of carcinogenesis that intermediate cells give rise primarily to papillary lesions, whereas K5-basal cells are likely progenitors of CIS, muscle-invasive lesions and SCC depending on the genetic background. Our results provide a cellular and genetic basis for the diversity in bladder cancer lesions and provide a possible explanation for their clinical and morphological differences.

Related: Transitional Cell Cancer of the Renal Pelvis and Ureter

Maebayashi T, Ishikawa H, Yorozu A, et al.
Patterns of practice in the radiation therapy for bladder cancer: survey of the Japanese Radiation Oncology Study Group (JROSG).
Jpn J Clin Oncol. 2014; 44(11):1109-15 [PubMed] Related Publications
OBJECTIVE: To retrospectively analyze the clinical outcomes of radiation therapy with or without chemotherapy for bladder cancer in Japan.
METHODS: A questionnaire-based survey of patients with pathologically proven bladder cancer treated by definitive radiation therapy between 2002 and 2006 was conducted by the Japanese Radiation Oncology Study Group, and the clinical records of 159 patients were collected from 17 institutions. Concurrent intra-arterial chemoradiotherapy and concurrent systemic chemoradiotherapy were administered in 51 and 33 patients, respectively.
RESULTS: The 5-year overall survival and bladder preservation rates were 48 and 39%, respectively. Eighty-nine (56%) patients developed recurrence (bladder, 48; regional lymph nodes, 4; distant sites, 41). The results of multivariate analysis revealed that adoption of chemotherapy was the only significant prognostic factor for overall survival (relative risk = 0.615 [95% confidence interval: 0.439-0.862], P = 0.005). The type of chemotherapy administered did not significantly affect the local control or overall survival rates. The actuarial 5-year overall survival rates and bladder preservation in the radiation therapy combined with intra-arterial chemotherapy group were 64 and 58%, respectively, and the corresponding rates in the radiation therapy combined with systemic chemotherapy group were 67 and 42%, respectively.
CONCLUSIONS: The results of this survey revealed the current status of practice of radiation therapy for bladder cancer in Japan. A multi-institutional prospective study is needed based on the results of this study to determine the optimal radiotherapeutic approach, including the need for concurrent chemotherapy and the appropriate chemotherapy regimen for invasive bladder cancer.

Colt JS, Friesen MC, Stewart PA, et al.
A case-control study of occupational exposure to metalworking fluids and bladder cancer risk among men.
Occup Environ Med. 2014; 71(10):667-74 [PubMed] Related Publications
OBJECTIVES: Metalworking has been associated with an excess risk of bladder cancer in over 20 studies. Metalworking fluids (MWFs) are suspected as the responsible exposure, but epidemiological data are limited. We investigated this association among men in the New England Bladder Cancer Study using state-of-the-art, quantitative exposure assessment methods.
METHODS: Cases (n=895) and population controls (n=1031) provided occupational histories during personal interviews. For selected jobs, exposure-oriented modules were administered to collect information on use of three MWF types: (1) straight (mineral oil, additives), (2) soluble (mineral oil, water, additives) and (3) synthetic (water, organics, additives) or semisynthetic (hybrid of soluble and synthetic). We computed ORs and 95% CIs relating bladder cancer risk to a variety of exposure metrics, adjusting for smoking and other factors. Non-metalworkers who had held jobs with possible exposure to mineral oil were analysed separately.
RESULTS: Bladder cancer risk was elevated among men who reported using straight MWFs (OR=1.7, 95% CI 1.1 to 2.8); risk increased monotonically with increasing cumulative exposure (p=0.041). Use of soluble MWFs was associated with a 50% increased risk (95% CI 0.96 to 2.5). ORs were non-significantly elevated for synthetic/semisynthetic MWFs based on a small number of exposed men. Non-metalworkers holding jobs with possible exposure to mineral oil had a 40% increased risk (95% CI 1.1 to 1.8).
CONCLUSIONS: Exposure to straight MWFs was associated with a significantly increased bladder cancer risk, as was employment in non-metalworking jobs with possible exposure to mineral oil. These findings strengthen prior evidence for mineral oil as a bladder carcinogen.

Slater SE, Patel P, Viney R, et al.
The effects and effectiveness of electromotive drug administration and chemohyperthermia for treating non-muscle invasive bladder cancer.
Ann R Coll Surg Engl. 2014; 96(6):415-9 [PubMed] Related Publications
INTRODUCTION: Preliminary studies show that device assisted intravesical therapies appear more effective than passive diffusion intravesical therapy for the treatment of non-muscle invasive bladder cancer (NMIBC) in specific settings, and phase III studies are now being conducted. Consequently, we have undertaken a non-systematic review with the objective of describing the scientific basis and mechanisms of action of electromotive drug administration (EMDA) and chemohyperthermia (CHT).
METHODS: PubMed, and the Cochrane Library were searched to source evidence for this non-systematic review. Randomised controlled trials, systematic reviews and meta-analyses were evaluated. Publications regarding the scientific basis and mechanisms of action of EMDA and CHT were identified, as well as clinical studies to date.
RESULTS: EMDA takes advantage of three phenomena: iontophoresis, electro-osmosis and electroporation. It has been found to reduce recurrence rates in NMIBC patients and has been proposed as an addition or alternative to bacillus Calmette-Guérin (BCG) therapy in the treatment of high risk NMIBC. CHT improves the efficacy of mitomycin C by three mechanisms: tumour cell cytotoxicity, altered tumour blood flow and localised immune responses. Fewer studies have been conducted with CHT than with EMDA but they have demonstrated utility for increasing disease-free survival, especially in patients who have previously failed BCG therapy.
CONCLUSIONS: It is anticipated that EMDA and CHT will play important roles in the management of NMIBC in the future. Techniques of delivery should be standardised, and there is a need for more randomised controlled trials to evaluate the benefits of the treatments alongside quality of life and cost-effectiveness.

Rampias T, Vgenopoulou P, Avgeris M, et al.
A new tumor suppressor role for the Notch pathway in bladder cancer.
Nat Med. 2014; 20(10):1199-205 [PubMed] Related Publications
The Notch signaling pathway controls cell fates through interactions between neighboring cells by positively or negatively affecting the processes of proliferation, differentiation and apoptosis in a context-dependent manner. This pathway has been implicated in human cancer as both an oncogene and a tumor suppressor. Here we report new inactivating mutations in Notch pathway components in over 40% of human bladder cancers examined. Bladder cancer is the fourth most commonly diagnosed malignancy in the male population of the United States. Thus far, driver mutations in fibroblast growth factor receptor 3 (FGFR3) and, less commonly, in RAS proteins have been identified. We show that Notch activation in bladder cancer cells suppresses proliferation both in vitro and in vivo by directly upregulating dual-specificity phosphatases (DUSPs), thus reducing the phosphorylation of ERK1 and ERK2 (ERK1/2). In mouse models, genetic inactivation of Notch signaling leads to Erk1/2 phosphorylation, resulting in tumorigenesis in the urinary tract. Collectively our findings show that loss of Notch activity is a driving event in urothelial cancer.

Related: Transitional Cell Cancer of the Renal Pelvis and Ureter Signal Transduction NOTCH1 gene

Prakash MR, Vijayalaxmi SV, Maitreyee R, Ranjit KP
Complex mucinous cystadenoma of undetermined malignant potential of the urachus: a rare case with review of the literature.
Malays J Pathol. 2014; 36(2):145-8 [PubMed] Related Publications
Urachal carcinoma is an uncommon neoplasm. Benign urachal tumours are extremely rare. All urachal mucinous tumours, regardless of tumour type, have the potential to behave in an aggressive clinical manner that includes the development of pseudomyxoma peritonei. We report a 58-year-old man who presented with lower abdominal pain. Ultrasound and CT imaging defined a large lobulated cystic mass superior to the urinary bladder. At laparotomy, the multiloculated cystic mass, 10 x 8 x 6 cm, could be completely separated from the bladder and was excised. It was smooth-walled and filled with thick mucinous fluid. Histology revealed a complex mucinous cystadenoma of undetermined malignant potential of the urachus. The cystic spaces were lined by mucin-secreting columnar epithelium that showed focal areas of mild atypia. The epithelium lacked architectural features of villous adenoma. There was no stromal invasion to support an invasive neoplastic process. No pseudomyxoma peritonei was present. The patient was well, with no tumour recurrence, at 6 months follow-up.

Gupta A, Atoria CL, Ehdaie B, et al.
Risk of fracture after radical cystectomy and urinary diversion for bladder cancer.
J Clin Oncol. 2014; 32(29):3291-8 [PubMed] Article available free on PMC after 10/10/2015 Related Publications
PURPOSE: Radical cystectomy and urinary diversion may cause chronic metabolic acidosis, leading to long-term bone loss in patients with bladder cancer. However, the risk of fractures after radical cystectomy has not been defined. We assessed whether radical cystectomy and intestinal urinary diversion are associated with increased risk of fracture.
PATIENTS AND METHODS: Population-based study using SEER-Medicare-linked data from 2000 through 2007 for patients with stage 0-III bladder cancer. We evaluated the association between radical cystectomy and risk of fracture at any site, controlling for patient and disease characteristics.
RESULTS: The cohort included 50,520 patients, of whom 4,878 had cystectomy and urinary diversion. The incidence of fracture in the cystectomy group was 6.55 fractures per 100 person-years, compared with 6.39 fractures per 100 person-years in those without cystectomy. Cystectomy was associated with a 21% greater risk of fracture (adjusted hazard ratio, 1.21; 95% CI, 1.10 to 1.32) compared with no cystectomy, controlling for patient and disease characteristics. There was no evidence of an interaction between radical cystectomy and age, sex, comorbidity score, or cancer stage.
CONCLUSION: Patients with bladder cancer who have radical cystectomy and urinary diversion are at increased risk of fracture.

Related: USA

Gordetsky J, Bivalacqua T, Schoenberg M, Epstein JI
Ureteral and urethral frozen sections during radical cystectomy or cystoprostatectomy: an analysis of denudation and atypia.
Urology. 2014; 84(3):619-23 [PubMed] Related Publications
OBJECTIVE: To evaluate denudation (no urothelium present for evaluation) and atypia (urothelial carcinoma in situ [CIS] cannot be ruled out) on frozen sections (FSs) of ureteral and urethral margins in radical cystectomies and cystoprostatectomies.
MATERIALS AND METHODS: In radical cystectomies from 2000-2012, we compared FS diagnoses with the corresponding permanent section of the same tissue (frozen section control [FSC]). We also compared FS to "any CIS," which assessed whether there was any CIS in a given ureter or urethra, combining the diagnoses on "frozen section control" and on all submitted ureteral and urethral sections in a case.
RESULTS: We analyzed 1222 ureteral and 366 urethral FSs in 822 surgical cases. On FS for ureters, there were 56 diagnoses of atypia, 19 (33.9%) of which showed CIS on FSC, and 81 diagnoses of denudation, 1 (1.2%) of which showed CIS on FSC. On FS for urethras, there were 12 diagnoses of atypia, 2 (16.7%) of which showed CIS on FSC, and 17 diagnoses of denudation, 1 (5.9%) of which showed CIS on FSC. Twenty-three patients (38.3%) with atypia and 14 patients (15.0%) with denudation on FS had a finding of "any CIS." A diagnosis of either atypia or denudation on FS was predictive of finding CIS on FSC and "any CIS" in a given ureter or urethra (P <.0001). Half of margins positive for CIS on the first FS were converted to a final negative margin by resecting additional tissue.
CONCLUSION: After an FS diagnosis of atypia or denudation, urologists should obtain additional margins if surgically feasible.

Teoh JY, Chan NH, Cheung HY, et al.
Inflammatory myofibroblastic tumors of the urinary bladder: a systematic review.
Urology. 2014; 84(3):503-8 [PubMed] Related Publications
We systemically reviewed the literature on inflammatory myofibroblastic tumors (IMTs) of the urinary bladder and compared between anaplastic lymphoma kinase (ALK)-positive and ALK-negative IMTs. An extensive search of the literature was performed in Medline and Web of Science using the following terms: "inflammatory myofibrolastic tumor," "inflammatory pseudotumor," and "bladder." A manual search was also performed using the web-based search engine Google Scholar. Reference lists of the retrieved articles were reviewed for other relevant studies. Patients' and disease characteristics of each individual case were reviewed. Further analyses were performed to compare between ALK-positive and ALK-negative IMTs. Forty-one studies were identified, and 182 patients were included for review and subsequent analyses. Of the IMTs, 65% were ALK-positive. Local tumor recurrence rate was 4%, and no cases of distant metastases have been reported. Compared with ALK-negative IMTs, ALK-positive IMTs had a female predilection with a sex ratio (male:female) of 1:1.67 (P = .048). ALK-positive IMTs also appeared to occur in younger patients (P = .072). No significant differences were noted in terms of their clinical presentations and histologic features. On immunohistochemical staining, ALK-positive IMTs had more positive results for desmin (P = .042) and p53 (P = .05), and more negative results for clusterin (P = .003). In summary, ALK-positive IMTs of the urinary bladder had a female predilection, appeared to occur more frequently in younger patients, and had different immunohistochemical staining patterns when compared with ALK-negative IMTs. Regardless of its ALK status, IMT of the urinary bladder has a good prognosis after surgical resection.

Related: ALK

Krajewski W, Piszczek R, Krajewska M, et al.
Urinary diversion metabolic complications - underestimated problem.
Adv Clin Exp Med. 2014 Jul-Aug; 23(4):633-8 [PubMed] Related Publications
Bladder cancer is one of the most frequent human cancers. In 2011 more than six thousand people in Poland developed BC and more than three thousand died because of it. Treatment of bladder cancer depends on its stage. In less advanced tumours (Ta, Tcis, T1) transurethral resection of bladder tumor with adjuvant immunotherapy is often therapeutic. In more advanced cases (≥ T2) radical cystectomy is needed. There are several surgical types of post-cystectomy urinary diversion divided into two fundamental types - enabling and not enabling urine continence. The most common procedures include ureterocutaneostomy, ileal or colon conduit, orthopic ileal bladder, heterotopic continent bladder replacement (pouch) and urinary diversion via the rectum. Depending on type of cystectomy, various metabolic complications occur, because the absorptive-secretory function of used bowel segment is intact. Complications include bowel dysfunction, malabsorption of various vitamins, acid-base imbalance, electrolyte imbalance, abnormalities in bone metabolism, formation of renal calculi, secondary malignancies and disturbances in function of kidneys or liver. Early diagnosed complications can be treated easier, recognised in advanced stages are often irreversible. In our paper we present review of different approaches to bladder cancer treatment and metabolic complications occurring after these procedures.

Gu J, Tao J, Yang X, et al.
Effects of TSP-1-696 C/T polymorphism on bladder cancer susceptibility and clinicopathologic features.
Cancer Genet. 2014; 207(6):247-52 [PubMed] Related Publications
Thrombospondin-1 (TSP-1) is a glycoprotein that plays a major role in bladder cancer. We investigated the relationship between the distribution of the TSP-1 -696 C/T polymorphism (rs2664139) and the clinical features of bladder cancer. TaqMan assay was used to determine the genotype among the 609 cases and 670 controls in a Chinese population. Logistic regression was used to assess the association between the polymorphism and bladder cancer risk. Compared with the CT/TT genotypes, the CC genotype was associated with a significantly increased risk of bladder cancer (adjusted odds ratio [OR] 1.43, 95% CI 1.01-2.04), which was more prominent among the male participants (OR 1.82, 95% CI 1.20-2.76). The polymorphism was associated with a higher risk of developing grade 3 (OR 1.84, 95% CI 1.00-3.36), multiple-tumor (OR 1.81, 95% CI 1.08-3.02), and large-tumor (OR 1.94, 95% CI 1.22-3.10) bladder cancers. These observations suggest that the TSP-1 -696 C/T polymorphism may contribute to bladder cancer susceptibility in the Chinese population.

Abd El-Hakim TF, El-Shafie MK, Abdou AG, et al.
Value of urinary survivin as a diagnostic marker in bladder cancer.
Anal Quant Cytopathol Histpathol. 2014; 36(3):121-7 [PubMed] Related Publications
OBJECTIVE: To study the value of urinary survivin as a diagnostic marker for diagnosis of bladder cancer as compared to urine cytology.
STUDY DESIGN: This study was carried out on 40 patients presenting with bladder cancer and 20 patients presenting with benign urological disorders.
RESULTS: For bladder cancer diagnosis, urine cytology has lower sensitivity, accuracy, and negative predictive values as compared to survivin, while it has higher specificity and positive predictive value than survivin. On the other hand, the sensitivity, specificity, and the accuracy of combined survivin and urine cytology were 100%, 95% and 97%, respectively. Positive urine cytology and survivin were significantly higher in cases showing advanced stage and high grade as compared to cases presented with superficial stage and low grade.
CONCLUSION: Urinary survivin appears to be a reliable, noninvasive diagnostic test to identify patients with bladder cancer. The sensitivity of survivin test was superior to that of urine cytology in the diagnosis of bladder cancer, especially in cases presenting with superficial stage or low grade. Combined evaluation of both survivin and urine cytology gave better sensitivity, specificity, and accuracy for bladder cancer diagnosis.

Related: BIRC5

Zhang M, Wah C, Epstein JI
Metastatic renal cell carcinoma to the urinary bladder: a report of 11 cases.
Am J Surg Pathol. 2014; 38(11):1516-21 [PubMed] Related Publications
Metastatic renal cell carcinoma (RCC) to the urinary bladder is rarely seen. Herein, we report the histologic subtypes, immunohistochemical characteristics, and prognosis of 11 patients with metastatic RCC to the urinary bladder. The mean age at the time of diagnosis of metastatic RCC to the bladder was 66 years (range, 58 to 79 y). There were 9 male and 2 female patients. Four patients presented with hematuria, 2 with urinary retention/obstruction, and 1 with bladder calculi. Four patients were asymptomatic and presented for surveillance cystoscopy, wherein they were found to have bladder masses. Nine patients had prior histories of RCC. The remaining 2 patients presented with metastatic clear cell RCC to the bladder and were subsequently found to have renal masses. The average time between nephrectomy and metastasis to the bladder was 20.7 months (range, 0 to 87 mo). Of the 10 patients with radical/partial nephrectomy, 7 cases were clear cell (2 with sarcomatoid features), 2 papillary, and 1 chromophobe with histologic fidelity between the primary and metastasis. Of cases with available data, the primaries' ISUP nucleolar grades were 2 (n=2), 3 (n=4), and 4 for the 2 cases with sarcomatoid features. In 8 cases, the bladder RCC undermined overlying urothelium with extensive urothelial denudation, and in 3 cases the RCC was free floating without attachment to the urothelium. The 1 chromophobe RCC metastasized with pagetoid spread to a preexisting urothelial papilloma. PAX8 immunohistochemistry was used to confirm the diagnosis in 2 cases. Three patients have no evidence of disease (7, 9, and 13 mo). Two are alive with disease after chemotherapy (30, 37 mo). Six patients are dead of disease with multiorgan metastases; 4 are dead after therapy (5, 8, 25, 28 mo), and two died without radiation or chemotherapy at 10 and 71 months. Metastatic RCC to the urinary bladder is uncommon, with most cases clear cell RCC. In some cases, evidence supports "drop metastases" as the mechanism of spread and patients have relatively long survival. However, in other cases spread to the bladder is in the setting of metastases to other sites, and these patients tended to die relatively shortly after their bladder metastases.

Related: Kidney Cancer

Nishiyama N, Kitamura H, Hotta H, et al.
Construction of predictive models for cancer-specific survival of patients with non-muscle-invasive bladder cancer treated with bacillus Calmette-Guérin: results from a multicenter retrospective study.
Jpn J Clin Oncol. 2014; 44(11):1101-8 [PubMed] Related Publications
OBJECTIVE: The aims of this study were to clarify the prognostic factors and to validate the bacillus Calmette-Guérin failure classification advocated by Nieder et al. in patients with non-muscle-invasive bladder cancer who had intravesical recurrence after bacillus Calmette-Guérin therapy.
METHODS: Data from 402 patients who received intravesical bacillus Calmette-Guérin therapy between January 1990 and November 2011 were collected from 10 institutes. Among these patients, 187 with bacillus Calmette-Guérin failure were analyzed for this study.
RESULTS: Twenty-nine patients (15.5%) were diagnosed with progression at the first recurrence after bacillus Calmette-Guérin therapy. Eighteen (62.1%) of them died of bladder cancer. A total of 158 patients were diagnosed with non-muscle-invasive bladder cancer at the first recurrence after bacillus Calmette-Guérin therapy. Of them, 23 (14.6%) underwent radical cystectomy. No patients who underwent radical cystectomy died of bladder cancer during the follow-up. On multivariate analysis of the 135 patients with bladder preservation, the independent prognostic factors for cancer-specific survival were age (≥70 [P = 0.002]), tumor size (≥3 cm [P = 0.015]) and the Nieder classification (bacillus Calmette-Guérin refractory [P < 0.001]). In a subgroup analysis, the estimated 5-year cancer-specific survival rates in the groups with no positive, one positive and two to three positive factors were 100, 93.4 and 56.8%, respectively (P < 0.001).
CONCLUSIONS: Patients with stage progression at the first recurrence after bacillus Calmette-Guérin therapy had poor prognoses. Three prognostic factors for predicting survival were identified and used to categorize patients with non-muscle-invasive bladder cancer treated with bacillus Calmette-Guérin into three risk groups based on the number of prognostic factors in each one.

Paner GP, Cox RM, Richards K, et al.
Pseudoangiosarcomatous urothelial carcinoma of the urinary bladder.
Am J Surg Pathol. 2014; 38(9):1251-9 [PubMed] Related Publications
The pseudoangiosarcomatous pattern has been described mostly in cutaneous and some visceral squamous cell carcinomas and is unique for its striking morphologic resemblance to angiosarcoma. Herein, we describe the clinicopathologic features of 7 pseudoangiosarcomatous urothelial carcinomas that occurred in the urinary bladder. The patients included 6 men and 1 woman ranging in age from 47 to 87 years (median 70 y). The pseudoangiosarcomatous morphology was observed in 7 urothelial carcinomas including 3 with squamous differentiation and comprised 35% to 85% of the invasive tumor. Histologically, the pseudoangiosarcomatous carcinomas were characterized by tumor cell discohesion and lysis that created pseudolumina formations surrounded by attached residual tumor cells. Detached degenerating tumor cells variably admixed with inflammatory cells were common in the false lumina. Partly intact urothelial carcinoma nests contained irregular or cleft-like spaces and disintegrating tumor cells with stretched intercellular bridges. The tumor was commonly associated with a dense collagenous matrix, often surrounding the lytic nests. Similar tumor cell discohesion and breakdown were observed in 3 tumors with foci of squamous cell differentiation, distinguished by the presence of dyskeratosis and keratin formation. All 7 tumors contained other nonpseudoangiosarcomatous carcinoma components such as conventional urothelial carcinoma (5), squamous differentiation (4), sarcomatoid spindle cell carcinoma (2), small cell carcinoma (1), micropapillary carcinoma (1), and glandular differentiation (1). The pseudoangiosarcomatous urothelial carcinomas were all (7/7) diffusely CK7 positive, most (6/7) were GATA3 positive, and none (0/7) expressed vascular-associated markers. There was no evidence to suggest that apoptosis (by TUNEL assay and cleaved caspase-3 immunostaining) or loss of the adhesion molecules CD138 and e-cadherin were possible causes for the tumor cell discohesion and breakdown. All 7 tumors were high stage at cystectomy and included 1 pT3a, 2 pT3b, and 4 pT4a tumors, and 3 had pelvic lymph node involvement. Follow-up data available in 6 cases revealed a poor outcome with an overall median survival of 8.5 months. In conclusion, we present an unusual morphology of bladder carcinoma that has a striking resemblance to a malignant vasoformative tumor. Our series showed that bladder pseudoangiosarcomatous carcinoma morphology is associated with a higher tumor stage at cystectomy, commonly admixed with other aggressive carcinoma variant morphologies, and portend a poorer outcome. Knowledge of this pattern is also important to avoid misdiagnosis, particularly in limited tissue samples.

Zamora-Ros R, Sacerdote C, Ricceri F, et al.
Flavonoid and lignan intake in relation to bladder cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study.
Br J Cancer. 2014; 111(9):1870-80 [PubMed] Related Publications
BACKGROUND: There is growing evidence of the protective role of dietary intake of flavonoids and lignans on cancer, but the association with bladder cancer has not been thoroughly investigated in epidemiological studies. We evaluated the association between dietary intakes of total and subclasses of flavonoids and lignans and risk of bladder cancer and its main morphological type, urothelial cell carcinoma (UCC), within the European Prospective Investigation into Cancer and Nutrition (EPIC) study.
METHODS: A cohort of 477 312 men and women mostly aged 35-70 years, were recruited in 10 European countries. At baseline, dietary flavonoid and lignan intakes were estimated using centre-specific validated questionnaires and a food composition database based on the Phenol-Explorer, the UK Food Standards Agency and the US Department of Agriculture databases.
RESULTS: During an average of 11 years of follow-up, 1575 new cases of primary bladder cancer were identified, of which 1425 were UCC (classified into aggressive (n=430) and non-aggressive (n=413) UCC). No association was found between total flavonoid intake and bladder cancer risk. Among flavonoid subclasses, significant inverse associations with bladder cancer risk were found for intakes of flavonol (hazard ratio comparing fifth with first quintile (HRQ5-Q1) 0.74, 95% confidence interval (CI): 0.61-0.91; P-trend=0.009) and lignans (HRQ5-Q1 0.78, 95% CI: 0.62-0.96; P-trend=0.046). Similar results were observed for overall UCC and aggressive UCC, but not for non-aggressive UCC.
CONCLUSIONS: Our study suggests an inverse association between the dietary intakes of flavonols and lignans and risk of bladder cancer, particularly aggressive UCC.

Fang Y, Wang Y, Wang Y, et al.
A new tumour suppression mechanism by p27Kip1: EGFR down-regulation mediated by JNK/c-Jun pathway inhibition.
Biochem J. 2014; 463(3):383-92 [PubMed] Article available free on PMC after 10/10/2015 Related Publications
p27Kip1 is a potent inhibitor of cyclin-dependent kinases that drive G1-to-S cell-cycle transition. Reduced p27Kip1 expression is prevalent in a wide range of human tumours; however, the exact mechanism(s) of p27Kip1-mediated tumour suppression remains obscure. In the present study, we identified a close inverse relationship between p27Kip1 and EGFR (epidermal growth factor receptor) expression: the parental T24 human bladder cancer cells had high p27Kip1 expression but low EGFR expression and, in striking contrast, the metastatic derivative of T24 (T24T) had low p27Kip1 expression but high EGFR expression. This relationship was also found in various human cancer tissues, and was not only just correlative but also causal; depletion of p27Kip1 in MEF (mouse embryonic fibroblast) cells resulted in markedly elevated EGFR expression, a result reproducible with an Egfr promoter-luciferase reporter in both T24 and MEF cells, suggesting transcriptional repression of EGFR by p27Kip1. Indeed, p27Kip1 was found to regulate EGFR expression via the JNK (c-Jun N-terminal kinase)/c-Jun transcription factor: p27Kip1 deficiency activated JNK/c-Jun, whereas inhibition of JNK/c-Jun by dominant-negative mutants dramatically repressed Egfr transcription. Furthermore, the proximal promoter of the Egfr gene was crucial for its transcription, where the recruiting activity of c-Jun was much greater in p27Kip1-/- cells than in p27Kip1+/+ cells. Introduction of GFP-p27Kip1 into T24T cells suppressed JNK/c-Jun activation, EGFR expression and anchorage-independent growth. The results of the present study demonstrate that p27Kip1 suppresses JNK/c-Jun activation and EGFR expression in MEFs and human bladder cancer cells, and the results obtained are consistent with those from human cancer specimens. The present study provides new insights into p27Kip1 suppression of cancer cell growth, migration and metastasis.

Related: CDKN1B Lung Cancer Signal Transduction EGFR

Golabek T, Darewicz B, Kudelski J, et al.
Cadmium in urothelial carcinoma of the bladder.
Pol J Pathol. 2014; 65(1):55-9 [PubMed] Related Publications
The aim of this study was to examine the relationship between cadmium (Cd) and bladder cancer (urothelial carcinoma of the bladder). Cadmium concentrations in two 36-sample series of bladder cancer tissue and blood, from patients with the neoplasm, were matched with those of the control group. The amount of heavy metal in every tissue sample was determined using atomic absorption spectrometry. This was correlated with tumour stage. While the median cadmium concentration levels reached statistically lower values in the bladder cancer tissue, as compared with the non-cancer one (11.695 ng/g and 56.32 ng/g respectively, p < 0.001), the median Cd levels in the blood of the patients with this carcinoma showed no statistical difference when compared to those of the control group (8.237 μg/l and 7.556 μg/l respectively, p = 0.121). The median levels of cadmium in the bladder tissue, depending on the stage of the tumour, compared with the tissue without the neoplasm, observed the same relationship for both non-muscle invasive and muscle-invasive tumours (p < 0.002 and p < 0.02 respectively). This study has shown that patients with urothelial carcinoma of the bladder had lower tissue cadmium levels than people without tumour while no difference in the Cd blood levels between the two groups of patients under investigation was found.

Related: Transitional Cell Cancer of the Renal Pelvis and Ureter

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