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).

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.

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.

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.

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

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.

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

Yen HK, Fauzi AR, Din LB, et al.
Involvement of Seladin-1 in goniothalamin-induced apoptosis in urinary bladder cancer cells.
BMC Complement Altern Med. 2014; 14:295 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Selective Alzheimer Disease Indicator-1 (or Seladin-1) is a multifunctional protein first discovered by downregulation of its expression in Alzheimer's disease. Interestingly, the expression of this protein is upregulated in several cancers, including primary bladder cancer. However, its role in cancer formation has yet to be discovered. Goniothalamin is a natural product that has been demonstrated to induce apoptosis in various cancer cell lines. In this study, we have elucidated the role of Seladin-1 in goniothalamin-induced cytotoxicity towards human urinary bladder cancer cell line RT4.
METHODS: The cytotoxicity of goniothalamin in human urinary bladder cancer cell line RT4 was assessed using MTT assay and the mode of cell death was determined by Annexin V-FITC/PI labeling assay. Finally, the expression of Seladin-1 protein in goniothalamin-treated RT4 cells was determined by Western blot.
RESULTS: MTT assay showed that the cytotoxicity of goniothalamin on RT4 cells was concentration and time dependent with IC50 values of 61 μM (24 hr), 38 μM (48 hr) and 31 μM for 72 hr, respectively. Cell death induced was confirmed through apoptosis; as assessed using the Annexin V-FITC/PI labeling assay. Furthermore, the involvement of Seladin-1 in goniothalamin-induced apoptosis was evidenced through the cleavage of 60 kDa protein to 40 kDa and 20 kDa. This was followed by a gradual increase of 20 kDa fragment suggesting the involvement of Seladin-1 in goniothalamin-induced apoptosis on RT4 cells.
CONCLUSION: This study demonstrates that goniothalamin induce cytotoxicity and apoptosis on RT4 cells. The involvement of Seladin-1 in goniothalamin-induced apoptosis further suggested that Seladin-1 may play a role in the formation of primary bladder cancer.

Related: Apoptosis

Hemdan T, Lindén M, Lind SB, et al.
The prognostic value and therapeutic target role of stathmin-1 in urinary bladder cancer.
Br J Cancer. 2014; 111(6):1180-7 [PubMed] Related Publications
BACKGROUND: The oncoprotein-18/stathmin 1 (STMN1), involved in cell progression and migration, is associated with clinical outcome in breast cancer. Here we aim to investigate its clinical significance in urinary bladder cancer and its possibilities as a therapeutic target.
METHODS: Immunohistochemical analyses of STMN1 protein expression were performed in three patient cohorts: cohort I (n=115 Ta, n=115 T1, n=112 T2-4 stages), cohort II, based on randomised controlled trials (n=239 T1-T4), and cohort III of primary tumour/matched metastasis (n=90 T1-T4). The effects of STMN1 on cell proliferation and migration were evaluated in the urinary bladder cancer cell line, T24, by inhibiting STMN1-cellular expression using siRNA.
RESULTS: In cohort I, high STMN1 expression correlated to shorter disease-specific survival hazard ratio (HR)=2.04 (95% confidence interval (CI) 1.13-3.68; P=0.02), elevated p53- (P<0.001) and Ki67-protein levels (P<0.001). The survival result was validated in cohort II: HR=1.76 (95% CI 1.04-2.99; P=0.03). In the metastatic bladder cancer material, 70% of the patients were STMN1-positive in both the primary tumour and matched metastases. In vitro, the growth and migration of the T24 cells were significantly reduced (P<0.01, P<0.0001, respectively), when transfecting the cells with STMN1-siRNA.
CONCLUSIONS: STMN1 protein expression has prognostic significance but is primarily a potential treatment target in urinary bladder cancer.

Related: MKI67 TP53

Reese AC, Ball MW, Gandhi N, et al.
The utility of an extensive postchemotherapy staging evaluation in patients receiving neoadjuvant chemotherapy for bladder cancer.
Urology. 2014; 84(2):358-63 [PubMed] Related Publications
OBJECTIVE: To assess the utility of an extensive restaging examination performed after the completion of neoadjuvant chemotherapy (NAC) but before radical cystectomy (RC) in the management of patients with advanced bladder cancer.
METHODS: We studied 62 patients who underwent NAC with the intent of proceeding to consolidative RC. A restaging examination, including endoscopic and bimanual examination, as well as cross-sectional imaging of the abdomen and pelvis, was performed after chemotherapy. The impact of restaging on clinical management was determined. In patients proceeding to RC, the degree of correlation between clinical stage (at diagnosis vs on restaging) and pathologic stage was determined.
RESULTS: Restaging altered the treatment course in 6 patients (9.7%) in whom RC was not performed because of restaging findings. An additional 56 patients (90.3%) proceeded to RC. In these patients, compared with clinical stage at diagnosis, the postchemotherapy clinical stage correlated more strongly with pathologic stage (κ = 0.02 vs 0.17). On multivariate analysis, diagnostic clinical stage was not associated with pathologic stage (P = .85), whereas postchemotherapy clinical stage was strongly predictive of pathologic stage (P <.01).
CONCLUSION: An extensive restaging examination altered treatment strategy in a small, but clinically significant subset of patients treated with NAC for bladder cancer. Furthermore, restaging allowed for more accurate prediction of pathologic stage after RC, thereby improving assessment of patient prognosis. Consideration should be given to incorporating a restaging evaluation into the standard management paradigm for bladder cancer.

Raman SP, Fishman EK
Bladder malignancies on CT: the underrated role of CT in diagnosis.
AJR Am J Roentgenol. 2014; 203(2):347-54 [PubMed] Related Publications
OBJECTIVE: The purpose of this article is to review the utility of CT in diagnosing bladder malignancies, CT protocol options that may improve the conspicuity of bladder tumors, suggestive imaging features, and potential mimics.
CONCLUSION: Although evaluation of the bladder has traditionally been considered purely the realm of cystoscopy, many bladder tumors can be identified with CT. However, diagnosis requires optimization of CT technique and close attention to a number of potentially subtle findings.

Ku JH, Kim M, Jeong CW, et al.
Risk prediction models of locoregional failure after radical cystectomy for urothelial carcinoma: external validation in a cohort of korean patients.
Int J Radiat Oncol Biol Phys. 2014; 89(5):1032-7 [PubMed] Related Publications
PURPOSE: To evaluate the predictive accuracy and general applicability of the locoregional failure model in a different cohort of patients treated with radical cystectomy.
METHODS AND MATERIALS: A total of 398 patients were included in the analysis. Death and isolated distant metastasis were considered competing events, and patients without any events were censored at the time of last follow-up. The model included the 3 variables pT classification, the number of lymph nodes identified, and margin status, as follows: low risk (≤pT2), intermediate risk (≥pT3 with ≥10 nodes removed and negative margins), and high risk (≥pT3 with <10 nodes removed or positive margins).
RESULTS: The bootstrap-corrected concordance index of the model 5 years after radical cystectomy was 66.2%. When the risk stratification was applied to the validation cohort, the 5-year locoregional failure estimates were 8.3%, 21.2%, and 46.3% for the low-risk, intermediate-risk, and high-risk groups, respectively. The risk of locoregional failure differed significantly between the low-risk and intermediate-risk groups (subhazard ratio [SHR], 2.63; 95% confidence interval [CI], 1.35-5.11; P<.001) and between the low-risk and high-risk groups (SHR, 4.28; 95% CI, 2.17-8.45; P<.001). Although decision curves were appropriately affected by the incidence of the competing risk, decisions about the value of the models are not likely to be affected because the model remains of value over a wide range of threshold probabilities.
CONCLUSIONS: The model is not completely accurate, but it demonstrates a modest level of discrimination, adequate calibration, and meaningful net benefit gain for prediction of locoregional failure after radical cystectomy.

Amin MB, Trpkov K, Lopez-Beltran A, et al.
Best practices recommendations in the application of immunohistochemistry in the bladder lesions: report from the International Society of Urologic Pathology consensus conference.
Am J Surg Pathol. 2014; 38(8):e20-34 [PubMed] Related Publications
The bladder working group of the 2013 International Society of Urologic Pathology (ISUP) Conference on Best Practices Recommendation in the Application of Immunohistochemistry (IHC) in Urologic Pathology discussed 5 settings in which IHC is commonly used in clinical practice. With regard to markers for urothelial differentiation, the committee found that there is no ideal marker or established panel to confirm urothelial differentiation. On the basis of the differential diagnostic consideration, positivity for GATA3, CK20, p63, and either high-molecular weight cytokeratin (HMWCK) or cytokeratin (CK)5/6 is of value in proving urothelial differentiation in the appropriate morphologic and clinical context. With regard to the role of IHC in the distinction of reactive atypia from urothelial carcinoma in situ, the committee recommended that morphology remains the gold standard in this differential diagnosis and that, at best, the IHC panel of CK20/p53/CD44(s) has potential utility but is variably used and has limitations. The immunostaining pattern must be interpreted with strict morphologic correlation, because overreliance on IHC may be misleading, particularly in the posttreatment setting. IHC has no role in the distinction of dysplasia versus carcinoma in situ and in the grading of papillary urothelial carcinoma. IHC may have a limited but distinct role in staging of bladder cancer. In a subset of cases, depending on the clinical and histologic context, broad-spectrum cytokeratins (to identify early or obscured invasion) and desmin (distinction of muscle from desmoplasia and to highlight muscle contours for subclassification) may be helpful. Limited experience and conflicting data preclude smoothelin or vimentin to be recommended routinely for subclassifying muscle type at this time. In the workup of a spindled cell proliferation of the bladder and in limited specimens, we recommend an immunohistochemical panel of 6 markers including ALK1, SMA, desmin, cytokeratin (AE1/AE3), and p63 with either of HMWCK or CK5/6. Currently, there are no prognostic immunohistochemical or molecular studies that are recommended to be routinely performed on biopsy or resection specimens.

Related: Transitional Cell Cancer of the Renal Pelvis and Ureter

Amin MB, Smith SC, Eble JN, et al.
Glandular neoplasms of the urachus: a report of 55 cases emphasizing mucinous cystic tumors with proposed classification.
Am J Surg Pathol. 2014; 38(8):1033-45 [PubMed] Related Publications
Published experience remains limited for glandular neoplasms of the urachus, especially mucinous cystic tumors. We reviewed 55 glandular urachal neoplasms to evaluate their clinical features and histopathologic spectrum and to devise a classification system for the mucinous cystic forms. Within the 55 cases studied, we observed 2 groups with differing clinical, gross, and histopathologic features. The first group, invasive, noncystic adenocarcinomas (n=24), had clinicopathologic features in accord with the known spectrum of urachal adenocarcinoma (mean age 50 y, female:male ratio 1.7, with recurrence or death from disease in 9/16 cases over a 45 mo mean follow-up). The second group, mucinous cystic tumors (n=31), morphologically resembled mucinous cystic tumors of the ovary and appeared classifiable by the same approach (mean age 47 y, female:male ratio 1.4) and included mucinous cystadenoma (n=4), mucinous cystic tumor of low malignant potential (n=22, including 2 cases with intraepithelial carcinoma), and mucinous cystadenocarcinoma with microscopic (n=4) or frank invasion (n=1). Follow-up information was available for 13 patients with mucinous cystic tumors (mean 41 mo); we observed no local recurrence or distant metastasis. This experience suggests that there is a distinct group of glandular, cystic tumors of the urachus that is classifiable in a manner similar to ovarian neoplasms and that has a favorable prognosis after complete excision. As with cystic neoplasms of other organs, rigorous sampling is recommended to identify potentially small foci of carcinoma that could be missed by inadequate sampling. Accordingly, classification based on methods other than complete surgical excision may be hazardous.

Mohanty SK, Smith SC, Chang E, et al.
Evaluation of contemporary prostate and urothelial lineage biomarkers in a consecutive cohort of poorly differentiated bladder neck carcinomas.
Am J Clin Pathol. 2014; 142(2):173-83 [PubMed] Related Publications
OBJECTIVES: New immunohistochemical (IHC) markers of urothelial carcinoma (UCa) and prostatic adenocarcinoma (PCa) have emerged in recent years, yet comparative studies to establish markers remain lacking. We aimed to identify an effective but parsimonious approach for poorly differentiated bladder neck lesions, to establish a best practice panel approach in a setting simulating prospective use.
METHODS: We tested the performance of a panel of IHC markers on whole sections of a consecutive cohort of transurethral resection specimens of poorly differentiated, challenging bladder neck resections (n=36).
RESULTS: In the setting of poorly differentiated bladder neck carcinomas, biomarker sensitivities for UCa were as follows: GATA3, 100%; S100P, 88%; p63, 75%; and cytokeratin (CK) 5/6, 56%; specificities of each were 100%. CK7 and CK20 showed sensitivities of 75% and 63%, though these were only 85% and 80% specific. For PCa markers, NKX3.1, p501S, prostate-specific membrane antigen, and androgen receptor (AR) each showed 100% sensitivity, outperforming ERG (35%) and prostate-specific antigen (PSA; 25%). All the prostate histogenesis markers were 100% specific, except for AR, which was positive in 13% of the UCa cases.
CONCLUSIONS: Novel IHC markers show improved diagnostic performance that enables positive and negative support for identifying histogenesis with the use of as few as two markers for this critical therapeutic distinction. PSA underperforms newer markers.

Ishiguro H, Kawahara T, Zheng Y, et al.
Reduced glucocorticoid receptor expression predicts bladder tumor recurrence and progression.
Am J Clin Pathol. 2014; 142(2):157-64 [PubMed] Related Publications
OBJECTIVES: To assess the levels of glucocorticoid receptor (GR) expression in bladder tumors because the status and its prognostic value remain largely unknown.
METHODS: We immunohistochemically stained for GR in bladder tumor and matched non-neoplastic bladder tissue specimens.
RESULTS: Overall, GR was positive in 129 (87%) of 149 urothelial tumors, which was significantly (P=.026) lower than in non-neoplastic urothelium (90 [96%] of 94). Forty-two (79%) of 53 low-grade tumors vs 45 (47%) of 96 high-grade carcinomas (P<.001) and 61 (73%) of 84 non-muscle-invasive (NMI) tumors vs 26 (40%) of 65 muscle-invasive (MI) carcinomas (P<.001) were moderately to strongly immunoreactive for GR. Kaplan-Meier and log-rank tests revealed that loss or weak positivity of GR significantly or marginally correlated with recurrence of NMI tumors (P=.025), progression of MI tumors (P=.082), and cancer-specific survival of MI tumors (P=.067). Multivariate analysis identified low GR expression as a strong predictor for recurrence of NMI tumors (P=.034).
CONCLUSIONS: GR expression was downregulated in bladder tumors compared with nonneoplastic bladder tumors and in high-grade/MI tumors compared with low-grade/NMI tumors. Decreased expression of GR, as an independent prognosticator, predicted recurrence of NMI tumors. These results support experimental evidence suggesting an inhibitory role of GR signals in bladder cancer outgrowth.

Ye P, Mimura J, Okada T, et al.
Nrf2- and ATF4-dependent upregulation of xCT modulates the sensitivity of T24 bladder carcinoma cells to proteasome inhibition.
Mol Cell Biol. 2014; 34(18):3421-34 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
The ubiquitin-proteasome pathway degrades ubiquitinated proteins to remove damaged or misfolded protein and thus plays an important role in the maintenance of many important cellular processes. Because the pathway is also crucial for tumor cell growth and survival, proteasome inhibition by specific inhibitors exhibits potent antitumor effects in many cancer cells. xCT, a subunit of the cystine antiporter system xc (-), plays an important role in cellular cysteine and glutathione homeostasis. Several recent reports have revealed that xCT is involved in cancer cell survival; however, it was unknown whether xCT affects the cytotoxic effects of proteasome inhibitors. In this study, we found that two stress-inducible transcription factors, Nrf2 and ATF4, were upregulated by proteasome inhibition and cooperatively enhance human xCT gene expression upon proteasome inhibition. In addition, we demonstrated that the knockdown of xCT by small interfering RNA (siRNA) or pharmacological inhibition of xCT by sulfasalazine (SASP) or (S)-4-carboxyphenylglycine (CPG) significantly increased the sensitivity of T24 cells to proteasome inhibition. These results suggest that the simultaneous inhibition of both the proteasome and xCT could have therapeutic benefits in the treatment of bladder tumors.

Related: Bortezomib

Zhu Z, Xu T, Wang L, et al.
MicroRNA-145 directly targets the insulin-like growth factor receptor I in human bladder cancer cells.
FEBS Lett. 2014; 588(17):3180-5 [PubMed] Related Publications
The insulin-like growth factor receptor I (IGF-IR) is a proto-oncogene with potent mitogenic and antiapoptotic activities. It has been reported that expression of IGF-IR is up-regulated in bladder cancer. Here, we assessed whether microRNA-145 (miR-145) regulates IGF-IR expression in bladder cancer. In our study, miR-145 was shown to directly target IGF-IR 3'-untranslated region (UTR) in human bladder cancer cells. Small interfering RNA (siRNA)- and miR-145-mediated IGF-IR knockdown experiments revealed that miR-145 promotes cell apoptosis, and suppresses cell proliferation and migration through suppression of IGF-IR expression. Taken together, our data suggest that miR-145 may inhibit bladder cancer initiation by affecting IGF-IR signaling.

Related: Apoptosis IGF1R

Inoguchi S, Seki N, Chiyomaru T, et al.
Tumour-suppressive microRNA-24-1 inhibits cancer cell proliferation through targeting FOXM1 in bladder cancer.
FEBS Lett. 2014; 588(17):3170-9 [PubMed] Related Publications
Here, we found that microRNA-24-1 (miR-24-1) is significantly reduced in bladder cancer (BC) tissues, suggesting that it functions as a tumour suppressor. Restoration of mature miR-24-1 inhibits cancer cell proliferation and induces apoptosis. Forkhead box protein M1 (FOXM1) is a direct target gene of miR-24-1, as shown by genome-wide gene expression analysis and luciferase reporter assay. Overexpressed FOXM1 is confirmed in BC clinical specimens, and silencing of FOXM1 induces apoptosis in cancer cell lines. Our data demonstrate that the miR-24-1-FOXM1 axis contributes to cancer cell proliferation in BC, and elucidation of downstream signalling will provide new insights into the molecular mechanisms of BC oncogenesis.

Related: FOXM1

Batsi O, Giannopoulou I, Nesseris I, et al.
Immunohistochemical evaluation of CXCL12-CXCR4 axis and VEGFR3 expression in primary urothelial cancer and its recurrence.
Anticancer Res. 2014; 34(7):3537-42 [PubMed] Related Publications
AIM: The aim of this study was to investigate the expression of CXC chemokine ligand-12 (CXCL12), CXC chemokine receptor 4 CXCR4 and of vascular endothelial growth factor receptor 3 (VEGFR3) in primary urothelial bladder carcinoma and their recurrence in relation to grade and pT status.
MATERIALS AND METHODS: Immunohistochemistry was applied to 67 primary tumor (PC) sections and their recurrenct tumors (RC).
RESULTS: The expression of CXCL12 both in PC and in RC was positively associated with tumor grade (p<0.0001 and p<0.0001, respectively) and pT stage (p=0.001 and p=0.007, respectively). The expression of CXCR4 in both PC and RC was also positively related to grade (p=0.001 and p<0.0001, respectively) and pT stage (p=0.008 and p=0.005, respectively). We compared the expression of CXCL12 and CXCR4 in PC related to RC and found that both were more intense in RC than in PC (p<0.0001 and p<0.0001, respectively). In PC and in RC there was no association between the expression of VEGFR3 with tumor grade and pT stage.
CONCLUSION: CXCL12 and CXCR4 expression was related to adverse prognostic markers in urothelial bladder carcinoma through their association with grade and pT stage both in PC and RC. The CXCL12-CXCR4 axis may influence the expression of VEGFR3 in urothelial bladder carcinoma and promote tumor recurrence.

Jian W, Levitt JM, Lerner SP, Sonpavde G
The preclinical activity of lenalidomide in indolent urothelial carcinoma.
Anticancer Res. 2014; 34(7):3383-9 [PubMed] Related Publications
BACKGROUND: Lenalidomide is an IMiD® immunomodulatory drug, which may warrant evaluation in urothelial carcinoma (UC).
MATERIALS AND METHODS: The in vitro and in vivo activity of lenalidomide was evaluated in human and murine UC cell lines. Tumors were evaluated by immunohistochemistry for (CD31), cleaved caspase-3 (CC3) and CD3+/CD20+ lymphocyte infiltration. Cereblon, a molecular target of lenalidomide was analyzed by immunohistochemistry.
RESULTS: Significant pro-apoptotic activity, and reduction of cell viability was seen at low micromolar concentrations of lenalidomide against indolent human RT4 UC cells in vitro. Cereblon expression was quantitatively lower in sensitive RT4 cells compared to resistant 5637 cells. In RT4 xenografts, lenalidomide significantly reduced tumor size and CD31 expression, and increased expression of CC3 (p<0.05). Cereblon expression increased in lenalidomide-treated RT4 xenografts (p<0.05).
CONCLUSION: Lenalidomide demonstrated preclinical activity against superficially-invasive low-grade UC cells attributable to direct tumor cell apoptosis and anti-angiogenic activity. Clinical trials are warranted in patients with indolent UC.

Related: Angiogenesis Inhibitors Apoptosis Angiogenesis and Cancer Thalidomide Lenalidomide

Hoang LL, Tacha DE, Qi W, et al.
A newly developed uroplakin II antibody with increased sensitivity in urothelial carcinoma of the bladder.
Arch Pathol Lab Med. 2014; 138(7):943-9 [PubMed] Related Publications
CONTEXT: Uroplakin II is a 15-kDa protein component of the urothelial plaques that enhance the permeability barrier and strength of the urothelium. Studies have shown uroplakin II messenger RNA to be expressed in bladder cancer tissues and peripheral blood of patients with urothelial carcinoma. Little is known about the protein expression of uroplakin II in urothelial carcinoma, possibly because of the absence of a commercially available uroplakin II antibody. Pathologists have used the uroplakin III antibody (AU1) to identify tumors of urothelial origin; however, the use of AU1 is limited because of its poor sensitivity.
OBJECTIVES: To evaluate a newly developed mouse monoclonal uroplakin II antibody (BC21) in urothelial carcinoma and to compare it with previously developed mouse monoclonal uroplakin III (BC17 and AU1).
DESIGN: Uroplakin II and III antibodies were optimized for staining using a horseradish peroxidase-polymer detection system and were visualized with 3,3'-diaminobenzidine.
RESULTS: BC21, BC17, and AU1 demonstrated sensitivities in urothelial carcinoma of the bladder of 79% (44 of 56), 55% (31 of 56) (P = .002), and 34% (19 of 56) (P < .001), respectively. Subsequently, the increased staining sensitivity and intensity of BC21, compared with BC17, was validated in a larger study (134 of 174; 77% and 94 of 174; 54%, respectively) (P < .001). BC21 was found to be highly specific when evaluated in various normal and neoplastic tissues, including prostatic and renal carcinomas.
CONCLUSIONS: The mouse monoclonal uroplakin II antibody (BC21) demonstrated superior sensitivity and specificity in urothelial carcinoma, compared with uroplakin III (BC17 and AU1), suggesting its advantages in the differential diagnosis of urothelial carcinoma and in the detection of tumors of unknown origin.

Related: Transitional Cell Cancer of the Renal Pelvis and Ureter

Hamm R, Chen YR, Seo EJ, et al.
Induction of cholesterol biosynthesis by archazolid B in T24 bladder cancer cells.
Biochem Pharmacol. 2014; 91(1):18-30 [PubMed] Related Publications
BACKGROUND: Resistance of cancer cells towards chemotherapeutics represents a major cause of therapy failure. The objective of our study was to evaluate cellular defense strategies in response to the novel vacuolar H(+)-ATPase inhibitor, archazolid B.
EXPERIMENTAL APPROACH: The effects of archazolid B on T24 bladder carcinoma cells were investigated by combining "omics" technologies (transcriptomics (mRNA and miRNA) and proteomics). Free cholesterol distribution was determined by filipin staining using flow cytometry and fluorescence microscopy. Flow cytometry was performed for LDLR surface expression studies. Uptake of LDL cholesterol was visualized by confocal microscopy. SREBP activation was determined performing Western Blotting. The efficiency of archazolid B/fluvastatin combination was tested by cytotoxicity assays.
RESULTS: Archazolid B led to accumulation of free cholesterol within intracellular compartments and drastic disturbances in cholesterol homeostasis resulting in activation of SREBP-2 (sterol regulatory element-binding protein 2) and up-regulation of target genes including HMGCR (HMG-CoA reductase), the key enzyme of cholesterol biosynthesis. LDLR surface expression was reduced and LDL uptake was completely inhibited after 24h, indicating newly synthesized cholesterol to be the main source of cholesterol in archazolid B treated cells. By combining archazolid B with the HMGCR inhibitor fluvastatin, cholesterol was reduced and cell viability decreased by about 20% compared to archazolid B treatment alone.
CONCLUSIONS: Our study revealed cholesterol biosynthesis as an important resistance mechanism in T24 cells after archazolid B treatment. The combination of archazolid B with statins may be an attractive strategy to potentiate archazolid B induced cell killing by affecting cholesterol biosynthesis.

Feng Y, Kang Y, He Y, et al.
microRNA-99a acts as a tumor suppressor and is down-regulated in bladder cancer.
BMC Urol. 2014; 14:50 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
BACKGROUND: Increasing evidences have documented that microRNAs (miRNAs) act as oncogenes or tumor suppressors in a variety types of cancer. The discovery of tumor associated miRNAs in serum of patients gives rise to extensive investigation of circulating miRNAs in many human cancers which support the use of plasma/serum miRNAs as noninvasive means of cancer detection. However, the aberrant expression of miRNAs and the circulating miRNAs in bladder cancer are less reported.
METHODS: We used Taqman probe stem-loop real-time PCR to accurately measure the levels of miR-99a in bladder cancer cell lines, 100 pairs of bladder cancer tissues, the adjacent non-neoplastic tissues and plasma collected from bladder cancer patients or control patients. miR-99a mimics were re-introduced into bladder cancer cells to investigate its role on regulating cell proliferation which was measured by CCK-8 assay and cell cycle analysis.
RESULTS: miR-99a was significantly down-regulated in bladder cancer tissues, and even the lower expression of miR-99a was correlative with the more aggressive phenotypes of bladder cancer. Meanwhile, enforced expression of miR-99a can inhibit the cell proliferation of bladder cancer cells. Furthermore, investigation of the expression of miR-99a in plasma of bladder cancer patients showed that miR-99a was also decreased in plasma of bladder cancer patients. The results strongly supported miR-99a as the potential diagnostic marker of bladder cancer.
CONCLUSIONS: Our data indicated that miR-99a might act as a tumor suppressor in bladder cancer and was significantly down-regulated in development of bladder cancer.

Hunter BA, Eustace A, Irlam JJ, et al.
Expression of hypoxia-inducible factor-1α predicts benefit from hypoxia modification in invasive bladder cancer.
Br J Cancer. 2014; 111(3):437-43 [PubMed] Article available free on PMC after 29/07/2015 Related Publications
BACKGROUND: The addition of carbogen and nicotinamide (CON) to radiotherapy (RT) improves overall survival in invasive bladder cancer. We explored whether expression of the hypoxia marker hypoxia-inducible factor-1α (HIF-1α) alone or in combination with other markers predicted benefit from CON.
METHODS: A retrospective study was carried out using material from patients with high-grade invasive bladder carcinoma enrolled in the BCON phase III trial of RT alone or with CON (RT+CON). HIF-1α expression was studied in 137 tumours using tissue microarrays and immunohistochemistry. Data were available from other studies for carbonic anhydrase IX and glucose transporter 1 protein and gene expression and tumour necrosis.
RESULTS: Patients with high HIF-1α expression had improved 5-year local relapse-free survival with RT+CON (47%) compared with RT alone (21%; hazard ratio (HR) 0.48, 95% CI 0.26-0.8, P=0.02), no benefit was seen with low HIF-1α expression (HR 0.81, 95% CI 0.43-1.50, P=0.5). Combinations of markers including necrosis also predicted benefit but did not improve on prediction using necrosis alone.
CONCLUSIONS: HIF-1α may be used to predict benefit from CON in patients with bladder cancer but does not improve on use of necrosis.

Related: Transitional Cell Cancer of the Renal Pelvis and Ureter HIF1A

Clark BZ, Beriwal S, Dabbs DJ, Bhargava R
Semiquantitative GATA-3 immunoreactivity in breast, bladder, gynecologic tract, and other cytokeratin 7-positive carcinomas.
Am J Clin Pathol. 2014; 142(1):64-71 [PubMed] Related Publications
OBJECTIVES: To evaluate GATA-3 immunohistochemical expression semiquantitatively in breast, gynecologic, gastric, pancreatic-biliary tract, urothelial, and vulvar/cervical squamous cell carcinomas.
METHODS: GATA-3 expression was evaluated by immunohistochemistry in 198 invasive breast carcinomas on tissue microarrays. Tissue microarrays of other tissues included 144 gynecologic tumors, 28 bladder carcinomas, 63 cholangiocarcinomas, 20 pancreatic carcinomas, and 62 gastric carcinomas. Full tissue sections of 10 invasive squamous cell carcinomas were also stained. GATA-3 expression was semiquantitatively scored using an H-score method. H-score greater than 10 was considered a positive result.
RESULTS: Of 186 breast carcinomas, 95% were positive (mean H-score of 217). GATA-3 expression was uncommon in 139 nonsquamous gynecologic tumors, with often weak reactivity (mean H-score <50) seen in 18% of endocervical, 7% of endometrial, and 10% of ovarian tumors. Six (60%) of 10 squamous cell carcinomas expressed GATA-3 (mean H-score of 102). Of 22 urothelial carcinomas, 95% expressed GATA-3 (mean H-score of 170). A few cholangiocarcinomas (3%), pancreatic adenocarcinomas (10%), and gastric carcinomas (2%) weakly expressed GATA-3 (mean H-score <50).
CONCLUSIONS: Strong GATA-3 expression is a reliable marker of primary breast carcinoma in the appropriate clinical context. GATA-3 reactivity in around 70% of triple-negative breast carcinomas is also clinically useful. Significant reactivity in gynecologic squamous cell carcinomas suggests that GATA-3 alone cannot reliably distinguish these tumors from urothelial carcinoma.

Related: Breast Cancer GATA3 gene Gynacological Cancers

Bezerra SM, Lotan TL, Faraj SF, et al.
GATA3 expression in small cell carcinoma of bladder and prostate and its potential role in determining primary tumor origin.
Hum Pathol. 2014; 45(8):1682-7 [PubMed] Related Publications
GATA3 is a sensitive marker for urothelial carcinoma. We here evaluate, for the first time, GATA3 expression in small cell carcinoma of bladder and prostate and assess its utility in the differential diagnosis with small cell carcinoma of lung primary. Archival tissues from 60 small cell carcinomas (12 bladder, 15 lung, and 33 prostate primary cases) were used to build 2 tissue microarrays. We also assessed whole slide sections from 10 additional primary small cell carcinomas of bladder. GATA3 nuclear expression was evaluated using standard immunohistochemistry. Intensity (weak, moderate, and strong) and extent of expression were assessed in each tissue microarray spot. Extent positivity was categorized as focal (1%-25%), multifocal (>25%), and diffuse (>75%). Nuclear GATA3 expression was encountered in 7 bladder (7/22, 32%) and 2 lung (2/15, 13%) small cell carcinomas. All 33 primary prostate small cell carcinomas were negative. Among bladder tumors, strong and diffuse (>75%) GATA3 labeling was seen in 3 cases (3/22, 14%); focal positivity was observed in the 4 remaining cases (4/22, 18%). Both positive lung cases had only focal positivity. Our study is the first to reveal GATA3 expression in the small subset of lung small cell carcinoma that should be taken into consideration in assigning site of origin in advanced small cell carcinoma cases. Our novel finding of GATA3 positivity in one-third of bladder small cell carcinoma is of potential value in differentiating small cell carcinomas of prostate origin from those of bladder origin.

Related: GATA3 gene Lung Cancer Prostate Cancer

Moschini M, Suardi N, Pellucchi F, et al.
Impact of preoperative thrombocytosis on pathological outcomes and survival in patients treated with radical cystectomy for bladder carcinoma.
Anticancer Res. 2014; 34(6):3225-30 [PubMed] Related Publications
AIM: To investigate the impact of preoperative platelet count on pathological findings at the time of Radical Cystectomy for Bladder Cancer and postoperative cancer-specific and overall survival.
PATIENTS AND METHODS: A total of 906 consecutive patients treated with Radical Cystectomy for Bladder Cancer between 1995 and 2012 at a tertiary referral Center were included in the study. Thrombocytosis was defined as >400,000 platelets/μl, in agreement with the standard assumed by the central laboratory of our Institution. Univariable and multivariable logistic regression analyses were used to investigate the impact of preoperative platelet count on pathological stage. Univariate and multivariate Cox regression analyses were also adopted to predict both cancer-specific and overall survival.
RESULTS: The mean age at cystectomy was 67.25 years. The mean and median platelet counts were 242,100/μl and 227,500/μl. At a mean follow-up time of 41 months, the 2- and 5-year cancer-specific and overall survival were found to be 83.1% and 75.2% and 68.3 and 59.8%, respectively. At Univariable analysis, thrombocytosis count was significantly associated with adverse pathological disease stage (p ≤ 0.007) and lymph node invasion (p=0.05). Platelet count was significantly associated to patient survival at univariable analysis (Hazard Ratio=1.76 and 1.39 for overall survival and cancer specific survival, respectively; all p<0.05). At multivariate Cox regression analysis, platelet count was documented to be significantly related only to overall survival (Hazard Ratio=64,1.03-2.81; p=0.05).
CONCLUSION: Preoperative platelet count should be taken into account as a factor predictive of postoperative oncological outcomes after radical cystectomy for bladder cancer and patients should be counseled accordingly.

Related: Transitional Cell Cancer of the Renal Pelvis and Ureter

Mian C, Comploj E, Resnyak E, et al.
Long-term follow-up of intermediate-risk non-muscle invasive bladder cancer sub-classified by multi-coloured FISH.
Anticancer Res. 2014; 34(6):3067-71 [PubMed] Related Publications
AIM: To examine the long-term follow-up of patients with that previously underwent risk stratification based on multicolour FISH testing.
PATIENTS AND METHODS: On 81 patients with intermediate-risk urothelial carcinoma, a multicolour-FISH was performed. Patients were sub-divided into low- and high-risk groups based on chromosomal patterns. Univariate analysis, using Mantel-Cox log-rank test for disease-free, progression-free survival and overall survival, was employed to determine the prognostic significance of FISH analysis. Survival times were calculated according to the Kaplan-Meier product-limit method and multivariate analysis using Cox proportional hazards regression model.
RESULTS: The univariate Mantel-Cox log-rank test showed significant differences between the low-risk and the high-risk group for disease-free survival (p=0.005) and overall survival (p=0.038), but not for progression-free survival (p=0.129).
CONCLUSION: Our long-term follow-up data appear to be able to divide tumors into low and high risk groups for recurrence based on molecular/genetic changes observed with FISH.

Related: FISH

Li JR, Cheng CL, Yang WJ, et al.
FIP-gts potentiate autophagic cell death against cisplatin-resistant urothelial cancer cells.
Anticancer Res. 2014; 34(6):2973-83 [PubMed] Related Publications
BACKGROUND: Urothelial cancer (UC) is a common cancer among males. Once metastatic or chemoresistant diseases develop, there is little effective treatment available. A fungal immunomodulatory protein, ganoderma tsugae (FIP-gts) possesses antitumor activity against solid tumors and inhibits telomerase activity. FIP-gts induces autophagy in cancer cells and may provide an alternative pathway against chemo-resistance.
MATERIALS AND METHODS: Two UC cell lines were used to investigate the cytotoxicity effects and the autophagy regulation of FIP-gts using flow cytometry, acidic vesicular organelles (AVO) staining and western blotting.
RESULTS: MTT assay showed that FIP-gts and bafilomycin-A1 (Baf-A1) and or chloroquine (CQ) could enhance a significantly synergistic cytotoxicity. The treatment of UC cell lines with FIP-gts activated LC-3 II formation and AVO positive staining on western blot and flow cytometry. Interestingly, FIP-gts and Baf-A1 combined treatment was found to lead to enhancement of apoptosis along with inhibition of autophagy in parental and resistant UC cells.
CONCLUSION: FIP-gts may have the potential to be utilized as a therapeutic adjuvant for the treatment of resistant UC cancer down-regulating Beclin-1 to activate autophagic cell death.

Related: Apoptosis Cisplatin

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