Urothelial Carcinoma Of Urinary Bladder Research Articles

Annexin-I overexpression is associated with tumour progression and independently predicts inferior disease-specific and metastasis-free survival in urinary bladder urothelial carcinoma

In our previous studies, comparative proteomics and immunohistochemistry (IHC) demonstrated that annexin-I (ANXA1) is up-regulated in high grade urinary bladder urothelial carcinoma (UBUC) as compared to non-high grade carcinomas. However, the small sample size prohibited further correlation of ANXA1 expression to tumour progression. Therefore, in the present study, 81 primary localised UBUC specimens of various grades and primary tumour (pT) status were examined for ANXA1 expression to further confirm the proteomics data and to clarify the relevance of ANXA1 expression level to the prognosis of UBUC. IHC was implemented to investigate ANXA1 protein expression in 81 primary localised UBUC specimens. The association of ANXA1 expression with tumour progression and prognosis was analysed. Our data demonstrated that the ANXA1 expression level was strongly associated with an escalated pT status (p < 0.001) and a higher histological grade (p < 0.001), suggesting that ANXA1 might be related to tumour progression. Moreover, at the univariate level, ANXA1 overexpression, along with higher pT status and histological grade, significantly predicted disease-specific survival (DSS) and metastasis-free survival (MFS). More importantly, multivariate analyses revealed that the association of ANXA1 overexpression and prognosis remained significant for both DSS and MFS. The above results reinforced the comparative proteomics results and confirmed the prognostic role of ANXA1 in UBUC.

Ki-67, p53, bcl-2 and bax expression in urothelial carcinomas of urinary bladder

Ki-67, p53, bcl-2 and bax expression in urothelial carcinomas of urinary bladder

Osteoclast like Giant cell Urothelial Carcinoma of Urinary Bladder

Osteoclast like Giant cell Urothelial Carcinoma of Urinary Bladder

UP-3.038: Survivin: A Novel Target for Diagnosis of Urothelial Carcinoma of Bladder

Survivin has been studied as a potential apoptotic inhibitor and regulator of mitosis in several types of malignancies. The expression of this molecule in Indian bladder cancer patients has never been studied. We evaluated the expression of survivin in urinary and serum samples of patients with various grades and stages of urothelial carcinoma of urinary bladder.

Urine cytological findings of plasmacytoid urothelial carcinoma of urinary bladder: report of two cases

Urine cytological findings of plasmacytoid urothelial carcinoma of urinary bladder: report of two cases

Carcinoma urotelial de vejiga tipo nested. una variante histológica poco frecuente

The nested variant of urothelial carcinoma is a rare histological tumor of urinary bladder. The clinical symptoms are similar to those of the classic urothelial carcinomas. Its macroscopic appearance can be very subtle due to its preference for a submucosal growth leading to a possible delay in diagnosis. Microscopically, it is characterized by nests and tubules formation. While the neoplastic cells exhibit low-grade histological features, the growth pattern is widely infiltrative conferring this neoplasia a bad prognosis even if a radical treatment is performed.We present a case of a patient affected by a nested variant of urothelial carcinoma of urinary bladder to whom a radical cystoprostatectomy was performed and adjuvant chemotherapy was given. He is alive and free of disease one year after the diagnosis.

No Strong Association Between HER-2/neu Protein Overexpression and Gene Amplification in High-grade Invasive Urothelial Carcinomas

The generation of urothelial carcinoma is caused by the accumulation of various molecular changes, as in most malignancies. There are conflicting data about the status of HER-2/neu oncogene in urothelial carcinomas. The aim of this study was to determine the status of HER-2/neu oncogene in high-grade invasive urothelial carcinoma of urinary bladder both in protein and DNA level. We evaluated HER-2/neu protein overexpression by immunohistochemistry (IHC) and gene amplification by fluorescent in situ hybridization (FISH) and real-time quantitative PCR in paraffin-embedded samples of high-grade invasive urothelial carcinoma obtained from 36 patients. Polysomy 17 was also assessed by FISH. Immunohistochemically, HER-2/neu protein overexpression was observed in 22 (61.1%) tumors (ten tumors with score 3+ and 12 with score 2+). Fourteen of 36 tumors (38.9%) were evaluated as negative (score 0 or 1+). Complete concordance between FISH and the PCR was seen in all of the samples scored as 0 and 1+ by IHC. HER-2/neu gene amplification was observed in three of 27 (11.1%) tumors by FISH (nine samples were non-informative) and in eight of 36 (22.2%) tumors by the PCR. The complete concordance between HER2-2/neu protein overexpression and gene amplification was seen only in three of 27 tumors. Polysomy 17 was seen in nine tumors (33.3%). The results indicated that, in contrast to breast cancer, there was no strong association between HER-2/neu overexpression and gene amplification in invasive urothelial carcinomas, and polysomy 17 was higher in tumors showing HER-2/neu overexpression.

Overexpression of p27kip1 in urinary bladder urothelial carcinoma

Cyclins and cyclin-dependent kinase (CDK) complexes have important regulatory roles during cell cycle progression and can be used as prognostic markers in various kinds of malignant tumors. This study investigated the expression of proliferative cell nuclear antigen (PCNA), p53, Rb, p27(kip1), and cyclin D1 by immunostains in bladder tumors, especially urothelial papilloma, papillary urothelial neoplasm of low malignant potential, and low and high grade urothelial carcinoma, to see if their expression is associated with classification or grading of the urinary bladder urothelial carcinoma. Nuclear expression of PCNA, p53, Rb, p27(kip1), and cyclin D1 was determined immunohistochemically in a series of 89 urinary bladder tumor specimens, including 13 papilloma, 15 urothelial neoplasm of low malignant potential, 17 low grade urothelial carcinoma, and 44 high grade urothelial carcinoma. The results of immunoreactivity were analyzed with respect to the associations with tumor grade. Eighty-two percent (38/45) of the p27(kip1) positive tumors were urothelial carcinoma, and the percentage of the p27(kip1) positivity was higher with increasing grade of the urothelial carcinoma (P = 0.011). A tendency of higher percentage of positive p53 immunoreactivity was noted in the urothelial carcinoma (P = 0.053). There was no significant difference in cyclinD1, Rb and PCNA expression between benign, low malignant potential and urothelial carcinoma. We first noted an overexpression of p27(kip1) in urinary bladder urothelial carcinoma. The result indicates that some urothelial carcinomas may tolerate this inhibitor of cell cycle progression.

Microcystic urothelial carcinoma of the urinary bladder metastatic to the penis

Metastatic spread of primary bladder cancer to the penis is an extremely rare event. Microcystic urothelial carcinoma is a very rare variant of urothelial carcinoma. Due to its rareness and insufficient clinical follow-up data, the prognosis of microcystic urothelial carcinoma is still not clear. Here in we report a case of a penile metastasis from microcystic urothelial carcinoma of urinary bladder, in a 56-year-old man who died 6 months after radical cystoprostatectomy and total penectomy. To the best of our knowledge this is the first case report of microcystic variant of urothelial carcinoma which has metastasized to the penis.

Dermatomyositis in a patient with high grade papillary urothelial carcinoma of urinary bladder

Inflammatory myopathies like dermatomyositis are associated with increased incidence of malignancies. This association has been commonly reported with malignancies of ovaries, gastro-intestinal tract, breast and non-Hodgkin's lymphomas but occurrence of dermatomyositis with bladder cancer has been rarely reported. We report a patient with carcinoma bladder who developed dermatomyositis while being treated for the bladder cancer.

Behavior of Urothelial Carcinoma With Respect to Anatomical Location

Urothelial carcinoma is a disease of the entire urothelium. Recent molecular insights suggest that the biology of some upper urinary tract and bladder urothelial carcinoma differ. These differences may affect tumor phenotype. Observational studies conflict as to the significance of anatomical location on the behavior of urothelial carcinoma. We compared the biological outcome in a large series of urothelial carcinoma with respect to anatomical location. We analyzed urothelial carcinoma in 425 patients treated at 4 centers according to stage and anatomical location, including the bladder in 275, the ureter in 67 and the renal pelvis in 79. Relapse surveillance was performed for a median of 46 months (range 2 to 216). A separate invasive bladder urothelial carcinoma population was also included to pathologically balance upper and lower tract urothelial carcinoma cases to allow behavioral comparisons. As a whole, upper urinary tract urothelial carcinoma is more invasive and worse differentiated than bladder cancer (chi-square test p<0.0001 and 0.015, respectively). In pathologically matched cohorts recurrence to less aggressive disease, progression to more advanced disease and death occurred in 37%, 40% and 44% of patients with bladder urothelial carcinoma, and in 41%, 44% and 43% of those with upper urinary tract urothelial carcinoma, respectively. Multivariate analysis revealed that tumor stage and grade (Cox p=0.0001 and 0.012, respectively) but not location were associated with behavior. Urothelial carcinoma behaves identically in the upper and lower urinary tracts when stage and grade are considered. The majority of tumors relapse within 5 years of excision. The current move to minimally invasive/nephron sparing techniques for urothelial carcinoma of the upper urinary tract appears safe. Care could be analogous to that for bladder urothelial carcinoma.

Detection of urinary bladder cancer with flow cytometry and hexaminolevulinate in urine samples

Urinary bladder urothelial carcinoma is diagnosed by a combination of cystoscopy and biopsy, with cytology as a valuable additional technique. The accuracy of cytological diagnosis depends on the experience of the cytologist and can inevitably vary from one cytologist to another. There is a need for an easy, reliable and objective diagnostic method. In the present study a new method was designed for the detection of bladder cancer cells in urine. Flow cytometry was utilized to detect protoporphyrin IX in an artificial model consisting of normal urinary bladder transitional epithelial cells (NBECs) from healthy volunteers' urine and an established human urinary bladder carcinoma cell line, TCCSUP, after incubation with hexaminolevulinate (HAL). In addition, urine samples from 19 patients with histopathologically confirmed superficial bladder cancer were examined. Incubation of NBECs or TCCSUP cells with HAL for 1 hour resulted in production of protoporphyrin IX only in the TCCSUP cells. Incubation of a mixture of NBECs and TCCSUP cells with HAL gave rise to a separated subpopulation of cells with protoporphyrin IX fluorescence. After cell sorting by flow cytometry the protoporphyrin IX-containing subpopulation of cells was confirmed as TCCSUP cells on cytological examination. It was possible to detect 5% TCCSUP cells in the mixture of NBECs/TCCSUP cells. To test the feasibility of the method in clinica diagnosis, urine samples from patients with bladder cancer were also measured with comparable, although preliminary and limited, results to those of cytological examination. The preliminary results show that the technique may be feasible for the detection of bladder cancer cells in urine with possible advantages of simplicity, reliability and objectivity.

MP-12.01: Immunohistochemical demonstration of the gamma-2 chain of laminin-5 in urinary bladder urothelial carcinoma- impact for diagnosis and prognosis

MP-12.01: Immunohistochemical demonstration of the gamma-2 chain of laminin-5 in urinary bladder urothelial carcinoma- impact for diagnosis and prognosis

Survivin nuclear labeling index: a superior biomarker in superficial urothelial carcinoma of human urinary bladder

The caspase family proteases are key proapoptotic proteins while the inhibitor of apoptosis proteins (IAP) prevent apoptosis by antagonizing the caspases or other key proapoptotic proteins. Limited studies of IAPs suggested their deregulation contributed to urothelial neoplasia. However, the expression status and biologic or prognostic significance of the caspase and IAP family proteins in urothelial neoplasms is not clear. In the present study, we first systematically evaluated the expression profile of the major apoptosis regulators, including caspases (CASP3, 6, 7, 8, 9, 10, and 14), IAPs (survivin/BIRC5, CIAP1, CIAP2, XIAP, and LIVIN), APAF1, SMAC, and BCL2, as well as proliferation markers Ki67 and PHH3, in Ta/T1 human urinary bladder urothelial carcinomas and normal urothelium samples by immunohistochemistry. The analysis showed that survivin/BIRC5 nuclear labeling index (BIRC5-N), but not cytoplasmic staining, was the only apoptotic marker which correlated significantly with tumor grade, stage, and patient outcome. We further analyzed the prognostic value of BIRC5-N in 101 Ta/T1 urinary bladder urothelial carcinomas by univariate analysis, which showed that BIRC5-N as well as the more classical prognosticators (stage, grade, and Ki67 index) were of prognostic significance. However, multivariate analysis by Cox proportional hazard regression demonstrated BIRC5-N was a stronger prognosticator than tumor grade, stage, and Ki67 labeling index. BIRC5-N index of 8% or more predicted unfavorable disease-specific survival (relative risk (RR)=6.6, 95% confidence interval=1.6–26.7, P=0.0080) as well as progression-free survival (RR=4.4, 95% confidence interval=1.3–14.6, P=0.0151). We conclude that BIRC5-N is a superior biologic and prognostic marker for Ta/T1 urothelial carcinomas of urinary bladder.

Combined modality therapy (transurethral surgery, induction chemotherapy, followed by concurrent chemoradiotherapy) for bladder preservation for patients with muscle invasive bladder cancer: Preliminary report

4792 Background: Muscle-invasive urinary bladder urothelial carcinoma (UC) is traditionally treated with radical cystectomy. The combination of transurethral resection of the tumor (TURB), systemic chemo, & XRT may be as effective as radical cystectomy & thus allow the bladder to be preserved. We sought to incorporate our previously reported P-HDFL (Proc ASCO 20:344b, 2001; abstr 3128) or TP-HDFL (Proc ASCO 22:407b, 2003; abstr 1637) regimen into this multi-modality treatment approach. Methods: Between Sept 2002 & March 2004, we enrolled 20 patients (M:F = 15:5, median age 66, range 45 - 80) with muscle-invasive bladder cancer (stage T2–4NXM0, bladder:urethra = 18:2) in a trial of TURB, combination chemo & XRT (64.8 cGy using shrinkage-field technique) w/ concurrent chemo (CCRT). 11 patients underwent protocol A: Chemo w/ P-HDFL regimen (cisplatin 35 mg/m2, IV 24hr D 1, 8; 5FU 2,000 mg/m2 + leucovorin 300 mg/m2 IV 24hr D 1, 8, 15; q28d) for 3 cycles & concurrent PF regimen (cisplatin 25 mg/m2 IV 1hr; 5FU 425 mg/m2 IV 1hr weekly). 9 patients underwent protocol B: Chemo w/ TP-HDFL regimen (paclitaxel 70 mg/m2, IV 1hr D 1, 8; cisplatin 35 mg/m2 IV 24hr D 2, 9; 5-FU 2,000 mg/m2 + leucovorin 300 mg/m2 IV 24hr D 2, 9; q21d) for 3 cycles & concurrent TP regimen (paclitaxel 60 mg/m2 IV 1hr; cisplatin 25 mg/m2, IV 1hr weekly). Interval cystoscopy was employed after completion of combination chemo & when XRT achieved 40 cGy. Patients with < CR were referred for salvage cystectomy. Results: Up to April 2004, 14 patients had completed & 6 were still under the protocol treatment. All 6 patients who had CR after protocol treatment had functioning tumor-free bladder, 1 patient died of neutropenic sepsis during CCRT. Of the 7 patients did not have CR after protocol treatment, 5 underwent salvage cystectomy, & 2 who declined cystectomy subsequently died of distant mets 4 & 12 mo later. Conclusions: Sequential use of TURB, cisplatin/5FU-based combination chemotherapy, & cisplatin-based CCRT is feasible & may be considered a reasonable alternative in patients who are medically unfit for cystectomy or seeking an alternative to radical cystectomy. No significant financial relationships to disclose.

Overexpression of laminin-5 γ2 chain and its prognostic significance in urothelial carcinoma of urinary bladder: association with expression of cyclooxygenase 2, epidermal growth factor, and human epidermal growth factor 2

Laminin-5 (LN-5) and cyclooxygenase 2 (COX-2) play important roles in many kinds of cancers. Recently, it has been reported that epidermal growth factor receptor [corrected] (EGFR) and/or human epidermal growth factor receptor [corrected] 2 (HER2) expressions are associated with LN-5 and/or COX-2 expressions in a few carcinoma cell lines and human tumor tissue. LN-5, COX-2, EGFR, and HER2 expressions were examined immunohistochemically in 67 patients with urothelial carcinomas (UCs), and associations among these 4 biomarkers and clinicopathologic characteristics were investigated. Patients were classified into transurethral resection group and cystectomy group based on clinical end points, and prognostic significances of increased expressions were evaluated. Overexpression of LN-5, COX-2, EGFR, and HER2 was observed in 16 (23.9%), 34 (50.7%), 42 (62.7%), and 15 (22.4%) of 67 patients, respectively. LN-5 overexpression was associated high-grade (P = .002), invasive (pTa+1 versus pT2-4, P = .011), and nonpapillary (P = .027) UCs. Concerning EGFR and HER2, high-grade (EGFR, P = .0009; HER2, P = .003) and nonpapillary (EGFR, P = .016; HER2, P = .0002) UCs had a significantly higher overexpression rate. UCs penetrating basal membrane (pT1-4) showed significantly higher overexpression rates than pTa UCs on all biomarkers. In transurethral resection group, LN-5 overexpression could be proved as an independent prognostic parameter for intravesical recurrence (P = .007), whereas in cystectomy group, nodal involvement was an independent prognostic parameter for cause-specific survival (P = .025). The current study showed that the 4 biomarkers were associated with aggressive behaviors of UCs. Above all, LN-5 overexpression was considered to play an important role in intravesical recurrence of superficial UCs.

Molecular Genetic Evidence for a Common Clonal Origin of Urinary Bladder Small Cell Carcinoma and Coexisting Urothelial Carcinoma

In most cases, small-cell carcinoma of the urinary bladder is admixed with other histological types of bladder carcinoma. To understand the pathogenetic relationship between the two tumor types, we analyzed histologically distinct tumor cell populations from the same patient for loss of heterozygosity (LOH) and X chromosome inactivation (in female patients). We examined five polymorphic microsatellite markers located on chromosome 3p25-26 (D3S3050), chromosome 9p21 (IFNA and D9S171), chromosome 9q32-33 (D9S177), and chromosome 17p13 (TP53) in 20 patients with small-cell carcinoma of the urinary bladder and concurrent urothelial carcinoma. DNA samples were prepared from formalin-fixed, paraffin-embedded tissue sections using laser-assisted microdissection. A nearly identical pattern of allelic loss was observed in the two tumor types in all cases, with an overall frequency of allelic loss of 90% (18 of 20 cases). Three patients showed different allelic loss patterns in the two tumor types at a single locus; however, the LOH patterns at the remaining loci were identical. Similarly, the same pattern of nonrandom X chromosome inactivation was present in both carcinoma components in the four cases analyzed. Concordant genetic alterations and X chromosome inactivation between small-cell carcinoma and coexisting urothelial carcinoma suggest that both tumor components originate from the same cells in the urothelium.

463The diagnostic and prognostic value of immunhisto chemical demonstration of the gamma2 chain of laminin-5 in urinary bladder urothelial carcinoma

463The diagnostic and prognostic value of immunhisto chemical demonstration of the gamma2 chain of laminin-5 in urinary bladder urothelial carcinoma

Immunohistochemistry in diagnostic surgical pathology of the prostate

Immunohistochemistry (IHC) can play an important role in diagnostic surgical pathology of the prostate. Basal cell markers, such as the 34betaE12 antibody and antibodies directed against cytokeratin 5 and 6 or p63, are very useful for demonstration of basal cells as their presence argues against a diagnosis of invasive prostatic carcinoma (PC). However, several benign mimickers of PC, including atrophy, atypical adenomatous hyperplasia (AAH), nephrogenic adenoma, and mesonephric hyperplasia, can stain negatively with these markers, and thus, a negative basal cell marker immunostain alone does not exclude a diagnosis of benignancy. Although there are examples in the literature of high grade PC that stain focally with some of the basal cell markers, these cases are usually readily diagnosed based on H&E appearances and are unlikely to be confused with these benign mimickers. Alpha-methylacyl-coenzyme-A racemase (AMACR) is a sensitive marker of PC (except for a few uncommon variants: atrophic, foamy gland, and pseudohyperplastic variants), and its detection by immunohistochemical staining in atypical prostatic lesions can be very useful in confirming an impression of adenocarcinoma. AMACR expression can also be identified in high grade prostatic intraepithelial neoplasia (PIN), prostatic atrophy, AAH, and benign prostatic glands, and accordingly, a diagnosis of PC should not be based solely on a positive AMACR immunostain, especially when the luminal staining is weak and/or noncircumferential. The use of AMACR/basal cell antibody cocktails has been found to greatly facilitate the distinction between PC and its benign mimickers, especially when only limited tissue is available for staining. Prostate specific antigen (PSA) and prostate specific acid phosphatase (PSAP) are both quite sensitive and fairly specific markers of PC (there are a few nonprostatic tumors that can express one or both), and are both very helpful in establishing or confirming the diagnosis of PC when the differential diagnosis includes other tumors that can involve the prostate such as urinary bladder urothelial carcinoma. 34betaE12, p63, thrombomodulin, and uroplakin III are additional urothelial associated markers useful in this differential diagnosis. CDX2 and villin are useful markers to diagnostically separate colonic adenocarcinoma from PC. AMACR positivity and negative basal cell marker reactions are useful to confirm the presence of residual PC after hormonal or radiation therapy. Pan-cytokeratin, PSA, and PSAP can also highlight subtle infiltrates of PC with hormonal or radiation therapy effect. PSA and PSAP immunohistochemical stains are valuable in confirming metastatic carcinoma as being of prostatic origin and should always be utilized in the diagnostic evaluation of metastatic adenocarcinoma of unknown primary origin in males.

734: Immunhistochemical Demonstration of the γ 2 (Gamma 2) Chain of Laminin-5 in Urinary Bladder Urothelial Carcinoma - Impact for Diagnosis and Prognosis

734: Immunhistochemical Demonstration of the γ 2 (Gamma 2) Chain of Laminin-5 in Urinary Bladder Urothelial Carcinoma - Impact for Diagnosis and Prognosis