Cases Of Bladder Urothelial Carcinoma Research Articles

TROP-2, NECTIN-4 and predictive biomarkers in sarcomatoid and rhabdoid bladder urothelial carcinoma.

The surface protein TROP-2/TACSTD2 and the cell adhesion protein NECTIN-4/NECTIN4 are responsible for the efficacy of anticancer therapies based on antibody-drug conjugates (ADC) targeting intracellular microtubules. In contrast with common histologic subtypes of bladder urothelial carcinoma (BUC), little is known of TROP-2 and NECTIN-4 expression in sarcomatoid and rhabdoid BUC. In this study, we aimed to analyze TROP-2 and NECTIN-4 expression and additional predictive biomarkers by immunohistochemistry and fluorescence in situ hybridization (FISH) on 35 undifferentiated BUC (28 sarcomatoid and 7 rhabdoid). Wide genomic investigation was also performed on 411 BUC cases of the PanCancer Atlas, focusing on genes related to the microtubule pathways. Seven of 35 (20%) undifferentiated BUC showed expression of TROP-2. NECTIN-4 was expressed in 10 cases (29%). Seven cases (20%) co-expressed TROP-2 and NECTIN-4. HER-2 FISH was amplified in 5 cases (14%) while HER-2 immunoexpression was observed in 14 cases (40%). PD-L1 scored positive for combined proportion score (CPS) in 66% of cases and for tumor proportion score (TPS) in 51% of cases. Pan-NTRK1-2/3 was elevated in 9 cases (26%) and FGFR-2/3 was broken in 7 of 35 cases (20%). Of 28 sarcomatoid BUC, 9 (32%) were negative for all (TROP-2, NECTIN-4, PD-L1, HER-2, FGFR and pan-NTRK) biomarkers and 3 (11%) expressed all five biomarkers. Among cases with rhabdoid dedifferentiation, 1 of 7 (14%) showed activation of all biomarkers, whereas 2 of 7 (28%) showed none. The mRNA analysis identified microtubule-related genes and pathways suitable for combined ADC treatments in BUC. Sarcomatoid and rhabdoid BUC do harbor positive expression of the ADC targets TROP-2 or NECTIN-4 in a relatively modest subset of cases, whereas the majority do not. Different combinations of other positive biomarkers may help the choice of medical therapies. Overall, these findings have important clinical implications for targeted therapy for BUC.

HER2/neu expression status of post BCG recurrent non-muscle-invasive bladder urothelial carcinomas in relation to their primary ones.

Transurethral resection (TUR) followed by adjuvant therapy is still the treatment of choice of Non-Muscle-Invasive Bladder Urothelial Carcinoma (NMIBUC). However, recurrence is one of the most troublesome features of these lesions. Early second resection and adjuvant BCG therapy has been shown to improve the outcome. To evaluate the prognostic value of C-erbB-2 (HER2/neu) expression status in Non-Muscle-Invasive Bladder Urothelial Carcinoma cases, before and after intravesical Bacillus Calmette Guerin (BCG immunotherapy). HER2/neu expression was studied in 120 (Ta-T1) Non-Muscle-Invasive Urothelial Carcinoma cases. The expression was evaluated and compared to the expression after Bacillus Calmette Guerin (BCG) immunotherapy. HER2/neu expression in low and high grade of the Non- Muscle-Invasive Urothelial Carcinoma was (38%) and (83%) respectively. The difference of the expression rates by tumor grade was statistically significant. In recurring lesions post BCG therapy, C-erbB-2 expression was markedly decreased (31.6%) when compared to its expression before therapy (65%). The HER2/neu expression increased as the tumor grade rose. The reduction in expression following BCG treatment in Non-Invasive transitional cell carcinoma cases could reflect a reduction of the potential malignancy of the tumor.

Prognostic value of programmed cell death ligand-1 expression in patients with bladder urothelial carcinoma undergoing radical cystectomy: A meta-analysis.

BackgroundRadical cystectomy and removal of pelvic lymph nodes (RC-PLND) is a recommended treatment for high-risk non-muscle-invasive and muscle-invasive non-metastatic bladder cancer (BC). However, 50% of patients relapse after RC-PLND. This study aimed to evaluate the effect of programmed cell death ligand-1 (PD-L1) on the prognosis of bladder urothelial carcinoma (BUC) after RC-PLND.MethodsWe present this meta-analysis according to the Preferred Reporting Items for Systematic Review and Meta-Analyses Guidelines. The main outcomes were overall survival (OS), recurrence-free survival (RFS), and cancer-specific survival (CSS) of 3 and 5 years after RC-PLND.ResultsOverall, 11 studies and 1393 BUC cases were included in our meta-analysis. In tumor cells (TCs), the PD-L1 negative group had statistically significant advantage in 5-year OS (risk ratio [RR]: 0.85, 95% confidence interval [CI]: 0.74–0.97, P = 0.02), RFS (RR: 0.76, 95% CI: 0.58–0.99, P = 0.04), and CSS (RR: 0.73, 95% CI: 0.58–0.92, P = 0.009) compared with the PD-L1 positive group. But, no statistically significant difference in 5-year OS and RFS was observed between the PD-L1 negative and positive groups in tumor-infiltrating immune cells.ConclusionsOur study found that patients with BUC who tested positive for PD-L1 in TCs had a poor prognosis after RC-PLND. PD-1 or PD-L1 inhibitors could be used as a adjuvant medication for patients with BUC after RC-PLND who exhibit PD-L1 overexpression in TCs.Systematic review registration https://www.crd.york.ac.uk/prospero/, identifier CRD42022301424.

Hypomethylation of CLDN4 Gene Promoter Is Associated with Malignant Phenotype in Urinary Bladder Cancer.

The tight junction (TJ) protein claudin-4 (CLDN4) is overexpressed in bladder urothelial carcinoma (BUC) and correlates with cancer progression. However, the mechanism of CLDN4 upregulation and promotion of malignant phenotype is not clear. Here, we analyzed 157 cases of BUC and investigated the hypomethylation of CpG island in the CLDN4 promoter DNA and its correlation with cancer progression. In hypomethylated cases, CLDN4 expression, cell proliferation, stemness, and epithelial-mesenchymal transition were increased. Treatment of three human BUC cell lines with the demethylating agent aza-2′-deoxycytidine (AZA) led to excessive CLDN4 expression, and, specifically, to an increase in CLDN4 monomer that is not integrated into the TJ. The TJ-unintegrated CLDN4 was found to bind integrin β1 and increase stemness, drug resistance, and metastatic ability of the cells as well as show an anti-apoptosis effect likely via FAK phosphorylation, which reduces upon knockdown of CLDN4. Thus, CLDN4 is overexpressed in BUC by an epigenetic mechanism and the high expression enhances the malignant phenotype of BUC via increased levels of TJ-unintegrated CLDN4. CLDN4 promoter DNA methylation is expected to be a novel indicator of BUC malignant phenotype and a new therapeutic target.

Evaluation of prolyl-4-hydroxylase subunit beta and special AT-rich region-binding protein-1 immunoexpression in bladder transitional-cell carcinoma

Background Prolyl-4-hydroxylase subunit beta (P4HB) and special AT-rich region-binding protein-1 (SATB1) have been implicated in tumorigenesis and progression in many cancers, but their significance in bladder urothelial carcinoma remains to be elucidated. This study aimed to investigate the correlation and prognostic value of P4HB and SATB1 expression along with clinicopathological features in bladder transitional-cell carcinoma. Patients and methods This is a retrospective, selected, controlled study carried on 50 cases of bladder urothelial carcinoma to detect the expression of P4HB and SATB1 immunohistochemistry and statistical correlation with various clinicopathological parameters, including molecular subtypes. Results Prolyl-4-hydroxylase subunit beta (P4HP) is highly expressed in 48% of the study cases. P4HP expression was significantly associated with size of the tumor (P=0.002), muscle invasion (P=0.000), the grade of tumor (P=0.000), and the depth of invasion of the primary tumor (T) (P=0.000). High SATB1 expression was detected in 46% of the study cases. A significant association was detected between SATB1 expression and molecular subtypes (P=0.001), size of the tumor (P=0.004), histopathological type (P=0.024), muscle invasion (P=0.000), the grade of tumor (P=0.000), and the depth of invasion of the primary tumor (T) (P=0.000). Receiver operating characteristic curve was carried on for P4HP and SATB1 in relation to molecular classification and showed that SATB-1 has the highest sensitivity (75%) and specificity (70%) in discrimination between luminal versus nonluminal subtypes with significant relation (P=0.01). There was significant association between P4HP and SATB1 expression in bladder urothelial transitional-cell carcinoma (P=0.000). Conclusion This study highlighted important information about the link between P4HB and SATB1 pathways during the progression of urinary bladder transitional-cell carcinoma. P4HB and SATB1 could be used as a prognostic marker in cases in urinary bladder transitional-cell carcinoma.

Differential lysophosphatidylcholine acyltransferase 1 (LPCAT1) expression confers aggressiveness and independently predicts recurrence in bladder urothelial carcinomas

ABSTRACT Bladder urothelial carcinomas are diverse in terms of biological behavior and this reflects the underlying complex metabolic and molecular pathways. Novel biomarkers that could assist in the management and outcome prediction of bladder urothelial carcinomas are eagerly needed. Recently, overexpression of lysophosphatidylcholine acyltransferase 1 (LPCAT1), a key enzyme in lipid metabolism, has been implicated in the evolvement of several tumors. In this study, LPCAT1 immunohistochemical expression was evaluated and statistically analyzed in 60 bladder urothelial carcinomas in relation to other clinicopathological parameters including the patient outcome. Twenty non-neoplastic bladder tissues served as a control group. Cases were followed up for a mean period of 9 months. LPCAT1 was expressed in all bladder urothelial carcinoma cases with two distinct patterns designated as high and low nuclear expression. Low LPCAT1 nuclear expression was detected in urothelial carcinoma cases as compared to the control group. Similarly, low nuclear expression of LPCAT1 was associated with high grade and invasive tumors and could independently predict tumor recurrence and short survival. In conclusion, LPCAT1 downregulation might be involved in bladder urothelial carcinoma tumorigenesis and could contribute to tumor aggressive phenotype. Retained LPCAT1 expression is an independent predictor of tumor recurrence and it represents a promising prognostic marker for patients’ risk stratification.

Stratification of urothelial bladder carcinoma depending on immunohistochemical expression of GATA3 and CK5/6

ABSTRACT Bladder urothelial carcinoma (BUC) has two pathways with distinct molecular features and prognosis, non-muscle invasive (NMI) and muscle invasive (MI) tumors. The aim is to investigate the expression of GATA3 and CK5/6 in BUC with correlation to clinicopathologic parameters, including their impact on survival beside their potential use to stratify cases into prognostic subgroups. This study included 80 cases of BUC stained immunohistochemically by GATA3 and CK5/6. The cases were divided into four groups regarding expression status of both markers (luminal, basal, mixed, and null). GATA3 percentage of expression decreased in urothelial carcinoma with squamous differentiation, MI tumors, high-grade tumors, tumors with involved lymph nodes, presence of perineural invasion, presence of bilharziasis, presence of lympho-vascular invasion, and high mitotic count. CK5/6 positivity was higher in urothelial carcinoma cases with squamous differentiation, MI tumors, and presence of perineural invasion. Pure urothelial carcinoma and NMI were in favor of luminal group (GATA3 +ve/CK5/6 −ve). Univariate analysis showed that the presence of bilharziasis was associated with shorter PFS (p = .04). GATA3 and CK5/6 could be used for the stratification of urothelial bladder carcinoma into subtypes with different characteristics. Luminal bladder cancer represents the most common type (60%) that carries favorable features. Bilharziasis-associated urothelial carcinoma carries poor outcome manifested by short PFS.

Evaluation of HER2/neu and SPINK1 as an adjunct to the prognosis of urothelial dysplasia and urothelial carcinoma of the urinary bladder

Background: Urinary bladder carcinoma is one of the most common malignancies worldwide. Urothelial carcinoma (UC) is the commonest type of bladder cancer and comprises 90% of all bladder primary tumors. Urothelial dysplasia (UD) points to urothelial instability and is a sign for tumor progression or recurrence, developing into UC in 5–19% of cases. Thus, the identification of valuable markers can be useful for assessing tumor progression and response to targeted therapies. Aim: This study aimed to assess the immunohistochemical expression of HER2/neu and SPINK1 in UD and UC, and their relation to available clinicopathological parameters. Materials and methods: This study was carried out on 30 cases of UD; and 30 cases of UC. Immunohistochemistry was performed using HER2/neu and SPINK1 primary antibodies Results: HER2 expression was positive in 3 cases of carcinoma in situ (CIS) (out of 30 cases of UD) and 17 out of 30 UC cases. SPINK1 showed positive expression in 2 CIS cases and 19 UC cases. There was a statistically significant difference in HER2 and SPINK1 expression between UD and UC. HER2 and SPINK1 expression increased significantly with the increased tumor size, grade and pathologic stage. Only HER2 expression was significantly associated with tumor recurrence. Conclusions: HER2 overexpression is closely associated with aggressive tumors. HER2 can be a valuable predictive indicator for UC prognosis selecting patients who are likely to benefit from anti HER2 targeted therapy. High SPINK1 expression also correlated with features of biologically aggressive bladder UC cases but did not have independent prognostic value.

Correlation between immunohistochemical expression of Ki-67and P63 and aggressiveness of urinary bladder urothelial carcinoma

ABSTRACT Urothelial carcinoma is the most common urinary malignancy with a wide proportion of cancer morbidity and mortality. The aim of the present study is to evaluate Ki-67 and p63 immunoexpression and their correlation with grade and stage of bladder urothelial carcinoma. Fifty cases of bladder urothelial carcinoma were investigated and were submitted to immunohistochemical staining for p63 and Ki-67, which were assessed qualitatively and quantitatively. A high percentage of p63 immunoexpression showed a significant association with low-grade tumors (P < .05), while Ki-67 mean percentage of expression was higher in high-grade tumors, advanced stage and multiple tumors compared to low grade, early-stage and single tumors without statistical association. Furthermore, the mean percentage of p63 was higher in urothelial carcinoma with squamous differentiation compared to pure urothelial carcinoma with an absence of statistical significance. P63 could help in the identification of bladder tumors with squamous differentiation since identifying these cases is important regarding prognostic and therapeutic aspects. Ki 67 seems to be associated with features of bladder tumor progression as multiplicity, high grade and advanced stage.

Androgen receptor expression in the urinary bladder urothelial carcinoma and its relation to known prognostic factors

Objective: The current study was carried out to assess the prognostic value of androgen receptor expression in urothelial carcinoma of the bladder and correlate it to the disease outcome.Methods: Histologically confirmed cases of bladder urothelial carcinoma were studied. Clinical, pathological, and radiological data were collected. Paraffin embedded tissue sections were submitted for hematoxylin and eosin staining, as well as immunohistochemical staining for androgen receptor in tumor cells.Results: Nuclear androgen receptor expression was positive in 75% of the studied histopathological specimens. Additionally, a significant positive association between androgen receptor expression and tumor grade, muscle invasion &amp; tumor size were noticed.Conclusions: There is a significant association between large tumor size, high grade, deep invasion, and expression of Androgen receptor in urothelial bladder carcinoma. Antiandrogen could be an effective chemo preventive or therapeutic approach in treatment of urothelial bladder carcinoma.

The expression and clinical analysis of insulin-like growth factor 2 in bladder cancer

Objective To investigate the expression and clinical significance of IGF2 and its role in the development of bladder cancer. Methods The overall-survival time of patients with different expression level of IGF2 was analyzed by the cancer gene information database(The Cancer Genome Atlas, TCGA) .The expression level of IGF2 in 63 cases of bladder urothelial carcinoma and 17 cases of normal tissue were derected by the immunohistochemical staining.The relationship between IGF2 expression level and clinical factors was analyzed. Results The overall-survival time of patients with high-expression IGF2 was significantly lower than that of low-expression IGF2 patients(P=0.049). The expression level of IGF2 in bladder cancer tissues was significantly higher than that in the normal tissues (P<0.01). In the muscle invasive bladder cancer(T2-T4), the expression level of IGF2 was significantly higher than the non-muscle invasive bladder cancer(Ta-T1). Besides, the expression level of IGF2 in high-grade bladder cancer was also significantly higher than that of low-grade bladder cancer, there was statistically significant(P<0.05). Conclusions The expression level of IGF2 in bladder cancer is negatively related to the overall-survival time, and it's closely associated with the progression of bladder cancer, IGF2 may be an important protein molecule for the target therapy and prognosis of bladder cancer. Key words: Urinary Bladder Neoplasms; Insulin-Like Growth Factor II

Expression and clinical significance of costimulatory molecule B7-H4 and programmed death ligand 1 in bladder cancer

Objective To detect the expression of costimulatory molecules B7-H4 and programmed death ligand 1(PD-L1) in bladder cancer, and to explore the correlation between them and clinicopathological features of bladder cancer. Methods Immunohistochemical staining was used to detect the expression of B7-H4 and PD-L1 in 98 cases of bladder urothelial carcinoma, which were confirmed by pathology from August 2014 to December 2015 in our hospital. There were 23 females, aged 45-82 years, with an average age of 67.8 years. Among them, 42 cases of adjacent normal tissues were used as controls. The clinical stage, histological grade and recurrence of bladder cancer were collected, and the correlation between them was analyzed. Results The positive rates of B7-H4 and PD-L1 in bladder urothelial carcinoma were 54.1% (53/98) and 59.2% (58/98), respectively, and there was no expression in normal bladder tissues (P<0.05). The positive expression rate of B7-H4 in muscle invasive bladder cancer (MIBC) patients was higher than that in non-muscle invasive bladder cancer (NMIBC) [73.5% (25/34) vs. 43.8% (28/64), P=0.005]. The positive expression rate of B7-H4 in high-grade patients was higher than that of low-grade [70.0%(21/30) vs. 47.1%(32/68), P=0.036]. The expression rate of B7-H4 in high-risk group was higher than that of low-intermediate risk group [ 57.1%(20/35) vs. 27.6%(8/29), P=0.018]. The positive expression rate of PD-L1 in patients with MIBC was higher than that in NMIBC [79.4% (27/34) vs. 48.4% (31/64), P=0.003]. The PD-L1 expression rate of histological high-level group was higher than that of low-level group [ 73.3% (22/30) vs. 52.9% (36/68)], but the difference was not statistically significant (P=0.058). The PD-L1 expression rate in high-risk group was 68.6% (24/35), and also higher than low-middle group 24.1% (7/29) (P<0.05). There was a positive correlation between the expression of B7-H4 and PD-L1 in bladder urothelial carcinoma (r=0.318, P=0.002). The combined recurrence rate of the two groups was significantly higher than that of the negative expression of the two groups [66.7% ( 14/21) vs. 30.8% (8/26), P=0.014]. Conclusions The expression of B7-H4 and PD-L1 is up-regulated in bladder urothelial carcinoma, which is closely related to the clinical stage, histological grade, risk classification and recurrence of NMIBC. Key words: Costimulatory molecule; B7-H4; Programmed death-ligand 1; Bladder urothelial carcinoma

Overexpression of high mobility group box 1 contributes to progressive clinicopathological features and poor prognosis of human bladder urothelial carcinoma.

BackgroundHigh mobility group box 1 (HMGB1), a versatile protein with intranuclear and extracellular functions, plays an important role in a variety of human cancers. However, the clinical/prognostic significance of HMGB1 expression in human bladder urothelial carcinoma (BUC) remains unclear. The aim of this study was to investigate the HMGB1 expression in human BUC with regard to its clinical and prognostic significance.Patients and methodsHMGB1 mRNA and protein expressions in tumor and paired normal bladder tissues were detected in 20 BUC cases by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. HMGB1 protein expression in 165 primary BUC tissues was evaluated by immunohistochemistry (IHC), and its correlations with clinicopathological characteristics and prognosis were also analyzed. Student’s t-test, χ2 test, Kaplan–Meier plots, and Cox proportional hazard regression model were performed to analyze the data.ResultsBy using qRT-PCR and Western blot, the upregulated expression of HMGB1 mRNA and protein was detected in BUC, compared with paired normal tissue (P<0.05). By using IHC, high HMGB1 expression was examined in 84 of 165 (51.0%) BUC cases. High HMGB1 expression was significantly correlated with poorer differentiation and higher T and N classification (all P<0.05). Univariate analysis showed that high HMGB1 expression was significantly associated with a shortened patients’ overall survival (OS) and disease-free survival (DFS; both P<0.001). In different subgroups of BUC patients, HMGB1 expression was a prognostic factor in patients with different histological grades or T classification (all P<0.05), pN− (both P<0.001) for OS and DFS, and pT1/pN− (P<0.05) for OS. HMGB1 expression, as well as pT and pN status, was an independent prognostic factor for both OS (P=0.001, hazard ratio [HR] =2.973, 95% confidence interval [CI] =1.550–5.704) and DFS (P<0.001, HR =3.019, 95% CI =1.902–4.792) in multivariate analysis.ConclusionOverexpression of HMGB1 may be a new independent molecular marker for the poor prognosis of patients with BUC.

IMMUNOHISTOCHEMICAL EXPRESSION OF P63 IN UROTHELIAL CARCINOMA

Introduction: Urothelial carcinoma is the most common histologic type of urinary bladder cancer in Egypt. Detection of high-grade urothelial carcinoma is important for modification of therapy and improving the prognosis. P63 is expressed at high levels in the basal layers of different epithelial tissues, including the urothelium. Aim of the work: to study the diagnostic and prognostic value of p63 expression in urothelial carcinoma (UC). Materials and Methods: Fifty cases of bladder urothelial carcinoma were involved in the study; 12 cases of non-invasive UC, (3 HG & 9 LG), and 38 cases of invasive UC, (30 HG & 8 LG). Sixteen cases of UC showed Bilharziasis. All the specimens were stained with p63 using immunohistochemical technique. Results: P63 was expressed in 28/38 cases (73.7%) of invasive UC and in all cases of non-invasive UC, and also in 16/17 (94%) low-Grade and in 24/33 (72.7%) of high-grade UC, with a statistically significant relation between p63 expression and both invasion (p > 0.001) and the tumor grade (p> 0.034). Conclusion: P63 can be used as a diagnostic and a prognostic factor for high grade invasive UC

AB046. The evaluation of therapeutic efficiency of relapse prevention of alternating bladder perfusion with GEM and THP after TURBT of superficial bladder cancer

ObjectiveTo observe the therapeutic efficiency of relapse prevention of alternating bladder perfusion with GEM and THP after TURBT of superficial bladder cancer.MethodsNinety-two cases of bladder urothelial carcinoma (BUC) patients with TURBT after transurethral catheterization regularly alternating GEM and THP bladder perfusion, total time limit of 19 months after operation, respectively in 3, 6 and 12 months were followed up by cystoscope or CT. After the end of treatment, review again every 6 or 12 months according to the previous review results, for five consecutive years.ResultsDuring the five years, 23 cases of local recurrence, the recurrence rate was 26.4% (23/87), 4 cases of local recurrence and metastasis, recurrence and metastasis rate was 4.6% (4/87), 2 cases of death, mortality was 2.3% (2/87),died of the other disease not related with this one in 9 cases, 5 cases lost follow-up.ConclusionsGEM and THP as the adjuvant chemotherapy drugs after TURBT of superficial bladder cancer, has significant characteristic of curative effect does with small side effects to improve prognosis, decrease recurrence and the mortality rate, may become one of the important means to improve the postoperative curative effect.

Latent class analysis of bladder urothelial carcinoma to reveal sub-classes defined by alterations to chromatin and signal transduction networks.

469 Background: 70,000 new cases of bladder urothelial carcinoma are diagnosed in the United States each year. Previous studies of this disease suggest two divergent pathways of carcinogenesis, with ~70% of cases being driven by alterations in signal transduction pathways (FGFR3, HRAS) and the remainder featuring alterations in cell cycle genes (TP53, RB1). Other studies focus on the high prevalence of alterations in chromatin remodeling genes (ARID1A, CREBBP, EP300) in this tumor type. The relationship between chromatin modifier alterations and the two bladder TCC sub-classes is not yet understood. Methods: Comprehensive genomic profiling (CGP) on 638 clinically confirmed cases of advanced bladder urothelial carcinoma was performed using the FoundationOne platform. The coding exons of 287 cancer-related and 47 introns of 19 genes frequently rearranged in cancer were sequenced and analyzed for base substitutions, insertions, deletions, copy number alterations and select gene fusions. The resultant alteration profiles were analyzed for their information content with an entropy-based approach and the profiles were subjected to hierarchical latent class analysis (LCA). Results: CGP of 488 male and 150 female UCs of median age 66 (min: 29, max: 87) resulted in 3241 detected alterations across 302 unique genes, for a mean of ~5.1 known or likely somatic alterations per sample. The most commonly altered genes were TP53, CDKN2A/B, ARID1A, KDM6A, and MLL2. Information was concentrated in the 33 most frequently altered genes. Multiple high level clusters were defined by combinatorial patterns of alterations in TP53, CDKN2A/B, RB1, and FGFR3. Sub-classes were defined by mutually exclusive alterations in the chromatin modifiers KDM6A, MLL2, and ARID1A. Conclusions: We present a global picture of UC sub-classes that encompasses previously identified local relationships including the mutual exclusivities between FGFR3 and TP53, RB1 and CDKN2A/B, and KDM6A and MLL2. In the context of clinically relevant genomic alterations that auger response to targeted therapies, identification of sub-classes of UC may further delineate response to therapy.

Clinical characteristics and prognostic analysis in bladder urothelial carcinoma with glandular differentiation

Objective To investigate the clinical characteristics and prognosis of bladder urothelial carcinoma with glandular differentiation. Methods From January 2009 to April 2014, the clinical data of 53 cases of bladder urothelial carcinoma with glandular differentiation were analyzed and compared, retrospectively.This group included 45 men and 8 women, which the median age was 67 years old (range 39–81 years old). The initial symptoms included gross hematuria in 44 cases (83.0%), urinary irritation in 5 cases(9.4%), dysuria in 2 cases (3.8%) and found through physical examination in 2 cases(3.8%). TURBT was performed in 37 cases (69.8%). Partial and radical cystectomy were undergone in 6 (11.3%) and 10 (18.9%) cases, respectively.53 cases of bladder urothelial carcinoma without glandular differentiation were collected as control group, including 42 men and 11 women with a median age of 65 years (range 41–82 years).45 cases (84.9%) presented gross hematuria.Urinary irritation and dysuria was complained in each one case (1.9 %).6 cases(11.3%) were found through physical examination.TURBT was performed in 38 cases (71.7%). Partial and radical cystectomy were undergone in 6 (11.3%) and 9 (17.0%) cases, respectively. Results According to the 2004 WHO classification criteria, there were 28(52.8%)cases with pT1, 18(34.0%)cases with pT2, 5(9.4%)cases with pT3, 2(3.8%)cases with pT4 in the glandular group.In the control group, the stage classification included 2(3.8%)cases with pTa, 32(60.4%)cases with pT1, 16(30.2%)cases with pT2, 2(3.8%)cases with pT3, 1(1.9%)cases with pT4.There were 51 cases with high grade carcinoma and 2 cases with low grade carcinoma in the glandular group.In the control group, 40 cases showed high grade carcinoma and 13 cases exhibited low grade carcinoma.Significant difference was found in those groups (P<0.05). The mean duration of follow–up was 23 and 24 months in glandular and control group, respectively.In glandular group, 14 recurrence were recorded with a mean 16 months follow up and 2 cases were dead.In control group, 6 recurrence were recorded with a mean 25 months follow up and no patients dead(P<0.05). Conclusions Bladder urothelial carcinoma with glandular differentiation tends to have high level of malignant and higher recurrent incidence.Patients should be treated immediately after being diagnosed and intimate following up. Key words: Bladder; Urothelial carcinoma; Glandular differentiation; Treatment; Prognosis

The expression and correlation of ZEB1 and E-cadherin in human bladder urothelial carcinoma

Objective To explore the expression, correlation and clinic-pathological characters of zinc finger E-box binding homeobox 1 (ZEB1) and E-cadherin in normal bladder tissues and bladder urothelial carcinoma(BUC). Methods Immunohistochemical staining was performed on paraffin embedded sections to detect the expression of ZEB1 and E-cadherin in 86 cases of BUC, diagnosed by pathology, between March 2008 and March 2011. Among them, 51 cases were male and 35 cases were female. The mean age was (64.1±10.2)years, range 36 to 72 years.40 cases were older than 65 years old, and 46 cases were less than 65 years old. The pathological classification included G1 in 28 cases, G2-G3 in 58 cases. The TNM classification showed that Ta-T1 stage in 34 cases, T2-T4 in 52 cases. Single lesion was found in 49 cases and multi lesion was found in 37 cases. 55 cases were primary lesion; the other 31 cases were diagnosed as tumor recurrence. Normal bladder mucosa was obtained from 16 patients with BPH. Their age ranged from 51 to 75 years old, mean (58.6±18.4)years old. Similar immunohistochemical staining about ZEB1 and E-cadherin was performed. The expression of ZEB1 and E-cadherin in different tissue and its relationship with the clinic pathological were further analyzed. Results The positive rate of ZEB1 in bladder cancer group (39.5%, 34/86) was significantly higher than that in normal bladder mucosa group(0, 0/16) (P<0.01). The positive rate of ZEB1 in high grade bladder cancer (G2-G3) was 48.3% (28/58), which was significant higher than that in low grade bladder cancer (G1) (21.4%, 6/28) (P<0.05); The positive rate of ZEB1 in muscle-invasive bladder cancer (T2-T4) was 51.9% (27/52), which was significant higher than that in non-muscle-invasive cancer (Ta-T1) (20.6%, 7/34) (P<0.01). The abnormal rate of E-cadherin expression in bladder cancer (61.6%, 53/86) was significantly lower than that in normal bladder mucosa (81.2%, 13/16) (P<0.01). The abnormal expression rate of E-cadherin in high grade bladder cancer (G2-G3) (53.4%, 31/58) was significantly lower than that in low grade bladder cancer (G1) (78.6%, 22/28)(P<0.05); The abnormal rate of E-cadherin expression in invasive bladder cancer (T2-T4) was 51.9% (27/52), which was lower than that in non-muscle invasive (Ta-T1) cancer (76.5%, 26/34) (P<0.05). In bladder cancer, there was a negative correlation between the abnormal expression of E-cadherin and positive expression of ZEB1 (r=0.247, P<0.05). Conclusion The expressions of ZEB1 and E-cadherin in bladder cancer were negatively correlated, which had high correlated with tumor grade and stage. Key words: Zinc finger E-box binding homeobox 1; E-cadherin; Bladder cancer; Immunohistochemistry

The value of serum CYFRA21-1 examination in the detection of urothelial carcinoma

Objective To evaluate the value of CYFRA21-1 examination in the detection of urothelial carcinoma (UC).Methods Serum concentrations of CYFRA21-1 were examined by electrochemiluminescence technique in 65 cases with UC,61 cases of non-UC patients (including 21 cases of renal carcinoma,20 cases of benign prostatic hyperplasia,10 cases of prostatic carcinoma,10 cases of urolithiasis) and 43 hea]thy individuals.Sixty-five UC cases including 9 renal pelvis UC cases,4 ureter UC cases,52 bladder UC cases,61 non-UC cases including 21 renal carcinoma cases,20 benign prostatic hyperplasia cases,10 prostatic carcinoma cases,10 urolithasis cases.Results The serum CYFRA21-1 concentration in UC patients (7.57± 12.76) μg/L was significantly higher than the healthy controls (2.58±0.97) μg/L and also the non-UC patients (2.75± 1.34) μg/L (P＜0.01).The difference between the healthy individuals and the nonUC patients was not significant (P＞0.05).According to the manual in the reagent kit,the positive value of serum CYFRA21-1 was defined as greater than 3.3 μg/L.The false positive rate in healthy controls and the non-UC patients was 10％-30％.The positive percentage of serum CYFRA21-1 of the 65 UC patients was 67.7％ (44/65).In low,middle and high grade UC cases,the positive rates were 50.0％ (10/20),62.5％ (5/8) and 78.3％ (29/37) respectively.The difference of the positive rates between the high grade group and middle,low grade groups was significant (x2 =4.55,P＜0.05).The positive rates in non-muscle invasive (Ta-Ti) UC and in healthy controls were 40.9％ (9/22) and 23.2％ (10/43) respectively,and the difference between the two groups was not significant (x2=2.19,P＞0.05).The positive rate in muscle invasive (T2-T3) UC was 78.6％ (22/28) and the difference compared with healthy controls was significant (x2=20.96,P＜0.01).The positive rate in local advanced and metastatic UC (＞T3) was 86.7％ (13/15).The positive rates were not significantly deferent between the T2-T3 group and the ＞ T3 group (x2 =1.97,P＞0.05).Conclusions The serum CYFRA21-1 positive rate is 67.7％ in UC patients,which was higher than non-UC patients and healthy controls,and associated positively with the pathologic grade and the clinical stage of UC.Monitoring the serum CYFRA21-1 is effective in assessing the outcomes and prognosis of UC,if the serum CYFRA21-1 was positive.The serum CYFRA21-1 test has some significance in distinguishing UC from renal carcinoma and prostatic carcinoma. Key words: Urothelium; Carcinoma; Tumor markers; Keratins

Comparison of microscopic (pT3a) and gross extravesical extension (pT3b) in pathological staging of bladder cancer: analysis of patient outcomes

To determine the prognostic value of pT3 bladder urothelial carcinoma substaging in patients without lymphatic involvement. Pathologic and clinical data were reviewed on patients who underwent radical cystectomy for urothelial carcinoma between 1991 and 2010. Of the 460 reviewed patients, 74 patients were diagnosed with pathologic T3No urothelial carcinoma of the bladder. The impact of pathologic substaging (pT3a vs. pT3b) was examined to determine the effect on overall and disease-specific survival. Five years disease-specific and overall survival rates were 46.9 % and 39.6 % for patients with pT3aNo tumor, whereas these ratios were 34.4 and 30.3 %, respectively, for patients with pT3bNo tumor (p > 0.05). Mean disease-specific survival time was 43.94 ± 6.50 months for pT3aNo, while it was 39.01 ± 7.19 months for pT3bNo (p = 0.539). In multivariate cox regression analysis, age (p = 0.459), gender (p = 0.710), urinary diversion type (p = 0.088), and pT3 substaging (p = 0.554) were not noticed as an independent predictive factor for survival. Macroscopic extravesical extension (pT3b) is not associated with a worse outcome than pT3a disease in lymph node-negative cases of bladder urothelial carcinoma.