Detection Of Transitional Cell Carcinoma Research Articles

Diagnostic accuracy of NMP 22 and urine cytology for detection of transitional cell carcinoma urinary bladder taking cystoscopy as gold standard.

Objective:To determine diagnostic accuracy of NMP 22 and urine cytology in the detection of transitional cell carcinoma (TCC) urinary bladder taking cystoscopy as a gold standard in patients having provisional diagnosis of bladder cancer (BC).Methods:This cross sectional validational study enrolled 380 patients fulfilling selection criteria and was conducted at Armed Forces Institute of Urology (AFIU) Rawalpindi, Pakistan form July 2018 to July 2019. The urine sample collected underwent NMP22 and cytological analysis followed by rigid cystoscopy. Reports of all three tests divided patients into positive or negative for malignancy as per defined criteria. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and diagnostic accuracy of NMP 22, urine cytology and their combination was determined. Receiver operating characteristic (ROC) curve analysis performed and area under the curve (AUC) compared among these tests.Results:The average age of patients was 53.08 ± 12.41 years having male to female ratio 3.75:1(300 males and 80 females). NMP 22 had better sensitivity and comparable specificity to cytology (81.9 & 81.2% vs 54 & 93.9%). Combination of NMP 22 / cytology outperformed both in terms of sensitivity (91.63 vs 81.83 vs 53.96), NPV (87.59 vs 77.46 vs 61.02) and diagnostic accuracy (85.26 vs 81.58 vs 71.32) but at the cost of specificity (76.97 vs 81.21 vs 93.94) and PPV (83.83 vs 85.02 vs 92.06). ROC curve revealed statistically significant higher AUC (0.843 vs .815 vs .73) for combination as compared to NMP 22 and Cytology (p < 0.001).Conclusion:NMP22 is a quick, point of care test having higher sensitivity, NPV and accuracy but similar specificity and PPV to urine cytology for detection of TCC urinary bladder. Combination outperformed both in terms of sensitivity while having modest specificity.

Iodine Content Analysis Using Dual-Energy Computed Tomography as a Biomarker of Transitional Cell Carcinoma, an Experience with Separation of the Clotted Blood and Tumorous Tissue.

The aim of this study was to evaluate the possibility to discriminate the blood clot from tumorous tissue in the assessment of transitional cell carcinoma (TCC), when CT data are used only from single-phase dual-energy CT (DECT). A total of 18 patients were included into the retrospective analysis of the prospectively collected data (the average age was 67.3 years, range=62-79 years, 12 males, 6 females). DECT was performed in all patients after intravenous administration of the iodinated contrast material. DECT analysis using three-material decomposition algorithm was used to discriminate blood and enhancing tumorous tissue. In all patients, TCC was detected and subsequently kidney surgery or endoscopy was performed within the next two weeks. The findings were compared with DECT results. In our cohort of patients we found 9 TCC of the renal pelvis or ureter and 7 TCC of the urinary bladder. The accuracy of the TCC detection was 94% (17/18). The presence of coagulated blood within the urinary collecting system together with a tumor was detected in 7 CT examinations. The blood coagulum without a confirmed malignant tumor was found in one case with false positive DECT finding. In other 6 cases bleeding was confirmed during surgery or endoscopy (accuracy 87%). The dual-energy data analysis enables discrimination of a blood clot from tumorous tissue. It helps in detection of UCC in cases when the excretion potential of the kidneys is decreased due to fulfillment of the collecting system with blood clots.

An anti-ubiquitin antibody response in transitional cell carcinoma of the urinary bladder.

BackgroundTo use combinatorial epitope mapping (“fingerprinting”) of the antibody response to identify targets of the humoral immune response in patients with transitional cell carcinoma (TCC) of the bladder.MethodsA combinatorial random peptide library was screened on the circulating pool of immunoglobulins purified from an index patient with a high risk TCC (pTa high grade plus carcinoma in situ) to identify corresponding target antigens. A patient cohort was investigated for antibody titers against ubiquitin.ResultsWe selected, isolated, and validated an immunogenic peptide motif from ubiquitin as a dominant epitope of the humoral response. Patients with TCC had significantly higher antibody titers against ubiquitin than healthy donors (p<0.007), prostate cancer patients (p<0.0007), and all patients without TCC taken together (p<0.0001). Titers from superficial tumors were not significantly different from muscle invasive tumors (p = 0.0929). For antibody response against ubiquitin, sensitivity for detection of TCC was 0.44, specificity 0.96, positive predictive value 0.96 and negative predictive value 0.41. No significant titer changes were observed during the standard BCG induction immunotherapy.ConclusionsThis is the first report to demonstrate an anti-ubiquitin antibody response in patients with TCC. Although sensitivity of antibody production was low, a high specificity and positive predictive value make ubiquitin an interesting candidate for further diagnostic and possibly immune modulating studies.

Quantitation of rare circulating tumor cells by folate receptor α ligand-targeted PCR in bladder transitional cell carcinoma and its potential diagnostic significance.

Numerous attempts for detection of circulating tumor cells (CTC) have been made to develop reliable assays for early diagnosis of cancers. In this study, we validated the application of folate receptor α (FRα) as the tumor marker to detect CTC through tumor-specific ligand PCR (LT-PCR) and assessed its utility for diagnosis of bladder transitional cell carcinoma (TCC). Immunohistochemistry for FRα was performed on ten bladder TCC tissues. Enzyme-linked immunosorbent assay (ELISA) for FRα was performed on both urine and serum specimens from bladder TCC patients (n = 64 and n = 20, respectively) and healthy volunteers (n = 20 and n = 23, respectively). Western blot analysis and qRT-PCR were performed to confirm the expression of FRα in bladder TCC cells. CTC values in 3-mL peripheral blood were measured in 57 bladder TCC patients, 48 healthy volunteers, and 15 subjects with benign urologic pathologies by the folate receptor α ligand-targeted PCR. We found that FRα protein was overexpressed in both bladder TCC cells and tissues. The levels of FRα mRNA were also much higher in bladder cancer cell lines 5637 and SW780 than those of leukocyte. Values of FRα were higher in both serum and urine specimens of bladder TCC patients than those of control. CTC values were also higher in 3-mL peripheral blood of bladder TCC patients than those of control (median 26.5 Cu/3 mL vs 14.0 Cu/3 mL). Area under the receiver operating characteristic (ROC) curve for bladder TCC detection was 0.819, 95 % CI (0.738-0.883). At the cutoff value of 15.43 Cu/3 mL, the sensitivity and the specificity for detecting bladder cancer are 82.14 and 61.9 %, respectively. We concluded that quantitation of CTCs through FRα ligand-PCR could be a promising method for noninvasive diagnosis of bladder TCC.

Expression of CD147, BIGH3 and Stathmin and their potential role as diagnostic marker in patients with urothelial carcinoma of the bladder

BackgroundUrothelial carcinoma of the bladder is characterised by very high recurrence rate, followed up by cystoscopy which being invasive technique makes the need for non-invasive markers important for Transitional Cell Carcinoma (TCC) detection. CD147 is a transmembrane protein highly expressed in tumour cells which aids in tumour invasion and growth. BIGH3, an Extracellular matrix protein (ECM) which interacts with various ECM component in different tissue system and Stathmin(STMN1) is cytosolic microtubule destabilising protein also called as Oncoprotein18 due to its role in tumour promotion. So far the expression of BIGH3 and STMN1 remains undetermined in cancer subjects including TCC. We therefore studied the levels and molecular expression of these molecules in TCC patients, to evaluate their usefulness as diagnostic markers. MethodsThirty consecutive TCC patients and two sets of control- 15 Benign prostatic hyperplasia (BPH) patient and 15 healthy were taken. Serum and urine levels of these molecules were estimated by ELISA and relative mRNA expression by Q-PCR from tumour and normal urothelium. Post-Hoc analysis and ROC curve were determined to evaluate the significance and sensitivity and specificity. ResultsThe mean concentrations of these molecules were found to be significantly increased (p<0.001) in the serum and urine of TCC patients, with varying significance in each grade for different molecules. The urinary levels of CD147 (67pg/ml) and serum STMN1 concentration (1.38ng/ml) showed a specific increase as compared to the controls, while BIGH3 was elevated in both serum and urine samples. Molecular (mRNA) expression was elevated in the high grade (Muscle Invasive) stage of the disease for all the molecules, with a significant 3-fold increase that correlated with disease severity being observed for STMN1. ROC analysis gave optimal combination of sensitivity and specificity for diagnosis of the disease in urine and serum sample for STMN1. ConclusionOf CD147, BIGH3 and STMN1, significant results were obtained for STMN1 and it could serve as the best possible diagnostic marker for TCC detection in future.

LASP-1, a Novel Urinary Marker for Detection of Bladder Cancer

ObjectivesThe LIM and SH3 (LASP)-1 protein is a focal adhesion protein that has been linked to oncogenesis. The aim of this study was to evaluate the diagnostic use of the detection of LASP-1 in tumor specimens and in urine for noninvasive detection of transitional cell carcinoma (TCC). Materials and methodsImmunohistochemical staining for LASP-1 was performed on 72 archived bladder tumor specimens, and LASP-1 content was measured in 132 spontaneous urine sample sediments by Western blot analysis. ResultsIn the histologic specimens, immunohistochemical staining for LASP-1 showed abundant expression throughout the urothelium of the bladder and ureter. However, modest overexpression of LASP-1 was observed in the TCC specimens. Measurement of the LASP-1 protein concentrations in urinary cell pellets from healthy donors and bladder cancer patients was highly sensitive for the presence of TCC. The cut-off value was determined by receiver operating characteristic (ROC) analysis. When a cut-off value of 1 ng LASP-1/500 μl of urine was used, the sensitivity, specificity, and positive and negative predictive values of the assay were 83.1%, 85.3%, 83.1%, and 80.6%, respectively.The increased urinary LASP-1 content in TCC patients was attributable in part to a specific increase in cell shedding presumably caused by changes in cell adhesion, as confirmed by LASP-1 knockdown. Contamination with erythrocytes above 250 cells/μl and urinary infection gave false positive results and are therefore sample exclusion criteria. ConclusionsIn the absence of urinary infection or gross hematuria, urinary LASP-1 level is a promising marker for transitional cell carcinoma.

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We totally agree with the author of the Editorial Comment that patients with suspect of urothelial cell carcinoma due to symptoms such as painless gross hematuria should undergo a complete workup including cystoscopy, upper urinary tract (UUT) imaging, and urine markers. In these cases, urine markers cannot replace invasive diagnostic measures. But how do we proceed in patients with negative cystoscopy results, normal imaging findings, and a positive urine marker? Current guidelines provide no clear recommendations for these patients. Because of the risk of missing a non-papillary bladder tumor (eg, CIS) by cystoscopy and the high specificity of cytology, the presence of positive cytology results should alert urologists. One option for further diagnosis would be to re-perform 5-aminolaevulinic acid (ALA)–guided cystoscopy, which has been shown to be more sensitive than white-light cystoscopy, particularly for the detection of CIS. 1 Stenzl A. Penkoff H. Dajc-Sommerer E. et al. Detection and clinical outcome of urinary bladder cancer with 5-aminolevulinic acid-induced fluorescence cystoscopy: a multicenter randomized, double-blind, placebo-controlled trial. Cancer. 2001; 117: 938-947 Crossref Scopus (92) Google Scholar , 2 Hungerhuber E. Stepp H. Kriegmair M. et al. Seven years' experience with 5-aminolevulinic acid in detection of transitional cell carcinoma of the bladder. Urology. 2007; 69: 260-264 Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar In case of a negative finding, the performance of UUT urine sampling may help to identify the source of positive cytology. Given our findings, the manipulation associated with this procedure does not have a signficant effect on the result of cytology. In the case of positive UUT cytology results, ureteroscopy would be a further option to rule out UUT urothelial carcinoma. Because of studies showing that fluorescence in situ hybridization (FISH) might have a role as an anticipatory positive marker for urothelial carcinoma both in the primary setting and in the follow-up of patients with known bladder cancer. 3 Yoder B.J. Skacel M. Hedgepeth R. et al. Reflex UroVysion testing of bladder cancer surveillance patients with equivocal or negative urine cytology: a prospective study with focus on the natural history of anticipatory positive findings. Am J Clin Pathol. 2007; 127: 295-301 Crossref PubMed Scopus (158) Google Scholar , 4 Skacel M. Fahmy M. Brainard J.A. et al. Multitarget fluorescence in situ hybridization assay detects transitional cell carcinoma in the majority of patients with bladder cancer and atypical or negative urine cytology. J Urol. 2003; 169: 2101-2105 Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar and because of its relatively high specificity, we also recommend re-evaluation of patients with negative cystocopy and positive FISH results, especially in the case of a second positive urine marker (immunocytology or NMP22) or risk factors for urothelial carcinoma (such as smoking). For uCyt, we do not have a clear recommendation because of the relatively high variability of reported specificities. 5 Budman L.I. Kassouf W. Steinberg J.R. Biomarkers for detection and surveillance of bladder cancer. Can Urol Assoc J. 2008; 2: 212-221 PubMed Google Scholar In patients with isolated increased NMP22 and negative cystoscopy results, the low specificity, especially in the context of mechanical manipulation, urinary tract infection, and hematuria, does not justify further invasive measurements. However, the predictive role of positive urine markers has to be evaluated in larger studies to make clear recommendations, especially in the follow-up of patients with urothelial carcinoma. We also agree that aggressive work-up because of positive urine markers in patients without symptoms or risk factors for urothelial carcinoma should be avoided. Given our experience with these markers, we do not agree that further workup for isolated urine markers, especially in the case of present hematuria and positive FISH, cytology and uCyt, results “never reveals any malignant abnormality.” Editorial CommentUrologyVol. 79Issue 3PreviewThe authors have written a straightforward paper describing the false-positive rates for different urinary markers depending upon whether the urine samples were simply voided or were collected after instrumentation, as well as whether there was any evidence for inflammation at time of collection. Some of the markers were quite resistant and their sensitivities/specificities did not change much, whereas for others—specifically NMP22—their utility drops precipitously. Full-Text PDF

Urinary Survivin mRNA Expression and Urinary Nuclear Matrix Protein 22 BladderChek® and Urine Cytology in the Detection of Transitional Cell Carcinoma of the Bladder

Objective: To compare the diagnostic performance of urine cytology (UC), survivin mRNA expression, and the NMP22 BladderChek® (NMP22BC) test for the detection, grading and staging of transitional cell carcinoma (TCC) of the bladder. Materials and Methods: Voided urine samples collected from 25 healthy controls and 80 patients diagnosed with TCC of the bladder were subjected to UC, the NMP22BC test and reverse-transcription real-time PCR for survivin mRNA expression. Results: Survivin mRNA expression showed the highest sensitivity (87.5%) followed by the NMP22BC test (61.3%) while UC exhibited the lowest sensitivity (40%). All three urine markers had a similar specificity of 96% (95% CI 80.5–99.3%). Survivin mRNA expression was the only urine marker that showed a significant difference in relation to tumour histological grade (χ² 8.5, p = 0.015). None of the three urine markers was significantly related to tumour pathological stages. Conclusion: The diagnostic sensitivity of urinary survivin mRNA expression was superior to that of UC and the NMP22BC test and correlates with tumour pathological grade but not stage.

Chromosomal Aberrations in Bladder Cancer: Fresh versus Formalin Fixed Paraffin Embedded Tissue and Targeted FISH versus Wide Microarray-Based CGH Analysis

Bladder carcinogenesis is believed to follow two alternative pathways driven by the loss of chromosome 9 and the gain of chromosome 7, albeit other nonrandom copy number alterations (CNAs) were identified. However, confirmation studies are needed since many aspects of this model remain unclear and considerable heterogeneity among cases has emerged. One of the purposes of this study was to evaluate the performance of a targeted test (UroVysion assay) widely used for the detection of Transitional Cell Carcinoma (TCC) of the bladder, in two different types of material derived from the same tumor. We compared the results of UroVysion test performed on Freshly Isolated interphasic Nuclei (FIN) and on Formalin Fixed Paraffin Embedded (FFPE) tissues from 22 TCCs and we didn't find substantial differences. A second goal was to assess the concordance between array-CGH profiles and the targeted chromosomal profiles of UroVysion assay on an additional set of 10 TCCs, in order to evaluate whether UroVysion is an adequately sensitive method for the identification of selected aneuploidies and nonrandom CNAs in TCCs. Our results confirmed the importance of global genomic screening methods, that is array based CGH, to comprehensively determine the genomic profiles of large series of TCCs tumors. However, this technique has yet some limitations, such as not being able to detect low level mosaicism, or not detecting any change in the number of copies for a kind of compensatory effect due to the presence of high cellular heterogeneity. Thus, it is still advisable to use complementary techniques such as array-CGH and FISH, as the former is able to detect alterations at the genome level not excluding any chromosome, but the latter is able to maintain the individual data at the level of single cells, even if it focuses on few genomic regions.

UP-01.030 A Prospective Multi-Center Study of a Novel Urinary Diagnostic Test for the Detection of Transitional Cell Carcinoma (TCC) in Patients with Gross Hematuria

UP-01.030 A Prospective Multi-Center Study of a Novel Urinary Diagnostic Test for the Detection of Transitional Cell Carcinoma (TCC) in Patients with Gross Hematuria

A Prospective Comparison of the NMP22 Bladderchek® Assay and Voided Urine Cytology in the Detection of Bladder Transitional Cell Carcinoma: Is it Time up for Urine Cytology?

Objectives: To prospectively compare the performance of voided urine cytology (VUC) and the Matritech NMP22 BladderChek® assay (NMP22) in their ability to detect urothelial transitional cell carcinoma (TCC). Methods: Successive patients presenting to our haematuria clinic were enrolled. All patients underwent ultrasound scan (US), intravenous urography (IVU), flexible cystoscopy and VUC. If bladder TCC was detected, urine was tested using the NMP22 BladderChek® assay. The study group (group I) comprised 110 patients diagnosed with bladder tumour on flexible cystoscopy. The control group (group II) included 52 patients with a history of haematuria but no demonstrable bladder tumour. The TCC detecting ability of both the NMP22 BladderChek® assay and VUC were compared. Results: In group I, the NMP22 result was positive in 62.7% (69/110) patients, while a positive VUC result was noted in 52.0% (52/100) patients. The overall sensitivity, specificity, positive predictive and negative predictive values for NMP22 vs. VUC were 62.7% vs. 52.0%; 86.5% vs. 95.5%; 90.8% vs. 96.3% and 52.3% vs. 48.0% respectively (not significant). The performance of both urine tests improved with increasing tumour grade ( p ≤ 0.05). False positive rate in group II was 13.5% (7/52) for NMP22 and 4.5% (2/42) for VUC. Conclusion: The diagnostic accuracy of the NMP22 BladderChek® assay for TCC detection is equivalent to conventional VUC, but the NMP22 BladderChek® has distinct advantages to promote its use over VUC.

1169 URINE CYTOLOGY PROVIDES NO ADDITIONAL DIAGNOSTIC VALUE IN PATIENTS WITH A NEGATIVE CYSTOSCOPY AND NEGATIVE NMP22 BLADDERCHEK TEST FOR THE DETECTION OF TRANSITIONAL CELL CARCINOMA OF THE BLADDER

You have accessJournal of UrologyBladder Cancer: Detection and Screening1 Apr 20101169 URINE CYTOLOGY PROVIDES NO ADDITIONAL DIAGNOSTIC VALUE IN PATIENTS WITH A NEGATIVE CYSTOSCOPY AND NEGATIVE NMP22 BLADDERCHEK TEST FOR THE DETECTION OF TRANSITIONAL CELL CARCINOMA OF THE BLADDER John Terrell, Keren Elias, Chester Donnally, Richard Ho, Arthur Sagalowsky, and Yair Lotan John TerrellJohn Terrell More articles by this author , Keren EliasKeren Elias More articles by this author , Chester DonnallyChester Donnally More articles by this author , Richard HoRichard Ho More articles by this author , Arthur SagalowskyArthur Sagalowsky More articles by this author , and Yair LotanYair Lotan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.669AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Urine cytology (UC) is an imperfect diagnostic adjunct to cystoscopy (cysto) for the detection of transitional cell carcinoma (TCC). It suffers from a low sensitivity, increased expense, delay in result availability and frequent inconclusive findings. Urine markers have the potential of providing improved negative predictive value (NPV), immediate results and decreased cost. We examined 3 prospective multi-institutional studies with a cohort of almost 2500 patients (pts) to ascertain whether UC provides any additional diagnostic role in pts with both a negative NMP22 BladderChek test (BC) and a negative cysto. METHODS Initially we performed subset analyses of 2 large prospective multi-center databases evaluating the point-of-care NMP22 BladderChek test for bladder cancer detection (n=1331, Grossman HB, et al. JAMA 2005) and surveillance (n=668, Grossman HB, et al. JAMA 2006). These cohorts were analyzed for the presence of cancer and the result of UC in the setting of a negative cysto and BC to determine if UC would have provided a diagnostic role. Subsequently, the results were validated in a prospective cohort of 434 pts at our institution who had a BC test prior to evaluation. RESULTS In the detection database of 1331 pts, there were 1065 pts with a negative cysto and BC. There were only 3 cancers (stages Ta, Tis and T1) in this group. UC was atypical in one and reactive in 2 pts. In the surveillance cohort of 668 pts, there were 437 pts with a negative cysto and BC. Cancer was found in 2 pts (stages Tis and Ta). There was one atypical and one reactive UC in these 2 pts. Subsequent validation of these results in our cohort of 434 pts, in which 288 pts had a negative cysto and BC, revealed the presence of only one cancer. The one tumor was a Ta ureteral TCC with a reactive UC. Of the 6 pts with cancer out of 1790 pts, none had a positive UC. CONCLUSIONS In both the subset analyses of the multi-institutional studies evaluating BC and the prospective study at our institution, UC provided no additional diagnostic information for the detection of TCC in pts with a negative cysto and BC. There were very few cancers missed with only 6 in 1790 pts. The use of a point-of-care test in conjunction with cysto in lieu of cytology could decrease cost, provide immediate results, improve NPV and reduce the uncertainty that results from inconclusive cytologic results. Dallas, TX© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e453 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information John Terrell More articles by this author Keren Elias More articles by this author Chester Donnally More articles by this author Richard Ho More articles by this author Arthur Sagalowsky More articles by this author Yair Lotan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

1170 IMPACT OF INSTRUMENTED URINARY SAMPLING ON THE DIAGNOSTIC VALUE OF URINE TESTS (UROVYSIONR, UCYT+R) AND CYTOLOGY FOR TRANSITIONAL CELL CARCINOMA – RESULTS FROM A COHORT OF 2077 PATIENTS

You have accessJournal of UrologyBladder Cancer: Detection and Screening1 Apr 20101170 IMPACT OF INSTRUMENTED URINARY SAMPLING ON THE DIAGNOSTIC VALUE OF URINE TESTS (UROVYSIONR, UCYT+R) AND CYTOLOGY FOR TRANSITIONAL CELL CARCINOMA – RESULTS FROM A COHORT OF 2077 PATIENTS Christian Schwentner, Joerg Hennenlotter, Ursula Kuehs, Veronika Tews, Daniela Colleselli, Severine Huber, David Schilling, Karl-Dietrich Sievert, and Arnulf Stenzl Christian SchwentnerChristian Schwentner More articles by this author , Joerg HennenlotterJoerg Hennenlotter More articles by this author , Ursula KuehsUrsula Kuehs More articles by this author , Veronika TewsVeronika Tews More articles by this author , Daniela ColleselliDaniela Colleselli More articles by this author , Severine HuberSeverine Huber More articles by this author , David SchillingDavid Schilling More articles by this author , Karl-Dietrich SievertKarl-Dietrich Sievert More articles by this author , and Arnulf StenzlArnulf Stenzl More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.670AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Beside urine cytology, the UroVysion and uCyt+ tests systems are used for early detection of transitional cell carcinoma (TCC). Whereas instrumented urinary sampling (IUS) is an exclusion criterion for several test-kits, there are no specifications for the UroVysion and uCyt+ systems. Given the lack of data there are no recommendations if urinary tract manipulation interferes with these tests. Herein, we evaluate the impact of IUS on urine cytology, the UroVysion FISH test and the uCyt+-test. METHODS 2077 consecutive patients with suspected TCC underwent multimarker testing of the 3 mentioned tests followed by cystoscopy and transurethral resection. All patients were investigated regarding urinary specimen harvesting. IUS was defined as catheterized, irrigated or exprimated urine whereas spontaneous voiding was defined as urine collected without IUS. The test results were compared with regards to the invasiveness of urine collection by contingency analysis and Chi-square tests separately. RESULTS In 65.1% of patients samples were collected after urinary tract instrumentation. In plain cytology, false positive results occurred in 13.4 and 18.1% of patients without and with IUS, respectively (p=0.0097). False negative results appeared in 22.4 and 20.1% of patients without and with IUS (p=0.32). For the UroVysion test, false positive results occurred in 14.1 and 19.4% of patients without and with IUS, respectively (p=0.0246). False negative results were seen in 45.5 and 28.0% of patients without and with IUS (p=0.0374). For the uCyt+ test, false positive results occurred in 13.6 and 24.3% of patients without and with IUS, respectively (p=0.0021). False negative results were detected in 57.1 and 24.8% of patients without and with IUS (p=0.0161). CONCLUSIONS IUS influences the specificity of all investigated tests. The sensitivity of UroVysion and the uCyt+ are particularly deteriorated by IUS. Approximately 50% displayed false-negative tests in the group without IUS. Activated urothelial cells are misinterpreted as tumor cells. These manipulated urothelial cells provoke false positive results due to secondary molecular changes in the UroVysion and the uCyt+ tests. The enormous false negative rate for patients with regular voided specimens underlines the association of mechanical manipulation with molecular changes. These observations stress the outstanding relevance of urinary sampling for the appropriate interpretation of urinary test for the early detection of TCC. Tuebingen, Germany© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e453-e454 Peer Review Report Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Christian Schwentner More articles by this author Joerg Hennenlotter More articles by this author Ursula Kuehs More articles by this author Veronika Tews More articles by this author Daniela Colleselli More articles by this author Severine Huber More articles by this author David Schilling More articles by this author Karl-Dietrich Sievert More articles by this author Arnulf Stenzl More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

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We completely agree with the editor's comment that the evidence for the benefit of photodynamic diagnostics in the treatment of non–muscle-invasive bladder cancer seems solid. In preparation of the present contribution we were driven by a ubiquitous question in uro-oncological research: when may any innovation be held valid and warrant broader application? We are convinced that it takes a magnitude of data from multiple centers, reflecting various aspects of the novelty and the disease they are set out to manage. We believe that these criteria demand to be met by photodynamic diagnostics. 1 Hungerhuber E. Stepp H. Kriegmair M. et al. Seven years' experience with 5-aminolevulinic acid in detection of transitional cell carcinoma of the bladder. Urology. 2007; 69: 260-264 Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar However, we were aware of potential tribulations, as current data are based on 2 different fluorescent agents, namely, 5-aminolevulinic acid and hexaminolevulinate. Consequently, we intended to clarify the comparability of these agents and the transferability of respective data from one substance to another. Thus, we appreciate the editor's view on the purpose of our present contribution. Editorial CommentUrologyVol. 74Issue 6PreviewThe photodynamic agent 5-aminolaevulinic acid (5-ALA) was introduced into urology practice about 15 years ago, followed 5 years later by its hexyl ester derivative hexaminolevulinate (HEX, also referred to as HAL). Robust evidence from various multicenter, prospective, controlled or randomized trials on hundreds of patients reveals that photodynamic diagnosis using these agents improves the detection rate of non–muscle-invasive papillary bladder tumors (Ta-T1 and carcinoma in situ), and decreases the amount of residual cancer following transurethral resection of the bladder (TURB),1 leading to a reduction in rates of tumor recurrence at 9 months. Full-Text PDF Hexaminolevulinate Is Equal to 5-Aminolevulinic Acid Concerning Residual Tumor and Recurrence Rate Following Photodynamic Diagnostic Assisted Transurethral Resection of Bladder TumorsUrologyVol. 74Issue 6PreviewTo compare the outcomes of 5-aminolaevulinic acid (ALA) vs hexaminolaevulinate (HEX) vs white light (WL) transurethral resection of bladder tumors (TURB) to assess transferability of ALA findings to HEX. Extending WL-TURB with photodynamic diagnostic improves outcome. Two fluorescent agents have been commonly used for this. Although numerous and specific data exist on the older substance ALA, considerably less are available on hex, the only agent approved however. To date no such report has been published. Full-Text PDF

The significance of urine NMP22 in the screening of urothelial cancer (comparison of ELISA and immunochromatography method)

e16024 Background: The early diagnosis of urothelial cancer allows for effective local treatment and optimizes the success of surgical therapy. Urine nuclear matrix protein 22 (NMP22) was introduced for the detection of transitional cell carcinoma. Add to old NMP22 (ELISA), new NMP22 (immunochromotography method : BladderChek) can be available from 2004. The objective of this study is to determine whether there are any correlation between urine NMP22 (two methods) and the grade or stage of urothelial cancer, and whether it can serve as a biochemical marker of urothelial cancer. Methods: A total of 246 patients with hematuria or followed up after TUR-BT, from March 2007 to December 2007,visited our hospital and subsequently underwent cystoscopy. The 246 patients provided voided urine samples. We immediately examined urine cytology and NMP22 (two methods). We set the cut off value on 12.0U/ml for NMP22 (ELISA). NMP22 (BladderChek) was judged by qualitative analysis. We decided that in urine cytology, classI,II,III were negative, while IV,V were positive by Papanicolaou classification. Results: Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) were 66.7 %, 98.3 %, 81.8 %, 96.3 % in urine cytology, 40.7 %, 75.9 %, 16.2 %, 91.8 % in NMP22 (ELISA), 59.3 %, 79.3 %, 24.6 %, 94.5 % in NMP22 (BladderChek). In 9 cases with false negative of urine cytology, 4 cases were picked up by NMP22 (ELISA), and 5 cases by NMP22 (BladderChek). Sensitivity of grade 1 was 33.3 % in urine cytology, while 66.7 % in NMP22 (BladderChek). By adding NMP22 (BladderChek) to urine cytology, sensitivity rose about 18 %. Conclusions: The sensitivity of urine cytology was unexpectedly high. NMP22 (BladderChek) is more useful than NMP22 (ELISA) because of higher sensitivity, specificity and advantage of simplicity, rapidity. It seems that the addition of NMP22 (BladderChek) to urine cytology is beneficial. No significant financial relationships to disclose.

Quantitative Fluorescence in Situ Hybridization and its Ability to Predict Bladder Cancer Recurrence and Progression to Muscle-Invasive Bladder Cancer

Fluorescence in situ hybridization (FISH) testing is used to detect bladder cancer in urine specimens. The purpose of this study was to determine whether there are associations between the percentage of chromosomally abnormal cells by FISH and time to bladder cancer recurrence and progression to metastasis. Clinical records were searched to identify patients with urine FISH results, history of non-invasive bladder cancer, and at least one follow-up pathological diagnosis. Covariates analyzed included age, gender, smoking status, treatment after FISH, cystoscopy result, and prior stage of bladder cancer. The percentage of abnormal cells (hazard ratio [HR] 1.03, 95% CI 1.02-1.03; P < 0.001), age (HR 1.02, 95% CI 1.00-1.03; P = 0.033), male gender (HR 0.60, 95% CI 0.41-0.87; P < 0.001), treatment (HR 0.37, 95% CI 0.25-0.55; P < 0.001), and history of TIS/T1-stage tumors (HR 1.66, 95% CI 1.23-2.24; P = 0.001) were significantly associated with time to cancer recurrence. Time to invasive cancer was significantly associated with the percentage of abnormal cells (HR 1.02, 95% CI 1.01, 1.03; P < 0.001), history of TIS/T1 tumor (HR 3.73, 95% CI 1.88, 7.38; P = 0.001), and treatment (HR 0.33, 95% CI 0.13, 0.83; P = 0.019), suggesting that the percentage of abnormal cells independently predicts cancer recurrence and progression to invasive disease in patients with a history of non-invasive bladder cancer.

Is There a Role for FISH in the Management and Surveillance of Patients with Upper Tract Transitional-Cell Carcinoma?

Fluorescence in-situ hybridization (FISH) assay has been approved by the U.S. Food and Drug Administration for the detection of recurrent transitional-cell carcinoma (TCC) of the bladder and in the initial workup of hematuria. In this study, we retrospectively reviewed our initial 94 FISH specimens taken from patients monitored for upper-tract TCC. Between 2004 and 2007, 43 patients had one or more FISH assays performed as part of the workup and management of upper-tract TCC. Of 94 specimens sent for FISH analysis, 25 voided specimens collected at an outpatient encounter and 40 specimens taken as a bladder wash or selective upper-tract washing under anesthesia were followed by upper-tract endoscopy. The sensitivity and specificity of the FISH assay for detecting urothelial lesions in this population were calculated and compared with cytology specimens from the same sources. Overall sensitivity of FISH in the detection of TCC in this population was 52%, compared with 26% for urinary cytology. Both FISH and cytology showed superior sensitivity for high-grade (79% and 50%, respectively) nu low-grade tumors (41% and 12%, respectively). Selective upper-tract washings were more sensitive and specific for upper-tract TCC than bladder washings or voided specimens. While the sensitivity of FISH for upper-tract TCC parallels its performance in bladder cancer, the preponderance of low-grade, recurrent disease in the population undergoing surveillance and minimally invasive therapy for upper-tract TCC may limit its usefulness in this setting. Until a high-sensitivity marker for low-grade urothelial lesions is developed, the surveillance of upper-tract TCC will continue to require vigilant direct visual inspection.

Comparative Diagnostic Value of Urine Cytology, UBC-ELISA, and Fluorescence In Situ Hybridization for Detection of Transitional Cell Carcinoma of Urinary Bladder in Routine Clinical Practice

Fluorescence in situ hybridization (FISH) has been reported to have much better sensitivity for the detection of bladder transitional cell carcinoma (TCC) than urine cytology. We comparatively tested cytology, FISH, and the cytokeratin-detection test of urinary bladder cancer (UBC) in routine clinical practice. In a prospective study, FISH, the urinary bladder cancer test (UBC-enzyme-linked immunosorbent assay [ELISA]), and cytology were used in 166 patients. Of the 166 patients, 62 had primary TCC (group 1), 71 had undergone transurethral resection of primary TCC before routine secondary transurethral resection (group 2), and 33 control had not undergone TCC (group 3). All patients with false-positive test results were followed up for a mean follow-up time of 22 months. The overall sensitivity of FISH, UBC-ELISA, and cytology was 53.2% (95% confidence interval 40% to 66%), 40.3% (95% confidence interval 28% to 53%), and 71.0% (95% confidence interval 59% to 83%), respectively (P <0.05). For grade 3 TCC, both FISH and cytology reached a sensitivity of 93.3%. In the 104 patients without TCC, the specificity of FISH, UBC-ELISA, and cytology was 74.0%, 75.0%, and 83.7%, respectively. During follow-up, 33.3% of patients with a false-positive FISH result developed recurrence, as did 23.1% with false-positive UBC results and 29.4% with false-positive cytology findings (P >0.05). Receiver operating characteristic analysis showed an area under the curve for FISH, UBC, and cytology of 0.636, 0.577, and 0.773, respectively. Only cytology and FISH were significantly predictive of a TCC finding on histologic examination (P <0.001 and P = 0.003, respectively). In routine clinical practice, conventional cytology in experienced hands can be superior to FISH. False-positive results with all three test systems used warrant a high suspicion of subclinical precursor lesions of TCC recurrence.

An appraisal of urine cytology in the diagnosis of transitional cell carcinoma of the urinary bladder

Background: Urine cytology has an acceptable sensitivity, & specificity that justifies its use in the current diagnostic protocol. In Iraq transitional cell carcinoma (TCC) constitute about 62.1 % of bladder cancer (which ranks the third according to the results of Iraqi Cancer Registry 1995-1997). Urine cytology used in the primary diagnosis, follow up, and in the screening programs of asymptomatic but high-risk patients.Patients and methods: This study was conducted on 93 patients, diagnosed or clinically suspected to have TCC of the urinary bladder attending to the Urological department in ALKadhimiya Teaching Hospital, AL-Yarmouk Teaching Hospital, and Baghdad Medical City. During the period from July 2004to July 2005. 76 were males & 17 were females.Urine cytological examination was done to those patients using two types of stain (hematoxylin and eosin, and papanicoloau stain) to detect malignant cells with the identification of the degree of differentiation, if possible, the cytological findings were correlated with the histopathological findings. And the cytological findings compared regarding each type of stain.Results:. Mean age of the patients was 59 year. Male:female ratio was 4.4:1. Main clinical presentation was hematuria (45.8%) of the total. Urine cytological examination has a sensitivity of 87.7%, specificity of 100% with an overall accuracy of 78% in the detection of TCC of urinary bladder. The main chief complaint of patients with TCC was haematuriawitch constitute 45.8% of the total. The percentage of highgrade cases in urine cytology was higher than that in histopathology.the percentage of cases of TCC diagnosed by papanicoloau stain was more than that diagnosed by H & E (73.24% by pap stain versus 70.42% by H&E).Conclusion: Urine cytology has an acceptable sensitivity, specificity and an overall accuracy in the diagnosis of TCC of urinary bladder, and it offers a good chance for determination of the grade of the tumor especially in high grade tumor. Pap stain was better in the diagnosis of TCC.

A Comparison of Hexaminolevulinate Fluorescence Cystoscopy and White Light Cystoscopy for the Detection of Carcinoma In Situ in Patients With Bladder Cancer: A Phase III, Multicenter Study

We compared hexaminolevulinate (Hexvix) fluorescence cystoscopy with white light cystoscopy for detecting carcinoma in situ. In this multicenter study 298 patients with known or suspected bladder cancer underwent bladder instillation with 50 ml 8 mM hexaminolevulinate for 1 hour. Cystoscopy was then performed, first using standard white light and then hexaminolevulinate fluorescence cystoscopy. Lesions or suspicious areas identified under the 2 illumination conditions were mapped and biopsied for histological examination. In addition, 1 directed biopsy was obtained from an area appearing to be normal. Of 196 evaluable patients 29.6% (58 of 196) had carcinoma in situ, including 18 with carcinoma in situ alone, and 35 with carcinoma in situ and concomitant papillary disease, which was only detected on random biopsy in 5. Of the 18 patients with no concomitant papillary disease carcinoma in situ was detected only by hexaminolevulinate fluorescence in 4 and only by white light in 4. In the group with concomitant papillary disease carcinoma in situ was found only by hexaminolevulinate fluorescence in 5 patients and only by white light in 3. The proportion of patients in whom 1 or more carcinoma in situ lesions were found only by hexaminolevulinate cystoscopy was greater than the hypothesized 5% (p=0.0022). Overall more carcinoma in situ lesions were found by hexaminolevulinate than by white light cystoscopy in 22 of 58 patients (41.5%), while the converse occurred in 8 of 58 (15.1%). Biopsy results confirmed cystoscopy findings. Of a total of 113 carcinoma in situ lesions in 58 patients 104 (92%) were detected by hexaminolevulinate cystoscopy and 77 (68%) were detected by white light cystoscopy, while 5 were detected only on directed visually normal mucosal biopsy. Hexaminolevulinate instillation was well tolerated with no local or systemic side effects. In patients with bladder cancer hexaminolevulinate fluorescence cystoscopy with blue light can diagnose carcinoma in situ that may be missed with white light cystoscopy. Hexaminolevulinate fluorescence cystoscopy can be used in conjunction with white light cystoscopy to aid in the diagnosis of this form of bladder cancer.