European Urology
European Urology 41 (2002) 34±39
Qualitative and Quantitative Detection of Urinary Human Complement Factor H-Related Protein (BTA stat and BTA TRAK) and Fragments of Cytokeratins 8, 18 (UBC Rapid and UBC IRMA) as Markers for Transitional Cell Carcinoma of the Bladder M. Babjuka,*, M. KosÏtõÂrÏovaÂb, K. Mudrac, S. Pechera, H. SmolovaÂa, L. Pecend, Z. Ibrahima, J. DvorÏaÂcÏeka, L. JarolõÂma, J. NovaÂka, T. Zimab a
Department of Urology, General Teaching Hospital, 1st Medical Faculty, Charles University, Postgraduate Institute, Prague, Czech Republic Department of Clinical Biochemistry, General Teaching Hospital, 1st Medical Faculty, Charles University, Prague, Czech Republic c Department of Nuclear Medicine, General Military Hospital, Prague, Czech Republic d Institute of Computer Science, Academy of Sciences, Prague, Czech Republic b
Accepted 17 July 2001
Abstract Objective: To evaluate the role of BTA stat, BTA TRAK, UBC Rapid, UBC IRMA and voided urinary cytology in the detection of bladder transitional cell carcinoma (TCC). Methods: The study included 78 patients with TCC of the bladder (group A), 62 patients with a history of bladder TCC without tumor recurrence at the time of examination (B, control group), 20 patients with other malignancy of the urinary tract (C), 38 patients with non-malignant urinary tract diseases (D), 10 patients with urinary tract infection (E) and 10 healthy volunteers (F). Except in group F, voided urine was collected before cystoscopy or cystectomy. Results: The speci®city and sensitivity in bladder cancer detection were 87.1 and 74.4%, respectively with BTA stat, 79.3 and 48.7%, respectively with UBC Rapid, 100 and 33.3%, respectively with cytology, 72.6 and 75.6%, respectively with BTA TRAK, 64.5 and 70.5%, respectively with UBC IRMA. Conclusions: The BTA stat and BTA TRAK tests are superior to UBC Rapid, UBC IRMA and urinary cytology in detection of bladder TCC. In daily practice however cytology remains the best adjunct to cystoscopy because of its high sensitivity in Tis and 100% speci®city. Cystoscopy cannot be replaced by any of evaluated methods. # 2002 Elsevier Science B.V. All rights reserved. Keywords: TCC of the bladder; BTA stat and BTA TRAK; UBC Rapid and UBC IRMA; Urinary cytology 1. Introduction Cystoscopy is a routine method used to detect both primary and recurrent bladder tumors. This method is expensive, time-consuming and in spite of ¯exible instruments, still uncomfortable for the patient. Urinary cytology can supplement cystoscopy, especially in the detection of carcinoma in situ (Tis), but cannot be used as an independent method. Signi®cant improvement in bladder transitional cell carcinoma (TCC) *
Corresponding author. Tel. 420-2-24967888; Fax: 420-2-24921691. E-mail address:
[email protected] (M. Babjuk).
diagnosis could be achieved if a simple and noninvasive diagnostic test was designed. Recently, several methods have been introduced into daily practice which detect TCC using urine analysis [1±4]. These tests are based on different principles and according to various authors have greater sensitivity, but lower speci®city in TCC detection than cytology [5±8]. In our prospective study we evaluate the results of two methods, based on different antigen determination, which are available in quantitative forms and also in qualitative quick point of care tests. The bladder tumorassociated antigen detected by the BTA TRAK assay
0302-2838/02/$ ± see front matter # 2002 Elsevier Science B.V. All rights reserved. PII: S 0 3 0 2 - 2 8 3 8 ( 0 1 ) 0 0 0 1 5 - X
M. Babjuk et al. / European Urology 41 (2002) 34±39
and the BTA stat test has been identi®ed as a human complement factor H-related protein, similar in structure and function to human complement factor H [9]. Both UBC IRMA and UBC Rapid tests detect an urinary bladder cancer antigen. This antigen is composed of urinary fragments of cytokeratins 8 and 18, which are typically expressed in malignant urothelium [4]. We evaluate the sensitivity and speci®city of individual tests. The results are compared to the results of the urinary cytology. Finally, possibilities and contribution of their clinical application are discussed. 2. Patients and methods Urine samples were obtained from 218 subjects, who were divided into six groups (A±F, Table 1). Group A was comprised of 78 patients with histologically con®rmed bladder TCC. Urine samples were collected before transurethral resection or cystectomy. The tumors were classi®ed according to the TNM system [10]. Of the tumors, 58 were super®cial and 20 were invasive. Tumor grade was assessed according to the World Health Organization system, 27 tumors were grade I, 27 were grade II and 24 were grade III. Group B was comprised of 62 patients with a history of super®cial bladder cancer in whom cystoscopy did not reveal tumor recurrence. Excluded were patients with intravesical chemotherapy or immunotherapy applied up to 3 months previously. All of these 62 patients were followed for another 12±18 months later without signs of tumor recurrence. In group C patients with other malignancies and in group D patients with non-malignant urological disease were included. Group E was comprised of patients with a urinary tract infection con®rmed by means of urine culture. These patients suffered from benign urological disease with subvesical obstruction. All of the patients in groups C±E were negative for bladder carcinoma as con®rmed by cystoscopy. Group F was comprised of healthy volunteers, who never underwent treatment for disease of the urinary tract and did not suffer from urinary tract symptomatology. Their self-reported current health status was not con®rmed by medical examination or by cystoscopy. Except for group E, only patients with a negative urine culture were included. Due to urinary tract infection, 5 patients were excluded from the original number of 223.
35
Each subject included in the study submitted a single voided urine sample, not earlier than 48 h before the performed cystoscopy or cystectomy. The urine was immediately separated into six aliquots for individual evaluation and for urine culture. Aliquots 1 and 2 were used to perform the qualitative tests (BTA stat test, Bion Diagnostic Sciences, USA and IDeaL UBC Rapid test, IDL Biotech AB, Sweden). These tests were performed according to the instructions by a trained nurse. Because of problems with the distribution of UBC Rapid, this test was not performed in groups E and F and the number of investigated cases in group B had to be restricted to 29. Aliquot 3 was centrifuged and stained according to Papanicolaou's method and specimens were evaluated by an experienced cytopathologist. Cytology was reported negative if the slide contained only normal transitional cells or reactive changes. A sample was de®ned as positive when obvious cancer cells or highly suspicious cells were present. Features not clearly indicative of malignancy were reported as suspect. In the evaluation of this study, reported suspect cells were not considered abnormal. Aliquots 4 and 5 were sent separately to two laboratories to perform the quantitative tests (BTA TRAK, Bion Diagnostic Sciences, USA and IDeaL Monoclonal UBC IRMA, IDL Biotech AB, Sweden). All of the samples were processed according to the instructions inserted in the manufacturer's kit. Because of interindividual variations of urine concentrations, UBC IRMA results adjusted for urinary creatinine were also determined. Urinary creatinine was measured by an enzymatic colorimetric method in the analyzer. Aliquot 6 was submitted for standard urine culture analysis. Endoscopy and transurethral resections were performed by an experienced urologist. In cases with suspect ®ndings in groups B±E, a biopsy for histological evaluation was taken. Sensitivity was de®ned as the probability of the evaluated marker to be positive in the case of bladder cancer diagnosis. Speci®city was de®ned as the probability of a negative value of the evaluated marker in the case of negative cystoscopy. Patients from group B were used as the reference group for the determination of speci®city. Positive predictive value was de®ned as the probability that the patient with the positive marker had bladder cancer. Negative predictive value was de®ned as the probability that the patient with the negative marker had a negative cystoscopy. Accuracy was de®ned as the percentage of the sum of true positive and true negative results among evaluated cases. In quantitative tests the cut-offs suggested by the manufacturer's instructions (14 U/ml for BTATRAK and 12 mg/l for UBC IRMA) were used. For comparison of the two tests or of their combinations, the distributions of misclassi®ed cases were compared using Mahala-
Table 1 Patients characteristics Group
N
Sex distribution
Mean age
Group composition
A (bladder TCC)
78
31 Female, 47 male
69.4
B (history of bladder TCC without recurrence) C (other urinary tract malignancies)
62 20
24 Female, 38 male 7 Female, 13 male
67.4 60.5
20 pTaGI, 9 pTaGII, 7 pT1GI, 13 pT1GII, 6 pT1GIII, 3 pTisGIII 5 pT2GII, 2 pT2GIII, 8 pT3GIII, 5 pT4GIII
D (non-malignant urological diseases)
38
6 Female, 32 male
68.0
E (urinary tract infection) F (healthy volunteers)
10 10
4 Female, 6 male 5 Female, 5 male
68.9 37.2
9 Prostate cancers, 9 renal cell cancers, 2 bowel tumors with bladder wall infiltration 22 BPH, 6 urethral strictures, 4 neurogenic bladders, 5 urolithiasis, 1 pyeloureteral stenosis
36
M. Babjuk et al. / European Urology 41 (2002) 34±39
nobis' distance. This model was implemented in Statistical Analyses Software release 6.12, SAS Institute Inc., Cary, USA.
3. Results The median values of BTA TRAK and UBC IRMA were 100.0 (0.1±6900.0 U/ml) and 40.65 (0.1± 2357.0 mg/l) in group A and 7.99 (0.1±189.0 U/ml) and 4.16 (0.1±329.6 mg/l) in group B. In both methods these values were signi®cantly different (P < 0:0001 for both BTA TRAK and UBC IRMA, Kruskal±Wallis test). The number of positive results of BTA stat (P < 0:001), UBC Rapid (P < 0:009) and cytology (P < 0:001) differed signi®cantly between groups A and B. There was no statistical difference in age (P < 0:2895, Wilcoxon's test) and sex distribution (P < 0:6502, Chi-square test) between groups A and B. The median creatinine values were 1.090 g/l in group A, 1.165 g/l in group B, 0.980 g/l in group C, 1.080 g/l in group D, 1.075 in group E and 1.555 in group F, which was not statistically different (Wilcoxon's test). The diagnostic characteristics of urinary tumor markers are shown in Table 2. The speci®city and sensitivity in bladder cancer detection were 87.1 and 74.4%, respectively with BTA stat, 79.3% (calculated only on 29 patients in group B) and 48.7%, respectively with UBC Rapid, 100 and 33.3%, respectively with
cytology, 72.6 and 75.6%, respectively with BTA TRAK, 64.5 and 70.5%, respectively with UBC IRMA. The adjustment for urinary creatinine levels did not change the speci®city or sensitivity of UBC IRMA (data not shown). The results of BTA stat were signi®cantly better than those of UBC Rapid (P < 0:0001) and urinary cytology (P < 0:0001). The results of BTA TRAK were signi®cantly better then those of UBC IRMA (P < 0:01). Sensitivity in the detection of invasive tumors was higher as compared to the detection of super®cial tumors in all of the evaluated tests except in the case of UBC IRMA and it increased with increasing tumor grade (Table 3). Table 4 displays the results obtained by combining individual methods. Because only 29 patients were investigated with UBC Rapid in group B, combinations with this test are not mentioned. The best results were obtained by combining the BTA stat test with cytology, but even this combination was not signi®cantly better than the BTA stat test alone (P < 0:0843). The number of false positivities in patients with other urological diseases is mentioned in Table 5. In group C 30% of the results were false positive with BTA stat, 25% with UBC Rapid, 0% with cytology, 35% with BTATRAK, and 65% with UBC IRMA. In group D the false positives were 13.2, 15.8, 0, 28.9 and 60.5%, respectively. All investigated methods were negative in healthy volunteers.
Table 2 Sensitivity, specificity, negative and positive predictive values and accuracy of evaluated markersa
Specificity (%) Sensitivity (%) Negative predictive value (%) Positive predictive value (%) Accuracy (%) a
BTA stat
UBC Rapid
Cytology
BTA TRAK
UBC IRMA
87.1 74.4 73.0 87.9 80.0
79.3 48.7 36.5 86.4 57.0
100.0 33.3 54.4 100.0 67.7
72.6 75.6 70.3 77.6 74.3
64.5 70.5 63.5 71.4 67.9
UBC Rapid was performed in all patients with bladder cancer, but only in 29 of the cases in the reference group.
Table 3 Sensitivities (%) determined for various tumor characteristics
All superficial Ta T1 Tis All invasive T2 T3±4 GI GII GIII
No.
BTA stat
UBC Rapid
Cytology
BTA TRAK
UBC IRMA
58 29 26 3 20 7 13 27 27 24
69.0 58.6 76.9 100.0 90.0 85.7 92.3 59.3 74.1 91.7
44.8 37.9 46.2 100.0 60.0 57.1 61.5 33.3 51.9 62.5
29.3 3.5 50.0 100.0 45.0 28.6 53.9 3.7 40.7 58.3
72.4 55.2 88.5 100.0 85.0 85.7 84.6 59.3 77.8 91.7
70.7 62.1 80.9 66.7 70.0 57.1 76.9 59.3 74.1 79.2
M. Babjuk et al. / European Urology 41 (2002) 34±39
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Table 4 Specificities and sensitivities of the simultaneous evaluation of the various methods Specificity (%)
BTA stat cytology BTA TRAK UBC IRMA BTA TRAK cytology
87.1 46.8 72.6
Sensitivity (%) All
Superficial tumors
Invasive tumors
GI
GII
GIII
80.3 88.5 78.2
75.0 87.9 74.1
95.0 90.0 90.0
61.5 81.5 59.3
80.8 88.9 81.5
100.0 95.8 95.8
Table 5 Rates of false positive results in patients with other urinary tract disease and in healthy volunteers
Prostate Ca (9) Renal Ca (9) Colon Ca with bladder infiltration (2) BPH (22) Neurogenic bladder (4) Lithiasis (5) Urethral stricture (6) Pyeloureteral stenosis (1) Urinary tract infection (10) Healthy volunteers (10)
No. BTA stat (%)
No. UBC Rapid (%)
No. cytology (%)
No. BTA TRAK (%)
No. UBC IRMA (%)
0 4 2 1 1 2 1 0 7 0
2 1 2 2 1 2 1 0 ± ±
0 0 0 0 0 0 0 0 0 0
3 3 1 6 2 1 2 0 8 0
6 5 2 14 2 2 5 0 8 0
(0.0) (44.4) (100.0) (4.5) (25.0) (40.0) (16.7) (0.0) (70.0) (0.0)
4. Discussion Bladder cancer ranks as the 6th leading cause of cancer in men and the 13th in women in our country and its incidence is continually on the rise [11]. The social and economical importance of this disease indicates a need for a non-invasive method which will be able to detect bladder tumors both rapidly and reliably. In our study we evaluated methods based on the detection of different types of antigens. Voided urinary cytology was also included, because it is still considered the standard in non-invasive bladder cancer detection. By planning our study, we decided to include in our control group only patients with a history of super®cial bladder cancer in whom cystoscopy did not reveal tumor recurrence. We realized however the possible inaccuracy resulting from the inadequate sensitivity of cystoscopy. The positive ®ndings in the control group might possibly indicate tumor presence not visible during cystoscopy [12]. For this reason all patients in the control group were followed cystoscopically another 12±18 months without evidence of tumor recurrence. The sensitivity obtained using the BTA stat test correlated in our study with prior published results [2,5±8]. The high speci®city can be explained, similarly as in another studies, by the composition of the control group, from which patients with urinary tract infections and patients with previous intravesical therapy were excluded [7,13].
(22.2) (11.1) (100.0) (9.1) (25.0) (40.0) (16.7) (0.0)
(0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0)
(33.3) (33.3) (50.0) (27.3) (50.0) (20.0) (33.3) (0.0) (80.0) (0.0)
(66.7) (55.6) (100.0) (63.6) (50.0) (40.0) (83.3) (0.0) (80.0) (0.0)
The BTA stat showed in our study, the higher speci®city and the lower sensitivity than the BTA TRAK. With BTA TRAK a slightly higher sensitivity in GII and GIII tumors as compared to previously published results were found [14,15]. The previously published results of UBC Rapid showed high speci®city and sensitivity, which were superior to BTA stat test [16,17]. Our data however did not con®rm promising results of this test. In previous studies, the quantitative detection of cytokeratins 8 and 18 was performed by UBC ELISA [4,18,19]. Our data was obtained using UBC IRMA and showed similar sensitivities but lower speci®city. This ®nding is probably due to the high number of false positives in patients with other diseases of the lower urinary tract as is demonstrated in Table 5. As in some other studies [8,20] we decided to consider suspect cytological ®ndings as normal. This approach, in connection with the experience of a cytologist, allowed for 100% speci®city. If we put our suspect ®ndings abnormal, the sensitivity would increase up to 55.1%, but the speci®city would decrease to 90.3%. In this case, false positive results in groups C±E would appear. Later on, we discuss why we consider 100% speci®city of cytology as the most important contribution of the method for routine application. Lately, several studies have been published which utilize various methods to detect bladder TCC. In most of these articles however, a critical evaluation of the practical use of these markers is missing. Our results
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M. Babjuk et al. / European Urology 41 (2002) 34±39
demonstrate the statistical superiority of BTA stat and BTA TRAK tests to UBC Rapid, UBC IRMA and cytology. But is this superiority a real contribution for daily practice? In order to reach a clear conclusion concerning the routine application of evaluated methods, in our opinion three following questions that must be answered: 1. Can cystoscopy be replaced by any of evaluated methods? Clearly the answer is no, because none of the tests are 100% specific and 100% sensitive. 2. Is there any sense in using a method of evaluation as an adjunct to cystoscopy? Are any of these methods effective in improving the accuracy of cystoscopy in the detection of Tis? Such a method should be not only highly sensitive in Tis detection, but also should be highly specific in order to spare the patient unnecessary biopsies. According to our results, the best ``adjunctive method'' is cytology, which is 100% sensitive in Tis and in the hands of an experienced cytologist also 100% specific. The specificity of BTA stat and UBC Rapid is much lower and both quantitative tests with cut-off values set on the levels with 100% specificity (189 U/ml in BTA TRAK and 329.6 mg/l in UBC IRMA) reached only 33.3% sensitivity in Tis. 3. Can any of evaluated methods be used for extension of the interval between cystoscopies during surveillance after TUR of superficial bladder tumor? As such a method must be highly sensitive the best results in our study were obtained using quantitative tests with low cut-off levels. By decreasing the cut-off level of BTA TRAK to 2.89 U/ml, a sensitivity of 94.9% and a specificity of 19.4% was reached. In patients with a BTA TRAK value below this cut-off level, a longer interval between cystoscopies can be considered. The frequency of cystoscopies can thus be decreased in 20% of patients without tumor recurrence with a risk of later diagnosis in 5% of tumors. These results could be improved by combining BTA TRAK
with UBC IRMA. Using cut-off values of 7.75 U/ ml in BTA TRAK and 10.0 mg/l in UBC IRMA, a sensitivity of 94.9% and a specificity of 29.1% were reached. This application of the evaluated methods however, is accompanied by the risk of late tumor detection and is profitable only for a small group of patients, as well as being expensive. For these reasons, it is, in our opinion, not advised for routine use. These conclusions can of course be hindered by inaccurate patient numbers in the control group or in individual bladder tumor stage (for example only three patients with Tis). However, in our opinion, our results indicate the present role of the evaluated methods in the clinical setting. 5. Conclusions The BTA stat and BTA TRAK tests are superior to the UBC Rapid, UBC IRMA and voided urinary cytology in the detection of the bladder TCC. In daily practice however cytology remains the best adjunctive method to cystoscopy because of high sensitivity in Tis detection and 100% speci®city. Quantitative tests (BTA TRAK or its combination with UBC IRMA) can help select the group of patients in whom a longer interval between cystoscopies in the follow-up after TUR can be considered. This method of use however, is expensive and not 100% reliable, which currently prevents its routine application. Cystoscopy cannot be replaced by any of the evaluated methods. Acknowledgements We are grateful to our nurses, Eva Slavkovska and Jaroslava CejnarovaÂ, for their assistance. The study was partially supported by the projects IGA MZ NC 5961-3 and MSÏMT J 13/98111100005.
References [1] Soloway MS, Briggman JV, Carpinito GA, Chodak GW, Church PA, Lamm DL et al. Use of a new tumor marker, urinary NMP22, in the detection of occult or rapidly recurring transitional cell carcinoma of the urinary tract following surgical treatment. J Urol 1996;156:363±7. [2] Sarosdy MF, Hudson MA, Ellis WJ, Soloway MS, deVere White R, Sheinfeld J et al. Improved detection of recurrent bladder cancer using the Bard BTA stat test. Urology 1997;50:349±53. [3] Kavaler E, Landman J, Chang Y, Droller MJ, Liu BC. Detecting human bladder carcinoma cells in voided urine samples by assaying for the presence of telomerase activity. Cancer 1998;82:708±14.
[4] SaÂnches-Carbayo M, Herrero E, Megias J, Mira A, Espasa A, Chinchilla V et al. Initial evaluation of the diagnostic performance of the new urinary bladder cancer antigen test as a tumor marker for transitional cell carcinoma of the bladder. J Urol 1999;161:1110±5. [5] Wiener HG, Mian CH, Haitel A, Pycha A, Schatzl G, Marberger M. Can urine bound diagnostic tests replace cystoscopy in the management of bladder cancer. J Urol 1998;159:1876±80. [6] Ramakumar S, Bhuiyan J, Besse JA, Roberts SG, Wollan PC, Blute ML et al. Comparison of screening methods in the detection of bladder cancer. J Urol 1999;161:388±94.
M. Babjuk et al. / European Urology 41 (2002) 34±39 [7] Pode D, Shapiro A, Wald M, Nativ O, Laufer M, Kaver I. Noninvasive detection of bladder cancer with the BTA stat test. J Urol 1999;161:443±6. [8] Leyh H, Marberger M, Conort P, Sternberg C, Pansadoro V, Pagano F et al. Comparison of the BTA stat test with voided urine cytology and bladder wash cytology in the diagnosis and monitoring of bladder cancer. Eur Urol 1999;35:52±6. [9] Kinders R, Jones T, Root R, Bruce C, Murchison H, Corey M et al. Complement factor H or a related protein is a marker for transitional cell cancer of the bladder. Clin Cancer Res 1998;4:2511±20. [10] Sobin LH, Wittekind C. UICC TNM Classification of Malignant Tumours, 4th ed. New York, Wiley, 1997, p. 187±90. [11] Kolcova V, Geryk E, Jechova M. Zhoubne Novotvary. Praha, GaleÂn, 1999. [12] Blumenstein BA, Ellis WJ, Ishak LM. The relationship between serial measurements of the level of a bladder tumor-associated antigen and the potential for recurrence. J Urol 1999;161:57±61. [13] Sharma S, Zippe CD, Pandrangi L, Nelson D, Agarwal A. Exclusion criteria enhance the specificity and positive predictive value of NMP22 and BTA stat. J Urol 1999;162:53±7. [14] Ellis WJ, Blumenstein BA, Ishak LM, Enfield DL. The multi-center study group: Clinical evaluation of the BTA TRAK assay and comparison to voided urine cytology and the Bard BTA test in patients with recurrent bladder tumors. Urology 1997;50:882±7.
Editorial Comment G. Thalmann Bern, Switzerland
For urologists, cystoscopy is part of every day life, but for patients, this investigation may be disagreeable. A variety of urinary markers are available on the market which are suggested to be able to replace cystoscopy in the follow up of patients with super®cial bladder cancer. Babjuk and colleagues evaluated four of these test kits based either on the detection of human complement factor h-related protein or on the detection of fragments of cytokeratins 8 and 18 in the urine. In their not very large series of patients, the message is yet quite clear and consistent with others in the literature that in daily practice cystoscopy is irreplaceable. While
39
[15] Heicappell R, Wettig IC, Schostak M, MuÈller M, Steiner U, Sauter T et al. Quantitative detection of human complement factor H-related protein in transitional cell carcinoma of the urinary bladder. Eur Urol 1999;35:81±7. [16] SaÂnches-Carbayo M, Herrero E, Megias J, Mira A, Soria F. Initial evaluation of the new urinary bladder cancer rapid test in the detection of transitional cell carcinoma of the bladder. Urology 1999;54:656±61. [17] Mian CH, Lodde M, Haitel A, Vigl EE, Marberger M, Pycha A. Comparison of two qualitative assays, the UBC Rapid test and the BTA stat test, in the diagnosis of urothelial cell carcinoma of the bladder. Urology 2000;56:228±31. [18] SaÂnches-Carbayo M, Herrero E, MegõÂas J, Mira A, Soria F. Comparative sensitivity of urinary cyfra 21-1, urinary bladder cancer antigen, tissue polypeptide antigen and NMP22 to detect bladder cancer. J Urol 1999;162:1951±6. [19] Mian CH, Lodde M, Haitel A, Vigl EE, Marberger M, Pycha A. Comparison of the monoclonal UBC ELISA test and the NMP22 ELISA test for the detection of urothelial cell carcinoma of the bladder. Urology 2000;55:223±6. [20] GreÂgoire M, Fradet Y, Meyer F, Tetu B, Bois R, BeÂdard G et al. Diagnostic accuracy of urinary cytology and deoxyribonucleic acid flow cytometry and cytology on bladder washings during follow-up for bladder tumors. J Urol 1997;157:1660±4.
this may be evident to us urologists, we need to address the issue of urinary tumor markers with our referring general practitioners and our patients in an objective manner in order to avoid tumors being missed. As in most studies evaluating the value of urinary markers, these are compared to voided urinary cytology but not to barbotage cytology. Again as in these studies one is confronted with values for sensitivity, speci®city, positive predictive value and others more which deter us from the basic question: can cystoscopy be replaced? Ultimately, only randomized studies will provide the answer whether follow up by urinary markers is feasible without risk to the patient and at what costs. Furthermore, ``non invasive'' follow up by urinary markers alone needs to be compared to ``invasive'' follow up by cystoscopy and barbotage cytology.
