Introduction

Bladder cancer is the fourth most common type of cancer among men and the eighth most common among women. Each year more than 50,000 and 24,000 new bladder cancers are diagnosed in the US and in Germany, respectively.1,2 Patients with bladder cancer are treated for painless microhaematuria or gross haematuria in the absence of urinary tract infection (UTI) and/or irritative voiding symptoms.

The gold standard for detecting bladder cancer is cystoscopy. Cystoscopy is a reliable investigation that identifies nearly all papillary and sessile lesions. It is an invasive procedure causing some discomfort for patients. At initial diagnosis, 65% to 70% of bladder cancers are confined to the urothelium (Ta, Tis) or invade the lamina propria (T1) and can be managed with endoscopic resection and intravesical therapy. Thirty per cent to 35% of newly diagnosed bladder cancers have invaded the detrusor muscle (T2–T4).^3–5 Ta, grade 1 and grade 2 tumours recur in 30% to 70% and progress to muscle-invasive disease in less than 7% of patients. In contrast, high-grade stage T1 tumours have a progression rate of 30% to 50%.^3–5 The high recurrence rate and the risk of progression necessitate follow-up care after treatment for bladder cancer at regular intervals. Follow-up protocols include cystoscopy every three months for one to two years, every six months for an additional two to three years and then annually.

To improve early detection of bladder cancer, as well as to monitor treatment response and tumour recurrence, bladder tumour markers are critical. An ideal bladder cancer test would be non-invasive, highly sensitive and specific, inexpensive, easy to perform and yield highly reproducible results.⁶ The validity of a tumour marker test can be expressed as sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). Sensitivity and specificity are terms in statistics for the probability of the identification of those with or without the condition (bladder cancer). PPV and NPV are terms for the probability of the usefulness of a test in identifying true positives or true negatives. Definitions of these are shown in Figure 1. An accurate tumour marker also would have the potential to replace or delay cystoscopy in the follow-up of bladder cancer patients. If the test for a bladder cancer marker accomplished these criteria, this would improve the quality of life of patients and decrease the cost of surveillance by substituting a less expensive test for a more expensive procedure.7 In recent years several non-invasive tests for tumour markers have been approved by the US Food and Drug Administration (FDA). In this article, literature on the commercially available tests for the diagnosis of bladder cancer – ImmunoCyt/uCyt+, BTA TRAK^®, BTA stat^®, NMP22^®, NMP22 Bladder- Chek^®, and UroVysion™ – are summarised.

Bladder Tumour Markers

Urine Cytology

Currently, urine cytology is the standard non-invasive marker. In a recent literature review, specificity of cytology ranged from 83% to 99.7% with a mean ± standard deviation (SD) of 99% and sensitivity ranged from 20% to 53% with a mean ± SD of 34%.⁸ The poor sensitivity of 15% both in Ta and G1 bladder cancers and of 46% in T1 tumours is unfavourable. Other reviews of published studies have shown similar results with an overall sensitivity of 35% to 49% and a specificity of 90% to 95%.7,9 Due to the poor diagnostic sensitivity for superficial and low-grade bladder cancers, cytology cannot replace cystoscopy. Furthermore, cytology is subjective and requires highly trained cytopathologists.

ImmunoCyt/uCyt+ test

The ImmunoCyt/uCyt+ assay (Diagnocure Inc., Québec, Canada) is an immunocytologic fluorescence assay in combination with voided urine cytology. Its evaluation requires an experienced cytopathologist. The assay identifies two different mucins and a highmolecular- weight glycosylated carcinoembryonic antigen (CEA) present in tumour cells originating from transitional epithelium. The mucins and CEA are tagged to the two monoclonal anti-mucin antibodies M344 and LDQ10 ⁽¹⁴⁾ and the monoclonal anti-CEA antibody 19A21110,¹¹, which are labelled with fluorescein isothiocyanate (FITC) and Texas Red (TR), respectively. The ImmunoCyt/uCyt+ assay promises a higher diagnostic sensitivity than urine cytology. ImmunoCyt/uCyt+ has been demonstrated to have an overall sensitivity of 73% (range 39% to 100%) and an overall specificity of 80% (range 69% to 95%) (see Table 1).^12–20 The PPV and NPV were 52% (range 39% to 63%) and 89% (range 81% to 97%), respectively (see Table 7).^12,13,17,19 In the first study by Fradet et al.20 involving 198 patients with bladder cancer, ImmunoCyt/uCyt+ had an overall sensitivity of 90%, while overall sensitivity of urine cytology was 44%. Combined evaluation of ImmunoCyt/uCyt+ and cytology indicated 95% sensitivity. Specificity of ImmunoCyt/uCyt+ alone and in combination with cytology in 102 asymptomatic volunteers was 77%, whereas cytology alone had 100% specificity. These data were confirmed by the study pursued by Mian et al.,¹⁹ who diagnosed 264 consecutive patients including 79 with transitional cell carcinoma of the urinary tract. ImmunoCyt/uCyt+, urine cytology and both tests combined had an overall sensitivity of 86%, 47% and 90%, respectively. Specificity of ImmunoCyt/uCyt+ alone and combined with cytology amounted to 79%. Cytology alone was 98% specific. In the series of 121 patients, including 11 pTaG1–2, eight pT1G2–3 and seven pT2G2–3 carcinoma, 39% sensitivity for ImmunoCyt/uCyt+ and 35% for cytology was found. The combined sensitivity was 54%. Specificity of ImmunoCyt/uCyt+ and cytology was 84% and 92%; respectively. The combination of both tests revealed 82% specificity.¹⁵ These studies have shown a higher sensitivity for ImmunoCyt/uCyt+ compared with urine cytology. ImmunoCyt/uCyt+ cannot replace cystoscopy, but it may prove useful as an adjunct to cytology in the management of bladder cancer.