The high recurrence rate of BC requires long-term regular follow-ups . Non-invasive urine testing is ideal for both the patient and the healthcare system . Among non-invasive urine tests, urine tests with molecular biomarkers are promising tools for diagnosing BC. However, these tests are still not well established in daily clinical routine and in the standard diagnostic workup of BC. Further evaluation of the usefulness of these biomarkers in complex clinical situations is needed before they are recommended for widespread clinical use.
The BTA stat test is a molecular urine test for BC that that is currently subject to the most attention. The BTA stat test specifically recognizes bladder tumour-associated antigen (hCFHrp) in urine through monoclonal antibodies. This antigenic protein is considered to be isolated from the urine of patients with BC but cannot be detected in the urine of most healthy individuals . Previous studies have compared the sensitivity of the BTA stat test and cytology detection in patients with BC diagnosed by cystoscopy, and the sensitivity of the BTA stat test was found to be superior to urine cytology and bladder irrigation cytology [20–22]. However, its effectiveness in real-world clinical situations, especially its specificity under different interference situations, needs further observations. In this study, we investigated the sensitivity and specificity of the BTA stat test in patients who were diagnosed with BC, and more importantly, we investigated the influence of haematuria on the performance of the BTA stat test in a clinical cohort.
Our overall sensitivity results were similar to those published by Dov Pode et al. for the sensitivity of the BTA stat test in detecting bladder tumours . In a European multicentre study of 107 patients with a final diagnosis of BC confirmed by cystoscopy and biopsy, the overall sensitivity of the BTA stat test was 72% . In the Rüdiger Heicappell et al. study, they reported sensitivities for grade I, II, and III disease to be 59.1%, 50%, and 77.3%, respectively . By contrast, we demonstrated higher sensitivities of 80%, 70 and 97.75% for PUNLMP, low-grade and high-grade tumours, respectively. These results may be related to different tumour grading methods. More importantly, our analysis of the overall sensitivity included patients with haematuria, which may show higher sensitivity due to false positives. When patients with haematuria were removed from this analysis, the overall sensitivity of the BTA stat test was 80.77%. If you analyse only patients with haematuria, the overall sensitivity of the BTA stat test was 97.22%. In our study, the specificity of the BTA stat test was 100% in healthy volunteers, and this result was within the ranges reported by other authors, thus excluding the possibility of technical or analytical errors . Although the specificity of the BTA stat test is high in healthy individuals, disappointing results have nevertheless occurred in patients with other urologic diseases. In a multicentre US study, the specificity of the BTA stat test in patients with BPH, urolithiasis and UTI was 88.5%, 50% and 76%, respectively . These variations may be explained by inherent influencing variables such as infection, trauma, and calculi [10, 23]. Our study showed even lower specificity; the specificity of the BTA stat test decreased to only 31.89% and 15.52% in patients with urolithiasis and UTI, respectively. In patients with prostatic cancer and renal cancer, the specificity of the BTA stat test was only 44.87% and 48.39%, respectively. This may be because we did not exclude patients with haematuria from our total enrolment.
Our results suggested that haematuria leads to high positive rates. On the one hand, the majority of patients with BC will present with haematuria [13, 14]. Considering that hCFHrp is a serum factor, the BTA stat test can possibly concomitantly detect serum proteins that cause haematuria. Another study supports our conclusion; the Makito Miyake group built an experimental haematuria model. They added whole blood to BTA-negative urine samples and found that spiking BTA-negative urine samples with as little as 1 µl whole blood /10 ml urine was enough to produce a positive BTA stat test result . On the other hand, haematuria is the most common symptom in urology patients. In many benign or tumorous urologic diseases, haematuria is often the only manifestation . Even 9–18% of normal individuals also have some degree of haematuria . This fact means that the BTA stat test may be prone to detect particularly high false positives in haematuria patients. We analysed patients with haematuria symptoms in a clinical setting and found that the specificity of the BTA stat test was only 15.82% for all groups of patients with haematuria. The meaning of these data is that when only patients with haematuria symptoms who were suspected of having BC were considered, the specificity of diagnosing BC with the BTA stat test was only 15%. In addition, the proportion of BC patients with haematuria is very small. Previous studies have shown that only 0.7–1.3% of patients with haematuria actually have BC [13, 15, 16]. In this case, if the BTA stat test has such a high false-positive rate for haematuria, it will lack further directivity, and its clinical utility and benefit will be low. The cost of screening includes the cost of labelling each patient and the cost of evaluating patients with false-positive results. Adding any test to the clinical assessment will increase costs; thus, the cost-effectiveness needs to be balanced by the benefits. Optimal screening strategies require identifying a method with high specificity and reasonable sensitivity in a population with significant disease prevalence . The specificity of the marker plays a key role because more patients with false-positive results correlates with needing additional “unnecessary” tests. Our results suggest that the BTA stat test cannot achieve ideal effective specificity and that using it to screen and monitor for BC may lead to “unnecessary” costs. Of course, further studies can compare and analyse the specific costs involved in the clinical practice of qualitative urinary tract testing. However, there are no available data on this problem.