To our knowledge, this is the first meta-analysis of the diagnostic efficacy for TA in BC. We found that TA is optimal among various other indicators and proved to be an excellent diagnostic.
BC, as a malignant tumor with high morbidity and mortality, has received wide attention, both for its diagnosis and treatment . As accepted, cystoscopy has been the gold standard for the diagnosis of BC. Despite its reliability, as an invasive examination, it is performed under local anaesthesia, causing strong discomfort to patients . A simpler diagnostic would be preferable and would also minimize the damage caused by the examination. There is a shift in the continuous detection and development of BC test methods from macro to micro, and role of markers in urine is being explored for the detection and diagnosis of BC [18, 19].
Telomeres are composed of repeated gene sequences and related proteins. Their main role is to avoid end-to-end fusion and nuclear cleavage during chromosome division . Telomerase reverse telomeres shortening during cell division. This is one of the essential processes for the permanent life of tumor cells . We hypothesized that in tumor cells, telomerase activity would be higher than in normal cells. Many scholars have studied the relationship between TA and BC, but due to limitations in detection technology and in sample size, the conclusions were so far inconsistent. We integrated and analysed research done by other authors and included a sample group large enough for performance of meta-analysis, aiming at comprehensive evaluation of the diagnostic validity for looking into TA in BC, with a goal of providing better guidance for clinical practice.
A number of studies have shown that the sensitivity of the telomerase assay for urothelial carcinoma is lower in voided urine specimens than in bladder washings [17, 22, 24]. However, urine is easier to obtain than bladder washings and also easier to collect from the patient’s perspective. In our meta-analysis, the overall sensitivity was 0.79 (95% CI: 0.72–0.84), the specificity was 0.91 (95% CI: 0.87–0.94) and the Youden index was 0.7. AUC was 0.92 (95% CI: 0.90–0.94), which was in line with our initial predictions. Using these composite indicators, we showed that TA could be a good and accurate indicator for the diagnosis of BC. A diagnostic test can typically be considered to have a high value when both sensitivity and specificity are >0.7. In this study, consistently with our predictions, the sensitivity results reached this value for 16 articles, again indicating the superiority of TA in the diagnosis of BC. However, the sensitivity values provided in the other 2 studies were significantly lower [17, 22]. The reason for this analysis was that, due to technical level of the test, the sample size, and bias between the samples, it might have lead to different final results. In relation to the specificity results, 21 of the included studies reached 0.7 or higher, showing that the results were not significantly different between the studies and confirming our hypothesis and indicating the excellent specificity of TA for the diagnosis of BC. The higher the value of DOR, the better the diagnostic ability for the selected method. In our study, the DOR value was 37.90 (95% CI: 23.32–61.59), suggesting that the overall accuracy was high. The overall PLR value was 8.91 (95% CI: 5.91–13.43), suggesting that patients with BC have a TA 8.91 times higher than normal, and a total NLR of 0.24 (95% CI: 0.15–0.37), meaning that normal individuals suffering from BC was of 25%. In the judging criteria, PLR>10, NLR<0.1, the diagnostic efficiency for this method was higher. Taking this aspect into account, we can conclude that the diagnostic efficiency of TA for BC is suboptimal.
To investigate the TA relationship between different staging and grading, we performed a subgroup analysis. In terms of staging, we considered Tis, Ta, and T0 as low-stage tumors, while T2-T4 as high stage. When grading, grade 1 was considered a low-grade tumor, and grades 2 and 3 were considered high-grade tumours. Thus, through meta-analysis, the association between these was evaluated. We found there was no absolute difference in TA between high-stage and low-stage tumours (P>0.05) or between different grades, using meta-analysis. Our results showed that the TA in low-grade tumours was significantly lower than in high-grade tumours (P=0.001). We believe that this is because the higher the grade, the lower the degree of differentiation, the stronger the invasive ability, and the higher the TA, consistently with results reported by Bravaccini et al. . Detecting TA is not the only non-invasive method used in the diagnosis of BC, and other markers such as nuclear matrix protein (NMP)-22, bladder tumor antigen (BTA), Cytokeratin 20 could also be evaluated. Studies have reported that BTA and cytokeratin 20 are not sensitive markers for low-grade tumours. For grade 1 tumours, the sensitivity of BTA and cytokeratin were 13% and 6%, respectively, and NMP-22 had a specificity of 70% in the diagnosis of BC [9, 22, 25]. Therefore, as individual indicators, these markers may work better than invasive methods, but the diagnostic performance should take into consideration composite indicators. As seen by our meta-analysis, the overall diagnostic ability of TA proved to be superior.
We followed the PRISM guidelines for our meta-analysis . However, at present, our meta-analysis still has some limitations. Firstly, of all the studies included here, most of the research samples were from Europe and the United States, which may skew our research due to racial differences. Secondly, in each group of controlled studies, the patients studied may have presented with other diseases. Since the mechanisms are unknown for these, the interactions between the different diseases may have lead to changes in the accuracy of our results.. Due to the influence of the original data, we were unable have sufficient detail on the different stages and grades of tumours. Compared with cystoscopy, although not currently applied in the clinic, TA does have a higher advantage in the diagnosis of BC due to its relatively high sensitivity and non-invasiveness. A larger sample size, as well as a more rigorous study design, and longer follow-up randomized controlled trials will be needed to validate our results in the future.