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Diagnostic Accuracy of Bladder EpiCheck for Upper Tract Urothelial Carcinoma: A Meta-Analysis - Beyond the Abstract

Diagnostic evaluation of upper tract urothelial carcinoma (UTUC) typically combines CT urography (CTU), cytology, and ureteroscopy (URS) to enhance diagnostic accuracy.1 While CTU offers high sensitivity (Se) and specificity (Sp), it can yield false positives; and URS, although enabling minimally invasive direct visualization and biopsy, does not usually provide indeterminate results and can underestimate tumour grade, particularly for low-grade (LG) lesions.2 Urinary cytology has relatively low Se for LG tumours as well.3 Yet, discrepancies between CTU and URS may complicate clinical management.

In this context, various urinary biomarkers have emerged in the search for non-invasive, effective diagnosis tools; however, none are currently recommended for routine practice due to the need for further validation studies. In the manuscript published in Actas Urológicas Españolas,4 our group conducted a systematic review and meta-analysis on the diagnostic accuracy of Bladder EpiCheck® and its utility in the diagnostic and follow-up of UTUC.

Bladder EpiCheck® assesses DNA methylation changes using a panel of 15 genomic biomarkers, which, in the case of UTUC diagnosis, are preferentially collected from selective upper urinary tract urine samples. An EpiScore™ greater than 60 is considered a positive result.

This meta-analysis was performed following a comprehensive bibliographic search of PubMed, Web of Science, and Scopus databases through February 2024. Inclusion criteria comprised patients with suspected primary or recurrent UTUC. Articles providing exclusive data from bladder samples were excluded.

Overall, we combined the results of 334 patients (from four included articles: three prospective and one retrospective) with suspected UTUC. A previous history of UTUC and bladder cancer was present in 54 (33.3%) and 82 (32.54%) cases, respectively. UTUC was pathologically confirmed in 200 patients (59.5%), with the renal pelvis being the most common location. According to the OMS 2004/2016 classification, 79 patients (39.5%) were categorized as LG and 121 (60.5%) as HG.

The pooled Se, Sp, positive predictive value (PPV), and negative predictive value (NPV) were 0.85 (95% CI 0.55-0.96), 0.93 (95% CI 0.56-0.99), 0.74 (95% CI 0.54-0.87) and 0.84 (95% CI 0.77-0.89), respectively. The area under the curve (AUC) obtained and diagnostic odds ratio (DOR) were 0.912 and 9.8 (95% CI 5.57-17.25), respectively.

In bladder cancer, molecular assays—including Bladder EpiCheck®—are used more widely, and significant evidence supports their role in non-muscle invasive bladder cancer (NMIBC) detection and follow-up. Moreover, some groups already propose practical follow-up schedules integrating cystoscopy, Bladder EpiCheck®, cytology, and imaging tests, such as that outlined by Caño et al.5

Similar to bladder carcinoma, Bladder EpiCheck® performs better at diagnosing HG tumours in comparison to LG tumours,6 with Se values dropping from 95% to 68%, 100% to 57.7%, and 100% to 53.3% in the studies by Territo et al.7, Pycha et al.6 and Palermo et al, respectively.8 Similarly, Territo et al. also reported a decrease in NPV from 97% in HG cases to 80% in LG cases.7

While Bladder EpiCheck® has demonstrated excellent Se, Sp, and NPV, its PPV is somewhat more modest, so false positives can occur. Nonetheless, it can yield positive results even when tumors are not yet visible radiologically or endoscopically,9 as has already been demonstrated in NMIBC diagnosis.

In our analysis, Bladder EpiCheck® achieved 85% Se and 84% NPV for UTUC. Its high NPV makes it a valuable tool for ruling out UTUC, highlighting its potential as an adjunct to existing diagnostic tools (CTU, cytology, and URS). This test could help guide more accurate treatment decisions, aiding clinicians in choosing between nephroureterectomy and conservative kidney-sparing approaches. Furthermore, because Bladder EpiCheck® is minimally invasive, it could complement—or even replace—the need for a second-look URS, particularly for patients receiving kidney-sparing management.

Although this meta-analysis shows promising results regarding the performance of Bladder EpiCheck®, it is important to acknowledge its limitations, as significant heterogeneity was found between the included studies. This heterogeneity may stem from clinical and pathological differences; for example, Pierconti et al.10 included only an HG population, which could be associated with the test's overall better performance. To integrate Bladder EpiCheck® into clinical practice, further prospective, randomized, multicenter trials are needed.

Our conclusions:
Bladder EpiCheck® has proven to be an effective diagnostic tool for UTUC, demonstrating notable diagnostic accuracy and offering a promising option for diagnosis, treatment decision-making, and follow-up.

Its use in UTUC diagnosis and follow-up may reduce or delay the need for more invasive procedures, such as URS, thereby mitigating procedure-associated risks and improving patients’ quality of life

Written by: Artero Fullana, Silvia; Caño Velasco, Jorge; Polanco Pujol, Lucía; Lafuente Puentedura, Alfonso; Bataller Monfort, Victoria; Aragón Chamizo, Juan; Moralejo Gárate, Mercedes; Hernández Fernández, Carlos.

Urology Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain.

References:

  1. Zganjar AJ, Thiel DD, Lyon TD. Diagnosis, workup, and risk stratification of upper tract urothelial carcinoma. Transl Androl Urol. 2023;12:1456-1468.
  2. Freund JE, Duivenvoorden MJC, Sikma BT, Vernooij RWM, Savci-Heijink CD, Legemate JD, et al. The diagnostic yield and concordance of ureterorenoscopic biopsies for grading of upper tract urothelial carcinoma: a Dutch nationwide analysis. J Endourol. 2020;34:907-913.
  3. Messer J, Shariat SF, Brien JC, Herman MP, Ng CK, Scherr DS, et al. Urinary cytology has a poor performance for predicting invasive or high-grade upper-tract urothelial carcinoma. BJU Int. 2011;108:701-705.
  4. Artero Fullana S, Caño Velasco J, Lafuente Puentedura A, Polanco Pujol L, Bataller Monfort V, Moralejo Gárate M, et al. Diagnostic accuracy of Bladder EpiCheck for upper tract urothelial carcinoma: A meta-analysis. Actas Urol Esp (Engl Ed). 2025;501720. doi:10.1016/j.acuroe.2025.501720.
  5. Caño Velasco J, Polanco Pujol L, Moreno Cortés JC, Lafuente Puentedura A, Hernández Fernández C. Bladder Epicheck® for surveillance in high-risk non-muscle-invasive bladder cancer: initial experience and follow-up proposal. Actas Urol Esp (Engl Ed). 2023 Oct;47(8):471-473.
  6. Pycha S, Trenti E, Mian C, Schwienbacher C, Hanspeter E, Palermo M, et al. Diagnostic value of Xpert® BC Detection, Bladder Epicheck®, Urovysion® FISH and cytology in the detection of upper urinary tract urothelial carcinoma. World J Urol. 2023;41:1323-1328.
  7. Territo A, Gallioli A, Diana P, Boissier R, Fontana M, Gaya JM, et al. DNA methylation urine biomarkers test in the diagnosis of upper tract urothelial carcinoma: results from a single-center prospective clinical trial. J Urol. 2022;208:570-57.
  8. Palermo M, D’Elia C, Trenti E, Comploj E, Mian C, Schwienbacher C, et al. Prospective evaluation of the RT-PCR based urinary marker Bladder Epicheck® as a diagnostic tool in upper urinary tract tumor. Minerva Urol Nephrol. 2024;76:195-202.
  9. Overview | Bladder EpiCheck for detecting bladder cancer recurrence | Advice | NICE; 2022 [Accessed 30 June 2024].
  10. Pierconti F, Martini M, Fiorentino V, Cenci T, Racioppi M, Foschi N, et al. Upper urothelial tract high-grade carcinoma: comparison of urine cytology and DNA methylation analysis in urinary samples. Hum Pathol. 2021;118:42---8
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