Liquid-based biomarkers (LBBs), derived from urine and blood, are gaining attention in the management of upper tract urothelial carcinoma (UTUC) as potential tools to overcome limitations of current diagnostic and risk stratification pathways. This review evaluates emerging LBBs, focusing on diagnostic accuracy and their role in predicting high-grade and ≥pT2 disease.
A systematic search of MEDLINE, Embase, and the Cochrane CENTRAL (via Ovid) (January 2010-July 2024) identified studies reporting diagnostic performance of LBBs for UTUC, excluding urine cytology. Data on sensitivity, specificity, positive predictive value, negative predictive value, and area under the curve were extracted. A narrative synthesis was performed.
Thirty-two studies met the inclusion criteria. Among bladder-derived urine biomarkers, RNA-based panels (an eight-gene panel: sensitivity 86-92%, specificity 87-93%) (low certainty) and DNA methylation panels-GDF15, TMEFF2, and VIM (sensitivity 91%, specificity 100%), Bladder Care Index (sensitivity 96%, specificity 88%), NRN1 (sensitivity 92-96%, specificity 92-95%) and ONECUT (sensitivity 89%, specificity 94%) and protein-based panels (BTA-STAT, BTA, and survivin) showed favourable diagnostic profiles (very low certainty). Upper-tract urine assays, EpiCheck (sensitivity 65-83%, specificity 79-83%), demonstrated modest accuracy (very low certainty for sensitivity; low certainty for specificity) with strong performance for high-grade disease. Among blood biomarkers, circulating tumour DNA (ctDNA) with plasma copy number burden >6.5 achieved high accuracy for predicting ≥pT2 and high-grade disease (sensitivity 71%, specificity 94%) (low certainty).
RNA-based, DNA methylation-based, protein-based, and ctDNA-based assays showed promise for UTUC diagnosis and risk stratification. However, the current evidence is limited, with few validated studies. Large prospective cohorts and biomarker-driven interventional trials are needed before clinical integration.
European urology oncology. 2026 May 14 [Epub ahead of print]
Bhavan Prasad Rai, Karthik Rajan, Prabhakar Rajan, Benjamin Pradere, Otakar Capoun, Viktor Soukup, Paolo Gontero, Francesco Soria, Alison Birtle, Eva M Compérat, Jose-Luis Dominguez-Escrig, Yuhong Yuan, Fredrik Liedberg, Morgan Rouprêt, Thomas Seisen, Jeremy Y Teoh, Marco Moschini, Paramananthan Mariappan, Shahrokh F Shariat, Evanguelos Xylinas, Joyce Baard, David D'Andrea, Bas W G van Rhijn, Alexandra Masson-Lecomte
Department of Urology, Freeman Hospital, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK. Electronic address: ., Department of Urology, Freeman Hospital, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK., Centre for Cancer Cell and Molecular Biology, Barts Cancer Institute, Queen Mary University of London, London, UK; Department of Urology, Barts Health NHS Trust; Department of Urology, University College London Hospitals NHS Foundation Trust, London, UK., Department of Urology, La Croix Du Sud Hospital, Quint Fonsegrives, France., Department of Urology, General University Hospital and 1st Faculty of Medicine, Charles University Praha, Prague, Czech Republic., Department of Urology, Città della Salute e della Scienza, University of Torino School of Medicine, Torino, Italy., Rosemere Cancer Centre, Lancashire Teaching Hospitals NHS Foundation Trust, Preston, University of Manchester and University of Lancashire, UK., Department of Pathology, Medical University of Vienna, Vienna, Austria., Department of Urology, Fundación Instituto Valenciano de Oncología, Valencia, Spain., Department of Medicine, London Health Science Centre, Western University, London, Ontario, Canada., Institute of Translational Medicine, Lund University, Malmö, Sweden; Department of Urology, Skåne University Hospital, Malmö, Sweden., GRC 5, Predictive Onco-Urology, Department of Urology, Pitié-Salpêtrière Hospital, AP-HP, Sorbonne University, Paris, France., S.H. Ho Urology Centre, Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China., Department of Urology, San Raffaele Hospital and Scientific Institute, Milan, Italy., Edinburgh Bladder Cancer Surgery (EBCS), Western General Hospital, The University of Edinburgh, Edinburgh, UK., Department of Urology, Comprehensive Cancer Center, Vienna General Hospital, Medical University Vienna, Vienna, Austria., Department of Urology, Bichat-Claude Bernard Hospital, Assistance Publique-Hôpitaux de Paris, Université de Paris Cité, Paris, France., Department of Urology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands; Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands., Department of Urology, University of Vienna, Austria., Department of Surgical Oncology (Urology), Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands., Department of Urology, APHP, Saint Louis Hospital, Université de Paris, Paris, France.