{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T06:01:06Z","timestamp":1792389666319,"version":"4.4.0"},"reference-count":45,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,3,16]],"date-time":"2022-03-16T00:00:00Z","timestamp":1647388800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Beyond laboratory, imaging and endoscopic procedures, new diagnostic tools are increasingly being sought for the diagnosis of upper urinary tract urothelial carcinoma (UTUC), especially those that are non-invasive. In this systematic review, we aimed to determine the effectiveness of non-invasive tests in the diagnosis of UTUC. PubMed and Embase electronic databases were searched to identify studies assessing effectiveness of non-invasive tests in the primary diagnosis of UTUC. The study protocol was registered with PROSPERO (CRD42020216480). Among 10,084 screened publications, 25 were eligible and included in the analysis. Most of them were conducted on small samples of patients and the control groups were heterogenous. The test used in the largest number of studies was voided urinary cytology, which has poor sensitivity (11\u201371.1%) with favorable specificity (54\u2013100%). Fluorescence in situ hybridization in diagnostic cytology showed higher sensitivity (35\u201385.7%) with equally good specificity (80\u2013100%). There were also studies on the use of tests known to diagnose bladder cancer such as NMP22, uCYT or BTA test. Other urine or blood tests have been the subject of only isolated studies, with varying results. To conclude, currently there is a lack of high-quality data that could confirm good effectiveness of non-invasive tests used in the diagnosis of UTUC.<\/jats:p>","DOI":"10.3390\/cancers14061520","type":"journal-article","created":{"date-parts":[[2022,3,16]],"date-time":"2022-03-16T22:09:58Z","timestamp":1647468598000},"page":"1520","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Non-Invasive Biomarkers in the Diagnosis of Upper Urinary Tract Urothelial Carcinoma\u2014A Systematic Review"],"prefix":"10.3390","volume":"14","author":[{"given":"\u0141ukasz","family":"Bia\u0142ek","sequence":"first","affiliation":[{"name":"Department of Urology, Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konrad","family":"Bilski","sequence":"additional","affiliation":[{"name":"Department of Urology, Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jakub","family":"Dobruch","sequence":"additional","affiliation":[{"name":"Department of Urology, Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wojciech","family":"Krajewski","sequence":"additional","affiliation":[{"name":"Department of Minimally Invasive and Robotic Urology, Wroclaw Medical University, 50-556 Wroc\u0142aw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomasz","family":"Szyde\u0142ko","sequence":"additional","affiliation":[{"name":"Department of Minimally Invasive and Robotic Urology, Wroclaw Medical University, 50-556 Wroc\u0142aw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2551-0296","authenticated-orcid":false,"given":"Piotr","family":"Kryst","sequence":"additional","affiliation":[{"name":"Second Department of Urology, Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7664-9816","authenticated-orcid":false,"given":"S\u0142awomir","family":"Poletajew","sequence":"additional","affiliation":[{"name":"Second Department of Urology, Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S248","DOI":"10.21037\/tau.2018.05.07","article-title":"The complex relationship between upper urinary tract and bladder cancer: Clinical and predictive issues","volume":"7","author":"Sanguedolce","year":"2018","journal-title":"Transl. Androl. Urol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e1395","DOI":"10.1002\/onco.13839","article-title":"Comparison of Genomic Characterization in Upper Tract Urothelial Carcinoma and Urothelial Carcinoma of the Bladder","volume":"26","author":"Yang","year":"2021","journal-title":"Oncologist"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"636","DOI":"10.21037\/tau.2016.03.23","article-title":"Why are upper tract urothelial carcinoma two different diseases?","volume":"5","author":"Szarvas","year":"2016","journal-title":"Transl. Androl. Urol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1097\/PAS.0000000000001141","article-title":"Universal Lynch Syndrome Screening Should be Performed in All Upper Tract Urothelial Carcinomas","volume":"42","author":"Ju","year":"2018","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1007\/s00345-016-1928-x","article-title":"Epidemiology, diagnosis, preoperative evaluation and prognostic assessment of upper-tract urothelial carcinoma (UTUC)","volume":"35","author":"Soria","year":"2017","journal-title":"World J. Urol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1111\/j.1464-410X.2010.09675.x","article-title":"Incidence and survival of patients with carcinoma of the ureter and renal pelvis in the USA, 1973\u20132005","volume":"107","author":"Raman","year":"2011","journal-title":"BJU Int."},{"key":"ref_7","first-page":"716","article-title":"Does preoperative symptom classification impact prognosis in patients with clinically localized upper-tract urothelial carcinoma managed by radical nephroureterectomy?","volume":"29","author":"Raman","year":"2011","journal-title":"Urol. Oncol. Semin. Orig. Investig."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Moher, D., Liberati, A., Tetzlaff, J., Altman, D.G., and PRISMA Group (2009). Preferred reporting items for systematic reviews and meta-analyses: The PRISMA Statement. PLoS Med., 6.","DOI":"10.1371\/journal.pmed.1000097"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1016\/S0090-4295(01)01307-3","article-title":"The BTA stat test: A tumor marker for the detection of upper tract transitional cell carcinoma","volume":"58","author":"Walsh","year":"2001","journal-title":"Urology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1002\/dc.23796","article-title":"The combined application of urinary liquid-based cytology with fluorescence in situ hybridization and p16\/Ki-67 dual immunostaining is valuable for improving the early diagnosis of upper tract urothelial carcinomas","volume":"45","author":"Sun","year":"2017","journal-title":"Diagn. Cytopathol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1016\/S0090-4295(01)01182-7","article-title":"Detection of upper urinary tract transitional cell carcinoma with ImmunoCyt: A preliminary report","volume":"58","author":"Lodde","year":"2001","journal-title":"Urology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1771","DOI":"10.1111\/cas.14000","article-title":"Diagnostic potential of TERT promoter and FGFR 3 mutations in urinary cell-free DNA in upper tract urothelial carcinoma","volume":"110","author":"Hayashi","year":"2019","journal-title":"Cancer Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1159\/000330246","article-title":"Diagnostic Value of the Nuclear Matrix Protein 22 Test and Urine Cytology in Upper Tract Urothelial Tumors","volume":"87","author":"Jovanovic","year":"2011","journal-title":"Urol. Int."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.cancergencyto.2010.07.133","article-title":"Evaluation of upper urinary tract tumors by FISH in Chinese patients","volume":"203","author":"Shan","year":"2010","journal-title":"Cancer Genet. Cytogenet."},{"key":"ref_15","first-page":"8620","article-title":"Fluorescence in situ hybridization (FISH) in the diagnosis of bladder and upper tract urothelial carcinoma: The largest single-institution experience to date","volume":"24","author":"Gomella","year":"2017","journal-title":"Can. J. Urol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1016\/j.urology.2007.06.1103","article-title":"Fluorescence In Situ Hybridization for Detecting Upper Urinary Tract Tumors\u2014A Preliminary Report","volume":"70","author":"Akkad","year":"2007","journal-title":"Urology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1007\/s10147-019-01447-5","article-title":"High diagnostic efficacy of 5-aminolevulinic acid-induced fluorescent urine cytology for urothelial carcinoma","volume":"24","author":"Yamamichi","year":"2019","journal-title":"Int. J. Clin. Oncol."},{"key":"ref_18","first-page":"1148","article-title":"Impact of different grades of microscopic hematuria on the performance of urine-based markers for the detection of urothelial carcinoma","volume":"31","author":"Hennenlotter","year":"2013","journal-title":"Urol. Oncol. Semin. Orig. Investig."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1089\/end.2008.0096","article-title":"Is There a Role for FISH in the Management and Surveillance of Patients with Upper Tract Transitional-Cell Carcinoma?","volume":"22","author":"Chen","year":"2008","journal-title":"J. Endourol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"183","DOI":"10.3892\/ol.2016.4592","article-title":"Prospective evaluation of FISH for detecting upper tract urothelial carcinoma in voided urine specimens","volume":"12","author":"Yu","year":"2016","journal-title":"Oncol. Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3928","DOI":"10.3892\/ol.2017.5926","article-title":"Prospective evaluation of fluorescence in situ hybridization for diagnosing urothelial carcinoma","volume":"13","author":"Lin","year":"2017","journal-title":"Oncol. Lett."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1016\/j.urology.2010.07.498","article-title":"Utility of a Modality Combining FISH and Cytology in Upper Tract Urothelial Carcinoma Detection in Voided Urine Samples of Chinese Patients","volume":"77","author":"Xu","year":"2011","journal-title":"Urology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"647","DOI":"10.4103\/jcrt.JCRT_74_17","article-title":"Utility of fluorescence in situ hybridization analysis for detecting upper urinary tract-urothelial carcinoma","volume":"13","author":"Yu","year":"2017","journal-title":"J. Cancer Res. Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/j.eururo.2006.08.045","article-title":"Utility of Fluorescence In Situ Hybridization as a Non-invasive Technique in the Diagnosis of Upper Urinary Tract Urothelial Carcinoma","volume":"51","author":"Mengual","year":"2007","journal-title":"Eur. Urol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.cancergencyto.2008.10.015","article-title":"Utility of fluorescence in situ hybridization in the diagnosis of upper urinary tract urothelial carcinoma","volume":"189","author":"Luo","year":"2009","journal-title":"Cancer Genet. Cytogenet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1159\/000341622","article-title":"Distinguishing Urothelial Carcinoma in the Upper Urinary Tract from Benign Diseases with Hematuria Using, FISH","volume":"56","author":"Wang","year":"2012","journal-title":"Acta Cytol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"355","DOI":"10.4149\/neo_2012_046","article-title":"Fluorescence in situ hybridization assay detects upper urinary tract transitional cell carcinoma in patients with asymptomatic hematuria and negative urine cytology","volume":"59","author":"Huang","year":"2012","journal-title":"Neoplasma"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.ejca.2013.08.025","article-title":"Accurate detection of upper tract urothelial carcinoma in tissue and urine by means of quantitative GDF15, TMEFF2 and VIM promoter methylation","volume":"50","author":"Almeida","year":"2014","journal-title":"Eur. J. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5842","DOI":"10.1158\/1078-0432.CCR-10-1312","article-title":"Three epigenetic biomarkers, GDF15, TMEFF2, and VIM, accurately predict bladder cancer from DNA-based analyses of urine samples","volume":"16","author":"Costa","year":"2010","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"19","DOI":"10.2298\/ACI0704019J","article-title":"Evaluation of the bard BTA-test in the diagnosis of upper urinary tract tumours","volume":"54","author":"Jovanovic","year":"2007","journal-title":"Acta Chir. Iugosl."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Kriebel, S., Schmidt, D., Holdenrieder, S., Goltz, D., Kristiansen, G., Moritz, R., Fisang, C., M\u00fcller, S.C., and Ellinger, J. (2015). Analysis of Tissue and Serum MicroRNA Expression in Patients with Upper Urinary Tract Urothelial Cancer. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0117284"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"6752","DOI":"10.3892\/mmr.2015.4257","article-title":"Identification of circulating microRNA signatures for upper tract urothelial carcinoma detection","volume":"12","author":"Tao","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Tanaka, T., Yoneyama, T., Noro, D., Imanishi, K., Kojima, Y., Hatakeyama, S., Tobisawa, Y., Mori, K., Yamamoto, H., and Imai, A. (2017). Aberrant N-Glycosylation Profile of Serum Immunoglobulins is a Diagnostic Biomarker of Urothelial Carcinomas. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18122632"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"108744","DOI":"10.1016\/j.biopha.2019.108744","article-title":"Identification of plasma secreted phosphoprotein 1 as a novel biomarker for upper tract urothelial carcinomas","volume":"113","author":"Li","year":"2019","journal-title":"Biomed. Pharm."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.eururo.2020.05.042","article-title":"European Association of Urology Guidelines on Upper Urinary Tract Urothelial Carcinoma: 2020 Update","volume":"79","author":"Babjuk","year":"2021","journal-title":"Eur. Urol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1007\/s00345-019-02875-8","article-title":"Diagnostic performance of multidetector computed tomographic (MDCTU) in upper tract urothelial carcinoma (UTUC): A systematic review and meta-analysis","volume":"38","author":"Janisch","year":"2020","journal-title":"World J. Urol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1097\/JU.0000000000001370","article-title":"The Impact of Ureteroscopy following Computerized Tomography Urography in the Management of Upper Tract Urothelial Carcinoma","volume":"205","author":"Gallioli","year":"2021","journal-title":"J. Urol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1016\/j.juro.2009.12.031","article-title":"Gadolinium enhanced magnetic resonance urography for upper urinary tract malignancy","volume":"183","author":"Takahashi","year":"2010","journal-title":"J. Urol."},{"key":"ref_39","unstructured":"Ruvolo, C.C., Nocera, L., Stolzenbach, L.F., Wenzel, M., Califano, G., Tian, Z., Verze, P., Shariat, S.F., Saad, F., and Briganti, A. (2021). Tumor Size Predicts Muscle-invasive and Non-organ-confined Disease in Upper Tract Urothelial Carcinoma at Radical Nephroureterectomy. Eur. Urol. Focus."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.euo.2019.09.004","article-title":"Diagnostic Value of 18F-fluorodeoxyglucose Positron Emission Tomography with Computed Tomography for Lymph Node Staging in Patients with Upper Tract Urothelial Carcinoma","volume":"3","author":"Voskuilen","year":"2020","journal-title":"Eur. Urol. Oncol."},{"key":"ref_41","first-page":"101","article-title":"Upper urinary tract washing in the diagnosis of transitional cell carcinoma of the renal pelvis and calices. A comparison with voided urine","volume":"41","author":"Raica","year":"1995","journal-title":"Rom. J. Morphol. Embryol. Rev. Roum. Morphol. Embryol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.jasc.2018.10.001","article-title":"Variability among observers utilizing the CellSolutions BestCyte Cell Sorter imaging system for the assessment of urinary tract cytology specimens","volume":"8","author":"Gelwan","year":"2019","journal-title":"J. Am. Soc. Cytopathol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1002\/cncy.22443","article-title":"A deep learning system to diagnose the malignant potential of urothelial carcinoma cells in cytology specimens","volume":"129","author":"Nojima","year":"2021","journal-title":"Cancer Cytopathol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Garc\u00eda-Guti\u00e9rrez, M.S., Navarrete, F., Sala, F., Gasparyan, A., Austrich-Olivares, A., and Manzanares, J. (2020). Biomarkers in Psychiatry: Concept, Definition, Types and Relevance to the Clinical Reality. Front. Psychiatry, 11.","DOI":"10.3389\/fpsyt.2020.00432"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"445","DOI":"10.2174\/1389201018666170601091205","article-title":"Advantages and Limitations of Current Biomarker Research: From Experimental Research to Clinical Application","volume":"18","author":"Kim","year":"2017","journal-title":"Curr. Pharm. Biotechnol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/6\/1520\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:37:21Z","timestamp":1760135841000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/6\/1520"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,16]]},"references-count":45,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2022,3]]}},"alternative-id":["cancers14061520"],"URL":"https:\/\/doi.org\/10.3390\/cancers14061520","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,16]]}}}