Urine biomarkers for the detection of urothelial (transitional cell) carcinoma of the bladder
- Anirban P Mitra, MD, PhD
Anirban P Mitra, MD, PhD
- Resident, Institute of Urology
- University of Southern California
- Keck School of Medicine & Norris Comprehensive Cancer Center
- Marc Birkhahn, MD
Marc Birkhahn, MD
- Urologie am Ring
- David F Penson, MD, MPH
David F Penson, MD, MPH
- Professor of Urologic Surgery
- Director of Vanderbilt Center for Surgical Quality and Outcomes Research
- Richard J Cote, MD, FRCPath
Richard J Cote, MD, FRCPath
- Professor and Chair
- Department of Pathology
- University of Miami Miller School of Medicine
Urine biomarkers that currently are approved or are under development are discussed in this topic. The clinical presentation and initial diagnosis of bladder cancer, the rationale and overall approach to screening high-risk populations, and the approach to surveillance in patients who have been treated for non-muscle invasive disease are discussed separately. (See "Clinical presentation, diagnosis, and staging of bladder cancer" and "Screening for bladder cancer" and "Treatment of primary non-muscle invasive urothelial bladder cancer", section on 'Posttreatment surveillance'.)
Urine biomarkers have potential applications in individuals in whom bladder cancer is suspected based upon the presence of hematuria, overactive bladder symptoms, or an unusually high risk of tumor. Urine biomarkers may also have a role in detecting recurrences in patients who have been treated for non-muscle-invasive disease. They may also be used in the evaluation of upper tract radiographic abnormalities and for monitoring patients after treatment of ureteral or renal pelvic transitional cell carcinoma.
●Initial diagnosis – The diagnosis of bladder cancer commonly is suggested by the presence of hematuria, which may be either gross or microscopic. However, hematuria is frequently seen in a wide range of benign conditions. The diagnosis of bladder cancer ultimately requires a histologic diagnosis, which usually comes from a biopsy that is obtained at cystoscopy. Cytology may provide strong evidence for the presence of malignancy, and a positive cytology should prompt further investigation. Urine biomarkers could have a significant role in determining which individuals require cystoscopy as well as determining those who might need evaluation of the upper urinary tract. (See "Malignancies of the renal pelvis and ureter" and "Etiology and evaluation of hematuria in adults" and "Clinical presentation, diagnosis, and staging of bladder cancer", section on 'Diagnostic approach'.)
●Surveillance – Patients who have been treated for non-muscle-invasive bladder cancer are at risk for recurrence in the bladder as well as for the development of urothelial tumors in the renal pelvis, ureter, or urethra. These patients thus require prolonged follow-up. (See "Treatment of primary non-muscle invasive urothelial bladder cancer", section on 'Posttreatment surveillance'.)
Cystoscopy is the gold standard for surveillance in patients with a history of bladder cancer. Because it does not detect all recurrences nor does it visualize the upper urinary tract, a biomarker test should accompany cystoscopy in order to minimize the risk of missing a high-grade tumor. Furthermore, cystoscopy is a minimally invasive procedure. Cystoscopy is easily performed in an office setting with flexible instrumentation. However, it can be uncomfortable and promote anxiety, which can lead to suboptimal compliance with management recommendations. (See "Treatment of primary non-muscle invasive urothelial bladder cancer", section on 'Transurethral resection'.)
- Laucirica R, Bentz JS, Souers RJ, et al. Do liquid-based preparations of urinary cytology perform differently than classically prepared cases? Observations from the College of American Pathologists Interlaboratory Comparison Program in Nongynecologic Cytology. Arch Pathol Lab Med 2010; 134:19.
- Birkhahn M, Mitra AP, Williams AJ, et al. A novel precision-engineered microfiltration device for capture and characterisation of bladder cancer cells in urine. Eur J Cancer 2013; 49:3159.
- Mitra AP, Cote RJ. Molecular screening for bladder cancer: progress and potential. Nat Rev Urol 2010; 7:11.
- Tilki D, Burger M, Dalbagni G, et al. Urine markers for detection and surveillance of non-muscle-invasive bladder cancer. Eur Urol 2011; 60:484.
- Chou R, Gore JL, Buckley D, et al. Urinary Biomarkers for Diagnosis of Bladder Cancer: A Systematic Review and Meta-analysis. Ann Intern Med 2015; 163:922.
- Abd El Gawad IA, Moussa HS, Nasr MI, et al. Comparative study of NMP-22, telomerase, and BTA in the detection of bladder cancer. J Egypt Natl Canc Inst 2005; 17:193.
- Raitanen MP, FinnBladder Group. The role of BTA stat Test in follow-up of patients with bladder cancer: results from FinnBladder studies. World J Urol 2008; 26:45.
- Lotan Y, Roehrborn CG. Sensitivity and specificity of commonly available bladder tumor markers versus cytology: results of a comprehensive literature review and meta-analyses. Urology 2003; 61:109.
- Eissa S, Swellam M, Sadek M, et al. Comparative evaluation of the nuclear matrix protein, fibronectin, urinary bladder cancer antigen and voided urine cytology in the detection of bladder tumors. J Urol 2002; 168:465.
- Grossman HB, Messing E, Soloway M, et al. Detection of bladder cancer using a point-of-care proteomic assay. JAMA 2005; 293:810.
- Grossman HB, Soloway M, Messing E, et al. Surveillance for recurrent bladder cancer using a point-of-care proteomic assay. JAMA 2006; 295:299.
- Shariat SF, Savage C, Chromecki TF, et al. Assessing the clinical benefit of nuclear matrix protein 22 in the surveillance of patients with nonmuscle-invasive bladder cancer and negative cytology: a decision-curve analysis. Cancer 2011; 117:2892.
- Attallah AM, Sakr HA, Ismail H, et al. An office-based immunodiagnostic assay for detecting urinary nuclear matrix protein 52 in patients with bladder cancer. BJU Int 2005; 96:334.
- Getzenberg RH, Konety BR, Oeler TA, et al. Bladder cancer-associated nuclear matrix proteins. Cancer Res 1996; 56:1690.
- Myers-Irvin JM, Landsittel D, Getzenberg RH. Use of the novel marker BLCA-1 for the detection of bladder cancer. J Urol 2005; 174:64.
- Konety BR, Nguyen TS, Dhir R, et al. Detection of bladder cancer using a novel nuclear matrix protein, BLCA-4. Clin Cancer Res 2000; 6:2618.
- Black PC, Brown GA, Dinney CP. Molecular markers of urothelial cancer and their use in the monitoring of superficial urothelial cancer. J Clin Oncol 2006; 24:5528.
- Yoder BJ, Skacel M, Hedgepeth R, et al. Reflex UroVysion testing of bladder cancer surveillance patients with equivocal or negative urine cytology: a prospective study with focus on the natural history of anticipatory positive findings. Am J Clin Pathol 2007; 127:295.
- Hajdinjak T. UroVysion FISH test for detecting urothelial cancers: meta-analysis of diagnostic accuracy and comparison with urinary cytology testing. Urol Oncol 2008; 26:646.
- Lokeshwar VB, Habuchi T, Grossman HB, et al. Bladder tumor markers beyond cytology: International Consensus Panel on bladder tumor markers. Urology 2005; 66:35.
- Schlomer BJ, Ho R, Sagalowsky A, et al. Prospective validation of the clinical usefulness of reflex fluorescence in situ hybridization assay in patients with atypical cytology for the detection of urothelial carcinoma of the bladder. J Urol 2010; 183:62.
- Kipp BR, Karnes RJ, Brankley SM, et al. Monitoring intravesical therapy for superficial bladder cancer using fluorescence in situ hybridization. J Urol 2005; 173:401.
- Whitson J, Berry A, Carroll P, Konety B. A multicolour fluorescence in situ hybridization test predicts recurrence in patients with high-risk superficial bladder tumours undergoing intravesical therapy. BJU Int 2009; 104:336.
- Savic S, Zlobec I, Thalmann GN, et al. The prognostic value of cytology and fluorescence in situ hybridization in the follow-up of nonmuscle-invasive bladder cancer after intravesical Bacillus Calmette-Guérin therapy. Int J Cancer 2009; 124:2899.
- Halling KC, King W, Sokolova IA, et al. A comparison of cytology and fluorescence in situ hybridization for the detection of urothelial carcinoma. J Urol 2000; 164:1768.
- Bubendorf L, Grilli B, Sauter G, et al. Multiprobe FISH for enhanced detection of bladder cancer in voided urine specimens and bladder washings. Am J Clin Pathol 2001; 116:79.
- Sarosdy MF, Schellhammer P, Bokinsky G, et al. Clinical evaluation of a multi-target fluorescent in situ hybridization assay for detection of bladder cancer. J Urol 2002; 168:1950.
- Skacel M, Fahmy M, Brainard JA, et al. Multitarget fluorescence in situ hybridization assay detects transitional cell carcinoma in the majority of patients with bladder cancer and atypical or negative urine cytology. J Urol 2003; 169:2101.
- Lokeshwar VB, Selzer MG. Urinary bladder tumor markers. Urol Oncol 2006; 24:528.
- Lokeshwar VB, Obek C, Pham HT, et al. Urinary hyaluronic acid and hyaluronidase: markers for bladder cancer detection and evaluation of grade. J Urol 2000; 163:348.
- Passerotti CC, Srougi M, Bomfim AC, et al. Testing for urinary hyaluronate improves detection and grading of transitional cell carcinoma. Urol Oncol 2011; 29:710.
- Kim NW, Piatyszek MA, Prowse KR, et al. Specific association of human telomerase activity with immortal cells and cancer. Science 1994; 266:2011.
- Mucciardi G, Gali' A, Barresi V, et al. Telomere instability in papillary bladder urothelial carcinomas: Comparison with grading and risk of recurrence. Indian J Urol 2014; 30:245.
- Birkhahn M, Mitra AP, Cote RJ. Molecular markers for bladder cancer: the road to a multimarker approach. Expert Rev Anticancer Ther 2007; 7:1717.
- Shariat SF, Casella R, Khoddami SM, et al. Urine detection of survivin is a sensitive marker for the noninvasive diagnosis of bladder cancer. J Urol 2004; 171:626.
- Margulis V, Lotan Y, Shariat SF. Survivin: a promising biomarker for detection and prognosis of bladder cancer. World J Urol 2008; 26:59.
- Smith SD, Wheeler MA, Plescia J, et al. Urine detection of survivin and diagnosis of bladder cancer. JAMA 2001; 285:324.
- Moussa O, Abol-Enein H, Bissada NK, et al. Evaluation of survivin reverse transcriptase-polymerase chain reaction for noninvasive detection of bladder cancer. J Urol 2006; 175:2312.
- Kenney DM, Geschwindt RD, Kary MR, et al. Detection of newly diagnosed bladder cancer, bladder cancer recurrence and bladder cancer in patients with hematuria using quantitative rt-PCR of urinary survivin. Tumour Biol 2007; 28:57.
- Pu XY, Wang ZP, Chen YR, et al. The value of combined use of survivin, cytokeratin 20 and mucin 7 mRNA for bladder cancer detection in voided urine. J Cancer Res Clin Oncol 2008; 134:659.
- Ku JH, Godoy G, Amiel GE, Lerner SP. Urine survivin as a diagnostic biomarker for bladder cancer: a systematic review. BJU Int 2012; 110:630.
- Tsihlias J, Grossman HB. The utility of fibrin/fibrinogen degradation products in superficial bladder cancer. Urol Clin North Am 2000; 27:39.
- Berger AP, Parson W, Stenzl A, et al. Microsatellite alterations in human bladder cancer: detection of tumor cells in urine sediment and tumor tissue. Eur Urol 2002; 41:532.
- Rouprêt M, Hupertan V, Yates DR, et al. A comparison of the performance of microsatellite and methylation urine analysis for predicting the recurrence of urothelial cell carcinoma, and definition of a set of markers by Bayesian network analysis. BJU Int 2008; 101:1448.
- van der Aa MN, Zwarthoff EC, Steyerberg EW, et al. Microsatellite analysis of voided-urine samples for surveillance of low-grade non-muscle-invasive urothelial carcinoma: feasibility and clinical utility in a prospective multicenter study (Cost-Effectiveness of Follow-Up of Urinary Bladder Cancer trial [CEFUB]). Eur Urol 2009; 55:659.
- de Bekker-Grob EW, van der Aa MN, Zwarthoff EC, et al. Non-muscle-invasive bladder cancer surveillance for which cystoscopy is partly replaced by microsatellite analysis of urine: a cost-effective alternative? BJU Int 2009; 104:41.
- Christensen M, Wolf H, Orntoft TF. Microsatellite alterations in urinary sediments from patients with cystitis and bladder cancer. Int J Cancer 2000; 85:614.
- Têtu B, Tiguert R, Harel F, Fradet Y. ImmunoCyt/uCyt+ improves the sensitivity of urine cytology in patients followed for urothelial carcinoma. Mod Pathol 2005; 18:83.
- Mian C, Pycha A, Wiener H, et al. Immunocyt: a new tool for detecting transitional cell cancer of the urinary tract. J Urol 1999; 161:1486.
- Lodde M, Mian C, Wiener H, et al. Detection of upper urinary tract transitional cell carcinoma with ImmunoCyt: a preliminary report. Urology 2001; 58:362.
- Pfister C, Chautard D, Devonec M, et al. Immunocyt test improves the diagnostic accuracy of urinary cytology: results of a French multicenter study. J Urol 2003; 169:921.
- Mian C, Lodde M, Comploj E, et al. The value of the ImmunoCyt/uCyt+ test in the detection and follow-up of carcinoma in situ of the urinary bladder. Anticancer Res 2005; 25:3641.
- Mian C, Maier K, Comploj E, et al. uCyt+/ImmunoCyt in the detection of recurrent urothelial carcinoma: an update on 1991 analyses. Cancer 2006; 108:60.
- Lodde M, Mian C, Comploj E, et al. uCyt+ test: alternative to cystoscopy for less-invasive follow-up of patients with low risk of urothelial carcinoma. Urology 2006; 67:950.
- Cha EK, Tirsar LA, Schwentner C, et al. Immunocytology is a strong predictor of bladder cancer presence in patients with painless hematuria: a multicentre study. Eur Urol 2012; 61:185.
- Sheinfeld J, Reuter VE, Melamed MR, et al. Enhanced bladder cancer detection with the Lewis X antigen as a marker of neoplastic transformation. J Urol 1990; 143:285.
- Golijanin D, Sherman Y, Shapiro A, Pode D. Detection of bladder tumors by immunostaining of the Lewis X antigen in cells from voided urine. Urology 1995; 46:173.
- Pode D, Golijanin D, Sherman Y, et al. Immunostaining of Lewis X in cells from voided urine, cytopathology and ultrasound for noninvasive detection of bladder tumors. J Urol 1998; 159:389.
- Shirahama T, Ikoma M, Muramatsu T, Ohi Y. Expression of SSEA-1 carbohydrate antigen correlates with stage, grade and metastatic potential of transitional cell carcinoma of the bladder. J Urol 1992; 148:1319.
- Friedrich MG, Hellstern A, Hautmann SH, et al. Clinical use of urinary markers for the detection and prognosis of bladder carcinoma: a comparison of immunocytology with monoclonal antibodies against Lewis X and 486p3/12 with the BTA STAT and NMP22 tests. J Urol 2002; 168:470.
- Toma MI, Friedrich MG, Hautmann SH, et al. Comparison of the ImmunoCyt test and urinary cytology with other urine tests in the detection and surveillance of bladder cancer. World J Urol 2004; 22:145.
- Loy TS, Alexander CJ, Calaluce RD. Lewis X antigen immunostaining in the diagnosis of transitional cell carcinoma. Mod Pathol 1995; 8:587.
- Cheng Y, Deng X, Yang X, et al. Urine microRNAs as biomarkers for bladder cancer: a diagnostic meta-analysis. Onco Targets Ther 2015; 8:2089.
- Chen L, Cui Z, Liu Y, et al. MicroRNAs as Biomarkers for the Diagnostics of Bladder Cancer: a Meta-Analysis. Clin Lab 2015; 61:1101.
- Pignot G, Cizeron-Clairac G, Vacher S, et al. microRNA expression profile in a large series of bladder tumors: identification of a 3-miRNA signature associated with aggressiveness of muscle-invasive bladder cancer. Int J Cancer 2013; 132:2479.
- Vriesema JL, van der Poel HG, Debruyne FM, et al. Neural network-based digitized cell image diagnosis of bladder wash cytology. Diagn Cytopathol 2000; 23:171.
- van der Poel HG, Witjes JA, van Stratum P, et al. Quanticyt: karyometric analysis of bladder washing for patients with superficial bladder cancer. Urology 1996; 48:357.
- van der Poel HG, Boon ME, van Stratum P, et al. Conventional bladder wash cytology performed by four experts versus quantitative image analysis. Mod Pathol 1997; 10:976.
- van der Poel HG, van Rhijn BW, Peelen P, et al. Consecutive quantitative cytology in bladder cancer. Urology 2000; 56:584.
- POTENTIAL APPLICATIONS
- URINE BIOMARKERS
- Bladder tumor antigen (BTA) assays
- Nuclear matrix protein 22
- Other nuclear matrix proteins
- - NMP 52
- - BLCA-4 and BLCA-1
- HA and HAase
- Fibrin degradation products
- Microsatellite analysis
- DD23 monoclonal antibody
- Lewis X antigen
- MicroRNA markers
- Automated image cytometry