Urinary cytology has a well-established role in the detection and monitoring of urothelial carcinoma. The main strength of cytology is the high specificity for high-grade urothelial carcinoma and carcinoma in situ, but it has a low sensitivity for low-grade, non-invasive tumors. There are several other limitations of cytology. Cytology of the upper urinary tract and after intravesical therapy with bacillus Calmette-Guerin is notoriously difficult to interpret. In addition, there is a poorly defined but commonly used category of atypical cytology of uncertain significance. The UroVysion multiprobe fluorescence in situ hybridization has emerged as a helpful tool to address these limitations. It consists of fluorescently labeled DNA probes to detect increased copy numbers (polysomy) of the chromosomes 3, 7 and 17 and deletion of 9p21, the site of the P16 tumor suppressor gene. Multiple studies have shown that fluorescence in situ hybridization in voided urine and washing specimens can help in patient management due to its superior sensitivity over cytology in different situations. It can be particularly useful to clarify equivocal cytological findings. However, some aspects remain to be further addressed including cost efficiency, optimal cut-off values and the true performance under real-life conditions.

1.
Parkin DM: The global burden of urinary bladder cancer. Scand J Urol Nephrol Suppl 2008:12–20.
2.
Botteman MF, Pashos CL, Redaelli A, Laskin B, Hauser R: The health economics of bladder cancer: a comprehensive review of the published literature. Pharmacoeconomics 2003;21:1315–1330.
3.
Kaufman DS, Shipley WU, Feldman AS: Bladder cancer. Lancet 2009;374:239–249.
4.
van Rhijn BW, Burger M, Lotan Y, Solsona E, Stief CG, Sylvester RJ, Witjes JA, Zlotta AR: Recurrence and progression of disease in non-muscle-invasive bladder cancer: from epidemiology to treatment strategy. Eur Urol 2009;56:430–442.
5.
Babjuk M, Oosterlinck W, Sylvester R, Kaasinen E, Bohle A, Palou-Redorta J: EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder. Eur Urol 2008;54:303–314.
6.
Koss LG, Deitch D, Ramanathan R, Sherman AB: Diagnostic value of cytology of voided urine. Acta Cytol 1985;29:810–816.
7.
Renshaw AA: Compassionate conservatism in urinary cytology. Diagn Cytopathol 2000;22:137–138.
8.
Murphy WM: What’s the trouble with cytology? J Urol 2006;176:2343–2346.
9.
Renshaw AA: Subclassifying atypical urinary cytology specimens. Cancer 2000;90:222–229.
10.
Piaton E, Advenier AS, Bubendorf L: Atypical urothelial cells in the urine. Ann Pathol 2010;30:121–122.
11.
Brimo F, Vollmer RT, Case B, Aprikian A, Kassouf W, Auger M: Accuracy of urine cytology and the significance of an atypical category. Am J Clin Pathol 2009;132:785–793.
12.
Jiang F, Katz RL: Use of interphase fluorescence in situ hybridization as a powerful diagnostic tool in cytology. Diagn Mol Pathol 2002;11:47–57.
13.
Oliveira AM, French CA: Applications of fluorescence in situ hybridization in cytopathology: a review. Acta Cytol 2005;49:587–594.
14.
Savic S, Bubendorf L: Fluorescence in situ hybridization. A new diagnostic dimension in cytology. Pathologe 2007;28:384–392.
15.
Halling KC, Kipp BR: Fluorescence in situ hybridization in diagnostic cytology. Hum Pathol 2007;38:1137–1144.
16.
Sokolova I, Halling KC, Jenkins RB, Burkhardt HB, Meyer RG, Seelig SA, King W: The development of a multitarget, multicolor fluoroescence in situ hybridization assay for the detection of urothelial carcinoma in urine. J Molec Diagn 2000;2:116–123.
17.
Knowles MA: Bladder cancer subtypes defined by genomic alterations. Scand J Urol Nephrol Suppl 2008:116–130.
18.
Bubendorf L, Grilli B: UroVysion multiprobe FISH in urinary cytology. Methods Mol Med 2004;97:117–131.
19.
Kipp BR, Fritcher EG, del Rosario KM, Stevens CL, Sebo TJ, Halling KC: A systematic approach to identifying urothelial cells likely to be polysomic by fluorescence in situ hybridization. Anal Quant Cytol Histol 2005;27:317–322.
20.
Halling KC, King W, Sokolova IA, Meyer RG, Burkhardt HM, Halling AC, Cheville JC, Sebo TJ, Ramakumar S, Stewart CS, Pankratz S, O’Kane DJ, Seelig SA, Lieber MM, Jenkins RB: A comparison of cytology and fluorescence in situ hybridization for the detection of urothelial carcinoma. J Urol 2000;164:1768–1775.
21.
Bubendorf L, Grilli B, Sauter G, Mihatsch MJ, Gasser TC, Dalquen P: Multiprobe FISH for enhanced detection of bladder cancer in voided urine specimens and bladder washings. Am J Clin Pathol 2001;116:79–86.
22.
Hajdinjak T: UroVysion FISH test for detecting urothelial cancers: meta-analysis of diagnostic accuracy and comparison with urinary cytology testing. Urol Oncol 2008;26:646–651.
23.
Kipp BR, Tanasescu M, Else TA, Bryant SC, Karnes RJ, Sebo TJ, Halling KC: Quantitative fluorescence in situ hybridization and its ability to predict bladder cancer recurrence and progression to muscle-invasive bladder cancer. J Mol Diagn 2009;11:148–154.
24.
Zellweger T, Benz G, Cathomas G, Mihatsch MJ, Sulser T, Gasser TC, Bubendorf L: Multi-target fluorescence in situ hybridization in bladder washings for prediction of recurrent bladder cancer. Int J Cancer 2006;119:1660–1665.
25.
Savic S, Zlobec I, Thalmann GN, Engeler D, Schmauss M, Lehmann K, Mattarelli G, Eichenberger T, Dalquen P, Spieler P, Schoenegg R, Gasser TC, Sulser T, Forster T, Zellweger T, Casella R, Bubendorf L: The prognostic value of cytology and fluorescence in situ hybridization in the follow-up of nonmuscle-invasive bladder cancer after intravesical bacillus Calmette-Guerin therapy. Int J Cancer 2009;124:2899–2904.
26.
Brankley SM, Adams EJ, Christensen MR, Everts CR, Lund JD, Oberg TN, Plagge AM, Zieman AH, Kipp BR, Halling KC: A study of the reproducibility of a fluorescence in situ hybridization bladder cancer detection assay. Anal Quant Cytol Histol 2008;30:145–151.
27.
Daniely M, Rona R, Kaplan T, Olsfanger S, Elboim L, Freiberger A, Lew S, Leibovitch I: Combined morphologic and fluorescence in situ hybridization analysis of voided urine samples for the detection and follow-up of bladder cancer in patients with benign urine cytology. Cancer 2007;111:517–524.
28.
Smith GD, Bentz JS: ‘FISHing’ to detect urinary and other cancers: validation of an imaging system to aid in interpretation. Cancer Cytopathol 2010;118:56–64.
29.
Ntouroupi TG, Ashraf SQ, McGregor SB, Turney BW, Seppo A, Kim Y, Wang X, Kilpatrick MW, Tsipouras P, Tafas T, Bodmer WF: Detection of circulating tumour cells in peripheral blood with an automated scanning fluorescence microscope. Br J Cancer 2008;99:789–795.
30.
Sarosdy MF, Schellhammer P, Bokinsky G, Kahn P, Chao R, Yore L, Zadra J, Burzon D, Osher G, Bridge JA, Anderson S, Johansson SL, Lieber M, Soloway M, Flom K: Clinical evaluation of a multi-target fluorescent in situ hybridization assay for detection of bladder cancer. J Urol 2002;168:1950–1954.
31.
Sarosdy MF, Kahn PR, Ziffer MD, Love WR, Barkin J, Abara EO, Jansz K, Bridge JA, Johansson SL, Persons DL, Gibson JS: Use of a multitarget fluorescence in situ hybridization assay to diagnose bladder cancer in patients with hematuria. J Urol 2006;176:44–47.
32.
Caraway NP, Katz RL: A review on the current state of urine cytology emphasizing the role of fluorescence in situ hybridization as an adjunct to diagnosis. Cancer Cytopathol 2010;118:175–183.
33.
Halling KC, Kipp BR: Bladder cancer detection using FISH (UroVysion assay). Adv Anat Pathol 2008;15:279–286.
34.
Glatz K, Willi N, Glatz D, Barascud A, Grilli B, Herzog M, Dalquen P, Feichter G, Gasser TC, Sulser T, Bubendorf L: An international telecytologic quiz on urinary cytology reveals educational deficits and absence of a commonly used classification system. Am J Clin Pathol 2006;126:294–301.
35.
Kipp BR, Halling KC, Campion MB, Wendel AJ, Karnes RJ, Zhang J, Sebo TJ: Assessing the value of reflex fluorescence in situ hybridization testing in the diagnosis of bladder cancer when routine urine cytological examination is equivocal. J Urol 2008;179:1296–1301.
36.
Lotan Y, Bensalah K, Ruddell T, Shariat SF, Sagalowsky AI, Ashfaq R: Prospective evaluation 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 2008;179:2164–2169.
37.
Schlomer BJ, Ho R, Sagalowsky A, Ashfaq R, Lotan Y: 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;183:62–67.
38.
Skacel M, Fahmy M, Brainard JA, Pettay JD, Biscotti CV, Liou LS, Procop GW, Jones JS, Ulchaker J, Zippe CD, Tubbs RR: 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;169:2101–2105.
39.
Kapur U, Venkataraman G, Wojcik EM: Diagnostic significance of ‘atypia’ in instrumented versus voided urine specimens. Cancer 2008;114:270–274.
40.
Solomon D, Davey D, Kurman R, Moriarty A, O’Connor D, Prey M, Raab S, Sherman M, Wilbur D, Wright T Jr, Young N: The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA 2002;287:2114–2119.
41.
Ali SZ: Thyroid cytopathology: bethesda and beyond. Acta Cytol 2011;55:4–12.
42.
Kipp BR, Karnes RJ, Brankley SM, Harwood AR, Pankratz VS, Sebo TJ, Blute MM, Lieber MM, Zincke H, Halling KC: Monitoring intravesical therapy for superficial bladder cancer using fluorescence in situ hybridization. J Urol 2005;173:401–404.
43.
Fritsche HM, Burger M, Dietmaier W, Denzinger S, Bach E, Otto W, Doblinger M, Schwarz S, Buchner H, Hartmann A: Multicolor FISH (UroVysion) facilitates follow-up of patients with high-grade urothelial carcinoma of the bladder. Am J Clin Pathol 2010;134:597–603.
44.
Mengual L, Marin-Aguilera M, Ribal MJ, Burset M, Villavicencio H, Oliver A, Alcaraz A: Clinical utility of fluorescent in situ hybridization for the surveillance of bladder cancer patients treated with bacillus Calmette-Guerin therapy. Eur Urol 2007;52:752–759.
45.
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;104:336–339.
46.
Gudjonsson S, Isfoss BL, Hansson K, Domanski AM, Warenholt J, Soller W, Lundberg LM, Liedberg F, Grabe M, Mansson W: The value of the UroVysion assay for surveillance of non-muscle-invasive bladder cancer. Eur Urol 2008;54:402–408.
47.
Karnwal A, Venegas R, Shuch B, Bassett J, Rajfer J, Reznichek R: The role of fluorescence in situ hybridization assay for surveillance of non-muscle invasive bladder cancer. Can J Urol 2010;17:5077–5081.
48.
Youssef RF, Schlomer BJ, Ho R, Sagalowsky AI, Ashfaq R, Lotan Y: Role of fluorescence in situ hybridization in bladder cancer surveillance of patients with negative cytology. Urol Oncol 2010, Epub ahead of print.
49.
Parwani AV, Levi AW, Epstein JI, Ali SZ: Urinary bladder biopsy with denuded mucosa: denuding cystitis-cytopathologic correlates. Diagn Cytopathol 2004;30:297–300.
50.
Gupta R, Paner GP, Amin MB: Neoplasms of the upper urinary tract: a review with focus on urothelial carcinoma of the pelvicalyceal system and aspects related to its diagnosis and reporting. Adv Anat Pathol 2008;15:127–139.
51.
Oosterlinck W, Solsona E, van der Meijden AP, Sylvester R, Bohle A, Rintala E, Lobel B: EAU guidelines on diagnosis and treatment of upper urinary tract transitional cell carcinoma. Eur Urol 2004;46:147–154.
52.
Akkad T, Brunner A, Pallwein L, Gozzi C, Bartsch G, Mikuz G, Steiner H, Verdorfer I: Fluorescence in situ hybridization for detecting upper urinary tract tumors – a preliminary report. Urology 2007;70:753–757.
53.
Chen AA, Grasso M: Is there a role for FISH in the management and surveillance of patients with upper tract transitional-cell carcinoma? J Endourol 2008;22:1371–1374.
54.
Luo B, Li W, Deng CH, Zheng FF, Sun XZ, Wang DH, Dai YP: Utility of fluorescence in situ hybridization in the diagnosis of upper urinary tract urothelial carcinoma. Cancer Genet Cytogenet 2009;189:93–97.
55.
Mian C, Mazzoleni G, Vikoler S, Martini T, Knuchel-Clark R, Zaak D, Lazica A, Roth S, Mian M, Pycha A: Fluorescence in situ hybridisation in the diagnosis of upper urinary tract tumours. Eur Urol 2010;58:288–292.
56.
Johannes JR, Nelson E, Bibbo M, Bagley DH: Voided urine fluorescence in situ hybridization testing for upper tract urothelial carcinoma surveillance. J Urol 2010;184:879–882.
57.
Marin-Aguilera M, Mengual L, Ribal MJ, Musquera M, Ars E, Villavicencio H, Algaba F, Alcaraz A: Utility of fluorescence in situ hybridization as a non-invasive technique in the diagnosis of upper urinary tract urothelial carcinoma. Eur Urol 2007;51:409–415.
58.
Shan Z, Wu P, Zheng S, Tan W, Zhou H, Zuo Y, Qi H, Zhang P, Peng H, Wang Y: Evaluation of upper urinary tract tumors by FISH in Chinese patients. Cancer Genet Cytogenet 2010;203:238–246.
59.
Wojcik EM, Brownlie RJ, Bassler TJ, Miller MC: Superficial urothelial (umbrella) cells. A potential cause of abnormal DNA ploidy results in urine specimens. Anal Quant Cytol Histol 2000;22:411–415.
60.
Lee HO, Davidson JM, Duronio RJ: Endoreplication: polyploidy with purpose. Genes Dev 2009;23:2461–2477.
61.
Chrouser K, Leibovich B, Bergstralh E, Zincke H, Blute M: Bladder cancer risk following primary and adjuvant external beam radiation for prostate cancer. J Urol 2005;174:107–110.
62.
Nieder AM, Soloway MS, Herr HW: Should we abandon the FISH test? Eur Urol 2007;51:1469–1471.
63.
Renshaw AA: UroVysion, urine cytology, and the College of American Pathologists: where should we go from here? Arch Pathol Lab Med 2010;134:1106–1107.
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