Ancillary Studies in Urinary Cytology

  • Lukas Bubendorf
  • Nancy P. Caraway
  • Andrew H. Fischer
  • Ruth L. Katz
  • Matthew T. Olson
  • Fernando Schmitt
  • Margareta Strojan Fležar
  • Theodorus H. Van Der Kwast
  • Philippe Vielh

Abstract

In the last two decades, different markers and diagnostic assays have been developed to overcome limitations of urinary cytology and improve the timely detection of urothelial carcinoma (UC). Among ancillary tests that can be used on cytological preparations, namely cell-based tests UroVysion® Fluorescence in situ Hybridization (U-FISH; Abbott Laboratories, Abbott Park, IL, USA) and ImmunoCyt/UCyt+® (uCyt; Diagnocure Inc, Quebec, Canada) have been approved by the U.S. Food and Drug Administration (FDA) for diagnosis of UC in patients with hematuria and/or monitoring for tumor recurrence in patients previously diagnosed with UC. The pre-analytical procedures, technique, and evaluation of U-FISH including imaging and automation are described, followed by discussion on the performance of the assay. U-FISH is used for the determination of neoplasia after an interpretation of atypical urinary cytology or finding residual neoplastic cells after intravesical bacillus Calmette-Guerin (BCG) treatment. This seems to be the most important indication. uCyt is another promising diagnostic assay; however, further validation studies are needed.

Most commonly used liquid- or non-cytology-based urine tests are the BTA and the NMP22 (Bladder Check). Both were approved by the FDA for detection of UC in symptomatic patients and for monitoring of patients with a history of UC.

No single ancillary test is being recommended as part of the routine evaluation in the Guidelines of the American Urological Association and the European Association of Urology at this time.The classification in The Paris System for Reporting Urinary Cytology lays the ground for prospective studies in search of cost-effective combinations of urine cytology with ancillary testing to improve diagnosis and clinical outcome of UC.

Keywords

Urothelial carcinoma Atypical Urine cytology Ancillary testing Marker Biomarker FISH UroVysion Immunocyt NMP22 BTA 

References

  1. 1.
    Kamat AM, Hegarty PK, Gee JR, Clark PE, Svatek RS, Hegarty N, et al. ICUD-EAU International Consultation on Bladder Cancer 2012: screening, diagnosis, and molecular markers. Eur Urol. 2013;63:4–15.CrossRefPubMedGoogle Scholar
  2. 2.
    Bubendorf L, Piaton E. UroVysion(R) multiprobe FISH in the triage of equivocal urinary cytology cases. Ann Pathol. 2012;32:e52–6. 438–43. [article in French].CrossRefPubMedGoogle Scholar
  3. 3.
    Halling KC, Kipp BR. Bladder cancer detection using FISH (UroVysion assay). Adv Anat Pathol. 2008;15:279–86.CrossRefPubMedGoogle Scholar
  4. 4.
    Marganski WA, El-Sirgany Costa V, Kilpatrick MW, Tafas T, Yim J, Matthews M. Digitized microscopy in the diagnosis of bladder cancer: analysis of >3000 cases during a 7-month period. Cancer Cytopathol. 2011;119:279–89.CrossRefPubMedGoogle Scholar
  5. 5.
    Smith GD, Riding M, Oswald K, Bentz JS. Integrating a FISH imaging system into the cytology laboratory. Cytojournal. 2010;7:3.PubMedCentralCrossRefPubMedGoogle Scholar
  6. 6.
    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.CrossRefPubMedGoogle Scholar
  7. 7.
    Daniely M, Rona R, Kaplan T, Olsfanger S, Elboim L, Zilberstien Y, et al. Combined analysis of morphology and fluorescence in situ hybridization significantly increases accuracy of bladder cancer detection in voided urine samples. Urology. 2005;66:1354–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Bubendorf L. Multiprobe fluorescence in situ hybridization (UroVysion) for the detection of urothelial carcinoma - FISHing for the right catch. Acta Cytol. 2011;55:113–9.CrossRefPubMedGoogle Scholar
  9. 9.
    Furrer D, Jacob S, Caron C, Sanschagrin F, Provencher L, Diorio C. Validation of a new classifier for the automated analysis of the human epidermal growth factor receptor 2 (HER2) gene amplification in breast cancer specimens. Diagn Pathol. 2013;8:17.PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    Hajdinjak T. UroVysion FISH test for detecting urothelial cancers: meta-analysis of diagnostic accuracy and comparison with urinary cytology testing. Urol Oncol. 2008;26:646–51.CrossRefPubMedGoogle Scholar
  11. 11.
    Kipp BR, Halling KC, Campion MB, Wendel AJ, Karnes RJ, Zhang J, et al. 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;179:1296–301. discussion 301.CrossRefPubMedGoogle Scholar
  12. 12.
    Savic S, Zlobec I, Thalmann GN, Engeler D, Schmauss M, Lehmann K, 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-Guerin therapy. Int J Cancer. 2009;124:2899–904.CrossRefPubMedGoogle Scholar
  13. 13.
    Gayed BA, Seideman C, Lotan Y. Cost-effectiveness of fluorescence in situ hybridization in patients with atypical cytology for the detection of urothelial carcinoma. J Urol. 2013;190:1181–6.CrossRefPubMedGoogle Scholar
  14. 14.
    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;179:2164–9.CrossRefPubMedGoogle Scholar
  15. 15.
    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;183:62–7.CrossRefPubMedGoogle Scholar
  16. 16.
    Kim PH, Sukhu R, Cordon BH, Sfakianos JP, Sjoberg DD, Hakimi AA, et al. Reflex fluorescence in situ hybridization assay for suspicious urinary cytology in patients with bladder cancer with negative surveillance cystoscopy. BJU Int. 2014;114:354–9.PubMedCentralCrossRefPubMedGoogle Scholar
  17. 17.
    Seideman C, Canter D, Kim P, Cordon B, Weizer A, Oliva I, et al. Multicenter evaluation of the role of UroVysion FISH assay in surveillance of patients with bladder cancer: does FISH positivity anticipate recurrence? World J Urol. 2014. doi:10.1007/s00345-014-1452-9. Epub ahead of print.PubMedGoogle Scholar
  18. 18.
    Skacel M, Fahmy M, Brainard JA, Pettay JD, Biscotti CV, Liou LS, 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;169:2101–5.CrossRefPubMedGoogle Scholar
  19. 19.
    Yoder BJ, Skacel M, Hedgepeth R, Babineau D, Ulchaker JC, Liou LS, 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;127:295–301.CrossRefPubMedGoogle Scholar
  20. 20.
    Fritsche HM, Burger M, Dietmaier W, Denzinger S, Bach E, Otto W, et al. Multicolor FISH (UroVysion) facilitates follow-up of patients with high-grade urothelial carcinoma of the bladder. Am J Clin Pathol. 2010;134:597–603.CrossRefPubMedGoogle Scholar
  21. 21.
    Kipp BR, Karnes RJ, Brankley SM, Harwood AR, Pankratz VS, Sebo TJ, et al. Monitoring intravesical therapy for superficial bladder cancer using fluorescence in situ hybridization. J Urol. 2005;173:401–4.CrossRefPubMedGoogle Scholar
  22. 22.
    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;104:336–9.CrossRefPubMedGoogle Scholar
  23. 23.
    Mengual L, Marin-Aguilera M, Ribal MJ, Burset M, Villavicencio H, Oliver A, et al. Clinical utility of fluorescent in situ hybridization for the surveillance of bladder cancer patients treated with bacillus Calmette-Guerin therapy. Eur Urol. 2007;52:752–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Huysentruyt CJ, Baldewijns MM, Ruland AM, Tonk RJ, Vervoort PS, Smits KM, et al. Modified UroVysion scoring criteria increase the urothelial carcinoma detection rate in cases of equivocal urinary cytology. Histopathology. 2011;58:1048–53.CrossRefPubMedGoogle Scholar
  25. 25.
    Tapia C, Glatz K, Obermann EC, Grilli B, Barascud A, Herzog M, et al. Evaluation of chromosomal aberrations in patients with benign conditions and reactive changes in urinary cytology. Cancer Cytopathol. 2011;119:404–10.CrossRefPubMedGoogle Scholar
  26. 26.
    Zellweger T, Benz G, Cathomas G, Mihatsch MJ, Sulser T, Gasser TC, et al. Multi-target fluorescence in situ hybridization in bladder washings for prediction of recurrent bladder cancer. Int J Cancer. 2006;119:1660–5.CrossRefPubMedGoogle Scholar
  27. 27.
    Hossain D, Hull D, Kalantarpour F, Maitlen R, Qian J, Bostwick DG. Does polyomavirus infection interfere with bladder cancer fluorescence in situ hybridization? Diagn Cytopathol. 2014;42:225–9.CrossRefPubMedGoogle Scholar
  28. 28.
    Kamat AM, Vlahou A, Taylor JA, Hudson ML, Pesch B, Ingersoll MA, et al. Considerations on the use of urine markers in the management of patients with high-grade non-muscle-invasive bladder cancer. Urol Oncol. 2014;32:1069–77.CrossRefPubMedGoogle Scholar
  29. 29.
    Schmitz-Drager BJ, Todenhofer T, van Rhijn B, Pesch B, Hudson MA, Chandra A, et al. Considerations on the use of urine markers in the management of patients with low-/intermediate-risk non-muscle invasive bladder cancer. Urol Oncol. 2014;32:1061–8.CrossRefPubMedGoogle Scholar
  30. 30.
    Sullivan PS, Nooraie F, Sanchez H, Hirschowitz S, Levin M, Rao PN, et al. Comparison of ImmunoCyt, UroVysion, and urine cytology in detection of recurrent urothelial carcinoma: a “split-sample” study. Cancer. 2009;117:167–73.PubMedGoogle Scholar
  31. 31.
    Todenhofer T, Hennenlotter J, Esser M, Mohrhardt S, Tews V, Aufderklamm S, et al. Combined application of cytology and molecular urine markers to improve the detection of urothelial carcinoma. Cancer Cytopathol. 2013;121:252–60.CrossRefPubMedGoogle Scholar
  32. 32.
    Yang M, Zheng Z, Zhuang Z, Zhao X, Xu Z, Lin H. ImmunoCyt and cytology for diagnosis of bladder carcinoma: a meta analysis. Chin Med J (Engl). 2014;127:758–64.Google Scholar
  33. 33.
    Fradet Y, Lockhard C. Performance characteristics of a new monoclonal antibody test for bladder cancer: ImmunoCyt trade mark. Can J Urol. 1997;4:400–5.PubMedGoogle Scholar
  34. 34.
    Allard P, Fradet Y, Tetu B, Bernard P. Tumor-associated antigens as prognostic factors for recurrence in 382 patients with primary transitional cell carcinoma of the bladder. Clin Cancer Res. 1995;1:1195–202.PubMedGoogle Scholar
  35. 35.
    Comploj E, Mian C, Ambrosini-Spaltro A, Dechet C, Palermo S, Trenti E, et al. uCyt+/ImmunoCyt and cytology in the detection of urothelial carcinoma: an update on 7422 analyses. Cancer Cytopathol. 2013;121:392–7.CrossRefPubMedGoogle Scholar
  36. 36.
    Mian C, Pycha A, Wiener H, Haitel A, Lodde M, Marberger M. Immunocyt: a new tool for detecting transitional cell cancer of the urinary tract. J Urol. 1999;161:1486–9.CrossRefPubMedGoogle Scholar
  37. 37.
    Piaton E, Daniel L, Verriele V, Dalifard I, Zimmermann U, Renaudin K, et al. Improved detection of urothelial carcinomas with fluorescence immunocytochemistry (uCyt+ assay) and urinary cytology: results of a French Prospective Multicenter Study. Lab Invest. 2003;83:845–52.CrossRefPubMedGoogle Scholar
  38. 38.
    Tetu B, Tiguert R, Harel F, Fradet Y. ImmunoCyt/uCyt+ improves the sensitivity of urine cytology in patients followed for urothelial carcinoma. Mod Pathol. 2005;18:83–9.CrossRefPubMedGoogle Scholar
  39. 39.
    Mowatt G, Zhu S, Kilonzo M, Boachie C, Fraser C, Griffiths TR, et al. Systematic review of the clinical effectiveness and cost-effectiveness of photodynamic diagnosis and urine biomarkers (FISH, ImmunoCyt, NMP22) and cytology for the detection and follow-up of bladder cancer. Health Technol Assess. 2010;14:1–331. iii-iv.CrossRefGoogle Scholar
  40. 40.
    Moatamed NA, Rao JY, Alexanian S, Cobarrubias M, Levin M, Lu D, et al. ProEx C as an adjunct marker to improve cytological detection of urothelial carcinoma in urinary specimens. Cancer Cytopathol. 2013;121:320–8.CrossRefPubMedGoogle Scholar
  41. 41.
    Vergara-Lluri ME, Hu E, Rao JY, Levin M, Apple SK, Moatamed NA. Comparative evaluation of ProEx C and ImmunoCyt/uCyt assays in atypical urine cytology. Arch Pathol Lab Med. 2014;138:1215–22.CrossRefPubMedGoogle Scholar
  42. 42.
    Piaton E, Carre C, Advenier AS, Decaussin-Petrucci M, Mege-Lechevallier F, Lantier P, et al. p16 INK4a overexpression and p16/Ki-67 dual labeling versus conventional urinary cytology in the evaluation of urothelial carcinoma. Cancer Cytopathol. 2014;122:211–20.CrossRefPubMedGoogle Scholar
  43. 43.
    Tetu B. Diagnosis of urothelial carcinoma from urine. Mod Pathol. 2009;22 Suppl 2:S53–9.CrossRefPubMedGoogle Scholar
  44. 44.
    van der Aa MN, Steyerberg EW, Bangma C, van Rhijn BW, Zwarthoff EC, van der Kwast TH. Cystoscopy revisited as the gold standard for detecting bladder cancer recurrence: diagnostic review bias in the randomized, prospective CEFUB trial. J Urol. 2010;183:76–80.CrossRefPubMedGoogle Scholar
  45. 45.
    Kinders R, Jones T, Root R, Bruce C, Murchison H, Corey M, et al. Complement factor H or a related protein is a marker for transitional cell cancer of the bladder. Clin Cancer Res. 1998;4:2511–20.PubMedGoogle Scholar
  46. 46.
    Cheng ZZ, Corey MJ, Parepalo M, Majno S, Hellwage J, Zipfel PF, et al. Complement factor H as a marker for detection of bladder cancer. Clin Chem. 2005;51:856–63.CrossRefPubMedGoogle Scholar
  47. 47.
    Tilki D, Burger M, Dalbagni G, Grossman HB, Hakenberg OW, Palou J, et al. Urine markers for detection and surveillance of non-muscle-invasive bladder cancer. Eur Urol. 2011;60:484–92.CrossRefPubMedGoogle Scholar
  48. 48.
    van Rhijn BW, van der Poel HG, van der Kwast TH. Urine markers for bladder cancer surveillance: a systematic review. Eur Urol. 2005;47:736–48.CrossRefPubMedGoogle Scholar
  49. 49.
    Leyh H, Marberger M, Conort P, Sternberg C, Pansadoro V, Pagano F, et al. Comparison of the BTA stat test with voided urine cytology and bladder wash cytology in the diagnosis and monitoring of bladder cancer. Eur Urol. 1999;35:52–6.CrossRefPubMedGoogle Scholar
  50. 50.
    Oge O, Kozaci D, Gemalmaz H. The BTA stat test is nonspecific for hematuria: an experimental hematuria model. J Urol. 2002;167:1318–9. discussion 9-20.CrossRefPubMedGoogle Scholar
  51. 51.
    Soloway MS, Briggman V, Carpinito GA, Chodak GW, Church PA, Lamm DL, et al. Use of a new tumor marker, urinary NMP22, in the detection of occult or rapidly recurring transitional cell carcinoma of the urinary tract following surgical treatment. J Urol. 1996;156(2 Pt 1):363–7.CrossRefPubMedGoogle Scholar
  52. 52.
    Miyake M, Goodison S, Giacoia EG, Rizwani W, Ross S, Rosser CJ. Influencing factors on the NMP-22 urine assay: an experimental model. BMC Urol. 2012;12:23.PubMedCentralCrossRefPubMedGoogle Scholar
  53. 53.
    Zhou AG, Hutchinson LM, Ceosar EF. Urine cytopathology and ancillary methods. Surg Pathol Clin. 2014;7:77–88.CrossRefGoogle Scholar
  54. 54.
    Grossman HB, Messing E, Soloway M, Tomera K, Katz G, Berger Y, et al. Detection of bladder cancer using a point-of-care proteomic assay. JAMA. 2005;293:810–6.CrossRefPubMedGoogle Scholar
  55. 55.
    Yafi FA, Brimo F, Auger M, Aprikian A, Tanguay S, Kassouf W. Is the performance of urinary cytology as high as reported historically? A contemporary analysis in the detection and surveillance of bladder cancer. Urol Oncol. 2014;32:27. e1-6.PubMedGoogle Scholar
  56. 56.
    Kamat AM, Karam JA, Grossman HB, Kader AK, Munsell M, Dinney CP. Prospective trial to identify optimal bladder cancer surveillance protocol: reducing costs while maximizing sensitivity. BJU Int. 2011;108:1119–23.CrossRefPubMedGoogle Scholar
  57. 57.
    Sapre N, Anderson PD, Costello AJ, Hovens CM, Corcoran NM. Gene-based urinary biomarkers for bladder cancer: an unfulfilled promise? Urol Oncol. 2014;32:48. e9-17.CrossRefPubMedGoogle Scholar
  58. 58.
    Zuiverloon TC, van der Aa MN, van der Kwast TH, Steyerberg EW, Lingsma HF, Bangma CH, et al. Fibroblast growth factor receptor 3 mutation analysis on voided urine for surveillance of patients with low-grade non-muscle-invasive bladder cancer. Clin Cancer Res. 2010;16:3011–8.CrossRefPubMedGoogle Scholar
  59. 59.
    Chen LM, Chang M, Dai Y, Chai KX, Dyrskjot L, Sanchez-Carbayo M, et al. External validation of a multiplex urinary protein panel for the detection of bladder cancer in a multicenter cohort. Cancer Epidemiol. 2014;23:1804–12.CrossRefGoogle Scholar
  60. 60.
    Kandimalla R, Masius R, Beukers W, Bangma CH, Orntoft TF, Dyrskjot L, et al. A 3-plex methylation assay combined with the FGFR3 mutation assay sensitively detects recurrent bladder cancer in voided urine. Clin Cancer Res. 2013;19:4760–9.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Lukas Bubendorf
    • 1
  • Nancy P. Caraway
    • 2
  • Andrew H. Fischer
    • 4
  • Ruth L. Katz
    • 3
  • Matthew T. Olson
    • 5
  • Fernando Schmitt
    • 6
  • Margareta Strojan Fležar
    • 7
  • Theodorus H. Van Der Kwast
    • 8
  • Philippe Vielh
    • 9
  1. 1.Institute of PathologyUniversity Hospital BaselBaselSwitzerland
  2. 2.Department of PathologyThe University of Texas MD Anderson Cancer CenterHoustonUSA
  3. 3.Department of PathologyMD Anderson Cancer Center, The University of TexasHoustonUSA
  4. 4.Department of Pathology and Cell BiologyUniversity of Massachusetts Memorial Medical CenterWorcesterUSA
  5. 5.Department of PathologyThe Johns Hopkins Hospital, The Johns Hopkins UniversityBaltimoreUSA
  6. 6.Laboratoire National de SantéLuxembourg CityLuxembourg
  7. 7.Institute of Pathology, Faculty of Medicine, University of LjubljanaLjubljanaSlovenia
  8. 8.Department of Laboratory Medicine & PathobiologyToronto General Hospital, University of TorontoTorontoCanada
  9. 9.Department of BiopathologyGustave Roussy Comprehensive Cancer CenterVillejuifFrance

Personalised recommendations