Molecular Diagnosis of Bladder and Kidney Cancer

  • Marino E. LeonEmail author
  • Dahui Qin
  • Debra L. Zynger
Part of the Cancer Growth and Progression book series (CAGP, volume 16)


This chapter will review the molecular diagnosis of bladder and kidney cancer. In current clinical practice, early detection and diagnosis of urothelial carcinoma is based on urinary cytology. UroVysion™ bladder cancer fluorescence in situ hybridization (FISH) has become a useful ancillary test in the detection of urothelial carcinoma for initial diagnosis and recurrence; this test is applicable to routine cytologic urine specimens. Multiple studies have shown that UroVysion™ FISH in voided urine and washing specimens can help in patient management due to its superior sensitivity over cytology in certain situations. Within the renal cortex, molecular studies have not achieved routine use; the most widely available tests are used to identify Xp11.2 translocations/TFE fusions for the subclassification of renal cell carcinoma.


Carcinoma Bladder Diagnosis Molecular Urothelial 



Bacillus Calmette-Guerin


Bladder Tumor Antigen


Chromosome Enumeration Probes


Fibrinogen Degradation Products


Fibrinogen Degradation


Fibroblast Growth Factor Receptor 3


Fluorescent in Situ Hybridization


Human Complement Factor H Related Protein


Locus Specific Identifier


Tissue Polypeptide Specific


  1. 1.
    Johansson SL, Cohen SM (1997) Epidemiology and etiology of bladder cancer. Semin Surg Oncol 13(5):291–298PubMedCrossRefGoogle Scholar
  2. 2.
    Cohen SM, Johansson SL (1992) Epidemiology and etiology of bladder cancer. Urol Clin North Am 19(3):421–428PubMedGoogle Scholar
  3. 3.
    Cohen SM, Shirai T et al (2000) Epidemiology and etiology of premalignant and malignant urothelial changes. Scand J Urol Nephrol Suppl 205:105–115PubMedCrossRefGoogle Scholar
  4. 4.
    Czerniak B, Chaturvedi V et al (1999) Superimposed histologic and genetic mapping of chromosome 9 in progression of human urinary bladder neoplasia: implications for a genetic model of multistep urothelial carcinogenesis and early detection of urinary bladder cancer. Oncogene 18(5):1185–1196PubMedCrossRefGoogle Scholar
  5. 5.
    Heney NM (1992) Natural history of superficial bladder cancer. Prognostic features and long-term disease course. Urol Clin North Am 19(3):429–433PubMedGoogle Scholar
  6. 6.
    Kaufman DS, Shipley WU et al (2009) Bladder cancer. Lancet 374(9685):239–249PubMedCrossRefGoogle Scholar
  7. 7.
    Koch M, McPhee MS et al (1988) Five year follow-up of patients with cancer of the bladder – the Northern Alberta experience. Clin Invest Med 11(4):253–258PubMedGoogle Scholar
  8. 8.
    Holmang S, Hedelin H et al (1999) Recurrence and progression in low grade papillary urothelial tumors. J Urol 162(3 Pt 1):702–707PubMedCrossRefGoogle Scholar
  9. 9.
    Millan-Rodriguez F, Chechile-Toniolo G et al (2000) Primary superficial bladder cancer risk groups according to progression, mortality and recurrence. J Urol 164(3 Pt 1):680–684PubMedCrossRefGoogle Scholar
  10. 10.
    Holmang S, Andius P et al (2001) Stage progression in Ta papillary urothelial tumors: relationship to grade, immunohistochemical expression of tumor markers, mitotic frequency and DNA ploidy. J Urol 165(4):1124–1128, discussion 1128–1130PubMedCrossRefGoogle Scholar
  11. 11.
    Cheng L, Davidson DD et al (2010) The origins of urothelial carcinoma. Expert Rev Anticancer Ther 10(6):865–880PubMedCrossRefGoogle Scholar
  12. 12.
    Chuang S-T, Tracy RA et al (2010) Carcinogenetic pathway of superficial low-grade urothelial carcinoma. In: Coppola D (ed) Mechanisms of oncogenesis, vol 12. Springer, New York, pp 279–284CrossRefGoogle Scholar
  13. 13.
    Cheng L, Zhang S et al (2010) Bladder cancer: translating molecular genetic insights into clinical practice. Hum Pathol 42(4):455–481PubMedCrossRefGoogle Scholar
  14. 14.
    van der Kwast TH, Bapat B (2009) Predicting favourable prognosis of urothelial carcinoma: gene expression and genome profiling. Curr Opin Urol 19(5):516–521PubMedCrossRefGoogle Scholar
  15. 15.
    Cordon-Cardo C, Cote RJ et al (2000) Genetic and molecular markers of urothelial premalignancy and malignancy. Scand J Urol Nephrol Suppl 205:82–93PubMedCrossRefGoogle Scholar
  16. 16.
    Hartmann A, Rosner U et al (2000) Clonality and genetic divergence in multifocal low-grade superficial urothelial carcinoma as determined by chromosome 9 and p53 deletion analysis. Lab Invest 80(5):709–718PubMedCrossRefGoogle Scholar
  17. 17.
    Marano A, Pan Y et al (2000) Chromosomal numerical aberrations detected by fluorescence in situ hybridization on bladder washings from patients with bladder cancer. Eur Urol 37(3):358–365PubMedCrossRefGoogle Scholar
  18. 18.
    Obermann EC, Junker K et al (2003) Frequent genetic alterations in flat urothelial hyperplasias and concomitant papillary bladder cancer as detected by CGH, LOH, and FISH analyses. J Pathol 199(1):50–57PubMedCrossRefGoogle Scholar
  19. 19.
    Tsukamoto M, Matsuyama H et al (2002) Numerical aberrations of chromosome 9 in bladder cancer. A possible prognostic marker for early tumor recurrence. Cancer Genet Cytogenet 134(1):41–45PubMedCrossRefGoogle Scholar
  20. 20.
    Bubendorf L, Grilli B et al (2001) Multiprobe FISH for enhanced detection of bladder cancer in voided urine specimens and bladder washings. Am J Clin Pathol 116(1):79–86PubMedCrossRefGoogle Scholar
  21. 21.
    Veltman JA, Fridlyand J et al (2003) Array-based comparative genomic hybridization for genome-wide screening of DNA copy number in bladder tumors. Cancer Res 63(11):2872–2880PubMedGoogle Scholar
  22. 22.
    Sokolova IA, Halling KC et al (2000) The development of a multitarget, multicolor fluorescence in situ hybridization assay for the detection of urothelial carcinoma in urine. J Mol Diagn 2(3):116–123PubMedCrossRefGoogle Scholar
  23. 23.
    Dickinson SI (2010) Carcinogenetic pathway of urothelial carcinoma. In: Coppola D (ed) Mechanisms of oncogenesis, vol 12. Springer, New York, pp 285–293CrossRefGoogle Scholar
  24. 24.
    Amling CL (2001) Diagnosis and management of superficial bladder cancer. Curr Probl Cancer 25(4):219–278PubMedCrossRefGoogle Scholar
  25. 25.
    Nese N, Gupta R et al (2009) Carcinoma in situ of the urinary bladder: review of clinicopathologic characteristics with an emphasis on aspects related to molecular diagnostic techniques and prognosis. J Natl Compr Canc Netw 7(1):48–57PubMedGoogle Scholar
  26. 26.
    Caraway NP, Katz RL (2010) A review on the current state of urine cytology emphasizing the role of fluorescence in situ hybridization as an adjunct to diagnosis. Cancer Cytopathol 118(4):175–183PubMedCrossRefGoogle Scholar
  27. 27.
    Koss LG, Deitch D et al (1985) Diagnostic value of cytology of voided urine. Acta Cytol 29(5):810–816PubMedGoogle Scholar
  28. 28.
    Bischoff CJ, Clark PE (2009) Bladder cancer. Curr Opin Oncol 21(3):272–277PubMedCrossRefGoogle Scholar
  29. 29.
    Koss LG, Esposti L et al (1986) The role of cytology in the diagnosis, detection and follow-up of bladder cancer. Prog Clin Biol Res 221:97–108PubMedGoogle Scholar
  30. 30.
    Lokeshwar VB, Habuchi T et al (2005) Bladder tumor markers beyond cytology: international consensus panel on bladder tumor markers. Urology 66(6 Suppl 1):35–63PubMedCrossRefGoogle Scholar
  31. 31.
    Murphy WM (1990) Current status of urinary cytology in the evaluation of bladder neoplasms. Hum Pathol 21(9):886–896PubMedCrossRefGoogle Scholar
  32. 32.
    Shirodkar SP, Lokeshwar VB (2008) Bladder tumor markers: from hematuria to molecular diagnostics – where do we stand? Expert Rev Anticancer Ther 8(7):1111–1123PubMedCrossRefGoogle Scholar
  33. 33.
    Bubendorf L (2011) Multiprobe fluorescence in situ hybridization (UroVysion) for the detection of urothelial carcinoma – FISHing for the right catch. Acta Cytol 55(2):113–119PubMedCrossRefGoogle Scholar
  34. 34.
    Halling KC (2003) Vysis UroVysion for the detection of urothelial carcinoma. Expert Rev Mol Diagn 3(4):507–519PubMedCrossRefGoogle Scholar
  35. 35.
    Tapia C, Glatz K et al (2011) Evaluation of chromosomal aberrations in patients with benign conditions and reactive changes in urinary cytology. Cancer Cytopathol 119(6):404–410PubMedCrossRefGoogle Scholar
  36. 36.
    Murata S, Iseki M et al (2010) Molecular and immunohistologic analyses cannot reliably solve diagnostic variation of flat intraepithelial lesions of the urinary bladder. Am J Clin Pathol 134(6):862–872PubMedCrossRefGoogle Scholar
  37. 37.
    Vrooman OP, Witjes JA (2009) Molecular markers for detection, surveillance and prognostication of bladder cancer. Int J Urol 16(3):234–243PubMedCrossRefGoogle Scholar
  38. 38.
    Bergman J, Reznichek RC et al (2008) Surveillance of patients with bladder carcinoma using fluorescent in-situ hybridization on bladder washings. BJU Int 101(1):26–29PubMedGoogle Scholar
  39. 39.
    Halling KC, Kipp BR (2008) Bladder cancer detection using FISH (UroVysion assay). Adv Anat Pathol 15(5):279–286PubMedCrossRefGoogle Scholar
  40. 40.
    Ferra S, Denley R et al (2009) Reflex UroVysion testing in suspicious urine cytology cases. Cancer 117(1):7–14PubMedGoogle Scholar
  41. 41.
    Savic S, Zlobec I et al (2009) 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 124(12):2899–2904PubMedCrossRefGoogle Scholar
  42. 42.
    Galvan AB, Salido M et al (2011) A multicolor fluorescence in situ hybridization assay: a monitoring tool in the surveillance of patients with a history of non-muscle-invasive urothelial cell carcinoma: a prospective study. Cancer Cytopathol 119(6):395–403PubMedCrossRefGoogle Scholar
  43. 43.
    Halling KC, King W et al (2002) A comparison of BTA stat, hemoglobin dipstick, telomerase and Vysis UroVysion assays for the detection of urothelial carcinoma in urine. J Urol 167(5):2001–2006PubMedCrossRefGoogle Scholar
  44. 44.
    (2010) UroVysion Bladder Cancer Kit. Retrieved 31 July 2011, from
  45. 45.
    (2005) FDA 510(k) #K050840: DuetTM System. BioView, Ltd., Retrieved 31 July 2011, from
  46. 46.
    (2007) FDA 510(k) #K062577: Ikoniscope® oncoFISHTM Bladder Test System. Ikonisys, Inc., Retrieved 31 July 2011, from
  47. 47.
    Marganski WA, El-Sirgany Costa V et al (2011) Digitized microscopy in the diagnosis of bladder cancer: analysis of >3000 cases during a 7-month period. Cancer Cytopathol 119(4):279–289PubMedCrossRefGoogle Scholar
  48. 48.
    Smith GD, Bentz JS (2010) “FISHing” to detect urinary and other cancers: validation of an imaging system to aid in interpretation. Cancer Cytopathol 118(1):56–64PubMedCrossRefGoogle Scholar
  49. 49.
    Smith GD, Riding M et al (2010) Integrating a FISH imaging system into the cytology laboratory. CytoJournal 7:3PubMedCrossRefGoogle Scholar
  50. 50.
    Halling KC, King W et al (2000) A comparison of cytology and fluorescence in situ hybridization for the detection of urothelial carcinoma. J Urol 164(5):1768–1775PubMedCrossRefGoogle Scholar
  51. 51.
    Karnwal A, Venegas R et al (2010) The role of fluorescence in situ hybridization assay for surveillance of non-muscle invasive bladder cancer. Can J Urol 17(2):5077–5081PubMedGoogle Scholar
  52. 52.
    Dalquen P, Kleiber B et al (2002) DNA image cytometry and fluorescence in situ hybridization for noninvasive detection of urothelial tumors in voided urine. Cancer 96(6):374–379PubMedCrossRefGoogle Scholar
  53. 53.
    Yoder BJ, Skacel M et al (2007) 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 127(2):295–301PubMedCrossRefGoogle Scholar
  54. 54.
    Wild PJ, Fuchs T et al (2009) Detection of urothelial bladder cancer cells in voided urine can be improved by a combination of cytology and standardized microsatellite analysis. Cancer Epidemiol Biomarkers Prev 18(6):1798–1806PubMedCrossRefGoogle Scholar
  55. 55.
    Caraway NP, Khanna A et al (2007) Combination of cytologic evaluation and quantitative digital cytometry is reliable in detecting recurrent disease in patients with urinary diversions. Cancer 111(5):323–329PubMedCrossRefGoogle Scholar
  56. 56.
    Giella JG, Ring K et al (1992) The predictive value of flow cytometry and urinary cytology in the follow up of patients with transitional cell carcinoma of the bladder. J Urol 148(2 Pt 1):293–296PubMedGoogle Scholar
  57. 57.
    Koss LG, Wersto RP et al (1989) Predictive value of DNA measurements in bladder washings. Comparison of flow cytometry, image cytophotometry, and cytology in patients with a past history of urothelial tumors. Cancer 64(4):916–924PubMedCrossRefGoogle Scholar
  58. 58.
    Mora LB, Nicosia SV et al (1996) Ancillary techniques in the follow up of transitional cell carcinoma: a comparison of cytology, histology and deoxyribonucleic acid image analysis cytometry in 91 patients. J Urol 156(1):49–54, discussion 54–55PubMedCrossRefGoogle Scholar
  59. 59.
    Tribukait B, Gustafson H (1980) Impulse cytophotometric studies on DNA in bladder carcinoma. Onkologie 3(6):278–288PubMedCrossRefGoogle Scholar
  60. 60.
    Bakhos R, Shankey TV et al (2000) Comparative analysis of DNA flow cytometry and cytology of bladder washings: review of discordant cases. Diagn Cytopathol 22(2):65–69PubMedCrossRefGoogle Scholar
  61. 61.
    Jitsukawa S, Tachibana M et al (1987) Flow cytometry based on heterogeneity index score compared with urine cytology to evaluate their diagnostic efficacy in bladder tumor. Urology 29(2):218–222PubMedCrossRefGoogle Scholar
  62. 62.
    Murphy WM, Emerson LD et al (1986) Flow cytometry versus urinary cytology in the evaluation of patients with bladder cancer. J Urol 136(4):815–819PubMedGoogle Scholar
  63. 63.
    Ring KS, Karp F et al (1990) Enhanced detection of bladder cancer using the epithelial surface marker epithelial membrane antigen: a preliminary report. J Occup Med 32(9):904–909PubMedCrossRefGoogle Scholar
  64. 64.
    Dyrskjot L, Ostenfeld MS et al (2009) Genomic profiling of microRNAs in bladder cancer: miR-129 is associated with poor outcome and promotes cell death in vitro. Cancer Res 69(11):4851–4860PubMedCrossRefGoogle Scholar
  65. 65.
    Dyrskjot L, Zieger K et al (2007) Gene expression signatures predict outcome in non-muscle-invasive bladder carcinoma: a multicenter validation study. Clin Cancer Res 13(12):3545–3551PubMedCrossRefGoogle Scholar
  66. 66.
    Guo B, Che T et al (2011) Screening and identification of specific markers for bladder transitional cell carcinoma from urine urothelial cells with suppressive subtractive hybridization and cDNA microarray. Can Urol Assoc J 5(6):E129–E137PubMedCrossRefGoogle Scholar
  67. 67.
    Klein A, Zemer R et al (1998) Expression of cytokeratin 20 in urinary cytology of patients with bladder carcinoma. Cancer 82(2):349–354PubMedCrossRefGoogle Scholar
  68. 68.
    Tetu B (2009) Diagnosis of urothelial carcinoma from urine. Mod Pathol 22(Suppl 2):S53–S59PubMedCrossRefGoogle Scholar
  69. 69.
    van Rhijn BW, van der Poel HG et al (2005) Urine markers for bladder cancer surveillance: a systematic review. Eur Urol 47(6):736–748PubMedCrossRefGoogle Scholar
  70. 70.
    Zieger K (2008) High throughput molecular diagnostics in bladder cancer – on the brink of clinical utility. Mol Oncol 1(4):384–394PubMedCrossRefGoogle Scholar
  71. 71.
    Chiong E, Gaston KE et al (2008) Urinary markers in screening patients with hematuria. World J Urol 26(1):25–30PubMedCrossRefGoogle Scholar
  72. 72.
    Shariat SF, Karam JA et al (2008) Urine cytology and urine-based markers for bladder urothelial carcinoma detection and monitoring: developments and future prospects. Biomark Med 2(2):165–180PubMedCrossRefGoogle Scholar
  73. 73.
    Olsson H, Zackrisson B (2001) ImmunoCyt a useful method in the follow-up protocol for patients with urinary bladder carcinoma. Scand J Urol Nephrol 35(4):280–282PubMedCrossRefGoogle Scholar
  74. 74.
    Babjuk M, Kostirova M et al (2002) Qualitative and quantitative detection of urinary human complement factor H-related protein (BTA stat and BTA TRAK) and fragments of cytokeratins 8, 18 (UBC rapid and UBC IRMA) as markers for transitional cell carcinoma of the bladder. Eur Urol 41(1):34–39PubMedCrossRefGoogle Scholar
  75. 75.
    Heicappell R, Wettig IC et al (1999) Quantitative detection of human complement factor H-related protein in transitional cell carcinoma of the urinary bladder. Eur Urol 35(1):81–87PubMedCrossRefGoogle Scholar
  76. 76.
    Thomas L, Leyh H et al (1999) Multicenter trial of the quantitative BTA TRAK assay in the detection of bladder cancer. Clin Chem 45(4):472–477PubMedGoogle Scholar
  77. 77.
    Gray M, Sims TW (2004) NMP-22 for bladder cancer screening and surveillance. Urol Nurs 24(3):171–172, 177–179, 186PubMedGoogle Scholar
  78. 78.
    Voutsinas GE, Stravopodis DJ (2009) Molecular targeting and gene delivery in bladder cancer therapy. J BUON 14(Suppl 1):S69–S78PubMedGoogle Scholar
  79. 79.
    Mitra AP, Bartsch CC et al (2009) Strategies for molecular expression profiling in bladder cancer. Cancer Metastasis Rev 28(3–4):317–326PubMedCrossRefGoogle Scholar
  80. 80.
    Mitra AP, Cote RJ (2009) Molecular pathogenesis and diagnostics of bladder cancer. Annu Rev Pathol 4:251–285PubMedCrossRefGoogle Scholar
  81. 81.
    Argani P, Ladanyl M (2004) Renal carcinomas associated with Xp11.2 translocations/TFE gene fusions. In: Eble JN, Sauter G, Epstein JI, Sesterhenn IA (eds) Pathology and genetics of tumours of the urinary system and male genital organs, vol 6. IARC Press, Lyon, pp 37–38Google Scholar
  82. 82.
    Argani P, Antonescu CR et al (2001) Primary renal neoplasms with the ASPL-TFE3 gene fusion of alveolar soft part sarcoma: a distinctive tumor entity previously included among renal cell carcinomas of children and adolescents. Am J Pathol 159(1):179–192PubMedCrossRefGoogle Scholar
  83. 83.
    Heimann P, El Housni H et al (2001) Fusion of a novel gene, RCC17, to the TFE3 gene in t(X;17)(p11.2;q25.3)-bearing papillary renal cell carcinomas. Cancer Res 61(10):4130–4135PubMedGoogle Scholar
  84. 84.
    Argani P, Ladanyi M (2003) Recent advances in pediatric renal neoplasia. Adv Anat Pathol 10(5):243–260PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  1. 1.Department of Anatomic PathologyH. Lee Moffitt Cancer Center and Research Institute, University of South Florida College of MedicineTampaUSA
  2. 2.Department of Hematopathology and Laboratory Medicine and Anatomic PathologyH. Lee Moffitt Cancer Center and Research Institute, University of South Florida College of MedicineTampaUSA
  3. 3.Department of PathologyThe Ohio State University, Wexner Medical CenterColumbusUSA

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