Skip to main content
SpringerLink
Log in

Molecular Pathology of Urinary Bladder Cancer

  • Chapter
  • First Online:
Book cover Molecular Surgical Pathology

Abstract

The staggering advances in genetics and genomics achieved following the completion of the human genome project have deeply impacted clinical management and diagnostics in solid tumor oncology. Molecular diagnostics is now an integral part of routine clinical management in lung, colon, and breast cancer patients. In sharp contrast, molecular biomarkers have been largely excluded from current management algorithms of urologic malignancies. The need for new treatment alternatives to improve upon the so far modest outcome in muscle invasive bladder cancer patients is evident. Well-validated prognostic molecular biomarkers that can help clinicians identify patients in need of early aggressive management are lacking. Identifying robust predictive biomarkers that will stratify response to emerging targeted therapeutics is another crucially needed development. The following is an overview of the molecular pathways involved in bladder cancer oncogenesis with a focus on promising candidate biomarkers that may soon make their transition to the realm of clinical management of urothelial carcinoma.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Suggested Reading

  • Baak JP, Bol MG, van Diermen B, et al. DNA cytometric features in biopsies of TaT1 urothelial cell cancer predict recurrence and stage progression more accurately than stage, grade, or treatment modality. Urology. 2003;61:1266–72.

    Article  PubMed  Google Scholar 

  • Beekman KW, Bradley D, Hussain M. New molecular targets and novel agents in the treatment of advanced urothelial cancer. Semin Oncol. 2007;34:154–64.

    Article  PubMed  CAS  Google Scholar 

  • Birkhahn M, Mitra AP, Williams AJ, et al. Predicting recurrence and progression of noninvasive papillary bladder cancer at initial presentation based on quantitative gene expression profiles. Eur Urol. 2010;57:12–20.

    Article  PubMed  CAS  Google Scholar 

  • Black PC, Agarwal PK, Dinney CP. Targeted therapies in bladder cancer—an update. Urol Oncol. 2007;25:433–8.

    Article  PubMed  CAS  Google Scholar 

  • Bolenz C, Lotan Y. Translational research in bladder cancer: from molecular pathogenesis to useful tissue biomarkers. Cancer Biol Ther. 2010;10:407–15.

    Article  PubMed  CAS  Google Scholar 

  • Bolenz C, Shariat SF, Karakiewicz PI, et al. Human epidermal growth factor receptor 2 expression status provides independent prognostic information in patients with urothelial carcinoma of the urinary bladder. BJU Int. 2010;106:1216–22.

    Article  PubMed  Google Scholar 

  • Catto JW, Miah S, Owen HC, et al. Distinct microRNA alterations characterize high- and low-grade bladder cancer. Cancer Res. 2009;69:8472–81.

    Article  PubMed  CAS  Google Scholar 

  • Catto JW, Azzouzi AR, Rehman I, et al. Promoter hypermethylation is associated with tumor location, stage, and subsequent progression in transitional cell carcinoma. J Clin Oncol. 2005;23:2903–10.

    Article  PubMed  CAS  Google Scholar 

  • Chatterjee SJ, Datar R, Youssefzadeh D, et al. Combined effects of p53, p21, and pRb expression in the progression of bladder transitional cell carcinoma. J Clin Oncol. 2004;22:1007–13.

    Article  PubMed  CAS  Google Scholar 

  • Cheng L, Lopez-Beltran A, Bostwick DG. Bladder pathology. Hoboken, NJ: Wiley-Blackwell; 2012.

    Book  Google Scholar 

  • Cheng L, Zhang S, Alexander R, MacLennan GT, et al. Sarcomatoid carcinoma of the urinary bladder: the final common pathway of urothelial carcinoma dedifferentiation. Am J Surg Pathol. 2011a;35:e34–46.

    Article  PubMed  Google Scholar 

  • Cheng L, Davidson DD, Maclennan GT, et al. The origins of urothelial carcinoma. Expert Rev Anticancer Ther. 2010;10:865–80.

    Article  PubMed  CAS  Google Scholar 

  • Cheng L, Zhang S, Maclennan GT, et al. Bladder cancer: translating molecular genetic insights into clinical practice. Hum Pathol. 2011b;42:455–81.

    Article  PubMed  CAS  Google Scholar 

  • Comperat E, Camparo P, Haus R, et al. Aurora-A/STK-15 is a predictive factor for recurrent behaviour in noninvasive bladder carcinoma: a study of 128 cases of noninvasive neoplasms. Virchows Arch. 2007;450:419–24.

    Article  PubMed  CAS  Google Scholar 

  • Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer. 2003;3:11–22.

    Article  PubMed  CAS  Google Scholar 

  • Ferra S, Denley R, Herr H, et al. Reflex UroVysion testing in suspicious urine cytology cases. Cancer. 2009;117:7–14.

    PubMed  Google Scholar 

  • Hernandez S, Lopez-Knowles E, Lloreta J, et al. Prospective study of FGFR3 mutations as a prognostic factor in NMI urothelial bladder carcinomas. J Clin Oncol. 2006;24:3664–71.

    Article  PubMed  CAS  Google Scholar 

  • Highshaw RA, McConkey DJ, Dinney CP. Integrating basic science and clinical research in bladder cancer: update from the first bladder specialized program of research excellence (SPORE). Curr Opin Urol. 2004;14:295–300.

    Article  PubMed  Google Scholar 

  • Hussain MH, MacVicar GR, Petrylak DP, et al. Trastuzumab, paclitaxel, carboplatin, and gemcitabine in advanced human epidermal growth factor receptor-2/neu-positive urothelial carcinoma: results of a multicenter phase II national cancer institute trial. J Clin Oncol. 2007;25:2218–24.

    Article  PubMed  CAS  Google Scholar 

  • Iyer G, Milowsky MI, Bajorin DF. Novel strategies for treating relapsed/refractory urothelial carcinoma. Expert Rev Anticancer Ther. 2010;10:1917–32.

    Article  PubMed  Google Scholar 

  • Karnwal A, Venegas R, Shuch B, et al. The role of fluorescence in situ hybridization assay for surveillance of non-MI bladder cancer. Can J Urol. 2010;17:5077–81.

    PubMed  Google Scholar 

  • Kompier LC, Lurkin I, van der Aa MN, et al. FGFR3, HRAS, KRAS, NRAS and PIK3CA mutations in bladder cancer and their potential as biomarkers for surveillance and therapy. PLoS One. 2010;5:e13821.

    Article  PubMed  Google Scholar 

  • Kruger S, Mess F, Bohle A, Feller AC. Numerical aberrations of chromosome 17 and the 9p21 locus are independent predictors of tumor recurrence in noninvasive transitional cell carcinoma of the urinary bladder. Int J Oncol. 2003;23:41–8.

    PubMed  Google Scholar 

  • Lindgren D, Frigyesi A, Gudjonsson S, et al. Combined gene expression and genomic profiling define two intrinsic molecular subtypes of urothelial carcinoma and gene signatures for molecular grading and outcome. Cancer Res. 2010;70:3463–72.

    Article  PubMed  CAS  Google Scholar 

  • Lindgren D, Liedberg F, Andersson A, et al. Molecular characterization of early-stage bladder carcinomas by expression profiles, FGFR3 mutation status, and loss of 9q. Oncogene. 2006;25:2685–96.

    Article  PubMed  CAS  Google Scholar 

  • Lopez-Beltran A, Luque RJ, Alvarez-Kindelan J, et al. Prognostic factors in stage T1 grade 3 bladder cancer survival: the role of G1-S modulators (p53, p21Waf1, p27kip1, cyclin D1, and cyclin D3) and proliferation index (ki67-MIB1). Eur Urol. 2004;45:606–12.

    Article  PubMed  CAS  Google Scholar 

  • Lopez-Knowles E, Hernandez S, Malats N, et al. PIK3CA mutations are an early genetic alteration associated with FGFR3 mutations in superficial papillary bladder tumors. Cancer Res. 2006;66:7401–4.

    Article  PubMed  CAS  Google Scholar 

  • Maffezzini M, Campodonico F, Capponi G, et al. Prognostic significance of fluorescent in situ hybridisation in the follow-up of non-muscle-invasive bladder cancer. Anticancer Res. 2010;30:4761–5.

    PubMed  Google Scholar 

  • Margulis V, Lotan Y, Karakiewicz PI, et al. Multi-institutional validation of the predictive value of ki-67 labeling index in patients with urinary bladder cancer. J Natl Cancer Inst. 2009;101:114–9.

    Article  PubMed  Google Scholar 

  • Mengual L, Burset M, Ribal MJ, et al. Gene expression signature in urine for diagnosing and assessing aggressiveness of bladder urothelial carcinoma. Clin Cancer Res. 2010;16:2624–33.

    Article  PubMed  CAS  Google Scholar 

  • Mitra AP, Cote RJ. Molecular screening for bladder cancer: progress and potential. Nat Rev Urol. 2010;7:11–20.

    Article  PubMed  CAS  Google Scholar 

  • Mitra AP, Pagliarulo V, Yang D, et al. Generation of a concise gene panel for outcome prediction in urinary bladder cancer. J Clin Oncol. 2009;27:3929–37.

    Article  PubMed  Google Scholar 

  • Mitra AP, Datar RH, Cote RJ. Molecular pathways in invasive bladder cancer: new insights into mechanisms, progression, and target identification. J Clin Oncol. 2006;24:5552–64.

    Article  PubMed  CAS  Google Scholar 

  • Netto GJ, Cheng L. Emerging critical role of molecular testing in diagnostic genitourinary pathology. Arch Pathol Lab Med. 2012;36:372–90.

    Article  Google Scholar 

  • Netto GJ. Molecular diagnostics in urologic malignancies: a work in progress. Arch Pathol Lab Med. 2011;135:610–21.

    PubMed  CAS  Google Scholar 

  • Netto GJ, Epstein JI. Theranostic and prognostic biomarkers: genomic applications in urological malignancies. Pathology. 2010;42:384–94.

    Article  PubMed  Google Scholar 

  • Philips GK, Halabi S, Sanford BL, et al. A phase II trial of cisplatin (C), gemcitabine (G) and gefitinib for advanced urothelial tract carcinoma: results of cancer and leukemia group B (CALGB) 90102. Ann Oncol. 2009;20:1074–9.

    Article  PubMed  CAS  Google Scholar 

  • Platt FM, Hurst CD, Taylor CF, et al. Spectrum of phosphatidylinositol 3-kinase pathway gene alterations in bladder cancer. Clin Cancer Res. 2009;15:6008–17.

    Article  PubMed  CAS  Google Scholar 

  • Rothman N, Garcia-Closas M, Chatterjee N, et al. A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci. Nat Genet. 2010;42:978–84.

    Article  PubMed  CAS  Google Scholar 

  • Sanchez-Carbayo M, Socci ND, Lozano J, et al. Defining molecular profiles of poor outcome in patients with invasive bladder cancer using oligonucleotide microarrays. J Clin Oncol. 2006;24:778–89.

    Article  PubMed  CAS  Google Scholar 

  • Sanchez-Carbayo M, Socci ND, Charytonowicz E, et al. Molecular profiling of bladder cancer using cDNA microarrays: defining histogenesis and biological phenotypes. Cancer Res. 2002;62:6973–80.

    PubMed  CAS  Google Scholar 

  • Sarosdy MF, Kahn PR, Ziffer MD, et al. Use of a multitarget fluorescence in situ hybridization assay to diagnose bladder cancer in patients with hematuria. J Urol. 2006;176:44–7.

    Article  PubMed  Google Scholar 

  • 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-guerin therapy. Int J Cancer. 2009;124:2899–904.

    Article  PubMed  CAS  Google Scholar 

  • Schultz L, Albadine R, Hicks J, et al. Expression status and prognostic significance of mammalian target of rapamycin pathway members in urothelial carcinoma of urinary bladder after cystectomy. Cancer. 2010;116:5517–26.

    Article  PubMed  Google Scholar 

  • Shariat SF, Karakiewicz PI, Palapattu GS, et al. Outcomes of radical cystectomy for transitional cell carcinoma of the bladder: a contemporary series from the bladder cancer research consortium. J Urol. 2006;176:2414–22.

    Article  PubMed  Google Scholar 

  • 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;169:2101–5.

    Article  PubMed  CAS  Google Scholar 

  • Soloway MS, Sofer M, Vaidya A. Contemporary management of stage T1 transitional cell carcinoma of the bladder. J Urol. 2002;167:1573–83.

    Article  PubMed  Google Scholar 

  • Sylvester RJ, van der Meijden AP, Oosterlinck W, et al. Predicting recurrence and progression in individual patients with stage ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol. 2006;49:466–77.

    Article  PubMed  Google Scholar 

  • van der Kwast TH, Bapat B. Predicting favourable prognosis of urothelial carcinoma: gene expression and genome profiling. Curr Opin Urol. 2009;19:516–21.

    Article  PubMed  Google Scholar 

  • van Rhijn BW, Zuiverloon TC, Vis AN, et al. Molecular grade (FGFR3/MIB-1) and EORTC risk scores are predictive in primary non-muscle-invasive bladder cancer. Eur Urol. 2010;58:433–41.

    Article  PubMed  Google Scholar 

  • van Rhijn BW, Vis AN, van der Kwast TH, et al. Molecular grading of urothelial cell carcinoma with fibroblast growth factor receptor 3 and MIB-1 is superior to pathologic grade for the prediction of clinical outcome. J Clin Oncol. 2003;21:1912–21.

    Article  PubMed  Google Scholar 

  • Wu XR. Urothelial tumorigenesis: a tale of divergent pathways. Nat Rev Cancer. 2005;5:713–25.

    Article  PubMed  CAS  Google Scholar 

  • 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;127:295–301.

    Article  PubMed  Google Scholar 

  • Zuiverloon TC, van der Aa MN, van der Kwast TH, 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.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology, Johns Hopkins University, Baltimore, MD, USA

    George J. Netto MD

  2. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

    Liang Cheng MD

Authors
  1. George J. Netto MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Liang Cheng MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. , Molecular Pathology Laboratory, Indiana University School of Medicine, 350 West 11th Street, Rm 4010, Indianapolis, 46202, Indiana, USA

    Liang Cheng

  2. Department of Pathology, and Laboratory Medicine, Indiana University School of Medicine, 635 Barnhill Drive, Room 128, Indianapolis, 46202, Indiana, USA

    John N. Eble

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

Netto, G.J., Cheng, L. (2013). Molecular Pathology of Urinary Bladder Cancer. In: Cheng, L., Eble, J. (eds) Molecular Surgical Pathology. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-4900-3_11

Download citation

  • DOI: https://doi.org/10.1007/978-1-4614-4900-3_11

  • Published:

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-1-4614-4899-0

  • Online ISBN: 978-1-4614-4900-3

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation