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Confocal Laser Endomicroscopy of Bladder and Upper Tract Urothelial Carcinoma: A New Era of Optical Diagnosis?

  • Urothelial Cancer (A Sagalowsky, Section Editor)
  • Published:
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Abstract

Urothelial carcinoma of the bladder and upper tract pose significant diagnostic and therapeutic challenges. White light endoscopy plays a central role in the management of urothelial carcinoma but has several well-recognized shortcomings. New optical imaging technologies may improve diagnostic accuracy, enhance local cancer control, and better stratify treatment options. Confocal laser endomicroscopy enables dynamic imaging of the cellular structures below the mucosal surface and holds promise in providing real time optical diagnosis and grading of urothelial carcinoma. A variety of imaging probes are available that are compatible with the full spectrum of cystoscopes and ureteroscopes. We review the underlying principles and technique of confocal laser endomicroscopy in the urinary tract, with emphasis on specific application towards urothelial carcinoma. While the available data are largely related to urothelial carcinoma of the bladder, the lessons learned are directly applicable to the upper tract, where the clinical needs are significant. Ongoing efforts to optimize this technology offer an exciting glimpse into future advances in optical imaging and intraoperative image guidance.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. U.S. Cancer Statistics Working Group. United States Cancer Statistics: 1999–2010 incidence and mortality web-based report. (U.S. Department of Health and Human Services, Centers for Disease Control and Prevention and National Cancer Institute, 2013).

  2. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9–29.

    Article  PubMed  Google Scholar 

  3. Kirkali Z et al. Bladder cancer: epidemiology, staging and grading, and diagnosis. Urology. 2005;66:4–34.

    Article  PubMed  Google Scholar 

  4. Morgan TM, Clark PE. Bladder cancer. Curr Opin Oncol. 2010;22:242–9.

    Article  PubMed  Google Scholar 

  5. Sylvester RJ 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 

  6. Cauberg Evelyne CC, de la Rosette JJMCH, de Reijke TM. Emerging optical techniques in advanced cystoscopy for bladder cancer diagnosis: A review of the current literature. Indian J Urol IJU J Urol Soc India. 2011;27:245–51.

    Article  CAS  Google Scholar 

  7. Rouprêt M et al. European guidelines for the diagnosis and management of upper urinary tract urothelial cell carcinomas: 2011 update. Eur Urol. 2011;59:584–94.

    Article  PubMed  Google Scholar 

  8. Hall MC et al. Prognostic factors, recurrence, and survival in transitional cell carcinoma of the upper urinary tract: a 30-year experience in 252 patients. Urology. 1998;52:594–601.

    Article  CAS  PubMed  Google Scholar 

  9. Linton KD, Catto JW. Upper tract urothelial carcinoma. J Clin Urol. 2013;6:272–9.

    Google Scholar 

  10. Azémar M-D, Comperat E, Richard F, Cussenot O, Rouprêt M. Bladder recurrence after surgery for upper urinary tract urothelial cell carcinoma: frequency, risk factors, and surveillance. Urol Oncol. 2011;29:130–6.

    Article  PubMed  Google Scholar 

  11. Lee CSD, Yoon CY, Witjes JA. The past, present and future of cystoscopy: the fusion of cystoscopy and novel imaging technology. BJU Int. 2008;102:1228–33.

    Article  PubMed  Google Scholar 

  12. Liu J-J, Droller MJ, Liao JC. New optical imaging technologies for bladder cancer: considerations and perspectives. J Urol. 2012;188:361–8.

    Article  PubMed Central  PubMed  Google Scholar 

  13. Wu K et al. Dynamic real-time microscopy of the urinary tract using confocal laser endomicroscopy. Urology. 2011;78:225–31. This paper describes the suggested optical diagnostic criteria for normal urothelium, benign inflammatory urothelium, low grade urothelial carcinoma, and high grade urothelial carcinoma.

    Article  PubMed Central  PubMed  Google Scholar 

  14. Schmidbauer J et al. Improved detection of urothelial carcinoma in situ with hexaminolevulinate fluorescence cystoscopy. J Urol. 2004;171:135–8.

    Article  PubMed  Google Scholar 

  15. Fradet Y et al. A comparison of hexaminolevulinate fluorescence cystoscopy and white light cystoscopy for the detection of carcinoma in situ in patients with bladder cancer: a phase III, multicenter study. J Urol. 2007;178:68–73. discussion 73.

    Article  PubMed  Google Scholar 

  16. Jocham D et al. Improved detection and treatment of bladder cancer using hexaminolevulinate imaging: a prospective, phase III multicenter study. J Urol. 2005;174:862–6. discussion 866.

    Article  PubMed  Google Scholar 

  17. Kolozsy Z. Histopathological ‘self control’ in transurethral resection of bladder tumours. Br J Urol. 1991;67:162–4.

    Article  CAS  PubMed  Google Scholar 

  18. Babjuk M, Soukup V, Petrík R, Jirsa M, Dvorácek J. 5-aminolaevulinic acid-induced fluorescence cystoscopy during transurethral resection reduces the risk of recurrence in stage Ta/T1 bladder cancer. BJU Int. 2005;96:798–802.

    Article  CAS  PubMed  Google Scholar 

  19. Daniltchenko DI et al. Long-term benefit of 5-aminolevulinic acid fluorescence assisted transurethral resection of superficial bladder cancer: 5-year results of a prospective randomized study. J Urol. 2005;174:2129–33. discussion 2133.

    Article  CAS  PubMed  Google Scholar 

  20. Klän R, Loy V, Huland H. Residual tumor discovered in routine second transurethral resection in patients with stage T1 transitional cell carcinoma of the bladder. J Urol. 1991;146:316–8.

    PubMed  Google Scholar 

  21. Brausi M et al. Variability in the recurrence rate at first follow-up cystoscopy after TUR in stage Ta T1 transitional cell carcinoma of the bladder: a combined analysis of seven EORTC studies. Eur Urol. 2002;41:523–31.

    Article  PubMed  Google Scholar 

  22. Margulis V et al. Outcomes of radical nephroureterectomy: a series from the Upper Tract Urothelial Carcinoma Collaboration. Cancer. 2009;115:1224–33.

    Article  PubMed  Google Scholar 

  23. Straub J, Strittmatter F, Karl A, Stief CG, Tritschler S. Ureterorenoscopic biopsy and urinary cytology according to the 2004 WHO classification underestimate tumor grading in upper urinary tract urothelial carcinoma. Urol Oncol. 2013;31:1166–70.

    Article  PubMed  Google Scholar 

  24. Wang JK, Tollefson MK, Krambeck AE, Trost LW, Thompson RH. High rate of pathologic upgrading at nephroureterectomy for upper tract urothelial carcinoma. Urology. 2012;79:615–9.

    Article  PubMed  Google Scholar 

  25. Smith AK et al. Inadequacy of biopsy for diagnosis of upper tract urothelial carcinoma: implications for conservative management. Urology. 2011;78:82–6.

    Article  PubMed  Google Scholar 

  26. Tavora F et al. Small endoscopic biopsies of the ureter and renal pelvis: pathologic pitfalls. Am J Surg Pathol. 2009;33:1540–6.

    Article  PubMed  Google Scholar 

  27. Cutress ML et al. Ureteroscopic and percutaneous management of upper tract urothelial carcinoma (UTUC): systematic review. BJU Int. 2012;110:614–28.

    Article  PubMed  Google Scholar 

  28. Elliott DS, Segura JW, Lightner D, Patterson DE, Blute ML. Is nephroureterectomy necessary in all cases of upper tract transitional cell carcinoma? Long-term results of conservative endourologic management of upper tract transitional cell carcinoma in individuals with a normal contralateral kidney. Urology. 2001;58:174–8.

    Article  CAS  PubMed  Google Scholar 

  29. Gadzinski AJ, Roberts WW, Faerber GJ, Wolf Jr JS. Long-term outcomes of nephroureterectomy versus endoscopic management for upper tract urothelial carcinoma. J Urol. 2010;183:2148–53.

    Article  PubMed  Google Scholar 

  30. Lopez A, Liao JC. Emerging endoscopic imaging technologies for bladder cancer detection. Curr Urol Rep. 2014;15:406.

    Article  PubMed  Google Scholar 

  31. Sonn GA et al. Optical biopsy of human bladder neoplasia with in vivo confocal laser endomicroscopy. J Urol. 2009;182:1299–305. This paper was the initial feasibility study of in vivo confocal laser endomicroscopy in the urinary tract.

    Article  PubMed  Google Scholar 

  32. Neumann H, Kiesslich R, Wallace MB, Neurath MF. Confocal laser endomicroscopy: technical advances and clinical applications. Gastroenterology. 2010;139:388–92. 392.e1–2.

    Article  PubMed  Google Scholar 

  33. Thiberville L, Salaün M. Bronchoscopic advances: on the way to the cells. Respir Int Rev Thorac Dis. 2010;79:441–9.

    Google Scholar 

  34. Sonn GA et al. Fibered confocal microscopy of bladder tumors: an ex vivo study. J Endourol Endourol Soc. 2009;23:197–201.

    Article  Google Scholar 

  35. Chang TC, Liu J-J, Liao JC. Probe-based confocal laser endomicroscopy of the urinary tract: the technique. J Vis Exp JoVE. 2013;e4409. doi:10.3791/4409. This on-line video paper demonstrates a step-by-step approach of confocal laser endomicroscopy in the lower urinary tract.

  36. Wallace MB et al. The safety of intravenous fluorescein for confocal laser endomicroscopy in the gastrointestinal tract. Aliment Pharmacol Ther. 2010;31:548–52.

    Article  CAS  PubMed  Google Scholar 

  37. Becker V et al. High-resolution miniprobe-based confocal microscopy in combination with video mosaicing (with video). Gastrointest Endosc. 2007;66:1001–7.

    Article  PubMed  Google Scholar 

  38. Chang TC et al. Interobserver agreement of confocal laser endomicroscopy for bladder cancer. J Endourol Endourol Soc. 2013;27:598–603. This paper describes the interobserver agreement of confocal laser endomicroscopy of bladder lesions and provides an updated optical diagnostic criteria.

    Article  Google Scholar 

  39. Aron M et al. Utility of a triple antibody cocktail intraurothelial neoplasm-3 (IUN-3-CK20/CD44s/p53) and α-methylacyl-CoA racemase (AMACR) in the distinction of urothelial carcinoma in situ (CIS) and reactive urothelial atypia. Am J Surg Pathol. 2013;37:1815–23.

    Article  PubMed  Google Scholar 

  40. Wallace MB et al. Preliminary accuracy and interobserver agreement for the detection of intraepithelial neoplasia in Barrett’s esophagus with probe-based confocal laser endomicroscopy. Gastrointest Endosc. 2010;72:19–24.

    Article  PubMed Central  PubMed  Google Scholar 

  41. Viera AJ, Garrett JM. Understanding interobserver agreement: the kappa statistic. Fam Med. 2005;37:360–3.

    PubMed  Google Scholar 

  42. Kuiper T, Kiesslich R, Ponsioen C, Fockens P, Dekker E. The learning curve, accuracy, and interobserver agreement of endoscope-based confocal laser endomicroscopy for the differentiation of colorectal lesions. Gastrointest Endosc. 2012;75:1211–7.

    Article  PubMed  Google Scholar 

  43. Gómez V et al. Interobserver agreement and accuracy among international experts with probe-based confocal laser endomicroscopy in predicting colorectal neoplasia. Endoscopy. 2010;42:286–91.

    Article  PubMed  Google Scholar 

  44. Lee YC et al. Interobserver reliability in the endoscopic diagnosis and grading of Barrett’s esophagus: an Asian multinational study. Endoscopy. 2010;42:699–704.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Kiesslich R et al. In vivo histology of Barrett’s esophagus and associated neoplasia by confocal laser endomicroscopy. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc. 2006;4:979–87.

    Google Scholar 

  46. Gaddam S et al. Novel probe-based confocal laser endomicroscopy criteria and interobserver agreement for the detection of dysplasia in Barrett’s esophagus. Am J Gastroenterol. 2011;106:1961–9.

    Article  PubMed  Google Scholar 

  47. Bui D, Mach KE, Lopez A, Liu JJ, Chang T, Lavelle J, et al. Optical biopsy of upper tract urothelial carcinoma with confocal laser endomicroscopy. Eur Urol. 2014;13:e630.

    Article  Google Scholar 

  48. André B, Vercauteren T, Buchner AM, Wallace MB, Ayache N. A smart atlas for endomicroscopy using automated video retrieval. Med Image Anal. 2011;15:460–76.

    Article  PubMed  Google Scholar 

  49. André B et al. Software for automated classification of probe-based confocal laser endomicroscopy videos of colorectal polyps. World J Gastroenterol WJG. 2012;18:5560–9.

    Article  Google Scholar 

  50. Hsiung P-L et al. Detection of colonic dysplasia in vivo using a targeted heptapeptide and confocal microendoscopy. Nat Med. 2008;14:454–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Becker A et al. Receptor-targeted optical imaging of tumors with near-infrared fluorescent ligands. Nat Biotechnol. 2001;19:327–31.

    Article  CAS  PubMed  Google Scholar 

  52. Sturm MB et al. Targeted imaging of esophageal neoplasia with a fluorescently labeled peptide: first-in-human results. Sci Transl Med. 2013;5:184ra61.

    Article  CAS  PubMed  Google Scholar 

  53. Miller SJ et al. In vivo fluorescence-based endoscopic detection of colon dysplasia in the mouse using a novel peptide probe. PLoS One. 2011;6:e17384.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Thekkek N et al. Pre-clinical evaluation of fluorescent deoxyglucose as a topical contrast agent for the detection of Barrett’s-associated neoplasia during confocal imaging. Technol Cancer Res Treat. 2011;10:431–41.

    CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

The authors thank current and past members of the Liao Laboratory, particularly Katherine Wu and Kathy Mach, for technical support and helpful discussions. Funding support was provided in part by Stanford University School of Medicine MedScholars Fellowship (to S.P.C.) and NIH R01 CA160986 (to J.C.L.).

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Conflict of Interest

Stephanie P. Chen and Dr. Joseph C. Liao each declare no potential conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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Authors and Affiliations

  1. Department of Urology, Stanford University School of Medicine, 300 Pasteur Dr., S-287, Stanford, CA, 94305-5118, USA

    Stephanie P. Chen & Joseph C. Liao

  2. Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA

    Joseph C. Liao

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  1. Stephanie P. Chen
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  2. Joseph C. Liao
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Correspondence to Joseph C. Liao.

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This article is part of the Topical Collection on Urothelial Cancer

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Chen, S.P., Liao, J.C. Confocal Laser Endomicroscopy of Bladder and Upper Tract Urothelial Carcinoma: A New Era of Optical Diagnosis?. Curr Urol Rep 15, 437 (2014). https://doi.org/10.1007/s11934-014-0437-y

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  • DOI: https://doi.org/10.1007/s11934-014-0437-y

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