Blue Light Cystoscopy: A Look at Relevant Research and its Implementation According to the NCCN and AUA Guidelines

David Ambinder MD 

Blue light cystoscopy is a diagnostic technology that detects cancer based on the preferential accumulation of photoactive porphyrins  in neoplastic tissue. Under blue light, these porphyrins emit a red fluorescence.1 When a photosensitizing agent is introduced into the urothelial environment, it is both healthy and cancerous cell tissue and becomes incorporated into the heme biosynthesis pathway. In noncancerous cells, the agent is excreted with no residual photoactivity. However, in malignant cells, the photosensitizer creates photoactive porphyrins that can be detected by blue light cystoscopy. 

The purpose of the technology is to aid in the diagnosis of bladder lesions that are invisible or difficult to discern with white light cystoscopy. Blue light cystoscopy works by targeting a precursor of photoactive porphyrins known as hexaminolevulinic acid. The basic technique involves instilling an imaging solution containing hexaminolevulinate via a catheter approximately 1 hour before a transurethral resection of bladder tumor (TURBT) and then using blue light while performing the procedure.

 Blue light cystoscopy can be used to identify many tumors, but it plays an especially significant role in the detection of small papillary lesions and carcinoma-in-situ (CIS) that would not have been seen with standard cystoscopy alone.2 Jocham et al conducted a study in 2005 concluding that 96% of all bladder tumors were detected with blue light cystoscopy compared to  77% with standard white light cystoscopy. Their findings were especially meaningful in regard to  CIS and papillary tumors, where increased rates of detection were found compared with white light cystoscopy (CIS, 95% vs 68%; papillary tumors, 96% vs 85%).3 This ability to identify bladder lesions that otherwise would not have been found has been shown to decrease bladder tumor recurrence in multiple studies.4 Moreover, these findings have been confirmed in a multicenter prospective study involving 9 different centers and enrolling more than 500 patients. Those researchers found an increase in the detection of CIS and papillary lesions and estimated a 14% change in management based on the utilization of blue light cystoscopy.5 

Two notable large meta-analyses constitute a significant portion of the evidence supporting the use of blue light cystoscopy.6 The first, by Yuan et al, involved use of blue light cystoscopy during TURBT in patients with non-muscle-invasive bladder cancer (NMIBC). The study included 12 randomized control trials and accounted for 2258 patients with NMIBC. The investigators found  blue light cystoscopy resulted in lower rates of recurrence, with a delayed time to first recurrence of 7.39 weeks (P <0.0001). Additionally, there was an improvement in recurrence-free survival at 1 year (hazard ratio [HR], 0.69; P <0.00001) and 2 years (HR, 0.65; P = 0.0004) .7 The second study, conducted by Burger et al, looked at 1345 patients with NMIBC and included patients with non-muscle-invasive papillary carcinoma (Ta), tumor-infiltrating lamina propria (T1), and CIS. The clinicians found they were able to detect more Ta (14.7%, P <0.001; odds ratio [OR], 4.9; 95% CI, 1.9-12.4) and CIS (40.8%, P <0.001; OR, 12.4;95% CI, 6.3-0.9) with blue light cystoscopy.8 

Despite the currently available evidence, however, it remains unclear whether blue light cystoscopy aids in slowing or preventing the rate of progression to muscle-invasive bladder cancer. False-positive results with blue light cystoscopy have been associated with a recent TURBT, bacillus Calmette-Guérin (BCG) instillation, or incidence of cystitis. 

These findings have propelled the panel in the version 6.2021 of the National Comprehensive Cancer Network (NCCN Guidelines®) on bladder cancer management to advise that “enhanced (blue light and narrow band imaging) cystoscopy may be helpful in identifying lesions not visible using white light cystoscopy.”9 

Similarly, the 2016 American Urological Association (AUA) guidelines on diagnosis and treatment of NMIBC addressed the usage of blue light cystoscopy in 2 distinct guidelines.10 The first guideline states that in “a patient with a history of NMIBC with normal cystoscopy and positive cytology, a clinician should consider prostatic urethral biopsies and upper tract imaging, as well as enhanced cystoscopic techniques (blue light cystoscopy, when available), ureteroscopy, or random bladder biopsies (Expert opinion).” The second point emphasized in the guideline, focused on enhanced cystoscopy, specifies that “in a patient with NMIBC, a clinician should offer blue light cystoscopy at the time of TURBT, if available, to increase detection and decrease recurrence. (Moderate Recommendation; evidence strength: Grade B).”10 The guideline balances discussion of the concern about missing a potential CIS tumor, which can appear normal on white light standard cystoscopy, with cautions about the reported higher false-positive rate for blue light cystoscopy, especially in patients who had a recent TURBT, concurrent infection, recent intravesical BCG, or chemotherapy. The AUA also notes its recognition that blue light cystoscopy is not available in every center. 

In summary, significant data have been accumulated over the past 20 years that have consistently found benefit with the use of blue light cystoscopy, especially for patients with small papillary tumors or CIS. 

Using blue light cystoscopy can help reduce the incidence of recurrence in bladder cancer, but is unclear if it reduces progression to muscle-invasive bladder cancer. Current reports indicate that the technology is underutilized  in the United States,11 although several recent studies have found that its effectiveness and utility can be applied to the outpatient setting12 and incorporated safely into office-based biopsy strategies.13,14 It is with this in mind, that both the NCCN and AUA have recommended its utility. Limitations of blue light cystoscopy include its limited availability and its higher false-positive rate compared to white light cystoscopy. Clinicians should be cognizant of features that may increase the false-positive rate, including recent TURBT, infection, and intravesical instillations. They should also be aware that while blue light cystoscopy increases the rate of cancer detection and prevents recurrence, it is still not clear how its utilization  impacts progression from NMIBC to muscle-invasive bladder cancer. 

David Ambinder, MD is a urology resident at New York Medical College / Westchester Medical Center. His interests include surgical education, GU oncology and advancements in technology in urology. A significant portion of his research has been focused on litigation in urology.  

References

1.     Partin AW, Dmochowski RR, Kavoussi LR, Peters CA, Wein AJ (eds).  Campbell-Walsh-Wein Urology. 12th ed. Philadelphia: Elsevier; 2020.

2.     Schmidbauer J, Witjes F, Schmeller N, et al; the Hexvix PCB301/01 Study Group. Improved detection of urothelial carcinoma in situ with hexaminolevulinate fluorescence cystoscopy. J Urol. 2004;171(1):135-138.doi: 10.1097/01.ju.0000100480.70769.0e

3.     Jocham D, Witjes F, Wagner S, et al. Improved detection and treatment of bladder cancer using hexaminolevulinate imaging: a prospective, phase III multicenter study. J Urol. 2005;174(3):862-866. discussion 866. doi: 10.1097/01.ju.0000169257.19841.2a

4.     Grossman HB, Gomella L, Fradet Y, et al. A phase III, multicenter comparison of hexaminolevulinate fluorescence cystoscopy and white light cystoscopy for the detection of superficial papillary lesions in patients with bladder cancer. J Urol. 2007;178(1):62-67. doi:10.1016/j.juro.2007.03.034

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6.     Enhanced cystoscopy. Discussion section. Pg MS-4-MS-5 In NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Bladder Cancer. Version 6.2021. December 6, 2021. https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf

7.     Yuan H, Qiu J, Liu L, et al. Therapeutic outcome of fluorescence cystoscopy guided transurethral resection in patients with non-muscle invasive bladder cancer: a meta-analysis of randomized controlled trials. PLoS One. 2013;8(9):e74142. doi:10.1371/journal.pone.0074142

8.     Burger M, Grossman HB, Droller M, et al. Photodynamic diagnosis of non-muscle-invasive bladder cancer with hexaminolevulinate cystoscopy: a meta-analysis of detection and recurrence based on raw data. Eur Urol. 2013;64(5):846-854. doi:10.1016/j.eururo.2013.03.059

9.     Principles of surgical management. Section BL-B. In: NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Bladder Cancer. Version 6.2021. December 6, 2021. https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf

10. Chang SS, Boorjian SA, Chou R, et al. Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer: AUA/SUO Guideline. J Urol. 2016;196(4):1021-1029. doi:10.1016/j.juro.2016.06.049

11. Lewicki P, Arenas-Gallo C, Qiu Y, et al. Underutilization of blue light cystoscopy for bladder cancer in the United States. Eur Urol Focus. 2021;S2405-4569(21)00271-6. doi:10.1016/j.euf.2021.09.025

12. Andersson M, Berger M, Zieger K, Malmström PU, Bläckberg M. The diagnostic challenge of suspicious or positive malignant urine cytology findings when cystoscopy findings are normal: an outpatient blue-light flexible cystoscopy may solve the problem. Scand J Urol. 2021;55(4):263-267. doi:10.1080/21681805.2021.1928746

13. Lotan Y, Chaplin I, Ahmadi H, et al. Prospective evaluation of blue-light flexible cystoscopy with hexaminolevulinate in non-muscle-invasive bladder cancer. BJU Int. 2021;127(1):108-113. doi:10.1111/bju.15166

14. Daneshmand S, Patel S, Lotan Y, et al. Efficacy and safety of blue light flexible cystoscopy with hexaminolevulinate in the surveillance of bladder cancer: a phase III, comparative, multicenter study [published correction appears in J Urol. 2019;201(5):1017]. J Urol. 2018;199(5):1158-1165. doi:10.1016/j.juro.2017.11.096