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 Table of Contents  
REVIEW ARTICLE
Year : 2019  |  Volume : 52  |  Issue : 5  |  Page : 155-160

Blue-light cystoscopy and narrow-band imaging in bladder cancer management


Department of Urology, National University Health System, Singapore 119228, Singapore

Date of Submission18-Dec-2018
Date of Decision07-Jan-2019
Date of Acceptance10-Apr-2019
Date of Web Publication25-Oct-2019

Correspondence Address:
Prof. Edmund Chiong
Department of Urology, National University Health System, NUHS Tower Block, Level 8, 1E Kent Ridge Road, Singapore 119228
Singapore
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/fjs.fjs_133_18

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  Abstract 


Despite the high resolution of modern imaging technology including computed tomography and magnetic resonance imaging, cystoscopy remains the gold standard method for detecting bladder cancer. Cystoscopy is conventionally conducted with white light visualization, and the pitfalls of white light cystoscopy are well-recognized. Novel technologies to enhance visualization of bladder lesion have emerged during the past 20 years. Among them, blue-light cystoscopy (BLC) and narrow-band imaging (NBI) are the most promising and well-studied. Many clinical trials have suggested the benefit of these two technologies. In this review, we aim to summarize the data, evidence, and current role of BLC and NBI in clinical practice.

Keywords: Bladder cancer, blue-light cystoscopy, narrow-band imaging


How to cite this article:
Zang Z, Wu Q, Chiong E. Blue-light cystoscopy and narrow-band imaging in bladder cancer management. Formos J Surg 2019;52:155-60

How to cite this URL:
Zang Z, Wu Q, Chiong E. Blue-light cystoscopy and narrow-band imaging in bladder cancer management. Formos J Surg [serial online] 2019 [cited 2019 Dec 9];52:155-60. Available from: http://www.e-fjs.org/text.asp?2019/52/5/155/269924




  Introduction Top


Bladder cancer is the seventh-most common cancer worldwide in men, affecting more than 800,000 people. Up to 85% of cancer in the bladder is nonmuscle invasive bladder cancer (NMIBC), which is treated with bladder-sparing therapies (e.g., transurethral resection of bladder tumor [TURBT] coupled with immunotherapy or chemotherapy).[1] Despite treatment, bladder cancer still has an extremely high cancer recurrence rate after tumor resection. The recurrence rate is 15%–61% after 1 year and 31%–78% after 5 years. Moreover, up to 17% of the NMIBC will progress to a muscle-invasive tumor after 1 year and 45% after 5 years, respectively. Long-term surveillance is mandatory after bladder-retaining therapies in bladder cancer.[2]

The high recurrence rate of bladder cancer has been linked to overlooked tumors and inadequately resected tumors. White light cystoscopy (WLC), the current mainstay method, is known to miss occult bladder lesions such as small multifocal tumors and carcinoma in situ (CIS).[3],[4] Better visualization of bladder tumors has been achieved using novel optical technologies. Among them, blue-light cystoscopy (BLC) and narrow-band imaging (NBI) are the most well-studied. Both of the technologies have been approved by the Food and Drug Administration (FDA) for their applications in NMIBC diagnosis and treatment.


  Mechanism Top


BLC is also known as fluorescence cystoscopy or photodynamic diagnosis (PDD) of bladder tumor. It involves detection of bladder lesions using fluorescence. To generate fluorescence, photosensitizers such as hypericin and hematoporphyrin derivatives such as 5-aminolevulinic acid and hexaminolevulinate (HAL) hydrochloride are introduced into the bladder.[5] BLC first emerged in 1996.[6] In 2010, the FDA approved HAL as the only photosensitizer for bladder cancer detection. Intravesical incubation of HAL induces significant intracellular levels of protoporphyrin IX (PpIX) and other photoactive porphyrins (PAPs), which act as photosensitizers. PpIX and PAPs are preferentially accumulated in neoplastic or highly-proliferative cells due to the altered enzyme activities within these cells. This leads to the bright-red fluorescence of neoplastic tissues at wavelengths between 360 and 450 nm while the normal surrounding tissues display dark blue.

In contrast, NBI is an optical image enhancement technology that does not depend on any biochemical synthesis.[7] It involves two specific wavelengths of light (415 nm and 540 nm) which are strongly absorbed by hemoglobin. The 415 nm light mainly penetrates superficial layers of the bladder mucosa. It is absorbed by superficial blood vessels and appears brownish. The 540 nm light can reach a deeper layer of the bladder mucosa. It is absorbed by deeper blood vessels and gives off a cyan coloring. Compared to white light, NBI allows for the better detection of highly-vascularized abnormal tissues. This makes it a useful tool in detecting bladder tumors during cystoscopy. In 2014, FDA approved the application of NBI in bladder cancer management.


  Impact on Tumor Detection Top


BLC and NBI are significant technical advances in the field of bladder cancer management during the past two decades. Both offer several advantages over conventional WLC. First, BLC and NBI improve the detection rate of bladder tumors.[8],[9],[10] The better sensitivities are more pronounced in CIS and small lesions. On an average, BLC with HAL detected 14.7% more Ta and 40.8% more CIS lesions compared to WLC, based on a meta-analysis of six studies comprising 1345 patients.[9] About 24.9% of patients with at least one additional Ta/T1 tumor were seen with BLC.

Similarly, NBI has also superior sensitivity over WLC at per-patient (95.8% vs. 81.6%) and per-lesion levels (94.8% vs. 72.4%) in detecting NMIBC.[10] NBI cystoscopy allows detection of 9.9% more bladder cancer patients or 18.6% more bladder tumors that would otherwise be missed by WLC. When comparing the performance of BLC and NBI directly, both technologies had similar superior sensitivity in detecting bladder CIS and dysplasia compared to WLC (NBI: 95.7%, PDD: 95.7% vs. WLC: 65.2%, P < 0.05).[11]


  Impact on Tumor Recurrence Rate Top


More importantly, BLC- and NBI-assisted TURBT reduce the recurrence rate of bladder cancer after resection.[8],[12],[13] This is likely due to improved visualization of tumor margins as well as occult lesions during TURBT. Most of the randomized controlled clinical trials using BLC-assisted TURBT with HAL support this conclusion.[14],[15],[16],[17],[18],[19] BLC-assisted TURBT with HAL had a lower 12 months cancer recurrence rate (34.5%) compared to that of WLC-assisted TURBT (45.4%) overall (P = 0.006).[9] This difference is significant regardless of risk group (high vs. low risk) and clinical stage (Ta vs. T1 vs. CIS group). Long-term follow-up (median follow-up time 36.6 months) of BLC-assisted TURBT with HAL confirmed that it reduced recurrence risk (39% vs. 53.3%, P = 0.02) compared to WLC. It is worthy to note that a single shot of early postoperative intravesical mitomycin C was given to all patients in this trial, demonstrating that the benefit of BLC-assisted TURBT on reducing the cancer recurrence was not diminished by early postoperative single-shot mitomycin C.[19],[20]

Naselli et al. reported that NBI-assisted TURBT reduced the recurrence risk of NMIBC by at least 10% at 1 year.[21] A study by Naito et al. found a better 12-months (5.6% vs. 27.3%, P = 0.02) recurrence rate of NBI-assisted TURBT versus WLC-assisted TURBT in low-risk bladder cancer patients but not in intermediate- or high-risk group.[22] However, the use of adjuvant intravesical instillation therapy was not documented in this trial. The authors hypothesized that the recurrence in intermediate- or high-risk patients may be caused not only by the overlooked small tumors but also by regrowth of high-grade tumor cells disseminated during TURBT. A recent meta-analysis comprising six trials confirmed that NBI-TURBT reduces the 3 months, 1 year, and 2 years cancer recurrence risk when compared to WLC-TUR (P< 0.01 for all).[12]


  Impact on Tumor Progression and Survival Top


Even though BLC and NBI-assisted TURBT reduces the recurrence rate of bladder cancer, the two technologies do not appear to decrease the rate of disease progression into muscle-invasive bladder cancer significantly.[13],[23] Furthermore, most of the evidence suggests that BLC or NBI-assisted TURBT do not improve cancer-specific mortality or overall mortality;[24],[25] although there are conflicting reports.[26]


  Impact on Patients With Positive Urine Cytology but Negative White Light Cystoscopy Top


BLC and NBI are particularly valuable in evaluating patients with positive urine cytology but negative WLC, which is a clinical challenge that conventionally requires more aggressive approaches such as bilateral ureteroscopy, urine sampling, and random prostate and bladder biopsies under general anesthesia. Using BLC, Karl et al. were able to pinpoint the precise lesion locations in 63 of 77 (83%) patients with positive urine cytology but negative WLC.[27] The identified lesions included 18 moderate dysplasia, 27 carcinomas in situ (CIS), and 18 pTa-1/G1-3 tumors. Continuous surveillance (median 8.5 months) of the 14 remaining patients who had positive urine cytology and first negative BLC identified another eight patients with neoplastic disease. Zhu et al. conducted NBI and biopsy for 12 patients with positive or suspicious urine cytology but negative WLC.[28] NMIBC was diagnosed in 5 of 12 (42%) patients on the first NBI. One patient had CIS on the repeated NBI 3 months later.


  Limitations and Concerns Top


Neither BLC-assisted nor NBI-assisted visualization is cancer-specific. Thus, the main concern of the two technologies is false positivity of tumor detection, which leads to unnecessary biopsy and resection. In Kausch's meta-analysis, all six studies using BLC with HAL had higher false-positive detection rates on lesion basis, ranging from 11% to 39% versus 9% to 31% in the WLC groups.[29] Nevertheless, other investigators found that the false positivity of BLC is not statistically different from WLC.[18],[30] In addition, Xiong et al. found that the specificity of NBI is significantly lower when compared to WLC (73.6% vs. 79.2% at the per-patient level and 65.6% vs. 79.1% at the per-lesion level).[10]

The false positivity of BLC and NBI could be contributed by both lesion factor and operator factor. The inflammatory changes of the bladder mucosa may mimic malignant/premalignant alterations under BLC and NBI.[31],[32] Individual surgeon variability on lesion visualization and assessment can also be a problem. Palou et al. described wide variability on the false-positive rate (6.1%–39.3%) in BLC with HAL involving eight Spanish medical centers.[33] In a NBI study, individual surgeon variability of diagnosis specificities was noted from three expert urologists (79%, 58%, and 79%) and one trainee urologist (67%), although no significant difference was found overall.[34] To control false positivity, both techniques are contraindicated in patients with active gross hematuria, intravesical Bacillus Calmette-Guerin or chemotherapy or TURBT within 90 days.[31] About 10–30 training procedures are recommended to achieve good agreement between surgeons.[33],[35]

In addition, BLC and NBI were performed after WLC in the vast majority of the studies, raising the concerns that the better sensitivity of bladder cancer detection of BLC and NBI might arise from “2nd look” cystoscopy. Shen et al. compared the results from NBI followed by WLC verses WLC followed by NBI. They concluded that the “second look” did not compromise the superiority of NBI over WLC.[36]

Both technologies require investments in hardware. BLC requires the extra cost of HAL after equipment setup. Concerns have been raised regarding the cost-effectiveness of the two technologies, given that bladder cancer is the most expensive human malignancy to treat.[37] Studies suggest the overall cost of bladder cancer management can be reduced by the lower recurrence rate of BLC-assisted TURBT.[38] Similarly, the reduced cancer recurrence rate of NBI-assisted TURBT may justify the investment of NBI hardware, although no cost-effectiveness study of NBI has been published yet.


  Adverse Effects Top


Small risks (<2%–3%) of bladder spasm, dysuria, hematuria, bladder pain, and headache have been linked to BLC with HAL, yet none of the above has been classified as probably or definitely related to HAL. While no serious adverse events (AEs) were directly related to HAL, the potential risk of anaphylactoid AE after repeated administration of HAL has been a concern traditionally. Thus, the FDA has only approved HAL for single use in the USA. However, recent studies have suggested the excellent safety profile of HAL even after repeated administration.[39],[40]


  Guidelines and Recommendations Top


In view of the compelling evidence, clinical guidelines of NMIBC of all major urology associations recommend incorporating BLC and NBI technology into clinical practice [Table 1].[41],[42],[43],[44] Overall, the level of evidence of BLC is stronger than NBI, likely reflecting the fact that NBI is a more recent technology and fewer trials have been done. Nevertheless, NBI is a promising alternative of BLC in view of its efficiency, simplicity, and other characteristics [Table 2].
Table 1: Evidence and recommendations on BLC and NBI in the latest guidelines of NMIBC of AUA, SUO, EAU, NCCN and NICE

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Table 2: Comparison of characteristics of narrow-band imaging and blue-light cystoscopy technology

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  Conclusion Top


Both BLC and NBI enhance the visualization of bladder CIS, small lesions as well as tumor margins during TURBT, and reduce short-term and long-term cancer recurrence rate. The two enhanced cystoscopy modalities are valuable additions to WLC considering that bladder cancer remains as one of the most frequently recurrent human cancer types after tumor resection currently. To control false positivity, doctors should acquire adequate training and adhere to contraindications. More works are needed to further define the impact of BLC and NBI on progression-free survival in bladder cancer management.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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