MINIMALLY INVASIVE SURGERY (V BIRD AND M DESAI, SECTION EDITORS)

Role of Narrow Band Imaging in Managementof Urothelial Carcinoma

Emanuela Altobelli1,2 & Dimitar V. Zlatev1 & Joseph C. Liao1,3

Published online: 21 June 2015# Springer Science+Business Media New York 2015

Abstract Urothelial carcinoma of the bladder and upper tractis primarily diagnosed by white light endoscopy, which haswell-known limitations that contribute to the increased risk oftumor recurrence and progression. Narrow band imaging(NBI) is an optical imaging technology that facilitates detec-tion of tumor vasculature and differentiation of benignurothelium from neoplastic tissue. For urothelial carcinoma,NBI may be utilized in a variety of clinical settings, includingoffice cystoscopy for initial identification and surveillance,transurethral resection for pathological diagnosis, andureteroscopic management of upper tract lesions. Early evi-dence suggests that NBI increases the detection of urothelialcarcinoma in the bladder and upper tract, including flat high-grade lesions such as carcinoma-in-situ that are a diagnosticchallenge under white light. NBI also appears to improve the

quality of transurethral resection and thereby reduce the fre-quency of tumor recurrence.

Keywords Narrow band imaging . Urothelial carcinoma .

White light cystoscopy . Diagnostic ureteroscopy .

Transurethral resection

Introduction

Urothelial carcinomas are common cancers with significantmanagement challenges. Urothelial carcinoma of the bladderaccounts for more than 90 % of all urothelial carcinomas andmore than 95 % of bladder cancer, which is the sixth mostcommon cancer in the USAwith 74,690 new cases and 15,580deaths expected in 2014 [1]. In comparison, urothelial carci-noma of the upper tract (renal pelvis and ureter) accounts for5–10 % of all urothelial carcinomas [2, 3]. The natural historyof urothelial carcinoma is heterogeneous, ranging from non-muscle-invasive disease with a low progression rate amenablefor endoscopic management to muscle-invasive or metastaticcancer that requires radical surgery and/or systemic therapy[4]. Although 75–85 % of urothelial carcinoma of the bladderis non-muscle-invasive at initial diagnosis, there is a high as-sociated recurrence rate that reaches 61 % at 1 year and 78 %at 5 years [5, 6]. For upper tract urothelial carcinoma, approx-imately 50 % presents as non-muscle-invasive disease [7].Thus, the quality of endoscopy and tumor resection has acrucial role in the management of urothelial carcinomas andimparts a direct effect on clinical outcomes. The healthcarecost for urothelial carcinoma is among the highest of all can-cers in part because of high tumor recurrence rate and need forlifelong surveillance and repeat resection.

White light cystoscopy (WLC), the current standard forevaluation and endoscopic management of bladder cancer,

This article is part of the Topical Collection on Minimally InvasiveSurgery

* Joseph C. Liaojliao@stanford.edu

Emanuela Altobelliemanuela@stanford.edu

Dimitar V. Zlatevdzlatev@stanford.edu

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

2 Department of Urology, Campus Biomedico University,Rome 00128, Italy

3 Veterans Affairs Palo Alto Health Care System, PaloAlto, CA 94304, USA

Curr Urol Rep (2015) 16: 58DOI 10.1007/s11934-015-0527-5

has several well-known shortcomings. Although sufficient forthe detection of papillary lesions, under WLC, non-papillaryand flat lesions such as carcinoma-in-situ (CIS) are difficult todistinguish from inflammatory lesions, with CIS detectionrates estimated at 58–68% [8, 9]. Tumor grade or stage cannotbe reliably assessed byWLC [10]. Small or multifocal lesionscan be missed, contributing to a high rate of residual tumorfound in second-look transurethral resection (TUR) [11, 12].Finally, suboptimal visualization of tumor borders and submu-cosal margins during TUR can lead to incomplete resection,cancer understaging, and increased risk of tumor recurrenceand progression [13, 4].

Several emerging imaging technologies have been devel-oped to enhance white light endoscopy, with the goal to im-prove tumor detection and resection and thus reduce recur-rence [14]. Narrow band imaging (NBI) is an example of awide-field imaging technology that can be easily integratedinto current endoscopic protocols. NBI provides a similar fieldof view as WLC, but with additional enhancement of thevasculature within the urothelium. This review focuses onthe most recent literature on the utility of NBI in the manage-ment of urothelial carcinoma.

Principles and Mechanisms

NBI provides enhanced visualization of mucosal vasculatureand highlights the neoplastic neoangiogenesis of urothelialtumors. NBI devices filter out the red spectrum from whitelight, with the resultant blue (415 nm) and green (540 nm)spectra absorbed by hemoglobin and thus enhancing the con-trast between hypervascular tissue and normal mucosa. Theshorter (415 nm) blue bands penetrate the superficial mucosalayers and result in a brown-black appearance of the moresuperficial capillary vessels. The longer (540 nm) green bandspenetrate deeper to the submucosal layers and accentuate thesubmucosal vessels with a green appearance. Flat CIS lesionsare enhanced by dense superficial capillaries and typicallyappear dark brown, whereas papillary tumor areas are en-hanced by submucosal vasculature and appear brown-green(Fig. 1).

NBI has been commercialized (Olympus Corp, Tokyo, Ja-pan) and is available either in an integrated videoscope (flex-ible videocystoscope or videoureteroscope) or through a cam-era head that can be attached to standard rigid and fiber opticendoscopes. The surgeon can change the optical setting onthese devices to toggle between WLC and NBI, thereby facil-itating rapid real-time evaluation of suspected lesions. An im-portant advantage of NBI is that it does not require the admin-istration of exogenous contrast, which facilitates integration tostandard endoscopy workflow.

Although NBI provides an enhanced, but qualitative, im-pression of suspected urothelial lesions, there does not appear

to be a significant associated learning curve. In a study of 50patients who underwent WLC and NBI to evaluate for recur-rent bladder tumors, there was no significant difference be-tween new and experienced users in the detection rate of re-current bladder tumor [15]. In another study involving 23patients with known recurrences of urothelial cancer ofthe bladder, a new NBI user demonstrated a significant-ly improved detection rate of urothelial carcinoma withNBI compared to WLC that was statistically similar tothe improved detection rate demonstrated by experi-enced users [16].

Tumor Detection Rate

Since the initial study in 2008 reported that NBI detected asignificantly greater number of urothelial carcinomas thanWLC [17], multiple series have demonstrated a significantlyincreased detection rate of urothelial carcinoma by NBI com-pared to WLC (78–100 vs. 78–93 % sensitivity) [18–22]. Theassociated high negative predictive value suggests that NBI issuitable for excluding a diagnosis of urothelial carcinoma.However, these studies also showed a higher false-positiverate by NBI compared to WLC (69–85 vs. 76–89 % specific-ity) [17–22], with the resultant increased number of unneces-sary negative biopsies potentially contributing to increasedmorbidity and cost. Two recent meta-analyses, each includingmore than 1000 patients, found that detection of bladder can-cer was higher by NBI compared to WLC on both per-personand per-lesion basis [23, 24].

A significant challenge in urothelial cancer diagnosis is thedetection of CIS, a high-grade subtype that presents as a flatred velvety lesion difficult to detect onWLC and is associatedwith significant risk of cancer progression. Several studieshave addressed the role of NBI in CIS detection. In a studyof 427 patients undergoing evaluation for recurrent bladdercancer, the detection of CIS was significantly improved bythe combination of NBI and WLC in comparison to WLCalone (100 vs. 83 % sensitivity) [25]. A multicenter prospec-tive study of 104 patients with definite or suspected bladdercancer demonstrated a significantly increased sensitivity forCIS detection from 50 % for WLC to 90 % for NBI [22]. Aprospective randomized controlled trial involving 220 patientswith non-muscle-invasive bladder tumor reported a signifi-cantly improved detection rate of CIS for NBI compared withWLC (95 vs. 68 %) [26]. A meta-analysis including 1040patients with non-muscle-invasive bladder cancer reportedan additional 28 % detection of CIS lesions by NBI comparedto WLC, a significantly higher CIS detection rate by NBI(11 % rate difference, p=0.03), and no significant differencein the false-positive detection rate between NBI and WLC[23].

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Tumor Recurrence Rate

Multiple studies have shown that NBI-assisted TUR of blad-der tumor reduces the frequency of tumor recurrence. In a 6-year study, a cohort of 126 patients with recurrent low-gradebladder tumor was followed for tumor recurrence for 3 yearsby conventional WLC and then for the next 3 years by NBI,thus using patients as their own controls. In comparison toWLC, NBI cystoscopy was associated with reduced per-patient rate of tumor recurrence (94 vs. 62 %), fewer meannumber of recurrent tumors (5.2 vs. 2.8), and longerrecurrence-free survival time (13 vs. 29 months, p=0.001)[27]. In a randomized prospective trial composed of 148 pa-tients aimed to assess the impact of NBI on 1-year bladdercancer recurrence risk, TUR performed under NBI significant-ly reduced recurrence risk in comparison to WLC (33 vs.51 %, p=0.0141) [28•]. A recent single-center randomizedcontrolled trial to assess whether NBI improved TUR of blad-der tumors in 254 patients with a 2-year follow-up reported asignificantly reduced recurrence rate (22 vs. 33 %, p=0.05)and significantly improved recurrence-free survival (22 vs.19 months, p=0.02) by NBI-TUR compared to WLC-TUR[29•]. An international multicenter randomized controlled trialto compare the recurrence rate of bladder tumor at 1-yearbetween NBI- and WLC-assisted TUR was launched in2010 and is currently at the data analysis phase [30, 31•].

NBI After BCG Therapy

The intravesical instillation of bacillus Calmette-Guérin(BCG) is the standard treatment for patients with high-risknon-muscle-invasive bladder cancer including CIS, high-grade Ta or T1, and early recurring disease [32]. An intenseinflammatory reaction results commonly after BCG treatmentand appear as erythematous velvety lesions on WLC, whichcan be difficult to distinguish from residual CIS. In a studyinvolving 61 patients with high-risk non-muscle-invasive

bladder tumor evaluated 3 months after BCG therapy, all pa-tients had abnormal erythematous lesions on WLC; however,only 22 patients (36 %) had residual tumor. Under NBI, theBCG pattern was hypothesized to appear as a green tint ofprominent mucosal vessels in the absence of the brown orblack capillary density typical of CIS. NBI correctly identifiedtumor in 21 out of 22 patients, and only 1 out of 30 patientswith negative NBI findings had residual tumor. However, thefalse-positive rate was 32 %, with 10 patients having unnec-essary biopsy for false-positive NBI findings [33].

NBI of Upper Tract Urothelial Carcinoma

White light endoscopic detection of urothelial carcinoma ofthe upper urinary tract is technically more challenging primar-ily because the small caliber and tortuous anatomic course ofthe ureter impedes easy endoscopic access and management.Following significant technological advancements, a newgeneration of digital flexible ureteroscopes with improvedmaneuverability allows complete exploration of the upper uri-nary tract in more than 92 % of patients in one recent study[34]. As a result, although nephroureterectomy with bladdercuff removal remains the standard for upper tract urothelialcarcinoma [35], conservative management with endoscopictumor ablation and subsequent ureteroscopic surveillance inselect patients with low-grade, low-stage tumors has becomepossible and has been shown to provide comparable outcomesto radical treatment in patients with low-grade disease[36–38]. Ureteroscopy with integrated NBI capability hasthe potential to improve the detection rate of upper tracturothelial carcinoma. In a small pilot study of 27 patients withknown or suspected upper tract disease, NBI ureteroscopyimproved the individual tumor detection rate by 23 % com-pared with WLC [34]. Additional studies are required to fur-ther define the role of NBI during ureteroscopy for manage-ment of upper tract tumor.

Fig. 1 Large papillary tumor ofthe anterior bladder wall shownunder white light cystoscopy (left)and narrow band imaging (right).Note the contrast enhancement oftumor vasculature under narrowband imaging. Final pathologyshowed pT1 high-grade urothelialcarcinoma

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Other Optical Imaging Technologies

In addition to NBI, other optical imaging technologies havebeen developed to enhance the endoscopic evaluation ofurothelial carcinoma. These technologies can be categorizedbroadly based on their field of view. Similar to NBI, photody-namic diagnosis (PDD) is an example of a macroscopic im-aging modality that surveys a large area of mucosa. Micro-scopic imaging technologies such as confocal laserendomicroscopy (CLE) and optical coherence tomography(OCT) provide optical biopsy with real-time subsurface tissuecharacterization similar to histology.

PDD requires the topical administration of a contrast agent(hexaminolevulinate) that preferentially accumulates in neo-plastic cells and emits a red fluorescence under blue lightexcitation. Multiple clinical trials have demonstrated im-proved detection [39, 40] and reduced residual tumor rates[41] of bladder cancer in patients evaluated with PDD. Feasi-bility of the application of PDD in the upper tract has beendemonstrated only with an oral contrast agent [42]. Recentlyapproved for clinical use in the urinary tract, CLE is per-formed with intravesical or intravenous fluorescein as the con-trast agent, small optic probes compatible with standard endo-scopes, and a clinical system for image rendering [43]. CLEprovides high-resolution images sufficient for tumor grading[44] and has been shown to enhance the detection of neoplas-tic bladder lesions [45]. OCT is an optical biopsy technologythat utilizes near-infrared light (890–1300 nm) without the useof an exogenous contrast agent to provide a cross-sectionalimage with a 2-mm depth of penetration. In the bladder, sev-eral studies have evaluated the detection and invasiveness ofneoplastic lesions by OCT [46–48]. A recent pilot study re-ported the application of OCT in the upper urinary tract [49].Additional imaging modalities under investigation includeendoluminal ultrasonography [50] and the Storz professionalimage enhancement system (SPIES) [51]. No studies havedirectly compared NBI to other adjunct optical imaging tech-nologies for the enhanced detection of urothelial carcinoma.

Conclusions

NBI is a promising adjunct technology to WLC in the evalu-ation of urothelial carcinoma. Notable advantages of NBI overother emerging imaging modalities include its integration inflexible endoscopes and the lack of requirement of exogenouscontrast administration. As a result, NBI is currently the onlyadjunct imaging technology that can be utilized in the officesetting for surveillance cystoscopy and intraoperatively duringureteroscopy for evaluation of upper tract disease. Early datahave shown that NBI increases the detection of urothelial car-cinoma in the bladder, increases the detection of flat lesionssuch as CIS, appears to improve the quality of TUR, reduces

the frequency of tumor recurrence, and can potentially adddiagnostic utility in the surveillance for urothelial carcinomafollowing intravesical BCG therapy. However, the improvedcancer detection rate by NBI is associated with an increasedfalse-positive rate and unnecessary negative biopsies, with apresumed added patient morbidity that is yet to be defined.The effects of NBI on cost and clinical outcomes are also notyet determined. Finally, the use of NBI for the endoscopicevaluation of upper tract disease and in the outpatient evalua-tion and management of urothelial carcinoma of the bladderrequires additional investigation.

Compliance with Ethics Guidelines

Conflict of Interest The authors declare that they have no competinginterests.

Human and Animal Rights and Informed Consent This article doesnot contain any studies with human or animal subjects performed by anyof the authors.

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