Current Urology Reports (2018) 19:84

https://doi.org/10.1007/s11934-018-0833-9

UROTHELIAL CANCER (S DANESHMAND, SECTION EDITOR)

Enhanced Endoscopy in Bladder Cancer

Shane Pearce 1 & Siamak Daneshmand 1

# Springer Science+Business Media, LLC, part of Springer Nature 2018

Abstract
Purpose of Review Endoscopy coupled with targeted resections represents a cornerstone in the diagnosis, staging, and treatment
of patients with bladder cancer. Direct visualization can be challenging and imprecise due to patient-, tumor-, and surgeon-
specific factors. We will review contemporary endoscopic technologies and techniques used to improve our ability to safely
identify and resect malignant lesions in patients with bladder cancer.
Recent Findings Enhanced endoscopic imaging technology may improve detection rates for bladder cancer throughout the upper
and lower urinary tract, which may lead to improvements in recurrence and progression rates for non-muscle invasive bladder
cancer (NMIBC). New techniques including narrow-band imaging (NBI), photodynamic diagnosis (PDD), Storz Professional
Image Enhancement System (SPIES), optical coherence tomography (OCT), and others have shown benefit and may further
improve our ability to detect and stage bladder tumors.
Summary Enhanced endoscopy technologies have already demonstrated value in improving the sensitivity of bladder cancer
detection and early results suggest they may improve short- and long-term oncologic outcomes.

Keywords Bladder cancer . Endoscopy . Cystoscopy . Transurethral resection . Diagnosis . Surveillance

Introduction patients presenting with high-grade, invasive disease [4].

Regardless of primary site, grade, or depth of invasion, diag-
Urothelial carcinoma (UC) involving the bladder is the fourth nosis and staging of UC is highly dependent on endoscopic
most common malignancy diagnosed in the USA men and the evaluation. Endoscopic resection and ablation is also thera-
eighth most common cause of cancer death [1]. Bladder can- peutic and potentially curative in well-selected patients. It is
cer is the most expensive cancer on a per-patient basis due to important to note that detection of lesions and endoscopic
the need for frequent cystoscopy during follow-up, surveil- treatment is only as effective as the imaging modality that is
lance imaging, and costly treatments [2, 3]. utilized. Conventional white light cystoscopy (WLC) can miss
Approximately 75% of diagnosed cases in the bladder are up to 43% of bladder cancers and is particularly limited in the
non-muscle invasive (NMIBC) and therefore amenable to en- diagnosis of carcinoma in situ (CIS) and small, papillary le-
doscopic treatment with or without intravesical therapy. In sions [5••]. Due to the oncologic risk and financial toxicity of
comparison, upper tract urothelial carcinoma (UTUC) is a missed diagnoses, novel endoscopic imaging techniques are
rare, aggressive disease with approximately two thirds of needed to improve detection and treatment of urothelial cancer
in the bladder and upper urinary tract.
Photodynamic diagnosis (PDD) was first described in 1964
This article is part of the Topical Collection on Urothelial Cancer
by Whitmore et al.; however, it did not enter clinical practice until
the 1990s and it has gained significant traction in recent years
* Shane Pearce
[email protected] with the use of hexylaminolevulinate (HAL) [6]. PDD requires
intravesical instillation of a photosensitizing agent followed by
Siamak Daneshmand cystoscopy with blue light resulting in emission of red fluores-
[email protected] cence from cells that accumulate the photosensitizing agent.
1
Narrow-band imaging (NBI) relies on filtering out red light from
Institute of Urology, USC Keck/Norris Comprehensive Cancer normal white light in order to enhance contrast between normal
Center, University of Southern California, 1441 Eastlake Ave, Suite
7416, Los Angeles, CA 90089, USA mucosa and hypervascular areas that can be associated with
84 Page 2 of 8 Curr Urol Rep (2018) 19:84

tumor neoangiogenesis. This allows for better demarcation of illumination leading to rapid dissemination and use around
tumor margins and improves detection rates [7]. This review will the world [13]. The introduction and integration of camera
also discuss the Storz Professional Image Enhancement System equipment, digital imaging using distal chip sensor technology,
(SPIES), which utilizes four different visualization modes to im- and transmission of images to outside monitors has led us to the
prove image quality, and other emerging technologies including current state of cystoscopy today [9]. The production of high-
optical coherence tomography (OCT) and confocal laser quality images by current cystoscopes allows modern day in-
endomicroscopy (CLE). novators to push boundaries and improve patient care with a
variety of new technologies, which will be the focus of the
remainder of this review.
Historical Perspective

The modern cystoscopic equipment that we use today is the Photodynamic Diagnosis
result of over 200 years of innovation and development.
Understanding our past is critical for mapping the future. PDD is dependent on preoperative intravesical instillation of a
The earliest reported attempt at cystoscopy was in 1805 by fluorophore that is a precursor in the heme biosynthesis path-
Philip Bozzini, who was trying to locate bullets in his patient way. Metabolically active cells preferentially accumulate the
as a German army surgeon. His instrument utilized viewing photosensitizing agent, initially 5-aminolevulinic acid (5-
funnels illuminated by a candle in a sharkskin-covered box. ALA) and more recently its derivative hexylaminolevulinate
Unfortunately, this instrument provided poor visualization and (HAL), leading to concentration in neoplastic cells. These
inflicted burns [8, 9]. Twenty years later, Pierre Segalas in prodrugs are converted to protoporphyrin IX (PPIX), which
Paris and John Fischer in Boston independently produced emits red light (600–740 nm) when exposed to blue light
functional cystoscopes, which relied upon a thin cylindrical (380–480 nm). PDD has been used in Europe for over
tube for insertion in the bladder and light from a pretroleum- 20 years. The initial investigation of 5-ALA as a diagnostic
fuelled lamp deflected with mirrors into the inspected cavity tool for bladder cancer was inspired by fluorescence detection
[9]. Antoine Desormeaux refined the instrument and carried of nonmelanoma skin lesions and head and neck cancer [14].
out the first endoscopic intervention, performing a transure- Pre-clinical studies in rat bladders supported the feasibility
thral excision of urethral papilloma in 1853 [10]. The intro- and utility of intravesical instillation of 5-ALA and the first
duction of optical lenses to cystoscopes later in the nineteenth clinical experience in humans was published by Steinbach et
century enhanced the visual field, but produced small, al. in 1994 [15, 16]. This initial clinical study demonstrated
inverted images, resulting in a steep learning curve. that 5-ALA localized to the mucosal lining of the bladder
Additional advances during this time period included the de- without any spread to stromal tissue suggesting safety of
velopment of cystoscopes with an additional inflow channel to intravesical instillation. Kriegmair et al. reported clinical out-
allow hydrodistention of the bladder, where previous itera- comes from 68 patients diagnosed with bladder cancer using
tions relied on air distension. fluorescence cystoscopy and 5-ALA, demonstrating the po-
The German urologist Maximilian Carl-Friedrich Nitze in tential value of the technology by identifying nearly 10% of
collaboration with Joseph Leiter introduced the first working malignant or dysplastic lesions were only identified by fluo-
cystoscope in 1878 by coupling a magnifying glass with a rescence cystoscopy and would have been missed during rou-
platinum wire electrode at the tip of the instrument for a light tine cystoscopic examination [17]. In recent years, HAL, the
source. This instrument was also limited by burns from the lipophilic hexyl ester of 5-ALA, has become established as the
filament [11]. The invention of the light bulb and integration preferred intravesical agent and is now approved by European
with cystoscopes advanced the technology rapidly in the late and US regulatory bodies for the detection of bladder cancer.
1800s. Edwin Beer of New York incorporated electrocautery Multiple studies have now shown that PDD can improve
with the cystoscopy to perform the first transurethral resection the detection rates of CIS and papillary bladder tumors com-
of a bladder tumor in 1910 [12]. Additional developments in pared to white light cystoscopy (WLC) (Fig. 1) [18–20,
the USA at the turn of the century including refined hemi- 21•,22]. Rink et al. performed a review of 26 studies using
spherical lenses, the Amici prism for production of a true 5-ALA, 15 studies using HAL, and 3 studies that used both
image, and the Albarran lever culminated in the Brown- [20]. They found that PDD improved the detection of papil-
Berger combination cystoscope, which was the staple of lary tumors by 7–29% and CIS by 25–30% compared to WLC
American urologists for the next 60 years [9]. independent of the specific fluorophore that was used. PDD-
Fiber optic technology was discovered in the mid-twentieth guided transurethral resection of bladder tumors (TURBT)
century by Harold Hopkins and applied to cystoscopy in 1959. results in a lower rate of residual disease upon second-look
This system, purchased by the German businessman Karl Storz, TURBT or cystectomy [20]. Two meta-analyses of relevant
in 1967, produced excellent images with outstanding randomized controlled trials (RCTs) have demonstrated that
Curr Urol Rep (2018) 19:84 Page 3 of 8 84

Fig. 1 Representative images of

bladder tumors seen with standard
white light cystoscopy (a and c)
compared to Blue Light
Cystoscopy using HAL (b) and
narrow-band imaging (d)

tumors resected using PDD recur at lower rates compared to published the initial series of 103 patients undergoing flexible
those resected using WLC [23, 24]. PDD reduced recurrence BLC in the office setting, showing safety and improved de-
rates by 50% and led to improved recurrence free survival at 1 tection rate of recurrent bladder cancer [35••]. One of the
and 2 years, with similar findings in a recent single-center limitations of PDD is the concern for false-positive detections;
matched analysis [23, 25]. Chou et al. confirmed lower recur- however, recent studies have shown that the false-positive rate
rence rates at short-, intermediate-, and long-term follow-up in of PPD is similar to that of NBI and WLC [32]. False-positive
a review of 14 RCTs [21•]. This group also identified a re- rates also vary between surgeons and higher false-positive
duced risk of progression in subgroup analysis of trials that rates must be balanced with improved sensitivity for diagnosis
used HAL, with a relative risk of 0.51 compared to WLC. of bladder cancer [5••].
Kamat et al. reported a trend towards reduced progressions PDD is now being applied in the setting of upper tract
for patients undergoing PDD-guided TURBT re-analyzing urothelial carcinoma (UTUC). A review article published in
data from a phase III trial [26]. The rate of progression was 2017 identified seven studies, none of which were random-
12.2% for PDD compared to 17.6% for WLC (p = 0.085) and ized, including a total of 194 patients who underwent PDD
the time to progression was longer for PDD (p = 0.05). A with flexible ureteroscopy [36]. Consistent with results for
retrospective study recently evaluated recurrence-free surviv- PDD in the bladder, they found that PDD improved sensitivity
al, cancer-specific survival, and overall survival in 224 pa- for the diagnosis of CIS and dysplasia compared to white light
tients who underwent radical cystectomy at a single German ureteroscopy. Most of the studies reviewed used oral 5-ALA,
center including 66 after HAL-guided TURBT, 23 after ALA- which was fairly well tolerated. The most common toxicity
guided TURBT, and 135 after WLC-guided TURBT [27]. was hypertension and patients must avoid strong light sources
The investigators found that HAL-guided TURBT was an for 24 h after administration. The largest study of PDD for
independent predictor of improved survival after TURBT in UTUC included 106 renal units and demonstrated a sensitivity
multivariable analysis. of 96% for PDD compared to 54% for white light (p < 0.0001)
The Blue Light Cystoscopy (BLC) with Cysview Registry [37].
Group published results of a multicenter prospective registry Cost is an important consideration for any new surgical
highlighting the direct clinical impact of PDD-guided TURBT technology, particularly for management of bladder cancer,
by showing that 25% of patients had lesions detected only which has the highest lifetime costs per patient of all cancers
with BLC (Table 1) [5••]. This study demonstrated that BLC [38]. This is due to the high recurrence rate and need for
resulted in risk-group migration for patients with NMIBC and ongoing invasive monitoring. PDD at the time of initial
resulted in clear changes in patient management in 14% of TURBT can clearly increase lesion detection, improve the
patients. This study also established the safety of repeat quality of resection, and reduce recurrences. Economic
HAL instillation, which has been confirmed in other single modeling indicates that the use of HAL at the time of primary
institutional experiences [34]. Daneshmand et al. also recently TURBT is cost-effective versus WLC alone and results in
 84

Table 1 Recent publications reporting outcomes for photodynamic diagnosis and narrow-band imaging

Study Study design No. of Photosensitizing Sensitivity Specificity Lesions detected only by Recurrence rate Additional outcomes
Page 4 of 8

patients agent enhanced endoscopy (%)

Photodynamic diagnosis
Daneshmand Multicenter prospective 533 HAL 91% NR 206 lesions in 133 patients NR 74 (14%) patients with change in
et al. 2018 registry (25%) management, 33 (6%) patients
[5••] with AUA-risk group migration
Gallagher et Comparison of 3-year 345 HAL NR NR NR 3 years: 39 vs 53% for WL,
al. 2017 recurrence rates for “good OR 0.56, p = 0.02
[25] quality” TURBT using
PDD versus WL
Bach et al. Multicenter noninterventional 403 HAL NR NR 34 lesions (6.8%) NR Need to screen 16 patients with
2017 [28] study in Germany PDD to diagnose 1 additional
patient with cancer
Pagliarulo et Cohort study of patients 64 HAL 87.10% 87.90% 50 lesions identified with NR PDD had nearly perfect agreement
al. 2017 undergoing radical PDD vs. 18 with WLC with final pathology after
[29] cystectomy after PDD-guided cystectomy (kappa 0.89 vs.
cystoscopy 0.27 for WLC)
Drăgoescu et Prospective, randomized study 113 HAL NR NR 26.3% more tumors identified 20% reduction in
al. 2017 of patients with NMIBC in PDD vs. WLC group recurrence after 5-years
[30]
Narrow-band imaging
Kim et al. Single surgeon, randomized, 198 N/A NR NR 27 (42%) additional tumors 1 year recurrence-free
2018 [31•] prospective study and 13 (35%) additional survival: 85% in NBI vs.
patients with tumors by 72% in WLC (p = 0.3)
performing NBI after WLC
Drejer et al. Multicenter Danish study with 955 N/A NBI: 100.0% vs NBI: 90.2% 23 patients (3.1%) had NR Impact of NBI was greater in
2017 [32] assessing all patients with WLC: 88.7%, vs WLC: pathology suspected based patients with history of NMIBC.
flexible WLC and NBI p < .05 92.4, p > .05 only on NBI NBI changed clinical
decision in 1.9% of patients
Naito et al. Multicenter randomized 965 N/A NR NR Lesion detected in 99.6% in 12-month recurrence NBI reduced recurrences in
2016 trial comparing NBI-guided NBI group vs. 98.1% in rate: 27.1% for NBI vs. low-risk patients at 3 months,
[33••] TURBT to WLC-assisted WLC group (0.03) 25.4% for WLC 1 year, and 3 years
TURBT (p = 0.585) (no difference in intermediate-
or high risk). TURBT took
longer for the NBI group
(38.1 min vs 35.0 min,
p = 0.039).
Comparative series
Drejer et al. Multicenter comparative 136 HAL NBI: 95.7%, PDD: NBI: 52.0%, NR NR No difference in specificity or
2017 [32] study from Denmark and 95.7% vs WL: PDD: 48.0%, positive predictive value per
Curr Urol Rep (2018) 19:84

Norway for detection of 65.2%, p < .05 and WL: biopsy for NBI, PDD, or WLC.
CIS or dysplasia 56.8%
Curr Urol Rep (2018) 19:84 Page 5 of 8 84

improved quality-adjusted life-years and reduced cost over follow-up, have failed to show an overall reduction in recur-
time [39, 40]. Improved detection and resection results in less rences for NBI-guided TURBT [31•, 33••]. The study coordi-
need for repeat procedures and hospital visits later on com- nated by the Clinical Research Office of the Endourological
pared to WLC alone. This yields an obvious benefit for pa- Society (CROES) did demonstrate lower recurrence rates in
tients and health care systems overall. patients with low-risk disease [33••]. Overall, the evidence
suggests that NBI certainly improves detection rates for
NMIBC compared to WLC and NBI-guided TURBT may
Narrow-Band Imaging reduce recurrence rates. PDD and NBI are now included in
the American Urologic Association-Society of Urologic
NBI uses filtered white light to remove the red spectrum Oncology joint guidelines statement with PDD and NBI given
resulting in green (415 nm) and blue (540 nm) bands that have grade B and C recommendations, respectively, to increase
differential depths of penetration resulting in enhancement of detection and reduce recurrences [44]. NBI has the advantage
mucosal and submucosal vasculature [41]. Hemoglobin ab- of avoiding the need for preoperative instillation of a
sorbs these wavelengths preferentially, which results in dark fluorophore as required by PDD-based platforms.
appearing blood vessels that strongly contrast with the light
background of normal mucosa capitalizing on the
neovascularity associated with bladder cancer to improve de- Storz Professional Image Enhancement
tection rates. This filter-based technology has been employed System
in the office setting with flexible cystoscopes, as well as dur-
ing rigid cystoscopy and TURBT. Karl-Storz® has developed the SPIES endoscopic imaging
A recent meta-analysis examined the impact of NBI on the platform, which utilizes normal white light with four unique
detection rate of NMIBC and bladder cancer recurrence risk software-based visualization modes [45]. The spectra A and
compared to WLC identifying 25 studies appropriate for in- spectra B modalities shift the specific color rendering of the
clusion [42]. Twenty studies covering a total of 2806 patients recorded visible spectrum on the imaging system to improve
provided necessary within-patient characteristics necessary to color contrast. The Clara modality enhances local brightness
determine the additional detection rate of NBI compared to and Chroma modality enhances the sharpness of the image,
WLC. Overall, NBI yielded a 9.9% increased detection rate on particularly for red colors as seen in neovascularity associated
a per-patient basis and a 19.2% increase on a per-lesion-based with bladder tumors. The Clara and Chroma modes have also
analysis. For CIS, the impact was greater with a 25.1% im- been combined. Kamphuis et al. found that the SPIES system
provement on per-patient analysis and 31.1% increase on per- produced images of bladder tumors that were graded as higher
lesion analysis [42]. Per patient, the sensitivity and specificity quality compared to WLC by a group of 73 urologists [46].
of NBI were 95.8 and 73.6%, respectively, compared to 81.6 Images captured with the combined Clara and Chroma mo-
and 79.2% for WLC. In a subset of six studies that provided dalities allowed the observers to better identify the boundaries
data on recurrence rates, NBI was associated with a statistical- of the tumors and identify additional areas of abnormality in
ly significant 53% reduction in recurrence rate at 3 months and the images. Based on the results of this pilot study, CROES
19% at 12 months compared to WLC. has endorsed an RCT to compare SPIES-assisted (Clara +
Lee et al. performed a network meta-analysis including Chroma modality) versus WL-guided TURBT [47].
four RCTs using NBI, five RCTs using HAL for PDD, and
six studies using 5-ALA for PDD-guided TURBT [24]. With
a total of 266 patients undergoing NBI-guided TURBT, they Optical Coherence Tomography
found that NBI reduced recurrence rates compared to WLC
(OR 0.47, 95% CI 0.31–0.72). While all of the enhanced OCT is a high-resolution imaging technique that uses near-
endoscopy modalities outperformed WLC with respect to re- infrared light to measure tissue characteristics such as texture
currence rate, none were found to impact rate of progressions and elasticity. It provides cross-sectional images at targeted
and there were no significant differences comparing NBI to tissue depths [41]. OCT has shown promise as an independent
PDD-guided approaches (HAL or 5-ALA). Similar findings technology or when paired with traditional endoscopic plat-
were also reported in another recently published meta-analy- forms [48]. The current technology uses a 2.7-mm-diameter
sis, showing that NBI-guided TURBT was associated with probe that can be passed through a standard cystoscopy to
improvements in 3-month, 1-year, and 2-year recurrence risk allow real-time examination [41]. OCT has demonstrated util-
rates (RR 0.39, 0.52, and 0.60, respectively, all p < 0.01) [43]. ity for the early detection of bladder cancer, in addition to
Enthusiasm for the technology has been tempered in recent accurately discriminating superficial versus invasive tumors
years. The two most recently reported RCTs, including a large (T1 or higher) [49–51]. OCT has resolution that that is 10–
multinational RCT with nearly 1000 patients and 1 year of 25 times greater than high-frequency ultrasound. For
84 Page 6 of 8 Curr Urol Rep (2018) 19:84

classification of lesions as benign or malignant, the sensitivity, Conclusions

specificity, and negative predictive values of OCT were 100%,
90%, and 89% respectively [50]. The sensitivity and specific- Missed diagnoses and understaging continue to represent a
ity for detection of muscle invasion was similarly high in a major barrier to optimal management of patients with
series of 32 patients [52]. Ren et al. have shown that three- urothelial cancer. PDD, NBI, and potentially SPIES can im-
dimensional OCT has particularly high sensitivity (96%) and prove the diagnostic yield compared to standard white light
specificity (92%) for the detection of CIS [53, 54]. A recent endoscopy. These imaging techniques may also improve en-
meta-analysis including 468 patients confirmed the high sen- doscopic ablation and resection of urothelial tumors leading to
sitivity and specificity of OCT for the detection of bladder better oncologic outcomes. Other emerging technologies such
cancer [55]. as OCT and CLE provide high-resolution imaging that could
Integration of OCT with fluorescence cystoscopy has greatly improve the urologists’ ability to make real-time diag-
also been investigated and shown to improve the specific- noses, while also potentially allowing for accurate staging and
ity of fluorescence cystoscopy, reducing the number of grading of lesions. Various combinations of these techniques,
unnecessary biopsies [56]. Because OCT images are dig- with the aid of computer processing and machine learning,
itized, the technology generates huge amounts of data that may further improve the yield of the individual approaches.
can be processed using computer-aided texture analysis Modern urologists need to understand and become familiar
and machine learning algorithms to reduce subjectivity with these imaging technologies.
[57, 58]. Early studies using OCT have demonstrated
promising clinical utility, but OCT is still limited by a Compliance with Ethical Standards
1–2-mm depth of penetration and questions regarding
real-world implementation. Larger, prospective clinical Conflict of Interest Shane Pearce declares no potential conflicts of
interest.
trials are needed to confirm findings from the small series
Siamak Daneshmand is a section editor for Current Urology Reports.
discussed in this review.
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.
Confocal Laser Endomicroscopy

Confocal laser endomicroscopy (CLE) uses fiber-optic ca-

bles to transmit 488-nm wavelength laser light to tissues
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