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Review
Despite being the current gold standard, white-light endoscopy polyps and inflammatory bowel diseases. Moreover, DLC tech-
may miss a significant proportion of lesions within the colorec- niques enable a more precise characterization of lesions through-
tum, thus leading to a misinterpretation of various disease find- out the whole luminal GI tract, thereby potentially enabling more
ings. Traditionally, dye-based chromoendoscopy is used to accurate endoscopic therapies. In the present review we focus
improve both detection and characterization of lesions during on the newly introduced dye-less chromoendoscopy technique
luminal gastrointestinal (GI) endoscopy. Recently introduced dye- i-scan and give an additional outlook on the recent development
less chromoendoscopy (DLC) techniques have overcome many of of optical enhancement technology.
the limitations of dye-based chromoendoscopy, thereby poten-
tially improving lesion recognition and characterization. In detail, Key words: chromoendoscopy, inflammatory bowel disease
DLC techniques allow for better detection of esophageal lesions, (IBD), i-scan, optical enhancement technology, polyp
gastric cancer and colorectal pathologies including colorectal
INTRODUCTION six were cancers. These data were recently confirmed by Pohl
and coworkers in a randomized two-center trial including
E NDOSCOPIC IMAGING OF the gastrointestinal (GI)
tract is routinely carried out by using white-light endos-
copy. However, standard white-light endoscopy may miss a
more than 1000 patients.6 DBC with methylene blue has also
been shown to allow a more accurate diagnosis of the extent
and severity of the inflammatory activity in inflammatory
significant amount of lesions, especially within the colorec-
bowel diseases compared with conventional colonoscopy.7 In
tum, and may also lead to a misinterpretation of findings,
addition, DBC allowed for the early detection of intraepithe-
thereby resulting in delayed or suboptimal therapies.1,2 In an
lial neoplasia and colitis-associated cancer in patients with
attempt to overcome the limitations of white-light endos-
long-standing ulcerative colitis.7
copy, dye-based chromoendoscopy (DBC) techniques were
Moreover, the impact of DBC for detection and charac-
introduced more than one decade ago.3,4 DBC has been
terization of esophageal lesions, including esophageal squa-
proven to be feasible for improved detection and character-
mous cell cancer, non-erosive reflux disease and Barrett’s
ization rates of various GI lesions. In this context, one early
esophagus, has been demonstrated.8–11
study evaluated the efficacy of indigocarmine dye spraying
In terms of stomach lesions, indigocarmine DBC has rou-
in 52 patients undergoing screening colonoscopy.5 Among
tinely been used after detection of gastric lesions by white-
48 patients with mucosa of normal appearance, 27 patients
light endoscopy for an extended period of time, especially in
showed 178 lesions after staining with a mean size of 3 mm.
Japan, although there was no clear evidence that DBC could
On histological investigation, 67 lesions were adenomas and
actually improve detection and characterization of gastric
lesions. In this context, Kawahara et al. have recently shown
that indigocarmine dye-spraying significantly improved
Corresponding: Helmut Neumann, Department of Medicine 1,
University of Erlangen-Nuremberg, Ulmenweg 18, Erlangen diagnostic accuracy of tumor extents and that a mixture of
91054, Germany. Email: helmut.neumann@uk-erlangen.de acetic acid and indigocarmine could lead to much higher
Received 17 June 2013; accepted 2 September 2013. accuracy in 108 already-known early gastric cancers.12
Optical DLC NBI Olympus, Tokyo, Japan Evis Exera II & III
CBI Aohua Photoelectricity, Shanghai, China AQ-100
Virtual DLC i-scan Pentax, Tokyo, Japan EPKi, EPKi-5000, EPKi-7000
FICE Fujifilm, Tokyo, Japan EPX-4400
CBI, Compound Band Imaging; FICE, Fuji Intelligent Color Enhancement; NBI, narrow band imaging.
Additionally, intravital staining of the duodenum with Table 2 Potential applications and clinical advantages of virtual
indigocarmine was shown to be useful for detecting mucosal chromoendoscopy using i-scan
abnormalities, delineating their extent, and allowing targeted Esophagus
biopsies.13 Taken together, DBC may unmask mucosal • Early squamous cell cancer
lesions that are not easily identified by routine white-light • Gastric inlet patch
endoscopy. In addition, DBC facilitates visualization of the • Minimal change gastroesophageal reflux disease
margins of flat or depressed lesions and helps to predict • Barrett’s esophagus and early adenocarcinoma
lesion histology for an optimized endoscopic therapy. Nev- Stomach
ertheless, DBC has some potential limitations, as the dye • Atrophic gastritis
does not always coat the surface evenly, thereby often result- • Gastric antral vascular ectasia (GAVE)
ing in overstained and less stained mucosal areas, which, in • Early gastric cancer
turn, may affect the diagnosis and characterization of Duodenum
lesions. In addition, there are additional costs for dye spray- • Celiac disease
ing, including those for the dye and the spraying catheter. • Whipple’s disease
Furthermore, the procedure requires a learning phase and the
Colon
mucosa should be well prepared, as mucus or residual stool
• Polyps
may result in false-positive findings.
• Inflammatory bowel diseases
In an attempt to overcome the limitations of DBC, • Food allergies
dye-less chromoendoscopy (DLC) techniques have been
introduced (Table 1). These are divided into optical chromo-
endoscopy techniques, including narrow band imaging
(NBI; Olympus, Tokyo, Japan) and Compound Band time without any noticeable time delay. Currently, two
Imaging (CBI; Aohua Photoelectricity, Shanghai, China), virtual chromoendoscopy techniques are available, including
and virtual chromoendoscopy techniques including Fujifilm FICE and i-scan. While FICE has no standardized image
Intelligent Color Enhancement (FICE; Fujifilm, Tokyo, settings, a recent international consensus recommended
Japan) and i-scan (Pentax, Tokyo, Japan). DLC is activated uniform settings for i-scan, thereby allowing even the com-
simply by pushing a button on the handle of the endoscope, parison of different studies.14 As a standard feature, the
thereby enabling high-contrast imaging of the mucosal i-scan system is integrated into the EPKi high-definition
surface without any time delay or the need for special video processor units (Pentax, Tokyo, Japan). A detailed
equipment. description of the technology was recently presented by
In the present review, we will focus on present and future Kodashima and Fujishiro.15 In short, i-scan consists of three
perspectives of virtual chromoendoscopy using i-scan and different image algorithms: (i) surface enhancement (SE);
give an outlook on the advent of the recently introduced (ii) tone enhancement (TE); and (iii) contrast enhancement
optical enhancement technology (Table 2). (CE). Switching between different modes is done by pushing
a button on the handle of the endoscope. As explained by
Kodashima and Fujishiro, SE enhances light-dark contrast
TECHNIQUE OF VIRTUAL
by obtaining luminance intensity data for each pixel and
CHROMOENDOSCOPY
applying an algorithm that allows detailed observation of the
each pixel and applying an algorithm that allows detailed visible changes and, afterwards, targeted biopsies were
observation of subtle irregularities around the surface and a carried out. It was found that Lugol’s solution significantly
detailed inspection of the mucosal vascular pattern morphol- improved the identification of patients with esophagitis and
ogy. Last, TE dissects and analyses the individual red-green- reduced misclassification, whereas i-scan and DBC helped
blue (RGB) components of a normal endoscopic image in to identify reflux-associated lesions. These data were also
real time and then alters the color frequencies of each com- confirmed by a recent prospective study from Korea includ-
ponent and recombines the components to a single, new ing over 500 patients.18 White-light endoscopy identified
color image without visible delay for the examiner. Thereby, reflux esophagitis in approximately 22% of patients,
TE enhances minute mucosal structures and subtle changes whereas i-scan identified reflux associated lesions in 30%
in color.15 of patients. The detection rate of minimal change GERD
Based on current consensus, three i-scan settings are rec- was significantly higher in the i-scan group as compared to
ommended as follows:14 (i) i-scan 1 for detection of lesions. white-light endoscopy, but was not different for erosive
This algorithm uses only SE to refine imaging of subtle reflux esophagitis grade A and grade B according to the
surface abnormalities without altering the brightness of the Los Angeles classification (LA). Additionally, i-scan
endoscopic picture. (ii) i-scan 2 mode was established for showed better interobserver agreement than white-light
characterization of lesions. This algorithm combines SE and endoscopy. These data were also confirmed by Kim and
TE, thereby enhancing minute mucosal changes and vessel coworkers.19
structures. (iii) Last, i-scan 3 adds CE to the endoscopic
image (in addition to SE and TE) and is recommended for
demarcation of lesions as it digitally adds blue color to PRESENT APPLICATIONS OF i-SCAN
darker edges within the endoscopic image. TECHNOLOGY IN THE STOMACH
A B
A B C
Figure 2 Intestinal-type intramucosal gastric cancer. (a) White-light endoscopy shows a small reddish depression in the lower gastric
body. (b) i-scan enhances the atrophic changes in the background as well as the tumor itself, which reveals that the tumor is located on
the atrophic border. (c) i-scan additionally reveals a clear demarcation line of the tumor to the surrounding tissue.
(50–80%) it increased for the subsequent 22 lesions (71– significantly more patients with colorectal neoplasia (38%)
83%). In the last teaching sessions, two investigators compared with standard resolution endoscopy (13%). More-
reached the proposed negative predictive value ≥90% over, significantly more neoplastic (adenomatous and can-
according to the ASGE PIVI statement (80–100%). The cerous) lesions and more flat adenomas were detected by
authors concluded that accurate interpretation of i-scan using i-scan. Of interest, the final histological result could be
images for prediction of hyperplastic and adenomatous predicted with a nearly 99% accuracy. These data were also
colorectal lesions follows a learning curve but can be confirmed by Testoni et al. showing that i-scan during the
learned rapidly. withdrawal phase of colonoscopy significantly increased the
Another recent multicenter study including eight expert detection of colonic mucosal lesions, particularly the detec-
endoscopists assessed interobserver agreement in the visu- tion of small and non-protruding polyps.30 In contrast to
alization of the surfaces and margins of colorectal polyps these studies, one prospective, randomized, back-to-back
and in distinguishing neoplastic from non-neoplastic polyps trial was not able to show a significantly improved adenoma
by using i-scan.27 A total of 400 images were stored for detection rate when using i-scan.31 Patients were randomized
analysis. Distinction between neoplastic and non-neoplastic to the first withdrawal with either conventional high-
tissue was based on Kudo’s pit pattern classification, con- definition white-light or i-scan. In addition, all patients
sidering patterns I and II as non-neoplastic lesions and pat- underwent a second examination with high-definition white-
terns III, IV and V as neoplastic lesions (III and IV as light as the criterion standard. The adenoma detection rates
adenomatous and V as carcinomas). Overall, there was a during the first withdrawal of high-definition, i-scan 1 mode,
kappa agreement of 0.370 (P < 0.001) and 0.306 (P < 0.001) and i-scan 2 mode were 32%, 37%, and 33%, respectively
regarding pit pattern and margins, respectively. The kappa (P = 0.742), and the adenoma miss rates of each group were
agreement for the differentiation between neoplastic and 23%, 19%, and 16%, respectively (P = 0.513). Based on the
non-neoplastic lesions was 0.446 (P < 0.001). Accordingly, a multivariate analysis, the application of i-scan was not asso-
good interobserver agreement was observed for the evalua- ciated with an improvement in adenoma detection and the
tion of neoplastic and non-neoplastic lesions and a less good prevention of missed polyps. However, the prediction of
agreement for the evaluation of pit pattern and margins. The neoplastic and non-neoplastic colorectal lesions was more
authors concluded that adequate training is required in order precise in the i-scan group as compared with the high-
to interpret images acquired with the i-scan technique. definition white-light group.
One recent study compared the detection rate of mucosal The group from Frankfurt tested the efficacy of high-
lesions using i-scan and the withdrawal time of the instru- definition white-light endoscopy alone and in combination
ment among non-expert and expert endoscopists during with i-scan or methylene blue-aided chromoendoscopy in
screening colonoscopy for colorectal cancer.28 Overall, 542 screening for colorectal cancer.32 In 69 patients studied,
colonoscopies were carried out. Notably, it was found that i-scan augmented the identification of lesions from 176 to
i-scan enabled less experienced endoscopists to achieve 335 (P < 0.001) and chromoendoscopy to 646 (P < 0.001).
results comparable to those of experienced ones in detecting Additional detected lesions were mainly flat polyps and the
mucosal lesions (Fig. 3). number of neoplasias detected was not significantly different
Hoffman and coworkers prospectively compared high- between groups (high-definition: 5, i-scan: 11, chromoen-
definition colonoscopy with i-scan versus standard video doscopy: 11), but all could be correctly predicted using
colonoscopy.29 In their study, a total of 220 patients were i-scan or chromoendoscopy. Of note, i-scan was able
randomized in a 1:1 ratio. In this study, i-scan detected to predict neoplasia as precisely as chromoendoscopy.
A B
The potential of i-scan for real-time prediction of colorectal OPTICAL ENHANCEMENT TECHNOLOGY
polyp histology was also highlighted by a study from the
Modena group in Italy reporting on a sensitivity, specificity,
and accuracy of 95%, 82%, and 92%, respectively.33 Among
the subset of polyps with good or excellent quality images,
N EW IMAGE-ENHANCED ENDOSCOPIC technol-
ogy using band-limited light, optical enhancement
(OE), was developed by HOYA Co. (Tokyo, Japan) and is
sensitivity and accuracy of i-scan significantly improved to now equipped with the latest endoscopy system (Pentax
97% and 94%, respectively. Video Processor EPK-i7000; HOYA Co.). The new technol-
ogy combines digital signal processing in a similar way to
i-scan and optical filters that limit the spectral characteristics
of the illumination light.
PRESENT APPLICATIONS OF i-SCAN
Previous i-scan technology uses white light alone as an
TECHNOLOGY FOR INFLAMMATORY
illumination light and digital post-processing of the reflec-
BOWEL DISEASE
tion afterwards creates images yielding the virtual chromo-
A B C
Figure 5 Superficial esophageal cancer with submucosal invasion. (a) White-light image. (b) Mode 2 image. (c) Mode 1 with magnifica-
tion image.
useful for detection and characterization of gastrointestinal lesions. The new optical enhancement technology offers a
neoplasms, respectively.40 new potential for enhanced diagnosis of lesions throughout
the whole luminal gastrointestinal tract. This new technology
is promising to overcome higher miss rates and lower accu-
CONCLUSION racy of characterization. Accumulation of cases and well-
designed clinical trials in the near future are warranted and
A LTHOUGH RECENTLY INTRODUCED, various
large and prospective studies have already shown the
benefit of i-scan for patient management during ongoing
highly anticipated.
A B C
Figure 6 Intestinal-type intramucosal gastric cancer. (a) White-light image. (b) Mode 2 image. (c) Mode 1 with magnification image.
A B C
Figure 7 Laterally spreading-type intramucosal colon cancer. (a) White-light image. (b) Mode 2 image. (c) Mode 1 with magnification
image.
Birmingham, USA. Mitsuhiro Fujishiro has served as a lec- 5 Kiesslich R, von Bergh M, Hahn M. Chromoendoscopy
turer for Eisai Pharmaceuticals Co., Ltd and his department with indigocarmine improves the detection of adenomatous and
has obtained a donation from Dainihon Sumitomo Pharma- nonadenomatous lesions in the colon. Endoscopy 2001; 33:
ceuticals Co., Ltd. He is also a chief investigator in a coop- 1001–6.
6 Pohl J, Schneider A, Vogell H, Mayer G, Kaiser G, Ell C.
erative study between The University of Tokyo and HOYA
Pancolonic chromoendoscopy with indigo carmine versus stan-
Corporation regarding optical enhanced technology. The
dard colonoscopy for detection of neoplastic lesions: A ran-
other authors have no relevant conflicts of interest to disclose. domised two-centre trial. Gut 2011; 60: 485–90.
7 Kiesslich R, Fritsch J, Holtmann M et al. Methylene blue-aided
chromoendoscopy for the detection of intraepithelial neoplasia
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