Endoscopic imaging in Barretts esophagus:

current practice and future applications

Raghubinder Singh Gilla, Rajvinder Singhb

Gosford Hospital, NSW Australia; Lyell McEwin Hospital, University of Adelaide, SA Australia

Abstract

Barretts esophagus (BE) is a condition that develops as a consequence of chronic gastro-

esophageal reflux disease in which stratified squamous epithelium is replaced by metaplastic
columnar epithelium which in turn predisposes to the development of adenocarcinoma of
esophagus. In this review article, we discuss recent advances in the endoscopic imaging
techniques for the detection of dysplasia and early carcinoma in BE. This will include some of the
current available novel technologies as well as future applications specifically concentrating on
high-resolution endoscopy, narrow band imaging, chromoendoscopy, confocal laser
endomicroscopy and autofluorescence imaging.

Keywords Barretts esophagus, autofluorescence imaging, chromoendoscopy, confocal laser

endomicroscopy, high-resolution endoscopy, narrow band imaging, optical coherence tomography

a
Gastroenterology Advanced Trainee, Gosford Hospital, Division of Gastroenterology, NSW,
Australia (Raghubinder Singh Gill); bLyell McEwin Hospital, Elizabeth Vale, SA Australia, University
of Adelaide, SA Australia (Rajvinder Singh)

Conflict of Interest: None

Correspondence to: Raghubinder Singh Gill, Lyell McEwin Hospital, Elizabeth Vale, SA Australia, Senior Clinical
Lecturer,
University of Adelaide, SA Australia, Tel: +61 8818 29909,
e-mail: [email protected]

Received 3 January 2012; accepted 9 February 2012

Introduction

Barretts esophagus (BE) is a premalignant condition which develops as a consequence of gastro-

esophageal reflux disease (GERD) [1-3]. In the United States, BE is defined as a change in the distal
esophageal epithelium of any length that can be recognized as columnar type mucosa at endoscopy
and confirmed to have intestinal metaplasia (IM) by biopsies [4], whereas the British Society of
Gastroenterology has excluded the need for IM. It is thought that BE progresses in a step wise
manner from low-grade dysplasia (LGD) to high-grade dysplasia (HGD) and finally esophageal
adenocarcinoma (EAC) [5] which has been attributed to DNA alterations in the mucosa [6].

Epidemiology

BE is usually seen in middle-aged and older adults whose mean age at the time of diagnosis by
endoscopy is 55 years [7]. The male to female ratio is 2:1 [8]. Estimates of frequency of BE in
general population has varied widely ranging from 0.9-20% [9-12]. This may be partly explained by
the different populations studied and definitions used.

Screening

In order to decrease mortality from EAC, endoscopic screening for BE in patients having GERD
symptoms has been recommended by the American College of Gastroenterology (ACG) [13,14]. It
is however unclear if screening patients with GERD symptoms has any impact on identifying
individuals at increased risk of EAC as 40% of patients diagnosed with EAC have no history of
heartburn [15]. This presents a major limitation in screening patients with GERD symptoms for BE
and EAC [16,17]. Although highly controversial, screening may be recommended in patients with
the following risk factors:
Age 50 years or older
Male sex and white race with chronic GERD symptoms
Patients with evidence of a hiatal hernia
Patients with an elevated body mass index and intra-abdominal distribution of body fat

The American Gastroenterology Association (AGA) recommends against screening the general
population with GERD symptoms [18].

Surveillance

The annual rate of incidence of cancer in patients having BE has been estimated at ranging
between 0.12-2.0% [19-27]. A recent large population based Danish study reported that the annual
risk of EAC among patients with BE was 0.12%, or 1 case of EAC per 860 patient years [27]. This
was similar to another large population based study from Northern Ireland in which incidence rate
of EAC was reported to be 1.3 cases per 1000 patient years (excluding cases that were diagnosed
during the first year) [26]. These studies have brought into question the cost effectiveness of
current surveillance protocols.

Surveillance is performed by taking four quadrant biopsies every 1-2 cm, however only a very tiny
fraction of Barretts mucosa is sampled this way [28,29]. Lesions harboring dysplasia or EAC can be
easily missed. Some studies suggest a risk of occult carcinoma in patients with HGD of around 40%
[30-32]. The present recommended surveillance interval by the ACG is depicted in Table 1.
Endoscopic surveillance can potentially detect curable early neoplasia. Asymptomatic cancers found
during surveillance are less advanced when compared with symptomatic cancer patients who have
dysphagia and weight loss [33,34]. During the last decade, novel endoscopic techniques have
enabled increased recognition of dysplasia and early cancers in BE. This review will discuss some of
the advances in endoscopic imaging in BE.

Paris classification

Endoscopic appearance of lesions in BE may point towards the lesions potential to invade the
submucosa (hence endoscopically unresectable). The updated Paris classification categorizes
superficial lesions in esophagus into: protruding pedunculated (type 0Ip), protruding sessile (0Is),
slightly elevated (0IIa), completely flat (0IIb), slightly depressed (0IIc), excavated (0III), or a mixed
pattern [35]. A Danish retrospective study of endoscopic resection in BE suggested that type 0-I and 0-
IIc lesions have higher submucosal infiltration rates [36]. There is surgical literature for patients with
HGD in BE suggesting that a visible lesion on white light examination (WLE) is associated with an
increased risk of coexisting cancer [37,38].

WLE with high-resolution and magnification endoscopy

High-resolution endoscopes (HRE) are endoscopes equipped with high-density charged coupled
device (CCD) chips enabling improved optics and images to be displayed at up to 850,000 pixels
[39] (Fig. 1A). Magnification endoscopy enables the images to be magnified by up to 115 times by
optical magnification [39]. These are major advancements in technology allowing for better
visualization of the mucosa. Magnification endoscopy is best used in conjunction with
chromoendoscopy [40-43]. A study by Sharma et al demonstrated that magnification
chromoendoscopy helped to identify areas with IM and HGD [44]. The issue with this modality of
imaging has been the high interbserver variability [45]. A study by Mayinger et al suggested that
one reason for this is the difficulty in differentiating gastric cardiac mucosa from non-dysplastic
Barretts mucosa [46].
Chromoendoscopy

Dyes can be used to better visualize the mucosal surface of the gastrointestinal tract. Methylene
blue (MB) has been used to visualize the presence of IM/HGD, and cancer [47]. It is a vital stain
that is actively absorbed by mucosa and is taken up by IM, but not gastric or squamous mucosa.
Multiple reports have however shown discrepant results [48-51]. A meta-analysis by
Ngamruengphong et al of 450 patients with BE in 9 studies concluded that MB chromoendoscopy
had a yield for detection of specialized IM comparable to conventional four-quadrant random
biopsies [52]. There is also a theoretical risk of acceleration of carcinogenesis with MB [53]. Indigo
carmine has been used to evaluate dysplasia or cancer [54]. Acetic acid is another stain which has
been used. However its utility in detecting dysplasia is not yet established [45,55,56]. The
limitations to chromoendoscopy include the high interobserver variability secondary to lack of
standardization of pit pattern classification systems [45], lack in training of general endoscopists,
and a significant increase in the time taken for the examination. Studies looking at the impact of
chromoendoscopy on patient outcomes are required.

NBI

NBI was first described in 2004 [57]. It is a technique that uses filtered light where an increased
contribution of the short wavelength blue light (440-460 nm) leads to better visualization of the
mucosal surface pattern. The superficial capillary network is also highlighted as blue light has an
increased affinity to and is better absorbed by hemoglobin in blood [58] (Fig. 1B/1C).
Different pit pattern classifications have been described with this technology in BE [58-60]. These
classification systems are in itself a limitation in the use of NBI as they make reproducibility in the
community a problem. It requires further validation in large randomized multicenter trials [61].
Sharma et al described NBI images with mucosal patterns (ridge/villous, circular, irregular) and
vascular patterns (normal and abnormal) [59]. They demonstrated that presence of irregular
mucosal or vascular patterns had a high sensitivity, specificity and positive predictive value for the
diagnosis of HGD and cancer [59]. A prospective cohort study of 109 patients with BE exhibited
that the presence of villous/ridged/absent pit patterns were highly suggestive of specialized IM
(SIM) [60]. In another study it was found that NBI with optical magnification was superior to WLE
and optical magnification in the prediction of dysplastic tissue in BE (p<0.05) [62], whereas in a
randomized crossover study comparing WLE with NBI by Kara et al no difference was found in the
detection of HGD/intramucosal cancer (IMC) [63]. In another study by Wolfsen et al, NBI was found
to have a higher detection rate of dysplasia, compared with WLE (57% vs. 43%) [64]. However an
important bias in this study was that NBI was used with a high-resolution system when compared
with WLE which used standard resolution. A systematic review by Curvers et al found good
sensitivity (77-100%), specificity (79-94%), and accuracy (88-96%) of NBI in differentiating gastric
mucosa from IM [65].

The advantage of NBI is that both the mucosal and vascular pattern can be studied. It can easily be
combined with other modalities for better mucosal examination. Some of the other advantages of
NBI include its wide availability, ease of use and integration into standard endoscopy with no
additional risks to the patient.

Autofluorescence imaging (AFI)

AFI takes advantage of the phenomenon in which tissue after exposure to light of a shorter
wavelength emits fluorescent light with a longer wavelength. Examples of tissue fluorophores are
collagen, amino acids, flavins, etc. This phenomenon is called auto fluorescence [66,67] (Fig. 2A,
2B). Initial studies using point spectroscopy techniques demonstrated a difference between
fluorescence pattern of Barretts dysplasia/cancer and normal tissue [68-70]. Initial systems using
fiber optic endoscopy with AFI were compared to WLE, and showed no difference in the number of
patients detected with HGD/early stage cancer [71,72]. A plausible reason could be the
substandard image quality of fiber optic endoscopy.
More recently endoscopic trimodal imaging (ETMI) system has been developed incorporating
autofluorescence, HRE, and NBI. A prospective multi-center study in 4 tertiary referral centers
demonstrated that AFI increases the detection rate of high grade intraepithelial neoplasia (HGIN),
and early neoplasia (EN) from 53% to 90%. The problem with AFI is its false positive rate of 81%. In
this study, the use of NBI reduced the false positive rate of AFI to 26% [73]. Another study using
ETMI demonstrated that overall detection of patients with HGIN/EN was not statistically different
from standard endoscopy (84% vs. 73%) [74]. In a recent multi-center, randomized, cross over
study in a community practice setting, no significant difference in the overall histological yield
between ETMI and standard video endoscopy was observed [75].

Confocal laser endomicroscopy (CLE)

CLE is a technique that allows the gastroenterologist to perform real-time histological assessment
of the gastrointestinal lining. There are two systems available, endoscope based confocal system
(eCLE) and a probe based system (pCLE). Both systems uses blue laser light which is focused on
the mucosa while an intra venous (IV) contrast agent (fluorescein sodium) is injected [76]. The
microscopic images of the mucosa are magnified up to 1250-fold, up to 250 m below the mucosal
surface [77]. It is essential for the gastroenterologist performing CLE to have basic histopathology
knowledge and ability to differentiate between normal and dysplastic mucosa [78]. Classification
systems for BE have been described for both eCLE and pCLE [79,80].

Kiesslich et al reported an accuracy of 97.4%, sensitivity and specificity of 94.1% and 98.5%
respectively for the prediction of BE associated neoplasia [79]. Dunbar et al in their single center,
randomized, cross over study with eCLE reported that, when compared with standard endoscopy,
eCLE increases the yield of unlocalized neoplasia from 17% to 34%. It was also reported that eCLE
required fewer biopsies to achieve a comparable overall diagnosis [81]. Pohl et al, in a study using
pCLE to distinguish dysplastic and non-dysplastic BE, demonstrated a very good negative
predictive value of 98%, with good interobserver agreement (k=0.6) [80]. A blinded multi-center
study by Wallace et al demonstrated a high sensitivity and specificity (91% and 100% respectively)
and a very accurate interobserver agreement of (k=0.83) amongst endoscopists with prior pCLE
experience for diagnosis of HGIN and cancer [82].

Optical coherence tomography (OCT)

OCT uses short coherence length broadband light for cross-sectional imaging of esophageal
mucosa. It is similar to ultrasonography but uses light waves rather than acoustic waves [83].
There are several studies which have described the normal and abnormal esophageal mucosa on
OCT during endoscopy. In normal esophagus, the epithelium, lamina propria and muscularis
mucosa are clearly identified [83,84]. One of the earliest prospective studies to establish the
sensitivity and specificity of OCT for the diagnosis of SIM following a specific criterion found the
sensitivity and specificity to be 97% and 92% respectively [85]. Qi et al, using a computer aided
diagnostic algorithm with histology as a reference standard, reported the sensitivity, specificity,
and accuracy of 82%, 74%, and 83% respectively [86]. Evans et al developed an algorithm for
diagnosis of SIM using 2 blinded investigators [89]. They reported a sensitivity of 81% and a
specificity of 66% for both OCT readers. The interobserver agreement was good (k=0.53) [87]. OCT
however is not widely available currently [88].

Spectroscopy
 Spectroscopy-based devices can assess the interaction between light and mucosal surface to
provide information about the nuclear size, crowding, vascularity, and organization of glands. This
technology can only examine potentially suspicious regions and is currently being investigated to
differentiate between normal and abnormal tissue [88]. The different spectroscopic modalities are
light scattering, reflectance, and Raman-based. Light scattering spectroscopy gives information
about cell nuclei characteristics. Various studies have demonstrated dysplasia detection in BE
using this technique [89-91]. Reflectance spectroscopy also assists in differentiating normal from
neoplastic tissue [92,93]. A new system called Endoscopic Polarized Scanning Spectroscopy (EPSS)
shows great promise in the detection of dysplasia in BE. Unlike other spectroscopic modalities, it
scans the entire esophagus and combines polarized light scattering spectroscopy with diffuse
reflectance spectroscopy in the same instrument [94]. Raman spectroscopy is used to study the
different characteristics of molecular vibrations in cancerous and normal cells in BE thus
differentiating one from the other [95]. A major drawback of Raman scattering is that the signal is
typically very weak and the differences may be too small to be appreciated.

Conclusion

There has been great advancement in the imaging techniques used for the detection of dysplasia
in BE. Most of these techniques have been studied in tertiary centers with investigators having
special interest in BE. It would be interesting to see if these results could be reproduced in the
hands of the general endoscopist. Ease of availability, cost, procedural time, and medico-legal
issues associated with image interpretation are some of the concerns which need addressing.
Currently, however, a detailed examination of the BE segment with WLE and random 4-quadrant
biopsies is probably still the best approach, with other imaging modalities used in addition to
increase the yield of detecting dysplastic areas in BE.

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