Advances in endoscopic imaging: Advantages and limitations

Abstract

Endoscopic imaging is emerging beyond the confines of traditional white light endoscopy. There is a plethora of advanced imaging technologies which aim to improve visualization of the vascular network and surface texture of the mucosa and thereby improve tissue characterization, differentiation, and diagnosis. These include the wide field technologies like chromoendoscopy, narrow band imaging and autofluorescence endoscopy and point enhancement or virtual histology technologies like endocytoscopy and confocal endomicroscopy. This review attempts to define the current status of these newer technologies and the advantages and limitations in current clinical practice.

Full text

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Journal of Digestive Endoscopy
Vol 3 | Supplement | January 2012
Address for correspondence:
Dr. Rupa Banerjee, Asian Institute of Gastroenterology, Hyderabad, India. E‑mail: dr_rupa_banerjee@hotmail.com
Introduction
Gastrointestinal endoscopy revolutionized the diagnosis
and therapy of many gastrointestinal diseases in the last two
decades. Endoscopic imaging is again undergoing a profound
evolutionary change. The perspective of diagnostic endoscopy
is changing from diagnosing evident disease to the detection
of subtle abnormalities.
Conventional white light endoscopy (WLE) has been limited to
detecting lesions on the basis of gross morphological changes.
Diagnosis is primarily based on biopsy sampling of obvious
macroscopic endoscopic features, or “blind” biopsy sampling of
normal appearing mucosa. These random biopsies are clearly
inefficient and miss significant histology. WLE is often unable to
identify subtle mucosal alteration in flat lesions which prevents early
detection of GI malignancies in the resectable and curative stages.
The newer endoscopic imaging technologies attempt to
visualize what was formerly possible only with biopsy and
histologic interpretation. High resolution, high definition
systems have CCDs of more than a million pixels which
are 3 times higher than the conventional scopes. It focuses
on early detection and categorization and optimization of
treatment.
The aims of advanced imaging beyond WLE include:
a) Improved detection of minute lesions and mucosal
alterations with a potential for neoplasia.
b) To provide characterization of the tissue of interest
neoplastic/nonneoplastic or inflammatory.
c) In vivo histology and optical biopsy.
These advances can be categorized into:
a) Image enhanced endoscopy or field enhancement as
a red flag technology to survey the entire lumen of
the gastrointestinal tract. This encompasses contrast
enhancement using dye, optical, and/or electronic methods
and include Chromoendoscopy, NBI, I scan, FICE and
autofluorescence endoscopy.
b) Virtual histology or point enhancement for
in vivo
hislogical examination during endoscopy. Confocal laser
endomicroscopy, endocytoscopy and OCT provide cellular
and subcellular imaging for real time optical biopsy.
This review attempts to define the current status of these newer
technologies and the advantages and limitations in current
clinical practice.
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DOI:
10.4103/0976-5042.95023
Abstract Endoscopic imaging is emerging beyond the confines of traditional white light endoscopy.
There is a plethora of advanced imaging technologies which aim to improve visualization of the
vascular network and surface texture of the mucosa and thereby improve tissue characterization,
differentiation, and diagnosis. These include the wide field technologies like chromoendoscopy,
narrow band imaging and autofluorescence endoscopy and point enhancement or virtual
histology technologies like endocytoscopy and confocal endomicroscopy. This review attempts
to define the current status of these newer technologies and the advantages and limitations
in current clinical practice.
Key words Newer imaging, NBI, optical biopsy, confocal endomicroscopy, endocytoscopy
Advances in endoscopic imaging: Advantages and
limitations
Rupa Banerjee, D. Nageshwar Reddy
Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, India
Review Article
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Chromoendoscopy
Chromoendoscopy involves the application of stains or dyes to
the gastrointestinal mucosa during endoscopy to improve tissue
visualization, characterization and diagnosis by enhancing
the contrast.[1]
The stain/dye solutions are classified into:
a) Vital stains which are taken up by specific epithelial cells.
Eg Lugols iodine, methylene blue, toluidine blue and crystal
violet.
b) Contrast stains which are not absorbed but pool up in the
crevices of the mucosa and highlight the fine mucosal
irregularities. Eg Indigo carmine.
c) Reactive stains which undergo color change based on the
presence of a alkaline/acidic pH. e.g. Congo red, phenol red.
Chromoendoscopy has been mostly studied for
i. Detection of dysplasia and early carcinomas of stomach
and esophagus. Lugols iodine most commonly used. It
also improves the visualization of the lateral margins of
the lesion and delineates the extent.
ii. Detection and characterization of polyps.[2‑5] Indigo
carmine has been used most commonly. The sensitivity
and specificity of differentiation ranges from 82‑98% and
52‑95% respectively.
iii. Detection of dysplasia in chronic ulcerative colitis.[6‑8]
Chromoendoscopy is considered a simple, safe and inexpensive
technique that is useful in identifying premalignant conditions
and minute cancerous lesions as well as predicting the
histological type and submucosal invasion. Some limitations
have prevented the widespread use of chromoendoscopy
in clinical practice beyond few specified conditions. These
include the lack of standardized classification systems for
chromoendoscopic findings and poor reproducibility. Also, the
routine use of these dyes can be messy and time consuming
and the cost effectiveness is yet undefined.
Digital chromoendoscopy
These are novel optical technologies that enhance surface pit
pattern and microvasculature without the use of dyes. These
include
a) Narrow band imaging (NBI), b) I scan and c) FICE
Narrow band imaging
This is the most widely used advanced imaging technology
primarily because of the ease of usage and availability at the
switch of a button.[9] NBI technology involves the placement
of narrow band pass filters in front of a conventional white
light source to obtain tissue illumination at selected narrow
wavelength bands. This provides a real time on demand optical
image enhancement that enhances visualization of the vascular
network and surface texture of the mucosa thereby assisting
in tissue characterization, differentiation and diagnosis.[9,10]
The NBI system components are identical to the conventional
RGB sequential or color CCD endoscopes. The primary
modifications are within the light source where an optical filter
with narrow band transmission is placed. NBI systems have
also been coupled with electronic or optical zoom facilities for
enhanced visualization of mucosal details. The commercially
available NBI systems include the 2‑band NBI RGB sequential
endoscopes (Evis Lucera 260 Spectrum) and the color CCD
endoscopes (Evis Exera II 180, Olympus Medical Systems,
Tokyo, Japan).
Current role of Narrow band imaging in clinical
practice
NBI has primarily been applied in the analysis of the surface
architecture of the epithelium (pit pattern) and the analysis
of the vascular network. It can demonstrate and distinguish
the alteration in the pit pattern and vasculature between
inflammatory and neoplastic lesions of the esophagus, stomach
and large bowel.[11]
Currently available literature supports the use of NBI for
surveillance in Barrett’s oesophagus and in patients considered
at high risk for squamous cancers of the oropharynx, oesophagus
and stomach.[9,10,12,13] NBI targeted biopsy can enhance
dysplasia detection compared to WLE in the surveillance of
inflammatory bowel disease.[14] Emerging data also supports
the use of NBI in therapeutic procedures including ablation
of Barrett’s, endoscopic mucosal resection and ESD where the
assessment of the margin is critical. However interpretation of
contrast enhanced images require familiarity and may not be
straight forward with considerable inter observer variation. The
presence of blood or bile prevents optimal viewing.
NBI is an emerging technology. The classifications of various
conditions described on NBI need to be further standardized
and validated for use in routine clinical practice.
I scan/Fuji Intelligent Chromo Endoscopy
I scan from Pentax (Montvale, NJ)[15] and Fuji Intelligent Chromo
Endoscopy (FICE) (Fujinon, Wayne, NJ) are based on post
imaging processing and involve spectral estimation technology.[16]
This involves taking an ordinary endoscopic image from the
video processor and production of an image of a given, dedicated
wavelength of light after arithmetic estimation. There is no optical
filter involved in contrast to narrow band imaging.
Only a limited number of studies for these technologies
have been reported. These have reported has enhanced
adenoma detection rates and differentiation of neoplastic and
non‑neoplastic colorectal lesions compared to WLE.[17] Head to
head comparisons between these technologies are not available.
Autouorescence endoscopy
Autofluorescence imaging (AFI) is based on the detection
of the relative concentration of endogenous fluorophores
and fluorescence emission thereby allowing differentiation
between healthy and neoplastic tissue. AFI endoscopy provides
real time images from the CCD computerization of captured
fluorescence based on the same principles. The endogenous
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tissue fluorophores of the gastrointestinal tract include tyrosine,
tryptophan, NADH, FAD, elastin, collagen and porphyrins.
These fluorophores are excited on exposure to short wavelength
light leading to the emission of a fluorescent light of a longer
wavelength (autofluorescence).[18] The autofluorescence
characteristics of normal, metaplastic and dysplastic epithelial
structures are dependent on the type, concentration and
distribution of different fluorophores together with the
biochemical composition and perfusion characteristics.[19]
Malignant transformation of tissue is associated with emission
of relatively longer wavelengths of light. The initial AFI
endoscopy systems used fiber optic technology and hence the
quality of images was poor.[20,21] The more recent video systems
have substantially improved the quality and resolution of the
images. Dysplastic lesions are displayed in a brilliant magenta
color against a green/cyancoloured normal background. Non
neoplastic tissues appear green.
The primary goal of this wide area functional imaging is as
a red flag technology to rapidly examine a large surface of
gastrointestinal mucosa for early identification of a possible
dysplastic area and image guided targeted biopsy.
Several controlled trials have shown the superiority of AFI
over white light endoscopy in detecting high grade dysplasia
in Barrett’s esophagus, superficial esophageal squamous cell
carcinoma and early gastric cancer. AFI colonoscopy has been
useful in the distinction between adenomatous and hyperplastic
polyps. Uedo and colleagues found that AFI endoscopy
accurately identified the extent of superficial oesophageal
carcinoma in 5 of 5 patients and gastric carcinoma in 15 of
22 (68%) whereas WLE detected only 2 of 5 and 22% cases
respectively.[22] Kara
et al
. similarly increased detection rates of
high grade dysplasia in Barrett’s oesophagus from 22% to 33%.[23]
However there are still too many false positives to make AFI
useful as a standalone technique in clinical practice. The
image quality though improved is still poorer than the high
definition systems. Subsurface changes cannot be identified.
Also the color tone is unstable related to the presence of mucus,
instrument angulation and air insufflation.
Summarily AFI is primarily a wide area imaging technology
which can be used as a red flag. The rate of false positives is
however high and further improvements in fluorescence image
quality is required. Trimodal imaging appears promising and
larger validation studies are warranted.
Trimodal imaging
False positivity is the major drawback of AFI. To decrease
false positivity AFI has been combined with high resolution
WLE and NBI (Trimodal imaging).[24]
A novel prototype trimodal endoscope is available which
incorporates high resolution WLE, NBI and autofluorescence.
In a multicenter study on 84 patients with Barrett’s oesophagus
AFI increased the detection rate from 16 of 30 on WLE to 27
of 30. AFI also increased the detection rate of biopsy proven
lesions from 21 with WLE to 40 with AFI. However false
positive rates was high (81%). NBI reduced the false positivity
to 26%.[25]
Optical biopsy:
In vivo
histologic assessment
Recent advances in endoscopic imaging technology have now
made microscopic observation possible at the cellular level
assisting in tissue characterization of a variety of neoplastic and
non neoplastic lesions of the gastrointestinal tract. These include
i) Endocytoscopy (EC) ii) Confocal laser endomicroscopy (CLE)
iii) Optical Coherence Tomography (OCT)
Endocytoscopy
The Endocytoscope (E‑C) system is based on the principle of
light contact microscopy and enables on the spot assessment for
cellular atypia. It has been primarily been used for the
in vivo
assessment of the oesophageal mucosa.[26]
The prototype EC system (Olympus Corporation, Tokyo,
Japan) consists of two flexible endoscopes (3.2 mm diameter)
each that can easily pass through the accessory channel of any
endoscope with a working channel of 3.7 mm. A prototype
unified NBI system integrated with EC facilities is also under
evaluation.
The endocytoscope is passed through the accessory channel
of a regular endoscope or colonoscope and the tip placed
in direct contact with the surface after application of 1%
methylene blue.[27]
The normal cells are arranged homogenously with a normal
nuclear cytoplasmic ratio. Mitotic cells on the other hand
appear heterogenous in shape with altered nuclear cytoplasmic
ratio and are arranged in irregular clusters.
The EC system has been used successfully in detection
of mitotic changes
in vivo
in oesophageal carcinoma.[26]
Preliminary reports show good correlation with histology. We
have recently reported the use of intra‑operative endocytoscopy
in detecting pancreatic head carcinoma in a patient with
chronic pancreatitis. The targeted biopsies correlated with the
frozen section and conventional histopathology.
There are key challenges before endocytoscopy can be accepted
into routine clinical practice. The presence of mucus or blood
may obscure view. Respiratory and cardiac movements can
also hamper visualization. It is difficult to map the exact area
of involvement since the whole area cannot be observed at
the same time.
Confocal laser endomicroscopy
Confocal endomicroscopy (CEM) provides images from layers
of tissue using the principle of optical sectioning at the cellular
and subcellular structures after the topical/IV application of
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exogenous fluorescence contrast agents including fluorescein,
acriflavin or cresyl violet.[28] CEM is an accepted standard
method for localization of specific proteins of cellular structures
in basic research. Endoscopically this new imaging modality
not only provides conventional histology but also indicates the
pathophysiology as cellular interaction can be observed over
time. The current CLE incorporates a confocal laser microscope
into the tip of a flexible endoscope (Pentax EC 3830FK, Tokyo,
Japan) allowing a 1000‑fold magnification with high resolution
and real time
in vivo
histology of the gastrointestinal tract
mucosa. A probe based confocal endomicroscope (Cellvizio,
Mauna Kea technologies, France) is also available. These
confocal miniprobes can be passed over the working channel
of all standard endoscopes.[29] An ERCP dedicated mini
probe (Cholangioflex) for the cholangioscope allows real time
microscopic level visualization of the bile and pancreatic ducts.
Clinical applications of CLE have aimed at the prediction
of gastrointestinal neoplasias and the generation of targeted
biopsies. The cellular information obtained by pCLE has
been used to target tissue sampling (brushings, biopsies or fine
needle aspiration) and to assist in making treatment decisions
on the spot.
Preliminary results in detection of intraepithelial neoplasias
in Barrett’s esophagus, ulcerative colitis surveillance,
differentiation of nature of colorectal polyps and
characterization of CBD strictures have been encouraging.[30]
CLE adds a new dimension to the endoscopic armamentarium
in gastroenterology and is likely to have great impact on
gastrointestinal endoscopy in the future. However, this
technology is not suited for screening of large surfaces as
during UC surveillance. Additionally, it is an examiner
dependent technology and training on interpretation is of
crucial importance before reliable histologic diagnoses can
be made.
Optical coherence tomography
OCT Optical coherence tomography (OCT) is an optical
imaging modality that performs high‑resolution, crosssectional,
subsurface tomographic imaging of the microstructure of
tissues. The physical principle of OCT is similar to that of
B‑mode ultrasound imaging, except that it uses infrared light
waves rather than acoustic waves. OCT can be done by using
narrowdiameter, catheter‑based probes that can be inserted
through the accessory channel of an endoscope.[31]
OCT imaging of the gastrointestinal wall is characterized
by a multiple layer architecture that permits an accurate
evaluation of the mucosa, lamina propria, muscularis
mucosae, and part of the submucosa. The technique has
been used to identify pre‑neoplastic conditions, such as
Barrett’s epithelium and dysplasia, and evaluate the depth
of penetration of early neoplastic lesions of the GI and
pancreatobiliary system.
A few preliminary studies involving small number of patients
are currently available. Larger carefully conducted prospective
trials are necessary to determine the clinical utility of this
imaging modality.
Imaging modalities in the pipeline
Fluorescence, light scattering and Raman
spectroscopy
These are optical spectroscopic techniques based on the analysis
of specific light –tissue interactions such as fluorescence, elastic
scattering and inelastic (Raman) scattering.[32,33] Spectral
differences in the optical signals based on the microstructure
and biochemical nature of the tissues can differentiate between
neoplastic and non neoplastic tissues. Several proof of concept
studies have demonstrated the usefulness of spectroscopy for
the optical detection of dysplasia in Barretts and early gastric
carcinomas and the differentiation of colorectal polyps. Future
technologic developments and the development of highly
selective fluorophores as biomarkers will enhance diagnostic
accuracy of spectroscopic imaging.
Reectance spectroscopy
Reflectance spectroscopy is a point probe optically based
endoscopic technique that quantitatively measures the color
and intensity of reflected light. It thereby provides information
about tissue haemoglobin concentrations and oxygenation
status. The inherent property of malignant tissue to promote
angiogenesis enables differentiation between mitotic and
benign tissues.
Targeted endoscopic imaging
This attempts to acquire real time data about the molecular
expression of cells and tissues within the digestive tract.
Changes in molecular expression occur well before that of
structural features and fluorescence/CLE imaging of these
expressed targets can enable the earliest detection of cancer as
well as response to therapy. The best studied intracellular targets
are proteolytic enzymes and surface targets transmembrane
proteins and glycoproteins.
This is the upcoming technology for the future management of
patients who have an increased likelihood of cancer including
risk stratification, early detection, therapeutic monitoring and
evaluation of recurrence.
The future of advanced imaging: Multimodal
imaging
Different modalities can be merged into new multimodal
devices making it possible to measure multiple parameters in
one procedure. This also paves the way for fusion of diagnostic
and therapeutic imaging enabling patients to have a one‑session
procedure. Multimodal imaging can in fact utilize the strengths
of each individual technique and minimize the limitations and
thereby enhance visualization of not only mucosal surface and
microvasculature but also the cellular and subcellular architecture.
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A proposed algorithm for enhanced multimodal imaging is
depicted below Table 1.
A novel trimodal imaging system has recently become available
that incorporates high‑resolution endoscopy, AFI and NBI in
one single system: Known as endoscopic tri‑modality imaging
(ETMI). AFI alone has a high false positive rate but with
ETMI characterization the false positive rate dropped down.
Trimodal imaging can actually serve as a ‘red flag’ technique
for the detection of early neoplastic lesions by AFL followed
by NBI to verify surface pattern characteristics.
Trimodal imaging has been reported to be effective in
screening for early neoplasia in Barretts oesophagus and
dysplasia in ulcerative colitis. We have used the ETMI for
differentiation between adenomatous and hyperplastic polyps
as well as between neoplastic and non neoplastic lesions with
good concordance with histopathology [Figures 1a ‑ c].
Conclusion
Gastrointestinal cancers are a leading cause of cancer‑related
death worldwide. The best chances of cure are associated with
early diagnosis. However these precancerous changes are often
subtle and cannot be identified during standard white light
endoscopy. Recent advances in imaging allow better detection
of these early neoplastic lesions and increase the effectiveness
of endoscopic surveillance and screening.
These tools have a potential to improve with further
technologic improvement. Future applications may include
Table 1: Algorithm for multiplmodal imaging
Figure 1a: WLE showing a well demarcated ulcer with raised margins
in the duodenum Figure 1b: Distinct magenta hue at the margins on AFI
Figure 1c: Characteristic light blue crest on NBI. Inset shows irregular pit pattern at the periphery. Biopsy suggestive of neuroendocrine tumour
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targeted detection of intracellular and surface targets
expressed by the mucosa using fluorescence or confocal
endomicroscopy even prior to the development of cancer.
However, there are many challenges ahead. As with all
emerging newer technologies, the limitations include lack of
standardized classification systems and poor reproducibility.
Personal skills and experiences affect detection and diagnostic
ability. Systematic additional training may be required before
endoscopists can interpret cellular and subcellular images.
The cost effectiveness and ultimate impact on patient care
also needs to be evaluated before incorporation of these
technologies into routine clinical practice.
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How to cite this article: Banerjee R, Reddy DN. Advances in endoscopic
imaging: Advantages and limitations. J Dig Endosc 2012;3:7‑12.
Source of Support: Nil, Conict of Interest: None declared.
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