Endomicroscopy-targeted Endoscopic Mucosa Resection for Barrett's Oesophagus-associated Neoplasia
Barrett's oesophagus is a common complication in patients suffering from gastro-oesophageal
reflux disease (GERD). By means of chronic acid exposure the squamous epithelium of the
oesophagus turns into a specialised columnar epithelium (SCE) with goblet cells. This
histological change is prevalent in 1% of the normal population, and in up to 4, 9% of
patients with reflux symptoms . Although the Barrett's epithelium itself does not
necessarily cause additional symptoms, its presence has to be diagnosed accurately, since
affected patients are at increased risk of 0.5% per year of developing Barrett's associated
cancer. An important prognostic factor is made up by the grade of dysplasia within the
Barrett's mucosa. While most patients with no dysplasia or low-grade dysplasia remain
clinically inconspicuous, the annual risk of developing cancer is up to 10% in those
patients with high-grade dysplasia. If a Barrett's associated neoplastic lesion is found
during endoscopy, Barrett's associated cancer is also present at another site of Barrett's
oesophagus in up to 30% .
Consequently, they undergo periodically screening, consisting of endoscopy of the oesophagus
with 4-quadrant biopsy every 2 to 3 cm or, in case of HGIN, local ablative therapy. The time
period between controls depends on the grade of dysplasia diagnosed at upper
gastrointestinal endoscopy. If no dysplasia is present, the recommended follow-up period is
less than 5 years. In case of low grade dysplasia endoscopic controls should be performed
every year. Patients with high grade dysplasia should be examined every 3 months or prepared
for a therapeutic intervention .
Early detection of Barrett's associated neoplasms, which can be histologically classified as
adenocarcinoma, has important therapeutic implications. Cancerous infiltration of submucosal
structures is associated with a significant risk of lymph node metastases and should be
therefore treated by surgery. However, oesophagectomy has been shown to suffer from
mortality rates between 3 and 12%, apart from substantial short- and long-term morbidity.
Hence it is essential to detect early neoplastic lesions to have a broader range of
therapeutic options at disposal. Patients with high grade intraepithelial neoplasia (HGIN)
or mucosal cancer are perfect candidates for curative endoscopic interventions like
endoscopic ablation (with radiofrequency, for example), endoscopic submucosal dissection
(ESD) or endoscopic mucosal resection (EMR). The latter techniques are preferred as the
resected specimens can be evaluated histologically, which provides definite information
about the invasion depth and whether the resection borders are free from neoplastic tissue.
Because of high rates of newly occurring neoplasia, remaining areas of Barrett's mucosa
should be ablated or resected after histological confirmation of Barrett's oesophagus
associated neoplasia [3, 4].
Trying to improve the diagnostic yield in the surveillance of patients with high risk for
Barrett's oesophagus associated neoplasia, many new endoscopic inventions have been
introduced into the management of Barrett's oesophagus in order to optimize the detection
rates of early lesions. Among those are developments that improved the image quality of
conventional white light endoscopes like high-resolution and high-definition endoscopes.
Another approach, called chromoendoscopy, uses in vivo staining with methylene blue, indigo
carmine or acetic acid. These dyes help to increase the tissue contrast which leads to
improvement of detection rates comparable to high-resolution endoscopy. High contrast levels
without staining agents can be achieved by the use of narrow band imaging (NBI). This
technology additionally improves the visibility of capillaries, veins and other subtle
tissue structures by the use of light with wavelength restricted to small bands in the blue
and green spectrum. In a prospective randomized crossover study it showed equal results to
high-resolution endoscopy plus indigo carmine [4, 5].
The newest development that has been introduced in the endoscopic management of the
gastrointestinal tract is the so called confocal laser endomicroscope (CLE). Confocal
microscopy was developed by Marvin Minsky in the late 1950s. Its principle is the
microscopic scanning of focal points below the surface of an object. In comparison to
conventional light microscopy it uses a special filter system to avoid image overlapping by
surrounding tissue. In detail, a light source (normally a laser) is focused by a microscope
objective lens to a diffraction limited spot on or inside the object. Light that is
scattered, or fluorescence excited (achieved through fluorescein staining, for example) and
emitted, at the focus in the sample will partially return back through the optics along the
path from which it arrived. A beam-splitter placed into the path reflects the return light
towards a detector. The optics will focus the light from the focal point in the specimen to
its conjugate focus near the detector (hence the technology is termed "con-focal"). Here a
spatial filter ("pinhole") is used to extinguish all light deriving from areas outside the
focal point. Light reflections from the focal point itself will be forwarded to the detector
which is connected to a computer system that digitalises the optical signal and creates the
in vivo histological image .
Focussing on its clinical impact, confocal microscopy is the first technique to allow in
vivo evaluation of tissue structures beneath their surface. Because of many breakthroughs in
miniaturisation (mostly in the 1990s) this technology could be applied for intraluminal use
in gastroenterology, integrated into a otherwise standard endoscope. It allows the in vivo
histological visualisation of the upper 250 micrometers of all walls within the
gastrointestinal tract, additionally to the normal function of white light endoscopy
(provided by two separate screens on top of the workstation) .
Using CLE in a first clinical approach, Kiesslich et al. found high sensitivity and
specificity rates for the detection of Barrett's oesophagus as well as for the prediction of
Barrett's associated neoplastic changes - for both results CLE derived pictures were
compared to conventional histology . In a first prospective, randomized, double-blind,
controlled, crossover trial Dunbar et al. proved these findings, as CLE-targeted biopsies
had a higher diagnostic yield for Barrett's oesophagus associated neoplasia than standard
endoscopy with 4-quadrant random biopsy .
In our clinical investigation we want to use confocal laser endomicroscopy (CLE) to
accurately target Barrett's oesophagus associated neoplasia for subsequent endoscopic
mucosal resection (EMR). To our knowledge this combination is only documented in one case
report so far, describing the successful resection of a high-grade dysplastic
Barrett-segment by the use of CLE-targeted EMR .
We want to show that CLE is suitable to detect the exact borders of high grade
intraepithelial neoplasia. In our experience this feasibility cannot be reliably provided by
any other established technique like chromoendoscopy or narrow band imaging, which often
causes the need for re-treatment or even surgery.
To guarantee accurate documentation of mucosal CLE-mapping, the dimensions of the neoplastic
lesion will be marked in terms of colour, photographed by simultaneously available white
light endoscopy and finally evaluated by histological assessment of the specimen. Analysing
the borders of the resected specimen in concern of tumour infiltration we will be able to
calculate the en-bloc resection rate of CLE-targeted EMR.
In order to evaluate CLE concerning true negative results we will resect all remaining
mucosal areas affected by Barrett within the second phase of the examination or (if the
lesions are too big for one-time resection) within a second examination. Once again, CLE
will be applied for all lesions to search for malignancies. If CLE detects further areas of
neoplasia, CLE-mapping as mentioned above will be performed. All resected tissue parts will
be evaluated histologically to check the results of CLE.
If CLE provides reliable data in our investigation this would be a big step on the way to
establishing this new technology within the pre-interventional endoscopic management of
patients suffering from Barrett's oesophagus. This could help to increase the en-bloc
resection rate, decrease the amount of repetitive resections and consequentially improve the
Prospective clinical trial without randomisation or blinding
Patients referred to our department for endoscopic mucosal resection (EMR) of Barrett's
mucosa with high grade intraepithelial neoplasia (HGIN) that has been detected during
routine upper endoscopy or Barrett's surveillance endoscopy at our department or at another
- patients allergic to one of the drug components (including drugs used for conscious
sedation like propofol or midazolam as well as fluorescein, the fluorescent dye used
for CLE )
- patients presenting with contraindications to EMR (low platelet count, therapeutic
anticoagulation, coagulation disorders)
- refusal to participate in the study
Our investigation will be performed at the Medical University of Vienna, department of
medicine III, clinical division of gastroenterology and hepatology. Patient recruitment will
start on the 1st of July 2010. The study will last for two years. The number of patients
included within this period will be 40, based on the current number of EMR performed at our
department for Barrett's with intraepithelial neoplasia.
All patients who fulfil the listed inclusion criteria, will receive the patient information
form of this study together with the usual informed consent form of the respective
endoscopic examination they are about to undergo. Patient information will be done at least
24 hrs. before the intervention, as practised at our unit. If the patient agrees to
participate in the study he will be prepared for endoscopy with our confocal laser
endomicroscope (Pentax EC3870K with the ISC-1000 confocal endomicroscopy processor - Pentax,
Tokyo, Japan and Optiscan Pty Ltd, Notting Hill, Victoria, Australia) by administration of
intravenous propofol and/or midazolam as routinely used for conscious sedation during
endoscopic procedures at our department. Additionally, 5-10 ml of a 10% solution of
fluorescein sodium will be administered intravenously to enhance tissue fluorescence during
All drugs will be administered by medical specialists (such as the project director),
assistant doctors (such as the project assistant) or registered nurses, as routinely
practised at our institution.
Confocal laser endomicroscopy is a safe new technique that has already been studied in
clinical trials [7, 8]. Its safety is being guaranteed by the use of low intensity laser
light that can at worst cause local bleaching of fluorescein containing cells, which is
harmless, reversible and even used as diagnostic sign in experimental conditions .
Endoscopic mucosal resection is a well established technique for the minimal invasive,
non-surgical curative treatment of intramucosal neoplasia. It has been studied in many
clinical trials and is routinely performed at our unit for lesions in the oesoophagus, the
stomach, duodenum and colo-rectum. Although severe complications like prolonged bleeding or
perforations can potentially occur, the risk/benefit profile of this procedure is very good,
compared to surgical treatments of neoplastic diseases of the oesophagus .
This study protocol has been submitted to the ethic commission of the Medical University of
Vienna (EK-Nr. 697/2009) and was handled at the meeting on the 8th of September 2009. A
positive vote was already delivered to our institution in written form.
Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Accuracy of CLE-EMR
Accuracy of CLE to detect the exact borders of high grade intraepithelial neoplasia within Barrett's epithelium, confirmed by histological evaluation of resected specimens.
Andreas Puespoek, MD
Medical University of Vienna