BARRETT’S ESOPHAGUS 1052–3359/02 $15.00
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ENDOSCOPY IN BARRETT’S
ESOPHAGUS
Surveillance During Reflux Management and
New Advances in the Diagnosis and Early
Detection of Dysplasia

Jihad ElKhoury, MD,

and Anand V. Sahai, MD, MSc (Epid), FRCPC

It is now widely accepted that, in some patients, Barrett’s esophagus

precedes progressive dysplastic changes that culminate in the develop-
ment of invasive adenocarcinoma. The prognosis of esophageal cancer
is extremely poor unless detected at an early stage. Endoscopic surveil-
lance can document dysplasia and cancer clearly at points when effective
(curative) therapy is still possible. Based on this, endoscopic surveillance
protocols have been endorsed by several medical organizations. Wide
application of these guidelines undoubtedly will benefit some patients,
but numerous questions regarding the large-scale benefits of surveillance
programs for patients and society remain. Consequently, research contin-
ues to improve the ability to detect dysplasia and early cancers effi-
ciently.
This article reviews issues relevant to the value of current and
emerging techniques of endoscopic surveillance and dysplasia detection
for patients in whom a histologic diagnosis of Barrett’s esophagus has
been established. One of the most effective means of preventing compli-
cations caused by Barrett’s esophagus might be ablation of the metaplas-
tic columnar epithelium. Several methods of endoscopic ablation of
Barrett’s mucosa are currently under investigation. A discussion of these

From the Centre Hospitalier de l’Université de Montréal, Hôpital Saint Luc, Montréal, Qué-
bec

CHEST SURGERY CLINICS OF NORTH AMERICA

VOLUME 12 • NUMBER 1 • FEBRUARY 2002 47

48 ElKHOURY & SAHAI

techniques is beyond the scope of this article; however, further refine-

ments and effectiveness data will be required before these techniques
are used routinely.

SURVEILLANCE DURING REFLUX MANAGEMENT

Barrett’s esophagus is an acquired condition that usually occurs in

patients who have chronic gastroesophageal reflux disease. The diagno-
sis of Barrett’s esophagus requires histologic documentation of intestinal
metaplasia in the tubular esophagus. The metaplastic epithelium that is
considered preneoplastic is characterized by the presence of goblet cells
that stain positive with hematoxylin-eosin-alcian blue. Whether the find-
ing of this type of metaplasia in the gastric cardia (carditis) also increases
the risk for adenocarcinoma is unclear. Endoscopic surveillance for pa-
tients who have this entity currently is not recommended,46 and further
discussion of this issue is beyond the scope of this article. The risk
for adenocarcinoma clearly is increased in patients who have Barrett’s
metaplasia, but estimates of the true incidence of malignant transforma-
tion range widely from 0.2% to 2.1% (corresponding to a likelihood of
30–125 times that of the general population).9, 12, 35 The risk for adenocar-
cinoma exists regardless of the extent of Barrett’s esophagus; however,
some factors for increased risk currently are recognized, including
greater length of Barrett’s epithelium, male sex, smoking, postgastrec-
tomy Barrett’s esophagus, Barrett’s ulcer, peptic stricture, and ethnicity
(rare in nonwhites).19, 22, 30
Strong evidence exists that the development of cancer follows a
sequential evolution from Barrett’s metaplasia, to low-grade dysplasia,
to high-grade dysplasia, to invasive cancer.30 Most patients, however,
who have Barrett’s esophagus will not develop dysplasia during their
lifetime, and studies suggest that only 19% to 26% of patients who
have high-grade dysplasia will evolve into adenocarcinoma.13 Dysplastic
changes also may regress completely.36 Prospective studies suggest that
progression of low-grade to high-grade dysplasia takes 18 to 48 years
and that the progression of high-grade dysplasia to cancer requires 5 to
21 months (mean 14 months).42 This time period may be short for
younger patients, but for older patients who have a shorter life expec-
tancy, this may be long enough to prevent the disease from having any
meaningful effect on the patient’s life span or quality-adjusted survival.
Only 2.5% of older patients who have Barrett’s esophagus die from
esophageal cancer, because these patients often have associated cardio-
pulmonary disease, which is the most common cause of death in these
patients.54
The rationale for endoscopic surveillance programs is based on data
suggesting that, although the prognosis for esophageal carcinoma is
generally dismal, surveillance allows detection of cancer or precancerous
lesions at a curable stage. Surveillance has been shown to allow detection
of early-stage disease in several studies,26, 43, 44 and in one retrospective
 ENDOSCOPY IN BARRETT’S ESOPHAGUS 49

comparative study, the 5-year survival rate for esophageal adenocarcino-

mas discovered through surveillance was higher than that of those
presenting with symptoms (62% versus 20%).56 Note, however, that even
the most rigorous of biopsy protocols have missed as much as 33% of
cancers found in patients eventually undergoing esophagectomy for
high-grade dysplasia34 and, in one cohort study, only 20% of all the
esophageal cancers diagnosed were identified by surveillance endosco-
pies.28
Current guidelines recommend endoscopic surveillance for patients
who have histologically proven Barrett’s esophagus if there is a potential
to prolong life expectancy and if they are eligible for therapy of an
early cancer.46 Because of ongoing developments in minimally invasive
techniques for cancer removal, this implies that patients need not neces-
sarily be surgical candidates. The American Society for Gastrointestinal
Endoscopy (ASGE) recommends that during surveillance endoscopies,
any macroscopic abnormalities should be biopsied and that, in benign-
appearing Barrett’s epithelium, four-quadrant biopsies should be taken
at 2-cm intervals beginning 1 cm below the esophagogastric junction
and extending 1 cm above the squamocolumnar junction.3 The use of
jumbo biopsy forceps has been suggested as a means to increase the
yield of endoscopic biopsies for cancer and currently is recommended
by the ASGE, but the only formal comparison of jumbo versus regular
biopsy forceps showed no difference in their ability to detect unsus-
pected cancers in patients enrolled in a Barrett’s esophagus surveillance
protocol (33% versus 38%; p  NS).17
Surveillance intervals depend on the degree of any dysplastic
changes that are found. In patients who have no dysplasia after system-
atic biopsies on two endoscopies, the surveillance interval can be ex-
tended to every 2 to 3 years. If persistent low-grade dysplasia is found,
endoscopy twice yearly (at 6-month intervals) and then yearly is recom-
mended. If high-grade dysplasia is found and confirmed by an expert
pathologist, then two possible options are recommended: esophagec-
tomy or surveillance endoscopy every 3 months.3, 46
Studies of physicians’ practice patterns suggest that they generally
accept the need for and carry out surveillance of Barrett’s esophagus,
but that recommended biopsy protocols frequently are not followed, and
that there is considerable disagreement as to how the surveillance should
be performed (e.g., surveillance intervals, number of biopsies, and so
forth).16, 20, 49, 55 There are many reasons for these discrepancies, but the
most important may be that recommended protocols may be too labor
intensive in the face of inadequate data on effectiveness and cost effec-
tiveness. Note also that simply getting pathologists to agree on the
existence or absence of dysplasia in a given patient may be difficult
because interobserver agreement for the presence of low- and high-grade
dysplasia may be extremely poor, with ␬ statistics as low as 0 to 0.28.48
Formal cost analyses are fraught with methodologic limitations that
may reduce their external validity. Nonetheless, the data published to
date suggest that the costs of Barrett’s esophagus surveillance are in
50 ElKHOURY & SAHAI

line with those of other medical interventions such as screening for

tuberculosis, heart transplantation, and outpatient management of insu-
lin-requiring diabetes.10, 41, 50 Most current guidelines recommend surveil-
lance intervals of no more than 2 to 3 years, and one computer-simulated
cohort study suggests that this interval optimizes quality-adjusted sur-
vival.50 When cost is the primary concern, however, cost-utility analysis
suggests that, in an American health-care setting, endoscopies performed
more than every 5 years increase cost and actually lower life expec-
tancy.41 Another potentially important variable affecting the cost of endo-
scopic surveillance protocols is the existence of transient positive diagno-
ses of dysplasia (i.e., cases in which dysplasia is found on one endoscopy
but is absent on follow-up procedures). One study showed that this
entity could account for 28% to 61% of endoscopies in surveillance
protocols, and the authors suggested that rapidly reducing the frequency
of surveillance endoscopies once dysplasia is no longer found in these
patients theoretically would reduce costs without reducing effective-
ness.36
In summary, endoscopic surveillance of Barrett’s esophagus may
produce positive outcomes and is recommended, but further studies are
needed to determine the optimal surveillance strategy—particularly the
best time intervals for surveillance endoscopies. A true consensus may
be difficult to obtain, however, since the optimal strategy may differ
greatly, depending on the desired outcomes (i.e., improvement in qual-
ity-adjusted survival versus cost). Randomized trials in which different
surveillance frequencies were compared and costs and quality of life as
outcomes were used could be useful in this regard.

NEW ADVANCES IN THE DIAGNOSIS AND EARLY

DETECTION OF DYSPLASIA

The main goal of surveillance endoscopy for patients who have

Barrett’s esophagus is to detect the presence of dysplastic changes before
they develop into cancer. These changes may be limited to an extremely
small proportion of the metaplastic epithelium (high-grade dysplasia
and early cancer have been shown to account for an average of less than
4% of the total surface of Barrett’s epithelium5). It is also well known
that dysplasia and cancer also often arise in normal-appearing Barrett’s
mucosa.57 Therefore, there is considerable interest in techniques that help
identify sites that are more likely to harbor dysplasia or early cancer or
that facilitate histologic assessment of larger areas of Barrett’s epithe-
lium. These techniques include the development of biopsy forceps de-
signed to make obtaining multiple biopsies easier and faster and the use
of brush and balloon cytology. To reduce the number of biopsy speci-
mens required, however, several other techniques have been developed.
The oldest techniques involve the application of special stains to high-
light abnormal areas (with or without high-magnification endoscopy).
Newer endoscopic methods include endoscopic ultrasonography, laser-
induced fluorescence endoscopy, light-scattering spectroscopy, and opti-
 ENDOSCOPY IN BARRETT’S ESOPHAGUS 51

cal coherence tomography. Another area of considerable interest is the

use of tumor markers in biopsy specimens as predictors of progression
to more severe stages of dysplasia and cancer. A discussion of these
techniques, however, is beyond the scope of this article, and the reader
is referred to excellent reviews on the subject.45, 62

TECHNIQUES AIMED AT SAMPLING LARGER AREAS

OF BARRETT’S MUCOSA

Obtaining four-quadrant biopsies at 2-cm intervals and sampling of

all isolated islands of metaplastic epithelium and irregular or raised
lesions may be harder than it sounds—particularly in patients who have
long segments of Barrett’s esophagus. The time required is long in the
context of busy endoscopy schedules and the high prevalence of Barrett’s
esophagus in the general population. The longer endoscopy times also
may be difficult for patients to tolerate without sedation. Biopsy forceps
with an associated suction channel have been developed to allow the
endoscopist to take multiple biopsies without having to remove the
biopsy forceps after each biopsy. Preliminary testing in animals suggests
that the technique is feasible,33 but there are no published results in
humans. Brush and balloon cytology have been used in an effort to
obviate biopsy forceps (and even endoscopy) altogether. Brush cytology
during endoscopy has been shown to have a sensitivity of 89% to 100%
for detecting cancer.15, 21 The sensitivity for dysplasia, however, was
shown to be no better than endoscopic biopsy in one study61 and as low
as 22% in another.15 Combining brush cytology and endoscopic biopsy
also seems to increase costs without increasing the yield for dysplasia
and cancer.2 Compared with brush cytology, balloon cytology (which
does not require endoscopy) showed a sensitivity of 80% for high-grade
dysplasia and cancer, but adequate specimens were obtainable in only
83% of patients (compared with 92% with endoscopy and brush cytol-
ogy).15 Given the reduced cost of balloon cytology compared with tradi-
tional sampling methods (6 times less than that of endoscopy with
biopsy) and the relative ease of brush cytology compared with endo-
scopic biopsy, the potential value of these techniques should be studied
further.

TECHNIQUES AIMED AT IDENTIFYING DYSPLASIA

AND CANCER BY TARGETING ENDOSCOPIC
BIOPSIES BETTER

Chromoendoscopy

This technique involves the application of stains to the esophageal

mucosa during endoscopy to highlight normal or abnormal areas. Four
vital stains have been used in patients who have Barrett’s esophagus:
52 ElKHOURY & SAHAI

Lugol’s iodine solution, indigo carmine, toluidine blue, and methylene

blue. Lugol’s solution selectively stains squamous epithelium, thus mak-
ing Barrett’s mucosa (particularly isolated islands) more visible. Indigo
carmine, combined with high-magnification endoscopy, permits better
delineation of abnormal surface patterns. Toluidine blue and methylene
blue are selective stains that are taken up by intestinal type epithelium.
Few or no published data exist on the use of the first three stains for
identifying dysplasia or cancer in Barrett’s esophagus. Thus far, the best-
studied agent for chromoendoscopy in Barrett’s esophagus is clearly
methylene blue.
Adequate staining with methylene blue requires a three-step proc-
ess. A mucolytic agent first is applied to remove surface mucus; the
stain then is applied; and finally, the mucosa must be washed to remove
the excess dye. Cells in areas of intestinal metaplasia and dysplasia take
up the dye selectively, but dysplastic areas may stain less intensely.18
Methylene blue staining has been shown to identify intestinal metaplasia
with a sensitivity of as much as 98%24 and an overall accuracy of as
much as 95%.6 In the latter study, the risk for dysplasia was 17.7 times
higher in stained compared with unstained areas.6 The dye also may
identify unsuspected zones of intestinal metaplasia in as much as 73%
of patients who have no endoscopically visible Barrett’s mucosa.24 In the
only study comparing methylene blue–directed biopsies with a standard
four-quadrant biopsy surveillance protocol, methylene blue–directed bi-
opsies identified dysplasia or cancer significantly more often (44% versus
28%, P0.03) and required fewer biopsies.7 Although these results are
encouraging, others have reported that the process increases patient
discomfort, increases the time of endoscopy by almost 50%, and is only
57% sensitive and 32% specific for diagnosing intestinal metaplasia.8
Also, areas suspicious for dysplasia or cancer have been shown to be
endoscopically apparent 75% of the time before the dye is applied.24
Given these conflicting data, more data confirming the usefulness of
methylene blue staining are required before it can be recommended as
standard practice.

Endoscopic Ultrasonography

Endosonography is clearly the most accurate means of locally stag-

ing established esophageal cancer. It permits high-resolution imaging of
the esophageal wall layers and surrounding structures. Using high-
frequency (20–30 MHz) catheter probes that can be introduced through
the operating channel of a standard endoscope, the esophageal wall can
be imaged to nine distinct layers that include the mucosa, the submucosa
(including the muscularis mucosae), and the individual layers of the
muscularis propria (inner circular and outer longitudinal). Accurate
imaging, however, may be technically difficult because acoustic coupling
must be obtained with a water interface. This interface probably is best
achieved with a water-filled condom fixed to the end of the endoscope.
The pressure applied to the mucosal surface by the water-filled condom
 ENDOSCOPY IN BARRETT’S ESOPHAGUS 53

may cause architectural distortion by compressing the esophageal wall,

however. Another technical problem is that, if suspicious sites are identi-
fied, accurately targeting them for biopsy may be difficult because the
catheter or condom assembly must be removed before actual biopsies
can be taken.
Despite the impressive resolution offered by high-frequency cathe-
ters, the ability to identify dysplasia and early cancers has been disap-
pointing at best. Barrett’s esophagus seems associated with mucosal
thickening by endosonography,51 but the technique has not been found
useful to differentiate dysplastic from nondysplastic epithelium.1,14,18
Nevertheless, areas of focal thickening that sometimes are seen may
represent early cancers.51
At this time, endosonography cannot be recommended as a tool to
screen for dysplasia. In patients who have high-grade dysplasia, how-
ever, it may help identify and stage suspicious masses that, if proved by
biopsy to be cancers, could help clarify the indication for surgery.

Laser-Induced Fluorescence Endoscopy

This technique uses a catheter to apply light at specific wavelengths
to distinguish normal from abnormal areas by differences in tissue
autofluorescence (produced by endogenous fluorophores) or exoge-
nously induced tissue fluorescence (produced by the intravenous admin-
istration of porphyrins). In the case of Barrett’s esophagus, intravenously
administered 5-aminolevulinic acid has been shown to concentrate in
the form of protoporphyrin IX in areas of dysplasia and to produce a
characteristic red fluorescence when illuminated with blue light. With
specially designed adapters, the required light sources can be fixed to
conventional endoscopes so that real-time fluorescence-guided biopsies
can be taken.11, 32
Several reports have documented the accuracy of laser-induced
fluorescence for distinguishing benign from dysplastic and cancerous
tissue in patients who have Barrett’s esophagus.4, 11, 31, 32, 37, 58, 59 The degree
of fluorescence seems to correlate with the severity of dysplastic changes
and is highest with cancers.59 The sensitivity for dysplasia has been
reported to be as much as 100% in two series,11, 29 but in other series, it
has ranged from 60% to 90%.4, 38 Specificity also has been generally
greater than 95% in the same series. Laser-induced fluorescence is there-
fore promising, but randomized trials comparing it with conventional
endoscopic biopsy remain to be published.

TECHNIQUES DESIGNED TO PROVIDE HISTOLOGIC

INFORMATION WITHOUT TISSUE REMOVAL BY
ENDOSCOPIC BIOPSY
Light-Scattering Spectroscopy
This technique uses spectral analysis of reflected white light to
distinguish between benign and dysplastic tissues (which reflect light
54 ElKHOURY & SAHAI

differently owing to differences in the size distribution of cellular nuclei).

An optical fiber probe is inserted through the operating channel of a
regular endoscope. The probe allows white light to be delivered and
reflected light to be collected. Areas of approximately 1 mm can be
sampled with each 50-millisecond optical pulse. To the best of the
authors’ knowledge, the only study published to date showed a sensitiv-
ity and specificity of 90% for diagnosing low- and high-grade dysplasia.60

Optical Coherence Tomography

This technique is somewhat similar to ultrasonography but uses

light instead of sound waves to generate two-dimensional cross-sectional
images of the esophageal wall layer ultrastructure with a 360-scanning
catheter probe. Because, however, resolution is inversely proportional to
wavelength and because the wavelength of light is considerably shorter
than that of sound, the resolution offered can be measured in terms of
micrometers instead of millimeters. The images produced resemble those
of histologic biopsy specimens and therefore have been referred to as
optical biopsies.
Published data on applications of this technique throughout the
gastrointestinal tract are accumulating rapidly.25, 27, 39, 40, 47, 52, 53 With re-
gards to Barrett’s esophagus, the sensitivity and specificity for identi-
fying intestinal metaplasia were 97% and 92%, respectively in one
study.40 It also has been shown to distinguish between Barrett’s epithe-
lium and cancer in one small series of 24 patients.23 There are currently,
however, no published series documenting its ability to diagnose low-
and high-grade dysplasia.
Although many of these techniques are interesting, the practical
issues of screening the enormous number of patients who have Barrett’s
esophagus cannot be ignored. Even if some of these techniques prove of
high efficacy (i.e., accurate in expert hands), their effectiveness (i.e.,
accuracy and practicality in the context of everyday use) and efficiency
(i.e., their ability to provide useful information at an acceptable cost and
with adequate availability to the general population) are not guaranteed.
As stated above, there are data suggesting that physicians have difficulty
following recommended surveillance guidelines using standard endo-
scopic biopsies. It is therefore probably reasonable to assume that, if
newer techniques do not simplify the surveillance process in a meaning-
ful way and at a reasonable cost, they are unlikely to come into wide-
spread use.

SUMMARY

Given the alarming rise in the incidence of esophageal cancer and

the fact that Barrett’s esophagus is clearly a precursor to this disease,
effective surveillance is desirable. Endoscopic surveillance is recom-
 ENDOSCOPY IN BARRETT’S ESOPHAGUS 55

mended by major endoscopic and gastrointestinal societies based on the

available data and hypothetic models suggest that the costs of endo-
scopic surveillance for Barrett’s esophagus may be reasonable when
compared with other commonly applied cancer screening strategies.
Although, however, most implicated physicians agree that surveillance
is warranted, recommended guidelines often are not followed. This
occurrence may reflect the importance of some of the practical limitations
inherent to carrying out intensive endoscopic biopsy protocols in large
numbers of eligible patients. In an effort to improve the surveillance
process, several new techniques have been tested and are in develop-
ment. These techniques are aimed at facilitating the histologic sampling
of larger areas of metaplastic epithelium, at better targeting sites more
likely to harbor dysplasia and cancer, and at replacing endoscopic biops-
ies with nonhistologic tissue analysis. Although many of these newer
techniques are promising, however, none are currently close to wide-
spread clinical application. The current standard for surveillance remains
the use of systematic endoscopic biopsies, with the frequency of surveil-
lance endoscopies determined by the severity of any dysplastic changes
that are found. Given the large number of patients that are likely to be
eligible for screening and the current constraints in terms of physician
availability and health-care resources, endoscopic biopsy will remain the
cornerstone of Barrett’s esophagus surveillance strategies unless newer
alternatives are clearly advantageous in terms of accuracy, cost, availabil-
ity, and ease of application. In the future, however, advances in tech-
niques for minimally invasive ablation of Barrett’s epithelium may make
endoscopic surveillance obsolete altogether.

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Address reprint requests to:

Anand V Sahai MD, MSc (Epid), FRCPC
Professeur Adjoint de Recherche
Département de Gastroentérologie
CHUM, Hôpital St Luc
1058 Rue Saint Denis
Montréal, Québec H2X 3J4

email: anand.sahai@sympatico.ca