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The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
Clinical Practice
This Journal feature begins with a case vignette highlighting
a common clinical problem. Evidence supporting various
strategies is then presented, followed by a review of formal
guidelines, when they exist. The article ends with the author’s
clinical recommendations.
B ARRETT ’ S E SOPHAGUS
STUART JON SPECHLER, M.D.
A 55-year-old obese white man has had frequent heartburn for more than 10 years. He has
treated himself with a histamine H2-receptor antagonist, which provides only partial relief. He
decided to consult a physician after reading a
magazine article warning that heartburn causes
cancer of the esophagus. The patient has no other medical problems, dysphagia, or recent, unexplained weight loss, and the findings on physical
examination are unremarkable. An endoscopy
reveals columnar epithelium lining the distal
5 cm of the esophagus. Esophageal-biopsy specimens show specialized intestinal metaplasia
with inflammation and “possible dysplasia.” How
should this patient’s condition be managed?
THE CLINICAL PROBLEM
Barrett’s esophagus is the condition in which columnar epithelium replaces the squamous epithelium
that normally lines the distal esophagus (Fig. 1). The
condition develops when gastroesophageal reflux disease damages the squamous esophageal mucosa and
the injury heals through a metaplastic process in which
columnar cells replace squamous ones. The abnormal columnar epithelium that characterizes Barrett’s
esophagus is an incomplete form of intestinal metaplasia (called specialized intestinal metaplasia) that predisposes patients to adenocarcinoma. Esophageal adenocarcinoma develops in approximately 0.5 percent
of patients with Barrett’s esophagus per year.1 This is
a tumor found predominantly in white men, among
whom the frequency of esophageal adenocarcinoma
has inexplicably quadrupled over the past few decades.2 Although gastroesophageal reflux disease is the
main recognized risk factor for this cancer,3 presumFrom the Dallas Department of Veterans Affairs Medical Center and the
University of Texas Southwestern Medical Center at Dallas, Dallas. Address
reprint requests to Dr. Spechler at the Division of Gastroenterology (111B1),
Dallas VA Medical Center, 4500 S. Lancaster Rd., Dallas, TX 75216.
Figure 1. Endoscopic Photograph Showing Traditional, or LongSegment, Barrett’s Esophagus.
Reddish, columnar epithelium extends more than 3 cm above
the gastroesophageal junction.
ably because it causes Barrett’s esophagus, it is not
clear whether the rising incidence of the tumor is due
to an increasing frequency of gastroesophageal reflux
disease in the general population.
The diagnosis of Barrett’s esophagus is based on the
endoscopic findings of columnar epithelium lining the
distal esophagus and confirmed by the presence of
specialized intestinal metaplasia in esophageal-biopsy
specimens. To document the finding of columnar epithelium in the distal esophagus, the endoscopist must
identify both the squamocolumnar and gastroesophageal junctions (Fig. 2).4 The juxtaposition of pale
squamous epithelium and reddish columnar epithelium forms a visible line called the Z line, or the squamocolumnar junction. The gastroesophageal junction,
the point at which the esophagus ends and the stomach begins, is the most proximal part of the gastric
folds. Often, the Z line and the gastroesophageal junction coincide (Fig. 2A). When the Z line is located
above the gastroesophageal junction (Fig. 2B), there
is a columnar lined segment of esophagus.
For decades, Barrett’s esophagus was identified predominantly in patients with severe gastroesophageal
reflux disease on the basis of the finding of long seg-
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C LINICA L PR AC TICE
Normal esophagus
Barrett’s esophagus
Squamocolumnar
junction
Squamocolumnar
junction
Columnar-epithelium–
lined esophagus
Gastroesophageal
junction
Gastroesophageal
junction
A
B
Figure 2. The Use of Endoscopic Landmarks to Distinguish Normal Esophagus (Panel A) from Barrett’s Esophagus (Panel B).
The squamocolumnar junction, or Z line, is the visible line formed by the juxtaposition of squamous and columnar epithelia. The
gastroesophageal junction is the imaginary line at which the esophagus ends and the stomach begins. The gastroesophageal junction is identified endoscopically as the most proximal part of the gastric folds. In normal esophagus, the squamocolumnar junction
and gastroesophageal junction often coincide, and there is no columnar epithelium between the two (Panel A). The inset in Panel A
shows normal stratified squamous epithelium. In Barrett’s esophagus, the squamocolumnar junction is proximal to the gastroesophageal junction (Panel B). The area between the two junctions consists of columnar epithelium with specialized intestinal metaplasia (inset in Panel B). Modified from Spechler4 with the permission of the publisher. (Inset in Panel A, hematoxylin and eosin,
¬80; inset in Panel B, hematoxylin and eosin, ¬100.) Photomicrographs provided by Dr. Edward Lee.
ments of columnar epithelium extending more than
3 cm above the gastroesophageal junction. In 1994,
specialized intestinal metaplasia was reported in biopsy specimens from short segments of esophageal
columnar epithelium, even in patients with no evidence of gastroesophageal reflux disease.5 Since then,
Barrett’s esophagus has been categorized according
to the extent of the metaplastic lining.6 Patients who
have segments of specialized intestinal metaplasia in
the esophagus measuring 3 cm or more have traditional, or long-segment, Barrett’s esophagus, whereas those with shorter segments have short-segment
disease. It is not clear whether these two types have
the same pathogenesis and natural history, or whether short-segment disease progresses to long-segment
disease. Although logic and indirect evidence suggest
that the risk of cancer should vary with the extent of
esophageal metaplasia, this contention has not been
proved.7 Currently, short-segment and long-segment
Barrett’s esophagus are managed similarly.
STRATEGIES AND EVIDENCE
Screening and Surveillance for Barrett’s Esophagus
A proposed strategy to decrease the risk of death
from esophageal cancer is to use endoscopy to screen
patients with chronic gastroesophageal reflux disease
for Barrett’s esophagus.8 Endoscopy shows that 3 to
5 percent of such patients have long-segment disease9
and 10 to 15 percent have short-segment disease.10
It has been suggested that screening should focus on
patients with gastroesophageal reflux disease who have
risk factors for Barrett’s esophagus, such as male sex,
white race, an age of more than 50 years, and a long
history of symptoms (more than five years).9 However, such an approach will have a limited impact on
the rates of death from cancer, because up to 40 percent of patients with esophageal adenocarcinoma have
no history of gastroesophageal reflux disease.3 There
is little evidence that present screening practices have
prevented deaths from esophageal adenocarcinoma.
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The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
A recent systematic review of studies of esophageal
resections for adenocarcinoma found that less than
5 percent of patients were known to have had Barrett’s
esophagus before they sought medical attention for
symptoms of cancer.11
Patients with Barrett’s esophagus should undergo
regular endoscopic surveillance for curable neoplasia
to decrease the risk of death from esophageal cancer.8
Available studies suggest that Barrett’s esophagus does
not affect longevity. Proponents of surveillance argue
that those studies included predominantly older patients, many of whom died of unrelated diseases; thus,
the results may not be applicable to younger patients
with Barrett’s esophagus.12
Small, retrospective studies have shown that endoscopic surveillance can detect curable neoplasms in patients with Barrett’s esophagus and that the cancers
identified are less advanced than those identified in
patients with symptoms of cancer, such as dysphagia
and unexplained weight loss.13,14 These results do not
prove that surveillance is beneficial, however. Early
esophageal cancers can remain asymptomatic for
years,15 and invasive therapies such as esophagectomy
are associated with substantial rates of morbidity and
mortality. In one series of 143 patients with Barrett’s
esophagus who were followed for a mean of 4.4 years,
for example, surveillance identified only 1 patient with
asymptomatic esophageal cancer, and this patient died
as a result of the ensuing esophageal surgery.16
A report from the United Kingdom estimated that
the cost of detecting one case of esophageal cancer
with the use of endoscopic surveillance was approximately $23,000 among male patients with Barrett’s
esophagus and $65,000 among female patients.17 A
U.S. study estimated that the cost was approximately
$38,000, which was lower than the cost of surveillance
mammography ($55,000 for each breast cancer detected).18 Both studies, however, used a considerably
higher incidence of cancer to calculate surveillance
costs than the current estimate of 0.5 percent per year.
A statistical-probability model has also been used to
evaluate surveillance strategies in a simulated cohort of
10,000 middle-aged patients with Barrett’s esophagus.19 Assuming an annual incidence rate of esophageal cancer of 0.4 percent, this analysis suggested that
endoscopic surveillance every five years was the preferred strategy, costing $98,000 per quality-adjusted
year of life gained. Using a different decision model,
another group estimated the incremental cost effectiveness of endoscopic surveillance performed every
other year at approximately $17,000 per year of life
saved 20; with another model, the estimated cost of
one-time endoscopic screening for 60-year-old patients with gastroesophageal reflux disease was approximately $25,000 per year of life gained.21 However,
it is important to appreciate the limitations of these
computer models, which incorporate multiple layers
of soft data and questionable assumptions.
Treatment of Gastroesophageal Reflux Disease
in Barrett’s Esophagus
The goals of antireflux therapy are to eliminate the
symptoms and signs of gastroesophageal reflux disease
and to prevent its complications. Usually this approach involves suppressing the secretion of gastric
acid through the administration of H2-receptor antagonists or proton-pump inhibitors.22 Antireflux surgery
attempts to create a barrier to gastroesophageal reflux
through fundoplication.23 Medical and surgical therapies are highly effective for improving or eliminating
the symptoms and signs of gastroesophageal reflux disease, but no antireflux therapy has been proved to decrease the risk of esophageal adenocarcinoma.
The efficacy of antisecretory therapy for gastroesophageal reflux disease is directly related to the degree of acid suppression achieved and inversely related
to the severity of the underlying reflux esophagitis.24
Long-segment Barrett’s esophagus is often associated with severe esophagitis, and proton-pump inhibitors are frequently prescribed as first-line treatment.25
Patients with short-segment disease often have only
mild esophagitis,4 and in these patients, H2-receptor
antagonists might be sufficient. For patients with Barrett’s esophagus whose symptoms resolve with conventional antisecretory therapy, monitoring of esophageal pH frequently reveals continued acid reflux.26
In fact, 80 percent of patients who are treated with
a proton-pump inhibitor twice daily have nocturnal
episodes of gastric acid breakthrough, during which
stomach pH falls below 4 for more than one hour.27
In some patients, almost complete achlorhydria can be
achieved through treatment with high doses of proton-pump inhibitors or the addition, at bedtime, of
an H2-receptor antagonist to a twice-daily regimen
of proton-pump inhibitors.28 However, the advisability of such aggressive antireflux therapy for all patients
with Barrett’s esophagus remains highly controversial.
Advocates of an aggressive approach contend that acid
reflux is the main factor contributing to carcinogenesis and that its elimination should prevent cancer.
Some studies have provided support for these hypotheses. Esophageal-biopsy specimens of specialized
intestinal metaplasia maintained in organ culture exhibit hyperproliferation when exposed briefly to acid.29,30 Brief exposure to esophageal acid has also been
shown to activate the mitogen-activated protein kinase
pathways that can increase proliferation and decrease
apoptosis in Barrett’s esophagus.31 The expression of
proliferating-cell nuclear antigen (a marker of proliferation) was reduced in esophageal-biopsy specimens
from patients in whom esophageal acid had been normalized by treatment with a proton-pump inhibitor,
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whereas the expression of the antigen was unchanged
in specimens from patients who had persistently abnormal acid reflux despite therapy with proton-pump
inhibitors.32 Another study found no significant
change in the proliferative activity of Barrett’s esophagus in patients treated with a proton-pump inhibitor
for two years, whereas the activity increased significantly in patients who received an H2-receptor antagonist, a less potent suppressor of acid secretion.33
Finally, therapy with proton-pump inhibitors has been
shown to cause partial regression of specialized intestinal metaplasia.34 These studies all suggest that aggressive acid control may be beneficial. However, the
short-term effects of acid on tissues in organ culture
may not parallel the long-term effects of acid reflux on
Barrett’s esophagus, and the effects of these agents on
markers of proliferation may not translate into a decrease in the risk of cancer. Furthermore, areas of apparent regression may have underlying intestinal metaplasia and worrisome proliferative abnormalities.35,36
Some have proposed that fundoplication may be
more effective than antisecretory therapy for preventing death from cancer in patients with Barrett’s
esophagus.37 Two recent studies provide little support
for that contention, however.38,39 In one, a randomized trial of medical and surgical therapies in 247 patients with complicated gastroesophageal reflux disease,38 esophageal adenocarcinoma developed in 4 of
the 165 patients in the medical group (2.4 percent)
and 1 of the 82 in the surgical group (1.2 percent)
during 10 to 13 years of follow-up; this difference was
not statistically significant. Furthermore, the surgical
group had an unexplained but significant decrease in
survival as a result of a higher than expected number
of deaths from heart disease. In the second trial, a
large Swedish, population-based cohort study in which
patients with gastroesophageal reflux disease were followed for up to 32 years, the relative risk of esophageal adenocarcinoma (as compared with that in the
general population) among 35,274 men who received
medical antireflux therapy was 6.3 (95 percent confidence interval, 4.5 to 8.7), whereas the relative risk
among 6406 men treated with fundoplication was
14.1 (95 percent confidence interval, 8.0 to 22.8).39
Dysplasia in Barrett’s Esophagus
Dysplasia is a histologic diagnosis suggesting that
one or more clones of epithelial cells have acquired genetic alterations rendering them neoplastic and prone
to malignancy. Endoscopic surveillance is performed
primarily to identify dysplasia, but it is an imperfect
predictor of malignancy. The histologic abnormalities
of low-grade dysplasia are not specific for neoplasia
because similar changes can occur in normal tissue in
response to injury. Among experienced pathologists,
the extent of interobserver agreement for the diagno-
sis of low-grade dysplasia in Barrett’s esophagus may
be less than 50 percent.40-42 In the case of high-grade
dysplasia, in contrast, the extent of interobserver agreement is approximately 85 percent. Since dysplasia has
no distinctive gross features, endoscopists collect random samples of esophageal tissue for biopsy; thus,
sampling error is a major problem.43 By the time biopsy specimens show high-grade dysplasia in patients
with Barrett’s esophagus, approximately one third of
patients already have an invasive cancer. Extensive
sampling can reduce this problem44 but cannot eliminate it.
Researchers have assessed the value of other markers
of the risk of cancer (e.g., the expression of p53 and
flow-cytometric results) and endoscopic techniques for
recognizing early neoplasia in patients with Barrett’s
esophagus (e.g., staining the mucosa with vital dyes
and endoscopic ultrasonography). Currently, there are
insufficient data to justify the routine use of any of
these approaches in clinical practice. Despite its shortcomings, endoscopy with random sampling for dysplasia remains the clinical standard for managing Barrett’s
esophagus.
Natural History of High-Grade Dysplasia
The natural history of dysplasia in Barrett’s esophagus is not well defined. In a recent study of 76 patients with high-grade dysplasia who had no evidence
of cancer on an extensive initial evaluation, the fiveyear cumulative incidence of esophageal cancer was
59 percent.45 In another study of 100 such patients,
esophageal adenocarcinoma was found in 32 percent
during eight years of follow-up.46 A lower rate of
esophageal cancer — 16 percent, over a period of 7.3
years — was reported in one study,47 but this study
lacked external confirmation of the diagnosis of highgrade dysplasia.
Some experts have recommended intensive endoscopic surveillance (i.e., every three to six months) for
patients with high-grade dysplasia, with invasive therapies withheld until biopsy specimens show unequivocal adenocarcinoma.44,47 Relatively few published reports support the safety of this practice, however, and
there is concern that the tumors might be incurable
by the time surveillance reveals cancer. In one study
of 12 patients in whom adenocarcinoma developed
during surveillance for high-grade dysplasia, the cancers were deemed potentially curable at the time of detection in all 11 patients who were compliant with the
surveillance program.47 In other small series, 1 of 32
patients43 and 1 of 4 patients48 had incurable disease
when the cancer was first detected by surveillance endoscopy.
Low-grade dysplasia cannot be diagnosed reliably
in patients with Barrett’s esophagus,40-42 and there are
few meaningful data on its natural history. Rates of
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progression to high-grade dysplasia or adenocarcinoma
within five years range from 10 to 28 percent.41,44,49
Consensus among pathologists regarding the diagnosis of dysplasia was identified as a risk factor for neoplastic progression.41
Fit patients with Barrett’s esophagus who have verified high-grade dysplasia must choose among three
proposed management options: esophagectomy, endoscopic ablative therapy, and intensive surveillance.
Esophagectomy, the only therapy that can clearly prevent the progression from dysplasia to invasive cancer,
is associated with an operative mortality rate of 3 to
12 percent and with a rate of serious operative complications of 30 to 50 percent.50 Endoscopic ablative
therapies use thermal or photochemical energy to
destroy the metaplastic esophageal epithelium.51 Although endoscopic examination performed a mean of
19 months after photodynamic therapy for dysplasia
revealed no evidence of dysplastic epithelium in the
majority of patients in one study, minor side effects
were frequent, and esophageal strictures developed
in approximately one third of the patients.52 Ablative
therapies are expensive, and they may not eradicate
all of the tissue with a neoplastic predisposition. No
study has shown that these treatments decrease the
long-term risk of cancer, and thus, endoscopic ablative therapies should be considered experimental.
Helicobacter pylori and Barrett’s Esophagus
Helicobacter pylori infection causes a chronic gastritis that is associated with the development of intestinal metaplasia and cancer.53 H. pylori does not infect
the esophagus, however, and its presence is not associated with an increased risk of Barrett’s esophagus
or esophageal adenocarcinoma. In fact, some data suggest that gastric H. pylori infection may protect the
esophagus from the effects of acid reflux, perhaps by
decreasing gastric acidity.53 Currently, routine screening for or treatment of H. pylori infection is not recommended in patients with gastroesophageal reflux
disease and Barrett’s esophagus.
AREAS OF UNCERTAINTY
No study has established that endoscopic screening
and surveillance programs for Barrett’s esophagus decrease the rates of death from cancer, and decisions regarding the optimal interval for surveillance are based
on conjecture and questionable models. Treatment of
gastroesophageal reflux disease has not been proved
to affect the risk of adenocarcinoma among patients
with Barrett’s esophagus. Consequently, it is not clear
whether to prescribe only the minimal amount of
medication necessary to control the symptoms of
esophageal reflux or to prescribe aggressive antireflux
therapy in order to abolish acid reflux. Although dysplasia is an imperfect biomarker for malignant con-
ditions, random sampling of esophageal tissue for
dysplasia remains the clinical standard. The role of endoscopic ablative therapies in Barrett’s esophagus is
not clear. Finally, there are limited data on the safety
and efficacy of intensive endoscopic surveillance for
patients with high-grade dysplasia.
GUIDELINES
A number of organizations have published guidelines regarding the management of Barrett’s esophagus.8,54-57 Perhaps the most comprehensive are those
of the American College of Gastroenterology (available at http://www.acg.gi.org).8 According to these
guidelines, treatment of esophageal reflux in patients
with Barrett’s esophagus should be the same as that
in patients with gastroesophageal reflux disease who
do not have Barrett’s esophagus. Patients with Barrett’s
esophagus should undergo surveillance endoscopy and
biopsy at intervals that are based on the presence or
absence and grade of dysplasia. Patients without dysplasia should undergo endoscopy every two to three
years. When low-grade dysplasia is found, endoscopy
should be repeated after 6 and 12 months and then
yearly thereafter if there has been no progression.
When high-grade dysplasia is identified, the diagnosis
should be confirmed by an experienced pathologist.
If the diagnosis is confirmed, the American College
of Gastroenterology endorses either of two management strategies: intensive endoscopic surveillance (every three months) or esophagectomy.
The International Society for Diseases of the Esophagus and the consensus panel of the Society for Surgery of the Alimentary Tract, the American Gastroenterological Association, and the American Society
for Gastrointestinal Endoscopy do not specifically endorse intensive endoscopic surveillance for high-grade
dysplasia and instead recommend that fit patients with
this lesion be considered for esophagectomy.54,57 The
guidelines of the American College of Gastroenterology do not explicitly address the role of endoscopic
ablative therapies for high-grade dysplasia, but the
consensus panel concluded that these techniques require further study and should be limited to patients
enrolled in clinical trials.57
CONCLUSIONS
Endoscopic screening for Barrett’s esophagus should
be considered for patients who have chronic symptoms
of gastroesophageal reflux disease (i.e., symptoms that
have lasted for more than five years). The group at
highest risk for cancer consists of obese white men over
the age of 50 years. Among black and Asian women,
the risk of cancer in association with Barrett’s esophagus is so low that it probably does not warrant even the
small risk associated with endoscopy, if the procedure
is performed solely to screen for Barrett’s esophagus.
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C LINICA L PR AC TICE
Barrett’s esophagus
without dysplasia
Barrett’s esophagus
with dysplasia
Perform surveillance
endoscopy every 3 to 5 years
Have diagnosis confirmed
by experienced pathologist
Low-grade dysplasia
High-grade dysplasia
Repeat endoscopy
after 6 and 12 months
followed by yearly endoscopy
if there is no progression
Perform esophagectomy
(the preferred approach in fit
patients under the age of 50 years)
or intensive endoscopic
surveillance in fit patients
Consider endoscopic ablative
therapies for patients at high risk
for surgical complications, but only
in the context of a clinical study
Figure 3. Management of Barrett’s Esophagus.
Evidence that aggressive antireflux therapy reduces
the risk of cancer is insufficient to warrant the substantial expense and inconvenience of the therapy in
routine clinical practice. Antireflux therapy should be
prescribed only as needed for the symptoms and signs
of gastroesophageal reflux disease.
A management algorithm for Barrett’s esophagus
is shown in Figure 3. This strategy assumes that patients have undergone an initial endoscopic examination with biopsy specimens obtained in four quadrants
at intervals of no more than 2 cm throughout the area
of Barrett’s esophagus. If sampling of tissues during
the initial endoscopy is not adequate or if there is any
question regarding the degree of dysplasia, the examination should be repeated. If inflammation is interfering with the histologic assessment of dysplasia, as it
was in the patient described in the case vignette, intensive antireflux therapy (at the least, twice-daily
treatment with a proton-pump inhibitor) for 8 to 12
weeks should be given, and endoscopic biopsy should
then be repeated to confirm the diagnosis.
The American College of Gastroenterology recommends that endoscopic surveillance be performed every two to three years in patients without dysplasia,
on the basis of an estimated incidence of cancer in patients with Barrett’s esophagus of 1 to 2 percent per
year. Recent studies suggest that the true incidence of
cancer is approximately 0.5 percent per year. Therefore, less frequent surveillance — every three to five
years — seems appropriate in patients without dysplasia.
Because studies of intensive endoscopic surveillance
for high-grade dysplasia are limited and have involved
primarily older patients, caution is warranted in applying the results of these studies to younger patients. In-
tensive endoscopic surveillance may be a valid alternative to immediate esophagectomy for older patients
with high-grade dysplasia who can comply with this
approach. For patients who are infirm, too old, or unwilling to undergo esophagectomy, endoscopic ablative therapy may be a reasonable alternative if the
procedure is performed as part of a study protocol.
Finally, the clinician should bear in mind that these
recommendations have not been validated by studies
demonstrating that this strategy prolongs survival or
enhances the quality of life.
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