The n e w e ng l a n d j o u r na l
clinical practice
From the Veterans Affairs Medical Cen-
ter, Kansas City, MO, and the Division of
Gastroenterology and Hepatology, Uni-
versity of Kansas School of Medicine,
Kansas City, KS. Address reprint requests
to Dr. Sharma at 4801 E. Linwood Blvd.,
Kansas City, KS 64129, or at psharma@
kumc.edu.
N Engl J Med 2009;361:2548-56.
Copyright © 2009 Massachusetts Medical Society.
An audio version
of this article
is available at
NEJM.org
2548
Downloaded from www.nejm.org by ANASTACIO Q. SOUSA MD on December 25, 2009 .
of m e dic i n e
Barrett’s Esophagus
Prateek Sharma, M.D.
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.
A 56-year-old obese man with long-standing gastroesophageal reflux who recently
received a diagnosis of Barrett’s esophagus presents for a follow-up visit. He has been
taking omeprazole at a dose of 20 mg twice daily and currently has no symptoms of
reflux. He has no dysphagia or weight loss. Endoscopic and histopathological exami-
nations show a 4-cm segment of Barrett’s esophagus without dysplasia. How should
Barrett’s esophagus be managed?
The Cl inic a l Probl em
Barrett’s esophagus is a premalignant lesion detected in the majority of patients
with esophageal and gastroesophageal adenocarcinoma — cancers that are associ-
ated with a low rate of survival (5-year survival rate, 15 to 20%).1 The incidence of
esophageal adenocarcinoma has been increasing in the United States.2 In 2009, it
is estimated that 16,400 new cases of esophageal cancer will be diagnosed in the
United States, of which approximately 60% will be adenocarcinomas.3 The risk of
esophageal adenocarcinoma is 30 to 40 times as high among patients with Barrett’s
esophagus as among patients without this condition. The progression of Barrett’s
esophagus may involve the development of low-grade dysplasia and high-grade
dysplasia before the eventual development of cancer.
Barrett’s esophagus is diagnosed in approximately 10 to 15% of patients with reflux
who are undergoing endoscopy; it has also been reported in patients without chronic
reflux symptoms, with a prevalence of 5.6% in one report of endoscopic screening.4
The prevalence of Barrett’s esophagus in the general U.S. population is not known.
In a population-based study conducted in Sweden, Barrett’s esophagus was diagnosed
in 1.6% of 3000 study participants.5 If these numbers are applied to the U.S. popu-
lation, 1.5 to 2.0 million adults may have this premalignant lesion. Risk factors for
Barrett’s esophagus include advanced age, male sex, white race, symptoms of reflux,
and obesity. Studies have reported inverse associations between the presence of
Barrett’s esophagus and consumption of red wine, Helicobacter pylori infection, and
black race.6,7
S t r ategie s a nd E v idence
Evaluation
Although endoscopic screening for Barrett’s esophagus in patients with symptoms
of chronic reflux has been suggested by some gastroenterology societies,8-10 such
screening is controversial. Several cohort and case–control studies have shown that
almost half the patients in whom esophageal adenocarcinoma developed had no previ-
ous symptoms of heartburn.11 Although the risk of esophageal adenocarcinoma is
elevated among persons with heartburn as compared with the general population,
n engl j med 361;26  nejm.org  december 24, 2009
Copyright © 2009 Massachusetts Medical Society. All rights reserved.
 clinical pr actice

the absolute risk is still less than 1 case per 1000

person-years. Furthermore, Barrett’s esophagus
may occur in the absence of symptoms of chronic
reflux.4 Finally, data that show a reduction in deaths
from esophageal adenocarcinoma as a result of en-
doscopic screening are lacking.11 A recent Clinical
Practice article in the Journal discussed this issue.12

Diagnosis
Barrett’s esophagus is a metaplastic change in the
esophageal lining from the usual squamous mu-
cosa to columnar epithelium, and is detected on
endoscopic examination as a columnar-lined dis-
tal esophagus (Fig. 1). In healthy persons, the
squamocolumnar junction and the gastroesopha- Figure 1. Endoscopic Detection of Barrett’s Esophagus.
AUTHOR Sharma RETAKE 1st
geal junction are located at the same level, whereas TheICM
red, columnar-lined esophagus (arrow) and the
REG F FIGURE 1 2nd
contrast between the squamous (arrowhead) and co-
in patients with Barrett’s esophagus, the squamo- CASE TITLE
lumnar (arrow) epithelium are characteristicRevised
of Bar-
3rd

columnar junction is displaced proximally. The EMail

gastroesophageal junction is evident endoscopi-
cally as the top of the gastric folds; the squamo-
columnar junction is seen as a transition from the
light pink squamous mucosa of the esophagus to
the red columnar mucosa of the stomach.
Historically, Barrett’s esophagus was arbitrarily
classified as short-segment disease (<3 cm) or
long-segment disease (≥3 cm) according to the
length of the metaplastic epithelium on endo-
scopic examination. However, it is not clear that
such classification is clinically meaningful or al-
ters management.1 The extent of Barrett’s esoph-
agus on endoscopic examination can also be
graded with the use of the Prague circumference
and maximum (C and M) criteria,13 a standard-
ized and validated system based on the circumfer-
ential and maximal extent of the columnar-lined
esophagus. Mucosal biopsy specimens are ob-
tained from the columnar segment to confirm the
presence of metaplastic or neoplastic epithelium.
Endoscopic Surveillance
Given the strong association between Barrett’s
esophagus and esophageal adenocarcinoma and
the high proportion of patients with esophageal
carcinoma who present with advanced disease, en-
doscopic surveillance programs have been estab-
lished in an effort to diagnose cancer at an early
stage in patients with Barrett’s esophagus. Case–
control and cohort studies have shown that endo-
scopic surveillance is significantly associated with
both an earlier stage of esophageal adenocarcino-
ma at diagnosis and improved survival.14 In a pop-
ulation-based cohort study, 11 of 23 patients with
rett’s esophagus. Line 4-C
Enon SIZE
FILL
ARTIST: mst H/T
Combo
H/T
16p6
AUTHOR, PLEASE NOTE:
cancer Figure
detected by redrawn
has been meansandoftypeendoscopic surveil-
has been reset.
Please check carefully.
lance (48%), as compared with none of the pa-
tientsJOB:
with36125
cancer who presented clinically, were
ISSUE: 12-24-09
alive at 2 years of follow-up (P = 0.001); however,
the possibility of lead-time bias makes it impos-
sible to conclude from these findings that sur-
veillance prolongs life.15 Surveillance of patients
with Barrett’s esophagus is recommended by all
major gastroenterology societies and published
guidelines.1,9,10,16,17 However, no randomized, con-
trolled trials have evaluated the efficacy of sur-
veillance, and it is not clear whether surveillance
reduces the mortality from esophageal cancer. Fur-
thermore, several factors limit the expected ben-
efits of current surveillance strategies, including
the low overall incidence of cancer in patients with
Barrett’s esophagus, the absence of a previous di-
agnosis of Barrett’s esophagus in the majority of
patients with esophageal adenocarcinoma, and dif-
ficulties in the diagnosis of dysplasia (a high miss
rate on evaluation of random biopsy specimens
and high variation among pathologists in the in-
terpretation of biopsy findings).1,18
Although the precise incidence of cancer in
patients with Barrett’s esophagus is unknown,
cancer does not develop in most patients; recent
studies suggest a risk of 0.5% or less annually. In
a large multicenter cohort of patients with Bar-
rett’s esophagus, the incidence of cancer was
1 case in 212 patient-years of follow-up (0.5% per
year).19 In patients with low-grade dysplasia, inci-
dence rates for esophageal adenocarcinoma range

n engl j med 361;26  nejm.org  december 24, 2009 2549

Downloaded from www.nejm.org by ANASTACIO Q. SOUSA MD on December 25, 2009 .

Copyright © 2009 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

from 0.6% to 1.6% per year.20,21 The lower end

of this range is similar to the incidence in patients A
with Barrett’s esophagus who do not have dyspla-
sia, whereas cases in which the diagnosis of low-
grade dysplasia is based on a consensus by two or
more expert pathologists may be associated with
progression rates that are higher than those for
cases in which consensus is lacking.22 Moreover,
the majority of patients with low-grade dysplasia
detected on endoscopic surveillance do not have
evidence of dysplasia on the subsequent endo-
scopic examination. In contrast, the risk of the
development of esophageal adenocarcinoma is
high among patients with high-grade dysplasia,
B
with an estimated incidence of 6.6 cases per 100
patient-years (95% confidence interval, 4.9 to 8.2)
in a recent meta-analysis.23
A detailed inspection of the metaplastic epithe-
lium with the use of a high-quality video endo-
scope should be performed. After obtaining target
biopsy specimens from any visible mucosal abnor-
malities (Fig. 2), a systematic four-quadrant biopsy
protocol, with specimens obtained every 2 cm
along the extent of the Barrett’s esophagus, can
in­crease the yield of both low-grade dysplasia
(by 17%) and high-grade dysplasia (by 3%) as
compared with randomly obtained biopsy spec- Figure 2. Early Adenocarcinoma in a Patient
imens.24 with Barrett’s Esophagus.
Recommendations regarding surveillance inter- Panel A shows nodular areas (arrows) that are visible
withICM AUTHOR Sharma
high-resolution, RETAKE
white-light endoscopy. Panel B1st
vals are largely based on longitudinal case series F FIGURE
REG the 2a&bof the distal esophagus after2nd
shows appearance en-
and expert opinion.9 For patients without dyspla- CASE
doscopic TITLE
resection of the nodular area. Revised
3rd

sia in whom two carefully performed endoscop- EMail Line 4-C

Enon SIZE
ic examinations a year apart have shown no evi- FILL
ARTIST: mst H/T
Combo
H/T
16p6
dence of disease progression, the surveillance ly compared with standard endoscopy, preliminary
AUTHOR, PLEASE NOTE:
interval may be extended up to 3 years. For pa- results Figure
with has
thebeen
useredrawn
of narrow-band imaging
and type has been reset. (elec-
Please check carefully.
tients with low-grade dysplasia in whom an ad- tronic chromoendoscopy) and confocal laser en-
vanced lesion has been ruled out, annual surveil- domicroscopy
JOB: 36125
suggest a high rate of accuracy (85
ISSUE: 12-24-09
lance is typically recommended (Fig. 3). to 92%) in the diagnosis of neoplasia in patients
with Barrett’s esophagus.25,26 Preliminary results
Advanced Imaging Techniques from a randomized, controlled crossover trial in-
The current practice of endoscopic surveillance in volving 123 patients with Barrett’s esophagus
patients with Barrett’s esophagus has limitations. showed that, as compared with a strategy of per-
Biopsies are performed randomly and sample only forming four-quadrant biopsies every 2 cm with
4 to 6% of the surface area of the metaplastic epi- the use of high-definition endoscopy, the use of
thelium, although it is recognized that dysplastic targeted biopsies with narrow-band imaging iden-
and cancerous lesions within the Barrett’s segment tified similar proportions of patients with meta-
have a focal and patchy distribution. More recently, plastic lesions (85% with each procedure) and neo-
enhanced optical imaging techniques have been plastic lesions (71% with targeted biopsies and
suggested to improve the efficiency and accuracy 55% with four-quadrant biopsies, P = 0.15) but in-
of endoscopic surveillance (Table 1). Although the volved fewer biopsy specimens per procedure (3.6
majority of these techniques have not been direct- vs. 7.6, P<0.001).27

2550 n engl j med 361;26  nejm.org  december 24, 2009

Downloaded from www.nejm.org by ANASTACIO Q. SOUSA MD on December 25, 2009 .

Copyright © 2009 Massachusetts Medical Society. All rights reserved.
 clinical pr actice

Diagnosis of Barrett’s esophagus

during endoscopy

Careful examination and grading

(e.g., with the use of Prague criteria)

Endoscopic biopsies (targeted

and four-quadrant every 2 cm)

Nondysplastic Barrett’s Acid-suppressive Dysplasia, cancer,

esophagus therapy or both

Endoscopic surveillance Confirmation by two expert

every 3 yr pathologists

Low-grade dysplasia High-grade dysplasia Early cancer

Endoscopic surveillance
twice every yr
Staging endoscopic
mucosal resection

High-grade
Mucosal cancer Invasive cancer
dysplasia

Endoscopic
Surgery
therapy

Figure 3. Proposed Treatment Algorithm for Patients with Barrett’s Esophagus.

AUTHOR: Sharma RETAKE: 1st
2nd
Management FIGURE: 3 of 4
mucosa; data showing that these interventions re-
3rd
Revised
Antireflux Interventions ARTIST: MRL duce the risk SIZE of esophageal carcinoma among
In patients with Barrett’s esophagus,
TYPE: Lineantireflux
Combo these
4-C patients
H/T
6are
col lacking. Indications for antire-
33p9
interventions are intended to control symptoms flux surgery in patients with Barrett’s esophagus
AUTHOR, PLEASE NOTE:
of reflux and promote healing ofFigure
the has
esophageal aretype
been redrawn and thehassame as those in patients with chronic re-
been reset.
Please check carefully.

JOB: 36126 ISSUE: 12-24-09

n engl j med 361;26  nejm.org  december 24, 2009 2551

Downloaded from www.nejm.org by ANASTACIO Q. SOUSA MD on December 25, 2009 .

Copyright © 2009 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 1. Advanced Imaging Techniques for Barrett’s Esophagus.

Technique Description Comments

High-resolution, white-light
endoscopy
Magnification endoscopy
Chromoendoscopy
Narrow-band imaging (electronic
chromoendoscopy)
Autofluorescence imaging
Confocal microscopy
Uses a charge-coupled device with up to 1 mil-
lion pixels and high-resolution components
Uses optical magnification (up to ×70–100)
to visualize subtle mucosal patterns and
lesions within the Barrett’s segment
Sprays various stains (e.g., methylene blue, indi-
go carmine), over the esophageal mucosa to
accentuate the contrast between the meta-
plastic and nonmetaplastic epithelium
Uses spectral narrow-band optical filters with
predominance of blue light rather than the
complete white-light spectrum; this high-
lights mucosal and vascular patterns indica-
tive of neoplastic tissue
Detects change in fluorescence from alteration
in the content of cellular molecules such as
NADPH and collagen, with neoplastic tissue
showing differential fluorescence (color)
Uses a single plane of focus with laser micro-
scopes, allowing for real-time viewing of cel-
lular details
Becoming the default standard, given improve-
ments in the quality, clarity, and resolution
of white-light imaging
Evaluated in case series; not directly compared
with standard endoscopy and tedious to
use, since it allows visualization of very
focal areas
Has been tested in randomized, controlled trials
with varying results; relatively inexpensive to
use; challenges include variability in use of
stains and spray catheter, and lack of stan-
dardization of technique
Relatively easy to use and tested in randomized,
controlled trials showing yield that is similar
to that of routine biopsies; difficulty with pat-
tern recognition and learning curve
Allows broad-based imaging; high false positive
rates, subjective color interpretation, and
lack of commercial availability
High-quality and detailed imaging of Barrett’s
glands and cells; challenges include imaging
of very focal areas, intravenous fluorescence
agent, and image interpretation

flux (e.g., a lack of response to or an inability to thelium.31 Furthermore, a meta-analysis of 34

tolerate proton-pump inhibitors); the presence of
Barrett’s esophagus should not be viewed as an
indication for antireflux surgery.12 In a multicenter
trial in Europe, 554 patients with symptoms of
chronic reflux, including 60 patients with Barrett’s
esophagus, were randomly assigned to either lap-
aroscopic antireflux surgery or a proton-pump in-
hibitor (esomeprazole at a dose of 20 to 40 mg
daily, adjusted according to symptoms). At 3 years,
symptoms and quality-of-life measures did not
differ significantly between the groups, although
the surgical group had significantly better esoph-
ageal pH control.28 Progression of Barrett’s esoph-
agus was not studied. The primary goal of both
treatment with proton-pump inhibitors and sur-
gery is symptom control; 24-hour pH monitoring
to document normalization of exposure to esoph-
ageal acid is not routinely recommended.
Whereas some retrospective cohort studies have
shown associations between the use of more rig-
orous acid suppression (with proton-pump in-
hibitors) and a decreased risk of or delay in the
progression to neoplasia,29,30 the data are incon-
sistent. Proton-pump–inhibitor therapy does not
reliably lead to regression of the metaplastic epi-
studies of antireflux interventions in patients with
Barrett’s esophagus showed no significant differ-
ence in the risk of esophageal cancer between pa-
tients who underwent antireflux surgery and those
who received medical therapy.32
Management of Neoplastic Barrett’s Esophagus
Multimodal endoscopic eradication therapy in-
volves the removal of visible neoplastic lesions by
means of endoscopic mucosal resection (Fig. 4),
followed by eradication of the remaining meta-
plastic epithelium with the use of mucosal ablative
techniques such as photodynamic therapy, radio-
frequency ablation, cryoablation, and argon plasma
coagulation.33 Endoscopic mucosal resection has
been used for both diagnostic and therapeutic pur-
poses. As a diagnostic tool, this procedure has
been shown to be superior to mucosal biopsies and
results in a change in the histologic diagnosis and
clinical management in approximately 25% of pa-
tients.34 The patients with Barrett’s esophagus who
are most likely to benefit from endoscopic eradi-
cation therapy are those with esophageal adeno-
carcinoma limited to the mucosa and those with
high-grade dysplasia. Esophagectomy has tradi-

2552 n engl j med 361;26  nejm.org  december 24, 2009

Downloaded from www.nejm.org by ANASTACIO Q. SOUSA MD on December 25, 2009 .

Copyright © 2009 Massachusetts Medical Society. All rights reserved.
 clinical pr actice
Esophagus
Mucosal
layer
Muscular
layer
Endoscope
Snare
is placed
over the
lesion
Lesion
Saline is injected
is sucked
below the lesion
into the
cap
Figure 4. Endoscopic Mucosal Resection.
Removal of early cancer with the use of endoscopic mucosal resection is shown in a patient with Barrett’s esophagus.
tionally been the primary treatment in patients
with high-grade dysplasia because of a high re-
ported prevalence of coexisting esophageal adeno-
carcinoma (up to 40% in some surgical series)35
and a high risk of progression of high-grade dys-
plasia to cancer. However, a recent systematic
review showed a 12.7% prevalence of invasive
esophageal cancer among patients undergoing
esophagectomy for high-grade dysplasia; this prev-
alence was lower than previous estimates. In the
absence of visualization of abnormal mucosal le-
sions during endoscopy, the prevalence decreased
to 3.0%.36 Furthermore, metaplastic epithelium
may recur after removal of the entire Barrett’s
esophagus segment by means of radical subtotal
esophagectomy; in one surgical case series, 47%
of patients had subsequent evidence of a columnar-
lined esophagus.37 Moreover, even in centers with
expertise in performing the procedure, esophagec-
tomy is associated with substantial morbidity
(with complications in 30 to 50% of patients,
including cardiac complications, pneumonia,
and anastomotic leak or stricture) and mortality
(1 to 5%).35,38
The use of endoscopic eradication therapy in
patients with high-grade dysplasia is supported by
the results of two randomized, controlled trials. In
n engl j med 361;26  nejm.org  december 24, 2009
Downloaded from www.nejm.org by ANASTACIO Q. SOUSA MD on December 25, 2009 .
Copyright © 2009 Massachusetts Medical Society. All rights reserved.
Snare
resects
the lesion
one trial involving 208 patients, the proportion of
patients in whom high-grade dysplasia remained
completely eradicated at 5 years was significantly
higher in the group of patients randomly assigned
to photodynamic therapy and omeprazole (20 mg COLOR FIGURE
twice daily) than in the group randomly assigned Draft 3 11/25/09
Author Sharma
to omeprazole alone (77% vs. 39%, P<0.001) 39
Fig # ; 4
the group receiving photodynamic therapyTitlealsoEndoscopic
resection
muscosal
had lower rates of progression to cancer (15% ME vs.
29%, P = 0.03), although the trial was notDE de- Solomon
Artist Knoper
40
signed to test this outcome. In a multicenter,AUTHOR PLEASE NOTE:
randomized, sham-controlled trial involving 63 Please check carefully
Figure has been redrawn and type has been reset
patients, the rate of complete eradication of high-
Issue date 12/24/09
grade dysplasia was significantly higher in the
group of patients assigned to radiofrequency
treatment than in the control group (81% vs.
19%, P<0.001), as was the rate of complete eradi-
cation of the entire Barrett’s esophagus (74% vs.
0%, P<0.001).41 Among patients with esophageal
adenocarcinoma, endoscopic eradication therapy
should be considered only for those with mucosal
disease, in whom the rate of lymph-node metasta-
sis is extremely low (≤3%); once the cancer in-
vades the submucosa, the risk of lymph-node
metastasis at diagnosis increases to 20 to 25%. In
a cohort of more than 200 patients with mucosal
esophageal adenocarcinoma who were followed
2553
 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 2. Guidelines for the Management of Barrett’s Esophagus.*

Surveillance Intervals
Screening Histologic Examination for Nondysplastic
Organization Recommended Required for Diagnosis Barrett’s Esophagus
American College of Gastroenterology No† Yes 3 yr
American Society for Gastrointestinal Endoscopy Yes Yes 3 yr
British Society of Gastroenterology No No 2 yr
French Society of Digestive Endoscopy Not indicated Yes <3 cm, 5 yr; 3–6 cm,
3 yr; >6 cm, 2 yr
Society for Surgery of the Alimentary Tract Yes Yes 2 yr

* For patients with Barrett’s esophagus, proton-pump–inhibitor therapy, antireflux surgery, or both are generally recom-
mended for the control of symptoms of reflux and treatment of esophagitis.
† Screening is not recommended for the general population. In selective populations at increased risk, the decision about
screening should be individualized.

for a mean of 5.1 years after endoscopic eradica-
tion therapy, the 5-year survival rate was 87%.42
Endoscopic eradication therapy is not currently
recommended in patients with nondysplastic Bar-
rett’s esophagus. Because of the overall low risk
of esophageal adenocarcinoma among patients
with Barrett’s esophagus, if the procedure is con-
firmed to be preventive, the estimated number of
patients who would need to be treated to prevent
one case of esophageal adenocarcinoma would be
250 or more. In addition, the potential complica-
tions of endoscopic eradication therapy (an over-
all rate of 10 to 15%, with complications including
chest pain, odynophagia, strictures, perforation,
and bleeding), as well as the lack of evidence that
endoscopic eradication therapy prevents the devel-
opment of cancer and that the eradication is du-
rable, underscore the need for more data.
A r e a s of Uncer ta in t y
Data are lacking from randomized, controlled tri-
als assessing the benefits of screening to detect
Barrett’s esophagus among patients with gastro­
esophageal reflux or of surveillance endoscopic ex-
aminations among patients with a diagnosis of
Barrett’s esophagus. Data from placebo-controlled
or sham-controlled trials of the effects of medi-
cal, surgical, and endoscopic therapies on the in-
cidence of esophageal adenocarcinoma and mor-
tality are also lacking. In addition, the optimal
techniques for surveillance and the optimal sur-
veillance intervals for patients with and those with- Guidelines for the management of Barrett’s esoph-
out dysplasia are unclear. Although epidemiologic agus have been published by the American Col-
and experimental studies have suggested a poten- lege of Gastroenterology,9 the American Society
tial role of nonsteroidal antiinflammatory drugs,
aspirin, and selective cyclooxygenase-2 inhibitors
in preventing esophageal cancer, confirmatory data
from large randomized trials are not available.43
A randomized, controlled trial investigating the
effects of aspirin and proton-pump–inhibitor ther-
apy on neoplastic progression in patients with
Barrett’s esophagus is ongoing (ClinicalTrials.gov
number, NCT00357682).44
Given the low overall risk of neoplastic progres-
sion of Barrett’s esophagus, there is an interest in
biomarkers that might identify persons at partic-
ular risk for the development of cancer. Among
biomarkers reported to be predictive of neoplastic
progression are abnormalities in the tumor-sup-
pressor genes CDKN2A (which encodes the cyclin-
dependent kinase inhibitor p16INK4a) and TP53
(which encodes tumor protein p53), and the pres-
ence of tetraploidy or aneuploidy in epithelial
cells.45 In two large prospective studies, the 5-year
cumulative incidence of esophageal adenocarci-
noma among patients with Barrett’s esophagus
was 43% in patients with aneuploidy, 56% in pa-
tients with tetraploidy, and 5% in patients with-
out aneuploidy or tetraploidy.46,47 However, data
are needed from large prospective studies to con-
firm the predictive value of these and other mark-
ers, and they are not currently used in routine
clinical management.
Guidel ine s

2554 n engl j med 361;26  nejm.org  december 24, 2009

Downloaded from www.nejm.org by ANASTACIO Q. SOUSA MD on December 25, 2009 .

Copyright © 2009 Massachusetts Medical Society. All rights reserved.
 clinical pr actice

for Gastrointestinal Endoscopy,8 the British Soci-
ety of Gastroenterology,16 the French Society of
Digestive Endoscopy,17 and the Society for Surgery
of the Alimentary Tract.10 The strategies proposed
in this article are generally consistent with these
guidelines (Table 2).
C onclusions a nd
R ec om mendat ions
Patients with Barrett’s esophagus, such as the pa-
tient described in the vignette, should be informed
that they are at increased risk for the development
of esophageal adenocarcinoma but that this risk
is low. Acid-suppressive therapy (proton-pump in-
hibitors), antireflux surgery, or both are useful in
controlling symptoms of reflux and healing ero-
sive esophagitis in patients with Barrett’s esoph-
agus, but there is currently no conclusive evidence
that such therapies reduce the risk of neoplastic
progression. Endoscopic surveillance with detailed
inspection and systematic biopsies is recommend-
ed for most patients with Barrett’s esophagus, but
decision making should take into account the pa-
tient’s age, coexisting conditions, life expectancy,
and the lack of conclusive evidence that surveil-
lance reduces mortality from esophageal adeno-
carcinoma. In patients with nondysplastic Barrett’s
esophagus, after at least two endoscopic exami-
nations with no evidence of disease progression,
surveillance periods can probably be extended to
3 years. In patients with high-grade dysplasia, en-
doscopic therapies or surgical resection should be
considered.
Dr. Sharma reports receiving consulting fees from AstraZen-
eca, Santarus, and Takeda and grant support from Given Imag-
ing, Barrx Medical, Olympus, Cogentus, Mauna Kea Technolo-
gies, and Takeda. No other potential conflict of interest relevant
to this article was reported.

References
1. Sharma P, McQuaid K, Dent J, et al.
A critical review of the diagnosis and
management of Barrett’s esophagus: the
AGA Chicago Workshop. Gastroenterolo-
gy 2004;127:310-30.
2. Pohl H, Welch HG. The role of over-
diagnosis and reclassification in the marked
increase of esophageal adenocarcinoma
incidence. J Natl Cancer Inst 2005;97:
142-6.
3. Jemal A, Siegel R, Ward E, Hao Y, Xu
J, Thun MJ. Cancer statistics, 2009. CA
Cancer J Clin 2009;59:225-49.
4. Rex DK, Cummings OW, Shaw M, et
al. Screening for Barrett’s esophagus in
colonoscopy patients with and without
heartburn. Gastroenterology 2003;125:
1670-7.
5. Ronkainen J, Aro P, Storskrubb T, et
al. Prevalence of Barrett’s esophagus in the
general population: an endoscopic study.
Gastroenterology 2005;129:1825-31.
6. Kubo A, Levin TR, Block G, et al. Al-
cohol types and sociodemographic char-
acteristics as risk factors for Barrett’s
esophagus. Gastroenterology 2009;136:
806-15.
7. Wong A, Fitzgerald RC. Epidemiologic
risk factors for Barrett’s esophagus and
associated adenocarcinoma. Clin Gastro-
enterol Hepatol 2005;3:1-10.
8. Hirota WK, Zuckerman MJ, Adler DG,
et al. ASGE guideline: the role of endos-
copy in the surveillance of premalignant
conditions of the upper GI tract. Gastro-
intest Endosc 2006;63:570-80.
9. Wang KK, Sampliner RE. Updated
guidelines 2008 for the diagnosis, sur-
veillance and therapy of Barrett’s esopha-
gus. Am J Gastroenterol 2008;103:788-97.
10. Society for Surgery of the Alimentary
Tract. SSAT patient care guidelines: man-
agement of Barrett’s esophagus. J Gastro-
intest Surg 2007;11:1213-5.
11. Lagergren J, Bergstrom R, Lindgren
A, Nyrén O. Symptomatic gastroesopha-
geal reflux as a risk factor for esophageal
adenocarcinoma. N Engl J Med 1999;
340:825-31.
12. Kahrilas PJ. Gastroesophageal reflux
disease. N Engl J Med 2008;359:1700-7.
13. Sharma P, Dent J, Armstrong D, et al.
The development and validation of an en-
doscopic grading system for Barrett’s
esophagus: the Prague C & M criteria.
Gastroenterology 2006;131:1392-9.
14. Cooper GS, Kou TD, Chak A. Receipt
of previous diagnoses and endoscopy and
outcome from esophageal adenocarcino-
ma: a population-based study with tem-
poral trends. Am J Gastroenterol 2009;104:
1356-62.
15. Corley DA, Levin TR, Habel LA, Weiss
NS, Buffler PA. Surveillance and survival
in Barrett’s adenocarcinomas: a popula-
tion-based study. Gastroenterology 2002;
122:633-40.
16. Watson A, Heading RC, Shepherd NA.
Guidelines for the diagnosis and manage-
ment of Barrett’s columnar-lined oesoph-
agus: a report of the Working Party of the
British Society of Gastroenterology. Lon-
don: British Society of Gastroenterology,
August 2005.
17. Boyer J, Laugier R, Chemali M, et al.
French Society of Digestive Endoscopy
SFED guideline: monitoring of patients
with Barrett’s esophagus. Endoscopy 2007;
39:840-2.
18. Montgomery E, Bronner MP, Gold-
blum JR, et al. Reproducibility of the di-
agnosis of dysplasia in Barrett esophagus:
a reaffirmation. Hum Pathol 2001;32:368-
78.
19. Sharma P, Falk GW, Weston AP, Reker
D, Johnston M, Sampliner RE. Dysplasia
and cancer in a large multicenter cohort
of patients with Barrett’s esophagus. Clin
Gastroenterol Hepatol 2006;4:566-72.
20. Wani S, Mathur S, Sharma P. How to
manage a Barrett’s esophagus patient with
low-grade dysplasia. Clin Gastroenterol
Hepatol 2009;7:27-32.
21. Wani S, Falk GW, Sampliner RE, et al.
Low-grade dysplasia is a poor marker for
cancer progression in patients with Bar-
rett’s esophagus: preliminary results from
a large, multi-center, cohort study. Gas-
troenterology 2009;136:A592. abstract.
22. Skacel M, Petras RE, Gramlich TL, et
al. The diagnosis of low-grade dysplasia
in Barrett’s esophagus and its implica-
tions for disease progression. Am J Gas-
troenterol 2000;95:3383-7.
23. Rastogi A, Puli S, El-Serag HB, Bansal
A, Wani S, Sharma P. Incidence of esopha-
geal adenocarcinoma in patients with
Barrett’s esophagus and high-grade dys-
plasia: a meta-analysis. Gastrointest En-
dosc 2008;67:394-8.
24. Abela JE, Going JJ, Mackenzie JF,
McKernan M, O’Mahoney S, Stuart RC.
Systematic four-quadrant biopsy detects
Barrett’s dysplasia in more patients than
nonsystematic biopsy. Am J Gastroenterol
2008;103:850-5.
25. Wolfsen HC, Crook JE, Krishna M,
et al. Prospective, controlled tandem en-
doscopy study of narrow band imag­
ing  for dysplasia detection in Barrett’s

n engl j med 361;26  nejm.org  december 24, 2009 2555

Downloaded from www.nejm.org by ANASTACIO Q. SOUSA MD on December 25, 2009 .

Copyright © 2009 Massachusetts Medical Society. All rights reserved.
 clinical pr actice

esophagus.Gastroenterology2008;135:24-
31.
26. Kiesslich R, Gossner L, Goetz M, et
al. In vivo histology of Barrett’s esopha-
gus and associated neoplasia by confocal
laser endomicroscopy. Clin Gastroenterol
Hepatol 2006;4:979-87.
27. Sharma P, Bansal A, Hawes R, et al.
Detection of metaplasia and neoplasia in
patients with Barrett’s esophagus using
high-definition white light endoscopy ver-
sus narrow band imaging: a prospective,
multi-center, randomized, crossover trial.
Gastrointest Endosc 2009;69:AB135. ab-
stract.
28. Attwood SE, Lundell L, Hatlebakk JG,
et al. Medical or surgical management of
GERD patients with Barrett’s esophagus:
the LOTUS trial 3-year experience. J Gas-
trointest Surg 2008;12:1646-54.
29. El-Serag HB, Aguirre TV, Davis S,
Kuebeler M, Bhattacharyya A, Sampliner
RE. Proton pump inhibitors are associat-
ed with reduced incidence of dysplasia in
Barrett’s esophagus. Am J Gastroenterol
2004;99:1877-83.
30. Hillman LC, Chiragakis L, Shadbolt
B, Kaye GL, Clarke AC. Proton-pump in-
hibitor therapy and the development of
dysplasia in patients with Barrett’s oe-
sophagus. Med J Aust 2004;180:387-91.
31. Sharma P, Sampliner RE, Camargo E.
Normalization of esophageal pH with
high-dose proton pump inhibitor therapy
does not result in regression of Barrett’s
esophagus. Am J Gastroenterol 1997;92:
582-5.
32. 32 Corey KE, Schmitz SM, Shaheen
NJ. Does a surgical antireflux procedure
decrease the incidence of esophageal ad-
enocarcinoma in Barrett’s esophagus?
A meta-analysis. Am J Gastroenterol 2003;
98:2390-4.
33. Wani S, Sayana H, Sharma P. Endo-
scopic eradication of Barrett’s esophagus.
Gastrointest Endosc 2009 October 29
(Epub ahead of print).
34. Larghi A, Lightdale CJ, Memeo L,
Bhagat G, Okpara N, Rotterdam H. EUS
followed by EMR for staging of high-grade
dysplasia and early cancer in Barrett’s
esophagus. Gastrointest Endosc 2005;62:
16-23.
35. Heitmiller RF, Redmond M, Hamilton
SR. Barrett’s esophagus with high-grade
dysplasia: an indication for prophylactic
esophagectomy. Ann Surg 1996;224:66-71.
36. Konda VJ, Ross AS, Ferguson MK, et
al. Is the risk of concomitant invasive
esophageal cancer in high-grade dyspla-
sia in Barrett’s esophagus overestimat-
ed? Clin Gastroenterol Hepatol 2008;6:
159-64.
37. Oberg S, Johansson J, Wenner J,
Walther B. Metaplastic columnar mucosa
in the cervical esophagus after esophagec-
tomy. Ann Surg 2002;235:338-45.
38. Hulscher JB, van Sandick JW, de Boer
AG, et al. Extended transthoracic resection
compared with limited transhiatal resec-
tion for adenocarcinoma of the esophagus.
N Engl J Med 2002;347:1662-9.
39. Overholt BF, Lightdale CJ, Wang KK,
et al. Photodynamic therapy with porfim-
er sodium for ablation of high-grade dys-
plasia in Barrett’s esophagus: internation-
al, partially blinded, randomized phase
III trial. Gastrointest Endosc 2005;62:
488-98.
40. Overholt BF, Wang KK, Burdick JS, et
al. Five-year efficacy and safety of photo-
dynamic therapy with Photofrin in Bar-
rett’s high-grade dysplasia. Gastrointest
Endosc 2007;66:460-8.
41. Shaheen NJ, Sharma P, Overholt BF, et
al. Radiofrequency ablation in Barrett’s
esophagus with dysplasia. N Engl J Med
2009;360:2277-88.
42. Pech O, Behrens A, May A, et al. Long-
term results and risk factor analysis for
recurrence after curative endoscopic ther-
apy in 349 patients with high-grade intra-
epithelial neoplasia and mucosal adeno-
carcinoma in Barrett’s oesophagus. Gut
2008;57:1200-6.
43. Corley DA, Kerlikowske K, Verma R,
Buffler P. Protective association of aspi-
rin/NSAIDs and esophageal cancer: a sys-
tematic review and meta-analysis. Gastro-
enterology 2003;124:47-56.
44. Das D, Chilton AP, Jankowski JA.
Chemoprevention of oesophageal cancer
and the AspECT trial. Recent Results Can-
cer Res 2009;181:161-9.
45. Fitzgerald RC. Complex diseases in
gastroenterology and hepatology: GERD,
Barrett’s, and esophageal adenocarcinoma.
Clin Gastroenterol Hepatol 2005;3:529-37.
46. Rabinovitch PS, Longton G, Blount
PL, Levine DS, Reid BJ. Predictors of pro-
gression in Barrett’s esophagus III: base-
line flow cytometric variables. Am J Gas-
troenterol 2001;96:3071-83.
47. Reid BJ, Levine DS, Longton G, Blount
PL, Rabinovitch PS. Predictors of progres-
sion to cancer in Barrett’s esophagus:
baseline histology and flow cytometry
identify low- and high-risk patient subsets.
Am J Gastroenterol 2000;95:1669-76.
Copyright © 2009 Massachusetts Medical Society.

collections of articles on the journal’s web site

The Journal’s Web site (NEJM.org) sorts published articles into
more than 50 distinct clinical collections, which can be used as convenient
entry points to clinical content. In each collection, articles are cited in reverse
chronologic order, with the most recent first.

2556 n engl j med 361;26  nejm.org  december 24, 2009

Downloaded from www.nejm.org by ANASTACIO Q. SOUSA MD on December 25, 2009 .

Copyright © 2009 Massachusetts Medical Society. All rights reserved.