REVIEW
Barrett’s Esophagus in 2008: an Update
Richard K. Wood and Yu-Xiao Yang

Division of Gastroenterology, Department of Medicine andCenter for Clinical Epidemiology and Biostatistics
University of Pennsylvania School of Medicine, Pennsylvania, USA(Received for publication on December 1, 2007)(Revised for publication on January 26, 2008)(Accepted for publication on March 27, 2008)

Abstract: With the rising incidence and overall poor prognosis of esophageal adenocarcinoma (EA) there is great interest in furthering our understanding of Barrett’s esophagus, theprecursor lesion for most cases of EA. The best available evidence from true populationbased analysis suggests that the prevalence of Barrett’s is 1.6%. In addition, nearly halfof the patients with Barrett’s are asymptomatic. Several risk factors for development ofBarrett’s have been identified including gastro-esophageal reflux disease (GERD), central
obesity, H. pylori eradication, and male gender. The precise incidence of progression from
Barrett’s to esophageal adenocarcinoma is not known, but it probably is less than 0.5% per
year, and our ability to predict who is at highest risk for progression remains poor. The degree of dysplasia is currently used as a marker for risk of progression to cancer though there
is increasing evidence that biomarkers and level of genetic instability may provide better
predictive measures. Intensive acid-suppression and COX-2 inhibition are potential strategies to reduce the risk of progression, though definitive studies are needed. Endoscopic surveillance remains the mainstay of management for non-dysplastic and low grade dysplasia
Barrett’s. The advent of various endoscopic ablative therapies has provided a promisingalternative to surgery for Barrett’s patients with high grade dysplasia (HGD). (Keio J Med 57(3) : 132－138, september 2008)
Key words: Barrett’s, High Grade Dysplasia, Barrett’s Surveillance

Introduction
Over the last 40 years, there has been a progressive risein the incidence rate of esophageal adenocarcinoma in
Western countries, and it now represents the most common form of cancer of the esophagus in the UnitedStates. This rise in incidence has affected whites andblacks of both sexes, though men are 6 to 8 times more
likely to develop esophageal adenocarcinoma than women, whereas whites are at a 3 to 4 times higher risk compared to blacks.1 On the positive side, our ability to detect disease at earlier stages has seen some improvement
over the past few decades with decreases in percentagesof distant or regional tumors and increases in cancer insitu.2 However, survival after diagnosis of esophageal
adenocarcinoma remains poor despite advances in ourdiagnostic and therapeutic endoscopic armamentarium.
One and five year survival rates for esophageal adenocarcinoma have increased over the past 30 years, though
they still remain dismal: 44% and 13% respectively.
The rising incidence of esophageal adenocarcinoma andits quite poor prognosis at the time of diagnosis have led
to increasing interest in preventative strategies. Barrett’s
esophagus is thought to be the precursor lesion in mostcases of esophageal adenocarcinoma, and a better understanding of this predisposing lesion could lead the way to
reducing the incidence and morbidity and mortality associated with adenocarcinoma of the esophagus.
Definition of Barrett’s
Barrett’s esophagus was first recognized in the early

Presented at the 1529th meeting of the keio Medical society in Tokyo, August 24, 2007
Corresponding Author: Yu-Xiao Yang, M.D., M.S.C.E. Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania 722 Blockley Hall, 423
Guardian Drive, Philadelphia, Pennsylvania 19104-6021, U.S.A., Phone: 1-215-573-5027, Fax: 1-215-349-5915, Email: yangy@mail.med.upenn.edu
132

Keio J Med 2008; 57 (3): 132 －138

1950’s with the advent of endoscopic visualization techniques and the condition was first termed “congenitallyshort esophagus pulling stomach into chest.” The definition of Barrett’s progressed through multiple variations
over the ensuing years until the consensus definition ofintestinal metaplasia of the distal esophagus of any
length was formulated in the 1990’s. Metaplasia issometimes subdivided according to the Japanese nomenclature as incomplete or complete based on the presence(complete) or absence (incomplete) of digestive enzymes. It is felt that incomplete metaplasia occurs laterin the transformative process in the esophagus and may
be an indicator of increased risk for high grade dysplasia
or cancer risk.3 Endoscopic characterization of Barrett’s
lesions has undergone further evolution. Previous attempts to develop a standardized reporting system led toa classification scheme which described lesions as short(<3cm) or long (>3cm) segments. This method of reporting is common in the literature, with long segment
Barrett’s felt to be associated with a higher risk of progression to esophageal adenocarcinoma. However, there
is wide variability in this reporting system and the lengthof an individual lesion does not sufficiently describe theburden of disease. A recent international working group
was formed to address this issue and developed a newclassification system which is comprised of the circumferential and the maximal extent of esophageal columnar
tissue, the Prague C and M criteria.4 Future investigations utilizing these new criteria will need to be done toassess its reporting variability and ability to discriminate
patients at higher risk for progression to esophageal adenocarcinoma.
Prevalence of Barrett’s
The true prevalence of Barrett’s esophagus in the general population is not known with certainty due to few
existing population-based studies. One study from theUnited States investigated a cohort of 961 patients over
the age of 40 undergoing colonoscopy and reported aprevalence of Barrett’s esophagus of 6.8% in all patients.5 The only true population-based study of 1000
Swedish volunteers found a prevalence of Barrett’s of
1.6%.6 Studies from Asia suggest an overall lower prevalence compared to Western countries. Two recent prospective studies in Japan found a prevalence of 0.4 to
1.2% of Barrett’s esophagus among patients undergoing
upper endoscopies for various indications.7 Among patients presenting with symptoms, prevalence rates of 2%
to 3% have been reported in the Asian literature.
Screening for Barrett’s
An effective screening program for Barrett’s would result in early detection of the condition or a cancerous le-133sion and lead to either intervention or surveillance, which
would decrease the incidence of esophageal adenocarcinoma or cancer-related deaths. The low prevalence ofBarrett’s esophagus in the general population makes thiscondition unfavorable for screening with upper endoscopy in the general population and The American Gastroenterological Association Chicago Workshop in 2003,
failed to endorse routine screening for Barrett’s with upper endoscopy due to a lack of well-designed and controlled studies demonstrating an improvement in outcome with screening protocols.8 Targeted screening ofpatients at higher risk for development of Barrett’s has
been considered and The American of College of Gastroenterology Practice Guidelines for Barrett’s Esophagus
states, “Patients with chronic GERD symptoms are thosemost likely to have Barrett’s esophagus and should undergo upper endoscopy.9” Several studies suggest thatscreening of older male patients with GERD symptoms
may be cost-effective.10-11 However, it remains unclear
who is most likely to benefit from a targeted screening
protocol since a large percentage of patients with incident cases of Barrett’s do not report GERD symptoms
and it remains difficult to predict those patients with Barrett’s who will progress to high grade dysplasia or cancer. Thus, screening for Barrett’s remains controversial.
However, if the prevalence of Barrett’s and esophageal
adenocarcinoma continue to rise, we may see a shift in
the pendulum favoring screening protocols in the future.
Esophageal capsule endoscopy (ECE) has attracted interest in its use for screening and surveillance for Barrett’s
due to its less invasiveness, lack of sedation and decreased complication rate. One recent study by Lin et al.
evaluated the operating characteristics of ECE for detection of Barrett’s in 96 patients and found ECE was only
67% sensitive and 84% specific for identifying Barrett’s
esophagus.1 2 Two recent studies compared traditional
upper endoscopy vs ECE for Barrett’s screening. In bothstudies, use of ECE for screening was found to be lesseffective and more expensive than traditional upper endoscopy screening.1 3-1 4. Based on the data gathered todate, ECE does not have a clear role in Barrett’s screening.
Risk Factors for Barrett’s
Gastroesophageal Reflux Disease
Several risk factors for the development of Barrett’s
esophagus and esophageal adenocarcinoma have been
identified. Gastro-esophageal reflux disease (GERD) duration and severity are associated with risk for Barrett’s
and esophageal adenocarcinoma. Compared with patients with symptoms of GERD for less than 1 year, theodds ratio for Barrett’s esophagus in patients with GERD
symptoms for 1-5 years was 3.0 and increased to 6.4 in134patients with symptoms for more than 10 years.15 In the
study by Rex et al. reporting of heartburn symptoms wasmore common among those with long-segment Barrett’s(55%) than those with short-segment Barrett’s (13%)
suggesting that greater burden of disease may be more
likely to be symptomatic.5 Consistent with these data,
in a Swedish study of 451 cases of esophageal adenocarcinoma, the risk of cancer increased with increasing frequency and duration of GERD symptoms16 Despite thisstrong association several recent studies have demonstrated that a substantial number of patients with Barrett’s and esophageal adenocarcinoma do not report heartburn symptoms. In the study by Ronkainen et al, 43% ofidentified cases of Barrett’s did not report heartburn
symptoms.6 Findings from a recent trial in which Barrett’s esophagus was detected in 25% of asymptomaticpatients undergoing colonoscopy lend further support tothe fact that development of Barrett’s can be asymptomatic.17 Data from a systematic review of incident esophageal adenocarcinoma cases found the prior prevalenceof Barrett’s at the time of surgical resection as low as 5%
suggesting that a large number of patients with underlying Barrett’s are going undetected prior to the development of adenocarcinoma.18 The data taken together suggest two likely explanations: 1. Patients with preceding
GERD symptoms are not being screened appropriately
and 2. A significant proportion of patients are asymptomatic at the time of diagnosis of Barrett’s and esophageal adenocarcinoma. It remains uncertain whether patients who do not report symptoms truly do not have
GERD, or if they have GERD without symptoms. Furthermore, it is unclear if Barrett’s in the absence of
GERD symptoms carries the same risk as symptomatic
Barrett’s.
Obesity
The rise in incidence of Barrett’s and esophageal adenocarcinoma mirrors the obesity epidemic in Westerncountries. This temporal relationship has generated interest in a possible link between the two conditions. In a
Swedish study of 189 cases of newly diagnosed esophageal adenocarcinoma, a strong positive association was
found between BMI and esophageal adenocarcinoma
when controlling for GERD symptoms.19 A study fromthe Veterans Association in the United States found thosewith a BMI > 30 had a 4 fold greater risk for Barrett’s
esophagus when compared to controls with a BMI < 25.
Central obesity in this study was independently associated with Barrett’s esophagus when controlling for BMI
suggesting that central obesity, and not only BMI, wasthe link with Barrett’s esophagus. 2 0 More recently,
Corely et al. found that waist circumference, but not
BMI, had modest independent associations with the riskof Barrett’s esophagus and Edelstein et al. found higher

Wood RK and Yang YX: Barrett’s Esophagus Update

waist to hip ratios to be associated with Barrett’s esophagus when adjusted for GERD symptoms and BMI.2 1-2 2Thus, it appears central adiposity may play a role in thedevelopment of Barrett’s esophagus and esophageal adenocarcinoma, independent of GERD symptoms and
BMI. Further investigation is needed to determine thepathophysiologic mechanism underlying this association.
Male Sex
There is a clear gender difference in the prevalence ofBarrett’s, with men outnumbering women by 8 fold.
This gender difference is attenuated in the progression toesophageal cancer with a male:female ratio of only 2:1
being observed. The gender difference observation raises the possibility of a protective effect of estrogen or
perhaps, a deleterious effect of androgen in Barrett’s development and/or progression. However, small studies
investigating childbearing status, hormone replacement
therapy or antiandrogen therapy23 have found these to be
non-protective factors. Further investigation is needed
to determine the underlying mechanisms leading to thesegender differences.
Helicobacter pylori eradication
Several studies have looked at the role Helicobacter
pylori infection may play in Barrett’s esophagus andesophageal adenocarcinoma. Two main mechanisticroles for formation of Barrett’s and esophageal adenocarcinoma have been postulated for H. pylori infection: 1.
Induction of atrophic gastritis which results in less gastric acid secretion and 2. Neutralization of the gastricacid by ammonia production independent of gastric atrophy. Ye et al. found Cag-A positive H. pylori infection
to be associated with a significantly reduced risk ofesophageal adenocarcinoma (OR 0.3), however this association was independent of gastric atrophy and suggested a mechanism other than a less acidic gastric refluxate.24 As the prevalence of H. pylori infection falls
throughout the world, particularly in countries like Japan, it remains to be seen if this will lead to an increase
in incidence for Barrett’s esophagus and esophageal adenocarcinoma.7 Additional factors likely play a role indevelopment of Barrett’s esophagus and adenocarcinoma. Duodenal reflux, smoking, and alcohol have all
been linked to these conditions and further investigationis needed to identify additional risk factors.
Progression of Barrett’s to Esophageal Adenocarcinoma
Incidence of Progression
Early studies reported 5% to 10% of patients diagnosed
with Barrett’s esophagus develop esophageal adenocar-

Keio J Med 2008; 57 (3): 132 －138

cinoma over their lifetime.25-26 Predicting who is likely
to progress from Barrett’s esophagus to dysplasia andadenocarcinoma is difficult and this uncertainty has leadto acceptance of surveillance protocols in patients with
documented Barrett’s esophagus. Adequate evaluationof the cost-effectiveness of these surveillance practices
requires knowledge of the true incidence of progression
from Barrett’s to cancer. However, the true incidence ofprogression in this population is uncertain for several
reasons. First, no longitudinal study has included asymptomatic Barrett’s patients. Second, the risk of adenocarcinoma of the esophagus in asymptomatic patientsis unknown. Lastly, it is unlikely that the risk of progression to adenocarcinoma is constant for each year in apatient with Barrett’s. Prior studies evaluating the reported incidence of adenocarcinoma in the Barrett’s population have noted a paucity of studies with small sample
sizes reporting lower incidence rates.27 One explanation
for this observation is publication bias. Alternatively,
heterogeneity in study factors such as patient risk, surveillance rigor, validity of Barrett’s diagnosis, and follow
up may also play a role in the observed inverse relationship in study size and reported cancer risk.
Predictors of Progression
The current management strategy for prevention andearly detection of cancer in patients with Barrett’s esophagus is targeted at detection of dysplasia as it is felt toprovide information on the likelihood for progression tocancer. However, low grade dysplasia is non-specific for
cancer and is associated high inter-observer and intraobserver variability. Due to these limitations, its significance regarding risk of progression to adenocarcinoma is
uncertain. Alternatively, the finding of high grade dysplasia has lower inter-observer and intra-observer variability and estimates suggest that 30-50% of these cases
harbor concurrent cancer. Thus, a histologic finding ofhigh grade dysplasia is felt to carry a significant likelihood of progression to cancer though overall it is an imperfect measure of cancer risk.
Dysplasia is the phenotypic expression of underlying
DNA damage and is an intermediate between undamaged cells and cancer. A more useful predictor for the
likelihood of progression to cancer would be a marker
for the DNA damage which could be detected prior to
the expression of dysplasia. Inactivation of the tumor
suppressor gene, p53, through a mutation that leads toloss of heterozygosity of 17p is found in 50% to 90% of
esophageal adenocarcinoma.2 8 Biopsies of Barrett’s
esophagus have found inactivation of the tumor suppressor gene p16 via methylation, loss of heterozygosity, or
mutation in 73%-87% of patients, and there is some evidence that this inactivation is the first genetic lesion in
neoplastic progression of Barrett’s cells.2 9-3 0 COX-2

135

over-expression has been detected in Barrett’s esophagus
as well as esophageal adenocarcinoma and in vitro studies have demonstrated reduced rates of apoptosis withoverexpression.31 Aneuploidy is a marker of genetic instability and is defined as a genetic abnormality in which
the total DNA content of cells is different from the normal diploid (2n) or tetraploid (4n) amount. Tetraploidy
is considered abnormal if it is found in > 6% of cells in atissue and this condition is referred to as an elevated 4n
fraction. Both aneuploidy and elevated 4n fraction conditions were recently evaluated in a large study of Barrett’s patients followed over 5 years in which flow cytometry was performed at baseline. In patients with aneuploidy as defined by populations with over 2.7n, the 5year incident rate for cancer was 64%, whereas patientswith an elevated 4n fraction had a 5 year incident rate of
57%. In those with both aneuploidy and tetraploidy, the5 year incident rate of cancer was 75% compared to only
5.2% in patients without either baseline condition, andall patients in the latter group had high grade dysplasia
on histology.3 2 Further understanding of the mechanisms underlying cancer formation will likely lead theway to identification of additional biomarkers and measures of genetic instability as well as refinement of existing measures with the goal of better predicting those
who are likely to progress from Barrett’s to cancer.
Management of Barrett’s
Surveillance
Once the Barrett’s diagnosis is made, the current
guidelines from the American College of Gastroenterology (ACG) recommend a surveillance protocol based
upon the histologic diagnosis. For Barrett’s patients who
have no dysplasia on biopsies from 2 endoscopies, surveillance endoscopy should be repeated every 3 years. A
patient with low-grade dysplasia (LGD) on biopsy
should have repeat endoscopy and if low-grade is confirmed, that patient should undergo repeat endoscopy every year until no dysplasia is observed. For those withhigh-grade dysplasia (HGD) on biopsy, a repeat endoscopy should be performed to evaluate for cancer and thepathology should be reviewed by an expert gastrointestinal pathologist. Further intervention is determined by
the specific findings. In focal high grade dysplasia, follow-up endoscopy is recommended in 3 months. For
multi-focal high grade dysplasia, surgery or photodynamic therapy is recommended. And if mucosal irregularity is seen, endoscopic mucosal resection followed bysurgery or photodynamic therapy is advised. These recommendations represent the most recent consensus algorithm from the ACG based on the data available at thetime it was formulated. It is important to note several
shortcomings associated with traditional optical endo-

136

scopic surveillance. There is a limitation to the biopsy
sample size with endoscopy and significant intra and inter-observer variability exists. Technological advances
may eliminate some of these limitations. Several new
promising techniques include narrow band imaging,
chromoendoscopy, high resolution endoscopy, and autofluorescence imaging. However, each of these techniques will need to demonstrate reproducibility, prove tobe easily applied, and cost-effective. Improved endoscopic mucosal resection and endoluminal eradication
techniques are being increasingly utilized for high grade
dysplastic and intramucosal carcinoma lesions and may
provide an alternative means to surgery for managementof these conditions.
Secondary Prevention
Secondary prevention in Barrett’s can be thought of in
two parts: anti-reflux surgery and chemoprevention. Anti-reflux surgery has been shown to effectively alleviate
reflux symptoms in Barrett’s patients. However, thelong-term durability of surgery is an ongoing question.
Furthermore, reports of post-operative development ofdysplasia and cancer in addition to the increasing recognition of a significant percentage of patients who develop Barrett’s and esophageal adenocarcinoma without
precedent GERD, raise significant questions about theutility of this procedure for secondary prevention.
The most data for chemoprevention in Barrett’s focus
on acid suppression and COX-2 inhibition. A study using ex vivo Barrett’s tissue appears to suggest that complete elimination of acid in the distal esophagus is required in order for acid suppression to have an impact on
reducing progression of intestinal metaplasia to dysplasia.33 Bearing this point in mind, it is important to notethat anti-acid therapy sufficient to eliminate symptomsof reflux may not adequately suppress acid exposure in
the distal esophagus.3 4 In a study comparing proton
pump inhibitor (PPI) to Histamine-2 blockers in patientswith Barrett’s, both were successful in eliminating symptoms of reflux though only the PPI therapy demonstrated
nearly complete elimination of acid exposure at the distal
esophagus and significant regression in the area andlength of Barrett’s. Whether acid suppression therapy
will reduce the cancer risk in Barrett’s will require a prospective randomized control study with a sufficient sample size and follow up time and documentation of abolished acid exposure.
COX-2 expression may affect Barrett’s progression
through several mechanisms including increasing proliferation, promoting angiogenesis, and increasing the invasiveness and metastatic potential of Barrett’s cells.
COX-2 overexpression in Barrett’s cells leads to reduced
apoptosis in vitro.3 1 Selective inhibition of COX-2 candecrease the rate of proliferation of Barrett’s cells as well

Wood RK and Yang YX: Barrett’s Esophagus Update

as esophageal adenocarcinoma cells in an animalmodel.35 Though COX-2 inhibition remains an intriguing area of research in the area of Barrett’s progression,
the cardiovascular risk associated with COX-2 inhibitors
recently described36 may limit the practical applicationsof these findings.
High Grade Dysplasia or Intra-mucosal Cancer: Endoscopic Therapy or Surgical Esophagectomy
Estimates for risk of progression from high-grade dysplasia (HGD) to cancer vary from 5% to 59% up to 7
years from initial diagnosis.37-38 Unsuspected carcinoma
may be detected at esophagectomy performed for highgrade dysplasia in 40% of cases.39 Currently, there is noagreement among the United States gastrointestinal society guidelines for management of HGD in Barrett’s
esophagus. However, it is recommended that whenever
HGD is found, it should be confirmed by an experienced
gastrointestinal pathologist.
Due to the malignant potential associated with Barrett’s
lesions with HGD, esophagectomy has traditionally been
the recommended treatment for patients with high grade
dysplasia or intramucosal cancer who were deemed appropriate surgical candidates. This remains an option for
selected patients though multiple studies have confirmed
improved outcomes at centers with high surgical volume.
Over the past 2 decades endoscopic esophageal mucosal
ablative techniques such as photodynamic therapy, argon
plasma coagulation, and laser therapy have been utilized
for advanced Barrett’s lesions. Additionally, endoscopic
mucosal resection techniques have been utilized toachieve potentially curative removal of the Barrett’s mucosa, allow for histological examination of resections
and reduce the morbidity associated with surgical esophagectomy. Endoscopic mucosal therapy is generally reserved for those at highest risk for cancer (HGD or intramucosal cancer) and currently does not have a role inpatients with low-grade dysplasia or non-dysplastic Barrett’s.
Existing data suggest that coupled with a rigorous surveillance program, mucosal ablative therapy may be areasonable alternative to surgery in carefully selected patients with HGD. In a Veterans Administration study ofBarrett’s esophagus, 79 of 1099 (7.2%) of patients were
found to have HGD. At one year follow up, 75 of the79 patients remained cancer free whereas at 7 year follow up, 12 of 79 (16%) developed cancer. 11 of 12 patients were subsequently considered cured with surgicalor ablative therapy.38 In a recent study comparing ablative therapy with photodynamic therapy (PDT)/endoscopic
mucosal resection (EMR) to surgical esophagectomy,
mortality rates were similar at 9% and 8.5% respectively.
30% of patients in the ablative group had recurrence of
HGD with 5.4% progressing onto cancer. Of note,Keio J Med 2008; 57 (3): 132 －138

12.7% of patients in the surgical group had cancer in resected specimen.4 0 Ongoing investigations with newer
techniques such as radiofrequency ablation and circumferential EMR in addition to combination EMR and thermal methods, should add to our understanding of theutility of endoscopic mucosal ablation for the management HGD. Though at this time, the optimal approachto management of HGD remains controversial.

137

9.

10.

11.

Conclusion
Barrett’s esophagus remains an area of great interest as
it is the precursor lesion in most cases of esophageal adenocarcinoma, a malignancy with increasing incidencein Western countries. Several risk factors for Barrett’s
esophagus have been identified in recent years thoughfurther work is needed to improve our ability to detect
Barrett’s in patients, particularly those who do not report
reflux symptoms. Furthermore, additional work is required to determine who with Barrett’s will progress to
HGD and cancer, and additional studies investigating
biomarkers and measures of genetic instability may allow us to more accurately identify those at high risk forprogression. The management of HGD remains controversial with many endoscopic ablative techniques available and ongoing studies to evaluate combination therapies and emerging technologies will hopefully add to ourknowledge in this area.

12.

References

18.

1.

2.

3.

4.

5.

6.

7.
8.

El-Serag HB, Mason AC, Petersen N, Key CR: Epidemiologicaldifferences between adenocarcinoma of the oesophagus and adenocarcinoma of the gastric cardia in the USA. Gut 2002; 50: 368－372
Eloubeidi MA, Mason AC, Desmond RA, El-Serag HB: Temporal
trends (1973-1997) in survival of patients with esophageal adenocarcinoma in the united states: A glimmer of hope? American
Journal of Gastroenterology 2003; 98: 1627－1633
Piazuelo MB, Haque S, Delgado, Alberto: Du, Joanna X., Rodriguez F, Correa P: Phenotypic differences between gastric andesophageal intestinal metaplasia. Modern Pathology 2004; 17: 62－74
Sharma P, Dent J, Armstrong D, Bergman JJGHM, Gossner L,
Hoshihara Y, et al.: The development and validation of an endoscopic grading system for barrett’s esophagus: The prague C & M
criteria. Gastroenterology 2006; 131: 1392－1399
Rex DK, Cummings OW, Shaw M, Cumings MD, Wong RKH,
Vasudeva RS, et al.: Screening for barrett’s esophagus in colonoscopy patients with and without heartburn. Gastroenterology
2003;125:1670－1677
Ronkainen J, Aro P, Storskrubb T, Johansson S, Lind T, BollingSternevald E, et al.: Prevalence of barrett’s esophagus in the general population: An endoscopic study. Gastroenterology 2005;
129: 1825－1831
Hongo M: Review article: Barrett’s oesophagus and carcinoma injapan. Alimentary Pharmacology & Therapeutics 2004; 20 Suppl
8: 50－54
Sharma P, McQuaid K, Dent J, Fennerty MB, Sampliner R,
Spechler S, et al.: A critical review of the diagnosis and management of barrett’s esophagus: The AGA chicago workshop. Gastro-

13.
14.

15.

16.
17.

19.
20.
21.
22.
23.

24.

25.
26.
27.

enterology 2004; 127: 310－330
Sampliner RE, Practice Parameters Committee of the American
College of Gastroenterology: Updated guidelines for the diagnosis, surveillance, and therapy of barrett’s esophagus. Am J Gastroenterol 2002; 97: 1888－1895
Inadomi JM, Sampliner R, Lagergren J, Lieberman D, Fendrick
AM, Vakil N: Screening and surveillance for barrett esophagus in
high-risk groups: A cost-utility analysis. Ann Intern Med 2003;
138: 176－186
Gerson LB, Groeneveld PW, Triadafilopoulos G: Cost-effectiveness model of endoscopic screening and surveillance in patientswith gastroesophageal reflux disease. Clin Gastroenterol Hepatol
2004; 2: 868－879
Lin OS, Schembre DB, Mergener K, Spaulding W, Lomah N,
Ayub K, et al.: Blinded comparison of esophageal capsule endoscopy versus conventional endoscopy for a diagnosis of barrett’s
esophagus in patients with chronic gastroesophageal reflux. Gastrointestinal Endoscopy 2007; 65: 577－583
Gerson L, Lin OS. Cost-benefit analysis of capsule endoscopy
compared with standard upper endoscopy for the detection of barrett’s esophagus. Clin Gastroenterol Hepatol 2007; 5: 319－325
Rubenstein JH, Inadomi JM, Brill JV, Eisen GM: Cost utility ofscreening for barrett’s esophagus with esophageal capsule endoscopy versus conventional upper endoscopy. Clin Gastroenterol
Hepatol 2007; 5: 312－318
Lieberman DA, Oehlke M, Helfand M: Risk factors for barrett’s
esophagus in community-based practice. GORGE consortium.
gastroenterology outcomes research group in endoscopy. Am J
Gastroenterol 1997; 92: 1293－1297
Lagergren J, Bergstrom R, Lindgren A, Nyren O: Symptomatic
gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med 1999; 340: 825－831
Gerson LB, Shetler K, Triadafilopoulos G: Prevalence of barrett’s
esophagus in asymptomatic individuals. Gastroenterology 2002;
123: 461－467
Dulai GS, Guha S, Kahn KL, Gornbein J, Weinstein WM: Preoperative prevalence of barrett’s esophagus in esophageal adenocarcinoma: A systematic review. Gastroenterology 2002; 122: 26－33
Lagergren J, Bergstrom R, Nyren O: Association between bodymass and adenocarcinoma of the esophagus and gastric cardia.
Ann Intern Med 1999; 130: 883－890
El-Serag HB, Kvapil P, Hacken-Bitar J, Kramer JR: Abdominal
obesity and the risk of barrett’s esophagus. American Journal of
Gastroenterology 2005; 100: 2151－216
Corley DA, Kubo A, Levin TR, Block G, Habel L, Zhao W, et al.:Abdominal obesity and body mass index as risk factors for Barrett’s esophagus. Gastroenterology 2007; 133: 34－41
Edelstein ZR, Farrow DC, Bronner MP, Rosen SN, Vaughan TL:
Central adiposity and risk of barrett’s esophagus. Gastroenterology 2007; 133: 403－411
Lagergren J, Nyren O: Do sex hormones play a role in the etiology of esophageal adenocarcinoma? A new hypothesis tested in a
population-based cohort of prostate cancer patients. Cancer Epidemiol Biomarkers Prev 1998; 7: 913－915
Ye W, Held M, Lagergren J, Engstrand L, Blot WJ, McLaughlin
JK, et al.: Helicobacter pylori infection and gastric atrophy: Riskof adenocarcinoma and squamous-cell carcinoma of the esophagus and adenocarcinoma of the gastric cardia. Journal of the National Cancer Institute 2004; 96: 388－396
Cameron AJ, Ott BJ, Payne WS: The incidence of adenocarcinoma in columnar-lined (barrett’s) esophagus. N Engl J Med 1985;
313: 857－859
Reid BJ, Weinstein WM: Barrett’s esophagus and adenocarcinoma. Annu Rev Med 1987; 38: 477－492
Shaheen NJ, Crosby MA, Bozymski EM, Sandler RS: Is there
publication bias in the reporting of cancer risk in barrett’s esophagus? Gastroenterology 2000; 119: 333－338

138
28. Galipeau PC, Prevo LJ, Sanchez CA, Longton GM, Reid BJ:
Clonal expansion and loss of heterozygosity at chromosomes 9p
and 17p in premalignant esophageal (barrett’s) tissue. J Natl Cancer Inst 1999; 91: 2087－2095
29. Wong DJ, Paulson TG, Prevo LJ, Galipeau PC, Longton G,
Blount PL, et al.: p16(INK4a) lesions are common, early abnormalities that undergo clonal expansion in barrett’s metaplastic epithelium. Cancer Res 2001; 61: 8284－8289
30. Maley CC, Galipeau PC, Finley JC, Wongsurawat VJ, Li X, Sanchez CA, et al.: Genetic clonal diversity predicts progression toesophageal adenocarcinoma. Nat Genet 2006; 38: 468－473
31. Wilson KT, Fu S, Ramanujam KS, Meltzer SJ: Increased expression of inducible nitric oxide synthase and cyclooxygenase-2 inbarrett’s esophagus and associated adenocarcinomas. Cancer Res
1998; 58: 2929－2934
32. Rabinovitch PS, Longton G, Blount PL, Levine DS, Reid BJ: Predictors of progression in barrett’s esophagus III: Baseline flow
cytometric variables. Am J Gastroenterol 2001; 96: 3071－3083
33. Fitzgerald RC, Omary MB, Triadafilopoulos G: Dynamic effectsof acid on barrett’s esophagus. an ex vivo proliferation and differentiation model. Journal of Clinical Investigation 1996; 98: 2120
－2028
34. Katzka DA, Castell DO: Successful elimination of reflux symptoms does not insure adequate control of acid reflux in patients

Wood RK and Yang YX: Barrett’s Esophagus Updatewith barrett’s esophagus. Am J Gastroenterol 1994; 89: 989－991
35. Buttar NS, Wang KK, Sebo TJ, Riehle DM, Krishnadath KK,
Lutzke LS, et al. Extent of high-grade dysplasia in barrett’s
esophagus correlates with risk of adenocarcinoma. Gastroenterology 2001; 120: 1630－1639
36. Kerr DJ, Dunn JA, Langman MJ, Smith JL, Midgley RS, StanleyA, et al.: Rofecoxib and cardiovascular adverse events in adjuvant treatment of colorectal cancer. N Engl J Med 2007; 357: 360－369
37. Reid BJ, Levine DS, Longton G, Blount PL, Rabinovitch PS: Predictors of progression to cancer in barrett’s esophagus: Baseline
histology and flow cytometry identify low- and high-risk patient
subsets. Am J Gastroenterol 2000; 95: 1669－1676
38. Schnell TG, Sontag SJ, Chejfec G, Aranha G, Metz A, O’Connell
S, et al.: Long-term nonsurgical management of barrett’s esophagus with high-grade dysplasia. Gastroenterology 2001; 120: 1607
－1619
39. Pellegrini CA, Pohl D: High-grade dysplasia in barrett’s esophagus: Surveillance or operation? J Gastrointest Surg 2000; 4: 131－
134
40. Prasad GA, Wang KK, Buttar NS, Wongkeesong L, Krishnadath
KK, Nichols FC,3rd, et al.: Long-term survival following endoscopic and surgical treatment of high-grade dysplasia in barrett’s
esophagus. Gastroenterology 2007; 132: 1226－1233