BARRETT'S ESOPHAGUS
From the 5th Annual Creighton University Medical Center Esophageal Conference
| DIAGNOSIS, SCREENING, AND SURVEILLANCE —Peter J. Kahrilas, MD, Gilbert H. Marquardt Professor of Medicine,
Division of Gastroenterology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago,
IL
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Esophageal Adenocarcinoma
| Incidence: exponential increase during last 20 yr related to increased incidence of gastroesophageal reflux disease
(GERD); largest increase seen among white men; overall incidence low (4-5 cases per 100,000 individuals)
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| Relationship to GERD: nationwide Swedish epidemiologic study identified all incident cases of esophageal adenocarcinoma;
symptoms during previous 5 yr ignored to avoid recall bias; 85% of eligible patients enrolled; one pathologist reviewed
all tissue samples; cases—118 of 189 patients with esophageal adenocarcinoma also had Barrett’s esophagus
(BE); comparative groups included individuals with adenocarcinoma of gastric cardia or esophageal squamous cell cancer
and controls; reflux—moderate to severe symptoms occurred in ≈10% of controls and ≈50% of individuals with
esophageal adenocarcinoma; moderate to severe symptoms uncommon among patients with squamous cell cancer and
only slightly increased among those with adenocarcinoma of gastric cardia; risk—patients with moderate to severe
symptoms of reflux have 20-fold higher risk (compared to those without symptoms) of developing adenocarcinoma, but
absolute risk low; applying relative risks found in Swedish study to United States population, absolute risk for adenocarcinoma
among patients with moderate to severe reflux symptoms estimated at 1 in 5000; obesity—significantly increases
risk for adenocarcinoma; incidence increases with body mass index (BMI) but remains relatively low;
conclusion—although GERD increases risk for adenocarcinoma, risk remains low (conclusion supported by data from
Veterans Affairs study)
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Barrett’s Esophagus
| Definitions: long-segment BE (LSBE)—metaplastic tongues extend \>3 cm onto esophageal mucosa; short-segment BE
(SSBE)—tongues <3 cm; histopathology—Alcian blue stains mucin-positive cells (hallmark); expanding definition—
traditionally, BE referred only to LSBE (2% of consecutive endoscopies in one series); by including patients with SSBE
(11% of endoscopic population) and intestinal metaplasia at gastroesophageal (GE) junction without visible correlates
(another 17%), up to 31% of population meet definition of BE; yet, adenocarcinoma rare
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| Genetic markers: numbers and types of mutations in epithelial cell lines provide surrogate markers of dysplasia (ie, potential
way to evaluate risk for cancer)
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| Risk reduction: large series shows risk for esophageal adenocarcinoma does not significantly decrease after medical or surgical
treatment for reflux; risk remains same as in general population, ie, ≈0.5% per year; published series exaggerate risk (series
with small numbers of patients make risk appear higher)
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| Symptom correlates: Swedish population-based endoscopic study found reflux symptoms, esophagitis, and presence of
Helicobacter pylori correlate poorly with presence of BE; esophagitis and presence of hiatal hernia somewhat predictive
of LSBE but not SSBE
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| Surveillance: Kaiser Permanente data—589 cases of esophageal and cardial adenocarcinoma identified; BE present in 135
patients, 112 of whom had late diagnoses (of these, 41 had endoscopy within 6 mo and nothing detected), leaving only 23 patients
(18 esophageal cancers and 5 cardial-cancers) eligible for surveillance; 8 of 23 patients had cancers detected due to
symptoms (dysphagia), leaving 15 patients for surveillance; 11 of 15 patients with surveillance-detected cancer survived long-
term (2.2% overall; 4 operative mortalities); screening and surveillance program in England—performed 30,000 endoscopies;
of 409 patients with LSBE, 35% eligible for surveillance (criteria based on age, health status, and willingness to participate);
143 patients in surveillance group; 144 endoscopies performed for changing symptoms, 379 surveillance
endoscopies detected cancer in 1 patient, who died 1 mo after esophagectomy; long-term follow-up (Chicago)—
surveillance appropriate for patients with adenocarcinomas that originate as high- or low-grade dysplasia; BE without dysplasia
rarely (if ever) develops into cancer; of 1125 high-risk patients, surveillance identified 22 incident cancers; only 1 cancer-
related death occurred; conclusion—intense surveillance of appropriate patients, followed by surgery only if cancer develops,
good approach to reducing mortality
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| Guidelines: American College of Gastroenterology guidelines for surveillance and treatment of BE, based on expert opinion;
screening endoscopy with biopsy recommended for patients with chronic GERD; patients with no dysplasia on 2
endoscopies—continue surveillance for 3 yr; patients with low-grade dysplasia—repeat endoscopy; perform annual endoscopies
until dysplasia absent; patients with high-grade dysplasia—repeat endoscopy with biopsy (evaluated by expert);
for patients with focal high-grade dysplasia, continue surveillance for 3 mo; perform endoscopic mucosal resection
for patients with mucosal irregularities; perform surgery on patients with multifocal dysplasia; conclusion—surveillance
in BE not effective; new strategy needed
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| GENETICS AND FAMILIAL PATTERNS —Henry T. Lynch, MD, Professor of Medicine, and Director and Chair, Department
of Preventive Medicine, Creighton University Medical Center, Omaha, NE
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| Family history: critical, but often neglected or insufficient; genetic counseling—full disclosure required before initiating;
patients need to understand risks (eg, insurance discrimination, psychologic effects, impact on family); currently, no evidence
for germline mutation for BE; cancer—detailed family history should include all types of cancer; little data correlating
BE with other types of cancer (colon cancer may have association); pedigree—detailed information about patient
(proband), his or her siblings and progeny, and maternal and paternal families; cancer history of older relatives especially
useful
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| Familial Barrett’s esophagus (FBE): patients with BE may have genetic predisposition to develop reflux (modified by environmental
factors); complex includes not only BE but also esophageal adenocarcinoma, and adenocarcinoma of GE
junction (both can arise in Barrett’s epithelium); relatives of patients with BE have increased prevalence of reflux and
may have increased risk for BE; overall prevalence of BE in reflux esophagitis in relatives may be greater than in general
population, but, when screening patients with reflux symptoms, age and duration of symptoms stronger predictors for development
of BE than having relative with BE; registry—initial findings show individuals with BE or associated conditions
more likely to have positive family history than controls; investigators recommend consideration of positive family
history when deciding whether to screen patients for BE
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| Prevalence of GERD: 10% to 20% of general population have GERD, and prevalence of BE in this group 3% to 7%; prevalence
of GERD among relatives of individuals with FBE higher than among relatives of individuals with sporadic BE
(≈45% vs ≈20%)
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| Endoscopic screening: study found LSBE, SSBE, and esophageal adenocarcinoma significantly more often among siblings
and offspring of patients with FBE than those with sporadic BE; endoscopic screening of relatives of probands with
sporadic BE did not identify any new familial BE pedigrees
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| Definition of FBE: inclusion criteria—if expanded to include GERD (among family members of proband), many cases
likely to be incorrectly identified as FBE; conservative definition—does not include SSBE or intestinal metaplasia of cardia
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| Risk factors for BE: Chak et al (2006) found no difference in major risk factors (eg, age, race) between groups (but differences
found in other studies)
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 | Prevalence of FBE: using strict definition of FBE, ≈7% of probands with BE fit criteria for FBE; ≈6.2% with adenocarcinoma
of esophagus and 9% with adenocarcinoma of GE junction have FBE; reasons for potential underestimation of
prevalence—not all relatives of probands underwent endoscopy; incomplete or unavailable medical histories for some
relatives
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| Etiology: FBE possibly related to environmental factors that may influence common germline mutation for susceptibility;
findings suggest autosomal dominant gene with incomplete but relatively high penetrance; once sufficient numbers of
families with FBE identified, modeling studies and linkage analysis may identify genes related to cancer susceptibility
and possible molecular evidence of germline mutation; incomplete penetrance—not all individuals with gene develop
traits, but they may transmit gene to progeny
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| Genetic testing: criteria—pedigree consistent with hereditary syndrome of concern; germline mutation identified; high-
risk patients identified with high degree of certainty; presence of cancer syndrome can be evaluated further and correlated
with phenotype; risks and benefits associated with genetic testing well understood; consent given after thorough explanation
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| ENDOSCOPIC INTERVENTION —Richard I. Rothstein, MD, Professor of Medicine, Dartmouth Medical School, Hanover;
Chief, Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, NH
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| Spectrum of disease: BE without dysplasia; BE with dysplasia; adenocarcinoma; goal of intervention—to alter progression
of disease
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| BE with high-grade dysplasia: treatment options—intensive surveillance to detect early cancer (followed by surgery);
esophagectomy for prophylaxis and to treat early cancer; endoscopic ablation and resection to remove neoplastic and
metaplastic mucosa (to prevent and treat early cancers)
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| Endoscopic therapy: goals—reduce risk for cancer; treat early cancer; avoid esophageal resection; techniques—
endoscopic mucosal resection (EMR); argon plasma multipolar coagulation; radiofrequency ablation (RFA); laser ablation;
cryoablation; photodynamic therapy (PDT); characteristics of ideal technique—access through mouth; removal of
all intestinal metaplasia; circumferential or focal ablation; short operative time; uniform ablation at target depth (to muscularis
mucosa; no deeper than submucosa); low risk for complications; EMR—associated with scarring, stricture formation,
and full-thickness surgical depth; target corrugated, thin-walled, not stationary, and immediately anterior to
mediastinum
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| Historical techniques: point-and-shoot—uses hand-held equipment; technically demanding; difficult to achieve uniform
depth; relies on visual end point; typically requires \>1 session; multipolar electrocoagulation—good results (85% complete
endoscopic reversal; 78% histologic reversal) but frequent complications (eg, strictures, chest pain, hospitalization);
argon plasma coagulation—early work showed good response but high frequency of buried glands and other complications;
summary—although older techniques associated with good early results, follow-up revealed complications and recurrence
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| Endoscopic mucosal resection: indications—high-grade intraepithelial neoplasia; well or moderately differentiated T1
mucosal lesions (ie, intramucosal cancer); absence of “suspicious” lymph nodes (staged with endoscopic ultrasonography);
techniques—inject and cut; simple snare techniques; cap-assisted EMR; EMR with ligation bands
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| Inject and cut: inject saline; raise and remove tissue (using, eg, needle knife)
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| Simple snare techniques: suction esophagus and pull lesion into open snare; slice off lesion; disadvantages—tedious and
problematic; status—mostly replaced by newer technologies
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| Cap-assisted EMR: mount cap on end of endoscope; inject saline into submucosal region of target lesion; position cap over
lesion; fold out snare from cap; suction and remove tissue
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| EMR with ligation bands: appropriate for focal and circumferential ablation and large-field removal; Duette system (Wilson-Cook)
uses multiband technology; snare can be passed through (no need to change endoscopes); good results;
candidates—patients with polypoid, elevated, or flat lesions, but not those with ulcerated or depressed lesions; lesions
<2 cm with low-grade malignancy; SSBE; not indicated for patients with—high-grade malignancies; LSBE (as primary
therapy); results—97% complete remission in patients with low-risk lesions; ≈60% complete remission in patients
with high-risk lesions; high rate of recurrence among patients with high-risk lesions; complications—stricture
(especially common with sequential resection); use in patients with LSBE—focal resection; combination with other
therapies (eg, RFA or cryoablation)
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| Photodynamic therapy: photosensitization of Barrett’s epithelium followed by laser-induced destruction of neoplastic
cells; done through balloon positioned in distal esophagus; mucosal sloughing seen 48 hr after treatment; 3 mo later, distal
esophagus appears mostly normal; disadvantages—persistent photosensitivity; multiple sessions associated with
high rate of stricture formation (may approach 50%); subsquamous Barrett’s mucosa may persist in some patients; disease
recurrence—5-yr follow-up found subsquamous cancer in 5% of patients and subsquamous Barrett’s mucosa in
5% of patients; combination therapy with omeprazole—in randomized trial, 2-yr follow-up showed 50% fewer cases of
high-grade dysplasia and cancer, compared to omeprazole alone; in previous study, 68% of patients suffered adverse
events, including strictures in 36%; 15 of 208 patients required multiple (up to 10) dilations; in recent paper comparing
PDT with outcome from experienced surgeons, mortality 9% with PDT, 8.5% with surgery
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| Radiofrequency ablation: radiofrequency generator used with balloon (eg, HALO360 ) or mounted on endoscope (eg,
HALO90 ); focal ablation to depth of 700 nm; HALO360 —first balloon measures esophageal circumference; appropriate-
sized electrode balloon fires energy (12 J for high- or low-grade dysplasia; 10 J for nondysplastic Barrett’s) in 1-sec allotments;
ablation completed in seconds; disadvantage—does not provide biopsy specimen for pathology (staging must already
be completed); clinical trials—RFA using 12 to 14 J eliminates high-grade dysplasia without submucosal injury;
smaller HALO90 used to treat ≈100 patients with nondysplastic BE; 2.5-yr follow-up showed complete response in
98.4% of patients and no buried glands; study of patients with high-grade dysplasia (13 of 23 previously treated with
EMR) found no stricture formation or serious adverse effects; technique associated with high rates of remission, regression
of genetic markers, and preservation of esophageal physiology; small study found similar results among patients
with low-grade dysplasia; open registry—included results from 13 centers using HALO360 ; complete regression of high-
grade dysplasia occurred in 88% of patients; complete regression of intestinal metaplasia occurred in 53% of patients
(100% regression anticipated after follow-up with HALO90 ); 1 small stricture; no buried glands; HALO90 —used to treat
high- and low-grade dysplasia and nondysplastic BE; so far, no strictures or serious adverse events; randomized trial under
way
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| Cryoablation: liquid nitrogen heated in catheter, then directed onto lesion; amount of freezing and depth of injury adjustable;
small study showed complete ablation of Barrett’s mucosa (resulting in complete endoscopic and histologic reversal
of Barrett’s epithelium) in 9 of 11 patients
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| Use in patients with nondysplastic BE: although patients at low risk for adenocarcinoma, treatment may be warranted if
safe and effective; support—nondysplastic mucosa may respond to treatment even better than dysplastic mucosa; small
treatment area; in theory, treatment can restore squamous epithelium; limitations—no proof of efficacy; potential for adverse
effects
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Suggested Reading
Anand O et al: Gastroesophageal reflux disease and Barrett’s esophagus. Endoscopy Dec 4, 2007 [Epub ahead of print];
Bright T et al: Randomized trial of argon plasma coagulation versus endoscopic surveillance for Barrett Esophagus after
antireflux surgery: late results. Ann Surg 246:1016, 2007; Chak A et al: Familiarity in Barrett’s esophagus, adenocarcinoma
of the esophagus, and adenocarcinoma of the gastroesophageal junction. Cancer Epidemiol Biomarkers Prev
15:1668, 2006; Dias Pereira A et al: Cancer risk in Barrett’s oesophagus. Eur J Gastroenterol Hepatol 19:915, 2007; Lagergren
J et al: Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. NEJM 340:825;
Larghi A et al: Long-term follow-up of complete Barrett’s eradication endoscopic mucosal resection (CBE-EMR) for the
treatment of high-grade dysplasia and intramucosal carcinoma. Endoscopy 39:1086, 2007; Roorda AK et al: Early experience
with radiofrequency energy ablation therapy for Barrett’s esophagus with and without dysplasia. Dis Esophagus
20:516, 2007; Peters FP et al: Endoscopic cap resection for treatment of early Barrett’s neoplasia is safe: a prospective
analysis of acute and early complications in 216 procedures. Dis Esophagus 20:510, 2007; Sappati Biyyani RS et al: Familial
trends of inheritance in gastroesophageal reflux disease, Barrett’s esophagus and Barrett’s adenocarcinoma: 20 families.
Dis Esophagus 20:53, 2007; Sharma P et al: Endoscopic therapy for high-grade dysplasia in Barrett’s esophagus:
ablate, resect, or both? Gastrointest Endosc 66:469, 2007; Society for Surgery of the Alimentary Tract: SSAT patient
care guidelines. Management of Barrett’s esophagus. J Gastrointest Surg 11:1213, 2007; Williams VA et al: Esophagectomy
for high-grade dysplasia is safe, curative, and results in good alimentary outcome. J Gastrointest Surg 11:1589, 2007.
Educational Objectives
| The goal of this program is to improve the management of Barrett’s esophagus (BE). After hearing and assimilating
this program, the clinician will be better able to:
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| 1. Discuss the impact of gastroesophageal reflux disease and BE on the relative and absolute risks for adenocarcinoma.
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| 2. Apply guidelines for screening, surveillance, and treatment of patients with BE.
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| 3. Compare and contrast sporadic and familial BE.
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| 4. List the endoscopic options for treating patients with BE, and describe the advantages and disadvantages of
each.
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| 5. Argue for or against the use of endoscopic therapies for the prophylactic treatment of patients with nondysplastic
BE.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and planning committe members to
disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified
conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or
commercial interest. For this program, the following has been disclosed: Dr. Kahrilas is affiliated with AstraZeneca; Dr. Rothstein
is affiliated with Bard, BARRX Medical, Boston Scientific, Ethicon, NDO, Olympus, and SafeStitch LLC. Dr. Lynch and the
planning committee reported nothing to disclose.
Acknowledgements
Drs. Kahrilas, Lynch, and Rothstein gave their scientific presentations at the 5th Annual Creighton University School of Medicine
Esophageal Conference held September 6-7, 2007, in Omaha, NE. The Audio-Digest Foundation thanks the speakers and
Creighton University School of Medicine for their cooperation in the production of this program.
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