Barrett`s Esophagus - Cleveland Clinic

Barrett’s Esophagus
Gary W. Falk, M.D., M.S.
Professor of Medicine
Division of Gastroenterology
Perelman School of Medicine of the
University of Pennsylvania
CCF Intensive Review of Gastroenterology & Hepatology
Barrett’s Esophagus
Columnar distal
esophagus
Intestinal Metaplasia
1
Definition of Barrett’s Esophagus:
2011 AGA Medical Position Paper
• Any extent of metaplastic columnar
epithelium that predisposes to cancer
replaces normal squamous epithelium in
distal esophagus
• Intestinal metaplasia required for diagnosis
• Only cell type that clearly predisposes to
malignancy
From Spechler SJ et al. Gastroenterology 2011;140:1084-91.
Barrett’s Esophagus 2012:
Definition Varies
• ACG, ASGE, AGA
• Recognizable change in lining of any length
• Intestinal metaplasia
• BSG, Montreal consensus
• Recognizable change in lining of any length
• Columnar metaplasia
2
Definition of Barrett’s Esophagus:
2011 AGA Medical Position Paper
• Cardia type epithelium may be
risk for malignancy
• Magnitude of risk unclear
• Surveillance not justified for
cardia type epithelium
From Spechler SJ et al. Gastroenterology 2011;140:1084-91
Incidence of Barrett's Esophagus Over Time
In The Netherlands
From Van Soest E M et al. Gut 2005;54:1062-1066.
3
Prevalence of Barrett’s Esophagus
in VA GERD Patients at Initial EGD
• 378 GERD patients
• Barrett’s esophagus in 13.2%
• LSBE-36%
• SSBE-64%
From Westhoff B et al. Gastrointest Endosc 2005;61:226-31.
Prevalence of Barrett’s Esophagus
in General Population of Sweden
Cases
(%)
% with
GERD
symptoms
% with
esophagitis
BE
LSBE
SSBE
(> 2cm) (< 2cm)
No BE
16
(1.6%)
56.3%
5
(0.5%)
80.0%
11
(1.1%)
45.5%
984
(98.4%)
39.7%
25.0%
60.0%
9.1%
15.4%
From Ronikainen J et al. Gastroenterology 2005;129:1825-31.
4
Barrett’s Esophagus Epidemiology:
Risk Factors
•
•
•
•
•
•
Male (4:1)
Caucasian
Increasing age
Frequent long standing reflux symptoms
Smoking
Obesity
• Especially central male pattern
Pathogenesis of Barrett’s
Esophagus
From Souza R et al. Am J Physiol 2008;295:G211-8.
5
Barrett’s Esophagus: Candidate
Cell of Origin
• Squamous epithelium
• Dedifferentiation
• Stem cells
• Basal layer of epithelium
• Submucosal glands
• Bone marrow
• Residual embryonal stem cells
• Transcription factor CDX2 promotes columnar
differentiation induced by
• Acid
• Bile
Diagnosis of Barrett’s Esophagus:
AGA Medical Position Paper
• Proximal extent of gastric folds as
landmark of GEJ
• Systemic recording using Prague
classification advocated
• Increased length as marker for:
• Intestinal metaplasia
• Cancer risk
• Severity of underlying GERD
From Spechler SJ et al. Gastroenterology 2011;140:1084-91.
6
Barrett’s Esophagus:
The Prague Classification
From Sharma P et al. Gastroenterology 2006;131:1392-9.
How Good is the Prague
Classification?
C value
Reliability
Coefficient
0.94
Intepretation
Almost perfect
M value
0.93
Almost perfect
Length > 1 cm
0.72
Substantial
Length < 1 cm
0.21
Slight
From Sharma P et al. Gastroenterology 2006;131:1392-9.
7
Yield of Endoscopy for Detection of
Intestinal Metaplasia
From Harrison R et al. Am J Gastroenterol 2007;102:1154-61.
Does IM Matter? Cellular DNA Content
in Gastric and Columnar Metaplasia
From Liu W et al. Am J Gastroenterol 2009;104:816-24.
8
To Biopsy Or Not To Biopsy?
• Normal Z-line
should not be
biopsied
• No markers able to
distinguish IM of
cardia from
esophagus
• DAS-1
• Cytokeratin
Adenocarcinoma in Barrett’s
Esophagus
9
Potential Mechanisms of Acid
Exposure and Carcinogenesis
From Souza RF. Inflammopharmacology 2007;15:95-100.
Incidence Trend in Esophageal
Adenocarcinoma (1973-2006)
From Pohl H et al. Cancer Epidemiol Biomarkers Prev 2010;19:1468-1470.
10
Estimates of New Esophageal
Cancer Cases and Mortality: 2012
20,000
17,460
15,070
15,000
10,000
5,000
0
New Cases
Deaths
From Siegel R et al. CA Cancer J Clin 2012;62:10-29.
Population Attributable Risks* of
Esophageal Adenocarcinoma
Risk Factor
PAR
95% CI
Ever smoker
39.7%
25.6-55.8
BMI quartile 2-4
41.1%
23.8-60.9
Any GER symptoms
29.7%
19.5-42.3
Low consumption of
fruits/vegetables
PAR for all factors combined
15.3%
5.8-34.6
78.7%
66.5-87.3
*Proportion of Disease Attributable to Given Risk Factor
From Engel LS et al. JNCI 2003;95:1404-13.
11
Annual Rate of Progression of
Nondysplastic Barrett’s To Cancer
From Wani S et al. Clin Gastroenterol Hepatol 2011;9:220-7.
Incidence of Adenocarcinoma Among
Barrett’s Patients in Denmark
From Hvid-Jensen F et al. N Engl J Med 2011;365:1375-83.
12
Cause Specific Mortality in
Barrett’s Esophagus
93% of deaths from causes
other than esophageal Ca
From Sikkema M et al. Clin Gastroenterol Hepatol 2010;8:235-44.
Preoperative Prevalence of Barrett’s Esophagus
in Patients Undergoing Resection for Incident
Esophageal Adenocarcinoma: A Systematic
Review
Summary estimate of
prior prevalence = 4.7%
From Dulai GS et al. Gastroenterology 2002;122:26-33.
13
Screening & Barrett’s Esophagus:
AGA Medical Position Paper
• Screening recommended if multiple risk
factors [weak recommendation/moderate
quality evidence]:
•
•
•
•
•
Age > 50 yrs
Male
Chronic GERD
Increased BMI
Abdominal obesity
From Spechler SJ et al. Gastroenterology 2011;140:1084-91.
Age & Sex Specific Yield for Confirmed
Barrett’s Esophagus: CORI Database
• Yield for males with
GERD yield increases
until plateau at age 50
• Yield for females with
GERD same as men
without GERD
From Rubenstein JH et al. Gastrointest Endosc 2010;71:21-7.
14
Screening & Barrett’s Esophagus:
AGA Medical Position Paper
• Screening not recommended for
general GERD population [strong
recommendation & low quality
evidence]
From Spechler SJ et al. Gastroenterology 2011;140:1084-91.
Barrett’s Esophagus On Repeat Endoscopy
Within 5 Years According To Finding At
Baseline: CORI Project
From Rodriguez S et al. Am J Gastroenterol 2008;103:1892-7.
15
Symptomatic GERD As A Risk Factor
For Esophageal Adenocarcinoma
Absence of heartburn, regurgitation or both > once weekly
100
80
%
60
40
20
0
Controls
Esophageal
Adenoca
Cardia Ca
Esophageal
Squamous
Cell Ca
From Lagergren J et al. NEJM 1999;340:825-31.
Surveillance & Survival in Barrett’s
Adenocarcinoma: A Population Based Study
From Corley DA et al. Gastroenterology 2002;122:633-40.
16
Surveillance & Cancer Stage in Barrett’s
Adenocarcinoma: A Population Based Study
 Surveillance detected
 Not detected in surveillance
From Corley DA et al. Gastroenterology 2002;122:633-40.
Surveillance of Barrett’s Esophagus:
White Light Endoscopy
17
Longer Barrett’s Inspection Time Associated
With Higher Detection Rate of HGD/Ca
Inspection
Time < 5
Minutes
32.4%
22.5%
Visible lesion
Final diagnosis
HGD/Ca
# of visible lesions 0.51
# of areas with
0.51
HGD/Ca
Mean BE length
3.3
(cm)
Inspection
Time > 5
Minutes
82.9%
53.7%
<0.001
0.002
1.95
2.29
<0.0001
0.004
4.4
P-value
0.11
From Gupta N et al. Gastrointest Endosc 2012;Jun 23. [Epub ahead of print ]
Surveillance of Barrett’s Esophagus:
AGA Medical Position Paper
• White light endoscopy
• Careful inspection remains standard of care
• Recommend against requiring:
• Chromoendoscopy
• Electronic chromoendoscopy
• Advanced imaging techniques i.e. confocal
endomicroscopy
From Spechler SJ et al. Gastroenterology 2011;140:1084-91.
18
Surveillance of Barrett’s Esophagus:
AGA Medical Position Paper
• 4 quadrant biopsies
• Q 2 cm if no dysplasia
• Q 1 cm if dysplasia
• Separate biopsy of any mucosal
irregularity
From Spechler SJ et al. Gastroenterology 2011;140:1084-91.
Surveillance of Barrett’s Esophagus:
AGA Medical Position Paper
• Dysplasia should be confirmed
by at least 1 additional
pathologist
From Spechler SJ et al. Gastroenterology 2011;140:1084-91
19
Adherence To Seattle Protocol
Increases Dysplasia Detection
From Abrams JA et al. Clin Gastroenterol Hepatol 2009;7:736-42.
Surveillance of Barrett’s Esophagus:
AGA Medical Position Paper
• Perform surveillance [weak
recommendation/weak evidence]
• Intervals:
• No dysplasia: 3-5 yrs
• LGD: 6-12 mos
• HGD: 3 mos if no eradication therapy
From Spechler SJ et al. Gastroenterology 2011;140:1084-91.
20
Adherence to Seattle Biopsy Protocol
In Community Setting By Segment
Length
From Abrams JA et al. Clin Gastro Hepatol 2009;7:736-42.
Interpretation of Barrett’s Esophagus in
Community Practice
100
80
%
Agreement
Gastric metaplasia
IM without dysplasia
Low-grade dysplasia
High-grade dysplasia
60
40
20
0
Pathologists’ Reading
From Alikhan M et al. Gastrointest Endosc 1999;50:23-6.
21
Limitations of Endoscopic Biopsy
Surveillance of Barrett’s Esophagus
• Dysplasia/early cancer
• Indistinguishable
• Patchy distribution
• Practice guidelines not followed
• Interobserver variability in dysplasia
interpretation
• Most patients never develop cancer
• Incidence 0.1-0.6%/year
Future Strategies for Surveillance of
Barrett’s Esophagus
• More efficient
• Target biopsies to at risk mucosa
• Optically sample larger area of mucosa
• Decrease number of biopsies
• Enhanced detection of dysplasia & cancer
• Decrease costs
• Less frequent
• Risk stratify patients
• Identify patients @ increased risk and focus efforts
on them
22
Enhancements To Endoscopic
Imaging
•
•
•
•
•
•
•
•
•
•
HD/High resolution white light
Chromoendoscopy
Magnification endoscopy
Electronic contrast enhancement
Autofluorescence endoscopy
Confocal endomicroscopy
Optical coherence tomography
Multispectral scanning
Low coherence interferometry
Molecular imaging
23
Adenocarcinoma Risk & Biomarker Panels
Biomarkers:
-17pLOH
-DNA content
-9pLOH
From Galipeau PC et al. PLOS Medicine 2007;4:342-54.
Surveillance of Barrett’s Esophagus:
AGA Medical Position Paper
• No biomarkers can be
recommended:
• Dysplasia diagnosis
• Risk stratification
From Spechler SJ et al. Gastroenterology 2011;140:1084-91.
24
Therapy of Barrett’s Esophagus
• Antisecretory therapy
• Surgery
• Chemoprevention
• Endoscopic ablation
PPIs Associated with Reduced Incidence of
Dysplasia in Barrett’s Esophagus
P < 0.001
From El-Serag H et al. Am J Gastroenterol 2004;99:1877-83.
25
Esophageal pH on High Dose Esomeprazole
in 31 Barrett’s Esophagus Patients
16-23% Patients Still Have Abnormal Acid Exposure
16.1%
22.6%
19.4%
From Spechler SJ et al. Am J Gastroenterol 2006;101:1964-71.
Systematic Review of Surgical Vs.
Medical Therapy of Barrett’s
Esophagus: Cancer Incidence
From Chang EY et al. Ann Surg 2007;246:11-21.
26
Protective Association of ASA & NSAIDS
With Esophageal Cancer: A Systematic
Review
Thun
Funkhouser
Farrow
Farrow
Coogan
Langman
Combined
.01
.1
.25
From Corley DA et al. Gastroenterology 2003;124:47-56.
.5 .75
.75
1.5
2.0
ASA/NSAIDs & Risk of Neoplastic
Progression in Barrett’s Esophagus
From Vaughan TL et al. Lancet Oncol 2005;6:945-52.
27
Prevention of Cancer in Barrett’s
Esophagus: AGA Medical Position Paper
• GERD therapy to treat symptoms & heal
esophagitis indicated
• No role for cancer prevention:
• > QD dosing of PPIs
• pH monitoring to titrate PPIs
• Antireflux surgery
• ASA use only for established
cardiovascular risk factors
From Spechler SJ et al. Gastroenterology 2011;140:1084-91.
Ablation Therapy
• Thermal
• Radiofrequency
• Cryotherapy
• Mechanical
• Endoscopic mucosal resection
• Endoscopic submucosal dissection
28
Grade of Dysplasia & Cancer Risk
Grade
IM
Cancer
Cancer Risk
Incidence
0.1-0.5%/yr Low
LGD
0.4-13%/yr
Intermediate
HGD
6-20%/yr
High
Grade of Dysplasia & Cancer Risk
Grade
IM
Cancer
Cancer Risk
Incidence
0.1-0.5%/yr Low
LGD
0.4-13%/yr
Intermediate
HGD
6-20%/yr
High
29
Radiofrequency Ablation
30
Radiofrequency Ablation of
Nondysplastic Barrett’s Epithelium:
5 Year Follow Up
Complete
Response
Per Protocol
(N=50)
46 (92%)
No buried IM noted in any biopsies
No strictures
No dysplasia
From Fleischer D et al. Endoscopy 2010;42:781-9.
Endoscopic Therapy of Barrett’s
Esophagus Without Dysplasia: AGA
Medical Position Paper
• Not suggested for nondysplastic
Barrett’s
• Option for select individuals at
increased risk for progression
• Specific criteria for identifying this
population have not been fully defined
From Spechler SJ et al. Gastroenterology 2011;140:1084-91.
31
Grade of Dysplasia & Cancer Risk
Grade
IM
Cancer
Cancer Risk
Incidence
0.1-0.5%/yr Low
LGD
0.4-13%/yr
Intermediate
HGD
6-20%/yr
High
The Problem of LGD: AGA Medical
Position Paper
• Tends to be overcalled in
community
• Especially problem in initial exam
if ongoing inflammation
From Spechler SJ et al. Gastroenterology 2011;140:1084-91.
32
Low Grade Dysplasia in Amsterdam
Community Based Cohort
• LGD diagnosed in 147 patients in
Amsterdam non-university registry
• Consensus review by 2 expert
pathologists:
•
•
•
•
HGD-1 [0.7%]
LGD-22 [15%]
Indefinite-14 [9.5%]
No dysplasia-110 [74.8%]
From Curvers WL et al. Am J Gastroenterol 2010;105:1523-30.
Risk Of Developing High Grade Dysplasia
in Patients Initially Labeled as LGD
From Curvers WL et al. Am J Gastroenterol 2010;105:1523-30.
33
RFA of Barrett’s Esophagus With Low
Grade Dysplasia: Complete Eradication
From Shaheen NJ et al. NEJM 2009;360:2277-88.
RFA of Barrett’s Esophagus With Low
Grade Dysplasia: Histological Progression
From Shaheen N et al. NEJM 2009; 2009;360:2277-88.
34
Endoscopic Therapy of Barrett’s
Esophagus With LGD: AGA Medical
Position Paper
• RFA is a treatment option for
confirmed LGD
From Spechler SJ et al. Gastroenterology 2011;140:1084-91.
Grade of Dysplasia & Cancer Risk
Grade
IM
Cancer
Cancer Risk
Incidence
0.1-0.5%/yr Low
LGD
0.4-13%/yr
Intermediate
HGD
6-20%/yr
High
35
Endoscopic Therapy of Barrett’s
Esophagus: AGA Medical Position Paper
• Eradication therapy recommended for
confirmed HGD-not surveillance
• Strong recommendation
• Moderate quality evidence
• EMR recommended for patients with
dysplasia & visible lesion
• Strong recommendation
• Moderate quality evidence
From Spechler SJ et al. Gastroenterology 2011;140:1084-91.
Endoscopic Mucosal Resection
Images courtesy of Christian Ell
36
AGA Technical Review: Role of
EMR
• Superior to EUS for T staging of HGD
and early adenocarcinoma
• Complete eradication therapy
• IM 75-100%
• Dysplasia/cancer 86-100%
From Spechler SJ et al. Gastroenterology 2011;140:e18-52.
EMR Changes Biopsy Diagnosis
SMC
Vascular invasion
HGD
From Peters F et al. Gastrointest Endosc 2008;67:604-9.
37
EMR Changes Biopsy
Diagnosis
• N=293 focal EMR
• EMR changed diagnosis in 49% of lesions
• Grade
• Depth
• Vascular invasion
• EMR led to change in treatment plan in
30%
From Peters F et al. Gastrointest Endosc 2008;67:604-9.
Radiofrequency Ablation of Barrett’s
Esophagus With High Grade Dysplasia
From Shaheen NJ et al. NEJM 2009;360:2277-88.
38
RFA of Barrett’s Esophagus With High
Grade Dysplasia: Histological Progression
From Shaheen N et al. NEJM 2009; 2009;360:2277-88.
AIM Dysplasia Trial: Durability of
Epithelial Reversion
Year 2
Year 3
All patients
CE-D
CE-IM
101/106 99/106
(95%)
(93%)
55/56
51/56
(98%)
(91%)
LGD
HGD
CE-D CE-IM CE-D CE-IM
51/52 51/52 50/54 48/54
(98%) (98%) (93%) (89%)
•4/14 with recurrent IM-subsquamous
•5/119 (4.2%) treated patients had disease progression
From Shaheen N et al. Gastroenterology 2011;141:460-8.
39
Detection of Recurrent IM After
Successful Ablation
•
•
•
•
N=47 with & without dysplasia
RFA with complete ablation
Incidence of new IM @ 1 yr: 26%
4/47 with dysplasia in absence of visible
BE at the GEJ
• 2 HGD
• 2 LGD
From Vaccaro BJ et al. Dig Dis Sci 2011;56:1996-2000.
Subsquamous Cancer After
Successful Ablation
From Titi M et al. Gastroenterology 2012 in press.
40
EMR of Early Cancer: Long-Term
Wiesbaden Results of 100 Patients
• Recurrent carcinoma
in 11%
• All successfully
removed
• The 2 deaths
unrelated to cancer
• Complications:
• Bleeding-11%
• Strictures-0%
From Ell C et al. Gastrointest Endosc 2007;65:3-10.
Factors Associated With
Recurrence After EMR of Early
Barrett’s Cancer (HGD/IMC)
From Pech O et al. Gut 2008;57:1200-6.
41
Caveats of Wiesbaden Results:
Low Risk Lesions
• Diameter < 20 mm
• Macroscopic type
•
•
•
•
I (polypoid)
IIa (flat & slightly elevated)
IIb (flat & level)
IIc (flat & depressed < 10 mm)
• Differentiation: Well or moderate
• Depth to mucosa
• No invasion of lymph vessels or veins
From Ell C et al. Gastrointest Endosc 2007;65:3-10.
RCT Of Stepwise Radical EMR Vs. EMR
+ RFA for HGD/Early Adenoca in
Barrett’s < 5 cm
CR HGD/Ca
CR IM
Sessions to CR
Total sessions
Acute
complications
Strictures
SRER (N=25)
100%
92%
2 [IQR 1-3]
6 [IQR 3-9]*
24%
EMR + RFA (N=22)
96%
96%
3 [IQR 3-4]
3 [IQR 3-4]
14%
88%*
14%
From Van Vilsteren et al. Gut 2011 Jan 5. [Epub ahead of print]
42
Cryotherapy of Barrett’s
Esophagus
From Johnston MH et al. Gastrointest Endosc 2005;62:842-8.
Liquid Nitrogen Cryotherapy in 60 Barrett’s
Esophagus HGD Patients: A Cohort Study
From Shaheen N et al. Gastrointest Endosc 2010 71:680-5.
43
Endoscopic Therapy of Barrett’s
Esophagus: AGA Medical Position Paper
• Current literature on cryotherapy
inadequate to recommend for
LGD or HGD
From Spechler SJ et al. Gastroenterology 2011;140:1084-91.
Long Term Survival Endoscopic Vs.
Surgical Treatment of HGD
•EMR preop
•Note 13%
unsuspected
Ca @ surgery
From Prasad GA et al. Gastroenterology 2007;132:1226-33.
44
Long Term Cancer Free Survival
Endoscopic Vs. Surgical Treatment of HGD
From Prasad GA et al. Gastroenterology 2007;132:1226-33.
Barrett’s Esophagus 2012:
Summary
• Incidence of Barrett’s esophagus and
esophageal adenocarcinoma
continues to rise
• Strict criteria exist for diagnosis of
Barrett’s esophagus:
• Endoscopic abnormality
• Columnar cells [intestinal metaplasia]
45
Barrett’s Esophagus 2012:
Summary
• Normal appearing Z-line should not
be biopsied
• Even once in a life time endoscopy in
GERD patients is controversial
• Repeated endoscopy in GERD
patients without erosive esophagitis
should not be done
Barrett’s Esophagus 2012:
Summary
• Surveillance recommended by all
guidelines
• Every 3 years sufficient if adequate
biopsies done
• Any diagnosis of dysplasia warrants
expert pathology confirmation
• Cornerstone of therapy is PPI therapy
at doses to control symptoms
46
Barrett’s Esophagus 2012:
Summary
• Ablation of nondysplastic Barrett’s
esophagus will not make sense unless
need for surveillance eliminated
• Ablation of low-grade dysplasia should
be considered if confirmed by expert
pathologists especially if multifocal
• Ablation of HGD/early cancer is an
excellent alternative to surgery
Barrett’s Esophagus 2012:
Summary
• No ablation technique completely
eliminates cancer risk
• Ablation requires:
• High quality imaging & staging
• Expert pathology
• Meticulous long term follow up
47
48