Barrett’s Esophagus
SLR Grand Rounds May 30, 2007
Norman Barrett (1903-1979)
Born in Australia
Moved to UK in 1913
Nicknamed “Pasty”
Spent most of career at St.
Thomas Hospital in
London
Norman Barrett (1903-1979)
1950: defined the
esophagus as lined by
squamous epithelium.
Proposed that columnarlined distal esophagus was
actually a part of the
stomach tethered to an
shortened esophagus
Norman Barrett (1903-1979)
1953: Allison and
Johnstone proposed that
the columnar epithelium
was actually abnormal
esophagus and called it
“Barrett’s ulcers”
1957: Barrett finally agreed
that it was esophagus and
not stomach
Barrett’s Esophagus
Definition: Esophagus in which normal
squamous epithelium changed to
columnar epithelium
– Intestinal epithelium: Goblet cells
Most commonly arises in the setting of
GERD
– Most commonly found on screening EGDs
done for GERD
Epidemiology
Incidence:
– Need endoscopy for diagnosis
– 20% of US population has reflux symptoms at
least once per week
– 10-15% of patients with GERD may have
Barrett’s
– Estimated that 25% of people with Barrett’s
have no reflux symptoms
Epidemiology
Premalignant condition
– Metaplasia to Dysplasia to Adenocarcinoma
Presence of Barrett’s: 30-125 increase in
risk of esophageal adenoca.
– 0.5% chance per year of developing adenoca
Incidence of esophageal adenoca has
increased by 350% for white males in US
over the past 30 years
Genetics
Multi-hit model from metaplasia to cancer
– APC
– DCC
– BMP4
– p16
– p53
Normal GEJ
Detection
Endoscopy
– Pink columnar
epithelium in contrast
to pale squamous
Long segment
– >3 cm from GEJ
Short segment
– <3cm from GEJ
Histology
Normal GEJ
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
Histology
Barrett’s Esophagus
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
Guidelines
American College of Gastroenterology
PPI
Intestinal Metaplasia without dysplasia
– EGD every 3 years
Low Grade Dysplasia
– EGD every year until no dysplasia x2 then
every 3 years
High Grade Dysplasia
– EGD every 3 months
Guidelines
Surgical Guidelines: not officially set
Intestinal Metaplasia without dysplasia
– Surveillance +/- anti-reflux surgery
Low Grade Dysplasia
– Surveillance +/- anti-reflux surgery
High Grade Dysplasia
– Esophagectomy
Guidelines: Medical v. Surgical
Pharmacologic v. Mechanical control of
reflux
Esophageal acidity can be corrected to
normal levels (pH <4.0 for <5% of time)
with varying doses of PPI for majority of
patients (85%)
Understanding the pathophysiology of
reflux
Biliary Reflux
Bile salts refluxed into stomach and then
into esophagus
Rat models demonstrate esophageal
exposure to duodenal contents leads to
adenocarcinoma
– Gastric acid inhibits formation of adenoca
Biliary Reflux
Bile salts deconjugated to bile acids in
neutral pH and by bacteria - overgrown
with reduced gastric acid
– Unconjugated able to cause damage at pH 7
– Very few conjugated salts damaging at pH 2
Concentration v. Volume
– Decreased acid production leads to
decreased refluxed volume
– Decreased acid production decreases the
volume bile is diluted with
Parrilla et al.
Long-Term Results of a Randomized
Prospective Study Comparing Medical and
Surgical Treatment of Barrett’s
Esophagus. Parrilla et al. Annals of
Surgery. 2003.
“There are no differences between the two
types [medical v. surgical] of treatment in
respect of preventing Barrett’s Esophagus
from progressing to dysplasia and
adenocarcinoma”
Parrilla et al.
High Grade Dysplasia
Esophagectomy the gold standard
Removes dysplastic regions and nodes
with possible metastatic disease
5 year survival rates between 94-100% for
dysplasia only
– Drops to 80-85% when carcinoma found in
surgical specimen
Highly morbid
– All comers, high volume centers: 5% mortality
50-60% peri-op complication rates
Esophagectomy
En Bloc:
– Greatest chance of complete resection
Transhiatal:
– Good esophageal resection but limited nodal
dissection
Vagal-Sparing:
– Patients end up with a highly selective vagotomy,
reducing rates of dumping syndrome
– Stripping of esophagus
– No mediastinal dissection, minimal hiatal dissection
Minimally Invasive Techniques
Endoscopic Therapy for HG
Dysplasia
Ablation or resection of the mucosa +/submucosa in an effort to remove all
disease
For dysplasia only, not carcinoma
Ablation or resection removes the
columnar mucosa -> neosquamous
overgrowth
Danger of hidden columnar glands(0-70%)
Endoscopic Therapy for HG
Dysplasia
All require multiple sessions per treatment
– Usually 3-5
Combination with anti-reflux surgery
Treatment before or after anti-reflux
surgery?
– RFA: orientation, correction of hiatal hernia
Endoscopic Therapy for HG
Dysplasia
Photodynamic therapy (PDT)
Laser Ablation
Multipolar Electrocoagulation
Argon Plasma Coagulation
Endoscopic Mucosal Resection (EMR)
Radiofrequency Ablation
Photodynamic Therapy (PDT)
Parenteral injection of porphyrin compunds
Activation with endoscopic laser
– Leads to oxygen free radicals -> cell death
Porfimer sodium
–
–
–
–
–
–
Downgrading of HGD to Barrett’s 90%
Resolution of Barrett’s 40%
Deep tissue penetration: 1cm
Strictures 25-50%
Needs 4-8 weeks of gradual exposure to light
13% rate of progression to carcinoma (no surgery)
Photodynamic Therapy (PDT)
ALA (aminolevulinic acid)
– Downgrading of HGD to Barrett’s 100%
– Resolution of Barrett’s 68%
– Shallow tissue penetration - 2mm
– No photosensitivity side effects
– 6% rate of progression to carcinoma (no
surgery)
– No reported strictures
Laser Ablation
Argon, KTP, Nd:YAG lasers
Availability sparse
Most studies are small with n < 15
– Generally have a response rate of 80-100%
– Complications of bleeding, pain, perforation,
stricture
Multipolar Electrocoagulation
(MPEC)
Electrocautery of Barrett’s
Widely available
One large study by Sampliner et al
– 58 patients: 85% regression of Barrett’s
metaplasia with 78% complete regression
– No dysplastic lesions included
– 43% morbidity rate: chest pain, odynophagia,
bleeding nausea
– 5% hidden gland rate
Argon Plasma Coagulation
(APC)
Stream of argon gas that is ionized by
electrocautery to ablate tissue
Widely available
Response rates vary with power used
– 70% with 30W to 100% with 90W
Return of Barrett’s in as high as 60% with low
wattage protocols
High power protocols carry morbidity rates of 4060% and stricture rates of 10%
Hidden glands occurred at rate of 25-50%
Radiofrequency Ablation
HALO360 from BARRX
Balloon dilatation of esophagus for uniform
depth
Circumferential ablation at depth of 1mm
– Depth of Barrett’s ~500nm
– Muscularis Mucosa ~1mm from surface
Shallow penetration allows circumferential
ablation without stricture
Radiofrequency Ablation
AIM I and II trials multi-center
AIM II- 1st year results
–
–
–
–
–
70 patients with metaplasia only
70% complete regression
25% partial regression
5% no regression
No hidden glands in 3000 biopsy samples over first
year of f/u
– 23% had transient adverse events, mostly pain
Endoscopic Mucosal Resection
(EMR)
Mimics surgical resection in that mucosa is
removed and not ablated
– Allows pathological analysis and improved staging
Goal is not to remove all of Barrett’s regions
Goal to remove suspicious lesions within
Barrett’s areas
– Chance of adenoca in otherwise non-descript
Barrett’s region “rare”
Remove focal adenoca while Barrett’s
metaplasia controlled with ant-acid therapy
Endoscopic Mucosal Resection
(EMR)
Saline injected into submucosa dissects it
off lamina propria
Tissue sucked into endoscopic cap
Snare cautery excises the tissue
Up to 1.5-2.0 cm sections can be removed
Multiple specimens can be taken per
session
Extensive resection can lead to stricture
Endoscopic Mucosal Resection
(EMR)
Endoscopic Mucosal Resection
(EMR)
Endoscopic Mucosal Resection
(EMR)
Endoscopic Mucosal Resection
(EMR)
Endoscopic Mucosal Resection
(EMR)
EMR as sole treatment for dysplasia
100 patients: 99% complete regression of
dysplasia
– Required multiple sessions (1-5, mean 1.5)
– 11 patients developed metachronous lesions:
all treated with resection
PPI therapy to control acid reflux
Total resection of Barrett’s
EMR for Staging
Stage 0 (in situ) v. Stage 1 (into but not through
lamina propria)
Invasion of muscularis mucosa important
predictor of nodal mets
– 4% if mucosa only
– 30% if invasion into submucosa
EUS good at determining invasion through
submucosa and evaluating mediastinal nodes
EMR of suspected lesions to determine invasion
into submucosa
– Directs esophagectomy method e.g. Vagal-Sparing
EMR for Staging Plus Ablation
EMR of suspected lesions to determine
presence of adenoca
No adenoca -> Complete RFA of Barrett’s
Anti-reflux surgery to further increase chance of
regression of abnormal tissue
References
Chandrasoma P. Controversies of the cardiac mucosa and Barrett's
oesophagus.Histopathology. 2005 Apr;46(4):361-73.
DeMeester SR. Adenocarcinoma of the esophagus and cardia: a review of the
disease and its treatment.Ann Surg Oncol. 2006 Jan;13(1):12-30.
DeMeester SR. EMR for intramucosal adenocarcinoma of the esophagus: does one
size fit all?Gastrointest Endosc. 2007 Jan;65(1):14-5.
Eickhoff,ﾊA.; Jakobs,ﾊR.; Weickert,ﾊU.; Hartmann,ﾊD.; Schilling,ﾊD.;
Alsenbesy,ﾊM.; Eickhoff,ﾊJ. C.; Riemann,ﾊJ. F.Long-Segment early squamous
cell carcinoma of the proximal esophagus: curative treatment and long-term follow-up
after 5-aminolevulinic acid (5-ALA)-photodynamic therapy. Endoscopy. 2006
Jun;38(6):641-3.
Ell C, May A, Pech O, Gossner L, Guenter E, Behrens A, Nachbar L, Huijsmans J,
Vieth M, Stolte M. Curative endoscopic resection of early esophageal
adenocarcinomas (Barrett's cancer).Gastrointest Endosc. 2007 Jan;65(1):3-10.
Gerson LB, Shetler K, Triadafilopoulos G. Prevalence of Barrett's esophagus in
asymptomatic individuals. Gastroenterology 2002;123:461-7.
Kanne JP, Rohrmann CA, Lichtenstein JE. Eponyms in Radiology of the Digestive
Tract: Historical Perspectives and Imaging AppearancesPart I. Pharynx, Esophagus,
Stomach, and Intestine. RadioGraphics 2006;26:129-142
Liebwin Gossner, Manfred Stolte, Ronald Sroka, Kai Rick, Andrea May, Eckhard
Gerhard Hahn and Christian Ell. Photodynamic ablation of high-grade dysplasia and
early cancer in Barrett's esophagus by means of 5-aminolevulinic acid.
Gastroenterology 1998; 114:448-455.
Manner H, May A, Miehlke S, Dertinger S, Widdinghaus B, Schimming W, Kramer W,
Niemann G, Stolte M, Ell C. Ablation of nonneoplastic Barrett's mucosa using argon
plasma coagulation with concomitant esomeprazole therapy (APBANEX): a
prospective multicenter evaluation.Am J Gastroenterol. 2006 Aug;101(8):1762-9.
Oh DS, Hagen JA, Chandrasoma PT, Dunst CM, Demeester SR, Alavi M, Bremner
CG, Lipham J, Rizzetto C, Cote R, Demeester TR. Clinical biology and surgical
therapy of intramucosal adenocarcinoma of the esophagus.J Am Coll Surg. 2006
Aug;203(2):152-61.
Overholt BF.Photodynamic therapy strictures: who is at risk?Gastrointest Endosc.
2007 Jan;65(1):67-9.
Parrilla P, Martinez de Haro LF, Ortiz A, Munitiz V, Molina J, Bermejo J, Canteras M.
Long-term results of a randomized prospective study comparing medical and surgical
treatment of Barrett's esophagus.Ann Surg. 2003 Mar;237(3):291-8.
Portale G, Hagen JA, Peters JH, Chan LS, DeMeester SR, Gandamihardja TA,
DeMeester TR. Modern 5-year survival of resectable esophageal adenocarcinoma:
single institution experience with 263 patients.J Am Coll Surg. 2006 Apr;202(4):58896.
Prasad GA, Wang KK, Buttar NS, Wongkeesong LM, Lutzke LS, Borkenhagen LS.
Predictors of stricture formation after photodynamic therapy for high-grade dysplasia
in Barrett's esophagus.Gastrointest Endosc. 2007 Jan;65(1):60-6.
Rastogi A, Sharma P. Barrett's esophagus.Endoscopy. 2006 Nov;38(11):1065-9.
Rossi M, Barreca M, de Bortoli N, Renzi C, Santi S, Gennai A, Bellini M, Costa F,
Conio M, Marchi S. Efficacy of Nissen fundoplication versus medical therapy in the
regression of low-grade dysplasia in patients with Barrett esophagus: a prospective
study.Ann Surg. 2006 Jan;243(1):58-63.
Sampliner RE, Faigel D, Fennerty MB, Lieberman D, Ippoliti A, Lewin K, Weinstein
WM. Effective and safe endoscopic reversal of nondysplastic Barrett's esophagus
with thermal electrocoagulation combined with high-dose acid inhibition: a multicenter
study.Gastrointest Endosc. 2001 May;53(6):554-8.
Sampliner RE. Updated guidelines for the diagnosis, surveillance, and therapy of
Barrett’s esophagus. Am J Gastroenterol. 2002 Aug;97(8):1888-95.
Schuchert MJ, Luketich JD. Barrett's esophagus-emerging concepts and
controversies.J Surg Oncol. 2007 Mar 1;95(3):185-9.
ShalautaMD , Saad R. Barrett's Esophagus. Am Fam Physician 2004;69: 21138,2120.
Sharma VK, Wang KK, Overholt BF, Lightdale CJ, Fennerty MB, Dean PJ, Pleskow
DK, Chuttani R, Reymunde A, Santiago N, Chang KJ, Kimmey MB, Fleischer DE.
Balloon-based, circumferential, endoscopic radiofrequency ablation of Barrett's
esophagus: 1-year follow-up of 100 patients.Gastrointest Endosc. 2007
Feb;65(2):185-95.
Sharma P, Jaffe PE, Bhattacharyya A, Sampliner RE. Laser and multipolar
electrocoagulation ablation of early Barrett's adenocarcinoma: long-term
follow-up. Gastrointest Endosc. 1999 Jan;49(4):442-446. Spechler SJ,
Sharma P, Traxler B, Levine D, Falk GW. Gastric and esophageal pH in
patients with Barrett's esophagus treated with three esomeprazole dosages:
a randomized, double-blind, crossover trial.Am J Gastroenterol. 2006
Sep;101(9):1964-71.
Todd JA, Basu KK, de Caestecker JS. Normalization of oesophageal pH
does not guarantee control of duodenogastro-oesophageal reflux in
Barrett's oesophagus.Aliment Pharmacol Ther. 2005 Apr 15;21(8):969-75.
Wang KK, Sampliner RE. Mucosal ablation therapy of barrett esophagus.
Mayo Clin Proc. 2001 Apr; 76(4):433-7.