Barrett’s Esophagus SLR Grand Rounds May 30, 2007

Barrett’s EsophagusBarrett’s Esophagus

SLR Grand Rounds May 30, 2007SLR Grand Rounds May 30, 2007

Norman Barrett Norman Barrett (1903-1979)(1903-1979)

Born in AustraliaBorn in Australia

Moved to UK in 1913Moved to UK in 1913

Nicknamed “Pasty”Nicknamed “Pasty”

Spent most of career at St. Spent most of career at St. Thomas Hospital in Thomas Hospital in LondonLondon


1950: defined the 1950: defined the esophagus as lined by esophagus as lined by squamous epithelium. squamous epithelium. Proposed that columnar-Proposed that columnar-lined distal esophagus was lined distal esophagus was actually a part of the actually a part of the stomach tethered to an stomach tethered to an shortened esophagusshortened esophagus


1953: Allison and 1953: Allison and Johnstone proposed that Johnstone proposed that the columnar epithelium the columnar epithelium was actually abnormal was actually abnormal esophagus and called it esophagus and called it “Barrett’s ulcers”“Barrett’s ulcers”

1957: Barrett finally agreed 1957: Barrett finally agreed that it was esophagus and that it was esophagus and not stomachnot stomach

Barrett’s EsophagusBarrett’s Esophagus

Definition: Esophagus in which normal Definition: Esophagus in which normal squamous epithelium changed to squamous epithelium changed to columnar epitheliumcolumnar epithelium– Intestinal epithelium: Goblet cellsIntestinal epithelium: Goblet cells

Most commonly arises in the setting of Most commonly arises in the setting of GERDGERD– Most commonly found on screening EGDs Most commonly found on screening EGDs

done for GERDdone for GERD

EpidemiologyEpidemiology

Incidence: Incidence: – Need endoscopy for diagnosisNeed endoscopy for diagnosis– 20% of US population has reflux symptoms at 20% of US population has reflux symptoms at

least once per weekleast once per week– 10-15% of patients with GERD may have 10-15% of patients with GERD may have

Barrett’sBarrett’s– Estimated that 25% of people with Barrett’s Estimated that 25% of people with Barrett’s

have no reflux symptomshave no reflux symptoms

EpidemiologyEpidemiology

Premalignant conditionPremalignant condition– Metaplasia to Dysplasia to AdenocarcinomaMetaplasia to Dysplasia to Adenocarcinoma

Presence of Barrett’s: 30-125 increase in Presence of Barrett’s: 30-125 increase in risk of esophageal adenoca.risk of esophageal adenoca.– 0.5% chance per year of developing adenoca0.5% chance per year of developing adenoca

Incidence of esophageal adenoca hasIncidence of esophageal adenoca has increased by 350% for white males in US increased by 350% for white males in US over the past 30 yearsover the past 30 years

GeneticsGenetics

Multi-hit model from metaplasia to cancerMulti-hit model from metaplasia to cancer– APCAPC– DCCDCC– BMP4BMP4– p16p16– p53p53

Normal GEJNormal GEJ

DetectionDetection

EndoscopyEndoscopy– Pink columnar Pink columnar

epithelium in contrast epithelium in contrast to pale squamousto pale squamous

Long segmentLong segment– >3 cm from GEJ>3 cm from GEJ

Short segmentShort segment– <3cm from GEJ<3cm from GEJ

HistologyHistologyNormal GEJNormal GEJ

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

HistologyHistologyBarrett’s EsophagusBarrett’s Esophagus

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are needed to see this picture.

GuidelinesGuidelines

American College of Gastroenterology American College of Gastroenterology PPIPPIIntestinal Metaplasia without dysplasiaIntestinal Metaplasia without dysplasia– EGD every 3 yearsEGD every 3 years

Low Grade DysplasiaLow Grade Dysplasia– EGD every year until no dysplasia x2 then EGD every year until no dysplasia x2 then

every 3 yearsevery 3 years

High Grade DysplasiaHigh Grade Dysplasia– EGD every 3 monthsEGD every 3 months

GuidelinesGuidelines

Surgical Guidelines: not officially set Surgical Guidelines: not officially set

Intestinal Metaplasia without dysplasiaIntestinal Metaplasia without dysplasia– Surveillance +/- anti-reflux surgerySurveillance +/- anti-reflux surgery

Low Grade DysplasiaLow Grade Dysplasia– Surveillance +/- anti-reflux surgerySurveillance +/- anti-reflux surgery

High Grade DysplasiaHigh Grade Dysplasia– EsophagectomyEsophagectomy

Guidelines: Medical v. SurgicalGuidelines: Medical v. Surgical

Pharmacologic v. Mechanical control of Pharmacologic v. Mechanical control of refluxrefluxEsophageal acidity can be corrected to Esophageal acidity can be corrected to normal levels (pH <4.0 for <5% of time) normal levels (pH <4.0 for <5% of time) with varying doses of PPI for majority of with varying doses of PPI for majority of patients (85%)patients (85%)Understanding the pathophysiology of Understanding the pathophysiology of refluxreflux

Biliary RefluxBiliary Reflux

Bile salts refluxed into stomach and then Bile salts refluxed into stomach and then into esophagusinto esophagus

Rat models demonstrate esophageal Rat models demonstrate esophageal exposure to duodenal contents leads to exposure to duodenal contents leads to adenocarcinomaadenocarcinoma– Gastric acid inhibits formation of adenocaGastric acid inhibits formation of adenoca

Biliary RefluxBiliary Reflux

Bile salts deconjugated to bile acids in Bile salts deconjugated to bile acids in neutral pH and by bacteria - overgrown neutral pH and by bacteria - overgrown with reduced gastric acidwith reduced gastric acid– Unconjugated able to cause damage at pH 7 Unconjugated able to cause damage at pH 7 – Very few conjugated salts damaging at pH 2Very few conjugated salts damaging at pH 2

Concentration v. VolumeConcentration v. Volume– Decreased acid production leads to Decreased acid production leads to

decreased refluxed volumedecreased refluxed volume– Decreased acid production decreases the Decreased acid production decreases the

volume bile is diluted withvolume bile is diluted with

Parrilla et al.Parrilla et al.

Long-Term Results of a Randomized Long-Term Results of a Randomized Prospective Study Comparing Medical and Prospective Study Comparing Medical and Surgical Treatment of Barrett’s Surgical Treatment of Barrett’s Esophagus. Parrilla et al. Esophagus. Parrilla et al. Annals of Annals of SurgerySurgery. 2003.. 2003.““There are no differences between the two There are no differences between the two types [medical v. surgical] of treatment in types [medical v. surgical] of treatment in respect of preventing Barrett’s Esophagus respect of preventing Barrett’s Esophagus from progressing to dysplasia and from progressing to dysplasia and adenocarcinoma”adenocarcinoma”

Parrilla et al.Parrilla et al.

High Grade DysplasiaHigh Grade DysplasiaEsophagectomy the gold standardEsophagectomy the gold standard

Removes dysplastic regions and nodes Removes dysplastic regions and nodes with possible metastatic diseasewith possible metastatic disease

5 year survival rates between 94-100% for 5 year survival rates between 94-100% for dysplasia onlydysplasia only– Drops to 80-85% when carcinoma found in Drops to 80-85% when carcinoma found in

surgical specimen surgical specimen

Highly morbidHighly morbid– All comers, high volume centers: 5% mortality All comers, high volume centers: 5% mortality

50-60% peri-op complication rates50-60% peri-op complication rates

EsophagectomyEsophagectomyEn Bloc:En Bloc:– Greatest chance of complete resectionGreatest chance of complete resection

Transhiatal:Transhiatal:– Good esophageal resection but limited nodal Good esophageal resection but limited nodal

dissectiondissection

Vagal-Sparing:Vagal-Sparing:– Patients end up with a highly selective vagotomy, Patients end up with a highly selective vagotomy,

reducing rates of dumping syndromereducing rates of dumping syndrome– Stripping of esophagusStripping of esophagus– No mediastinal dissection, minimal hiatal dissectionNo mediastinal dissection, minimal hiatal dissection

Minimally Invasive TechniquesMinimally Invasive Techniques

Endoscopic Therapy for HG Endoscopic Therapy for HG DysplasiaDysplasia

Ablation or resection of the mucosa +/- Ablation or resection of the mucosa +/- submucosa in an effort to remove all submucosa in an effort to remove all diseasedisease

For dysplasia only, not carcinomaFor dysplasia only, not carcinoma

Ablation or resection removes the Ablation or resection removes the columnar mucosa -> neosquamous columnar mucosa -> neosquamous overgrowthovergrowth

Danger of hidden columnar glands(0-70%)Danger of hidden columnar glands(0-70%)


All require multiple sessions per treatmentAll require multiple sessions per treatment– Usually 3-5 Usually 3-5

Combination with anti-reflux surgeryCombination with anti-reflux surgery

Treatment before or after anti-reflux Treatment before or after anti-reflux surgery?surgery?– RFA: orientation, correction of hiatal herniaRFA: orientation, correction of hiatal hernia


Photodynamic therapy (PDT)Photodynamic therapy (PDT)

Laser AblationLaser Ablation

Multipolar ElectrocoagulationMultipolar Electrocoagulation

Argon Plasma CoagulationArgon Plasma Coagulation

Endoscopic Mucosal Resection (EMR)Endoscopic Mucosal Resection (EMR)

Radiofrequency AblationRadiofrequency Ablation

Photodynamic Therapy (PDT)Photodynamic Therapy (PDT)Parenteral injection of porphyrin compundsParenteral injection of porphyrin compundsActivation with endoscopic laserActivation with endoscopic laser– Leads to oxygen free radicals -> cell deathLeads to oxygen free radicals -> cell death

Porfimer sodiumPorfimer sodium– Downgrading of HGD to Barrett’s 90%Downgrading of HGD to Barrett’s 90%– Resolution of Barrett’s 40%Resolution of Barrett’s 40%– Deep tissue penetration: 1cmDeep tissue penetration: 1cm– Strictures 25-50%Strictures 25-50%– Needs 4-8 weeks of gradual exposure to lightNeeds 4-8 weeks of gradual exposure to light– 13% rate of progression to carcinoma (no surgery)13% rate of progression to carcinoma (no surgery)

Photodynamic Therapy (PDT)Photodynamic Therapy (PDT)ALA (aminolevulinic acid)ALA (aminolevulinic acid)– Downgrading of HGD to Barrett’s 100%Downgrading of HGD to Barrett’s 100%– Resolution of Barrett’s 68%Resolution of Barrett’s 68%– Shallow tissue penetration - 2mmShallow tissue penetration - 2mm– No photosensitivity side effectsNo photosensitivity side effects– 6% rate of progression to carcinoma (no 6% rate of progression to carcinoma (no

surgery)surgery)– No reported stricturesNo reported strictures

Laser AblationLaser AblationArgon, KTP, Nd:YAG lasersArgon, KTP, Nd:YAG lasers

Availability sparseAvailability sparse

Most studies are small with n < 15Most studies are small with n < 15– Generally have a response rate of 80-100%Generally have a response rate of 80-100%– Complications of bleeding, pain, perforation, Complications of bleeding, pain, perforation,

stricturestricture

Multipolar Electrocoagulation Multipolar Electrocoagulation (MPEC)(MPEC)

Electrocautery of Barrett’sElectrocautery of Barrett’s

Widely availableWidely available

One large study by Sampliner et alOne large study by Sampliner et al– 58 patients: 85% regression of Barrett’s 58 patients: 85% regression of Barrett’s

metaplasia with 78% complete regressionmetaplasia with 78% complete regression– No dysplastic lesions includedNo dysplastic lesions included– 43% morbidity rate: chest pain, odynophagia, 43% morbidity rate: chest pain, odynophagia,

bleeding nauseableeding nausea– 5% hidden gland rate5% hidden gland rate

Argon Plasma Coagulation Argon Plasma Coagulation (APC)(APC)

Stream of argon gas that is ionized by Stream of argon gas that is ionized by electrocautery to ablate tissueelectrocautery to ablate tissueWidely availableWidely availableResponse rates vary with power usedResponse rates vary with power used– 70% with 30W to 100% with 90W70% with 30W to 100% with 90W

Return of Barrett’s in as high as 60% with low Return of Barrett’s in as high as 60% with low wattage protocolswattage protocolsHigh power protocols carry morbidity rates of 40-High power protocols carry morbidity rates of 40-60% and stricture rates of 10%60% and stricture rates of 10%Hidden glands occurred at rate of 25-50%Hidden glands occurred at rate of 25-50%


HALO360 from BARRXHALO360 from BARRX

Balloon dilatation of esophagus for uniform Balloon dilatation of esophagus for uniform depthdepth

Circumferential ablation at depth of 1mmCircumferential ablation at depth of 1mm– Depth of Barrett’s ~500nmDepth of Barrett’s ~500nm– Muscularis Mucosa ~1mm from surfaceMuscularis Mucosa ~1mm from surface

Shallow penetration allows circumferential Shallow penetration allows circumferential ablation without strictureablation without stricture


AIM I and II trials multi-centerAIM I and II trials multi-center

AIM II- 1st year resultsAIM II- 1st year results– 70 patients with metaplasia only70 patients with metaplasia only– 70% complete regression70% complete regression– 25% partial regression25% partial regression– 5% no regression5% no regression– No hidden glands in 3000 biopsy samples over first No hidden glands in 3000 biopsy samples over first

year of f/uyear of f/u– 23% had transient adverse events, mostly pain23% had transient adverse events, mostly pain

Endoscopic Mucosal Resection Endoscopic Mucosal Resection (EMR)(EMR)

Mimics surgical resection in that mucosa is Mimics surgical resection in that mucosa is removed and not ablatedremoved and not ablated– Allows pathological analysis and improved stagingAllows pathological analysis and improved staging

Goal is not to remove all of Barrett’s regionsGoal is not to remove all of Barrett’s regions

Goal to remove suspicious lesions within Goal to remove suspicious lesions within Barrett’s areasBarrett’s areas– Chance of adenoca in otherwise non-descript Chance of adenoca in otherwise non-descript

Barrett’s region “rare”Barrett’s region “rare”

Remove focal adenoca while Barrett’s Remove focal adenoca while Barrett’s metaplasia controlled with ant-acid therapymetaplasia controlled with ant-acid therapy


Saline injected into submucosa dissects it Saline injected into submucosa dissects it off lamina propriaoff lamina propria

Tissue sucked into endoscopic capTissue sucked into endoscopic cap

Snare cautery excises the tissueSnare cautery excises the tissue

Up to 1.5-2.0 cm sections can be removedUp to 1.5-2.0 cm sections can be removed

Multiple specimens can be taken per Multiple specimens can be taken per sessionsession

Extensive resection can lead to strictureExtensive resection can lead to stricture






EMR as sole treatment for dysplasiaEMR as sole treatment for dysplasia

100 patients: 99% complete regression of 100 patients: 99% complete regression of dysplasiadysplasia– Required multiple sessions (1-5, mean 1.5)Required multiple sessions (1-5, mean 1.5)– 11 patients developed metachronous lesions: 11 patients developed metachronous lesions:

all treated with resectionall treated with resection

PPI therapy to control acid refluxPPI therapy to control acid reflux

Total resection of Barrett’sTotal resection of Barrett’s

EMR for StagingEMR for StagingStage 0 (in situ) v. Stage 1 (into but not through Stage 0 (in situ) v. Stage 1 (into but not through lamina propria)lamina propria)Invasion of muscularis mucosa important Invasion of muscularis mucosa important predictor of nodal metspredictor of nodal mets– 4% if mucosa only4% if mucosa only– 30% if invasion into submucosa30% if invasion into submucosa

EUS good at determining invasion through EUS good at determining invasion through submucosa and evaluating mediastinal nodessubmucosa and evaluating mediastinal nodesEMR of suspected lesions to determine invasion EMR of suspected lesions to determine invasion into submucosainto submucosa– Directs esophagectomy method e.g. Vagal-SparingDirects esophagectomy method e.g. Vagal-Sparing

EMR for Staging Plus AblationEMR for Staging Plus AblationEMR of suspected lesions to determine EMR of suspected lesions to determine presence of adenocapresence of adenocaNo adenoca -> Complete RFA of Barrett’sNo adenoca -> Complete RFA of Barrett’sAnti-reflux surgery to further increase chance of Anti-reflux surgery to further increase chance of regression of abnormal tissueregression of abnormal tissue

Chandrasoma P. Controversies of the cardiac mucosa and Barrett's Chandrasoma P. Controversies of the cardiac mucosa and Barrett's oesophagus.Histopathology. 2005 Apr;46(4):361-73.oesophagus.Histopathology. 2005 Apr;46(4):361-73.DeMeester SR. Adenocarcinoma of the esophagus and cardia: a review of the 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.disease and its treatment.Ann Surg Oncol. 2006 Jan;13(1):12-30.DeMeester SR. EMR for intramucosal adenocarcinoma of the esophagus: does one DeMeester SR. EMR for intramucosal adenocarcinoma of the esophagus: does one size fit all?Gastrointest Endosc. 2007 Jan;65(1):14-5.size fit all?Gastrointest Endosc. 2007 Jan;65(1):14-5.Eickhoff,Eickhoff, ﾊﾊ AA.; Jakobs,.; Jakobs, ﾊﾊ RR.; Weickert,.; Weickert, ﾊﾊ UU.; Hartmann,.; Hartmann, ﾊﾊ DD.; Schilling,.; Schilling, ﾊﾊ DD.; .; Alsenbesy,Alsenbesy, ﾊﾊ MM.; Eickhoff,.; Eickhoff, ﾊﾊ JJ. C.; Riemann,. C.; Riemann, ﾊﾊ JJ. F.. F.Long-Segment early squamous Long-Segment early squamous cell carcinoma of the proximal esophagus: curative treatment and long-term follow-up cell carcinoma of the proximal esophagus: curative treatment and long-term follow-up after 5-aminolevulinic acid (5-ALA)-photodynamic therapy. Endoscopy. after 5-aminolevulinic acid (5-ALA)-photodynamic therapy. Endoscopy. 2006 2006 Jun;38(6):641-3.Jun;38(6):641-3.Ell C, May A, Pech O, Gossner L, Guenter E, Behrens A, Nachbar L, Huijsmans J, 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 Vieth M, Stolte M. Curative endoscopic resection of early esophageal adenocarcinomas (Barrett's cancer).Gastrointest Endosc. 2007 Jan;65(1):3-10. adenocarcinomas (Barrett's cancer).Gastrointest Endosc. 2007 Jan;65(1):3-10. Gerson LB, Shetler K, Triadafilopoulos G. Prevalence of Barrett's esophagus in Gerson LB, Shetler K, Triadafilopoulos G. Prevalence of Barrett's esophagus in asymptomatic individuals. Gastroenterology 2002;123:461-7.asymptomatic individuals. Gastroenterology 2002;123:461-7.Kanne JP, Rohrmann CA, Lichtenstein JE. Eponyms in Radiology of the Digestive Kanne JP, Rohrmann CA, Lichtenstein JE. Eponyms in Radiology of the Digestive Tract: Historical Perspectives and Imaging AppearancesPart I. Pharynx, Esophagus, Tract: Historical Perspectives and Imaging AppearancesPart I. Pharynx, Esophagus, Stomach, and Intestine. RadioGraphics 2006;26:129-142Stomach, and Intestine. RadioGraphics 2006;26:129-142

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Barrett’s Esophagus SLR Grand Rounds May 30, 2007