Barrett’s Esophagus

• A 58 year-old, obese white man has had heartburn for more than 20 years.

• He read a magazine article saying that heartburn is a risk factor for Barrett’s esophagus, which can lead to cancer of the esophagus.

• The article scared him, and he asks you what he should do.

• The article went on to say that people with heartburn should have an endoscopy to look for Barrett’s esophagus.

يسبب مما المرئ قناة الى المعدة من الحمضية العصارة رجوعاألعراض منها األعراض من العديد ظهور إلى تؤدى بالمرىء التهاباتعلى المتكرر الحرقان و بالحموضة الشعور مثل الواضحة المباشرةمرة بعصارة الشعور أو المرئ عبر الطعام برجوع الشعور أو الصدر

الحلق إلى تعودالغذائية (Heartburn) حرقة الوجبات تناول –بعد

ق ) الغذاء (سلرفع Regurgitation

وليس : دونه أو الفم ملء شراب أو طعام بطنه من خرج جل الر قلسبقيء

• Endoscopy reveals Barrett’s esophagus.

• Biopsy specimens show high-grade dysplasia.

Barrett’s EsophagusBarrett’s EsophagusThe condition in which a

metaplastic columnar epithelium that predisposes

to cancer development replaces the stratified

squamous epithelium that normally lines the distal

esophagus

AGA Medical Position Statement. Gastroenterology 2011;140:1084.

StratifiedSquamousEpithelium

Meta

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Colu

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Epith

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Met

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Affects 5.6% of adult

Barrett’s Metaplasia

EsophagealAdenocarcinoma

Metaplasia One adult cell type replaces another type

GERD

Stratified SquamousEpithelium

(Normal Esophagus)

Specialized IntestinalMetaplasia

(Barrett’s Esophagus)

Response to Chronic Tissue Injury

RefluxEsophagitis

GEJ(Gastro-Esophageal

Junction)

Z-Line(Squamo-Columnar

Junction)

Columnar LinedEsophagus

Adapted from Spechler. Gastroenterology 1999;117:218.

X

Specialized IntestinalMetaplasia

• Age >50 years Uncommon in children

Risk Factors for Barrett’s Esophagus

• Chronic GERDHeartburn, hiatal hernia

• ObesityIntra-abdominal fat distribution

• Male gender• White ethnicity

Less common in African-AmericansUncommon in Asians

and Esophageal Adenocarcinoma

Guidelines for Endoscopy in GERD

• “Upper endoscopy is not required in the presence of typical GERD symptoms.”

• “Endoscopy is recommended in the presence of alarm symptoms and for screening of patients at high risk for complications [Barrett’s esophagus].”

ACG Guidelines. Katz. Am J Gastroenterol 2013;108:308.

ACP Guidelines. Shaheen. Ann Intern Med 2012;157:808.

• “Upper endoscopy is indicated in men and women with heartburn and alarm symptoms (dysphagia, bleeding, anemia, weight loss, and recurrent vomiting).”

• “Upper endoscopy is indicated in men and women with typical GERD symptoms that persist despite a therapeutic trial of 4 to 8 weeks of twice-daily proton pump inhibitor therapy.”

Gastroenterology 2011;140:1084.

AGA Medical Position Statement on Endoscopic Screening for Barrett’s Esophagus• We recommend against screening the general

population with GERD for Barrett’s esophagus.• In patients with multiple risk

factors associated with esophageal adenocarcinoma, we suggest screening for Barrett’s esophagus.Chronic GERD, hiatal hernia, age ≥50, male gender, white race, elevated BMI, intra-abdominal body fat distributionNorman

Barrett

Incidence of Esophageal Adenocarcinoma Has Been Rising

1975 1980 1985 1990 1995 2000 20050

5

1015

2025

30In

cide

nce

per

1,00

0,00

0Incidence

Time Trend

Pohl H. Cancer Epidemiol Biomarkers Prev 2010;19:1468.

3.6 per million 19733.6 per million 1973

25.6 per 25.6 per millionmillion

20062006

7-Fold IncreaseIn 3 Decades

• 2000s Estimate: 0.5% per year1 in 200 patients per yearShaheen. Gastroenterology 2000;119:333.

• 1990s Estimate: 1% per year 1 in 100 patients per year

Drewitz. Am J Gastroenterol 1997;92:212.

• 2014 Estimate: 0.25% per year1 in 400 patients per year

Estimates of Cancer Risk for Individual Patients with Non-Dysplastic Barrett’s Have Been Getting Lower

Endoscopic Surveillance Might Not Decrease Mortality from Esophageal Adenocarcinoma

Corley DA. Gastroenterology 2013;145:312.

8,272 pts. with Barrett’s esophagus (BE)

351 pts. with esophageal adenocarcinoma (EAC)

70 EAC in pts. with prior diagnosis of BE (≥6 months)

Cases38 pts. with confirmed death

from esophageal cancer

Controls101 living Barrett’s pts. matchedfor age, sex, follow-up duration

55%surveillance endoscopy

performed within 3 years

60%surveillance endoscopy

performed within 3 years

Surveillance endoscopy within 3 years was NOT associated with decreased risk of death from esophageal cancer

(adjusted odds ratio 0.99; 95% CI 0.36-2.75)

High Definition White Light Endoscopy (HD-WLE)

• 1 million pixels (standard low-resolution endoscopes 300,000)

• help in detecting the subtle mucosal and vascular changes

Chromoendoscopy

• Lugol’s iodine, acetic acid, and methylene blue• Absent staining and heterogeneity are associated

with the presence of dysplasia. (vital dye that is actively absorbed by the epithelial cells of the small intestine and colon. It is not absorbed by

nonabsorptive epithelium)• methylene-blue-directed biopsies• pre-treated with a mucolytic (NAC)

• Methylene blue-stained Barrett’s epithelium with a focal, superficial malignancy unstained by methylene blue (arrow).

Endoscopic high-magnification image of Barrett’s mucosa after methylene blue staining showing a tubular mucosal pit pattern.

Narrow-Band Imaging (NBI)

• filter blue light corresponding to the absorption peaks of hemoglobin making the vascular pattern stand out in contrast to the mucosal pattern.

• difficult initial learning (steep learning curve).

Left: WLE and Right: NBI.

The red lines indicate the border of the vascular and mucosal abnormalities based on the NBI appearance.Blue lines illustrate the extension of the neoplastic lesion based on the mucosal relief.

early neoplastic lesion in the distal esophagus (A)with high-resolution WLE, (B) with NBI, (C) after indigo carmine spraying, (D) after acetic acid spraying.

Autofluorescence Imaging (AFI) • Certain endogenous molecules, such as collagen and elastin,

known as fluorophores emit long-wavelength light when excited by shorter wavelength light.

• Dysplastic epithelium is associated with decreased autofluorescence.

• Nondysplastic BE appears green while dysplastic BE appears blue or violet.

• sensitivity of 40–60 % and a high rate of false positives.• trimodal: HD-WLE, followed by AFI. Visible lesion and

abnormal areas further characterized by NBI “endoscopic trimodal imaging” (ETMI)

• neoplastic lesions in BE

• lesion is hard to detect with WLE

• . In E and F, the lesion is located at the gastric folds, which makes the interpretation of AFI difficult, resulting in high false-positive rates for AFI. NBI reduced the false-positive rate

Confocal Laser Endomicroscopy (CLE)

• 1000-fold magnification• Intravenous sodium fluorescein is used as a

contrast or topically (acriflavine, cresyl violet and tetracycline).

• endoscope (eCLE) or as a probe-based system (pCLE) that can be integrated into standard endoscopes.

ERD & NERD

1. Dilated intercellular space2. Hyperplasia of the epithelial basal cell3. Elongation of the intrapapillary capillary loops

(IPCLs), >5 IPCLs within the endomicroscopic field ( visible following intravenous fluorescein )

• surface squamous epithelium of ERD. Marked dilatation of intercellular spaces and an increased number of IPCLs are visible (arrow);

• Intrapapillary loops (arrow) and squamous epithelium in the deeper portion

Endoscopic Optical Coherence Tomography (OCT)

• Infrared light in the 700 to 1500 nm range of wavelength is used instead of sound waves.

• histologic morphology in real time• cautery marking laser light is integrated

• (a)

• (b)

• Figure : Barrett’s esophagus (BE) without dysplasia. (a) Cross-sectional OCT imaging showing clear differences in layered architecture between gastric (GA), normal squamous (NS), and BE regions. BE regions exhibit distortion of the layered architecture and abnormal glandular features. (b) Cross-sectional OCT images around GEJ. BE glands (red arrows) are clearly observed (EP: epithelium; MM: muscularis mucosae in photos A–C).

• Intramucosal esophageal adenocarcinoma. dense large glands within the specimen. Lamina propria and muscularis mucosae (MM) layers are not clearly visible due to the infiltration of metaplasia into the MM layer.

• Figure

• Optical coherence tomography radial image of Barrett’s epithelium with early esophageal cancer (arrow)

Fluorescent tagged peptides and lectins

Do Proton Pump Inhibitors (PPIs) Prevent Cancer in Barrett’s Esophagus?

• Evidence that PPIs prevent carcinogenesis in Barrett’s esophagus is indirect and not proven in controlled trials.

• PPIs are the most effective medical treatment for reflux esophagitisDecrease gastric acid productionDecrease acid refluxHeal reflux esophagitis

Gastroenterology 2011;140:1084.

AGA Medical Position Statement on the Treatment of GERD in Barrett’s Esophagus

NormanBarrettAge 13

• GERD therapy with medication effective to treat GERD symptoms and to heal reflux esophagitis is clearly indicated.

• Antireflux surgery is not more effective than medical therapy for prevention of cancer in Barrett’s esophagus.

• We recommend against attempts to eliminate esophageal acid exposure (PPIs in doses >once daily or antireflux surgery) for cancer prevention.

Gastroenterology 2011;140:1084.

• We suggest that endoscopic surveillance [with biopsy] be performed in patients with Barrett’s esophagus.

AGA Medical Position Statement on Endoscopic Surveillance for Barrett’s Esophagus

• We suggest the following surveillance intervals:▪ No dysplasia: 3-5 years▪ Low-grade dysplasia: 6-12 months▪ High-grade dysplasia in the absence of eradication therapy: 3 monthsNorman

Barrett

The Cancer Risk for High-Grade Dysplasia in Barrett’s is Sufficient to Warrant Intervention

Rastogi . Gastrointest Endosc 2008;67:394. Spechler. Am J Gastroenterol 2005;100:927.

AGA Medical Position Statement. Gastroenterology 2011;140:1084.

High Grade Dysplasia Cancer

~6% per year

Management Options for High-Grade Dysplasia in Barrett’s Esophagus

Intensive endoscopic surveillance (every 3 months)

Endoscopic ablation

Endoscopic mucosal resection

Esophagectomy

Gastroenterology 2011;140:1084.

• We recommend endoscopic eradication therapy rather than surveillance for treatment of

patients with confirmed high-grade dysplasia in Barrett’s

esophagus.

AGA Medical Position Statement on the Management of Barrett’s Esophagus

NormanBarrett

Drawing courtesy of Tom Rice

HGD T2T1

MucosaSubmucosa

Muscularismucosae

BasementmembraneEpithelium

Lamina propria

Drawing courtesy of Tom Rice

T1T2

T3 T4

T Staging of Esophageal Cancer

None considered curable by endoscopic therapy.

Mucosa

SubmucosaSubmucosaSubmucosa

MucosaMucosaMuscularismucosae

Muscularis

propria

Drawing courtesy of Tom Rice

HGD T2T1

MucosaSubmucosa

IntramucosalCarcinoma

T1a

High GradeDysplasia

T1b

Potentially curable withendoscopic therapy

Muscularismucosae T1b: LN mets >10%

Potentially metastatic

Systematic Review: Risk of Lymph Node Metastases for High Grade Dysplasia (HGD) or Intramucosal Carcinoma

(IMC) in Barrett’s Esophagus

Dunbar K, Spechler S. Am J Gastroenterol

2012;107:850.

• Reviewed studies that included:- Patients who had esophagectomy for HGD or IMC and- Final surgical pathology results (lymph node status)• Identified 70 relevant articles

• 1,874 patients who had esophagectomy for HGD (524 patients) or IMC (1,350 patients)

• Lymph node metastases in 26 of 1,874 patients (1.39%, 95% CI .86% - 1.92%)

Accurate T Staging Crucial to Determine if Curative Endoscopic Therapy Feasible

• High Grade Dysplasia and Intramucosal Carcinoma Lymph node metastases in 1%-2%Curative endoscopic therapy feasible

• Submucosal invasionLymph node metastases in >10%Failure rate for endoscopic therapy unacceptable

• Endoscopic mucosal resection (EMR) the best procedure for T staging

EMR is as much a staging procedure as it is a therapeutic procedure.

If EMR shows submucosal invasion, then endoscopic therapy is not advised.

Radiofrequency Ablation (RFA)

RadiofrequencyEnergy Generator

Closely spaced electrodes

Radiofrequency Ablation of Barrett’s Esophagus

AblatedAblatedBarrett’sBarrett’s

MetaplasiaMetaplasia

Complications of Radiofrequency Ablation in 84 Patients

5 esophageal strictures (6%)

1 UGI Bleed (1%)

2 hospitalizations for chest pain (2%)

Shaheen. N Engl J Med 2009;360:2277-88.

Endoscopic Therapy for Mucosal NeoplasiaIn Barrett’s Esophagus 2014

• EMR of mucosal irregularities for staging and therapy

• Ablate the remaining Barrett’s metaplasia to minimize metachronous neoplasia

335 pts with HGD (72%), IMC (24%) or LGD (4%)

270 (81%) complete eradication of dysplasiaMean 2.5 RFA treatments

Haidry. Gastroenterology 2013. 145:87-95.

U.K. Experience with EMR and RFA for Treatment of Mucosal Neoplasia in Barrett’s Esophagus

208 (62%) complete eradication of Barrett’s metaplasia10 (3%) progressed to invasive cancer

30 (9%) strictures requiring dilation, 1 perforation

One year protocol

120 24 36 48Months from end of protocol

% fr

ee o

f dis

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25

50

75

100

0

Dysplasia

Barrett’sMetaplasia

RFA for Non-Dysplastic Barrett’s Esophagus?• Generally requires several endoscopies for

complete eradication• Complication rate low, but not trivial• Substantial rate of recurrence of metaplasia

• Efficacy in preventing cancer not established

• Does not obviate surveillance

• Frequency and importance of subsquamous intestinal metaplasia not clear

Chronic GERD symptoms and ≥1 risk factor(s) for adenocarcinoma(Age>50, male, white, hiatal hernia, obesity, intra-abdominal body fat, smoking)

Consider screening endoscopyNo more screening No Barrett’s

No dysplasia Low-grade dysplasia High-grade dysplasia or intramucosal Ca

Have diagnosis confirmed by expert pathologist

Low-grade dysplasia High-grade dysplasia or intramucosal Ca

Surveillanceendoscopy

every 3-5 yrs

Endoscopic eradicationSurveillance endoscopyevery 6-12 months or

endoscopic eradication

on screeningBarrett’s esophagus

AGA Medical Position Statement on the Management of Barrett’s Esophagus

Gastroenterology 2011;140:1084.

• Endoscopic eradication therapy is not suggested for the general population of patients with Barrett’s esophagus in the absence of dysplasia.

• RFA should be a therapeutic option for select individuals with non-dysplastic Barrett’s esophagus who are judged to be at increased risk for progression to HGD or cancer.

Specific criteria that identify this population have not been fully defined.Norman

Barrett