Barretts Esophagus Core Curriculum Review Sheet Fellow: Suresh Pola Faculty: Nedret Copur -Dahi December 8, 2009

DEFINITION A change in the distal esophageal epithelium of any length that can be recognized as columnar

type mucosa at endoscopy and is confirmed to have intestinal metaplasia by biopsy. A premalignant condition?

- Unmasking of underlying BE after chemotherapy for adenocarcinoma of the distal esophagus

The most serious histologic complication from GERD

PATHOGENESIS severe GERD, usually with chronic reflux symptoms for more than 10 years other findings: low LES pressures, poor esophageal motility, large hiatal hernias, and extensive

acid and bile reflux Epidemiology

Mean age 55 Predominantly seen in Caucasians (more severe GERD, less HP infections) Can occur in children (rarely occurs before age five) uncommon in Blacks and Asians prevalence in Hispanics appears to be similar to that in Caucasians male to female ratio is approximately 2:1 frequency of Barrett's esophagus in the general population from 0.9 to 4.5 percent depending in

part upon the population studied and the definitions used In patients with GERD, 6-12% have BE In patients undergoing EGD for chronic GERD, long segment Barrett's found in 3 -5%, short-

segment Barrett's in 10-15% clinically recognized Barrett's esophagus ~ 10x less than in autopsy studies (~23 per 100,000) Most have GERD symptoms but 25% are asymptomatic

DIAGNOSIS The endoscopist must document that columnar epithelium lines the distal esophagus Histologic examination of biopsy specimens from that columnar epithelium must reveal specialized

intestinal metaplasia with acid mucin-containing golbet cells. Identifying the Squamocolumnar (SC) and Gastroesophageal (GE) junctions endoscopically:

Columnar epithelium has a reddish color and velvet-like texture Squamous epithelium has a pale, glossy appearance The juxtaposition of these epithelia at the SC junction forms a visible line called the Z-line.

the GE junction is the imaginary line at which the esophagus ends and the stomach begins

anatomically (level of the most proximal extent of the gastric folds) Figure 42-14 Barrett's esophagus. A, Endoscopy showing classic long-segment Barrett's esophagus with a 5 cm segment of circumferential reddish-pink columnar mucosa extending proximally from the esophageal-gastric junction. B, Short-segment Barrett's esophagus with several tongues (at 2 to 5 o'clock) above a small hiatal hernia. C, Histopathology showing specialized intestinal metaplasia with glandular epithelium and characteristic goblet cells. On the right of the photomicrograph is normal esophageal

squamous mucosa. Sleisenger & Fordtrans Gastrointestinal and Liver Disease, 8th edition

CLASSIFICAITON Normal: the SC and GE junctions coincide, thus the entire esophagus is lined by squamous

epithelium. Barretts: the SC junction is located proximal to the GE junction (there is a columnar-lined segment

of esophagus) & biopsy specimens from that segment show specialized intestinal metaplasia - long segment Barrett's: distance between the Z-line and the GEJ is 3 cm

increased risk for developing adenocarcinoma

- short-segment Barrett's: distance is

The risk of adenocarcinoma has been estimated to be 2 to 15 times higher in patients with long

segment Barrett's. Lower incidence of dysplasia when less mucosa is involved (6 to 8% in short segment versus 15 to

24 % in long segment Barrett's)

SCREENING FOR BE There is little evidence that screening all patients with longstanding GERD prevents deaths from

esophageal adenocarcinoma It is not clear that patients who are known to have Barrett's esophagus benefit from surveillance The Practice Parameters Committee of the American College of Gastroenterology has

recommended the following guideline on initial evaluation for patients with GERD: - Initial GERD: Typical for uncomplicated GERD-> initial trial of empiric therapy (including

lifestyle modification) - Patients in whom empiric therapy is unsuccessful or who have symptoms suggesting

complicated disease (anorexia, weight loss, dysphagia, odynophagia, bleeding, and signs of systemic illness) should have further diagnostic testing such as endoscopy

- Patients with chronic GERD symptoms are those most likely to have Barrett's esophagus and should undergo upper endoscopy

Other authorities feel that there is insufficient evidence to support the practice of routine endoscopic screening of patients with chronic GERD symptoms

?cost effective: one-time screening endoscopy had a cost-effectiveness ratio of $10,000 per quality-adjusted life-year of survival gained if follow-up endoscopies were done only in Barrett's patients with dysplasia

MANAGEMENT OF BARRETTS ESOPHAGUS 1) Treatment of Reflux similar to typical GERD treatment initial therapy with a proton pump inhibitor (PPI) with the goal to control reflux symptoms.

- HOWEVER, in a study of 48 patients with Barrett's esophagus, 50 percent had persistently abnormal esophageal acid exposure documented by pH monitoring while they were receiving dosages of PPIs that abolished GERD symptoms Conventional-dose antisecretory therapy reduces, but does not eliminate, gastric acid secretion in

most patients with Barrett's esophagus ~ 80% of breakthrough reflux overnight in one study Reliable clinical predictors of persistent abnormal esophageal acid exposure in patients with

Barrett's esophagus treated with PPIs have not been identified Adding a bedtime dose of an H2RA to a regimen of a PPI administered twice daily has also been

suggested but the efficacy of this approach is unclear It is not clear whether GERD predisposes to malignancy by causing the initial esophageal

metaplasia (ie, by causing Barrett's esophagus itself) vs. by promoting carcinogenesis in established Barrett's esophagus (or both).

An observational trial in a VA population suggested that patients with Barrett's esophagus who had received a prescription for a proton pump inhibitor were less likely to develop dysplasia compared with those who received no therapy or an H2 receptor antagonist.

Aggressive antireflux therapy can cause partial regression of the specialized intestinal metaplasia in Barrett's esophagus.

Most patients treated with PPIs develop islands of squamous epithelium (evidence of partial regression) within their metaplastic columnar lining

Regression of Barrett's epithelium has also been observed with fundoplication (and possibly to a greater degree than with medical therapy)

Fundoplication vs. PPI: - Controlled studies show no difference in preventing cancer - Available data suggest that antireflux surgery should not be advised with the expectation

that the procedure will prolong life by preventing esophageal cancer

2) Surveillance for dysplasia Four quadrant biopsies every 2 cm within the metaplastic tissue Although prospective studies are not available, case series confirm that esophageal cancers

detected by endoscopic surveillance are at an earlier, more favorable stage for survival than cancers found when patients present with dysphagia and their Barrett's esophagus is noted.

Recommended intervals are based on retrospective data (ACG guidelines) 2008 ACG Guidelines:

-surveillance of high grade dysplasia is more contraversial because rate of cancer progression varies greatly (16% to 59%) and may differ in unifocal and multifocal cases -some groups downstage the dysplasia and follow with surveillance q3 months

A survival benefit in patients undergoing surveillance has not been demonstrated in randomized prospective trials

- Such trials: large, costly, ?ethical No study has established the reliability of surveillance in detecting curable dysplasia The development of incurable malignancies in some patients despite adherence to endoscopic

surveillance programs has been documented Some cost-effectiveness models have suggested that endoscopic screening and surveillance for

Barrett's esophagus can be beneficial under certain conditions Cost effective? One study estimated surveillance costing $98,000 per quality-adjusted life year

gained

Another study found screening for Barrett's esophagus to be cost-effective, but surveillance, not. Few studies document the natural history of dysplasia, thus the rate at which low-grade dysplasia

progresses to high-grade dysplasia and cancer is unclear. The incidence of low-grade dysplasia was 4.3% per year in a prospective study of 1376 patients.

- Regression to no dysplasia was observed in 66 percent of patients - progression to high-grade dysplasia or cancer was observed in 21 percent

There is also considerable variation among reported estimates on the rate at which high-grade dysplasia in Barrett's esophagus progresses to cancer.

For patients without dysplasia, the risk of esophageal adenocarcinoma is approximately 0.5 percent per year

For patients with low-grade dysplasia, the risk of esophageal adenocarcinoma is approximately 0.6 percent per year

For patients with high-grade dysplasia, the rate of cancer development is 4 to 6 percent per year Surgical literature shows that esophagectomy specimens following high-grade dysplasia showed

41% of specimens had cancer Extensive biopsy sampling of the Barrett esophagus can reduce biopsy sampling error, but cannot

eliminate the problem entirely.

Endoscopic techniques to help identify dysplasia: vital dyes (chromoendoscopy), endosonography, optical coherence tomography, high resolution endoscopy, confocal microendoscopy, and spectroscopy using reflectance, absorption, light-scattering, fluorescence, narrow band imaging, and Raman detection methods

- None of these techniques has yet been shown to provide sufficient clinical information to justify its routine application for surveillance purposes.

3) Treatment of Dysplasia

A. Esophagectomy: high mortality (3-12.2%) depending on center expertise and morbidity (complication rate as high as 30-50%) except in select centers

B. Albation (photodynamic therapy, YAG laser, multipolar electrocoagulation, APC, RFA) use thermal, photochemical, or radiofrequency energy to ablate the abnormal

epithelium in Barrett's esophagus given PPIs so that the injured mucosa heals with the growth of new squamous

epithelium. great for high grade dysplasia and early cancer especially with elderly or comorbid

patients when combined with EMR, reverses Barretts in 70-80% of patients can have buried glands that can give rise to adenocarcinoma adverse reactions range from mild chest pain, sore throat, or odynophagia to

esophageal strictures, perforation, and death cost-effectiveness is debated especially for non-dysplastic or low-grade dysplasia

Radiofrequency ablation the HALO system that ablates Barrett's esophagus using radiofrequency energy delivered by a balloon that has a series of closely spaced electrodes

advantages: rapidly generates a circumferential thermal injury with controlled depth and uniformity; may result in low rates of stricture formation and buried metaplasia.

Data: when compared with a sham procedure, higher rate of complete eradication of dysplasia (91 versus 23 percent) as well as intestinal metaplasia. Also had less disease progression (4 versus 16 percent) and fewer cancers (1 versus 9 percent) during 12 months follow-up

Complications: chest pain, gastrointestinal bleeding, and development of an esophageal stricture.

Photodynamic therapy uses photosensitizers to produce cytotoxicity in the presence of oxygen after stimulation by light of an appropriate wavelength

Advantages: ease of use, the need for fewer endoscopic sessions compared to thermal ablative techniques, and reduced morbidity, mortality, and cost when compared to surgery

Disadvantages: 5 year survival similar to esophagectomy patients, limited availability, stricturing, buried glands

Data: superior to omeprazole alone for eradicating dysplasia and preventing cancer in Barrett's esophagus

15 percent of patients who received photodynamic therapy ultimately developed esophageal cancer in one study

C. Endoscopic mucosal resection (EMR) - excision of a large segment of esophageal mucosa down to the submucosa, providing large tissue specimens that can be examined by the pathologist to determine the character and extent of the lesion, and the adequacy of resection.

Advantage: both diagnostic (revealing submucosal invasion may lead to esophagectomy) and therapeutic.

Disadvantages: histopathologic interpretation of EMR specimens is not always straightforward

Complications: bleeding, strictures D. Intensive endoscopic surveillance in which invasive therapies are withheld until biopsy specimens reveal adenocarcinoma.

few published data directly support the safety and efficacy of intensive surveillance for high-grade dysplasia: mixed data.

All in all, efficacy of these therapies of dysplasia in reducing cancer deaths is not established, although at least two cost-effectiveness analyses concluded that endoscopic ablation provided the longest quality adjusted life expectancy E. Chemoprevention:

A recent meta-analysis of previous cohort studies showed that low-dose aspirin and NSAIDs, even with infrequent use, led to a significant risk reduction in esophageal cancer

How? specialized intestinal metaplasia of Barrett's esophagus exhibits increased

expression of COX-2 and inhibition of COX-2 has been shown to have anti-proliferative and pro-apoptotic effects in Barrett's-associated esophageal adenocarcinoma cell lines

Benefits would need to outweigh risks of NSAIDs or ASA including cardiovascular GI risks

Published Guidelines for Management of Barretts Esophagus: American College of Gastroenterology 2008 most comprehensive guideline

Screening for Barrett's esophagus remains controversial. The highest yield for Barrett's is in older (age 50 or more) Caucasian males with longstanding heartburn.

The grade of dysplasia determines the appropriate surveillance interval. Any grade of dysplasia by histology should be confirmed by an expert pathologist. The ACG suggests that patients be advised of the benefits and risks of surveillance endoscopy. Consideration of beginning a surveillance program should consider the patients age, likelihood of survival over the next five years, the patient's understanding of the process and limitations of detection of cancer, and willingness to adhere to the recommendations.

Surveillance should be performed in patients whose reflux symptoms are controlled with proton pump inhibitors. Four quadrant biopsies should be obtained in every 2 cm of the Barrett's mucosa and, ideally, submitted to pathology in separate containers to permit focusing of subsequent biopsies should dysplasia be detected.

Patients with low grade dysplasia should have a follow-up endoscopy within six months. If none is found, then yearly endoscopy is warranted until no dysplasia is present on two consecutive annual endoscopies.

The finding of high grade dysplasia in flat mucosa should lead to confirmation by an expert GI pathologist and a subsequent endoscopy within three months. Patients with high grade dysplasia with mucosal irregularity should undergo endoscopic mucosal resection. Patients with confirmed high grade dysplasia, even if unifocal, should be counseled regarding therapeutic options including intensive surveillance, esophagectomy or ablative therapies.

Patients who appear to have lost their dysplasia on surveillance should be treated according to the highest degree of dysplasia previously found.

American Society of Gastrointestinal Endoscopy (ASGE) similar to ACG guidelines

Screening EGD for Barrett's esophagus should be considered in selected patients with chronic, longstanding GERD. After a negative screening examination, further screening endoscopy is not judged to be indicated.

The cost effectiveness of surveillance in patients without dysplasia is controversial. Surveillance endoscopy is appropriate for patients fit to undergo therapy, should endoscopic/histologic findings dictate. For patients with established Barrett's esophagus of any length and with no dysplasia, after two consecutive examinations within one year, an acceptable interval for additional surveillance is every three years.

Patients with HGD are at significant risk for prevalent or incident cancer. Patients who are surgical candidates may elect to have definitive therapy. Patients who elect surveillance endoscopy should undergo follow-up every three months for at least one year, with multiple large capacity biopsy specimens obtained at 1 cm intervals. After one year of no cancer detection, the interval of surveillance may be lengthened if there are no dysplastic changes on two subsequent endoscopies performed at three-month intervals. High-grade dysplasia should be confirmed by an expert GI pathologist.

Surveillance in patients with LGD is recommended. The significance of LGD as a risk factor for cancer remains poorly defined; therefore the optimal interval and biopsy protocol has not been established. A follow-up EGD (ie, at six months) should be performed with concentrated biopsies in the area of dysplasia. If LGD is confirmed, then one possible management scheme would be surveillance at 12 months and yearly thereafter as long as dysplasia persists.

If the presence or degree of dysplasia is indeterminate and there is evidence of acute inflammation due to GE reflux, repeat biopsy should be performed after eight weeks of effective acid-suppression therapy.

French Society of Digestive Endoscopy (FSDE) differ somewhat from the ASGE and the ACG (in the case of circular Barrett's esophagus, four biopsies (one in each side) should be obtained every 2 cm from the cardioesophageal junction. In the case of Barrett's esophagus of less than 3 cm, two to four biopsies should be obtained every 1 cm)

Subsequent surveillance recommendations are as follows: In the absence of dysplasia, surveillance should take place every two years for Barrett's esophagus

>3 cm, and every three years for Barrett's esophagus

References 1. Wang, Kenneth K and Sampliner, Richard E. Practice guidelines Updated Guidelines 2008 for the

Diagnosis, Surveillance and Therapy of Barretts Esophagus. American Journal of Gastroenterology, 2008.

2. Sleisenger & Fordtrans Gastrointestinal and Liver Disease, 8th edition 3. UpToDate Online Endoscopic mucosal resection for treatment of high-grade dysplasia and early

cancer in Barrett's esophagus 2009. 4. UpToDate Online Epidemiology, clinical manifestations, and diagnosis of Barrett's esophagus 2009. 5. UpToDate Online Management of Barrett's esophagus 2009.