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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%, shortsegment 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 <3 cm


3-5 times more common than long segment
lower cancer risk
Patients who develop long segments Barrett's were predisposed to more severe reflux
Patients with long segment Barrett's tend to have upright and supine reflux in contrast to
those with short segment Barrett's who have predominantly upright reflux.
Compared to patients with long segment Barrett's, those with short segments tend to have
higher LES pressures and increased distal esophageal peristaltic amplitudes.

Intestinal Metaplasia at the GEJ: If the Z-line and the GEJ coincide and biopsy specimens at the Zline show intestinal metaplasia (histologic without endoscopic criteria for BE)
- African Americans and women have a higher frequency of this lesion than other patients
- Etiology: early form of GERD vs HP.
- low if any cancer risk

Contraversies in diagnosis
- significant inter-observer variability in defining the length of Barrett's esophagus, especially
in the presence of a hiatus hernia
- intestinal metaplasia may not always be apparent on EGD especially with short segment
(34% sensitivity in one study)

Japanese definition- the GE junction is the distal end of the lower-esophageal palisade vessels.
- one study found that using the palisade vessels had lower inter-observer reliability than
using the gastric folds as a landmark

The Prague C & M Criteria Endoscopic Grading System for assessing the presence and extent of
Barrett's esophagus
- the circumferential extent (the C value)
- and maximum extent (the M value) above the GEJ
- A validation study found that the criteria had good inter-observer reliability for Barrett's
esophagus 1 cm in length.

DYSPLASIA AND ADENOCARINCOMA


Annual cancer incidence in patients with Barrett's esophagus is 0.2 to 2.0 percent
The absolute risk of developing cancer is relatively low
Rates of progression to cancer or high-grade dysplasia were twice as high as for men.
Epidemiologic data suggest that the mean interval from developing Barrett's esophagus to
evolution to cancer may be 20 to 30 years
Rising incidence of adenocarcinoma of the esophagus (fivefold in past 20 years)- an incidence
increase exceeding that of any other cancer
Most patients with Barretts esophagus, however, diet of unrelated causes
Long segment Barretts: 30-125 times increased risk of developing esophageal cancer compared
with the general population (0.5% annual risk)

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 antiproliferative 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 acidsuppression 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 <3 cm.
In the case of definite low-grade dysplasia (confirmed during two subsequent examinations and by
two independent specialists), endoscopy should take place every six months (or one year).
In the case of doubtful or probable low-grade dysplasia, repeat examination should take place after
two months of treatment with double-dose proton pump inhibitor.
In the case of severe dysplasia, an endoscopy should be repeated after one month of treatment
with a double-dose proton pump inhibitor with four-quadrant biopsies obtained every 1 cm.
Need for future research:
1) Prospective study to determine optimal surveillance, keeping in mind cost-effectiveness and survival
benefit
2) RCT to evaluate chemoprevention
3) Using molecular markers as alternatives to random biopsy sampling to seek dysplasia in Barrett's
esophagus (p53 and cyclin D1 expression, and abnormal cellular DNA content demonstrable by flow
cytometry)
4) Use of NBI, chromoendoscopy or other endoscopic techniques for assessing Barretts 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.