Barrett’s Esophagus: Clinical aspects, importance & controversies

1
Barretts Esophagus Clinical aspects,
importance controversies 

• John Marshall, MDProfessor of MedicineDivision
  of GastroenterologyUniversity of Missouri School
  of MedicineColumbia, MO

2
Barretts esophagus Overview

• Definition Replacement of the squamous
  epithelium of the distal esophagus by metaplastic
  specialized columnar epithelium, resembling
  intestine, containing goblet cells.
• Complication of gastroesophageal reflux disease.
• Premalignant lesion for adenocarcinoma of the
  esophagus, which is a deadly form of cancer.
• The incidence of esophageal adenocarcinoma has
  increased 6-fold over past 30 years.

3
Barretts esophagus Key questions

• Do current medical and surgical GERD treatments
  prevent esophageal adenocarcinomas?
• Are current screening and surveillance
  recommendations evidence-based?
• Have current screening and surveillance practices
  made a positive difference in preventing cancers
  and saving lives?
• Are current screening and surveillance practices
  justified based on the evidence?
• What does the future hold?

4
Barretts esophagusOutline

• 1 The Facts
• ? Definition of BE
• ? Prevalence of BE
• ? Importance of BE
•  
• 2 Current Practice
•  
• 3 Are current screening and surveillance
  recommendations evidence-based?
• Are they justified?
•  
• 4 Prospects for the future

5
Barretts Esophagus Part 1 Just the Facts
6
Barretts esophagus Definition has changed
over last 25 years

• At least 3-cm of columnar-lined distal esophagus
• Requirement of finding of intestinal metaplasia
• Intestinal metaplasia of the distal
  esophaguswithout specification of length
  (long-segment BE if gt3-cm short-segment BE if lt
  3-cm)

7
NEJM 2002 346 836-842
8
Histology of Barretts Esophagus

• Columnar epithelium and specialized intestinal
  metaplasia

Courtesy of Dr. C. Mel Wilcox
9
Pathogenesis of Barretts Esophagus
10
Estimated prevalence of Barretts esophagus

• 6-12 of patients who undergo EGD for GERD.
•         ? Short-segment BE 6-12
•        ? Long-segment BE 1-5
• 1-2 of unselected patients who undergo EGD
•  
• Most cases go undetected in the general
  population Autopsy data. Perhaps 5 of patients
  with BE are currently being diagnosed.

11
Why are most Barretts esophagus (BE) cases
missed?

• GERD symptoms may be mild.
• Most patients with chronic GERD symptoms arent
  screened for BE.
• Esophageal sensitivity to acid perfusion may be
  impaired in many Barretts patients. At least 25
  have no esophageal complaints.

12
Risk factors for developmentof Barretts
esophagus

• Male gender 3 times gt female gender
• White race gtgt Blacks Asians
• Abdominal adiposity (obesity)
• Genetic factors suspected in some
  patients/families
• Chronic reflux symptoms for gt 5-10 years
• Age gt40-50 years mean age at diagnosis 55 yrs

13
Is Helicobacter pylori infection a risk
factorfor development of Barretts esophagus?

• No.
• Individuals with H. pylori infection/gastritis
  tend to have less problems with GERD.
• They have less parietal cell mass and reduced
  acid secretion.
• Thus, H. pylori infection may even have a
  protective effect against GERD and BE.
• Eradicating H. pylori infection can sometimes
  exacerbate GERD symptoms.

14
Why do we care about Barretts esophagus?

• Patients with BE have an increased risk of
  developing esophageal adenocarcinoma.
• Over the past 30 years, the incidence of squamous
  cell cancer of the esophagus has stayed constant,
  while the incidence of adenocarcinoma has
  increased 6-fold! This is an increase that
  exceeds that of any other cancer.
• Today, adenocarcinoma accounts for more than half
  of esophageal cancers.
• Patients with BE have about a 30-40 fold
  increased risk of adenocarcinoma of esophagus.
• Risk of a BE patient developing cancer is
  estimated to be about 1 per 200 patient-years
  follow-up.
• Despite all this, most patients with BE do not
  develop esophageal cancer. Less than 5

15
Dramatic rise in esophageal adenocarcinoma
National Cancer Institutes Surveillance,
Epidemiology, and End Results database
J Natl Cancer Inst 200597 142-146
16
Intestinal metaplasia (IM) of the gastric cardia

• IM of the gastric cardia is not to be confused
  with Barretts esophagus (IM of distal esophagus)
• Reported in 10-32 of biopsies from unselected
  patients undergoing EGD with biopsies of cardia.
• Etiology controversial.
• Cancer risk appears to be minimal, if at all.
• When trying to make Dx of BE, it is important for
  the endoscopist to biopsy the distal esophagus,
  not the gastric cardia or GE junction, or a
  mistaken diagnosis of BE can occur! This causes
  undo patient alarm and unnecessary surveillance
  endoscopy.

17
Long-segment versus short-segment Barretts
esophagus

• Long-segment BE (LSBE)  gt3-cm segment of distal
  esophagus (columnar mucosa with intestinal
  metaplasia)
• Short-segment BE (SSBE)  lt3-cm segment (usually
  tongues or islands of columnar mucosa with
  intestinal metaplasia)
• Patients with LSBE tend to have greater
  esophageal acid exposure than SSBE, as well as
  lower LES pressures and more esophageal
  dysmotility.
• LSBE (classic BE) is much better studied.
• We are currently managing LSBE and SSBE
  similarly.
• However, questions remain
• Does SSBE have the same pathogenesis?
• Does SSBE have a lower risk of cancer?
• Does SSBE progress to LSBE?
• Does the length of BE correlate with cancer risk?

18
Long-segment Barretts esophagus
NEJM 2002 346 836
19
Short Segment Barretts Irregular z-line above
hiatal hernia
Courtesy of Dr. C. Mel Wilcox
20
What we want to prevent -- Cancer Arising in
Barretts
Courtesy of Dr. C. Mel Wilcox
21
Development of esophageal adenocarcinoma from
Barretts esophagus

• Compelling evidence exists for a
  dysplasia-carcinoma sequence in BE.
• Specialized columnar epithelium progresses in
  some patients ? low-grade dysplasia ? high-grade
  dysplasia ? adenocarcinoma.
• Not every patient with low-grade dysplasia
  progresses, and low-grade dysplasia can even
  spontaneously revert back to no dysplasia.
• Time course for development of cancer highly
  variable.
• Most patients never progress to dysplasia. Less
  than 5 of Barretts patients will develop cancer.

22
Barretts Esophagus Part 2 Current Practice 
23
Potential ways of reducing the cancer
riskassociated with Barretts esophagus

• Aggressive anti-reflux medical therapy or
  surgical fundoplication.
• Screen individuals with chronic GERD for BE.
• In patients known to have BE, perform
  surveillance to take biopsies to look for
  dysplasia.

24
Does aggressive medical therapy for GERDreduce
the cancer risk in patients with BE?

• Proton pump inhibitors are the cornerstone of
  medical therapy for BE. They consistently result
  in symptomatic GERD relief and heal esophagitis.
• PPI therapy rarely results in significant
  regression of BE.
• While it makes theoretical sense that PPIs might
  reduce cancer risk in BE, there is little proof
  to date.
• Even when reflux symptoms resolve, esophageal
  acid exposure is not always normalized. Some have
  suggested that 24-hr esophageal pH studies should
  be performed in BE patients on PPI to assess the
  response to therapy. However, no strong data to
  support this practice.

25
Does anti-reflux surgery reducecancer risk in
patients with BE?

• Anti-reflux surgery effectively alleviates GERD
  symptoms in BE patients. Effectiveness depends on
  the skill of the particular surgeon.
• Incomplete regression of BE is occasionally seen
  after surgery, but complete regression is rare.
• No credible evidence to date that anti-reflux
  surgery decreases cancer risk.
• Long-term durability of anti-reflux surgery is
  still an on-going question.

26
Chemoprevention in BE?

• Chemoprevention strategies in BE are just
  starting to be examined (e.g. COX-2 inhibitors).
• However, there is no current proof that
  chemopreventive agents effectively reduce cancer
  risk.

27
Screening for Barretts esophagus in patients
with GERD
28
American College of Gastroenterology Practice
GuidelineScreening for Barretts
Esophagus (Am J Gastroenterol 2002 97
1888-1895)

• Patients with chronic GERD symptoms are those
  most likely to have Barretts esophagus and
  should undergo upper endoscopy
• Screening is best done with patients on PPIs,
  since erosions and ulcers can obscure BE and
  since active inflammation makes pathologic
  interpretation more difficult.
• Well look at the evidence for screening
  momentarily.

29
Once we find Barretts esophagus --Rationale for
surveillance (EGD with Bx)

• Endoscopic surveillance can detect dysplasia in
  BE, which is a further marker of cancer risk
• No dysplasia--  cancer risk 2
• Low-grade dysplasia--  cancer risk 7
• High-grade dysplasia--  cancer risk 22
• Asymptomatic cancers detected during surveillance
  are less advanced than those which present with
  symptoms. If wait for symptoms, 5-year survival
  only 14.

30
Age-adjusted survival after diagnosisof
Barretts adenocarcinomas
Gastroenterology 2002 122 633-640
31
ACG Practice GuidelineSurveillance in Barretts
esophagus(Am J Gastro 2002971888)
32
Biopsy protocolFor Surveillance Endoscopy in
Barretts Esophagus(Am J Gastroenterol 2002
97 1888-1895)

• Four-quadrant biopsies every 2-cm of the BE.
• Additional biopsies of any mucosal abnormality
  (e.g. erosion, ulcer, nodule, stx).
• In setting of high-grade dysplasia, biopsies
  taken every 1-cm.

33
Biopsy Sampling of Barretts Esophagus
Courtesy of Dr. C. Mel Wilcox
34
Management of high-grade dysplasia in Barretts
esophagus

• Controversial. No consensus on best treatment.
• Options
•      1. Esophagectomy
• ? High mortality, except in high-volume centers
•  
•      2. Endoscopic treatments (e.g.
  photodynamic therapy, endoscopic mucosal
  resection, other)
• ?   Residual intestinal metaplasia can form
  beneath the new squamous epithelium
•  
•      3. Intensive endoscopic surveillance
  (until Bx reveals adenocarcinoma)

35
Life Expectancy in Patients With Barretts
Esophagus Similar to Age- and Sex-Matched
General Population
Am J Med 200111133-37
36
Does what we are doing make sense based on the
current evidence?

• When considering the benefits of
• screening and surveillance for BE, it is
• important to appreciate that enthusiasm
• to help patients is not enough.

Modified quote of Raymond Playford, MD 2005
37
Barretts Esophagus Part 3 Answering these key
questions 

• Are current screening and surveillance
  recommendations evidence-based?
• Have current screening and surveillance practices
  made a positive difference in preventing cancers
  and saving lives?
• Are current screening and surveillance practices
  justified based on the evidence?

38
American College of Gastroenterology Practice
GuidelineScreening and Surveillance for
Barretts Esophagus (Am J Gastroenterol 2002
97 1888-1895)

• No direct evidence has validated their use.
• No level I evidence (RCTs) or level II evidence
  (cohort or case-controlled trials). Rather,
  current practice is based on level III evidence
  (decision analyses, case series, case reports, or
  flawed clinical trials) and level IV evidence
  (opinions of expert authorities based on
  available evidence).

39
Critical issues relating to screening and
surveillanceIn Barretts esophagus

• No data proving effectiveness of current
  strategies.
• Currently lt5 of patients with esoph adenoCA
  diagnosed during BE screening surveillance.
• Small number of cases/year of esoph adenoCA in
  U.S. (7,000).
• Large pool of potential subjects to be screened
  (gt10 million). Huge haystack, few needles in
  it.
• Perhaps 40 of esoph adenoCA patients dont have
  GERD symptoms.
• Economic models of surveillance in pts with no
  dysplasia do not demonstrate cost effectiveness.

40
So, where do we stand as regards our Key
Questions?

• Do current medical and surgical GERD treatments
  prevent esophageal adenocarcinomas? Sounds
  appealing, but no data to show that they do.
• Are current screening and surveillance
  recommendations evidence-based? No.
• Have current screening and surveillance practices
  made a positive difference in preventing cancers
  and saving lives? Their overall impact has been
  quite small.
• Are current screening and surveillance practices
  justified based on the evidence? Modification of
  current practice guidelines is urgently needed.
•  

41
So, what are gastroenterologists and internists
to do?

• The evidence for what we are doing isnt very
  strong. Many unresolved questions.
• Current ACG practice guidelines are too strongly
  worded and rigid based on available evidence.
• Eisen, Lieberman, Fennerty Sonnenberg proposed
  in 2004 that a NIH consensus conference be
  convened to review updated data and to develop
  updated, more rational guidelines (Clin Gastro
  Hepatol 2004 2 861-864).
• Until this happens, physicians will feel
  obligated to follow current practice guidelines
  to reduce the perceived likelihood of litigation.

42
Barretts Esophagus Part 4 Prospects for the
Future

• Some of our national organizations are
  re-examining the evidence. Hopefully new practice
  guidelines will be forthcoming.
• Much more evidence is needed.
• Limit screening to individuals at highest risk of
  BE (e.g. 50-yo white males with chronic GERD
  symptoms).
• Esophageal capsule endoscopy and unsedated
  endoscopy with ultrathin scopes offer less
  invasive options for screening. Acceptance and
  cost-effectiveness remain to be defined.
• Perhaps long-term surveillance is not needed in
  BE patients without dysplasia. 
• Are there histologic or tissue genetic markers
  which will predict outcomes with greater
  accuracy?
• Newer endoscopic techniques to target biopsies in
  BE are increasingly available (e.g. narrow band
  imaging, chromoendoscopy, autofluoresence
  spectroscopy).
• Chemopreventative drug therapy needs further
  study (e.g. aspirin, NSAIDs)