Barrett’s Esophagus: Clinical aspects, importance & controversies

1. Barrett’s Esophagus:Clinical aspects, importance & controversies John Marshall, MDProfessor of MedicineDivision of GastroenterologyUniversity of Missouri School of MedicineColumbia, MO

2. Barrett’s 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. Barrett’s 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. Barrett’s esophagus:Outline #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. Barrett’s EsophagusPart 1: “Just the Facts”

6. Barrett’s 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 >3-cm; short-segment BE if < 3-cm)

7. NEJM 2002; 346: 836-842

8. Histology of Barrett’s Esophagus • Columnar epithelium and specialized intestinal metaplasia Courtesy of Dr. C. Mel Wilcox

9. GERD Damage to the squamous esophageal mucosa Injury heals through a metaplastic process (columnar cells replace squamous cells) Injury heals with restoration of squamous mucosa Pathogenesis of Barrett’s Esophagus

10. Estimated prevalence of Barrett’s 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 Barrett’s esophagus (BE) cases missed? • GERD symptoms may be mild. • Most patients with chronic GERD symptoms aren’t screened for BE. • Esophageal sensitivity to acid perfusion may be impaired in many Barrett’s patients. At least 25% have no esophageal complaints.

12. Risk factors for developmentof Barrett’s esophagus • Male gender 3 times > female gender • White race >> Blacks & Asians • Abdominal adiposity (obesity) • Genetic factors suspected in some patients/families • Chronic reflux symptoms for > 5-10 years • Age >40-50 years; mean age at diagnosis = 55 yrs

13. Is Helicobacter pylori infection a risk factorfor development of Barrett’s 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 Barrett’s 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. Rate ratio (relative to 1975) Esophageal adenocarcinoma Melanoma Prostate cancer Breast cancer Lung cancer Colorectal cancer Dramatic rise in esophageal adenocarcinoma *National Cancer Institute’s Surveillance, Epidemiology, and End Results database JNatl Cancer Inst 2005;97: 142-146

16. Intestinal metaplasia (IM) of the gastric cardia • IM of the gastric cardia is not to be confused with Barrett’s 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 Barrett’s esophagus • Long-segment BE (LSBE):  >3-cm segment of distal esophagus (columnar mucosa with intestinal metaplasia) • Short-segment BE (SSBE):  <3-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 Barrett’s esophagus NEJM 2002; 346: 836

19. Short Segment Barrett’sIrregular z-line above hiatal hernia Courtesy of Dr. C. Mel Wilcox

20. What we want to prevent -- Cancer Arising in Barrett’s Courtesy of Dr. C. Mel Wilcox

21. Development of esophageal adenocarcinoma from Barrett’s 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 Barrett’s patients will develop cancer.

22. Barrett’s EsophagusPart 2: Current Practice

23. Potential ways of reducing the cancer riskassociated with Barrett’s 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 Barrett’s esophagus in patients with GERD

28. American College of Gastroenterology Practice Guideline:Screening for Barrett’s Esophagus(Am J Gastroenterol 2002; 97: 1888-1895) • “Patients with chronic GERD symptoms are those most likely to have Barrett’s 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. • We’ll look at the evidence for screening momentarily.

29. Once we find Barrett’s 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 Barrett’s adenocarcinomas Gastroenterology 2002; 122: 633-640

31. ACG Practice Guideline:Surveillance in Barrett’s esophagus(Am J Gastro 2002;97:1888)

32. Biopsy protocolFor Surveillance Endoscopy in Barrett’s 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 Barrett’s Esophagus Courtesy of Dr. C. Mel Wilcox

34. Management of high-grade dysplasia in Barrett’s 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. Probability of survival (%) Patients with Barrett’s esophagus General population Years after first diagnosis Life Expectancy in Patients With Barrett’s Esophagus Similar to Age- and Sex-Matched General Population Am J Med 2001;111:33-37

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. Barrett’s EsophagusPart 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 Guideline:Screening and Surveillance for Barrett’s 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 Barrett’s esophagus • No data proving effectiveness of current strategies. • Currently <5% 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 (>10 million). [“Huge haystack, few needles in it.”] • Perhaps 40% of esoph adenoCA patients don’t 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 isn’t 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. Barrett’s EsophagusPart 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)