UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Barrett's esophagus: Pathogenesis and malignant transformation

Author
Stuart J Spechler, MD
Section Editor
Nicholas J Talley, MD, PhD
Deputy Editor
Shilpa Grover, MD, MPH

INTRODUCTION

Barrett's esophagus is the condition in which any extent of metaplastic columnar epithelium that predisposes to cancer development replaces the stratified squamous epithelium that normally lines the distal esophagus. The condition develops as a consequence of chronic gastroesophageal reflux disease (GERD) and predisposes to the development of adenocarcinoma of the esophagus.

The pathogenesis of Barrett's esophagus and the mechanisms of transformation into adenocarcinoma will be reviewed here. The clinical manifestations, diagnosis, and management of this disorder (including surveillance for adenocarcinoma) are discussed, separately. (See "Barrett's esophagus: Epidemiology, clinical manifestations, and diagnosis" and "Barrett's esophagus: Surveillance and management".)

PATHOPHYSIOLOGY

Barrett's esophagus develops through the process of metaplasia, in which one kind of fully differentiated (adult) tissue replaces another [1]. Metaplasia commonly is a consequence of chronic inflammation, and Barrett’s metaplasia results from chronic reflux esophagitis caused by the gastroesophageal reflux of acid, bile, and other noxious substances. In most patients, reflux-induced mucosal damage is repaired by the regeneration of more squamous cells. In some patients, for reasons that are not clear, the reflux-damaged esophagus is repaired through a columnar metaplasia in which columnar cells replace squamous cells. For more than a decade, the prevailing hypothesis has been that Barrett’s metaplasia is the result of transcommitment, in which progenitor cells in the esophagus that normally would differentiate into squamous cells instead differentiate into columnar cells. Research in animal models has challenged this transcommitment hypothesis by providing evidence that Barrett’s metaplasia might result from the proximal migration of stem cells from the gastric cardia [2], or from the expansion of a nest of residual embryonic-type cells located at the gastroesophageal junction [3]. Finally, in a rat model of reflux esophagitis, Barrett’s metaplasia appears to occur when circulating stem cells from the bone marrow are transported through the blood to the damaged esophagus, where they differentiate into columnar cells [4]. It is not clear which, if any, of these hypotheses on the pathogenesis of Barrett’s metaplasia is correct.

The metaplastic columnar cells of Barrett's esophagus are in some ways a favorable adaptation to chronic reflux since they appear to be more resistant to reflux-induced injury than the native squamous cells. Unfortunately, esophageal columnar metaplasia predisposes to the development of adenocarcinoma [5].

The pattern of acid secretion may be an important determinant in the neoplastic progression of Barrett's metaplasia. An ex vivo study demonstrated that pulsed acid exposure increased cell proliferation, but continuous acid exposure decreased cell proliferation [6]. Another report found that the length of Barrett's esophagus correlated with the percent of supine reflux and percent of total time that esophageal pH was <4 [7]. Other studies have demonstrated that patients with longstanding and severe reflux symptoms are at increased risk for adenocarcinoma of the esophagus [8].

        

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Nov 2016. | This topic last updated: Thu May 12 00:00:00 GMT+00:00 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
References
Top
  1. Spechler SJ. Laser photoablation of Barrett's epithelium: burning issues about burning tissues. Gastroenterology 1993; 104:1855.
  2. Quante M, Bhagat G, Abrams JA, et al. Bile acid and inflammation activate gastric cardia stem cells in a mouse model of Barrett-like metaplasia. Cancer Cell 2012; 21:36.
  3. Wang X, Ouyang H, Yamamoto Y, et al. Residual embryonic cells as precursors of a Barrett's-like metaplasia. Cell 2011; 145:1023.
  4. Sarosi G, Brown G, Jaiswal K, et al. Bone marrow progenitor cells contribute to esophageal regeneration and metaplasia in a rat model of Barrett's esophagus. Dis Esophagus 2008; 21:43.
  5. Morales CP, Souza RF, Spechler SJ. Hallmarks of cancer progression in Barrett's oesophagus. Lancet 2002; 360:1587.
  6. Fitzgerald RC, Omary MB, Triadafilopoulos G. Dynamic effects of acid on Barrett's esophagus. An ex vivo proliferation and differentiation model. J Clin Invest 1996; 98:2120.
  7. Fass R, Hell RW, Garewal HS, et al. Correlation of oesophageal acid exposure with Barrett's oesophagus length. Gut 2001; 48:310.
  8. Lagergren J, Bergström R, Lindgren A, Nyrén O. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med 1999; 340:825.
  9. Cameron AJ, Lomboy CT. Barrett's esophagus: age, prevalence, and extent of columnar epithelium. Gastroenterology 1992; 103:1241.
  10. Fletcher J, Wirz A, Young J, et al. Unbuffered highly acidic gastric juice exists at the gastroesophageal junction after a meal. Gastroenterology 2001; 121:775.
  11. Fletcher J, Wirz A, Henry E, McColl KE. Studies of acid exposure immediately above the gastro-oesophageal squamocolumnar junction: evidence of short segment reflux. Gut 2004; 53:168.
  12. Iijima K, Henry E, Moriya A, et al. Dietary nitrate generates potentially mutagenic concentrations of nitric oxide at the gastroesophageal junction. Gastroenterology 2002; 122:1248.
  13. Cook MB, Shaheen NJ, Anderson LA, et al. Cigarette smoking increases risk of Barrett's esophagus: an analysis of the Barrett's and Esophageal Adenocarcinoma Consortium. Gastroenterology 2012; 142:744.
  14. Paull A, Trier JS, Dalton MD, et al. The histologic spectrum of Barrett's esophagus. N Engl J Med 1976; 295:476.
  15. Spechler SJ. Clinical practice. Barrett's Esophagus. N Engl J Med 2002; 346:836.
  16. Lewin KJ, Appelman HD. Tumors of the esophagus and stomach. Atlas of tumor pathology (electronic fascicle). Third series, fascicle 18, Armed Forces Institute of Pathology, Washington, DC 1996.
  17. Morales CP, Spechler SJ. Intestinal metaplasia at the gastroesophageal junction: Barrett's, bacteria, and biomarkers. Am J Gastroenterol 2003; 98:759.
  18. Ormsby AH, Goldblum JR, Rice TW, et al. Cytokeratin subsets can reliably distinguish Barrett's esophagus from intestinal metaplasia of the stomach. Hum Pathol 1999; 30:288.
  19. Yang L, Lu X, Nossa CW, et al. Inflammation and intestinal metaplasia of the distal esophagus are associated with alterations in the microbiome. Gastroenterology 2009; 137:588.
  20. Spechler SJ. Disputing dysplasia. Gastroenterology 2001; 120:1864.
  21. Goldblum JR. Barrett's esophagus and Barrett's-related dysplasia. Mod Pathol 2003; 16:316.
  22. Reid BJ, Haggitt RC, Rubin CE, et al. Observer variation in the diagnosis of dysplasia in Barrett's esophagus. Hum Pathol 1988; 19:166.
  23. Skacel M, Petras RE, Gramlich TL, et al. The diagnosis of low-grade dysplasia in Barrett's esophagus and its implications for disease progression. Am J Gastroenterol 2000; 95:3383.
  24. Montgomery E, Bronner MP, Goldblum JR, et al. Reproducibility of the diagnosis of dysplasia in Barrett esophagus: a reaffirmation. Hum Pathol 2001; 32:368.
  25. Cameron AJ, Lomboy CT, Pera M, Carpenter HA. Adenocarcinoma of the esophagogastric junction and Barrett's esophagus. Gastroenterology 1995; 109:1541.
  26. Mendes de Almeida JC, Chaves P, Pereira AD, Altorki NK. Is Barrett's esophagus the precursor of most adenocarcinomas of the esophagus and cardia? A biochemical study. Ann Surg 1997; 226:725.
  27. Galipeau PC, Cowan DS, Sanchez CA, et al. 17p (p53) allelic losses, 4N (G2/tetraploid) populations, and progression to aneuploidy in Barrett's esophagus. Proc Natl Acad Sci U S A 1996; 93:7081.
  28. Souza RF, Morales CP, Spechler SJ. Review article: a conceptual approach to understanding the molecular mechanisms of cancer development in Barrett's oesophagus. Aliment Pharmacol Ther 2001; 15:1087.
  29. Weston AP, Banerjee SK, Sharma P, et al. p53 protein overexpression in low grade dysplasia (LGD) in Barrett's esophagus: immunohistochemical marker predictive of progression. Am J Gastroenterol 2001; 96:1355.
  30. Barrett MT, Sanchez CA, Prevo LJ, et al. Evolution of neoplastic cell lineages in Barrett oesophagus. Nat Genet 1999; 22:106.
  31. Ouatu-Lascar R, Fitzgerald RC, Triadafilopoulos G. Differentiation and proliferation in Barrett's esophagus and the effects of acid suppression. Gastroenterology 1999; 117:327.
  32. Buttar NS, Wang KK, Anderson MA, et al. The effect of selective cyclooxygenase-2 inhibition in Barrett's esophagus epithelium: an in vitro study. J Natl Cancer Inst 2002; 94:422.
  33. Huo X, Juergens S, Zhang X, et al. Deoxycholic acid causes DNA damage while inducing apoptotic resistance through NF-κB activation in benign Barrett's epithelial cells. Am J Physiol Gastrointest Liver Physiol 2011; 301:G278.
  34. Wang C, Yuan Y, Hunt RH. Helicobacter pylori infection and Barrett's esophagus: a systematic review and meta-analysis. Am J Gastroenterol 2009; 104:492.
  35. Rokkas T, Pistiolas D, Sechopoulos P, et al. Relationship between Helicobacter pylori infection and esophageal neoplasia: a meta-analysis. Clin Gastroenterol Hepatol 2007; 5:1413.