Definition, Derivation, and Diagnosis of Barrett’s Esophagus: Pathological Perspectives

  • H. Lowes
  • T. Somarathna
  • Neil A. ShepherdEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 908)


More than 60 years have elapsed since Barrett described the condition that continues to bear his name. Despite much research, clinical and basic, the defining features and the diagnosis of columnar-lined esophagus (CLO) are still embroiled with controversy and uncertainty. For pathologists, these controversies are notorious. The disease has been defined by the pathological demonstration of “specialized intestinal metaplasia” and yet there is compelling evidence that this approach is flawed due to sampling issues, poor levels of agreement between expert pathologists as to what constitutes “goblet cells,” and the fact that most glandular epithelium in the esophagus is “intestinalized,” even if goblet cells are not demonstrable. We believe that reliance on such pathological features can result in erroneous diagnoses of CLO and that the endoscopic diagnosis of CLO is more reliable with pathology corroborative in uncertain cases, when there is stricturing and/or ulceration and in shorter segment disease. Intriguingly, there are recent research findings that elucidate our understanding of the pathogenesis and the derivation of CLO and the way that initial gastric metaplasia converts to the unstable and neoplasia-associated intestinal phenotype. Even so, more research is required to enable a better understanding of the pathogenesis of CLO and to further improve the current management of the disease and its neoplastic complications.


Barrett’s esophagus Diagnosis Definition Derivation Dysplasia Neoplasia Esophagus Management 


  1. 1.
    Hopcroft SA, Shepherd NA. The changing role of the pathologist in the management of Barrett’s oesophagus. Histopathology. 2014;65(4):441–55.PubMedCrossRefGoogle Scholar
  2. 2.
    Barrett NR. Chronic peptic ulcer of the oesophagus and oesophagitis. Br J Surg. 1950;38:175–82.PubMedCrossRefGoogle Scholar
  3. 3.
    Spechler SJ. The columnar-lined esophagus. History, terminology, and clinical issues. Gastroenterol Clin North Am. 1997;26(3):455–66.PubMedCrossRefGoogle Scholar
  4. 4.
    Williamson JM, Almond LM, Shepherd NA, Barr H. Current management of Barrett’s oesophagus. Br J Hosp Med (Lond). 2012;73(5):271–7.CrossRefGoogle Scholar
  5. 5.
    Winters Jr C, Spurling TJ, Chobanian SJ, Curtis DJ, Esposito RL, Hacker 3rd JF, et al. Barrett’s esophagus. A prevalent, occult complication of gastroesophageal reflux disease. Gastroenterology. 1987;92(1):118–24.PubMedCrossRefGoogle Scholar
  6. 6.
    Eisen GM, Sandler RS, Murray S, Gottfried M. The relationship between gastroesophageal reflux disease and its complications with Barrett’s esophagus. Am J Gastroenterol. 1997;92(1):27–31.PubMedGoogle Scholar
  7. 7.
    Csendes A, Smok G, Burdiles P, Quesada F, Huertas C, Rojas J, et al. Prevalence of Barrett’s esophagus by endoscopy and histologic studies: a prospective evaluation of 306 control subjects and 376 patients with symptoms of gastroesophageal reflux. Dis Esophagus. 2000;13(1):5–11.PubMedCrossRefGoogle Scholar
  8. 8.
    Lieberman DA, Oehlke M, Helfand M. Risk factors for Barrett’s esophagus in community-based practice. GORGE consortium. Gastroenterology Outcomes Research Group in endoscopy. Am J Gastroenterol. 1997;92(8):1293–7.PubMedGoogle Scholar
  9. 9.
    Edelstein ZR, Farrow DC, Bronner MP, Rosen SN, Vaughan TL. Central adiposity and risk of Barrett’s esophagus. Gastroenterology. 2007;133(2):403–11.PubMedCrossRefGoogle Scholar
  10. 10.
    Eloubeidi MA, Provenzale D. Clinical and demographic predictors of Barrett’s esophagus among patients with gastroesophageal reflux disease: a multivariable analysis in veterans. J Clin Gastroenterol. 2001;33(4):306–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Corley DA, Kubo A, Levin TR, Block G, Habel L, Rumore G, et al. Race, ethnicity, sex and temporal differences in Barrett’s oesophagus diagnosis: a large community-based study, 1994–2006. Gut. 2009;58(2):182–8.PubMedCrossRefGoogle Scholar
  12. 12.
    El-Serag HB, Kvapil P, Hacken-Bitar J, Kramer JR. Abdominal obesity and the risk of Barrett’s esophagus. Am J Gastroenterol. 2005;100(10):2151–6.PubMedCrossRefGoogle Scholar
  13. 13.
    Singh P, Taylor RH, Colin-Jones DG. Esophageal motor dysfunction and acid exposure in reflux esophagitis are more severe if Barrett’s metaplasia is present. Am J Gastroenterol. 1994;89(3):349–56.PubMedGoogle Scholar
  14. 14.
    Prach AT, MacDonald TA, Hopwood DA, Johnston DA. Increasing incidence of Barrett’s oesophagus: education, enthusiasm, or epidemiology? Lancet. 1997;350(9082):933.PubMedCrossRefGoogle Scholar
  15. 15.
    van Soest EM, Dieleman JP, Siersema PD, Sturkenboom MC, Kuipers EJ. Increasing incidence of Barrett’s oesophagus in the general population. Gut. 2005;54(8):1062–6.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Cook MB, Shaheen NJ, Anderson LA, Giffen C, Chow WH, Vaughan TL, et al. Cigarette smoking increases risk of Barrett’s esophagus: an analysis of the Barrett's and Esophageal Adenocarcinoma Consortium. Gastroenterology. 2012;142(4):744–53.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Kubo A, Levin TR, Block G, Rumore G, Quesenberry Jr CP, Buffler P, et al. Cigarette smoking and the risk of Barrett’s esophagus. Cancer Causes Control. 2009;20(3):303–11.PubMedCrossRefGoogle Scholar
  18. 18.
    Menke-Pluymers MBE, Hop WCJ, Dees J, van Blankenstein M, Tilanus HW. Risk factors for the development of an adenocarcinoma in columnar-lined (Barrett) esophagus. Cancer. 1993;72(4):1155–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Hvid-Jensen F, Pedersen L, Drewes AM, Sorensen HT, Funch-Jensen P. Incidence of adenocarcinoma among patients with Barrett’s esophagus. N Engl J Med. 2011;365(15):1375–83.PubMedCrossRefGoogle Scholar
  20. 20.
    Bombeck CT, Dillard DH, Nyhus LM. Muscular anatomy of the gastroesophageal junction and role of phrenoesophageal ligament; autopsy study of sphincter mechanism. Ann Surg. 1966;164(4):643–54.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Takubo K, Arai T, Sawabe M, Miyashita M, Sasajima K, Iwakiri K, et al. Structures of the normal esophagus and Barrett’s esophagus. Esophagus. 2003;1(1):37–47.CrossRefGoogle Scholar
  22. 22.
    Riddell RH. The biopsy diagnosis of gastroesophageal reflux disease, “carditis”, and Barrett’s esophagus, and sequelae of therapy. Am J Surg Pathol. 1996;20 Suppl 1:S31–50.PubMedCrossRefGoogle Scholar
  23. 23.
    Paull A, Trier JS, Dalton MD, et al. The histologic spectrum of Barrett’s esophagus. N Engl J Med. 1976;295:476–80.PubMedCrossRefGoogle Scholar
  24. 24.
    Spechler SJ. Barrett’s esophagus: is the goblet half-empty? Clin Gastroenterol Hepatol. 2012;10(11):1237–8.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Flejou JF, Svrcek M. Barrett’s oesophagus—a pathologist’s view. Histopathology. 2007;50(1):3–14.PubMedCrossRefGoogle Scholar
  26. 26.
    Sampliner RE. Updated guidelines for the diagnosis, surveillance, and therapy of Barrett’s esophagus. Am J Gastroenterol. 2002;97:1888–95.PubMedCrossRefGoogle Scholar
  27. 27.
    American Gastroenterology Association. AGA medical position statement on the management of Barrett’s esophagus. Gastroenterology. 2011;140:1084–91.CrossRefGoogle Scholar
  28. 28.
    Wang KK, Sampliner RE. Updated guidelines for Barrett’s esophagus. Am J Gastroenterol. 2008;103:788–97.PubMedCrossRefGoogle Scholar
  29. 29.
    Westerhoff M, Hovan L, Fau-Lee C, Lee C, Fau-Hart J, Hart J. Effects of dropping the requirement for goblet cells from the diagnosis of Barrett’s esophagus. Clin Gastroenterol Hepatol. 2012;10(11):1232–6.PubMedCrossRefGoogle Scholar
  30. 30.
    Koop H, Fuchs KH, Labenz J, Lynen Jansen P, Messmann H, Miehlke S, et al. S2k guideline: gastroesophageal reflux disease guided by the German Society of Gastroenterology: AWMF register no. 021-013. Z Gastroenterol. 2014;52(11):1299–346.Google Scholar
  31. 31.
    Watson AJ, Heading R, Shepherd NA. Guidelines for the diagnosis and management of Barrett’s columnar lined oesophagus. A report of the working party of the British Society of Gastroenterology. 2005. Accessed 18 May 2015.
  32. 32.
    Aoki T. Report of research committee on definition of Barrett’s esophagus (epithelium). Japanese Society of Esophageal Diseases: Chiba; 2000.Google Scholar
  33. 33.
    Harrison R, Perry I, Haddadin W, McDonald S, Bryan R, Abrams K, et al. Detection of intestinal metaplasia in Barrett’s esophagus: an observational comparator study suggests the need for a minimum of eight biopsies. Am J Gastroenterol. 2007;102(6):1154–61.PubMedCrossRefGoogle Scholar
  34. 34.
    Weston AP, Krmpotich P, Makdisi WF, Cherian R, Dixon A, McGregor DH, et al. Short segment Barrett’s esophagus: clinical and histological features, associated endoscopic findings, and association with gastric intestinal metaplasia. Am J Gastroenterol. 1996;91(5):981–6.PubMedGoogle Scholar
  35. 35.
    Wang H, Brown I, Kumarasinghe P, Langner C, Lauwers G, Shepherd N, Vieth M, Srivastava A, Odze R. Poor agreement for detection of goblet cells in esophageal and GEJ biopsies. Modern Pathol. 2012;25(Suppl):184–185A.Google Scholar
  36. 36.
    Spechler SJ, Goyal RK. Barrett’s esophagus. N Engl J Med. 1986;315:362–71.PubMedCrossRefGoogle Scholar
  37. 37.
    Takubo K, Aida J, Naomoto Y, et al. Cardiac rather than intestinal-type background in endoscopic resection specimens of minute Barrett adenocarcinoma. Hum Pathol. 2009;40:65–74.PubMedCrossRefGoogle Scholar
  38. 38.
    Watanabe G, Ajioka Y, Takeuchi M, Annenkov A, Kato T, Watanabe K, Tani Y, Ikegami K, Yokota Y, Fukuda M. Intestinal metaplasia in Barrett’s oesophagus may be an epiphenomenon rather than a preneoplastic condition, and CDX2-positive cardiac-type epithelium is associated with minute Barrett's tumour. Histopathology. 2014;66:201–14.PubMedCrossRefGoogle Scholar
  39. 39.
    McDonald SAC, Graham TA, Lavery DL, Wright NA, Jansen M. The Barrett’s gland in phenotype space. Cell Mol Gastroenterol Hepatol. 2015;1:41–54.Google Scholar
  40. 40.
    Takubo K, Vieth M, Aida J, Sawabe M, Kumagai Y, Hoshihara Y, et al. Differences in the definitions used for esophageal and gastric diseases in different countries: endoscopic definition of the esophagogastric junction, the precursor of Barrett’s adenocarcinoma, the definition of Barrett’s esophagus, and histologic criteria for mucosal adenocarcinoma or high-grade dysplasia. Digestion. 2009;80(4):248–57.PubMedCrossRefGoogle Scholar
  41. 41.
    Riddell RH, Odze RD. Definition of Barrett’s esophagus: time for a rethink--is intestinal metaplasia dead? Am J Gastroenterol. 2009;104(10):2588.PubMedCrossRefGoogle Scholar
  42. 42.
    Hahn HP, Blount PL, Ayub K, Das KM, Souza R, Spechler S, et al. Intestinal differentiation in metaplastic, non-goblet columnar epithelium in the esophagus. Am J Surg Pathol. 2009;33(7):1006–15.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Golden K, Srivastava A, Sanchez CA, et al. High goblet cell density protects against progression to adenocarcinoma in patients with Barrett’s esophagus. Mod Pathol. 2011;24:149A.Google Scholar
  44. 44.
    Fitzgerald RC, di Pietro M, Ragunath K, Ang Y, Kang J-Y, Watson P, et al. British Society of Gastroenterology guidelines on the diagnosis and management of Barrett’s oesophagus. Gut. 2013.Google Scholar
  45. 45.
    Glickman JN, Spechler SJ, Souza RF, Lunsford T, Lee E, Odze RD. Multilayered epithelium in mucosal biopsy specimens from the gastroesophageal junction region is a histologic marker of gastroesophageal reflux disease. Am J Surg Pathol. 2009;33(6):818–25.PubMedCrossRefGoogle Scholar
  46. 46.
    Allison PR, Johnstone AS. The oesophagus lined with gastric mucous membrane. Thorax. 1953;8(2):87–101.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Johns BA. Developmental changes in the oesophageal epithelium in man. J Anat. 1952;86(4):431–42.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Rector CM. Aberrant mucosa in the esophagus in infants and in children. Arch Pathol. 1941;31:285–94.Google Scholar
  49. 49.
    Barrett NR. The lower oesophagus lined by columnar epithelium. London: Butterworth & Co.; 1958.Google Scholar
  50. 50.
    Barrett NR. Benign stricture in the lower esophagus. J Thorac Cardiovasc Surg. 1962;43:703–15.PubMedGoogle Scholar
  51. 51.
    Chong VH. Heterotopic gastric mucosal patch of the proximal esophagus. Croatia: InTech Publishing; 2011.Google Scholar
  52. 52.
    von Rahden BH, Stein HJ, Becker K, Liebermann-Meffert D, Siewert JR. Heterotopic gastric mucosa of the esophagus: literature-review and proposal of a clinicopathologic classification. Am J Gastroenterol. 2004;99(3):543–51.CrossRefGoogle Scholar
  53. 53.
    Moersch RN, Ellis Jr FH, Mc DJ. Pathologic changes occurring in severe reflux esophagitis. Surg Gynecol Obstet. 1959;108(4):476–84.PubMedGoogle Scholar
  54. 54.
    Kortan P, Warren RE, Gardner J, Ginsberg RJ, Diamant NE. Barrett’s esophagus in a patient with surgically tested achalasia. J Clin Gastroenterol. 1981;3(4):357–60.PubMedCrossRefGoogle Scholar
  55. 55.
    Meyer W, Vollmar F, Bar W. Barrett-esophagus following total gastrectomy. A contribution to it’s pathogenesis. Endoscopy. 1979;11(2):121–6.PubMedCrossRefGoogle Scholar
  56. 56.
    Hamilton SR, Yardley JH. Regnerative of cardiac type mucosa and acquisition of Barrett mucosa after esophagogastrostomy. Gastroenterology. 1977;72(4 Pt 1):669–75.PubMedGoogle Scholar
  57. 57.
    Naef AP, Savary M, Ozzello L. Columnar-lined lower esophagus: an acquired lesion with malignant predisposition. Report on 140 cases of Barrett’s esophagus with 12 adenocarcinomas. J Thorac Cardiovasc Surg. 1975;70(5):826–35.PubMedGoogle Scholar
  58. 58.
    Radigan LR, Glover JL, Shipley FE, Shoemaker RE. Barrett esophagus. Arch Surg. 1977;112(4):486–91.PubMedCrossRefGoogle Scholar
  59. 59.
    Ransom JM, Patel GK, Clift SA, Womble NE, Read RC. Extended and limited types of Barrett’s esophagus in the adult. Ann Thorac Surg. 1982;33(1):19–27.PubMedCrossRefGoogle Scholar
  60. 60.
    Mangla JC. Barrett’s esophagus: an old entity rediscovered. J Clin Gastroenterol. 1981;3(4):347–56.PubMedCrossRefGoogle Scholar
  61. 61.
    Gillen P, Keeling P, Byrne PJ, West AB, Hennessy TP. Experimental columnar metaplasia in the canine oesophagus. Br J Surg. 1988;75(2):113–5.PubMedCrossRefGoogle Scholar
  62. 62.
    Bremner CG, Lynch VP, Ellis Jr FH. Barrett’s esophagus: congenital or acquired? An experimental study of esophageal mucosal regeneration in the dog. Surgery. 1970;68(1):209–16.PubMedGoogle Scholar
  63. 63.
    Wong J, Finckh ES. Heterotopia and ectopia of gastric epithelium produced by mucosal wounding in the rat. Gastroenterology. 1971;60(2):279–87.PubMedGoogle Scholar
  64. 64.
    Spechler SJ, Schimmel EM, Dalton JW, Doos W, Trier JS. Barrett’s epithelium complicating lye ingestion with sparing of the distal esophagus. Gastroenterology. 1981;81(3):580–3.PubMedGoogle Scholar
  65. 65.
    Sartori S, Nielsen I, Indelli M, Trevisani L, Pazzi P, Grandi E. Barrett esophagus after chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF): an iatrogenic injury? Ann Intern Med. 1991;114(3):210–1.PubMedCrossRefGoogle Scholar
  66. 66.
    Collen MJ, Lewis JH, Benjamin SB. Gastric acid hypersecretion in refractory gastroesophageal reflux disease. Gastroenterology. 1990;98(3):654–61.PubMedCrossRefGoogle Scholar
  67. 67.
    Stein HJ, Eypasch EP, DeMeester TR, Smyrk TC, Attwood SE. Circadian esophageal motor function in patients with gastroesophageal reflux disease. Surgery. 1990;108(4):769–77. discussion 77-8.PubMedGoogle Scholar
  68. 68.
    Lavery DL, Nicholson AM, Poulsom R, Jeffery R, Hussain A, Gay LJ, et al. The stem cell organisation, and the proliferative and gene expression profile of Barrett’s epithelium, replicates pyloric-type gastric glands. Gut. 2014;63(12):1854–63.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Seery JP. Stem cells of the oesophageal epithelium. J Cell Sci. 2002;115:1783–9.PubMedGoogle Scholar
  70. 70.
    Schepers AG, Snippert HJ, Stange DE, van den Born M, van Es JH, van de Wetering M, et al. Lineage tracing reveals Lgr5+ stem cell activity in mouse intestinal adenomas. Science. 2012;337(6095):730–5.PubMedCrossRefGoogle Scholar
  71. 71.
    Merlos-Suarez A, Barriga FM, Jung P, Iglesias M, Cespedes MV, Rossell D, et al. The intestinal stem cell signature identifies colorectal cancer stem cells and predicts disease relapse. Cell Stem Cell. 2011;8(5):511–24.PubMedCrossRefGoogle Scholar
  72. 72.
    Barker N, Huch M, Kujala P, van de Wetering M, Snippert HJ, van Es JH, et al. Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell Stem Cell. 2010;6(1):25–36.PubMedCrossRefGoogle Scholar
  73. 73.
    Moyes LH, McEwan H, Radulescu S, Pawlikowski J, Lamm CG, Nixon C, et al. Activation of Wnt signalling promotes development of dysplasia in Barrett’s oesophagus. J Pathol. 2012;228(1):99–112.PubMedGoogle Scholar
  74. 74.
    Smith RR, Hamilton SR, Boitnott JK, Rogers EL. The spectrum of carcinoma arising in Barrett’s esophagus. A clinicopathologic study of 26 patients. Am J Surg Pathol. 1984;8(8):563–73.PubMedCrossRefGoogle Scholar
  75. 75.
    Skinner DB, Walther BC, Riddell RH, Schmidt H, Iascone C, DeMeester TR. Barrett’s esophagus. Comparison of benign and malignant cases. Ann Surg. 1983;198(4):554–65.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Bhat S, Coleman HG, Yousef F, Johnston BT, McManus DT, Gavin AT, et al. Risk of malignant progression in Barrett’s esophagus patients: results from a large population-based study. J Natl Cancer Inst. 2011;103(13):1049–57.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    McDonald SA, Greaves LC, Gutierrez-Gonzalez L, Rodriguez-Justo M, Deheragoda M, Leedham SJ, et al. Mechanisms of field cancerization in the human stomach: the expansion and spread of mutated gastric stem cells. Gastroenterology. 2008;134(2):500–10.PubMedCrossRefGoogle Scholar
  78. 78.
    Snippert HJ, Schepers AG, van Es JH, Simons BD, Clevers H. Biased competition between Lgr5 intestinal stem cells driven by oncogenic mutation induces clonal expansion. EMBO Rep. 2014;15(1):62–9.PubMedCrossRefGoogle Scholar
  79. 79.
    Slack JM. Metaplasia and transdifferentiation: from pure biology to the clinic. Nat Rev Mol Cell Biol. 2007;8(5):369–78.PubMedCrossRefGoogle Scholar
  80. 80.
    Wang X, Ouyang H, Yamamoto Y, Kumar P, Wei T, Dagher R, Vincent M, Lu X, Bellizzi A, Ho KY, Crum C, Xian W, McKeon F. Residual embryonic cells as precursors of a Barrett’s-like metaplasia. Cell. 2011;145:1023–35.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Lord RVN, Wickramasinghe K, Johansson JJ, et al. Cardiac mucosa in the remnant esophagus after esophagectomy is an acquired epithelium with Barrett’s-like features. Surgery. 2004;136:633–40.PubMedCrossRefGoogle Scholar
  82. 82.
    O’Riordan JM, Tucker ON, Byrne PJ, et al. Factors influencing the development of Barrett’s epithelium in the esophageal remnant postesophagectomy. Am J Gastroenterol. 2004;99:205–11.PubMedCrossRefGoogle Scholar
  83. 83.
    Chaves P, Pereira AD, Cruz C, et al. Recurrent columnar-lined esophageal segments-study of the phenotypic characteristics using intestinal markers. Dis Esophagus. 2002;15:282–6.PubMedCrossRefGoogle Scholar
  84. 84.
    Dresner SM, Griffin SM, Wayman J, et al. Human model of duodenogastro-oesophageal reflux in the development of Barrett’s metaplasia. Br J Surg. 2003;90:1120–8.PubMedCrossRefGoogle Scholar
  85. 85.
    Lindahl H, Rintala R, Sariola H, et al. Cervical Barrett’s esophagus: a common complication of gastric tube reconstruction. J Pediatr Surg. 1990;25:446–8.PubMedCrossRefGoogle Scholar
  86. 86.
    Tobey NA, Argote CM, Awayda MS, et al. Effect of luminal acidity on the apical cation channel in rabbit esophageal epithelium. AMJ Physiol Gastrointest Liver Physiol. 2007;292:G796–805.CrossRefGoogle Scholar
  87. 87.
    Dixon J, Strugala V, Griffin SM, et al. Esophageal mucin: an adherent mucus gel barrier is absent in the normal esophagus but present in columnar-lined Barrett’s esophagus. Am J Gastroenterol. 2001;96:2575–83.PubMedCrossRefGoogle Scholar
  88. 88.
    Jovov B, Van Itallie CM, Shaheen NJ, et al. Claudin-18: a dominant tight junction protein in Barrett’s esophagus and likely contributor to its acid resistance. Am J Physiol Gastrointest Liver Physiol. 2007;293:G1106–13.PubMedCrossRefGoogle Scholar
  89. 89.
    Coad RA, Woodman AC, Warner PJ, Barr H, Wright NA, Shepherd NA. On the histogenesis of Barrett’s oesophagus and its associated squamous islands: a three-dimensional study of their morphological relationship with native oesophageal gland ducts. J Pathol. 2005;206(4):388–94.PubMedCrossRefGoogle Scholar
  90. 90.
    Barbera M, Fitzgerald RC. Cellular origin of Barrett’s metaplasia and oesophageal stem cells. Biochem Soc Trans. 2010;38(2):370–3.PubMedCrossRefGoogle Scholar
  91. 91.
    Sarosi G, Brown G, Jaiswal K, Feagins LA, Lee E, Crook TW, et al. Bone marrow progenitor cells contribute to esophageal regeneration and metaplasia in a rat model of Barrett’s esophagus. Dis Esophagus. 2008;21(1):43–50.PubMedGoogle Scholar
  92. 92.
    Okamoto R, Yajima T, Yamazaki M, et al. Damaged epithelia regenerated by bone marrow-derived cells in the human gastrointestinal tract. Nat Med. 2002;8:1011–7.PubMedCrossRefGoogle Scholar
  93. 93.
    Aikou S, Aida J, Takubo K, Yamagata Y, Seto Y, Kaminishi M, Nomura S. Columnar metaplasia in a surgical mouse model of gastro-esophageal reflux disease is not derived from bone-marrow cell. Cancer Sci. 2013;104:1154–61.PubMedCrossRefGoogle Scholar
  94. 94.
    Barbera M, di Pietro M, Walker E, Brierley C, MacRae S, Simons BD, Jones PH, Stingl J, Fitzgerald RC. The human squamous oesophagus has widespread capacity for clonal expansion from cells at diverse stages of differentiation. Gut. 2015;64:11–9.PubMedCrossRefGoogle Scholar
  95. 95.
    Groisman GM, Amar M, Meir A. Expression of the intestinal marker Cdx2 in the columnar-lined esophagus with and without intestinal (Barrett’s) metaplasia. Mod Pathol. 2004;17(10):1282–8.PubMedCrossRefGoogle Scholar
  96. 96.
    Phillips RW, Frierson Jr HF, Moskaluk CA. Cdx2 as a marker of epithelial intestinal differentiation in the esophagus. Am J Surg Pathol. 2003;27(11):1442–7.PubMedCrossRefGoogle Scholar
  97. 97.
    Going JJ, Fletcher-Monaghan AJ, Neilson L, et al. Zoning of mucosal phenotype, dysplasia, and telomerase activity measured by telomerase repeat assay protocol in Barrett’s esophagus. Neoplasia. 2004;6:85–92.PubMedPubMedCentralGoogle Scholar
  98. 98.
    Chandrasoma P, Lokuhetty DM, Demeester TR, et al. Definition of histopathologic changes in gastroesophageal reflux disease. Am J Surg Pathol. 2000;24:344–51.PubMedCrossRefGoogle Scholar
  99. 99.
    Guo R-J, Suh ER, Lynch JP. The role of Cdx proteins in intestinal development and cancer. Cancer Biol Ther. 2004;3:593–601.PubMedCrossRefGoogle Scholar
  100. 100.
    Souza RF, Krishnan K, Spechler SJ. Acid, bile, and CDX: the ABCs of making Barrett’s metaplasia. Am J Physiol Gastrointest Liver Physiol. 2008;295:G211–8.PubMedCrossRefGoogle Scholar
  101. 101.
    Theodorou D, Ayazi S, Demeester SR, et al. Intraluminal pH and goblet cell density in Barrett’s esophagus. J Gastrointest Surg. 2012;16:469–74.PubMedCrossRefGoogle Scholar
  102. 102.
    Bissell MJ, Radisky DC, Rizki A, Weaver VM, Peterson OW. The organizing principle: microenvironmental influences in the normal and malignant breast. Differentiation. 2002;70(9–10):537–46.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Sharma P, Dent J, Armstrong D, Bergman JJGHM, Gossner L, Hoshihara Y, et al. The development and validation of an endoscopic grading system for Barrett’s esophagus: the Prague C & M criteria. Gastroenterology. 2006;131(5):1392–9.Google Scholar
  104. 104.
    Aida J, Vieth M, Ell C, May A, Pech O, Hoshihara Y, et al. Palisade vessels as a new histologic marker of esophageal origin in ER specimens from columnar-lined esophagus. Am J Surg Pathol. 2011;35(8):1140–5.PubMedCrossRefGoogle Scholar
  105. 105.
    Hackelsberger A, Günther T, Schultze V, Manes G, Dominguez-Muñoz J-E, Roessner A, et al. Intestinal metaplasia at the gastro-oesophageal junction:Helicobacter pylori gastritis or gastro-oesophageal reflux disease? Gut. 1998;43(1):17–21.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Goldblum JR, Richter JE, Vaezi M, Falk GW, Rice TW, Peek RM. Helicobacter pylori infection, not gastroesophageal reflux, is the major cause of inflammation and intestinal metaplasia of gastric cardiac mucosa. Am J Gastroenterol. 2002;97(2):302–11.PubMedCrossRefGoogle Scholar
  107. 107.
    Levine DS. Management of dysplasia in the columnar-lined esophagus. Gastroenterol Clin North Am. 1997;26(3):613–34.PubMedCrossRefGoogle Scholar
  108. 108.
    Curvers WL, Singh R, Song LM, Wolfsen HC, Ragunath K, Wang K, et al. Endoscopic tri-modal imaging for detection of early neoplasia in Barrett’s oesophagus: a multi-centre feasibility study using high-resolution endoscopy, autofluorescence imaging and narrow band imaging incorporated in one endoscopy system. Gut. 2008;57(2):167–72.PubMedCrossRefGoogle Scholar
  109. 109.
    Pohl J, Pech O, May A, Manner H, Fissler-Eckhoff A, Ell C. Incidence of macroscopically occult neoplasias in Barrett’s esophagus: are random biopsies dispensable in the era of advanced endoscopic imaging? Am J Gastroenterol. 2010;105(11):2350–6.PubMedCrossRefGoogle Scholar
  110. 110.
    Alverez Herrero L, Curvers WL, Bansal A, Wani S, Kara M, Schenk E, et al. Zooming in on Barrett oesophagus using narrow-band imaging: an international observer agreement study. Eur J Gastroenterol Hepatol. 2009;21(9):1068–75.CrossRefGoogle Scholar
  111. 111.
    Takubo K, Nixon JM, Jass JR. Ducts of esophageal glands proper and paneth cells in Barrett’s esophagus: frequency in biopsy specimens. Pathology. 1995;27(4):315–7.PubMedCrossRefGoogle Scholar
  112. 112.
    Gore S, Healey CJ, Sutton CJ, Eyre-Brook IA, Gear MWL, Shepherd NA, Wilkinson SP. Regression of columnar line (Barrett’s oesophagus) with continuous omeprazole therapy. Aliment Pharmacol Ther. 1993;7:623–8.PubMedCrossRefGoogle Scholar
  113. 113.
    Malesci A, Savarino V, Zentilin P, Belicchi M, Mela GS, Lapertosa G, Bocchio P, Ronchi G, Franceschi M. Partial regression of Barrett’s esophagus by long term therapy with high-dose omeprazole. Gastrointest Endosc. 1996;44:700–5.PubMedCrossRefGoogle Scholar
  114. 114.
    Shields HM, Rosenberg SJ, Zwas FR, Ransil BJ, Lembo AJ, Odze R. Prospective evaluation of multilayered epithelium in Barrett’s esophagus. Am J Gastroenterol. 2001;96(12):3268–73.PubMedCrossRefGoogle Scholar
  115. 115.
    Glickman JN, Chen YY, Wang HH, Antonioli DA, Odze RD. Phenotypic characteristics of a distinctive multilayered epithelium suggests that it is a precursor in the development of Barrett’s esophagus. Am J Surg Pathol. 2001;25(5):569–78.PubMedCrossRefGoogle Scholar
  116. 116.
    Srivastava A, Odze RD, Lauwers GY, Redston M, Antonioli DA, Glickman JN. Morphologic features are useful in distinguishing Barrett esophagus from carditis with intestinal metaplasia. Am J Surg Pathol. 2007;31(11):1733–41.PubMedCrossRefGoogle Scholar
  117. 117.
    Shi L, Der R, Ma Y, Peters J, Demeester T, Chandrasoma P. Gland ducts and multilayered epithelium in mucosal biopsies from gastroesophageal-junction region are useful in characterizing esophageal location. Dis Esophagus. 2005;18(2):87–92.PubMedCrossRefGoogle Scholar
  118. 118.
    Takubo K, Aida J, Sawabe M, Arai T, Kato H, Pech O, et al. The normal anatomy around the oesophagogastric junction: a histopathologic view and its correlation with endoscopy. Best Pract Res Clin Gastroenterol. 2008;22(4):569–83.PubMedCrossRefGoogle Scholar
  119. 119.
    Spechler SJ, Sharma P, Souza RF, Inadomi JM, Shaheen NJ. American Gastroenterological Association technical review on the management of Barrett’s esophagus. Gastroenterology. 2011;140(3):e18–52. quiz e13.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Chandrasoma PT, Der R, Dalton P, et al. Distribution and significance of epithelial types in columnar-lined esophagus. Am J Surg Pathol. 2001;25:1188–93.PubMedCrossRefGoogle Scholar
  121. 121.
    Liu W, Hahn H, Odze RD, et al. Metaplastic esophageal columnar epithelium without goblet cells shows DNA content abnormalities similar to goblet cell containing epithelium. Am J Gastroenterol. 2009;104:816–24.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Rubio CA, Riddell R. Muculo-fibrous anomaly in Barrett’s mucosa with dysplasia. Am J Surg Pathol. 1988;12:885–9.PubMedCrossRefGoogle Scholar
  123. 123.
    Takubo K, Sasajima K, Yamashita K, et al. Double muscularis mucosae in Barrett’s esophagus. Hum Pathol. 1991;22:1158–61.PubMedCrossRefGoogle Scholar
  124. 124.
    Abraham SC, Krasinskas AM, Correa AM, et al. Duplication of the muscularis mucosae in Barrett esophagus: an underrecognized feature and its implication for staging of adenocarcinoma. Am J Surg Pathol. 2007;31:1719–25.PubMedCrossRefGoogle Scholar
  125. 125.
    Tang P, MicKinley MJ, Sporrer M, et al. Inlet patch: prevalence, histologic type, and association with esophagitis, Barrett esophagus, and antritis. Arch Pathol Lab Med. 2004;128:444–7.PubMedGoogle Scholar
  126. 126.
    Gutierrez O, Akamatsu T, Cardona H, Graham DY, El-Zimaity HM. Helicobacter pylori and heterotopic gastric mucosa in the upper esophagus (the inlet patch). Am J Gastroenterol. 2003;98(6):1266–70.PubMedCrossRefGoogle Scholar
  127. 127.
    Ormsby AH, Goldblum JR, Rice TW, Richter JE, Falk GW, Vaezi MF, Gramlich TL. Cytokeratin subsets can reliably distinguish Barrett’s esophagus from intestinal metaplasia of the stomach. Hum Pathol. 1999;30:288–94.PubMedCrossRefGoogle Scholar
  128. 128.
    Glickman JN, Wang H, Das KM, Goyal RK, Spechler SJ, Antonioli D, Odze RD. Phenotype of Barrett’s esophagus and intestinal metaplasia of the distal esophagus and gastroesophageal junction: an immunohistochemical study of ytokeratins 7 and 20, Das-I and 45 MI. Am J Surg Pathol. 2001;25:87–94.PubMedCrossRefGoogle Scholar
  129. 129.
    Ormsby AH, Vaezi MF, Richter JE, Goldblum JR, Rice TW, Falk GW, Gramlich TL. Cytokeratin immunoreactivity patterns in the diagnosis of short-segment Barrett’s esophagus. Gastroenterology. 2000;119:683–90.PubMedCrossRefGoogle Scholar
  130. 130.
    Lorinc E, Jakobsson B, Landberg G, Veress B. Ki67 and p53 immunohistochemistry reduces interobserver variation in assessment of Barrett’s oesophagus. Histopathology. 2005;46:642–8.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Gloucestershire Cellular Pathology LaboratoryCheltenham General HospitalCheltenhamUK

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