Primary Motility  Disorders of the  Esophagus
 The Esophageal
 Esophagogastric  Junction

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Volume: The Esophagogastric Junction
Chapter: Esophageal columnar metaplasia (Barrett s esophagus)

What is the evidence to support the presence of a multipotential precursor cell in the glandular epithelium?

M.M. Berenson (Salt Lake City)

Barrett's esophagus (BE) is an acquired metaplastic condition with genetic predisposition in which glandular epithelium replaces the normal stratified squamous tissue of the distal esophagus [1, 2]. Metaplasia of epithelial tissue is generally characterized by replacement of one differentiated tissue by a differently differentiated type. It may develop as a consequence of tissue regeneration accompanied by atypical differentiation [3]. Epithelial cell differentiation is a multistep process. Each step is regulated by a variety of factors. The factors link cell proliferation and differentiation [4]. Theoretically, metaplastic tissue has the potential to revert to normal [5].

The metaplastic epithelium of BE is composed of four histologic types:

- a junctional type consisting of mucous-secreting cells and glands indistinguishable from gastric cardiac mucosa;

- a fundic type resembling atrophic gastric glands containing parietal cells and chief cells;

- a specialized intestinal type characterized by a villous architecture, mucous-secreting glands, and goblet cells;

- an intermediate type with villiform columnar cells but no goblet cells, parietal cells, chief cells, Paneth's cells, or junctional type epithelial glands [6, 7]. These histologic types are randomly mixed in a mosaic that may contain all cell types of the stomach and small intestine, including neuroendocrine cells and Paneth's cells [8].

The cell of origin of the metaplastic tissue has not been directly established. Experimental animal studies by Wong et al. [9] and Bremner et al. [10] showed heterotopic columnar epithelial extensions or growth of gastric tissue into the distal esophagus after wounding or stripping of the mucosa immediately above the squamocolumnar border and creating esophageal reflux of gastroduodenal contents. Morphologic examination of the heterotopic tissue to detect the presence of atypism was not performed. It is conceivable that heterotopic gastric junctional mucosa could be modified to account for the other histologic types. However, it has now been established by Gillen et al. [11] that glandular epithelium can develop in denuded esophageal tissue separated from gastric junctional mucosa, precluding cephaled extension of the gastric mucosa. These investigators suggested that the glandular tissue originated from cells lining the ducts of the esophageal cardiac glands [12]. The distal two-thirds of these ducts are comprised of columnar or cuboidal cells; the proximal, superficial one-third, is comprised of squamous cells. Histologic sections of regenerated columnar tissue showed direct continuity of the ducts and glandular tissue. Alternatively, the glandular tissue may be derived from primordial stem cells in the basal layer of the stratified squamous epithelium or from cells in the lamina propria that migrate to areas undergoing repair [13, 14].

The cell of origin of the glandular epithelium must account for a diverse array of morphological and functional phenotypes. Morphologic phenotypes include all cell types of the stomach and small intestine [6-8], colonic epithelial epitopes [15], pancreatic cells [16], neuroendocrine cells of the adult [17], and immature [18] gastrointestinal tract, a novel double muscularis mucosa [19], and a unique hybrid surface epithelial cell with microvilli, intercellular ridges and surface microridges [20]. Functional phenotypes include variable mucins [21, 22], pepsinogens [23, 24], enzyme activities [25] and enzyme gene expression [26], cytokeratin profiles [27] and others [28-30]. It seems reasonable to suggest that only a primordial stem cell with the potential to differentiate along multiple pathways can account for these characteristics. The presence of stratified columnar and ciliated columnar tissue in the developing esophagus between weeks 1 to 16 of life indicates the multipotentiality of esophageal cells [31]. Finally, restoration of squamous mucosa after ablation of Barrett's epithelium totally surrounded by glandular tissue provides evidence of a progenitor cell within the esophageal tissue that has the potential to differentiate normally [32].


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3. Foulds L. Neoplastic development. New York and London; Academic Press, 1969.

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8. Thompson JJ, Zinsser KR, Enterline HT. Barrett's metaplasia and adenocarcinoma of the esophagus and gastroesophageal junction. Hum Pathol 1983;14:42-61.

9. Wong J, Finckh ES. Heterotopia and ectopia of gastric epithelium produced by mucosal wounding in the rat. Gastroenteroogyl 1971;60:279-287.

10. Bremner CG, Lynch BP, Ellis FH. Barrett's esophagus: congenital or acquired? Surgery 1970;68:209-216.

11. Gillen P, Keeling P, Byrne PJ, West AB, Hennessy TPJ. Experimental columnar metaplasia in canine esophagus. Br J Surg 1988;75:113-115.

12. Li H, Walsh TN, O'Dowd G, Gillen P, Byrne P, Hennessy TPJ. Mechanisms of columnar metaplasia and squamous regeneration in experimental Barrett's esophagus. Surgery 1994;115:176-181.

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14. Shields HM, Zwas F, Antonioli DA, Doos WG, Kim S, Spechler SJ. Detection by scanning electron microscopy of a distinctive esophageal surface cell at the junction of squamous and Barrett's epithelium. Dig Dis Sci 1993;38:97-108.

15. Das KM, Prasad I, Garia S, Amenta PS. Detection of a shared colon epithelial epitope on Barrett's epithelium by a novel monoclonal antibody. Ann Intern Med 1994;120:753-756.

16. Krishnamurthy S, Dayal Y. Pancreatic metaplasia in Barrett's esophagus. An immunohistochemical study. Am J Surg Pathol 1995;19:1172-1180.

17. Rindi G, Biship AE, Daly MJ, Isaacs P, Lee FI, Polak JM. A mixed pattern of endocrine cells in metaplastic Barrett's esophagus. Evidence that the epithelium derives from a pluripotential stem cell. Histochemistry 1987;87:377-383.

18. Feurle GE, Helmstaedter V, Buehring A, Bettendorf U, Eckard VF. Distinct immunohistochemical findings in columnar epithelium of esophageal inlet patch and of Barrett's esophagus. Dig Dis Sci 1990;35:86-92.

19. Takubo K, Sasajima K, Yamashita K, Tamaka Y, Fujita K. Double muscularis mucosa in Barrett's esophagus. Hum Pathol 1991;22:1158-1161.

20. Sawhey RA, Shields HM, Allan CH, Boch JA, Trier JS, Antonioli DA. Morphological characterization of the squamocolumnar junction of the esophagus in patients with and without Barrett's epithelium. Dig Dis Sci 1996;41:1088-1098.

21. Cooper BT, Barbezat GV. Barrett's esophagus: clinical study of 52 patients. Q J Med 1987;238:97-108.

22. Hughes NR, Bhathal PS, Francis DM. Phenotypic identity of gastric mucous neck cells and mucous cells of cardiac, pyloric, and Brunner's glands. J. Clin Pathol 1994;47:53-57.

23. Mangla JC, Schenk EA, Desbraillets L, Guarasci G, Kubasik NP, Turner MD. Pepsin secretion, pepsinogens and gastrin in Barrett's esophagus. Gastroenterology 1976;70:669-676.

24. Westerveld BD, Pals G, Bosma A, Detize J, Pronk JC, Frunts RR, Eriksson AW, Meuwissen SGM. Gastric proteases in Barrett's esophagus. Gastroenterology 1987;93:774-778.

25. Berenson MM, Herbst JJ, Freston JW. Enzyme and ultrastructural characteristics of esophageal columnar epithelium. Am J Dig Dis 1974;19:895-907.

26. Wu GD, Beer DG, Moore JH, Orringer MB, Appelman HD, Trabas PG. Sucrase-isomaltase gene expression in Barrett's esophagus and adenocarcinoma. Gastroenterology 1993;105:837-844.

27. Salo J, Kivilaakso E, Virtanen I. Barrett's esophagus originates from the squamous esophageal epithelium as judged from its cytokeratin profile. Gastroenterology 1991;100:A153.

28. Davidson JS, Triadafilopoulos G. Blood group-related antigen expression in normal and metaplasic human upper gastrointestinal mucosa. Gastroenterology 1992;103:1152-1161.

29. Hanby AM, Jankowski JA, Elia G, Poulson R, Wright NA. Expression of the trefoil peptides p52 and human spasmolytic polypeptide (hSP) in Barrett's metaplasia and the native oesophageal epithelium: delineation of epithelial phenotype. J Pathol 1994;173:213-219.

30. Jaskiewiez K, Louw J, Anichkau N. Barrett's oesophagus: mucin composition neuroendocrine cells, p53 protein, cellular proliferation and differentiation. Anticancer Res 1956;14:1907-1912.

31. Patten BM. Human embryology 2nd Ed. New York, Blakiston Co, Inc., 1953.

32. Berenson MM, Johnson TD, Markowitz NR, Buchi KN, Samowitz WS. Restoration of sqamous mucosa after ablation of Barrett's esophageal epithelium. Gastroenterology 1993;104:1686-1691.

Publication date: May 1998 OESO©2015