Advertisement

Histology of Barrett’s Metaplasia: Do Goblet Cells Matter?

Review
  • 29 Downloads

Abstract

This review has provided a summary of the biology of goblet cell metaplasia in CLE as it pertains to BE. Goblet cells are terminally differentiated nonproliferative cells that have many overlapping histochemical characteristics with mucinous columnar cells and pseudogoblet cells. There is an abundance of evidence that suggests that use of goblet cells as a biomarker of BE, and its progression to malignancy, is problematic. Some of these limitations include the fact that the background non-goblet epithelium in most patients with CLE is biologically intestinalized and contains molecular abnormalities similar to goblet cell CLE, goblet cells fluctuate with time and decrease in number with progression of neoplasia, and pathologists have problems with interpretation, and distinction, of goblet cells from other types of cells in the esophagus. Sampling error results in sensitivity and specificity issues that limit its positive predictive value. Goblet cells are fewest in number in the same population of patients with CLE that are hardest to detect endoscopically (i.e., those with short or ultrashort CLE). Nevertheless, the risk of cancer in patients with short-segment BE, a condition difficult to distinguish from the stomach, is very low regardless of the presence or absence of goblet cells so it is unclear what the role of goblet cells is in these patients as a biomarker. Nevertheless, if the answer to the following question, “Would you as a gastroenterologist recommend surveillance for a patient with clear endoscopic evidence of CLE, particularly if it is ≥ 3 cm in length, but in which goblet cells were not reported to be present by the pathologist,” is yes, then the US requirement for goblet cells as part of the criteria for “BE” is superfluous.

Keywords

Barrett’s esophagus Goblet cells Dysplasia GERD Columnar lined esophagus Biopsies Pseudogoblet cells 

Notes

Compliance with ethical standards

Conflict of interest

The author declares that they have no conflict of interest.

References

  1. 1.
    Shaheen NJ, Falk GW, Iyer PG, Gerson LB. ACG clinical guideline: diagnosis and management of Barrett’s esophagus. Am J Gastroenterol. 2016;111:1077.CrossRefPubMedGoogle Scholar
  2. 2.
    Fitzgerald RC, Di Pietro M, Ragunath K, et al. British society of gastroenterology guidelines on the diagnosis and management of Barrett’s oesophagus. Gut. 2014;63:7–42.CrossRefPubMedGoogle Scholar
  3. 3.
    Naini BV, Souza RF, Odze RD. Barrett’s esophagus: comprehensive and contemporary review for pathologists. Am J Surg Pathol. 2016;40:e45–e66.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Bhat S, Coleman HG, Yousef F, et al. Risk of malignant progression in Barrett’s esophagus patients: results from a large population-based study. J Natl Cancer Inst. 2011;103:1049–1057.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Spechler SJ, Sharma P, Souza RF, et al. American gastroenterological association medical position statement on the management of Barrett’s esophagus. Gastroenterology. 2011;140:1084–1091.CrossRefPubMedGoogle Scholar
  6. 6.
    Gatenby PAC, Ramus JR, Caygill CPJ, et al. Relevance of the detection of intestinal metaplasia in non-dysplastic columnar-lined oesophagus. Scand J Gastroenterol. 2008;43:524–530.CrossRefPubMedGoogle Scholar
  7. 7.
    Kelty CJ, Gough MD, Van Wyk Q, et al. Barrett’s oesophagus: intestinal metaplasia is not essential for cancer risk. Scand J Gastroenterol. 2007;42:1271–1274.CrossRefPubMedGoogle Scholar
  8. 8.
    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.CrossRefPubMedGoogle Scholar
  9. 9.
    Lavery DL, Martinez P, Gay LJ, et al. Evolution of esophageal adenocarcinoma from metaplastic columnar epithelium without goblet cells in Barrett’s oesophagus. Gut. 2016;65:907–913.CrossRefPubMedGoogle Scholar
  10. 10.
    Haggitt RC, Tryzelaar J, Ellis FH, et al. Adenocarcinoma complicating columnar epithelium-lined (Barrett’s) esophagus. Am J Clin Pathol. 1978;70:1–5.CrossRefPubMedGoogle Scholar
  11. 11.
    Riddell RH, Odze RD. Definition of Barrett’s esophagus: time for a rethink—is intestinal metaplasia dead? Am J Gastroenterol. 2009;104:2588–2594.CrossRefPubMedGoogle Scholar
  12. 12.
    Pohl H, Pech O, Arash H, et al. Length of Barrett’s oesophagus and cancer risk: implications from a large sample of patients with early oesophageal adenocarcinoma. Gut. 2016;65:196–201.CrossRefPubMedGoogle Scholar
  13. 13.
    Gopal DV, Lieberman DA, Magaret N, et al. Risk factors for dysplasia in patients with Barrett’s esophagus (BE): results from a multicenter consortium. Dig Dis Sci. 2003;48:1537–1541.CrossRefPubMedGoogle Scholar
  14. 14.
    Weston AP, Sharma P, Mathur S, et al. Risk stratification of Barrett’s esophagus: updated prospective multivariate analysis. Am J Gastroenterol. 2004;99:1657–1666.CrossRefPubMedGoogle Scholar
  15. 15.
    Anaparthy R, Gaddam S, Kanakadandi V, et al. Association between length of Barrett’s esophagus and risk of high-grade dysplasia or adenocarcinoma in patients without dysplasia. Clin Gastroenterol Hepatol. 2013;11:1430–1436.CrossRefPubMedGoogle Scholar
  16. 16.
    Rudolph RE, Vaughan TL, Storer BE, et al. Effect of segment length on risk for neoplastic progression in patients with Barrett esophagus. Ann Intern Med. 2000;132:612–620.CrossRefPubMedGoogle Scholar
  17. 17.
    Westerhoff M, Hovan L, Lee C, et al. Effects of dropping the requirement for goblet cells from the diagnosis of Barrett’s Esophagus. Clin Gastroenterol Hepatol. 2012;10:1232–1236.CrossRefPubMedGoogle Scholar
  18. 18.
    Oberg S, Johansson J, Wenner J, et al. Endoscopic surveillance of columnar-lined esophagus—Frequency of intestinal metaplasia detection and impact of antireflux surgery. Ann Surg. 2001;234:619–626.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Chandrasoma PT, Der R, Ma YL, et al. Histologic classification of patients based on mapping biopsies of the gastroesophageal junction. Am J Surg Pathol. 2003;27:929–936.CrossRefPubMedGoogle Scholar
  20. 20.
    Harrison R, Perry I, Haddadin W, 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;102:1154–1161.CrossRefPubMedGoogle Scholar
  21. 21.
    Soucy G, Onstad L, Vaughan TL, et al. Histologic features associated with columnar-lined esophagus in distal esophageal and gastroesophageal junction (GEJ) biopsies from GERD patients: a community-based population study. Am J Surg Pathol. 2016;40:827–835.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Srivastava A, Odze RD, Lauwers GY, et al. Morphologic features are useful in distinguishing Barrett esophagus from carditis with intestinal metaplasia. Am J Surg Pathol. 2007;31:1733–1741.CrossRefPubMedGoogle Scholar
  23. 23.
    Leedham SJ, Preston SL, McDonald SAC, et al. Individual crypt genetic heterogeneity and the origin of metaplastic glandular epithelium in human Barrett’s oesophagus. Gut. 2008;57:1041–1048.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Wang DH, Tiwari A, Kim ME, et al. Hedgehog signaling regulates FOXA2 in esophageal embryogenesis and Barrett’s metaplasia. J Clin Invest. 2014;124:3767–3780.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Lomo LC, Blount PL, Sanchez CA, et al. Crypt dysplasia with surface maturation—a clinical, pathologic, and molecular study of a Barrett’s esophagus cohort. Am J Surg Pathol. 2006;30:423–435.CrossRefPubMedGoogle Scholar
  26. 26.
    Glickman JN, Chen YY, Wang HH, et al. 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;25:569–578.CrossRefPubMedGoogle Scholar
  27. 27.
    Shields HM, Zwas F, Antonioli DA, et al. 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. https://doi.org/10.1007/BF01296780CrossRefPubMedGoogle Scholar
  28. 28.
    Slack JM. Metaplasia and transdifferentiation: from pure biology to the clinic. Nat Rev Mol Cell Biol. 2007;8:369–378.CrossRefPubMedGoogle Scholar
  29. 29.
    Mari L, Milano F, Parikh K, et al. A pSMAD/CDX2 complex is essential for the intestinalization of epithelial metaplasia. Cell Rep. 2014;7:1197–1210.CrossRefPubMedGoogle Scholar
  30. 30.
    Hahn HP, Blount PL, Ayub K, et al. Intestinal differentiation in metaplastic, nongoblet columnar epithelium in the esophagus. Am J Surg Pathol. 2009;33:1006–1015.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Chaves P, Cruz C, Pereira AD, et al. Gastric and intestinal differentiation in Barrett’s metaplasia and associated adenocarcinoma. Dis Esophagus. 2005;18:383–387.CrossRefPubMedGoogle Scholar
  32. 32.
    Dias Pereira ACP. Columnar-lined oesophagus without intestinal metaplasia: results from a cohort with a mean follow-up of 7 years. Aliment Pharmacol Ther. 2012;36:282–289.CrossRefPubMedGoogle Scholar
  33. 33.
    Peitz U, Vieth M, Pross M, Leodolter A, Malfertheiner P. Cardia-type metaplasia arising in the remnant esophagus after cardia resection. Gastrointest Endosc. 2004;59:810–817.CrossRefPubMedGoogle Scholar
  34. 34.
    Wang DH, Tiwari A, Kim ME, et al. Hedgehog signaling regulates FOXA2 in esophageal embryogenesis and Barrett’s metaplasia. J Clin Invest. 2014;124:3767–3780.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Bazerbachi F, Al Ustwani O, Reza Kermanshahi T. Non-goblet columnar epithelium in the distal esophagus: review of recent advances in understanding the origin and neoplastic potential. Transl Gastrointest Cancer. 2013;2:152–156.Google Scholar
  36. 36.
    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;17:1282–1288.CrossRefPubMedGoogle Scholar
  37. 37.
    Phillips RW, Frierson HF Jr, Moskaluk CA. Cdx2 as a marker of epithelial intestinal differentiation in the esophagus. Am J Surg Pathol. 2003;27:1442–1447.CrossRefPubMedGoogle Scholar
  38. 38.
    Kerkhof M, Bax DA, Moons LM, et al. Does CDX2 expression predict Barrett’s metaplasia in oesophageal columnar epithelium without goblet cells? Aliment Pharmacol Ther. 2006;24:1613–1621.CrossRefPubMedGoogle Scholar
  39. 39.
    Chaves P, Pereira AD, Cruz C, et al. Recurrent columnar-lined esophageal segments—study of the phenotypic characteristics using intestinal markers. Dis Esophagus. 2002;15:282–286.CrossRefPubMedGoogle Scholar
  40. 40.
    England J, Swager A, Schlachter S, et al. Role of mucosal glands in the progression of neoplasia in Barrett’s esophagus. Mod Pathol. 2015;29:170A.Google Scholar
  41. 41.
    Andrici J, Stachler M, Jeck W, et al. Low mucosal gland density in Barrett’s esophagus is associated with progression to high grade dysplasia and adenocarcinoma. Lab Invest. 2018;98:243.Google Scholar
  42. 42.
    Chandrasoma PT, Der R, Dalton P, et al. Distribution and significance of epithelial types in columnar-lined esophagus. Am J Surg Pathol. 2001;25:1188–1193.CrossRefPubMedGoogle Scholar
  43. 43.
    Glickman JN, Shahsafaei A, Odze RD. Mucin core peptide expression can help differentiate Barrett’s esophagus from intestinal metaplasia of the stomach. Am J Surg Pathol. 2003;27:1357–1365.CrossRefPubMedGoogle Scholar
  44. 44.
    McIntire MG, Soucy G, Vaughan TL, et al. MUC2 is a highly specific marker of goblet cell metaplasia in the distal esophagus and gastroesophageal junction. Am J Surg Pathol. 2011;35:1007–1013.CrossRefPubMedGoogle Scholar
  45. 45.
    Piazuelo MB, Haque S, Delgado A, et al. Phenotypic differences between esophageal and gastric intestinal metaplasia. Mod Pathol. 2004;17:62–74.CrossRefPubMedGoogle Scholar
  46. 46.
    Nurgalieva Z, Lowrey A, El-Serag HB. The use of cytokeratin stain to distinguish Barrett’s esophagus from contiguous tissues: a systematic review. Dig Dis Sci. 2007;52:1345–1354.CrossRefPubMedGoogle Scholar
  47. 47.
    McDole JR, Wheeler LW, McDonald KG, et al. Goblet cells deliver luminal antigen to CD103+ dendritic cells in the small intestine. Nature. 2012;483:345–349.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Srivastava A, Appelman H, Goldsmith JD, et al. The use of ancillary stains in the diagnosis of Barrett esophagus and Barrett esophagus-associated dysplasia: recommendations from the Rodger C. Haggitt gastrointestinal pathology society. Am J Surg Pathol. 2017;41:e8–e21.CrossRefPubMedGoogle Scholar
  49. 49.
    Srivastava A, Golden KL, Sanchez CA, et al. High goblet cell count is inversely associated with ploidy abnormalities and risk of adenocarcinoma in Barrett’s esophagus. PLoS ONE. 2015;10:e0133403.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Theodorou D, Ayazi S, DeMeester SR, et al. Intraluminal pH and goblet cell density in Barrett’s esophagus. J Gastrointest Surg. 2012;16:469–474.CrossRefPubMedGoogle Scholar
  51. 51.
    Thompson JJ, Zinsser KR, Enterline HT. Barrett metaplasia and adenocarcinoma of the esophagus and gastroesophageal junction. Hum Pathol. 1983;14:42–61.CrossRefPubMedGoogle Scholar
  52. 52.
    Wang H, Brown I, Kumarasinghe P, et al. Poor agreement for detection of goblet cells in esophageal and GEJ biopsies. Mod Pathol. 2012;25:184A.Google Scholar
  53. 53.
    Wright CL, Kelly JK. The use of routine special stains for upper gastrointestinal biopsies. Am J Surg Pathol. 2006;30:357–361.CrossRefPubMedGoogle Scholar
  54. 54.
    Jones TF, Sharma P, Daaboul B, et al. Yield of intestinal metaplasia in patients with suspected short-segment Barrett’s esophagus (SSBE) on repeat endoscopy. Dig Dis Sci. 2002;47:2108–2111.CrossRefPubMedGoogle Scholar
  55. 55.
    Kim SL, Waring JP, Spechler SJ, et al. Diagnostic inconsistencies in Barretts-esophagus. Gastroenterology. 1994;107:945–949.CrossRefPubMedGoogle Scholar
  56. 56.
    Goldstein NS. Gastric cardia intestinal metaplasia: biopsy follow-up of 85 patients. Mod Pathol. 2000;13:1072–1079.CrossRefPubMedGoogle Scholar
  57. 57.
    Sarbia M, Donner A, Gabbert HE. Histopathology of the gastroesophageal junction—a study on 36 operation specimens. Am J Surg Pathol. 2002;26:1207–1212.CrossRefPubMedGoogle Scholar
  58. 58.
    Srivastava A, Hornick JL, Li X, et al. Loss of goblet cell differentiation occurs with the progression of dysplasia in Barrett’s esophagus. Gastroenterology. 2006;130:A-264.Google Scholar
  59. 59.
    Rege TA, Sanchez C, Li X, et al. Conversion of goblet to non-goblet columnar metaplasia of the esophagus. A clinical/pathologic and molecular study of 10 cases. Gastroenterology. 2009;136:T1897.CrossRefGoogle Scholar
  60. 60.
    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;104:816–824.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Bandla S, Peters JH, Ruff D, et al. Comparison of cancer-associated genetic abnormalities in columnar-lined esophagus tissues with and without goblet cells. Ann Surg. 2014;260:72–80.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Aida J, Vieth M, Shepherd NA, et al. Is carcinoma in columnar-lined esophagus always located adjacent to intestinal metaplasia?: a histopathologic assessment. Am J Surg Pathol. 2015;39:188–196.CrossRefPubMedGoogle Scholar
  63. 63.
    Nunobe S, Nakanishi Y, Taniguchi H, et al. Two distinct pathways of tumorigenesis of adenocarcinomas of the esophagogastric junction, related or unrelated to intestinal metaplasia. Pathol Int. 2007;57:315–321.CrossRefPubMedGoogle Scholar
  64. 64.
    Chaves P, Crespo M, Ribeiro C, et al. Chromosomal analysis of Barrett’s cells: demonstration of instability and detection of the metaplastic lineage involved. Mod Pathol. 2007;20:788–796.CrossRefPubMedGoogle Scholar
  65. 65.
    Romagnoli S, Roncalli M, Graziani D, et al. Molecular alterations of Barrett’s esophagus on microdissected endoscopic biopsies. Lab Invest. 2001;81:241–247.CrossRefPubMedGoogle Scholar
  66. 66.
    Srivastava A, Sanchez CA, Cowan DS, et al. Foveolar and serrated dysplasia are rare high-risk lesions in Barrett’s esophagus: a prospective outcome analysis of 214 patients. Mod Pathol. 2010;23:168a.Google Scholar
  67. 67.
    Agoston AT, Srivastava A, Zheng Y, et al. Prevalence and concordance of subtypes of dysplasia in patients with Barrett’s esophagus-associated adenocarcinoma. Mod Pathol. 2014;27:162a.Google Scholar
  68. 68.
    Khor TS, Alfaro EE, Ooi EMM, et al. Divergent expression of MUC5AC, MUC6, MUC2, CD10, and CDX-2 in dysplasia and intramucosal adenocarcinomas with intestinal and foveolar morphology: is this evidence of distinct gastric and intestinal pathways to carcinogenesis in Barrett esophagus? Am J Surg Pathol. 2012;36:331–342.CrossRefPubMedGoogle Scholar
  69. 69.
    Demicco EG, Farris AB, Baba Y, et al. The dichotomy in carcinogenesis of the distal esophagus and esophagogastric junction: intestinal-type vs cardiac-type mucosa-associated adenocarcinoma. Mod Pathol. 2011;24:1177–1190.CrossRefPubMedGoogle Scholar
  70. 70.
    Vieth M, Barr H. Editorial: defining a bad Barrett’s segment: is it dependent on goblet cells? Am J Gastroenterol. 2009;104:825–827.CrossRefPubMedGoogle Scholar
  71. 71.
    Desai TK, Krishnan K, Samala N, et al. The incidence of oesophageal adenocarcinoma in non-dysplastic Barrett’s oesophagus: a meta-analysis. Gut. 2012;61:970–976.CrossRefPubMedGoogle Scholar
  72. 72.
    Chandrasoma P, Wijetunge S, DeMeester S, et al. Columnar-lined esophagus without intestinal metaplasia has no proven risk of adenocarcinoma. Am J Surg Pathol. 2012;36:1–7.CrossRefPubMedGoogle Scholar
  73. 73.
    Salimian KJ, Waters KM, Eze O, et al. Definition of Barrett esophagus in the United States: support for retention of a requirement for goblet cells. Am J Surg Pathol. 2018;42:264–268.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Pathology Department, Brigham and Women’s HospitalHarvard Medical SchoolBostonUSA

Personalised recommendations