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Comparison of six immunohistochemical markers for the histologic diagnosis of neoplasia in Barrett’s esophagus

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Abstract

In esophageal neoplasms, the histopathologic differentiation between Barrett’s esophagus with or without intraepithelial neoplasia and adenocarcinoma is often challenging. Immunohistochemistry might help to differentiate between these lesions. The expression of CDX2, LI-cadherin, mucin 2 (MUC2), blood group 8 (BG8, Lewisy), claudin-2, and villin was investigated in normal gastroesophageal (n = 23) and in Barrett’s (n = 17) mucosa, in low-grade (n = 12) and high-grade (n = 9) intraepithelial neoplasia (IEN) as well as in esophageal adenocarcinoma (n = 16), using immunohistochemistry. For CDX2 and LI-cadherin, the immunoreactivity score was highest in IEN while for MUC2, BG8, and villin, it dropped gradually from Barrett’s via IEN to adenocarcinoma, and expression of Claudin-2 was only weak and focal in all lesions. The expression of MUC2 and LI-cadherin differed significantly between all examined lesions except between low-grade and high-grade IEN. MUC2 and LI-cadherin are useful immunohistochemical markers for the differentiation between normal glandular mucosa, Barrett’s mucosa, IEN, and invasive carcinoma of the esophagus; however, none of the examined markers was helpful for the differentiation between low-grade and high-grade IEN.

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References

  1. Barrett NR (1950) Chronic peptic ulcer of the oesophagus and 'oesophagitis'. Br J Surg 38:175–182

    Article  PubMed  CAS  Google Scholar 

  2. Barrett NR (1957) The lower esophagus lined by columnar epithelium. Surgery 41:881–894

    PubMed  CAS  Google Scholar 

  3. Haggitt RC (1992) Adenocarcinoma in Barrett’s esophagus: a new epidemic? Hum Pathol 23:475–476

    Article  PubMed  CAS  Google Scholar 

  4. Sarosi G, Brown G, Jaiswal K et al (2008) Bone marrow progenitor cells contribute to esophageal regeneration and metaplasia in a rat model of Barrett’s esophagus. Dis Esophagus 21:43–50

    PubMed  CAS  Google Scholar 

  5. Sampliner RE (1998) Practice guidelines on the diagnosis, surveillance, and therapy of Barrett’sesophagus. The Practice Parameters Committee of the American College of Gastroenterology. Am J Gastroenterol 93:1028–1032

    Article  PubMed  CAS  Google Scholar 

  6. Weinstein WM, Ippoliti AF (1996) The diagnosis of Barrett’s esophagus: goblets, goblets, goblets. Gastrointest Endosc 44:91–95

    Article  PubMed  CAS  Google Scholar 

  7. Batts KP (2001) Barrett esophagus—more steps forward. Hum Pathol 32:357–359

    Article  PubMed  CAS  Google Scholar 

  8. Goldblum JR (2003) Barrett’s esophagus and Barrett's-related dysplasia. Mod Pathol 16:316–324

    Article  PubMed  Google Scholar 

  9. Blot WJ, Devesa SS, Kneller RW, Fraumeni JF Jr (1991) Rising incidence of adenocarcinoma of the esophagus and gastric cardia. JAMA 265:1287–1289

    Article  PubMed  CAS  Google Scholar 

  10. Vizcaino AP, Moreno V, Lambert R, Parkin DM (2002) Time trends incidence of both major histologic types of esophageal carcinomas in selected countries, 1973–1995. Int J Cancer 99:860–868

    Article  PubMed  CAS  Google Scholar 

  11. Eloubedi MA, Provenzale D (1999) Does this patient have Barrett’s esophagus? The utility of predicting Barrett’s esophagus at the index endoscopy. Am J Gastroenterol 94:937–943

    Article  Google Scholar 

  12. Freund JN, Domon-Dell C, Kedinger M, Duluc I (1998) The Cdx-1 and Cdx-2 homeobox genes in the intestine. Biochem Cell Biol 76:957–969

    Article  PubMed  CAS  Google Scholar 

  13. Suh E, Traber PG (1996) An intestine-specific homeobox gene regulates proliferation and differentiation. Mol Cell Biol 16:619–625

    PubMed  CAS  Google Scholar 

  14. Eda A, Osawa H, Yanaka I, Satoh K, Mutoh H, Kihira K, Sugano K (2002) Expression of homeobox gene CDX2 precedes that of CDX1 during the progression of intestinal metaplasia. J Gastroenterol 37:94–100

    Article  PubMed  CAS  Google Scholar 

  15. Eda A, Osawa H, Satoh K, Yanaka I, Kihira K, Ishino Y, Mutoh H, Sugano K (2003) Aberrant expression of CDX2 in Barrett’sepithelium and inflammatory esophageal mucosa. J Gastroenterol 38:14–22

    Article  PubMed  CAS  Google Scholar 

  16. Ko S, Chu KM, Luk JM, Wong BW, Yuen ST, Leung SY, Wong J (2005) CDX2 co-localizes with liver-intestine cadherin in intestinal metaplasia and adenocarcinoma of the stomach. J Pathol 205:615–622

    Article  PubMed  CAS  Google Scholar 

  17. Ranscht B (1994) Cadherins and catenins: interactions and functions in embryogenic development. Curr Opin Cell Biol 6:740–746

    Article  PubMed  CAS  Google Scholar 

  18. Takeichi M (1995) Morphogenetic roles of classic cadherins. Curr Opin Cell Biol 7:619–627

    Article  PubMed  CAS  Google Scholar 

  19. Takeichei M (1993) Cadherins in cancer: implications for invasion and metastasis. Curr Opin Cell Biol 5:806–811

    Article  Google Scholar 

  20. Hirohashi S (1998) Inactivation of the E-cadherin-mediated cell adhesion system in human cancers. Am J Pathol 153:333–339

    PubMed  CAS  Google Scholar 

  21. Berndorff D, Gessner R, Kreft B, Schnoy N, Lajous-Petter AM, Loch N, Reutter W, Hotsch M, Tauber R (1994) Liver–intestine cadherin: molecular cloning and characterization of a novel Ca2+-dependent cell adhesion molecule expressed in liver and intestine. J Cell Biol 125:1353–1369

    Article  PubMed  CAS  Google Scholar 

  22. Gessner R, Tauber R (2000) Intestinal cell adhesion molecules. Liver–intestine cadherin. Ann NY Acad Sci 915:136–143

    Article  PubMed  CAS  Google Scholar 

  23. Hinoi T, Lucas PC, Kuick R, Hanash S, Cho KR, Fearon ER (2002) CDX2 regulates liver intestine-cadherin expression in normal and malignant colon epithelium and intestinal metaplasia. Gastroenterology 123:1565–1577

    Article  PubMed  CAS  Google Scholar 

  24. Grötzinger C, Kneifel J, Patschan D, Schnoy N, Anagnostopoulos I, Faiss S, Tauber R, Wiedenmann B, Gessner R (2001) LI-cadherin: a marker of gastric metaplasia and neoplasia. Gut 49:8

    Article  Google Scholar 

  25. Wong BW, Luk JM, Ng IO, Hu MY, Liu KD, Fan ST (2003) Identification of liver–intestine cadherin in hepatocellular carcinoma—a potential disease marker. Biochem Biophys Res Commun 311:618–624

    Article  PubMed  CAS  Google Scholar 

  26. Takamura M, Sakamoto M, Ino Y, Shimamura T, Ichida T, Asakura H, Hirohashi S (2003) Expression of liver–intestine cadherin and its possible interaction with galectin-3 in ductal adenocarcinoma of the pancreas. Cancer Sci 94:425–430

    Article  PubMed  CAS  Google Scholar 

  27. Fitzgerald RC, Omary MB, Triadafilopoulos G (1997) Acid modulation of HT29 cell growth and differentiation: an in vitro model for Barrett’s esophagus. J Cell Sci 110:663–671

    PubMed  CAS  Google Scholar 

  28. Niwa T, Ikehara Y, Nakanishi H et al (2005) Mixed gastric- and intestinal-type metaplasia is formed by cells with dual intestinal and gastric differentiation. J Histochem Cytochem 53:75–85

    Article  PubMed  CAS  Google Scholar 

  29. Dudouet B, Robine S, Huet C et al (1987) Changes in villin synthesis and subcellular distribution during intestinal differentiation of HT29-18 clones. J Cell Biol 105:359–369

    Article  PubMed  CAS  Google Scholar 

  30. Furuse M, Sasaki H, Tsukita S (1999) Manner of interaction of heterogeneous claudin species within and between tight junction strands. J Cell Biol 147:891–903

    Article  PubMed  CAS  Google Scholar 

  31. Sawada N, Murata M, Kikuchi K, Osanai M, Tobioka H, Kojima T, Chiba H (2003) Tight junctions and human diseases. Med Electron Microsc 36:147–156

    Article  PubMed  Google Scholar 

  32. Offner S, Hekele A, Teichmann U, Weinberger S, Gross S, Kufer P, Itin C, Baeuerle PA, Kohleisen B (2004) Epithelial tight junction proteins as potential antibody targets for pancarcinoma therapy. Cancer Immunol Immunother 54:431–445

    Article  PubMed  CAS  Google Scholar 

  33. Michl P, Buchholz M, Rolke M, Kunsch S, Lohr M, McClane B, Tsukita S, Leder G, Adler G, Gress TM (2001) Claudin-4: a new target for pancreatic cancer treatment using Clostridium perfringens enterotoxin. Gastroenterology 121:678–684

    Article  PubMed  CAS  Google Scholar 

  34. Ho SB, Niehans GH, Lyftogt C, Yan PS, Cherwitz DL et al (1993) Heterogeneity of mucin gene expression in normal and neoplastic tissues. Cancer Res 53:641–651

    PubMed  CAS  Google Scholar 

  35. Burjonrappa SC, Reedimasu S, Nawaz Z et al (2009) Mucin expression profile in Barrett´s, dysplasia, adenocarcinoma sequence in the esophagus. Indian J Cancer 44:1–5

    Article  Google Scholar 

  36. Blaszczyk-Thurin M, Ramachandran M, Westerink MAJ et al (1996) Molecular recognition of the Lewis Y antigen by monoclonal antibodies. Prot Engineering 5:447–459

    Article  Google Scholar 

  37. Werner M, Flejou JF, Hainaut P, Hoefler H, Lambert R, Keller G, Stein HJ (2000) Adenocarcinoma of the oesophagus. In: Hamilton SR, Aaltonen LA (eds) WHO classification of tumours, pathology & genetics, tumors of the digestive system. IARC Press, Lyon, pp 20–26

    Google Scholar 

  38. Weimann A, Zimmermann M, Gross M, Slevogt H, Rieger A, Morawietz L (2010) CDX2 and LI-cadherin expression in esophageal mucosa: use of both markers can facilitate the histologic diagnosis of Barrett's esophagus and carcinoma. Int J Surg Pathol. doi:10.1177/1066896910364428

    PubMed  Google Scholar 

  39. Remmele W, Stegner HE (1987) Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathologe 8:138–140

    PubMed  CAS  Google Scholar 

  40. Conio M, Lapertosa G, Blanchi S, Filiberti R (2003) Barrett’s esophagus: an update. Crit Rev Oncol Hematol 46:187–206

    Article  PubMed  Google Scholar 

  41. Falk GW (2002) Barrett’s esophagus. Gastroenterology 122:1569–1591

    Article  PubMed  Google Scholar 

  42. Menke-Pluymers MB, Mulder AH, Hop WC, van Blankenstein M, Tilanus HW (1994) Dysplasia and aneuploidy as markers of malignant degeneration in Barrett’s oesophagus. The Rotterdam Oesophageal Tumour Study Group. Gut 35:1348–1351

    Article  PubMed  CAS  Google Scholar 

  43. Reid BJ, Levine DS, Longton G, Blount PL, Rabinovitch PS (2000) Predictors of progression to cancer in Barrett's esophagus: baseline histology and flow cytometry identify low- and high-risk patient subsets. Am J Gastroenterol 95:1669–1676

    PubMed  CAS  Google Scholar 

  44. Ko S, Chu KM, Luk JM, Wong BW, Yuen ST, Leung SY, Wong J (2004) Overexpression of LI-cadherin in gastric cancer is associated with lymph node metastasis. Biochem Biophys Res Commun 319:562–568

    Article  PubMed  CAS  Google Scholar 

  45. Phillips RW, Frierson HF Jr, Moskaluk CA (2003) Cdx2 as a marker of epithelial intestinal differentiation in the esophagus. Am J Surg Pathol 27:1442–1447

    Article  PubMed  Google Scholar 

  46. Noguchi M, Nakajima T, Hirohashi S, Akiba T, Shimosato Y (1989) Immunohistochemical distinction of malignant mesothelioma from pulmonary adenocarcinoma with anti-surfactant apoprotein, anti-Lewisa, and anti-Tn antibodies. Hum Pathol 20:53–57

    Article  PubMed  CAS  Google Scholar 

  47. Riera JR, Astengo-Osuna C, Longmate JA, Battifora H (1997) The immunohistochemical diagnostic panel for epithelial mesothelioma. A reevaluation after heat-induced epitope retrieval. Am J Surg Pathol 21:1409–1419

    Article  PubMed  CAS  Google Scholar 

  48. Kauer WK, Peters JH, DeMeester TR, Ireland AP, Bremner CG, Hagen JA (1995) Mixed reflux of gastric and duodenal juices is more harmful to the esophagus than gastric juice alone: the need for surgical therapy re-emphasized. Ann Surg 222:525–531

    PubMed  CAS  Google Scholar 

  49. Yamamoto H, Bai YQ, Yuasa Y (2003) Homeodomain protein CDX2 regulates goblet-specific MUC2 gene expression. Biochem Biophys Res Commun 300:813–818

    Article  PubMed  CAS  Google Scholar 

  50. Yamamichi N, Inada KI, Furukawa C, Sakurai K et al (2009) Cdx2 and the Brm-type SWI/SNF complex cooperatively regulate villin expression in gastrointestinal cells. Exp Cell Res 315:1779–1789

    Article  PubMed  CAS  Google Scholar 

  51. Jovov B, Van Itallie CM, Shaheen NJ, Carson JL et al (2007) Claudin-18: a dominant tight junction protein in Barrett’s esophagus and likely contributor to its acid resistance. Am J Physiol Gastrointest Liver Physiol 293:1106–1113

    Article  CAS  Google Scholar 

  52. Györffy H, Holczbauer A, Nagy P, Szabó Z et al (2005) Claudin expression in Barrett's esophagus and adenocarcinoma. Virchows Arch 447:961–968

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The excellent technical assistance of Mrs. Gabriele Fernahl is gratefully acknowledged.

Conflict of interest statement

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Institute for Laboratory Medicine and Pathobiochemistry, Charité–University Medical Center, Berlin, Germany

    Andreas Weimann, Mathias Zimmermann, Monica Gross & Peter Hoffmann

  2. Institute of Pathology, Charité–University Medical Center, Charitéplatz 1, 10117, Berlin, Germany

    Anja Rieger & Lars Morawietz

  3. Department of Internal Medicine/Infectious Diseases, Charité–University Medical Center, Berlin, Germany

    Hortense Slevogt

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  1. Andreas Weimann
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  2. Anja Rieger
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  4. Monica Gross
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  6. Hortense Slevogt
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  7. Lars Morawietz
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Correspondence to Lars Morawietz.

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Andreas Weimann and Anja Rieger contributed equally to this work

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Weimann, A., Rieger, A., Zimmermann, M. et al. Comparison of six immunohistochemical markers for the histologic diagnosis of neoplasia in Barrett’s esophagus. Virchows Arch 457, 537–545 (2010). https://doi.org/10.1007/s00428-010-0972-y

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  • DOI: https://doi.org/10.1007/s00428-010-0972-y

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