CDX2 and LI-Cadherin Expression in Esophageal Mucosa: Use of Both Markers Can Facilitate the Histologic Diagnosis of Barrett’s Esophagus and Carcinoma

Abstract

Background: Barrett’s mucosa is a risk factor for esophageal adenocarcinoma and should be detected at an early stage. CDX2 and liver—intestine (LI)-cadherin are intestine-specific markers.Aberrant CDX2 expression has been demonstrated in Barrett’s metaplasia, esophagitis, and intestinal metaplasia of the stomach. Methods: The relationship between CDX2 and LI-cadherin expression was investigated in normal gastroesophageal (n = 24) and in Barrett’s (n = 20) mucosa, in low-grade (n = 15) and high-grade (n = 13) intraepithelial neoplasia (IEN) as well as in esophageal adenocarcinoma (n = 16), using immunohistochemistry. Results: Nuclear positivity for CDX2 coupled with membranous expression of LI-cadherin was observed in about 70% of the epithelial cells of Barrett’s mucosa. The intensity of staining and the percentage of positive cells increased within the sequential steps of low-grade to high-grade IEN, whereas the normal cylindric epithelium lacked the expression of both. In adenocarcinoma, the expression of LI-cadherin and CDX2 was significantly weaker or absent. Conclusions: CDX2 and LI-cadherin are sensitive markers of intestinal metaplasia with or without dysplasia in the upper gastrointestinal tract. Both can be helpful for the early histologic diagnosis of Barrett’s esophagus and its subsequent lesions; however, they do not significantly discern between different grades of dysplasia.

Keywords

Barrett’s metaplasia esophageal adenocarcinoma CDX2 LI-cadherin immunohistochemistry

Get full access to this article

View all access options for this article.

References

Barrett NR Chronic peptic ulcer of the oesophagus and "oesophagitis". Br J Surg. 1950;38:175-182.

Barrett NR The lower esophagus lined by columnar epithelium. Surgery . 1957;41:881-894.

Sampliner RE Practice guidelines on the diagnosis, surveillance, and therapy of Barrett’s esophagus. The Practice Parameters Committee of the American College of Gastroenterology. Am J Gastroenterol . 1998;93:1028-1032.

Weinstein WM , Ippoliti AF The diagnosis of Barrett’s esophagus: goblets, goblets, goblets. Gastrointest Endosc. 1996;44:91-95.

Batts KP Barrett esophagus-more steps forward. Hum Pathol. 2001;32:357-359.

Goldblum JR Barrett’s esophagus and Barrett’s-related dysplasia. Mod Pathol. 2003;16:316-324.

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

Devesa SS , Blot WJ , Fraumeni JF Jr. Changing patterns in the incidence of esophageal and gastric carcinoma in the United States. Cancer. 1998;83:2049-2053.

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

10.

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

11.

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

12.

James R. , Erler T. , Kazenwadel J. Structure of the murine homeobox gene cdx-2. Expression in embryonic and adult intestinal epithelium. J Biochem. 1994;269:15229-15237.

13.

Suh E. , Chen L. , Taylor J. , Traber PG A homeodomain protein related to caudal regulates intestine-specific gene transcription. Mol Cell Biol. 1994;14:7340-7351.

14.

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

15.

Eda A. , Osawa H. , Yanaka I. , et al. Expression of homeobox gene CDX2 precedes that of CDX1 during the progression of intestinal metaplasia. J Gastroenterol . 2002;37:94-100.

16.

Eda A. , Osawa H. , Satoh K. , et al. Aberrant expression of CDX2 in Barrett’s epithelium and inflammatory esophageal mucosa. J Gastroenterol. 2003;38:14-22.

17.

Moons LM , Bax DA , Kuipers EJ , et al. The homeodomain protein CDX2 is an early marker of Barrett’s oesophagus. J Clin Pathol. 2004;57:1063-1068.

18.

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.

19.

Ko S. , Chu KM , Luk JM , et al. CDX2 co-localizes with liver-intestine cadherin in intestinal metaplasia and adenocarcinoma of the stomach. J Pathol. 2005;205:615-622.

20.

Mutoh H. , Hakamata Y. , Sato K. , et al. Conversion of gastric mucosa to intestinal metaplasia in Cdx2-expressing transgenic mice. Biochem Biophys Res Commun. 2002;294:470-479.

21.

Ranscht B. Cadherins and catenins: interactions and functions in embryogenic development . Curr Opin Cell Biol. 1994;6:740-746.

22.

Takeichi M. Morphogenetic roles of classic cadherins. Curr Opin Cell Biol. 1995;7:619-627.

23.

Takeichei M. Cadherins in cancer: implications for invasion and metastasis. Curr Opin Cell Biol. 1993;5:806-811.

24.

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

25.

Berndorff D. , Gessner R. , Kreft B. , et al. Liver-intestine cadherin: molecular cloning and characterization of a novel Ca2+-dependent cell adhesion molecule expressed in liver and intestine. J Cell Biol. 1994;125:1353-1369.

26.

Gessner R. , Tauber R. Intestinal cell adhesion molecules. Liver-intestine cadherin. Ann N Y Acad Sci. 2000;915:136-143.

27.

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

28.

Grötzinger C. , Kneifel J. , Patschan D. , et al. LI-cadherin: a marker of gastric metaplasia and neoplasia. Gut. 2001; 49:73-81.

29.

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

30.

Takamura M. , Sakamoto M. , Ino Y. , et al. Expression of liver-intestine cadherin and its possible interaction with galectin-3 in ductal adenocarcinoma of the pancreas. Cancer Sci. 2003;94:425-430.

31.

Werner M. , Flejou JF , Hainaut P. , et al. Adenocarcinoma of the oesophagus. In: Hamilton SR , Aaltonen LA , eds. WHO Classification of Tumours, Pathology and Genetics: Tumors of the Digestive System. Lyon, France: IARC Press ; 2000:20-26.

32.

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

33.

Haggit RC Barrett’s esophagus. Hum Pathol. 1994 ;25: 982-993.

34.

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

35.

Falk GW Barrett’s esophagus. Gastroenterology. 2002; 122:1569-1591.

36.

Phillips RW , Wong RK Barrett’s esophagus. Natural history, incidence, etiology, and complications . Gastroenterol Clin North Am. 1991;20:791-816.

37.

Jankowski JA , Odze RD Biomarkers in gastroenterology: between hope and hype comes histopathology . Am J Gastroenterol. 2009;104:1093-1096.

38.

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

39.

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

40.

Fléjou JF , Svrcek M. Barrett’s oesophagus-a pathologist’s view. Histopathology. 2007;50:3-14.

41.

Sikkema M. , Kerkhof M. , Steyerberg EW , et al. Aneuploidy and overexpression of Ki67 and p53 as markers for neoplastic progression in Barrett’s esophagus: a case-control study . Am J Gastroenterol. 2009;104:2673-2680.

42.

Lörinc E. , Jakobsson B. , Landberg G. , Veress B. Ki67 and p53 immunohistochemistry reduces interobserver variation in assessment of Barrett’s oesophagus. Histopathology. 2005;46:642-648.

43.

Ko S. , Chu KM , Luk JM , et al. Overexpression of LI-cadherin in gastric cancer is associated with lymph node metastasis. Biochem Biophys Res Commun. 2004;319: 562-568.

44.

Feith M. , Stein HJ , Mueller J. , Siewert JR Malignant degeneration of Barrett’s esophagus: the role of the Ki-67 proliferation fraction, expression of E-cadherin and p53. Dis Esophagus. 2004;17:322-327.

45.

Lorentz O. , Cadoret A. , Duluc I. , et al. Downregulation of the colon tumour-suppressor homeobox gene Cdx-2 by oncogenic ras. Oncogene. 1999;18:87-92.