Virchows Archiv

, Volume 445, Issue 3, pp 248–254 | Cite as

CDX2 as a marker of intestinal EC-cells and related well-differentiated endocrine tumors

  • Stefano La RosaEmail author
  • Elena Rigoli
  • Silvia Uccella
  • Anna Maria Chiaravalli
  • Carlo Capella
Original Article


Gastroenteropancreatic (GEP) endocrine tumors (ETs) are neoplasms showing different hormonal profiles and different clinical and prognostic features, which depend consistently on the site of origin. Histological features and general endocrine markers do not differentiate tumors in relation to their location, making it difficult to establish the site of origin of a GEP ET that has metastasized to the liver or lymph nodes. A site-specific marker would be particularly useful in the examination of small specimens where there is not sufficient material for an extensive study of the hormonal expression. CDX2 is a transcription factor that has been recently proposed as a marker of intestinal adenocarcinomas. Our aim was to evaluate the immunohistochemical expression of CDX2 in normal tissues and in 184 formalin-fixed and paraffin-embedded ETs to verify whether it could be used to identify intestinal ETs with a high degree of sensitivity and specificity. Of these cases, 154 were primary tumors (99 GEP and 55 non-GEP tumors), 101 were well-differentiated endocrine tumors, and 53 were poorly differentiated endocrine carcinomas (PDECs). Of the cases, 30 were metastases from differently located ETs. Nuclear CDX2 immunoreactivity was found in all EC-cells (serotonin-producing cells), in about 10% of G-cells (gastrin-producing cells), in about 30% of GIP-cells (gastric inhibitory peptide cells) and in a few motilin-positive cells of the normal intestinal mucosa, while other gastrointestinal endocrine cell types were CDX2 negative. All midgut EC-cell tumors, their metastases, and two of three pancreatic EC-cell ETs were diffusely and intensely CDX2 positive. The other GEP ETs, their metastases, as well as the non-GEP ETs, were all CDX2 negative, with the exception of four PDECs, five gastrinomas and one pheochromocytoma, which were only focally positive. We conclude that CDX2 may be considered a sensitive and specific marker of midgut EC-cells and EC-cell tumors, and its expression may be useful in the diagnosis of metastases from occult ETs.


CDX2 Endocrine tumor Gut Pancreas Immunohistochemistry 



Part of the work has been supported by a grant from the University of Insubria and Fondazione Cariplo, Varese, Italy.


  1. 1.
    Andrew A, Kramer B, Rawdon BB (1998) The origin of gut and pancreatic neuroendocrine (APUD) cells—the last word? J Pathol 186:117–118CrossRefPubMedGoogle Scholar
  2. 2.
    Barbareschi M, Murer B, Colby TV, Chilosi M, Macri E, Loda M, Doglioni C (2003) CDX-2 homeobox gene expression is a reliable marker of colorectal adenocarcinoma metastases to the lungs. Am J Surg Pathol 27:141–149CrossRefPubMedGoogle Scholar
  3. 3.
    Barbareschi M, Roldo C, Zamboni G, Capelli P, Cavazza A, Cangi MG, Chilosi M, Doglioni C (2004) CDX2 homeobox gene product expression in neuroendocrine tumors: its role as a marker of intestinal neuroendocrine tumors. Lab Invest 84[Suppl 1]:101AGoogle Scholar
  4. 4.
    Beck F, Chawengsaksophak K, Luckett J, Giblett S, Tucci J, Brown J, Poulsom R, Jeffery R, Wright NA (2003) A study of regional gut endoderm potency by analysis of cdx2 mutant chimeric mice. Dev Biol 255:399–406CrossRefPubMedGoogle Scholar
  5. 5.
    Burglin TR (ed) (1994) A comprehensive classification of homeobox genes. Sambrook and Tooze, New YorkGoogle Scholar
  6. 6.
    Capella C, Solcia E, Sobin LH, Arnold R (2000) Endocrine tumours of the small intestine. In: Hamilton SR, Aaltonen LA (eds) Pathology and genetics of the digestive system. IARC Press, Lyon, pp 77–82Google Scholar
  7. 7.
    Chawengsaksophak K, James R, Hammond VE, Kontgen F, Beck F (1997) Homeosis and intestinal tumours in cdx2 mutant mice. Nature 386:84–87CrossRefPubMedGoogle Scholar
  8. 8.
    Drummond F, Putt W, Fox M, Edwards YH (1997) Cloning and chromosome assignment of the human CDX2 gene. Ann Hum Genet 61:393–400CrossRefPubMedGoogle Scholar
  9. 9.
    Ee HC, Erler T, Bhathal PS, Young GP, James RJ (1995) Cdx-2 homeodomain protein expression in human and rat colorectal adenoma and carcinoma. Am J Pathol 147:586–592PubMedGoogle Scholar
  10. 10.
    Hsu SM, Raine L, Fanger H (1981) Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase technique. J Histochem Cytochem 25:577–589Google Scholar
  11. 11.
    Jenny M, Uhl C, Roche C, Duluc I, Guillermin V, Guillemont F, Jensen J, Kendinger M, Gradwohl G (2002) Neurogenin 3 is differentially required for endocrine cell fate specification in the intestinal and gastric epithelium. EMBO J 21:6338–6347CrossRefPubMedGoogle Scholar
  12. 12.
    Kaufmann O, Dietel M (2000) Expression of thyroid transcription factor-1 in pulmonary and extrapulmonary small cell carcinomas and other neuroendocrine carcinomas of various primary sites. Histopathology 36:415–420CrossRefPubMedGoogle Scholar
  13. 13.
    La Rosa S, Furlan D, Sessa F, Capella C (2003) The endocrine pancreas. In: Lloyd RV (ed) Endocrine pathology. Differential diagnosis and molecular advances. Humana Press, Totowa, pp 291–328Google Scholar
  14. 14.
    La Rosa S, Rigoli E, Uccella S, Capella C (2004) CDX2 is a marker of midgut EC-cell tumors and their metastases. Lab Invest 84[Suppl 1]:108AGoogle Scholar
  15. 15.
    Lan HY, Mu W, Nikolic-Paterson DJ, Atkins RC (1995) A novel, simple, reliable, and sensitive method for multiple immunoenzyme staining: use of microwave oven heating to block antibody cross-reactivity and retrieve antigens. J Histochem Cytochem 43:97–102PubMedGoogle Scholar
  16. 16.
    Larsson LI, St-Onge L, Hougaard DM, Sosa-Pineda B, Gruss P (1998) Pax 4 and 6 regulate gastrointestinal cell development. Mech Dev 79:153–159CrossRefPubMedGoogle Scholar
  17. 17.
    Le Dourain N (1988) On the origin of pancreatic endocrine cells. Cell 53:169–171PubMedGoogle Scholar
  18. 18.
    Lin X, Luckasevic T, Silverman JF, Medich D, Keenan RJ, Tung MT, Liu YL (2004) Diagnostic value of CDX2 and TTF1 expression in separating metastatic neuroendocrine neoplasms of unknown origin. Lab Invest 84[Suppl 1]:106AGoogle Scholar
  19. 19.
    Luckasevic TM, Silverman JF, Medich D, Celebrezze J, Tung MT, Liu YL (2004) Diagnostic value of CDX2 expression in endocrine neoplasms of gastrointestinal origin. Lab Invest 84[Suppl 1]:106AGoogle Scholar
  20. 20.
    Mason DY, Abdulaziz B, Falini H, Stein H (1983) Double immunoenzymatic labelling. In: Polak JM, Van Noorden S (eds) Immunocytochemistry. Practical applications in pathology and biology. Bristol, Wright, pp 113–128Google Scholar
  21. 21.
    Moskaluk CA, Zhang H, Powell SM, Cerilli LA, Hampton GM, Frierson HF Jr (2003) Cdx2 protein expression in normal and malignant human tissues: an immunohistochemical survey using tissue microarrays. Mod Pathol 16:913–919CrossRefPubMedGoogle Scholar
  22. 22.
    Pearse AGE, Polak JM (1971) Neural crest origin of the endocrine polypeptide (APUD) cells of the gastrointestinal tract and pancreas. Gut 12:783–788PubMedGoogle Scholar
  23. 23.
    Pearse AGE (1973) Cell migration and the alimentary system: endocrine contribution of the neural crest to the gut and its derivatives. Digestion 8:372–385PubMedGoogle Scholar
  24. 24.
    Qualtrough D, Hinoi T, Fearou E, Paraskeva C (2002) Expression of CDX2 in normal and neoplastic human colon tissue and during differentiation of an in vitro model system. Gut 51:184–190CrossRefPubMedGoogle Scholar
  25. 25.
    Silberg DG, Swain GP, Suh ER, Traber PG (2000) Cdx1 and cdx2 expression during intestinal development. Gastroenterology 119:961–971Google Scholar
  26. 26.
    Solcia E, Capella C, Fiocca R, Sessa F, La Rosa S, Rindi G (1998) Disorders of the endocrine system. In: Ming S, Goldman H (eds) Pathology of the gastrointestinal tract, 2nd edn. Williams & Wilkins, Baltimore, pp 295–322Google Scholar
  27. 27.
    Solcia E, Kloppel G, Sobin LH (eds) (2000) Histological typing of endocrine tumours. Springer, Berlin Heidelberg New YorkGoogle Scholar
  28. 28.
    Sosa-Pineda B, Chowdhury K, Torres M, Oliver G, Gruss P (1997) The Pax 4 gene is essential for differentiation of insulin-producing beta cells in the mammalian pancreas. Nature 386:399–402CrossRefPubMedGoogle Scholar
  29. 29.
    St-Onge L, Sosa-Pineda B, Chowdhury K et al (1997) Pax 6 is required for differentiation of glucagon-producing alpha-cells in mouse pancreas. Nature 387:406–409CrossRefPubMedGoogle Scholar
  30. 30.
    Suh ER, Traber PG (1996) An intestine-specific homeobox gene regulates proliferation and differentiation. Mol Cell Biol 16:619–625PubMedGoogle Scholar
  31. 31.
    Werling RW, Yaziji H, Bacchi CE, Gown AM (2003) CDX2, a high sensitive and specific marker of adenocarcinomas of intestinal origin. An immunohistochemical survey of 476 primary and metastatic carcinomas. Am J Surg Pathol 27:303–310CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Stefano La Rosa
    • 1
    • 2
    Email author
  • Elena Rigoli
    • 1
  • Silvia Uccella
    • 1
  • Anna Maria Chiaravalli
    • 1
  • Carlo Capella
    • 1
  1. 1.Department of PathologyOspedale di Circolo and University of InsubriaVareseItaly
  2. 2.Servizio di Anatomia PatologicaOspedale di CircoloVareseItaly

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