CDX2

Characteristics

CDX1 and CDX2 are homeobox* genes encoding nuclear homeodomain transcriptional factors essential to intestinal organogenesis. CDX1 is crucial for proliferation and CDX2 for differentiation of epithelium in the intestine, pancreas and biliary tract. CDX2 interacts with the tumour suppressor genes APC and E-cadherin, as well as bcl-2.
In the intestine (from duodenum to rectum) CDX2 nuclear protein is demonstrated strongly and uniformly in all types of epithelial cells: absorptive cells, goblet cells, Paneth cells and endocrine cells. In pancreas and biliary tract CDX2 protein is demonstrated in scattered ductal cells. In the stomach and esophagus, CDX2 only occurs in case of intestinal metaplasia.

In the prostate, CDX2 may be found in few glandular cells.

*A homeobox is a DNA sequence found within genes involved in the regulation of cellular development. The corresponding protein domain is called a homeodomain.

Neoplasms

Colorectal and appendiceal adenocarcinomas are CDX2 positive in the large majority of cases, usually showing a strong, uniform staining. When cases with focal staining are included, about 95% of the tumours are positive. The expression is more often lost in low differentiated tumours.

Intestinal and similar adenocarcinomas in other organs, like gastric and small intestinal adenocarcinoma, pulmonary mucinous adenocarcinoma, sinonasal adenocarcinoma, ovarian mucinous adenocarcinoma (particularly of teratomatous origin), ampullary adenocarcinoma, bladder adenocarcinoma, mucinous urothelial-type carcinoma of prostatic urethra, urachal mucinous carcinoma, intestinal type cervical adenocarcinoma, and pseudomyxoma peritonei are positive in most cases. The staining intensity and extent is often less pronounced than in typical colorectal adenocarcinomas.
The following carcinomas stain heterogeneously for CDX2 protein in a minor number of cases (10-20%): Adenocarcinomas of pancreatic duct, extrahepatic biliary tract, stomach and esophagus, pulmonary adenocarcinoma, endometrioid adenocarcinomas (endometrium and ovary), and non-intestinal type cervical adenocarcinoma.
Among gastrointestinal carcinoids and neuroendocrine carcinomas, those derived from the midgut are mostly positive, while those from the foregut and hindgut are mostly negative. Neuroendocrine tumours from pancreas and other organs are mostly negative.
Other tumours occasionally expressing cdx2 are large cell pulmonary carcinoma, prostate adenocarcinoma and yolk sac tumour.

Application CDX2 is a relatively sensitive and specific marker for “intestinal” adenocarcinomas. In the classification of (adeno-)carcinomas of the unknown primary, CDX2 is an important marker but should always be included in a panel. Also in order to identify the origin of neuroendocrine tumours, CDX2 is useful in a panel.   Visualization Well functioning antibodies are mAb ATM28 and CDX2-88. Heat induces epitope retrieval (HIER) is mandatory, an alkaline buffer is preferable. Control tissue: Appendix; the enterocyte nuclei must show a uniformly strong staining with no or little cytoplasmic reaction (photo).

Assessments

Run 22 2008

Selected references

Bai, Y.Q., Yamamoto, H., Akiyama, Y., Tanaka, H., Takizawa, T., Koike, M., Kenji Yagi, O., Saitoh, K., Takeshita, K., Iwai, T. and Yuasa, Y. Ectopic expression of homeodomain protein CDX2 in intestinal metaplasia and carcinomas of the stomach. Cancer Lett 2002;176:47-55.

Baratti D, Kusamura S, Nonaka D, Langer M, Andreola S, Favaro M, Gavazzi C, Laterza B, Deraco M. Pseudomyxoma Peritonei: Clinical Pathological and Biological Prognostic Factors in Patients Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC). Ann Surg Oncol. 2007 Nov 28; [Epub ahead of print]

Barbareschi M, Murer B, Colby TV, Chilosi M, Macri E, Loda M, Doglioni C. CDX-2 homeobox gene expression is a reliable marker of colorectal adenocarcinoma metastases to the lungs. Am J Surg Pathol. 2003 Feb;27(2):141-9.

Barbareschi M, Roldo C, Zamboni G, Capelli P, Cavazza A, Macri E, Cangi MG, Chilosi M, Doglioni C. CDX-2 homeobox gene product expression in neuroendocrine tumors: its role as a marker of intestinal neuroendocrine tumors. Am J Surg Pathol. 2004 Sep;28(9):1169-76.

Barbareschi, M., Murer, B., Colby, T.V., Chilosi, M., Macri, E., Loda, M. and Doglioni, C. CDX-2 Homeobox Gene Expression Is a Reliable Marker of Colorectal Adenocarcinoma Metastases to the Lungs. Am J Surg Pathol 2003;27:141-9.

Choi BJ, Kim CJ, Cho YG, Song JH, Kim SY, Nam SW, Lee SH, Yoo NJ, Lee JY, Park WS. Altered expression of CDX2 in colorectal cancers. APMIS. 2006 Jan;114(1):50-4.

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(6):957-69.

Gulluoglu MG, Karayıgıt E, Ozden I, Kapran Y, Dızdaroglu F. Does HepPar-1 immunoexpression have a role in differential diagnosis of periampullary cancer? Pathology. 2008 Jan;40(1):35-41.

Lin X, Saad RS, Luckasevic TM, Silverman JF, Liu Y. Diagnostic Value of CDX-2 and TTF-1 Expressions in Separating Metastatic Neuroendocrine Neoplasms of Unknown Origin. Appl Immunohistochem Mol Morphol. 2007 Dec;15(4):407-14.
Logani S, Oliva E, Arnell PM, Amin MB, Young RH. Use of novel immunohistochemical markers expressed in colonic adenocarcinoma to distinguish primary ovarian tumors from metastatic colorectal carcinoma. Mod Pathol. 2005 Jan;18(1):19-25.

McCluggage WG, Shah R, Connolly LE, McBride HA. Intestinal-Type Cervical Adenocarcinoma In Situ and Adenocarcinoma Exhibit a Partial Enteric Immunophenotype With Consistent Expression of CDX2. Int J Gynecol Pathol. 2008 Jan;27(1):92-100.

Strickland-Marmol LB, Khoor A, Livingston SK, Rojiani A. Utility of tissue-specific transcription factors thyroid transcription factor 1 and Cdx2 in determining the primary site of metastatic adenocarcinomas to the brain. Arch Pathol Lab Med. 2007 Nov;131(11):1686-90.

Werling RW, Yaziji H, Bacchi CE, Gown AM. CDX2, a highly sensitive and specific marker of adenocarcinomas of intestinal origin: an immunohistochemical survey of 476 primary and metastatic carcinomas. Am J Surg Pathol. 2003 Mar;27(3):303-10.

Werling, R.W., Yaziji, H., Bacchi, C.E. and Gown, A.M. CDX2, a Highly Sensitive and Specific Marker of Adenocarcinomas of Intestinal Origin: An Immunohistochemical Survey of 476 Primary and Metastatic Carcinomas. Am J Surg Pathol 2003;27:303-10.

Zhang MQ, Lin F, Hui P, Chen ZM, Ritter JH, Wang HL. Expression of mucins, SIMA, villin, and CDX2 in small-intestinal adenocarcinoma. Am J Clin Pathol. 2007 Nov;128(5):808-16.