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.
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.
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.
Pancreas is recommended as positive tissue control. Virtually all ductal epithelial cells must show an at least weak to moderate and distinct nuclear staining reaction.
Appendix and colon cannot be recommended as primary positive tissue controls, since the epithelial cells express high levels of CDX2 and cannot be used to evaluate whether the protocol applied has sufficient analytical sensitivity.
Tonsil can be used as negative tissue control for CDX2. In order to monitor the specificity, no nuclear or cytoplasmic staining must be seen in endothelial cells and smooth muscle cells. The vast majority of lymphocytes should be negative, although weak nuclear staining reaction may be observed in a few lymphocytes.