CEA

(Carcinoembryonic antigen)
Characteristics
Carcinoembryonic antigen (CEA, CD66e) is a glycoprotein, 180-200 kDa, encoded together with structurally related proteins by the CEA gene family located on human chromosome 19q13.2. CEA and the other members of the CEA family belong to the immunoglobulin superfamily. The CEA family consists of two branches identified as the CEACAM (CEA cell adhesion molecule) and the PSG (pregnancy-specific glycoprotein) branches. The CEA family includes membrane proteins such as CEA (CEACAM5), non-specific cross-reacting antigen, (NCA, CEACAM6) and biliary glycoprotein (BGP; CEACAM1). The principal functions of the CEA family are unknown but they can act as homophilic and heterophilic cell adhesion molecules. Further functions attributed to the CEA family members include roles in signal transduction, cooperation with proto-oncogenes in cellular transformation and inhibition of proliferation of epithelial tumours. In normal adult tissue, CEA is expressed in the apical border and, to a lesser extent in the cytoplasm, of the columnar cells of colon, small intestine, and stomach (surface epithelium, mucous neck cells and weakly in pyloric mucous cells), pancreatic ducts, secretory epithelia of sweat glands, squamous epithelial cells of the tongue, esophagus and uterine cervix, and urothelium. The prostate is negative (apart from urothelium lined secretory ducts). BGP and NCA are more widely distributed in epithelia of many organs, and also in granulocytes and lymphocytes. In the liver BGP is characteristically located along the bile canaliculi.
Neoplasms
The expression of CEA is upregulated in many types of carcinoma. CEA is expressed in epithelial cell membranes and in the cytoplasm of the cells in almost all cases of colorectal adenocarcinoma as well as a high proportion of adenocarcinomas of the salivary glands, esophagus, stomach, biliary tract, pancreas, small intestine, lung, uterine cervix and ovary (mucinous type). CEA is seen less frequently in breast carcinoma, ovarian Brenner tumour, and endometrioid carcinoma. Among neuroendocrine tumours, CEA is found in the large majority of medullary thyroid carcinoma, less often and more weakly expresed in carcinoid tumour, neuroendocrine carcinoma and rarely in small cell carcinoma. In urotelial malignancies, CEA is particularly seen in high grade lesions. Among germ cell tumours, CEA is seen in most cases of embryonal carcinoma but rarely in the other types. Among squamous cell carcinomas, CEA is particularly detected in those derived from esophagus and uterine cervix. The following carcinomas are rarely CEA positive: ovarian serous and clear cell carcinoma, renal cell carcinoma, adrenal cortical carcinoma, prostate adenocarcinoma, hepatocellular carcinoma (except for the rare fibrolamellar variant) and follicular and papillary thyroid carcinoma. Among non-epithelial tumours, CEA may be detected in secretory meningioma (but not in other meningioma types) and in synovial and epitheloid sarcoma. Malignant mesothelioma is vertually always negative (provided that the Ab does not cross react with other CEA-like epitopes). Among mesenchymal tumours, CEA has been demonstrated in cases of epitheloid and synovial sarcomas.
Application
Monoclonal antibodies specific to CEA have a role in the panels used to identify adenocarcinomas of the digestive tract, to distinguish between malignant mesothelioma and peripheral pulmonary adenocarcinoma, to distinguish between endocervical and endometrioid endometrial adenocarcinoma, and to distinguish hepatocellular carcinoma from cholangiocarcinoma and metastatic liver adenocarcinoma.
Controls
Appendix, in combination with liver, is the recommended positive and negative tissue controls for CEA. In the appendix the vast majority of epithelial cells must show an at least weak to moderate cytoplasmic staining reaction. If only the glycocalyx is demonstrated, inadequate staining in neoplasias with low CEA expression is seen. Liver is recommended as negative tissue control. Bile canaliculi and leucocytes must be negative with no cross reaction to BGP or NCA to verify the specificity of the primary Ab. Hepatocytes must be negative to verify a high signal-to-noise ratio.
Selected references
Beauchemin N, et al. Redefined nomenclature for members of the carcinoembryonic antigen family. Exp Cell Res 1999;252:243-249. Bjerner J, Lebedin Y, Bellanger L, Kuroki M, Shively JE, Varaas T, Nustad K, Hammarstrom S, Bormer OP. Protein epitopes in carcinoembryonic antigen. Report of the ISOBM TD8 workshop. Tumour Biol. 2002 Jul-Aug;23(4):249-62. Esteban JM, Paxton R, Mehta P, Battifora H, Shively JE. Sensitivity and specificity of Gold types 1 to 5 anti-carcinoembryonic antigen monoclonal antibodies: immunohistologic characterization in colorectal cancer and normal tissues. Hum Pathol. 1993 Mar;24(3):322-8. Gold P and Goldenberg NA. The carcinoembryonic antigen (CEA): past, present, and future. McGill J Med 1997;3:46-66. Hammarstrom S. et al. Antigenic sites in carcinoembryonic antigen. Cancer Res 1989;49:4852-4858. Hammarstrom S. The carcinoembryonic antigen (CEA) family: structures, suggested functions and expression in normal and malignant tissues. Seminars in Cancer Biology 1999;9:67-81. Kaufmann O, Fietze E, Dietel M. [Immunohistochemical diagnosis in cancer metastasis of unknown primary tumor] Pathologe. 2002 May;23(3):183-97. German. Nap M, et al. Specificity and affinity of monoclonal antibodies against carcinoembryonic antigen. Cancer Res 1992;52:2329-2339. Ordonez NG. The immunohistochemical diagnosis of mesothelioma: a comparative study of epithelioid mesothelioma and lung adenocarcinoma. Am J Surg Pathol. 2003 Aug;27(8):1031-51.
10.04.13 - HH/MV/LE