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Carcinoembryonic antigen (CEA)

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 (Fig. 1A), small intestine (Fig. 1B), and stomach (surface epithelium, mucous neck cells and weakly in pyloric mucous cells)(Fig. 1C), pancreatic ducts, secretory epithelia of sweat glands, squamous epithelial cells of the tongue, esophagus (Fig. 1D) 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 (Fig. 1E).

 

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 (Figs. 2A-B) 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 (Fig 2C), ovarian Brenner tumour, and endometrioid carcinoma. Among neuroendocrine tumours, CEA is found in the large majority of medullary thyroid carcinoma (Fig 2D), 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 (Fig. 2C), to distinguish between endocervical and  endometrioid endometrial adenocarcinoma, and to distinguish hepatocellular carcinoma from cholangiocarcinoma and metastatic liver adenocarcinoma.

 

Visualization

The value of CEA in diagnostic immunohistochemistry is very much dependent on the reactivity of the antibodies used. According to their binding specificity, monoclonal antibodies have been classified into five epitope groups, GOLD 1-5. For proper detection of CEA, mAbs with high specificity (GOLD 1-3) must be used. They do not display the problem of wide reactivity and staining of inflammatory and necrotic tissue. mAbs GOLD 4-5 and pAbs, which recognize NCA, react with tissues containing neutrophils and necrotic cells, and those identifying BGP epitopes react widely with, e.g., tissues of the hepatobiliary system and the pancreas.

Often it is not specified in data sheets, which GOLD group a mAb belong to. As a guideline, it must be specified for a mAb that it does not react with leucocytes or liver cells.

A "CEA" pAb or mAb GOLD 4-5 crossreacting with BGP is, however, useful for the visualization of ramifying bile canaliculi in hepatocellular carcinoma (Fig. 2E), but hardly for any other purpose.

Recommended control tissue: Normal appendix in which the enterocytes should be distinctively stained, or esophagus or tonsil in which the squamous epithelium should be distinctively stained. No reaction should be seen in other cells or structures. Normal liver should be included as a negative CEA-control (and of course as a positive control for the detection of BGP).

 

Assessments

Run 12 2004

 

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.
 
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Last update 02-12-2004