Ep-CAM consists of two glycoproteins, 34 and 39 kDa, sometimes designated epithelial antigen, epithelial specific antigen, and epithelial glycoprotein. In paraffin sections, the protein is deteced with mAbs like Ber-EP4 and MOC-31. The glycoproteins are located on the cell membrane surface (preferentially basolaterally) and in the cytoplasm of virtually all epithelial cells with the exception of most squamous epithelia, hepatocytes, renal proximal tubular cells, gastric parietal cells and myoepithelial cells. However, focal positivity may be seen in the basal layer of squamous cell epithelium of endoderm (e.g., palatine tonsils) and mesoderm (e.g., uterine cervix). In liver lesions like hepatitis and cirrhosis, the hepatocytes frequently become Ep-CAM positive. Normal mesothelial cells are Ep-CAM negative, but may express focal reaction when undergoing reactive changes. Mesenchymal cells and cells from the neural crest are negative, with the exception of olfactory neurons.
Ep-CAM is found in the large majority of adenocarcinomas of most sites (50-100% in various studies) as well as neuroendocrine tumours, including small cell carcinoma. Renal cell carcinoma and hepatocellular carcinoma stain in about 30% of the cases. Squamous cell carcinoma of endoderm and mesoderm is usually Ber-EP4 positive, while that of ectoderm is negative. Basal cell and basosquamous carcinoma are Ber-EP4 positive in almost all cases. Choroid plexus papilloma and carcinoma are usually negative. Malignant mesothelioma (epithelioid and biphasic) is Ep-CAM positive in 4-26% of the cases. The staining is usually focal, but may occasionally be widespread. Synovial sarcoma (epitheloid and biphasic) and desmoplastic small round cell tumour stain for Ep-CAM in most cases. Seminoma, embryonal carcinoma, yolk sac tumour and choriocarcinoma reveal Ber-EP4 positivity in a minor proportion of cases. Among neural tumours, Ep-CAM positivity is seen only in olfactory neuroblastoma.
Ep-CAM can be of great help in the differential diagnosis of malignant involvement in the peritoneal and pleural cavities. The lack of reactivity in the majority of malignant mesothelioma can in an appropriate panel be utilized in the discrimination between this tumour and adenocarcinoma. The marker can also be useful in the distinction between squamous cell and basal cell or basosquamous carcinoma. As for a series of anti-epithelial antibodies, Ber-Ep4 or MOC-31 may may be used in the demonstration of epithelial cell differentiation in cases where anti-cytokeratins do not produce a clear-cut positivity or in cases where a false positivity for cytokeratin cannot be excluded, such as in submesothelial cells.
Kidney is a recommendable positive control: A moderate to strong membranous staining must be seen in the epithelial cells of the renal collecting tubules while an at least weak membranous staining should be seen in the epithelial cells of the proximal tubules.
Selected references
Latza et al: Ber-Ep4: new monoclonal antibody which distinguishes epithelia from mesothelia. J Clin Pathol. 1990;43:213-19. Ma et al: Comparative immunohistochemical study of primary and metastatic carcinomas of the liver. Am J Clin Pathol. 1993;99(5):551-7. Carella et al. Immunohistochemical panels for differentiating epithelial malignant mesotheliomas from lung adenocarcinoma: a study with logistic regression analysis. Am J Surg Pathol 2001; 25(1):43-50. Kommoss F, Oliva E, Bittinger F, Kirkpatrick CJ, Amin MB, Bhan AK, Young RH, Scully RE. Inhibin-alpha CD99, HEA125, PLAP, and chromogranin immunoreactivity in testicular neoplasms and the androgen insensitivity syndrome. Hum Pathol. 2000 Sep;31(9):1055-61. Davidsson et al. Detection of cancer cells in effusions from patients with gynaecological malignancies. Evaluation of five epithelial markers. Virchows Arch. 1999;435(1):43-9. Ordonez NG. Value of the Ber-Ep4 antibody in differentiating epithelial pleural mesothelioma from adenocarcinoma. The MD Anderson experience and a clinical review of the literature. Am J Clin Pathol 1998;109(1):85-89. Jones et al. The immunohistochemical characterization of the basosquamous cell carcinoma. Dermatol Surg 1997;23(3):181-4 Kaplan et al. Adenomatoid tumors of the pleura. Am J Surg Pathol 1996;20(10):1219-23. Thellechea et al. Monoclonal antibody Ber-Ep4 distinguishes basal cell carcinoma from squamous cell carcinoma of the skin. Am J Dermatopathol 1993;15(5):452-5.
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