Epithelial Membrane Antigen
Epithelial membrane antigen (EMA; MUC1) is a group of heavily glycosylated transmembrane proteins, 40-425 kDa, related to the high molecular weight glycoproteins of human milk fat globule (HMFG). EMA is present in a variety of glandular (secretory) epithelia such as breast, eccrine and apocrine glands, and pancreas, whereas little or no EMA is expressed in the gastrointestinal epithelium, endocervical epithelium, and prostate glands. The immunoreactivity is usually limited to apical cell membranes, but a staining of the Golgi zone may also be seen.
Among non-secretory epithelium EMA is expressed in urothelium, renal collecting tubules, and syncytiotrophoblast. Normal squamous epithelium is EMA negative, except for that covering the tonsils. Epididymis, rete testis, germ cells, hepatocytes, adrenal cortical cells, and thyroid follicular epithelium are negative.
EMA positive non-epithelial cells comprise arachnoid cells, ependyma, choroid plexus, perineural fibroblastic cells, and plasma cells. B-cells may become EMA positive after activation by T-cells. In mesothelium, a weak, membranous staining may seen, particularly when reactively changed.
EMA can be demonstrated in most types of adenocarcinomas derived from secretory epithelia. In well-differentiated carcinomas, the staining is mostly limited to (apical) cell membranes while in the less differentiated carcinomas, a cytoplasmic staining is seen with loss of staining polarity in the membranes. EMA is also found in most cases of renal cell carcinoma and in i minor proportion of hepatocellular carcinoma. Moreover, EMA is detected in urothelial tumours, squamous cell carcinoma and placental neoplasms. Overexpression of EMA in carcinomas is usually hypoglycosylated and may be related to more aggressive types.
Most endocrine tumours like carcinoid and adrenal cortical carcinoma, are EMA negative. Basal cell carcinoma does not express EMA.
Among non-epithelial tumours, EMA may be found in meningioma, ependymoma (membranous reaction in 90%), glial tumours (a smaller percentage of tumours, cytoplasmic - sometimes dot like - reaction), perineurioma, chordoma, solitary fibrous tumour, epitheloid and synovial sarcoma (including the spindle cell component). In malignant mesothelioma, EMA is demonstrated mainly in the long microvillous surfaces of the tumour cells with little cytoplasmic labelling (Fig. 1). Among malignant lymphomas, EMA may be seen in anaplastic large cell lymphoma (50-95%), diffuse large B-cell lymphoma, plasma cell neoplasms (most cases), T-cell neoplasms (20%), and nodular lymphocyte predominant Hodgkin's lymphoma (L&H cells). EMA is rarely or never found in malignant melanoma (except for the epitheloid variant), germ cell tumours or sex-cord stromal tumours.
Previously, antibodies against EMA were used to recognize epithelial differentiation when cytokeratin was difficult to visualize. With better protocols for cytokeratins and more reliable mAbs against epithelial markers, such as Ber-EP4 and MOC-31, this application is obsolete. In the identification of malignant mesothelioma, the distinct membranous EMA reaction serves to distinguish from adenocarcinomas which frequently show a cytoplasmic reaction. The expression of EMA in renal cell carcinoma may be used to distinguish from adrenal cortical carcinoma. EMA may be used in the identification of meningioma (in combination with vimentin) and ependymoma (ring like staining pattern in contrast to other gliomas). In spindle cell tumours EMA is useful for the identification of perineurioma, solitary fibrous tumour and synovial sarcoma. In the classification of haematolymphoid neoplasms, a positive EMA reaction may be an aid in the identification of diffuse large B-cell lymphoma, plasma cell neoplasms and nodular lymphocyte predominant Hodgkin's lymphoma.
One of the most frequently used mAbs is clone E29, which detects all forms of EMA; irrespective of the degree of glycosylation. HIER in an alkaline buffer is recommended. As control, normal breast tissue is appropriate.
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