Epithelial membrane antigen (EMA, MUC1)

This is one of several glycoproteins found in human milk fat globule membranes (HMFGP). Because HMFGP are packaged in the Golgi apparatus, globular reactivity of the Golgi apparatus may be seen. The glycoprotein identified with EMA is now known to be one of a series of glycoproteins or mucins and is designated MUC1.

It is a high molecular weight transmembrane glycoprotein. It consists of a constant cytoplasmic domain of 69 amino acids and an extracellular domain with variable numbers of 20 amino acid tandem repeats of serine and threonine residues with multiple O-linked oligosaccharide side chains. Most of the multiple antibodies which have been raised react with a dominant epitope within the variable tandem repeats. The extent of glycosylation varies and there are clusters of antibodies which recognise the various glycoforms⁵:

antibody	specificity	commercially available
E29 (anti-EMA)	all forms of MUC1, irrespective of the degree of glycosylation	yes
139H2	all forms of MUC1, irrespective of the degree of glycosylation	no
DF3	all forms of MUC1, except the hyperglycosylated forms in the small intestine, preference for membrane over Golgi MUC1	no
VU-4H5	only if the threonine residue of the tandem repeat is not glycosylated	yes
SM3	only hypoglycosylated MUC1	yes

The over-expression of MUC1 by carcinomas is usually hypoglycosylated and is related to greater tumour aggression⁵. In lymphomas expressing MUC1, glycosylation is normal⁵.

Immunohistochemical expression

Significant immunoreactivity is membranous: purely cytoplasmic staining should be ignored as spurious.

It is expressed by:

• most normal and neoplastic epithelia (usually show cytoplasmic staining) with certain exceptions: gastrointestinal surface epithelium, endocervical epithelium, prostatic acinar epithelium, epididymis, germ cells, hepatocytes, adrenal cortical cells, rete testis, squamous epidermal cells, thyroid follicular epithelium

• plasma cells⁵

• variably by peripheral blood B lymphocytes but only after activation by T cells⁵

• some erythroblasts in hyperplastic marrow, usually weak membrane or Golgi positivity^1,5

• mesotheliomas (said to show membrane staining)

• some mesenchymal tissues: notochord and perineural fibroblasts

• some lymphomas:

  • T cell rich B cell lymphoma¹

  • diffuse large B cell lymphoma¹ and variants

  • 95% of anaplastic large cell lymphomas, whether T or null cell¹

  • monocytoid B cell lymphoma¹

  • about 18% of cases of T cell lymphoma overall¹

  not:

  • hairy cell leukaemia¹

  • primary lymphoma of thyroid¹

• many myelomas

• the Reed-Sternberg cells of nodular lymphocyte predominant Hodgkin's disease, in 60% of cases¹

• large B cell lymphoma arising by transformation of nodular lymphocyte predominant Hodgkin's disease conserve EMA positivity¹

• blastic cells in erytholeukaemia and megakaryoblastic leukaemia¹

• sarcomas:

  • synovial sarcoma

  • epithelioid sarcoma

  • perineuromas and neurothekeomas

  • chordomas and parachordomas

Monoclonal antibodies against human milk fat globule membrane may be more specific to epithelia than polyclonal antibodies.

Diagnostic utility

The diagnostic utility is limited by the wide range of tumours expressing EMA and by the availability of more specific markers of epithelial differentiation.

• Differentiation of mesothelial reaction from mesothelioma: the membranous staining is said to be much stronger in mesothelioma⁴

• Differentiation of mesothelioma from adenocarcinoma: mesotheliomas are said to show cell membrane reactivity, compared with cytoplasmic staining in adenocarcinomas, although others do not find the patterns distinctive enough to be useful⁶.

	adenocarcinoma	mesothelioma
Gaffey 19927	not studied	11/22 (5/12 epithelioid, 6/10 biphasic, positivity noted in epithelioid areas only)
Dejmek 19972	9/43	82/110
Garcia-Prats8	21/23 (mainly cytoplasmic staining)	36/40 (membranous staining)
Brockstedt 20003	18/57	94/115
Comin 20014	2/23	41/42
Ordonez 2003	50/50 (all primary lung adenocarcinomas: 25 case >75% of cells stained, 10 cases 50-75% of cells, 12 cases 25-50% of cells and 3 cases 1-25% of cells. )	56/60 (all epithelioid mesotheliomas: 21 case >75% of cells stained, 19 cases 50-75% of cells, 9 cases 25-50% of cells and 7 cases 1-25% of cells.)
Overall	51% (100/196)	82% (320/389)

• Differentiation of basal cell, squamous cell and basosquamous cell carcinoma of skin

• Differentiation of nodal ALK positive anaplastic large cell lymphoma from other lymphomas

• Identification of ovarian granulosa cell tumours and differentiation from carcinomas (especially endometrioid carcinoma with a sex cord-like pattern)

References

¹Delsol G, New antibodies and new applications of old antibodies in the diagnosis of hematolymphoid neoplasms. In Immunohistochemistry Long Course, Nice 1998.

²Dejmek, A., Brockstedt, U., Hjerpe, A. Optimization of a battery using nine immunocytochemical variables for distinguishing between epithelial mesothelioma and adenocarcinoma. Apmis 1997;105:889-94.

³Brockstedt U, Gulyas M, Dobra K. An optimized batter of eight antibodies that can distinguish most cases of epithelial mesothelioma form adenocarcinoma. Am J Clin Pathol 2000;114:203-9.

⁴Comin, C. E., Novelli, L., Boddi, V., Paglierani, M., Dini, S. Calretinin, thrombomodulin, CEA, and CD15: a useful combination of immunohistochemical markers for differentiating pleural epithelial mesothelioma from peripheral pulmonary adenocarcinoma. Hum Pathol 2001;32:529-536.

Diagnostic Immunohistochemistry edited by Professor D. J. Dabbs, page 63.

⁵ten Berge, R. L., Snijdewint, F. G., von Mensdorff-Pouilly, S. et al. MUC1 (EMA) is preferentially expressed by ALK positive anaplastic large cell lymphoma, in the normally glycosylated or only partly hypoglycosylated form. J Clin Pathol 2001;54:933-939.

⁶Ordonez, N. G. (2003). "The immunohistochemical diagnosis of mesothelioma: a comparative study of epithelioid mesothelioma and lung adenocarcinoma." Am J Surg Pathol 27(8): 1031-51.

⁷Gaffey, M. J., S. E. Mills, et al. (1992). "Immunoreactivity for BER-EP4 in adenocarcinomas, adenomatoid tumors, and malignant mesotheliomas." Am J Surg Pathol 16(6): 593-9.

⁸Garcia-Prats, M. D., C. Ballestin, et al. (1998). "A comparative evaluation of immunohistochemical markers for the differential diagnosis of malignant pleural tumours." Histopathology 32(5): 462-72.

This page last revised 10.9.2003.

©SMUHT/PW Bishop