Epithelial membrane antigen (EMA, MUC1)

This is one of several glycoproteins9 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:

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 cells5,10

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

• some erythroblasts in hyperplastic marrow, usually weak membrane or Golgi positivity1,5

• mesotheliomas (said to show membrane staining)

• some mesenchymal tissues: notochord and perineural fibroblasts

• some lymphomas:

  • T cell rich B cell lymphoma14,15

  • diffuse large B cell lymphoma1 and variants

  • 95% of anaplastic large cell lymphomas, whether T or null cell1,12

  • monocytoid B cell lymphoma1

  • about 18% of cases of T cell lymphoma overall1

  not:

  • hairy cell leukaemia1

  • primary lymphoma of thyroid1

• many myelomas10,11

• the Reed-Sternberg cells of nodular lymphocyte predominant Hodgkin's disease, in 60% of cases1,10,13

• 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.

• 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

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

2 Dejmek, 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.

3 Brockstedt 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.

4 Comin, 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.

5 ten 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.

6 Ordonez, 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.

7 Gaffey, 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.

8 Garcia-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.

9 Swallow DM, Gendler S, Griffiths B, et al. The hypervariable gene locus PUM, which codes for the tumour associated epithelial mucins, is located on chromosome 1, within the region 1q21-24. Ann Hum Genet 1987; 51:289-94

10 Delsol G, Gatter KC, Stein H, et al. Human lymphoid cells express epithelial membrane antigen. Implications for diagnosis of human neoplasms. Lancet 1984; 2:1124-9

11 Pileri S, Poggi S, Baglioni P, et al. Histology and immunohistology of bone marrow biopsy in multiple myeloma. Eur J Haematol Suppl 1989; 51:52-9

12 Benharroch D, Meguerian-Bedoyan Z, Lamant L, et al. ALK-positive lymphoma: a single disease with a broad spectrum of morphology. Blood 1998; 91:2076-84.

13 Anagnostopoulos I, Hansmann ML, Franssila K, et al. European Task Force on Lymphoma project on lymphocyte predominance Hodgkin disease: histologic and immunohistologic analysis of submitted cases reveals 2 types of Hodgkin disease with a nodular growth pattern and abundant lymphocytes. Blood 2000; 96:1889-99 FULL TEXT

14 Fraga M, Sanchez-Verde L, Forteza J, et al. T-cell/histiocyte-rich large B-cell lymphoma is a disseminated aggressive neoplasm: differential diagnosis from Hodgkin's lymphoma. Histopathology 2002; 41:216-29

15 Lim MS, Beaty M, Sorbara L, et al. T-cell/histiocyte-rich large B-cell lymphoma: a heterogeneous entity with derivation from germinal center B cells. Am J Surg Pathol 2002; 26:1458-66

This page last revised 3.11.2006.

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