Ber-EP4

The Ber-EP4 antibody was generated using a membrane-enriched fraction derived from the MDF-7 breast cancer cell line. It reacts with an epitope present on two glycoproteins (of 30 and 34 kD respectively)³⁶.

Immunohistochemical expression

Present on all epithelial cells, except the superficial layers of squamous epithelium, hepatocytes and parietal cells.

Distal tubules of normal kidney³⁷
DSRCT
It is not usually expressed by mesotheliomas.

Diagnostic utility

Differentiation of mesothelioma from adenocarcinoma. The percentage of mesotheliomas expressing Ber-EP4 varies rather widely. This is in part because some authors count any single cell immunoreactivity as constituting positivity, while others set a cut-off. Some regard only basolateral membrane staining as true positivity. For example, Carella recommends a cut off level of at least 2% of cells stained, as well as the restrictive definition of "lateral membrane staining"⁹. While Ber-EP4 stains a high proportion of pulmonary adenocarcinomas, the rate of positivity is lower in non-pulmonary adenocarcinomas, falling to 35-50% for renal cell carcinomas.

adenocarcinoma

mesothelioma

Latza 1990¹¹

40/49 (various sites of origin)

0/2

Kuhlmann 1991¹⁶ (study done on cell blocks prepared from serous fluid)

18/20 (various sites of origin)

3/20

Sheibani 1992¹

72/83

1/115 (all histological types)

Gaffy 1992¹²

103/120 (various sites of origin. staining was membranous; diffuse in 82 and focal in 21 cases)

10/49 (6/32 epithelioid and 4/17 biphasic: staining was restricted to the epithelioid areas and was generally focal; in one epithelioid case, there was positivity of the majority of tumour cells)

Moch 1993¹⁷

34/34 (pulmonary adenocarcinomas)

2/27 (all histological types; staining was focal in 2 cases)

Dejmek 1994¹⁸

28/42 (various sites of origin)

14/93

Grove 1994¹⁹

16/19 (various sites of origin)

8/39 (epithelioid or biphasic types)

Maguire 1994²⁰ (study done on cell blocks prepared from serous fluid)

45/63 (13/23 pulmonary adenocarcinomas and 32/40 variously from breast, gastrointestinal tract, ovary, endometrium, and kidney)

2/44

Shield 1994²¹ (study done on cell blocks prepared from serous fluid)

33/102 (various sites of origin)

0/6

Ascoli 1995²² (study done on cell blocks prepared from serous fluid)

145/152 (various sites of origin)

0/33

Atanoos 1995²³

7/20 (renal cell carcinomas)

1/20

Doglioni 1996¹³

22/22 (these were pulmonary adenocarcinomas: all showed staining of more than 50% of cells.)

2/20 (two cases weakly positive.)

Bailey 1996²⁴ (study done on cell blocks prepared from serous fluid)

11/11 (pulmonary adenocarcinomas: all showed intense membrane staining)

0/5

Kuenen-Boumeester 1996²⁵ (study done on cell blocks prepared from serous fluid)

56/56 (various sites of origin)

7/8 (variable membranous staining)

Bateman 1997²

9/14 (primary and secondary adenocarcinomas within lung and pleura.)

1/17

Dejmek 1997³

28/43

14/110

Riera 1997⁴

135/211 (various sites of origin)

0/57 (all of epithelioid type)

Delahaye 1997²⁶ (study done on cell blocks prepared from serous fluid)

69/88 (various sites of origin)

1/41

Ordonez 1997²⁷

38/38 (pulmonary adenocarcinomas)

9/50

Wilson 1997²⁸

9/9 (lung and ovarian carcinomas)

4/21

Chenard-Neu 1998⁵

30/30 (various sites of origin)

4/28

Leers 1998¹⁴

19/21 (various sites of origin. 17 cases showing staining of >10% of cells, 2 cases showed staining of <10% of cells.)

7/20 ( 4 cases showing staining of >10% of cells, 3 cases showed staining of <10% of cells.)

Garcia-Prats 1998²⁹

16/18 (13/15 pulmonary and 3/3 extrapulmonary)

1/40 (0/26 epithelioid, 0/10 sarcomatoid, 1/4 biphasic)

Ordonez 1998³⁰

101/110 (20/20 pulmonary adenocarcinomas {staining diffuse], 55/59 non-pulmonary adenocarcinomas [variable extent of staining] and 26/31 adenocarcinomas of unknown origin [variable extend of staining]: all were metastatic to pleura)

18/70 (all epithelial pleural mesotheliomas: restricted to a limited number of cells)

Brockstedt 2000⁶

40/57

19/119

Dejmek 2000³¹ (study done on cell blocks prepared from serous fluid)

51/53 (various sites of origin)

6/36

Gonzalez-Lois 2001⁷

11/13 (various sites of origin)

6/44 (6/34 epithelioid, 0/6 sarcomatoid, 0/1 mixed and 0/1 lymphohistiocytoid mesotheliomas)

Harper 2001⁸

12/18

5/112

Carella 2001⁹

20/20 (pulmonary adenocarcinomas)

4/46

Comin 2001¹⁰

22/23 (in 17 cases, staining was >75% of cells, in 5 cases 50-75% of cells.)

5/42 (staining was always less than 25% of cells.)

Davidson 2001³² (study done on cell blocks prepared from serous fluid)

94/98 (various sites of origin)

4/12

Miettinen 2001³³

not studied

3/30 (3/23 epithelioid and 0/7 sarcomatoid mesotheliomas)

Abutaily 2002¹⁵

10/11

2/9

Ordonez 2003³⁴

50/50 (all primary lung adenocarcinomas: 37 case >75% of cells stained, 13 cases 50-75% of cells, . Staining was both cytoplasmic and membranous. Well-differentiated cases tend to show preferential staining of the basolateral membrane with negativity of the apical membrane.)

11/60 (epithelioid mesotheliomas: in 9 cases 1-25% of cells stained, in 2 cases <1% of cells stained)

Overall

80% (1394/1750)

12% (174/1445)

A systematic review of seventeen studies (consisting of 702 pulmonary adenocarcinomas and 899 epithelioid mesotheliomas) reported sensitivities and specificities of BerEP4 for pulmonary adenocarcinoma of 80% and 90%³⁸.

Differentiation of reactive mesothelial cells (negative) from carcinoma (positive) in effusions.

Differentiation of basal cell, squamous cell and basosquamous cell carcinoma of skin
Differentiation of hepatocellular carcinoma from cholangiocarcinoma and metastatic adenocarcinoma.
Often positive in papillary renal cell carcinoma but usually negative in clear cell renal cell carcinoma. For this differential use in combination with renal cell carcinoma carcinoma marker (more often positive in papillary renal cell carcinoma) and CD10 (more often positive in clear carcinoma)³⁷.

References

¹ Sheibani K, Esteban JM, Bailey A, Batifora H, Weiss I. Immunologic and molecular studies as an aid to the diagnosis or malignant mesothelioma. Human Pathology 1992; 23: 107-116.

² Bateman, A. C., al-Talib, R. K., Newman, T., Williams, J. H., Herbert, A. Immunohistochemical phenotype of malignant mesothelioma: predictive value of CA125 and HBME-1 expression. Histopathology 1997;30:49-56.

³ 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.

⁴ Riera, J. R. Astengo-Osuna, C. Longmate, J. A. Battifora, H. The immunohistochemical diagnostic panel for epithelial mesothelioma: a reevaluation after heat-induced epitope retrieval. Am J Surg Path 1997;21:1409-19.

⁵ Chenard-Neu, M. P., Kabou, A., Mechine, A., et al. [Immunohistochemistry in the differential diagnosis of mesothelioma and adenocarcinoma. Evaluation of 5 new antibodies and 6 traditional antibodies.] Ann Pathol 1998;18:460-5. [French]

⁶ Brockstedt U, Gulyas M, Dobra K. An optimized battery of eight antibodies that can distinguish most cases of epithelial mesothelioma from adenocarcinoma. Am J Clin Pathol 2000;114:203-9.

⁷ Gonzalez-Lois, C., Ballestin, C., Sotelo, M. T., Lopez-Rios, F., Garcia-Prats, M. D., Villena, V. Combined use of novel epithelial (MOC-31) and mesothelial (HBME-1) immunohistochemical markers for optimal first line diagnostic distinction between mesothelioma and metastatic carcinoma in pleura. Histopathology 2001;38:528-34.

⁸ Roberts, F., C. M. Harper, et al. (2001). "Immunohistochemical analysis still has a limited role in the diagnosis of malignant mesothelioma. A study of thirteen antibodies." Am J Clin Pathol 116(2): 253-62. Initially published in abstract as Harper CM. Evaluation of a commercially available immunohistochemical diagnostic panel for malignant mesothelioma. J Pathol 2001:193(suppl):39^A.

⁹ Carella R et al. Immunohistochemical panels for differentiating epithelial malignant mesothelioma from lung adenocarcinoma. Am J Surg Pathol 2001;25:43-50.

¹⁰Comin, 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.

¹¹ Latza, U., Niedobitek, G., Schwarting, R., Nekarda, H., Stein, H. Ber-EP4: new monoclonal antibody which distinguishes epithelia from mesothelial. J Clin Pathol 1990;42:213-219.

¹² Gaffey, M. J., Mills, S. E., Swanson, P. E., Zarbo, R. J., Shah, A. R., Wick, M. R. Immunoreactivity for BER-EP4 in adenocarcinomas, adenomatoid tumors, and malignant mesotheliomas Am J Surg Pathol 1992;16:593-599

¹³ Doglioni, C., Tos, A. P., Laurino, L., Iuzzolino, P., Chiarelli, C., Celio, M. R., Viale, G. Calretinin: a novel immunocytochemical marker for mesothelioma. Am J Surg Pathol 1996;20:1037-46.

¹⁴ Leers, M. P., Aarts, M. M., Theunissen, P. H. E-cadherin and calretinin: a useful combination of immunochemical markers for differentiation between mesothelioma and metastatic adenocarcinoma. Histopathology 1998;32:209-216.

¹⁵ Abutaily, A.S., Addis, B.J. and Roche, W.R. Immunohistochemistry in the distinction between malignant mesothelioma and pulmonary adenocarcinoma: a critical evaluation of new antibodies. J Clin Pathol 2002;55:662-8.

¹⁶ Kuhlmann, L., K. H. Berghauser, et al. (1991). "Distinction of mesothelioma from carcinoma in pleural effusions. An immunocytochemical study on routinely processed cytoblock preparations." Pathol Res Pract 187(4): 467-71.

¹⁷ Moch, H., M. Oberholzer, et al. (1993). "Diagnostic tools for differentiating between pleural mesothelioma and lung adenocarcinoma in paraffin embedded tissue. Part I: Immunohistochemical findings." Virchows Arch A Pathol Anat Histopathol 423(1): 19-27.

¹⁸ Dejmek, A. and A. Hjerpe (1994). "Immunohistochemical reactivity in mesothelioma and adenocarcinoma: a stepwise logistic regression analysis." Apmis 102(4): 255-64.

¹⁹ Grove, A., S. M. Paulsen, et al. (1994). "The value of immunohistochemistry of pleural biopsy specimens in the differential diagnosis between malignant mesothelioma and metastatic carcinoma." Pathol Res Pract 190(11): 1044-55.

²⁰ Maguire, B., D. Whitaker, et al. (1994). "Monoclonal antibody Ber-EP4: its use in the differential diagnosis of malignant mesothelioma and carcinoma in cell blocks of malignant effusions and FNA specimens." Diagn Cytopathol 10(2): 130-4.

²¹ Shield, P. W., J. J. Callan, et al. (1994). "Markers for metastatic adenocarcinoma in serous effusion specimens." Diagn Cytopathol 11(3): 237-45.

²² Ascoli, V., C. C. Scalzo, et al. (1995). "The diagnostic value of thrombomodulin immunolocalization in serous effusions." Arch Pathol Lab Med 119(12): 1136-40.

²³ Attanoos, R. L., H. Goddard, et al. (1995). "A comparative immunohistochemical study of malignant mesothelioma and renal cell carcinoma: the diagnostic utility of Leu-M1, Ber EP4, Tamm- Horsfall protein and thrombomodulin." Histopathology 27(4): 361-6.

²⁴ Bailey, M. E., R. W. Brown, et al. (1996). "Ber-EP4 for differentiating adenocarcinoma from reactive and neoplastic mesothelial cells in serous effusions. Comparison with carcinoembryonic antigen, B72.3 and Leu-M1." Acta Cytol 40(6): 1212-6.

²⁵ Kuenen-Boumeester, V., P. van Loenen, et al. (1996). "Quality control of immunocytochemical staining of effusions using a standardized method of cell processing." Acta Cytol 40(3): 475-9.

²⁶ Delahaye, M., F. van der Ham, et al. (1997). "Complementary value of five carcinoma markers for the diagnosis of malignant mesothelioma, adenocarcinoma metastasis, and reactive mesothelium in serous effusions." Diagn Cytopathol 17(2): 115-20.

²⁷ Ordonez, N. G. (1997). "The value of antibodies 44-3A6, SM3, HBME-1, and thrombomodulin in differentiating epithelial pleural mesothelioma from lung adenocarcinoma: a comparative study with other commonly used antibodies [see comments]." Am J Surg Pathol 21(12): 1399-408.

²⁸ Wilson JD, Merino MJ, Harris C et al. Mesothelioma vs adenocarcinoma: does immunohistochemistry help? Lab Invest 1997;76:174A.

²⁹ 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.

³⁰ Ordonez, N. G. (1998). "Value of the Ber-EP4 antibody in differentiating epithelial pleural mesothelioma from adenocarcinoma. The M.D. Anderson experience and a critical review of the literature." Am J Clin Pathol 109(1): 85-9.

³¹ Dejmek, A. and A. Hjerpe (2000). "Reactivity of six antibodies in effusions of mesothelioma, adenocarcinoma and mesotheliosis: stepwise logistic regression analysis." Cytopathology 11(1): 8-17.

³² Davidson, B., S. Nielsen, et al. (2001). "The role of desmin and N-cadherin in effusion cytology: a comparative study using established markers of mesothelial and epithelial cells." Am J Surg Pathol 25(11): 1405-12.

³³ Miettinen, M., J. Limon, et al. (2001). "Calretinin and other mesothelioma markers in synovial sarcoma: analysis of antigenic similarities and differences with malignant mesothelioma." Am J Surg Pathol 25(5): 610-7.

³⁴ 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.

³⁵ Miettinen, M., J. Limon, et al. (2001). "Calretinin and other mesothelioma markers in synovial sarcoma: analysis of antigenic similarities and differences with malignant mesothelioma." Am J Surg Pathol 25(5): 610-7.

³⁶ Ordonez, N. G. (1998). "Desmoplastic small round cell tumor: II: an ultrastructural and immunohistochemical study with emphasis on new immunohistochemical markers." Am J Surg Pathol 22(11): 1314-27.

³⁷ Pan, C. C., P. C. Chen, et al. (2004). "The diagnostic utility of MOC31, BerEP4, RCC marker and CD10 in the classification of renal cell carcinoma and renal oncocytoma: an immunohistochemical analysis of 328 cases." Histopathology 45(5): 452-9.

³⁸King JE, Thatcher N, Pickering CA, et al. Sensitivity and specificity of immunohistochemical markers used in the diagnosis of epithelioid mesothelioma: a detailed systematic analysis using published data. Histopathology 2006; 48:223-32

This page last revised 16.2.2006.

	adenocarcinoma	mesothelioma
Latza 1990¹¹	40/49 (various sites of origin)	0/2
Kuhlmann 1991¹⁶ (study done on cell blocks prepared from serous fluid)	18/20 (various sites of origin)	3/20
Sheibani 1992¹	72/83	1/115 (all histological types)
Gaffy 1992¹²	103/120 (various sites of origin. staining was membranous; diffuse in 82 and focal in 21 cases)	10/49 (6/32 epithelioid and 4/17 biphasic: staining was restricted to the epithelioid areas and was generally focal; in one epithelioid case, there was positivity of the majority of tumour cells)
Moch 1993¹⁷	34/34 (pulmonary adenocarcinomas)	2/27 (all histological types; staining was focal in 2 cases)
Dejmek 1994¹⁸	28/42 (various sites of origin)	14/93
Grove 1994¹⁹	16/19 (various sites of origin)	8/39 (epithelioid or biphasic types)
Maguire 1994²⁰ (study done on cell blocks prepared from serous fluid)	45/63 (13/23 pulmonary adenocarcinomas and 32/40 variously from breast, gastrointestinal tract, ovary, endometrium, and kidney)	2/44
Shield 1994²¹ (study done on cell blocks prepared from serous fluid)	33/102 (various sites of origin)	0/6
Ascoli 1995²² (study done on cell blocks prepared from serous fluid)	145/152 (various sites of origin)	0/33
Atanoos 1995²³	7/20 (renal cell carcinomas)	1/20
Doglioni 1996¹³	22/22 (these were pulmonary adenocarcinomas: all showed staining of more than 50% of cells.)	2/20 (two cases weakly positive.)
Bailey 1996²⁴ (study done on cell blocks prepared from serous fluid)	11/11 (pulmonary adenocarcinomas: all showed intense membrane staining)	0/5
Kuenen-Boumeester 1996²⁵ (study done on cell blocks prepared from serous fluid)	56/56 (various sites of origin)	7/8 (variable membranous staining)
Bateman 1997²	9/14 (primary and secondary adenocarcinomas within lung and pleura.)	1/17
Dejmek 1997³	28/43	14/110
Riera 1997⁴	135/211 (various sites of origin)	0/57 (all of epithelioid type)
Delahaye 1997²⁶ (study done on cell blocks prepared from serous fluid)	69/88 (various sites of origin)	1/41
Ordonez 1997²⁷	38/38 (pulmonary adenocarcinomas)	9/50
Wilson 1997²⁸	9/9 (lung and ovarian carcinomas)	4/21
Chenard-Neu 1998⁵	30/30 (various sites of origin)	4/28
Leers 1998¹⁴	19/21 (various sites of origin. 17 cases showing staining of >10% of cells, 2 cases showed staining of <10% of cells.)	7/20 ( 4 cases showing staining of >10% of cells, 3 cases showed staining of <10% of cells.)
Garcia-Prats 1998²⁹	16/18 (13/15 pulmonary and 3/3 extrapulmonary)	1/40 (0/26 epithelioid, 0/10 sarcomatoid, 1/4 biphasic)
Ordonez 1998³⁰	101/110 (20/20 pulmonary adenocarcinomas {staining diffuse], 55/59 non-pulmonary adenocarcinomas [variable extent of staining] and 26/31 adenocarcinomas of unknown origin [variable extend of staining]: all were metastatic to pleura)	18/70 (all epithelial pleural mesotheliomas: restricted to a limited number of cells)
Brockstedt 2000⁶	40/57	19/119
Dejmek 2000³¹ (study done on cell blocks prepared from serous fluid)	51/53 (various sites of origin)	6/36
Gonzalez-Lois 2001⁷	11/13 (various sites of origin)	6/44 (6/34 epithelioid, 0/6 sarcomatoid, 0/1 mixed and 0/1 lymphohistiocytoid mesotheliomas)
Harper 2001⁸	12/18	5/112
Carella 2001⁹	20/20 (pulmonary adenocarcinomas)	4/46
Comin 2001¹⁰	22/23 (in 17 cases, staining was >75% of cells, in 5 cases 50-75% of cells.)	5/42 (staining was always less than 25% of cells.)
Davidson 2001³² (study done on cell blocks prepared from serous fluid)	94/98 (various sites of origin)	4/12
Miettinen 2001³³	not studied	3/30 (3/23 epithelioid and 0/7 sarcomatoid mesotheliomas)
Abutaily 2002¹⁵	10/11	2/9
Ordonez 2003³⁴	50/50 (all primary lung adenocarcinomas: 37 case >75% of cells stained, 13 cases 50-75% of cells, . Staining was both cytoplasmic and membranous. Well-differentiated cases tend to show preferential staining of the basolateral membrane with negativity of the apical membrane.)	11/60 (epithelioid mesotheliomas: in 9 cases 1-25% of cells stained, in 2 cases <1% of cells stained)
Overall	80% (1394/1750)	12% (174/1445)