CEA (CD66e)

Immunohistochemical expression

CEA is an oncofetal glycoprotein. It is expressed by fetal epithelial cells and in small amounts by normal adult epithelial cells and benign tumours.  It is present in large amounts in adenocarcinomas of the gastrointestinal tract (including pancreas), lung and medullary carcinoma of the thyroid.

The rate of immunoreactivity in adenocarcinomas varies with different clones:

		DAKO clone II-7	BioGenex clone THF 3H8-1	E-Z-EM clone D14	NKI, Parlam 1
	Colonic carcinoma	25/2542	25/2542	25/2542	93/9443
	Pulmonary adenocarcinomas	22/3542	32/3542	19/3542
	Breast: ductal carcinoma	30/11942	86/11942	28/11942	43/10743
	Breast: lobular carcinoma	5/1042	7/1042	4/1042
	Gastric carcinomas	29/3942	28/3942	26/3942
	Pancreatic carcinoma	23/2642	24/2642	21/2642
	Ovarian carcinoma	0/2942	6/2942	0/2942	25/8643
	Renal carcinomas	0/4542	3/4542	0/4542

It is also expressed by:

• some myelomas

Diagnostic utility

• Differentiation of mesotheliomas from adenocarcinomas

	adenocarcinoma	mesothelioma
Wang 197912  (absorbed polyclonal antibody)	12/12	0/9
Corson 198215 (polyclonal antibody)	20/20 (all cases stained strongly or moderately)	9/20 (1 case moderate staining, 8 cases weak or equivocal)
Kwee 198216 (absorbed polyclonal antibody)	16/25 (adenocarcinoma metastatic to pleura)	0/37
Whitaker 198217 (absorbed polyclonal antibody)	21/26	0/43
Holden 198418 (polyclonal antibody)	18/18 (staining usually strong)	8/22 (staining usually weak)
Battifora 198519 (polyclonal antibody, Dako)	65/100 (all 24 lung adenocarcinomas positive)	2/12 (2 cases weakly positive)
Gibbs 198520 (polyclonal antibody)	24/27	0/29
Sheibani 198621 (absorbed polyclonal antibody)	38/50	0/28
Sheibani 198621 (monoclonal antibody)	36/50	0/28
Szpak 198622 (polyclonal antibody)	19/20	4/20
Dewar 198723 (monoclonal antibody, Amersham)	15/20 (intrapulmonary adenocarcinomas)	0/12 (epithelioid type)
Otis 198724 (absorbed polyclonal antibody, Dako)	10/14	2/19
Otis 198724 (monoclonal, clone CEA-5)	9/14	6/19
Pflatz 198725 (polyclonal antibody, Dako)	22/22	2/47
Ordonez 198926 (monoclonal, Hybritech clone CEJ065)	21/23 (all lung primaries)	0/19 (all epithelioid type)
O'Hara 199027 (absorbed polyclonal antibody, Dako)	22/28	0/20
Wick 199028 (monoclonal antibody, Hybritech clone CEJ065)	50/52 (peripheral adenocarcinomas of lung with pleural invasion)	0/51 (all epithelioid type)
Wick8 (Hybritech murine monoclonal, catalogue #0062)	28/43 (22/23 peripheral pulmonary adenocarcinomas involving pleura, 1/10 serous surface papillary adenocarcinomas of peritoneum, 5/10 breast carcinomas metastatic to pleura. staining was predominantly membranous)	0/41 (0/21 malignant epithelioid pleural mesotheliomas, 0/20 malignant epithelioid peritoneal mesotheliomas )
Delahaye 199129 (monoclonal antibody, on cytological smears)	3/10	1/24
Wirth 199130 (monoclonal antibody, Zymed)	19/20 (all lung primaries)	0/50
Sheibani 19921	44/83	0/115
Collins 19922	38/48	0/31
Gaffey 199241	not done	0/49 (32 epithelioid, 17 biphasic)
Brown 199331 (monoclonal antibody, Zymed)	100/103 (all lung primaries)	1/34 (all epithelioid type)
Moch 199332 (monoclonal antibody, Amersham)	18/24	0/27
Dejmek 199433 (absorbed polyclonal antibody, Dako)	20/20	13/61
Dejmek 199433 (monoclonal antibody, Dako, clone A5B7)	15/20	0/61
Dejmek 199433 (monoclonal antibody, Boehringer-Mannheim, clone CEJ065)	16/20	7/61
Dejmek 199433(monoclonal antibody, Biogenex, clone SP651)	16/20	1/61
Doglioni 19963 (antibody not stated)	20/22	2/20
Ordonez 19974 (polyclonal antibody, Incstar)	92/107	0/139
Dejmek 199710	29/43	1/110
Bateman 199734 (polyclonal antibody, Dako	10/14	2/17
Bateman 199734 (monoclonal antibody, Dako	10/14 (primary and secondary adenocarcinomas involving pleura)	0/17
Delahaye 199735 (monoclonal antibody, Euro-Diagnostics, clone PARLAM-4, on cytological preparations of pleural fluid)	18/24	0/41
Leers 199813	11/21 ( 11 cases stained > 10% of cells. In addition, 4 cases showed staining of <10% of cells.)	0/20 (2 cases showed staining of <10% of cells.)
Garcia-Prats 199836 (monoclonal antibody, Dako, clone A5B7)	12/18 (10/15 primary pulmonary adenocarcinomas and 2/3 extrapulmonary)	1/40 (0/26 epithelioid, 0/10 sarcomatoid, 1/4 biphasic)
Brockstedt 20005	37/57	2/119
Kayser 20016	112/146 (69/82 lung, 33/47 breast, 2/3 colon, 0/2 kidney, 8/12 site not known)	11/118 (11/99 epithelioid, 0/12 mixed and 0/7 sarcomatoid)
Gonzalez-Lois 20017(monoclonal antibody)	11/15 (metastatic to pleura from various sites)	3/44 (2/33 epithelioid, 1/5 sarcomatoid, 0/1 mixed and 0/1 lymphohistiocytoid mesotheliomas)
Carella 20019 (polyclonal antibody, Dako)	17/20	2/46
Comin 200111 (monoclonal antibody, Novocastra, clone 12.140.10)	22/23 (Staining was strong and evenly distributed throughout the cytoplasm.)	4/42 (The four positive cases showed staining of less than 5% of cells.)
Roberts 200137 (monoclonal antibody, Novocastra, clone 12.140.10)	15/18	1/112
Abutaily 200214 (monoclonal antibody, Dako)	9/11 (35 primary ppulmonary adenocarcinomas were studied but CEA was applied only to the 11 E-cadherin-positive / TTF-1 negative tumours)	1/41 (11 epithelioid, 7 sarcomatoid, and 23 mixed)
Ordonez 200338	44/50 (all primary lung adenocarcinomas: 16 case >75% of cells stained, 17 cases 50-75% of cells, 8 cases 25-50% of cells and 3 cases 1-25% of cells. Staining was cytoplasmic with acentuation along the cell membrane.)	0/60 (all epithelioid mesotheliomas)
Overall	78% (908/1160)	4.4% (56/1283)
Average for polyclonal antibodies, unabsorbed	83% % (299/360)	9% (31/361)
Average for polyclonal antibodies, absorbed	78% (127/163)	7% (15/208)
Average for monoclonal antibodies	82% (432/524)	2.3% (14/607)

A systematic review of fifty one studies (consisting of 1524 pulmonary adenocarcinomas and 1818 epithelioid mesotheliomas) reported sensitivities and specificities for CEA of 83% and 95% respectively. For twenty four studies (consisting of 949 pulmonary adenocarcinomas and 1007 epithelioid mesotheliomas) using monoclonal CEA, the sensitivities and specificities were 81% and 97% respectively⁴⁴.

Although CEA is very useful in the differentation of pulmonary adenocarcinoma from mesothelioma, it is less useful for serous carcinomas of the ovary and peritoneum, less than half of which are positive for CEA^8,39,40.

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

• differentiation of hepatocellular carcinoma from carcinoma metastatic to the liver: canalicular staining with polyclonal CEA is specific for hepatocellular carcinoma.

• differentiation of endocervical from endometrial adenocarcinoma.

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 Collins, C. L., Ordonez, N. G., Schaefer, R., Cook, C. D., Xie, S. S., Granger, J., Hsu, P. L., Fink, L., Hsu, S. M. Thrombomodulin expression in malignant pleural mesothelioma and pulmonary adenocarcinoma. Am J Pathol 1992;141:827-33

³ 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 Pathol1996;20:1037-46

⁴ Ordonez, N. G.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. Am J Surg Pathol 1997;21:1399-408.

⁵ 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.

⁶ K Kayser et al. Glyco- and immunohistochemical refinement of the differential diagnosis between mesothelioma and metastatic carcinoma and survival analysis of patients. J Pathol 2001;193:175-180.

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 Wick MR, Mills SE,Swanson PE Expression of "myelomonocytic" antigens in mesotheliomas and adenocarcinomas involving the serosal surfaces. Am J Clin Pathol 1990; 94:18-26

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

¹⁰ 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.

¹¹ 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.

¹² Wang, N. S., Huang, S. N., Gold, P. Absence of carcinoembryonic antigen-like material in mesothelioma: an immunohistochemical differentiation from other lung cancers. Cancer 1979;44:937-943.

¹³ 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.

¹⁴ 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.

¹⁵ Corson, J. M. and G. S. Pinkus (1982). "Mesothelioma: profile of keratin proteins and carcinoembryonic antigen: an immunoperoxidase study of 20 cases and comparison with pulmonary adenocarcinomas." Am J Pathol 108(1): 80-7.

¹⁶ Kwee, W. S., R. W. Veldhuizen, et al. (1982). "Histologic distinction between malignant mesothelioma, benign pleural lesion and carcinoma metastasis. Evaluation of the application of morphometry combined with histochemistry and immunostaining." Virchows Arch A Pathol Anat Histol 397(3): 287-99.

¹⁷ Whitaker, D., G. F. Sterrett, et al. (1982). "Detection of tissue CEA-like substance as an aid in the differential diagnosis of malignant mesothelioma." Pathology 14(3): 255-8.

¹⁸ Holden, J. and A. Churg (1984). "Immunohistochemical staining for keratin and carcinoembryonic antigen in the diagnosis of malignant mesothelioma." Am J Surg Pathol 8(4): 277-9.

¹⁹ Battifora, H. and M. I. Kopinski (1985). "Distinction of mesothelioma from adenocarcinoma. An immunohistochemical approach." Cancer 55(8): 1679-85.

²⁰ Gibbs, A. R., R. Harach, et al. (1985). "Comparison of tumour markers in malignant mesothelioma and pulmonary adenocarcinoma." Thorax 40(2): 91-5.

²¹ Sheibani, K., H. Battifora, et al. (1986). "Antigenic phenotype of malignant mesotheliomas and pulmonary adenocarcinomas. An immunohistologic analysis demonstrating the value of Leu M1 antigen." Am J Pathol 123(2): 212-9.

²² Szpak, C. A., W. W. Johnston, et al. (1986). "The diagnostic distinction between malignant mesothelioma of the pleura and adenocarcinoma of the lung as defined by a monoclonal antibody (B72.3)." Am J Pathol 122(2): 252-60.

²³ Dewar, A., M. Valente, et al. (1987). "Pleural mesothelioma of epithelial type and pulmonary adenocarcinoma: an ultrastructural and cytochemical comparison." J Pathol 152(4): 309-16.

²⁴ Otis, C. N., D. Carter, et al. (1987). "Immunohistochemical evaluation of pleural mesothelioma and pulmonary adenocarcinoma. A bi-institutional study of 47 cases." Am J Surg Pathol 11(6): 445-56.

²⁵ Pfaltz, M., B. Odermatt, et al. (1987). "Immunohistochemistry in the diagnosis of malignant mesothelioma." Virchows Arch A Pathol Anat Histopathol 411(4): 387-93.

²⁶ Ordonez, N. G. (1989). "The immunohistochemical diagnosis of mesothelioma. Differentiation of mesothelioma and lung adenocarcinoma." Am J Surg Pathol 13(4): 276-91.

²⁷ O'Hara, C. J., J. M. Corson, et al. (1990). "ME1. A monoclonal antibody that distinguishes epithelial-type malignant mesothelioma from pulmonary adenocarcinoma and extrapulmonary malignancies." Am J Pathol 136(2): 421-8.

²⁸ Wick, M. R., T. Loy, et al. (1990). "Malignant epithelioid pleural mesothelioma versus peripheral pulmonary adenocarcinoma: a histochemical, ultrastructural, and immunohistologic study of 103 cases." Hum Pathol 21(7): 759-66.

²⁹ Delahaye, M., H. C. Hoogsteden, et al. (1991). "Immunocytochemistry of malignant mesothelioma: OV632 as a marker of malignant mesothelioma." J Pathol 165(2): 137-43.

³⁰ Wirth, P. R., J. Legier, et al. (1991). "Immunohistochemical evaluation of seven monoclonal antibodies for differentiation of pleural mesothelioma from lung adenocarcinoma." Cancer 67(3): 655-62.

³¹ Brown, R. W., G. M. Clark, et al. (1993). "Multiple-marker immunohistochemical phenotypes distinguishing malignant pleural mesothelioma from pulmonary adenocarcinoma [see comments]." Hum Pathol 24(4): 347-54.

³² 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.

³³ Dejmek, A. and A. Hjerpe (1994). "Carcinoembryonic antigen-like reactivity in malignant mesothelioma. A comparison between different commercially available antibodies." Cancer 73(2): 464-9.

³⁴ Bateman, A. C., R. K. al-Talib, et al. (1997). "Immunohistochemical phenotype of malignant mesothelioma: predictive value of CA125 and HBME-1 expression." Histopathology 30(1): 49-56.

³⁵ 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.

³⁶ 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.

³⁷ 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. (Initial publication of data as abstract ⁸Harper CM. Evaluation of a commercially available immunohistochemical diagnostic panel for malignant mesothelioma. J Pathol 2001:193(suppl):39^A.)

³⁸ 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.

³⁹ Ordonez, N. G. (1998). "Role of immunohistochemistry in distinguishing epithelial peritoneal mesotheliomas from peritoneal and ovarian serous carcinomas." Am J Surg Pathol 22(10): 1203-14.

⁴⁰ Riera, J. R., C. Astengo-Osuna, et al. (1997). "The immunohistochemical diagnostic panel for epithelial mesothelioma: a reevaluation after heat-induced epitope retrieval [see comments]." Am J Surg Pathol 21(12): 1409-19.

⁴¹ 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.

⁴² Kaufmann, O., T. Deidesheimer, et al. (1996). "Immunohistochemical differentiation of metastatic breast carcinomas from metastatic adenocarcinomas of other common primary sites." Histopathology 29(3): 233-40.

⁴³ Lagendijk, J. H., H. Mullink, et al. (1999). "Immunohistochemical differentiation between primary adenocarcinomas of the ovary and ovarian metastases of colonic and breast origin. Comparison between a statistical and an intuitive approach." J Clin Pathol 52(4): 283-90.

⁴⁴ King 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.

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