Thrombomodulin (CD141)

This 75 kD glycoprotein converts thrombin from a procoagulant protease to an anticoagulant. It was originally thought to be useful as a vascular marker but lacks specificity for endothelium

Immunohistochemical expression

• mesothelium and less frequently in some adenocarcinomas¹⁹. The results are rather variable in different studies:

	conclusion regarding usefulness	adenocarcinoma	mesothelioma
Fink 199220	yes	1/15	8/8
Collins 19922	yes	4/48 (All cases were pulmonary adenocarcinomas.)	31/31
Brown 19933	no	62/103 (All cases were pulmonary adenocarcinomas.)	20/34 (all cases were epithelial pleural mesotheliomas.)
Ascoli 1995 (study done on cytospin preparations and cell blocks)4	yes	44/119 (Various sites of origin. Positivity was cytoplasmic. Also, all of the squamous carcinomas were positive.)	33/33 (There was thick membrane positivity.)
Attanoos 19955		1/20 (All cases were renal carcinomas.)	11/20 (10/14 epithelial mesotheliomas were positive)
Attanoos 19966	yes	2/32 (All cases were pulmonary primary adenocarcinomas.)	22/42 (including positivity in 8/12 pure epithelial-type mesotheliomas of the pleura and in all 4 papillary epithelial peritoneal mesotheliomas.)
Doglioni 19967	no	17/22 (All cases were pulmonary primary adenocarcinomas.)	16/20
Dejmek 19978		10/43	69/110
Kennedy 19979	yes	8/63 (6/23 cases of carcinoma metastatic to pleura from various sites[2 strong, 5-70% of cells and 2 strong, <5% of cells], 1/20 primary ovarian cell carcinomas, and 1/20 primary renal cell carcinomas [strong, >70% of cells]. )	49/57 (All cases were pleural mesotheliomas, 47 epithelioid and 10 sarcomatoid. The sarcomatoid cases were mostly negative)
Ordonez 199710	yes	7/46 (All cases were pulmonary adenocarcinomas: 3 cases 50-75% of cells, 2 cases 1-25% of cells, 2 cases trace only)	32/42 (28/35 epithelioid, 3/4 biphasic, 1/3 sarcomatoid. 4 cases > 75% of cells, 8 cases 50-75% of cells, 10 cases 25-50% of cells, 6 cases 1-25% of cells)
Riera 199711	no	13/211 (adenocarcinomas of various origins)	28/57 (cases were epitheloid mesotheliomas.)
Ordonez 199812	yes	1/45 (30 ovarian (10 primary and 20 metastatic to the peritoneum) and 15 primary papillary serous carcinomas of the peritoneum)	26/35 (All epithelial peritoneal mesotheliomas.)
Chenard-Neu 199813	no	4/30 (adenocarcinomas of various origins)	12/28 (various histological types)
Fetsch 1998 (This study was of malignant effusions.)14	no	21/40 (8/13 breast, 2/6 ovarian, 1/4 prostatic, 4/8 lung and 6/9 gastrointestinal adenocarcinomas were positive.)	24/36
Cury 200015	yes	12/63 (lung = 19; breast = 21; ovary = 6; colon = 10; kidney = 4; uterus, epididymis, pancreas = 1 case each)	55/61
Brockstedt 200016	yes	13/57 (adenocarcinomas of various origins)	74/119
Roberts 200026	no	2/18 (adenocarcinomas of various origins)	25/82
Carella 200117	yes	1/20 (All cases were pulmonary adenocarcinomas)	29/46 (various histological types)
Harper 2001 (Note that this is not a peer-reviewed paper.)18		2/18	32/112
Comin 200121	yes	5/23 (All cases were pulmonary adenocarcinomas)	39/42
Foster 200125	no	4/51 (All cases were pulmonary adenocarcinomas: in the 4 positive cases, staining was less than 50%, weak to intermediate)	23/67 (various histological types: only 8 cases showed more than 50% staining)
Miettinen 200323		not studied	25/28 (20/21 epithelioid [embrane staining], 5/7 sarcomatoid)
Miettinen 200323		32/256	16/27 (9 of 10 tubulopapillary, 4 of 5 combined tubulopapillary and poorly differentiated and 3 of 12 poorly differentiated solid epithelial tumours)
Abutaily 2002 24		2/35 (All cases were pulmonary adenocarcinomas. Cell membrane staining)	22/41 (cell membrane staining)
Ordonez 200327	no	7/50 (All cases were pulmonary adenocarcinomas. 5 cases showed positivty of 1-25% of cells and 2 cases <1% of cells)	46/60 (epithelioid mesotheliomas: in 3 cases >75% of cells stained, in 16 cases 50-75% of cells stained), in 16 cases 25-50% of cells stained, in 10 cases 1-25% of cells stained)
Overall	Limited	19% (273/1428)	62% (767/1238)

A systematic review of sixteen studies (consisting of 831 epithelioid mesotheliomas and 964 pulmonary adenocarcinomas) reported sensitivities and specificities of thrombomodulin for epithelioid mesothelioma of 61% and 80%²⁹.

Staining is membranous in mesotheliomas but, in those adenocarcinomas which stain, there is additional cytoplasmic staining²¹. Granular cytoplasmic staining in mesothelioma may be a manifestation of absorption and may be seen in association with degneration and necrosis²⁷.

Most studies compare mesothelioma with pulmonary adenocarcinoma. There are relatively few studies breaking down pulmonary adenocarcinomas by subtype, or of other types of pulmonary tumour. Common positivity limits the value of thrombomodulin in separating carcinomas other than adenocarcinoma from mesotheliomas.

adenocarcinoma	acinar type, differentiated	19/148 (17 cases showed more than 10% of tumour cells positive, 2 cases showed less than 10% of tumour cells positive.) 23
	acinar type, solid, poorly-differentiated, mucin-positive	7/49 (7 cases showed more than 10% of tumour cells positive.)  23
	bronchoalveolar, mucinous	1/6 (1 case showed more than 10% of tumour cells positive.) 23
	bronchoalveolar, non-mucinous	1/7 (1 case showed more than 10% of tumour cells positive.) 23
	acinar with focal neuroendocrine differentiation	0/22 23
	neuroendocrine	3/18 (3 cases showed more than 10% of tumour cells positive.) 23
	clear cell	1/6 (1 case showed more than 10% of tumour cells positive.) 23
large cell	NOS	29/117 (26 cases showed more than 10% of tumour cells positive, 3 cases showed less than 10% of tumour cells positive.) 23
	with focal neuroendocrine differentiation	3/10 (2 cases showed more than 10% of tumour cells positive, 1 cases showed less than 10% of tumour cells positive.) 23
	neuroendocrine carcinoma	6/33 (5 cases showed more than 10% of tumour cells positive, 1 cases showed less than 10% of tumour cells positive.) 23
small cell carcinoma		11/41 (4 cases showed more than 10% of tumour cells positive, 7 cases showed less than 10% of tumour cells positive.) 23
squamous cell	keratinising	62/62 (61 cases showed more than 10% of tumour cells positive: staining was typically extensive with membrane accentuation, 1 cases showed less than 10% of tumour cells positive.) 23
	non-keratinising	54/62 (47 cases showed more than 10% of tumour cells positive, 7 cases showed less than 10% of tumour cells positive.) 23
	NOS	33/331
sarcomatoid carcinoma, spindle cell		1/6 (1 case showed less than 10% of tumour cells positive.) 23
giant cell carcinoma		3/6 (2 cases showed more than 10% of tumour cells positive, 1 cases showed less than 10% of tumour cells positive.) 23

Most studies have been of mesothelioma versus primary pulmonary adenocarcinoma. Some metastatic carcinomas, such as renal cell carcinoma, pose particular problems.

• endothelium

• some squamous cells and some (acantholytic) squamous cell carcinomas¹⁹

• synovium

• mesangial cells

• syncytiotrophoblast and trophoblastic tumours¹⁹

• megakaryocytes

• osteoblasts²²

Diagnostic utility

• differentiation of mesothelioma from adenocarcinoma: vide supra.

• identification of vascular tumours, noting that immunoreactivity also occurs in some adenocarcinomas and mesotheliomas:

  • 100% of benign vascular tumours (pyogenic granuloma and haemangioma)

  • 95% of benign lymphatic lesions (lymphangioma and lymphangectasia)

  • 94% of malignant vascular tumours (angiosarcoma, epithelioid haemangioendothelioma and Kaposi's sarcoma)

• identification of choriocarcinomas.

References

¹ Tolnay, E., Wiethege, T., Muller, K. M. Expression and localization of thrombomodulin in preneoplastic bronchial lesions and in lung cancer. Virchows Arch 1997;430:209-12.

² Collins, C. L., Ordonez, N., Schaefer, R. Thrombomodulin expression in malignant pleural mesothelioma and pulmonary adenocarcinoma. Am J Pathol 1992;141:827-33.

³ Brown, R. W., Clark, G. M., Tandon, A. K., Allred, D. C. Multiple-marker immunohistochemical phenotypes distinguishing malignant pleural mesothelioma from pulmonary adenocarcinoma. Hum Pathol 1993;24:347-54.

⁴ Ascoli, V., Scalzo, C. C., Taccogna, S., Nardi, F. The diagnostic value of thrombomodulin immunolocalization in serous effusions. Arch Pathol Lab Med 1995; 119:1136-40.

⁵ Attanoos, R. L., Goddard, H., Thomas, et al. 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 1995;27:361-6.

⁶ Attanoos, R. L., Goddard, H., Gibbs, A. R. Mesothelioma-binding antibodies: thrombomodulin, OV 632 and HBME-1 and their use in the diagnosis of malignant mesothelioma. Histopathology 1996;29:209-15.

⁷ 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.

⁸ 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.

⁹ Kennedy, A. D., King, G., Kerr, K. M. HBME-1 and antithrombomodulin in the differential diagnosis of malignant mesothelioma of pleura. J Clin Pathol 1997;50:859-62.

¹⁰ Ordonez, N. G. Value of thrombomodulin immunostaining in the diagnosis of mesothelioma. Histopathology 1997;31:25-30.

¹¹ 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.

¹² Ordonez, N. G. Role of immunohistochemistry in distinguishing epithelial peritoneal mesotheliomas from peritoneal and ovarian serous carcinomas. Am J Surg Pathol 1998;22:1203-14.

¹³ 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.

¹⁴ Fetsch, P. A., Abati, A., Hijazi, Y. M. Utility of the antibodies CA 19-9, HBME-1, and thrombomodulin in the diagnosis of malignant mesothelioma and adenocarcinoma in cytology. Cancer 1998;84:101-8.

¹⁵ Cury, P. M., Butcher, D. N., Fisher, C. Value of the mesothelium-associated antibodies thrombomodulin, cytokeratin 5/6, calretinin, and CD44H in distinguishing epithelioid pleural mesothelioma from adenocarcinoma. Mod Pathol 2000;13:107-12.

¹⁶ Brockstedt U, Gulyas M, Dobra K. An optimized batter of eight antibodies that can distingusih most cases of epithelial mesothelioma from adenocarcinoma. Am J Clin Pathol 2000;114:203-9

¹⁷ Carella R et al. Immunohistochemical panels for differentiating epithelial malignant mesothelioma from lung adenocarcinoma. Am J Surg Pathol 2001;25:43-50.

¹⁸ Harper CM. Evaluation of a commercially available immunohistochemical diagnostic panel for malignant mesothelioma. J Pathol 2001:193(suppl):39^A.

¹⁹ Nicholson, S. A., McDermott, M. B., DeYoung, B. R., Swanson, P. E. CD31 immunoreactivity in small round cell tumors. Appl Immunohistochem Molecul Morphol 2000;8:19-24.

²⁰ Fink. Lab Invest 1992;66:113A

²¹ 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.

²² Diagnostic Immunohistochemistry edited by Professor D. J. Dabbs, page 71

²³ Miettinen, M. and Sarlomo-Rikala, M. Expression of calretinin, thrombomodulin, keratin 5, and mesothelin in lung carcinomas of different types: an immunohistochemical analysis of 596 tumors in comparison with epithelioid mesotheliomas of the pleura. Am J Surg Pathol 2003;27:150-8.

²⁴ 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.

²⁵ Foster, M. R., J. E. Johnson, et al. (2001). "Immunohistochemical analysis of nuclear versus cytoplasmic staining of WT1 in malignant mesotheliomas and primary pulmonary adenocarcinomas." Arch Pathol Lab Med 125(10): 1316-20.

²⁶ 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.)

²⁷ 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.

²⁸ 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.

²⁹ 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.

©SMUHT/PW Bishop